Bicyclic heterocyclyl derivatives as IRAK4 inhibitors

Abstract

To provide compounds useful for treatment of cancer and inflammatory diseases associated with interleukin-1 receptor associated kinase (IRAK).SOLUTION: There is provided a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1 and X3 independently are CH or N; X2 is CR2 or N; provided that only one of X1 to X3 is N; A is O or S; Y is -CH2- or O; Ring Z is aryl or heterocyclyl; R1 is halo or optionally substituted heterocyclyl; R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or -NRaRb; R3 is alkyl or hydroxyl; Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclyl; 'm' and 'n' are independently 0, 1 or 2; and 'p' is 0 or 1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to compounds useful in the treatment of cancer and inflammatory diseases associated with interleukin-1 receptor-associated kinase (IRAK), more particularly, compounds that modulate the function of IRAK-4. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of diseases associated with IRAK-4. [Background technology]

[0002] Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4) is a serine / threonine kinase enzyme that plays an essential role in signal transduction by the Toll / IL-1 receptor (TIR). Various IRAK enzymes are key components in the signal transduction pathways mediated by the interleukin-1 receptor (IL-1R) and Toll-like receptors (TLR) (Non-Patent Document 1). The mammalian IRAK family includes four members: IRAK-1, IRAK-2, IRAK-M, and IRAK-4. These proteins are characterized by a typical N-terminal death domain and a centrally located kinase domain that mediates interaction with MyD88-family adaptor proteins. IRAK proteins and MyD88 have been shown to play a role in transducing signals other than those derived from the IL-1R receptor, including those triggered by activation of the IL-18 receptor (Non-Patent Document 2) and the LPS receptor (Non-Patent Document 3). Of the four members of the mammalian IRAK family, IRAK-4 is considered the "master IRAK." Under overexpression conditions, all IRAKs can mediate the activation of nuclear factor-kB (NF-kB) and stress-induced mitogen-activated protein kinase (MAPK) signaling cascades. However, only IRAK-1 and IRAK-4 have been shown to have active kinase activity. While IRAK-1 kinase activity may be dispensable for its function in IL-1-induced NF-kB activation (Non-Patent Documents 4 and 5), IRAK-4 requires its kinase activity for signal transduction (Non-Patent Documents 6 and 7). Given the central role of IRAK4 in Toll-like / IL-1R signaling and immunological defense, IRAK4 inhibitors have been implicated as valuable therapeutics in inflammatory diseases, sepsis, and autoimmune disorders (Non-Patent Document 8).

[0003] Mice lacking IRAK-4 are viable and exhibit complete suppression of inflammatory cytokine production in response to IL-1, IL-18, or LPS (Non-Patent Document 9). Similarly, human patients lacking IRAK-4 are severely immunocompromised and unresponsive to these cytokines (Non-Patent Documents 10 and 11). Knock-in mice containing inactive IRAK4 are completely resistant to lipopolysaccharide- and CpG-induced shock (Non-Patent Documents 12 and 13), indicating that IRAK4 kinase activity is essential for cytokine production, activation of MAPK, and induction of NF-κB-regulated genes in response to TLR ligands (Non-Patent Document 14). Inactivation of IRAK4 kinase (IRAK4 KI) in mice leads to resistance to EAE due to a reduction in inflammatory cells infiltrating the CNS and reduced antigen-specific CD4+ T cell-mediated IL-17 production (Non-Patent Document 15).

[0004] The crystal structure revealed that IRAK-4 contains structural features characteristic of both serine / threonine and tyrosine kinases, as well as additional novel attributes, including a unique tyrosine gatekeeper residue. Structural analysis of IRAK-4 revealed fundamental similarities with the kinase family, namely an ATP-binding cleft sandwiched between a two-lobe configuration. The N-terminal lobe consists primarily of a twisted five-stranded antiparallel beta-sheet and an alpha-helix, while the larger C-terminal lobe is mostly alpha-helical. The structure also revealed several unique features of IRAK-4 kinase, including an additional alpha-helix from the N-terminal extension in the N-terminal lobe, a longer loop between helices alpha-D and alpha-E, and a significantly displaced helix alpha-G and its adjacent loop. The ATP-binding site in IRAK-4 does not have a deep pocket at the back, but does have a distinctive front pocket. This uniquely shaped binding pocket provides an excellent opportunity for designing IRAK-4 inhibitors.

[0005] The development of IRAK-4 kinase inhibitors has given rise to several novel classes of protein-binding agents, including thiazole and pyridine amides (Non-Patent Document 16), aminobenzimidazoles (Non-Patent Document 17), imidazo[1,2-a]pyridines (Non-Patent Documents 18 and 19), imidazo[1,2-b]pyridazines, and benzimidazole-indazoles (Patent Document 1; Patent Document 2). Apparently, all of them are still in early preclinical stages.

[0006] However, despite the various disclosures of different kinase inhibitors, with the increasing number of patients suffering from kinase enzyme-mediated diseases, there appears to be an unmet need for newer drugs that can more effectively treat these diseases. Due to the different kinase activities, there is still a need for newer kinase inhibitors, including multi-targeted kinase inhibitors, that can be more useful and have a broader role in the treatment of disorders. They may also be useful alone or in combination with protein kinase compounds well known by those skilled in the art as part of other therapeutic regimens for the treatment of disorders. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2008 / 030579 [Patent Document 2] International Publication No. 2008 / 030584 [Non-patent literature]

[0008] [Non-Patent Document 1] Janssens, S, et al. Mol. Cell. 11, 2003, 293-302 [Non-patent document 2] Kanakaraj, et al. J. Exp. Med. 189(7):1999, 1129-38 [Non-patent document 3] Yang, et al., J. Immunol. 163, 1999, 639-643

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

Non-licensed Document 14

[0009] One object herein is to provide bicyclic heterocyclyl compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as kinase inhibitors, particularly IRAK4 inhibitors.

[0010] Another object is to provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.

[0011] Yet another object is to provide the use of a bicyclic heterocyclyl derivative of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the treatment and prevention of diseases or disorders, in particular in diseases or disorders in which it is advantageous to inhibit kinase enzymes, more particularly the IRAK4 enzyme. [Means for solving the problem]

[0012] In one aspect according to the invention, it is of formula (I)

[0013] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X1 and X3 are independently CH or N, and X2 is CR2 or N, provided that only one of X1, X2, or X3 is N; A is O or S; Y is —CH— or O; Ring Z is aryl or heterocyclyl; R1, for each occurrence, is independently halo or optionally substituted heterocyclyl, where the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b wherein the substituents are alkyl, amino, halo, or hydroxyl; R3, for each occurrence, is alkyl or hydroxyl; R a and R b are independently hydrogen, alkyl, acyl, or heterocyclyl; "m" and "n" are independently 0, 1 or 2; "p" is 0 or 1.

[0014] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.

[0015] In yet another aspect, the present invention relates to the preparation of compounds of formula (I).

[0016] In yet a further aspect of the present application, there is provided the use of a bicyclic heterocyclyl derivative of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for the treatment and prevention of diseases or disorders mediated by the IRAK4 enzyme.

[0017] More particularly, the present invention relates to the use of bicyclic heterocyclyl derivatives of formula (I) and pharmaceutically acceptable salts and stereoisomers thereof, including mixtures thereof in any ratio, as pharmaceuticals by inhibiting IRAK or IRAK4 or other related kinases.

[0018] The bicyclic heterocyclyl derivatives of formula (I) of the present invention have a therapeutic role in inhibiting IRAK or IRAK4 or other related kinases, useful in the areas of diseases and / or disorders including, but not limited to, cancer, allergic diseases and / or disorders, autoimmune diseases and / or disorders, inflammatory diseases and / or disorders and / or conditions related to inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrotic diseases and / or disorders, metabolic disorders, muscular diseases and / or disorders, respiratory diseases and / or disorders, pulmonary diseases and / or disorders, genetic and developmental diseases and / or disorders, neurological and neurodegenerative diseases and / or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or cardiac diseases and / or disorders, ocular / ocular diseases and / or disorders, wound healing, infectious and viral diseases. Thus, inhibition of one or more kinases has multiple therapeutic indications. DETAILED DESCRIPTION OF THE INVENTION

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. As used in the specification and appended claims, unless otherwise specified, the following terms have the meanings indicated to facilitate understanding of the invention.

[0020] The singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0021] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted alkyl" refers to the fact that the "alkyl" can be substituted as well as the fact that the alkyl is not substituted.

[0022] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one skilled in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as by methods such as those described below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons so long as a stable structure results.

[0023] As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen radicals in a given structure with the radical of the specified substituent, including, but not limited to, halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, aryl, heterocyclyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, hydroxyl, hydroxyalkyl, cycloalkyl, aryl, heterocyclic, and aliphatic. It is understood that the substituent may be further substituted.

[0024] As used herein, the term "alkyl" refers to, but is not limited to, C1 to C 10 Straight chain alkyl group or C1-C 10 It refers to saturated aliphatic groups, including branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group may be optionally substituted.

[0025] The term "acyl" refers to the group R-CO-, where R is an alkyl group as defined above. Examples of "acyl" groups include, but are not limited to, CHCO-, CHCHCO-, CHCHCHCO-, or (CH)CHCO-.

[0026] As used herein, the term "alkoxy" refers to a straight or branched saturated aliphatic C1-C bonded to an oxygen atom which is attached to a core structure. 10It refers to a hydrocarbon group. Preferably, the alkoxy group has 1 to 6 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and 3-methylbutoxy.

[0027] As used herein, the term "haloalkyl" refers to an alkyl group (as defined above) substituted with one or more halogens. Monohaloalkyl groups may have, for example, a chlorine, bromine, iodine, or fluorine atom. Dihalo and polyhaloalkyl groups may have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, and difluoropropyl.

[0028] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms has been replaced with one or more halogens. Representative examples of "haloalkoxy" groups include, but are not limited to, difluoromethoxy (-OCHF), trifluoromethoxy (-OCF), or trifluoroethoxy (-OCHCF).

[0029] As used herein, the term "aryl," alone or in combination with other terms, refers to a carbocyclic aromatic system containing one or two rings, wherein such rings may be fused. The term "fused" means that a second ring is attached to or formed by having two adjacent atoms in common with the first ring. The term "fused" is equivalent to the term "condensed." Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indanyl, and the like. Unless otherwise specified, all aryl groups described herein may be substituted or unsubstituted.

[0030] As used herein, "amino" refers to the group --NH.sub.2.

[0031] As used herein, "alkylamino" refers to an amino group in which one of the amino group's hydrogen atoms has been replaced with an alkyl group.

[0032] As used herein, "arylamino" refers to an amino group in which one of the hydrogen atoms is replaced with an aryl group.

[0033] As used herein, "alkylaminoalkyl" refers to an alkyl group substituted with an "alkylamino" group as defined above.

[0034] As used herein, "arylaminoalkyl" refers to an arylamino group, as defined above, substituted with an alkyl group.

[0035] As used herein, "nitro" refers to the group --NO.sub.2.

[0036] As used herein, "alkylamino" or "cycloalkylamino" refers to an -N- group in which the nitrogen atom is bound to an alkyl or cycloalkyl, respectively. Representative examples of "alkylamino" and "cycloalkylamino" groups include, but are not limited to, -NHCH3 and -NH-cyclopropyl. The amino group can be optionally substituted with one or more suitable groups.

[0037] "Aminoalkyl" refers to an alkyl group, as defined above, in which one or more of the alkyl group's hydrogen atoms has been replaced with an amino group, as defined above. Representative examples of aminoalkyl groups include, but are not limited to, -CHNH, -CHCHNH, -CH(CH)NH, and -CHCH(CH)NH. An aminoalkyl group can be unsubstituted or substituted with one or more suitable groups.

[0038] As used herein, the term "cycloalkyl," alone or in combination with other terms, refers to a C to C 10 "Cycloalkyl" means a saturated cyclic hydrocarbon ring. Cycloalkyl may be a single ring, typically containing 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyl include bridged carbocyclyl, fused carbocyclyl, and spirocyclic carbocyclyl.

[0039] As used herein, the term "cyano" refers to a -CN group.

[0040] As used herein, the term "hydroxy" or "hydroxyl" refers to an --OH group.

[0041] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" means an alkyl substituted with one or more hydroxyl groups, where alkyl is as defined above. Examples of "hydroxyalkyl" include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and propan-2-ol.

[0042] The terms "halo" or "halogen," as used herein, alone or in combination with other terms, mean fluorine, chlorine, bromine, or iodine.

[0043] As used herein, the term "heterocyclyl" encompasses the definitions of "heterocycloalkyl" and "heteroaryl."

[0044] As used herein, the term "heterocycloalkyl" refers to a 3- to 15-membered non-aromatic saturated or partially saturated monocyclic or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O), NH, or C(O), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Examples of "heterocycloalkyl" include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, azepanyl, 2-aza-bicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups can be optionally substituted with one or more suitable groups, such as those described above. Preferably, "heterocycloalkyl" refers to a 4- to 7-membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, azepanyl, and N-oxides thereof. More preferably, "heterocycloalkyl" includes azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, or azepanyl. All heterocycloalkyls are optionally substituted with one or more of the aforementioned groups.

[0045] As used herein, the term "heteroaryl" refers to an aromatic heterocyclic ring system containing 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) fused together or covalently linked. Preferably, the "heteroaryl" is a 5- to 6-membered ring. The ring may contain 1 to 4 heteroatoms selected from N, O, and S, where the N or S atom is optionally oxidized, or the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.

[0046] Examples of heteroaryl include, but are not limited to: furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl; Examples thereof include benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzotridiazolyl, carbazolyl, dibenzothienyl, and acridinyl. Preferably, "heteroaryl" refers to a 5- to 6-membered ring selected from the group consisting of furanyl, thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably pyrazolyl, pyridyl, oxazolyl, and furanyl. All heteroaryls are optionally substituted with one or more of the aforementioned groups.

[0047] As used herein, the terms "including" and other forms such as "include," "includes," and "included" are not limiting.

[0048] The phrase "pharmaceutically acceptable" refers to a compound or composition that is physiologically tolerable and does not normally produce allergic or similar adverse reactions, including, but not limited to, stomach upset or dizziness, when administered to a mammal.

[0049] The term "pharmaceutically acceptable salt" refers to the product obtained by reaction of a compound of the present invention with a suitable acid or base. Pharmaceutically acceptable salts of the compounds of this invention include those derived from appropriate inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, and 4-methylbenzenesulfonate or p-toluenesulfonate salts. Certain compounds of the present invention (compounds of formula (I)) can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0050] As used herein, the term "stereoisomers" is the term used for all isomers of individual compounds of formula (I) that differ only in the orientation of the isomers' atoms in space. The term stereoisomers includes mirror image isomers (enantiomers) of compounds of formula (I), mixtures of mirror image isomers (racemates, racemic mixtures) of compounds of formula (I), geometric (cis / trans or E / Z, R / S) isomers of compounds of formula (I) and isomers of compounds of formula (I) with more than one chiral center that are not mirror images of one another (diastereoisomers).

[0051] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0052] As used herein, the term "pharmaceutical composition" refers to a composition containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and a conventional pharmaceutically acceptable carrier.

[0053] The pharmaceutical compositions of the present invention can be administered orally, for example in the form of tablets, coated tablets, pills, capsules, granules or elixirs. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams, or transdermally, in the form of a patch, or in other ways, for example in the form of an aerosol or nasal spray.

[0054] The pharmaceutical composition typically contains about 1% to 99% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, about 5% to 75% by weight, or about 10% to about 30% by weight. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition can range from about 1 mg to about 1000 mg, or from about 2.5 mg to about 500 mg, or from about 5 mg to about 250 mg, or any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the aforementioned ranges.

[0055] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline solution, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The compositions may also include stabilizers and preservatives. Examples of carriers, stabilizers, and adjuvants are described in such sources as Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Co., Easton, PA

[1975] .

[0056] The term "treatment" / "treating" means any treatment of a disease in a mammal, including (a) inhibiting the disease, i.e., slowing or arresting the onset of clinical symptoms, and / or (b) relieving the disease, i.e., causing regression of clinical symptoms, and / or (c) alleviating or arresting the disease and / or its associated symptoms.

[0057] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease.

[0058] As used herein, the term "subject" refers to an animal, preferably a mammal, and most preferably a human.

[0059] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, effective in producing a desired therapeutic response in a particular patient suffering from a disease or disorder mediated by a kinase enzyme, particularly an IRAK or IRAK4 enzyme. In particular, the term "therapeutically effective amount" includes an amount of a compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which, upon administration, is sufficient to induce a positive change in the disease or disorder to be treated or to prevent or alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject. A therapeutic amount of a compound may also be considered an amount of a compound used to treat a subject that is low enough to avoid excessive or severe side effects within the scope of sound medical judgment. The therapeutically effective amount of the compound or composition will vary depending on the particular condition being treated, the severity of the condition being treated or prevented, the duration of treatment, the nature of any concurrent treatments, the age and health of the end user, the particular compound or composition used, and the particular pharmaceutically acceptable carrier employed.

[0060] In one embodiment, the present invention provides a compound of formula (I)

[0061] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, X1 and X3 are independently CH or N, and X2 is CR2 or N, provided that only one of X1, X2, or X3 is N; A is O or S; Y is —CH— or O; Ring Z is aryl or heterocyclyl; R1, for each occurrence, is independently halo or optionally substituted heterocyclyl, where the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b wherein the substituents are alkyl, amino, halo, or hydroxyl; R3, for each occurrence, is alkyl or hydroxyl; R a and R b are independently hydrogen, alkyl, acyl, or heterocyclyl; "m" and "n" are independently 0, 1 or 2; "p" is 0 or 1.

[0062] In one embodiment, the group

[0063] [ka] but

[0064] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is as defined for compounds of formula (I).

[0065] In another embodiment, the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, wherein ring Z is aryl or 5- or 6-membered heterocyclyl.

[0066] In another embodiment, ring Z is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidethiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, or dihydropyranyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b and optionally substituted with R a and R b is independently hydrogen, alkyl or acyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0067] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring Z is phenyl, oxazolyl, furanyl, thienyl, or pyridyl, each of which is optionally substituted with one or more R1.

[0068] In another embodiment,

[0069] [ka] but

[0070] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 and "m" are defined as for compounds of formula (I).

[0071] In another embodiment, the compound of formula (I) has the formula (IA)

[0072] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A, Y, R1, R2, R3, "m", "p" and "n" are the same as defined for compounds of formula (I).

[0073] In another embodiment, the compound of formula (I) has the formula (IB)

[0074] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A, Y, R1, R2 and "n" are the same as defined for compounds of formula (I).

[0075] In yet another embodiment, the compound of formula (I) has the formula (IC)

[0076] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A, Y, R1, R2, R3 and "n" are the same as defined for compounds of formula (I).

[0077] The following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments illustrated.

[0078] According to one embodiment, specifically provided are compounds of formula (I) or (IA) or (IB) or (IC) wherein Y is O or CH2.

[0079] According to one embodiment, specifically provided is that R is an optionally substituted heterocyclyl, wherein the substituents are alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl, or -NR a R b and R a and R b is independently hydrogen, alkyl or acyl.

[0080] According to one embodiment, specifically provided is a compound in which R is pyridyl, pyrazolyl, pyrrolidinyl, or piperidinyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or -NR a R b and optionally substituted with R a and R b is independently hydrogen or acyl.

[0081] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is hydrogen.

[0082] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is optionally substituted cycloalkyl.

[0083] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is cyclopropyl.

[0084] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is optionally substituted heterocyclyl, wherein the substituents are alkyl, amino, halo, or hydroxyl.

[0085] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl or azabicyclo[3.2.1]octanyl, wherein the substituents are alkyl, amino, halo or hydroxyl.

[0086] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is optionally substituted aryl, wherein the substituent is halo.

[0087] According to one embodiment, specifically provided are compounds of formula (I) wherein R2 is optionally substituted phenyl, wherein the substituent is fluoro.

[0088] According to one embodiment, specifically provided is a compound in which R2 is -NR a R b where R a and R b is independently hydrogen or heterocyclyl.

[0089] According to one embodiment, specifically provided is a compound in which R2 is -NR a R b where R a and R b is independently hydrogen or pyrrolidinyl.

[0090] According to one embodiment, specifically provided is a compound in which A is O or S, Y is —CH— or O, and R is halo, pyridyl, pyrazolyl, pyrrolidinyl, each of which is alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl, or —NR a R b and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R bwhere the substituents are alkyl, amino, halo, or hydroxyl; R a and R b is independently hydrogen or alkyl.

[0091] According to one embodiment, specifically provided is a compound in which A is O or S, Y is —CH— or O, and R is pyridyl, pyrazolyl, pyrrolidinyl, each of which is alkyl, hydroxyl, hydroxyalkyl, or —NR a R b and optionally substituted with R a and R b are independently hydrogen, and R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or -NR a R b where the substituents are alkyl, amino, halo, or hydroxyl; R a and R b is independently hydrogen, alkyl, acyl or heterocyclyl.

[0092] According to one embodiment, specifically provided are compounds of formula (IA), (IB) and (IC) wherein "n" is 0, 1 or 2.

[0093] According to one embodiment, specifically provided are compounds of formula (IA) and (IB) wherein "p" is 0 or 1.

[0094] According to one embodiment, specifically provided are compounds of formula (IA) and (IB) wherein "m" is 0 or 2.

[0095] In yet a further embodiment, the present invention relates to a process for preparing the bicyclic heterocyclyl derivatives of formula (I).

[0096] In yet a further embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0097] In a further embodiment, the present invention provides a method of treating an IRAK4-mediated disorder or disease or condition in a subject, comprising administering a therapeutically effective amount of a compound of formula (I).

[0098] In further embodiments, the IRAK4-mediated disorder or disease or condition is selected from the group consisting of cancer, an inflammatory disorder, an autoimmune disease, a metabolic disorder, a genetic disorder, a hormone-related disease, an immunodeficiency disorder, a cell death-associated condition, a destructive bone disorder, a thrombin-induced platelet aggregation, a liver disease, and a cardiovascular disorder.

[0099] In further embodiments, the cancer is a solid tumor, benign or malignant tumor, carcinoma of the brain, kidney, liver, stomach, vagina, ovary, gastric tumor, breast, bladder colon, prostate, pancreas, lung, cervix, testis, skin, bone or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin and non-Hodgkin, breast cancer, follicular adenocarcinoma, papillary carcinoma, seminoma, melanoma; Hematological malignancies selected from leukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-like DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

[0100] In further embodiments, the inflammatory disorder is ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, thrombocytopenia, urticaria, urticaria, urticaria, urinary tract infections ... Glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (including, for example, idiopathic nephrotic syndrome or minimal change nephrosis), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal development Growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, anaphylaxis, fibrositis, gastritis, gastroenteritis, rhinosinusitis, ocular allergies, silica-induced disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, appendicitis, atrium Peptic ulcer dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, juvenile rheumatoid arthritis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,The disease is selected from the group consisting of polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0101] In a further embodiment, the present invention provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof for use for the treatment of cancer, inflammatory disorders, autoimmune diseases, metabolic disorders, genetic disorders, hormone-related diseases, immunodeficiency disorders, conditions associated with cell death, destructive bone disorders, thrombin-induced platelet aggregation, liver diseases, and cardiovascular disorders.

[0102] In a further embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof in the manufacture of a medicament for the treatment of cancer, inflammatory disorders, autoimmune diseases, metabolic disorders, genetic disorders, hormone-related diseases, immunodeficiency disorders, conditions associated with cell death, destructive bone disorders, thrombin-induced platelet aggregation, liver diseases, and cardiovascular disorders.

[0103] In further embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, and graft versus host disease.

[0104] Embodiments of the present invention provide IRAK4 inhibitor compounds according to Formula (I), which can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, it is understood that other experimental conditions can also be used unless otherwise specified. Optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. Furthermore, by utilizing the procedures described in detail, those skilled in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.

[0105] In a further embodiment, the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms constituting such compounds.For example, the present invention also encompasses isotopically labeled variants of the present invention that are identical to those cited herein, except that one or more atoms of the compounds are replaced by an atom having an atomic mass or mass number different from the predominant atomic mass or mass number normally found for that atom in nature.All isotopes of any particular atom or element as specified are considered to be within the scope of the compounds of the present invention and their use.Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example. 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and / or examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0106] The MS (mass spectral) data provided in the examples was obtained from instrument API 2000 LC / MS / MS / Triplequad, Agilent (1100) Technologies / LC / MS / DVL / Singlequad, and Shimadzu LCMS-2020 / Singlequad was obtained using

[0107] The NMR data provided in the examples is instrument- 1 H-NMR: Obtained using Varian -300, 400 and 600 MHz.

[0108] Abbreviations used throughout the specification may be summarized herein below along with their special meanings.

[0109] °C (Celsius); δ (delta); % (percentage); Ac2O (acetic anhydride); (BOC)2O (boc anhydride); bs (broad singlet); CDCl3 (deuterated chloroform); CH2Cl2 / DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); DIPEA / DIEA (N,N-diisopropylethylamine); DAST (diethylaminosulfur trifluoride); DMAP (dimethylaminopyridine); DMSO-d6 (deuterated DMSO); d (doublet); dd (doublet of doublets); EDCI.HCl (1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride); EtOAc (ethyl acetate); EtOH (ethanol); Fe (iron powder); g (gram); H or H2 (hydrogen); H2O (water); HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HOBt (1-hydroxybenzotriazole); H2SO4 (sulfuric acid); HCl (hydrochloric acid or hydrochloride salt); h or hr (hours); Hz (hertz); HPLC (high-performance liquid chromatography); J (coupling constant); K2CO3 (potassium carbonate); KOAc (potassium acetate); KNO3 (potassium nitrate); LiOH (lithium hydroxide); NaHMDS (sodium bis(trimethylsilyl)amide); MeOH / CH3OH (methanol); mmol (millimolar); M (molar concentration); ml (milliliter); mg (milligram); m (multiplet); mm (millimeter); MHz (megahertz); MS(ES) (mass spectrometry - electrospray); min (minute); NaH (sodium hydride); NaHCO3 (heavy salt) Sodium carbonate; Na2SO4 (sodium sulfate); NH4Cl (ammonium chloride); N2 (nitrogen); NMR (nuclear magnetic resonance spectroscopy); Pd(PPh3)2Cl2 (bis(triphenylphosphine)palladium(II) dichloride); Pd(OAc)2 (palladium diacetate); Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; RT (room temperature); S (singlet); TBAF (tetra-n-butylammonium fluoride); TEA (triethylamine); TFA (trifluoroacetic acid); TLC (thin layer chromatography); THF (tetrahydrofuran); TFA (trifluoroacetic acid); t (triplet); and Zn(CN)2 (zinc cyanide).

[0110] The compounds of this invention can be made by synthetic chemistry processes whose examples are given herein, it being understood that the order of steps in the processes can be varied, that reagents, solvents and reaction conditions can be substituted for those specifically described, and that sensitive moieties can be protected and deprotected as necessary.

[0111] A general approach for the synthesis of some of the compounds of general formula (ix) is illustrated in the following scheme: As used herein, in the following scheme, the terms Z, Y, R, R, R, m, n, and p represent all possible substitutions as disclosed in formula (I).

[0112] [ka]

[0113] The first general method for the synthesis of compounds of general formula (ix) is illustrated in Scheme 1. Compounds of formula (ii) can be obtained from compounds of formula (i) by reaction with potassium ethyl xanthate in a suitable solvent such as pyridine at higher temperatures. Compounds of formula (ii) can be alkylated with methyl iodide using a base such as potassium carbonate to obtain compounds of formula (iii), which can be subjected to nucleophilic substitution with a suitable nucleophile to obtain compounds of formula (iv). Compounds of formula (iv) can be nitrated to obtain compounds of formula (v). Compounds of formula (v) can be subjected to Suzuki reaction to obtain compounds of formula (vi), which can be reduced with a suitable reducing agent such as Zn and ammonium chloride to obtain compounds of formula (vii). Compounds of formula (vii) can be amide-coupled with a suitable acid, i.e., compound of formula (viii), using standard amide coupling reagents known in the literature, to obtain compounds of formula (ix).

[0114] Intermediates Intermediate 1: Synthesis of tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate

[0115] [ka] Step 1: Preparation of tert-butyl (5-bromopyridin-2-yl)carbamate To a solution of 5-bromopyridin-2-amine (5.0 g, 28.901 mmol) in DCM (50 mL) was added DMAP (5.28 g, 43.351 mmol) and Boc anhydride (7.56 g, 34.682 mmol) and stirred at room temperature overnight. The solvent was evaporated and purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as eluent to give the title compound (5.5 g, 69.62%). 1 HNMR (CDCl3, 300MHz): δ 8.327-8.320 (d, 1H), 8.10 (bs, 1H), 7.92-7.89 (d, 1H), 7.76-7.73 (dd, 1H), 1.55 (s, 9H). LCMS: m / z: 217.0 (M-Boc) + . Step 2: Preparation of tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate In a sealed tube, tert-butyl (5-bromopyridin-2-yl)carbamate (5.0 g, 0.18315 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6.02 g, 23.8 mmol), and potassium acetate (5.38 mg, 54.945 mmol) were placed in 1,4-dioxane (50 mL) and purged with argon for 10 min. Pd(dppf)Cl2 (669 mg, 0.915 mmol) was added and heated at 100 °C for 2 h. The solvent was evaporated and purified by 60-120 silica gel column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (5.0 g, 85.32%).

[0116] Intermediate 2: Synthesis of tert-butyl (6-carbamoyl-[2,3'-bipyridin]-6'-yl)carbamate

[0117] [ka] Step 1: Preparation of 6-bromopicolinamide Using the same reaction conditions as described in Step 6 of Example 1, 6-bromopicolinic acid (2 g, 9.9 mmol) was coupled with ammonium chloride (787 mg, 14.851 mmol) using EDCI.HCl (2.8 g, 14.851 mmol), HOBt (2.0 g, 14.851 mmol), and DIPEA (3.8 g, 29.750 mmol) in DMF (10 mL) to give the crude product. The resulting crude product was purified using 60-120 silica gel column chromatography, and the compound was eluted using 50% ethyl acetate in hexane as the eluent to give the title compound (2.0 g, 100%). 1 HNMR (CDCl3, 300MHz): δ 8.18-8.16 (d, 1H), 7.7.63-7.5656-7.63 (m, 2H), 5.80-5.60 (bs, 2H). Step 2: Preparation of tert-butyl (6-carbamoyl-[2,3'-bipyridin]-6'-yl)carbamate Using the same reaction conditions as described in Step 7 of Example 1, 6-bromopicolinamide (2.0 g, 9.95 mmol) was coupled with tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (Intermediate 1) (3.8 g, 11.94 mmol) using sodium carbonate (3.2 g, 29.85 mmol) and Pd(PPh)Cl (363 mg, 0.5 mmol) in 1,2-dimethoxyethane (10 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (2.8 g, 90.3%). 1 HNMR (CDCl 3, 300MHz): δ 8.908-8.901 (d, 1H), 8.30-8.26 (dd, 1H), 8.18-8.16 (d, 1H), 8.09-8.06 (d, 1H), 7.97-7.68 (m, 3H), 7.26 (s, 1H), 5.70-5.60 (s, 1H), 1.55 (s, 9H). LCMS: m / z: 259.1 (de-t-butyl). -

[0118] Intermediate 3: Synthesis of 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid

[0119] [ka] Step 1: Preparation of methyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate Using the same reaction conditions as described in Step 7 of Example 1, methyl 6-bromopicolinate (900 mg, 4.166 mmol) was coupled with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.39 g, 5 mmol) using sodium carbonate (1.324 g, 12.49 mmol) and Pd(PPh)Cl (339 mg, 0.416 mmol) in 1,2-dimethoxyethane (10 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (450 mg, 38%). LCMS: m / z: 288.1 (M+1). + . Step 2: Preparation of 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid A solution of methyl 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate (450 mg, 1.567 mmol) and lithium hydroxide (500 mg, 7.839 mmol) in THF methanol / HO (10 mL / 4 mL / 1 mL) was stirred at room temperature for 2 hours. The reaction mixture was acidified with citric acid, extracted with DCM (2×100 mL), dried over sodium sulfate, and the solvent was evaporated to give the title compound (300 mg, 70%). LCMS: m / z: 274.3 (M+1) + .

[0120] Intermediate 4: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid

[0121] [ka] Step 1: Preparation of methyl 6-(1-methyl-1H-pyrazol-4-yl)picolinate Using the same reaction conditions as described in Step 7 of Example 1, methyl 6-bromopicolinate (3.5 g, 16.28 mmol) was coupled with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.06 g, 19.53 mmol) using sodium carbonate (5.177 g, 48.846 mmol) and Pd(dppf)Cl (1.328 g, 1.628 mmol) in 1,2-dimethoxyethane (20 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (1.2 g, 33.9%). LCMS: m / z: 218.2 (M+1). + . Step 2: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (1.2 g, 5.529 mmol) was hydrolyzed using lithium hydroxide (696 mg, 16.58 mmol) in THF / methanol (8 / 2 mL) at room temperature for 2 hours to give the title compound (900 mg, 80.3%). LCMS: m / z: 204.0 (M+1) + .

[0122] Intermediate 5: Synthesis of 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid

[0123] [ka] Step 1: Preparation of methyl 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate Using the same reaction conditions as described in Step 4 of Example 12, methyl 3-bromo-5-fluorobenzoate (100 mg, 0.429 mmol) was coupled with tert-butyl(piperidin-4-ylmethyl)carbamate (110 mg, 0.515 mmol) using cesium carbonate (209 mg, 0.643 mmol), Xantphos (14 mg, 0.025 mmol), and Pd(dba) (8 mg, 0.0085 mmol) in toluene (5 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (110 mg, 70.06%). LCMS: 94.13%, m / z = 367.5 (M+1). + . Step 2: Preparation of 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid A solution of methyl 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate (110 mg, 0.02 mmol), lithium hydroxide (5 mg, 0.104 mmol), methanol (3 mL), THF (2 mL) and water (1 mL) was stirred at room temperature for 1 hour, acidified with 2N HCl, the solvent was distilled and the solid was filtered to give the crude product, which was then purified by preparative HPLC to give the title compound (105 mg, 100%). LCMS: m / z: 353.4 (M+1) + .

[0124] Intermediate 6: Synthesis of 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid

[0125] [ka] Step 1: Preparation of methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate Using the same reaction conditions as described in Step 1 of Example 11, methyl 2,5-difluorobenzoate (1 g, 4.6 mmol) was coupled with tert-butyl(piperidin-4-ylmethyl)carbamate (803 mg, 4.6 mmol) using potassium carbonate (1.289 mg, 9.3 mmol) in DMF (10 mL) at 90° C. overnight to give the crude product, which was purified by 60-120 silica gel column chromatography using ethyl acetate in hexane as the eluent to give the title compound (300 mg, 20%). 1 HNMR (DMSO-d6, 400MHz): δ 7.38-7.28 (m, 2H), 7.16-7.12 (m, 1H), 6.90-6.85 (t, 1H), 3.80 (s, 3H), 3.13-3.10 (d, 2H), 2.87-2.84 (m, 2H), 2.64-2.58 (t, 2H), 1.67-1.64 (d, 2H), 1.40 (s, 9H), 1.26-1.09 (m, 2H). LCMS: m / z: 367.3 (M+1) + . Step 2: Preparation of 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, methyl 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate (300 mg, 0.819 mmol) was hydrolyzed using lithium hydroxide (172 mg, 4.098 mmol) in THF / methanol / HO (5 mL / 1 ml / 0.5 ml) at room temperature for 2 hours to give the title compound (220 mg, 77%). 1HNMR (DMSO-d6, 300MHz): δ 7.86-7.83 (m, 1H), 7.74-7.70 (m, 1H), 7.55-7.54 (m, 1H), 7.01 (bs, 1H), 3.11-3.08 (m, 4H), 2.93-2.89 (t, 2H), 1.87-1.83 (d, 2H), 1.70-1.60 (bs, 1H), 1.40 (s, 9H), 1.35-1.30 (m, 2H). LCMS: m / z: 353.4 (M+1) + .

[0126] Intermediate 7: Synthesis of 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid

[0127] [ka] Step 1: Preparation of ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (298 mg, 1.70 mmol) using sodium carbonate (451 mg, 4.25 mmol) and Pd(PPh) (289 mg, 0.332 mmol) in 1,2-dimethoxyethane / water (15 / 3 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (200 mg, 59.8%). Step 2: Preparation of 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate (300 mg, 0.127 mmol) was hydrolyzed using lithium hydroxide (160 mg, 3.91 mmol) in THF / methanol / water (5 / 1 / 2 mL) at room temperature for 2 hours to give the title compound (160 mg, 57.3%). 1 HNMR (DMSO-d6, 300MHz): δ 13.5-12.5 (bs, 1H), 8.85 (s, 1H), 8.80-8.79 (d, 1H), 8.26-8.23 (dd, 1H), 7.02-6.99 (dd, 1H), 3.95 (s, 3H). LCMS: m / z = 221.1 (M+1) + .

[0128] Intermediate 8: Synthesis of 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid

[0129] [ka] Step 1: Preparation of ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate. Using the same reaction conditions as described in Step 7 of Example 1, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1 g, 7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g, 0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)Cl (289 mg, 0.332 mmol) in 1,2-dimethoxyethane / water (30 / 6 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (1 g, 59.8%). Step 2: Preparation of 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate (1 g, 4.3 mmol) was hydrolyzed using lithium hydroxide (542 mg, 12.9 mmol) in THF / water (25 / 4 mL) at room temperature for 2 hours to give the title compound (550 mg, 62.5%). 1 HNMR (DMSO-d6, 400MHz): δ 13.3 (s, 1H), 8.96 (s, 1H), 8.64-8.62 (dd, 1H), 8.32-8.03 (dd, 1H), 7.47-7.44 (q, 1H), 2.86 (s, 3H).LCMS: m / z = 205.0 (M+1) + .

[0130] Intermediate 9: Synthesis of 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid

[0131] [ka] Step 1: Preparation of ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, (2-fluoropyridin-3-yl)boronic acid (400 mg, 2.83 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (596 mg, 3.40 mmol) using sodium carbonate (902 mg, 8.51 mmol) and Pd(dppf)Cl (115 mg, 0.141 mmol) in 1,2-dimethoxyethane / water (25 / 4 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (400 mg, 60.6%). 1HNMR (DMSO-d6, 400MHz): δ 9.11 (s, 1H), 8.64-8.59 (m, 1H), 8.48-8.47 (d, 1H), 7.62-7.59 (m, 1H), 4.38-4.33 (q, 2H), 1.35-1.32 (t, 3H). Step 2: Preparation of 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate (400 mg, 1.69 mmol) was hydrolyzed using lithium hydroxide (213 mg, 5.07 mmol) in THF / water (10 / 2 mL) at room temperature for 2 hours to give the title compound (250 mg, 71.6%). 1 HNMR (DMSO-d6, 400MHz): δ 13.3-12.9 (bs, 1H), 12.4-12.2 (s, 1H), 8.81 (s, 1H), 8.20-8.17 (dd, 1H), 7.68-7.66 (dd, 1H), 6.41-6.37 (t, 1H). LCMS: m / z = 207.1 (M+1) + .

[0132] Intermediate 10: Synthesis of 2-(2-hydroxypyridin-5-yl)oxazole-4-carboxylic acid

[0133] [ka] Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate (product of Step 1 of Intermediate 7) (400 mg, 1.69 mmol) was hydrolyzed using lithium hydroxide (400 mg, 10.3 mmol) in THF / water (2 / 2 mL) at room temperature for 2 hours to give the crude title compound (300 mg). LCMS: m / z = 207.1 (M+1). + .

[0134] Intermediate 11: Synthesis of 2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid

[0135] [ka] The title compound was prepared by following the procedure described in the synthesis of Intermediate 7 using similar conditions and reagents. 1 HNMR (DMSO-d6, 300MHz): δ 8.38 (s, 1H) 8.34-8.32 (d, 1H) 7.53-7.52 (d, 1H) 7.33 (s, 1H) 3.91 (s, 3H). LCMS: m / z = 221.1 (M+1) + . The following intermediates were prepared by following the above protocol shown in Intermediate 8 and using the appropriate reagents.

[0136] [Table 1]

[0137] Intermediate 14: Synthesis of (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid

[0138] [ka] Step 1: Preparation of ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate A mixture of ethyl 2-chlorooxazole-4-carboxylate (100 mg, 0.5698 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol), DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) was heated at 120° C. for 2 hours. The reaction mass was quenched with ice water and extracted with DCM. The solvent was evaporated to give the title compound (170 mg, 91.89%). LCMS: m / z = 270.1 (Mt-butyl + 1). + . Step 2: Preparation of (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate (170 mg, 0.5224 mmol) was hydrolyzed using lithium hydroxide (33 mg, 0.7837 mmol) in THF / methanol / water (10 / 1 / 2 mL) at room temperature for 12 hours to afford the title compound (150 mg, 96.77%). LCMS: m / z = 242.0 (Mt-butyl) + .

[0139] Intermediate 15: Synthesis of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid

[0140] [ka] Step 1: Preparation of ethyl (S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 1 of Intermediate 14, ethyl 2-chlorooxazole-4-carboxylate (500 mg, 2.8490 mmol) was reacted with (S)-pyrrolidin-3-ol (298 mg, 3.4188 mmol) using sodium carbonate (453 mg, 4.2735 mmol) in DMF (10 mL) to afford the title compound (535 mg, 83.07%). LCMS: m / z = 227.1 (M+1) + . Step 2: Preparation of ethyl (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 2 of Example 41, ethyl (S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate (535 mg, 2.3672 mmol) was protected using TBDMS chloride (429 mg, 2.8407 mmol), imidazole (396 mg, 5.8072 mmol), and DMAP (29 mg, 0.2367 mmol) in DMF (5 mL) at room temperature for 2 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (520 mg, 64.5%). LCMS: m / z = 341.2 (M+1). + . Step 3: Preparation of (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate (520 mg, 1.5294 mmol) was hydrolyzed using lithium hydroxide (97 mg, 2.2941 mmol) in THF / methanol / water (10 / 5 / 5 mL) at room temperature for 2 hours to afford the title compound (350 mg, 73.37%). 1HNMR (CDCl3, 400MHz): δ 7.88 (s, 1H), 4.55-4.50(s, 1H), 3.75-3.60 (m, 3H), 3.5-3.4 (d, 1H), 2.05-1.90 (m, 2H), 0.9 (s, 9H). LCMS: m / z = 313.1 (M+1) + .

[0141] Intermediate 16: Synthesis of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylic acid

[0142] [ka] Step 1: Preparation of ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (273 mg, 0.982 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (125 mg, 0.892 mmol) using sodium carbonate (283 mg, 2.676 mmol) and Pd(dppf)Cl2 (65 mg, 0.089 mmol) in 1,2-dimethoxyethane / water (5 / 1 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (200 mg, 43.9%). LCMS: m / z = 292.3 (M+1). + . Step 2: Preparation of 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate (200 mg, 0.784 mmol) was hydrolyzed using lithium hydroxide (50 mg, 1.176 mmol) in THF / methanol / water (5 / 2 / 1 mL) at room temperature for 1 hour to give the title compound (206 mg, 100%). LCMS: m / z = 263.9 (M+1). + .

[0143] Intermediate 17: Synthesis of 5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid

[0144] [ka] Step 1: Preparation of methyl 5-(2-methylpyridin-4-yl)thiophene-2-carboxylate Using reaction conditions similar to those described in Step 7 of Example 1, methyl 5-bromothiophene-2-carboxylate (460 mg, 2.08 mmol) was coupled with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (680 mg, 3.10 mmol) using potassium carbonate (576 mg, 4.17 mmol), TBAB (100 mg, 0.310 mmol), and Pd(dppf)Cl (108 mg, 0.1538 mmol) in dioxane / water (10 mL / 3 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as the eluent to give the title compound (552 mg, 91%). LCMS: m / z = 234.0 (M+1). + . Step 2: Preparation of 5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, 5-(2-methylpyridin-4-yl)thiophene-2-carboxylate (550 mg, 2.36 mmol) was hydrolyzed using lithium hydroxide (200 mg, 4.72 mmol) in THF / methanol / water (10 / 5 / 5 mL) at 50° C. for 15 minutes to give the title compound (501 mg, 97%). LCMS: m / z = 220.0 (M+1). + .

[0145] Intermediate 18: Synthesis of 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid

[0146] [ka] Step 1: Preparation of methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate Using reaction conditions similar to those described in Step 7 of Example 1, methyl 5-bromofuran-2-carboxylate (214 mg, 1.0406 mmol) was coupled with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (340 mg, 1.561 mmol) using potassium carbonate (288 mg, 2.08 mmol), TBAB (50 mg, 0.156 mmol), and Pd(dppf)Cl (54 mg, 0.078 mmol) in dioxane / water (10 mL / 3 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as the eluent to give the title compound (301 mg, 89%). LCMS: 100%, m / z = 217.8 (M+1). + . Step 2: Preparation of 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate (300 mg, 1.38 mmol) was hydrolyzed using lithium hydroxide (116 mg, 2.76 mmol) in THF / methanol / water (10 / 5 / 5 mL) at 50° C. for 0.25 h to give the title compound (260 mg, 92.8%). LCMS: 100%, m / z = 204.1 (M+1). + .

[0147] Intermediate 19: Synthesis of 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid

[0148] [ka] Step 1: Preparation of ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (487 mg, 1.5223 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (165 mg, 1.1710 mmol) using sodium carbonate (373 mg, 3.5131 mmol) and Pd(dppf)Cl2 (43 mg, 0.0585 mmol) in 1,2-dimethoxyethane / water (10 / 5 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (200 mg, 43.9%). LCMS: m / z = 278.0 (M + 1-t-butyl). + . Step 2: Preparation of 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate (145 mg, 0.4349 mmol) was hydrolyzed using 10% sodium hydroxide solution (1 mL) in THF / methanol / water (10 / 5 / 2 mL) at room temperature for 10 minutes to give the title compound (75 mg, 56.81%). LCMS: m / z: 250.0 (M+1-de-t-butyl). + .

[0149] Intermediate 20: Synthesis of 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid

[0150] [ka] Step 1: Preparation of ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (2.78 g, 10.04 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1 g, 7.09 mmol) using sodium carbonate (106 mg, 21.2 mmol) and Pd(dppf)Cl2 (259 mg, 0.354 mmol) in 1,2-dimethoxyethane / water (30 / 5 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as the eluent to give the title compound (680 mg, 36%). LCMS: m / z: 276.3 (M+1). + . Step 2: Preparation of 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate (500 mg, 1.81 mmol) was hydrolyzed using lithium hydroxide (84 mg, 2 mmol) in THF / methanol / water (10 / 1 / 5 mL) at room temperature for 4 hours to give the title compound (360 mg, 81.08%). LCMS: m / z: 248.1 (M+1). + .

[0151] Intermediate 21: Synthesis of 2-(2-aminopyridin-4-yl)oxazole-4-carboxylic acid

[0152] [ka] Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate (product of Step 1 of Intermediate 20) (900 mg, 3.27 mmol) was hydrolyzed using lithium hydroxide (329 mg, 7.85 mmol) in THF / methanol / water (30 / 1 / 5 mL) at room temperature for 4 hours to give the title compound (750 mg, 96%). LCMS: m / z: 206.2 (M+1). + .

[0153] Intermediate 22: Synthesis of 5-(2-acetamidopyridin-4-yl)furan-2-carboxylic acid

[0154] [ka] Step 1: Preparation of methyl 5-(2-acetamidopyridin-4-yl)furan-2-carboxylate Using the same reaction conditions as described in Step 7 of Example 1, N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (1.91 g, 7.317 mmol) was coupled with methyl 5-bromofuran-2-carboxylate (1 g, 4.87 mmol) using sodium carbonate (1.54 g, 14.61 mmol) and Pd(dppf)Cl (178 mg, 0.243 mmol) in 1,2-dimethoxyethane / water (20 / 4 mL) at 80 °C for 3 hours to give the crude product. The resulting crude was purified by flash chromatography using 35% ethyl acetate in hexane as the eluent to give the title compound (451 mg, 35.6%). LCMS: m / z: 261.1 (M+1) + . Step 2: Preparation of 5-(2-acetamidopyridin-4-yl)furan-2-carboxylic acid Using the same reaction conditions as described in Step 2 of Intermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate (450 mg, 1.73 mmol) was hydrolyzed using lithium hydroxide (73 mg, 1.73 mmol) in THF / methanol / water (10 / 5 / 5 mL) at room temperature for 2 hours to give the title compound (396 mg, 93.17%). LCMS: m / z: 247.2 (M+1) + .

[0155] Intermediate 23: Synthesis of 2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0156] [ka] To a solution of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (WO2011 / 043371) (0.25 g, 1.22 mmol) in DMF was added ammonium chloride (0.131 g, 2.45 mmol), EDCI.HCl (0.351 g, 1.83 mmol), HOBT (0.248 g, 1.83 mmol), and DIPEA (0.790 g, 6.12 mmol). The reaction mixture was stirred at room temperature for 12 hours, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the title compound (0.180 g, 75%) as a white solid. 1 H NMR (300 MHz, CDCl3): δ 8.65 (d, 1H), 7.81-7.79 (m, 2H), 7.72 (d, 1H), 7.65 (s, 1H), 2.55 (s, 3H); MS (ES): m / z: 204 (M+1) + ; HPLC: 93.5% [Example]

[0157] [Example 1] 6'-Amino-N-(2-morpholinoxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide

[0158] [ka] Step 1: Preparation of oxazolo[4,5-b]pyridine-2-thiol A solution of 2-aminopyridin-3-ol (5.0 g, 45.45 mmol) and potassium ethylxanthate (8.0 g, 49.99 mmol) in pyridine (50 mL) was heated at 110° C. overnight. The reaction mixture was cooled to 0° C., ice water was added, and acidified with concentrated HCl. The solid was filtered and dried under vacuum to give the title compound (6.0 g, 86.95%). 1HNMR (DMSO-d6, 300MHz): δ 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H), 7.30-7.26 (m, 1H). LCMS: m / z: 153.0 (M+1) + . Step 2: Preparation of 2-(methylthio)oxazolo[4,5-b]pyridine To a stirred solution of oxazolo[4,5-b]pyridine-2-thiol (3.0 g, 19.73 mmol) in ethyl acetate (30 mL) was added potassium carbonate (3.81 g, 27.62 mmol) and methyl iodide (3.08 g, 21.71 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2 × 50 mL), dried over sodium sulfate, and concentrated to give the title compound (3.0 g, 93.75%). 1 HNMR (CDCl3, 300MHz): δ 8.46-8.44 (d, 1H), 7.71-7.68 (d, 1H), 7.20-7.15 (m, 1H), 2.81 (s, 3H). LCMS: m / z: 167.0(M+1) + . Step 3: Preparation of 2-morpholinooxazolo[4,5-b]pyridine To a solution of 2-(methylthio)oxazolo[4,5-b]pyridine (2.0 g, 12.12 mmol) in THF (5 mL) was added morpholine (5 mL) and heated overnight at 75° C. The solvent was evaporated to give the title compound (2.0 g, 83.3%). 1 HNMR (DMSO-d6, 300MHz): δ 8.20-8.10 (d, 1H), 7.80-7.70 (d, 1H), 7.15-7.00 (m, 1H), 3.75-3.72 (m, 4H), 3.63-3.52 (m, 4H). LCMS: m / z: 206.5 (M+1) + . Step 4: Preparation of 2-morpholino-6-nitrooxazolo[4,5-b]pyridine To a solution of 2-morpholinooxazolo[4,5-b]pyridine (1.0 g, 4.854 mmol) in acetic acid (10 mL) was added fuming nitric acid (6 mL) and heated at 100° C. for 4 hours. The reaction mixture was cooled to 0° C., ice was added, and the solid was filtered to give the title compound (800 mg, 66.6%). 1 HNMR (DMSO-d6, 300MHz): δ 9.11-9.10 (d, 1H), 8.567-8.560 (d, 1H), 3.75 (s, 8H). LCMS: m / z: 250.9(M+1) + . Step 5: Preparation of 2-morpholinooxazolo[4,5-b]pyridin-6-amine To a solution of 2-morpholino-6-nitrooxazolo[4,5-b]pyridine (700 mg, 2.8 mmol) in THF was added ammonium chloride (2.37 g, 44.80 mmol) and zinc dust (1.82 g, 28.0 mmol) in water (5 mL) and stirred at 50° C. for 1 h. The catalyst was filtered through Celite®, extracted with DCM (2×100 mL), and the solvent was evaporated to give the title compound (600 mg, 97.4%). LCMS: m / z: 221.1 (M+1) + . Step 6: Preparation of 6-bromo-N-(2-morpholinoxazolo[4,5-b]pyridin-6-yl)picolinamide A solution of 2-morpholinooxazolo[4,5-b]pyridin-6-amine (600 mg, 2.727 mmol), 6-bromopicolinic acid (661 mg, 3.27 mmol), EDCI.HCl (797 mg, 4.09 mmol), HOBt (552 mg, 4.09 mmol), and DIPEA (1.05 g, 8.181 mmol) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was quenched with ice water, and the compound was extracted into ethyl acetate (2 × 25 mL), dried over sodium sulfate, and concentrated. The resulting crude product was purified by filtration using a 60-120 silica gel column. The compound was eluted using 5% methanol in DCM as the eluent to give the title compound (350 mg, 31.8%). 1HNMR (CDCl3, 300MHz): δ 9.79 (s, 1H), 8.46-8.45 (d, 1H), 8.32-8.31 (d, 1H), 8.26-8.23 (d, 1H), 7.82-7.68 (m, 2H), 3.85-3.67 (m, 8H). LCMS: m / z: 405.6 (M+1) + Step 7: Preparation of tert-butyl (6-((2-morpholinoxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3'-bipyridin]-6'-yl)carbamate To a sealed tube was added 6-bromo-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide (350 mg, 0.866 mmol), tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (360 mg, 1.126 mmol) (Intermediate 1), and sodium carbonate (275 mg, 2.598 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL). The reaction mixture was purged with argon for 10 minutes, Pd(PPh)Cl (31 mg, 0.043 mmol) was added, and the mixture was heated at 95 °C overnight. The solvent was evaporated. The obtained crude material was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as the eluent to give the title compound (300 mg, 67.11%). LCMS: m / z: 517.7 (M+1) + . Step 8: 6'-amino-N-(2-morpholinoxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide TFA (5 mL) was added to a solution of tert-butyl (6-((2-morpholinoxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3'-bipyridin]-6'-yl)carbamate (300 mg, 0.580 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. After completion of the reaction, it was then purified by preparative HPLC to give the title compound (34 mg, 14.05%). 1HNMR (DMSO-d6, 300MHz): δ 10.06 (s, 1H), 8.96-8.95 (d, 1H), 8.58-8.44 (d, 1H), 8.44-8.40 (dd, 1H), 8.31-8.30 (d, 1H), 8.11-7.95 (m, 3H), 6.59-6.56 (d, 1H), 6.38 (s, 2H), 3.75-3.66 (m, 8H). LCMS: 98.20%, m / z = 418.1 (M+1) + . HPLC: 98.32%.

[0159] [Example 2] 6'-Amino-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide hydrochloride

[0160] [ka] Step 1: Preparation of 2-amino-6-chloropyridin-3-ol Using the same reaction conditions as described in Step 5 of Example 1, 6-chloro-2-nitropyridin-3-ol (35 mg, 0.201 mmol) was reduced with zinc dust (65 mg, 1.005 mmol) and ammonium chloride (54 mg, 1.005 mmol) in THF (2 mL) to give the title compound (25 mg, 89%). LCMS: m / z: 145.2 (M+1) + . Step 2: Preparation of 5-chlorooxazolo[4,5-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 2-amino-6-chloropyridin-3-ol (25 mg, 0.173 mmol) was cyclized using potassium ethylxanthate (33 mg, 0.208 mmol) in pyridine (1 mL) to give the title compound (25 mg, 78%). 1HNMR (DMSO-d6, 300MHz): δ 7.94-7.90 (d, 1H), 7.38-7.35 (d, 1H). LCMS: m / z: 187.1(M+1) + . Step 3: Preparation of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 1, 5-chlorooxazolo[4,5-b]pyridine-2-thiol (620 mg, 3.33 mmol) was methylated using potassium carbonate (689 mg, 4.99 mmol) and methyl iodide (567 mg, 3.99 mmol) in ethyl acetate (10 mL) to give the title compound (720 mg, 90%). LCMS: m / z: 201.1 (M+1). + . Step 4: Preparation of 5-chloro-2-morpholinooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, using morpholine (2 mL) and THF (10 mL) to substitute 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine, the title compound (750 mg, 88%) was obtained. 1 HNMR (DMSO-d6, 400MHz): δ 7.82-7.80 (d, 1H), 7.08-7.06 (d, 1H), 3.74-3.64 (m, 8H). LCMS: m / z: 240.2(M+1) + . Step 5: Preparation of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 4 of Example 1, 5-chloro-2-morpholinoxazolo[4,5-b]pyridine (50 mg) was nitrated using acetic acid (0.2 mL) and fuming nitric acid (0.1 mL) at 100° C. for 2 hours to give the title compound (25 mg, 43%). 1 HNMR (DMSO-d6, 300MHz): δ 8.60 (s, 1H), 3.72 (s, 8H) + . Step 6: Preparation of 5-cyclopropyl-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 7 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (25 mg, 0.088 mmol) was coupled with cyclopropylboronic acid (9 mg, 0.105 mmol) using potassium carbonate (24 mg, 0.176 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) in xylene (2 mL) to give the crude product (50 mg). LCMS: m / z: 291.1 (M+1). + . Step 7: Preparation of 5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-cyclopropyl-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (220 mg, 0.758 mmol) was reduced with zinc dust (394 mg, 6.068 mmol) and ammonium chloride (327 mg, 6.068 mmol) in THF / methanol / HO (5 mL / 1 mL / 0.5 mL) to afford the title compound (160 mg, 84%). LCMS: m / z: 261.0 (M+1). + . Step 8: Preparation of 6-bromo-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-amine (100 mg, 0.384 mmol) was coupled with 6-bromopicolinic acid (85 mg, 0.423 mmol) using EDCI.HCl (110 mg, 0.576 mmol), HOBt (77 mg, 0.576 mmol), TEA (0.22 mL, 1.538 mmol) in DMF (2 mL) to give the title compound (75 mg, 44%). LCMS: m / z: 444.2 (M+1). + . Step 9: Preparation of tert-butyl (6-((5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3'-bipyridin]-6'-yl)carbamate Using the same reaction conditions as described in Step 7 of Example 1, 6-bromo-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide (75 mg, 0.169 mmol) was coupled with tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (65 mg, 0.203 mmol) (Intermediate 1) using sodium carbonate (53 mg, 0.507 mmol) and Pd(PPh)Cl (7 mg, 0.0084 mmol) in 1,2-dimethoxyethane (5 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as the eluent to give the title compound (50 mg, 54%). LCMS: m / z: 558.2 (M+1) + . Step 10: Preparation of 6'-amino-N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (6-((5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate (50 mg, 0.089 mmol) was deprotected using methanolic HCl (5 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (40 mg, 90%). 1HNMR (DMSO-d6, 400MHz): δ 10.78 (s, 1H), 9.059-9.055 (d, 1H), 8.93-8.90 (dd, 1H), 8.40-8.25 (bs, 2H), 8.21-8.20 (d, 1H), 8.15-8.11 (t, 1H), 8.07-8.05 (d, 1H), 7.83 (s, 1H), 7.12-7.09 (d, 1H), 3.71-3.60 (m, 8H), 2.20-2.16 (m, 1H), 0.91-0.87 (m, 4H). LCMS: 96.48%, m / z = 458.2 (M+1) + . HPLC: 98.7%.

[0161] [Example 3] N-(5-cyclopropyl-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride

[0162] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 7 of Example 2) (60 mg, 0.23 mmol) was coupled with 2-(2-methyl-pyridin-4-yl)oxazole-4-carboxylic acid (71 mg, 0.396 mmol) using EDCI.HCl (66 mg, 0.396 mmol), HOBt (46 mg, 0.396 mmol), TEA (0.13 mL, 0.923 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC and treated with methanolic HCl to give the title compound (20 mg, 20%). 1HNMR (DMSO-d6, 400MHz): δ 10.22 (s, 1H), 9.27 (s, 1H), 8.85-8.83 (d, 1H), 8.25 (s, 1H), 8.14-8.13 (d, 1H), 7.72 (s, 1H), 3.71-3.59 (m, 8H), 2.63 (s, 3H), 2.17-2.14 (m, 1H), 0.89-0.86 (m, 4H). LCMS: 93.91%, m / z = 447.1 (M+1) + . HPLC: 99.0%.

[0163] [Example 4] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride

[0164] [ka] Step 1: Preparation of 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, using piperidine (8 mL) and THF (30 mL) substituting 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of Step 3 of Example 2) (3 g, 14.95 mmol) to give the title compound (3 g, 90%). LCMS: m / z = 238.1 (M+1) + . Step 2: Preparation of 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 4 of Example 20, 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (4 g, 168 mmol) was nitrated using potassium nitrate (3.4 g, 337 mmol) and concentrated sulfuric acid (20 mL) at room temperature for 3 hours to give the crude title compound (4 g). LCMS: m / z = 283.0 (M+1). + . Step 3: Preparation of 6-nitro-2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridine A mixture of 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (300 mg, 1.056 mmol) with piperidine (3 mL) was heated at 100° C. for 2 hours. The reaction was quenched with ice water and the solid was filtered to give the title compound (300 mg, 86%). LCMS: m / z: 332.1 (M+1). + . Step 4: Preparation of 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 6-nitro-2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridine (300 mg, 0.90 mmol) was reduced with zinc dust (468 mg, 7.207 mmol) and ammonium chloride (389 mg, 7.207 mmol) in THF / methanol / HO (5 mL / 1 mL / 0.5 mL) to give the title compound (250 mg, 92%). LCMS: m / z: 302.4 (M+1) + . Step 5: Preparation of N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100 mg, 0.33 mmol) was coupled with 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (Intermediate 3) (108 mg, 0.396 mmol) using EDCI.HCl (94 mg, 0.495 mmol), HOBt (66 mg, 0.495 mmol), TEA (0.2 mL, 1.324 mmol) in DMF (2 mL) to give the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (100 mg, 55%). LCMS: m / z: 557.4 (M+1). + . Step 6: Preparation of N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride Using the same reaction conditions as described in Step 8 of Example 1, N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide (100 mg, 0.179 mmol) was deprotected using methanolic HCl to give the crude product, which was then purified by preparative HPLC to give the title compound (40 mg, 50%). 1 HNMR (DMSO-d6, 300MHz): δ 10.8 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H), 8.04-7.94 (m, 3H), 3.62 (s, 4H), 2.94 (s, 4H), 1.75 (s, 4H), 1.62-1.55 (m, 8H). LCMS: 97.91%, m / z = 473.5 (M+1) + .HPLC: 96.5%.

[0165] [Example 5] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0166] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (100 mg, 0.33 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (74 mg, 0.363 mmol) using EDCI.HCl (94 mg, 0.495 mmol), HOBt (66 mg, 0.495 mmol), TEA (0.2 mL, 1.324 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (30 mg, 20%). 1 HNMR (DMSO-d6, 300MHz): δ 9.98 (s, 1H), 9.21 (s, 1H), 8.91-8.89 (d, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 8.09-8.08 (d, 1H), 3.61 (m, 7H), 2.98 (s, 3H), 2.71 (s, 3H), 1.81 (s, 3H), 1.61 (s, 7H).LCMS: 100%, m / z = 488.2 (M+1) + . HPLC: 92.1%.

[0167] [Example 6] N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

[0168] [ka] Step 1: Preparation of 2-morpholino-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine To a solution of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step-5 of Example 2) (30 mg, 0.1056 mmol) in THF (2 mL) was added piperidine (11 mg, 0.126 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with ice water, extracted with ethyl acetate (2 x 10 mL), dried over sodium sulfate, and the solvent was evaporated to give the title compound (30 mg, 89%). LCMS: m / z: 334.5 (M+1) + . Step 2: Preparation of 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 2-morpholino-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine (300 mg, 0.900 mmol) was reduced with zinc dust (468 mg, 7.207 mmol) and ammonium chloride (389 mg, 7.207 mmol) in THF / methanol / HO (5 mL / 1 mL / 0.5 mL) to give the title compound (260 mg, 96%). LCMS: m / z: 304.1 (M+1). + . Step 3: Preparation of N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (90 mg, 0.297 mmol) was coupled with 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (Intermediate 3) (97 mg, 0.356 mmol) using EDCI.HCl (85 mg, 0.445 mmol), HOBt (60 mg, 0.445 mmol), TEA (0.2 mL, 1.188 mmol) in DMF (4 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (60 mg, 38%). LCMS: m / z: 559.6 (M+1). + . Step 4: Preparation of N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 8 of Example 1, N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide (60 mg, 0.107 mmol) was deprotected using methanolic HCl (2 mL) to give the title compound (50 mg, 90%). 1 HNMR (DMSO-d6, 300MHz): δ 10.80 (s, 1H), 8.65 (s, 1H), 8.43 (s, 2H), 8.05-7.93 (m, 3H), 3.76-3.62 (m, 8H), 2.98 (s, 4H), 1.76 (s, 4H), 1.54 (s, 2H). LCMS: 92.69%, m / z = 475.5 (M+1) +. HPLC: 90.31%.

[0169] [Example 7] 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0170] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (100 mg, 0.331 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.397 mmol) using EDCI.HCl (94 mg, 0.496 mmol), HOBt (66 mg, 0.496 mmol), TEA (0.2 mL, 1.302 mmol) in DMF (2 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (35 mg, 22%). 1 HNMR (DMSO-d6, 300MHz): δ 9.80 (s, 1H), 9.20 (s, 1H), 8.90-8.88 (d, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.06-8.04 (d, 1H), 3.72-3.61 (m, 8H), 2.96 (s, 4H), 2.73 (s, 3H), 1.81 (s, 4H), 1.63 (s, 2H). LCMS: 81.6%, m / z = 490.2 (M+1) + . HPLC: 94.3%.

[0171] [Example 8] 6-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

[0172] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.2317 mmol) was coupled with 6-chloropicolinic acid (44 mg, 0.278 mmol) using EDCI.HCl (66 mg, 0.347 mmol), HOBt (46 mg, 0.347 mmol), TEA (0.2 mL, 0.926 mmol) in DMF (4 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (35 mg, 35%). 1 HNMR (DMSO-d6, 300MHz): δ 10.60 (s, 1H), 8.70 (s, 1H), 8.15-8.14 (t, 2H), 7.84-7.81 (m, 1H), 3.77-3.60 (m, 8H), 2.93-2.10 (t, 4H), 1.81 (s, 4H), 1.58 (s, 2H). LCMS: 99.3%, m / z = 443.2 (M+1) + . HPLC: 93.0%.

[0173] [Example 9] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide

[0174] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 4) (75 mg, 0.2483 mmol) was coupled with 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (Intermediate 4) (61 mg, 0.298 mmol) using EDCI.HCl (72 mg, 0.372 mmol), HOBt (51 mg, 0.372 mmol), DIPEA (0.17 mL, 0.9933 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (41 mg, 33.0%). 1 HNMR (DMSO-d6, 400MHz): δ 10.80 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 8.06-8.02 (t, 1H), 7.98-7.96 (d, 1H), 7.92-7.91 (d, 1H), 3.92 (s, 3H), 3.63 (s, 4H), 2.94 (s, 4H), 1.76 (s, 4H), 1.63 (s, 6H), 1.55 (s, 2H). LCMS: 98.9%, m / z = 487.2 (M+1) + . HPLC: 94.0%.

[0175] [Example 10] 2-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0176] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 4) (75 mg, 0.2483 mmol) was coupled with 2-(2-chloropyridin-4-yl)oxazole-4-carboxylic acid (71 mg, 0.298 mmol) using EDCI.HCl (72 mg, 0.372 mmol), HOBt (51 mg, 0.372 mmol), DIPEA (0.17 mL, 0.9933 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (62 mg, 45.9%). 1 HNMR (CD3OD, 400MHz): δ 8.82 (s, 1H), 8.64-8.62 (d, 1H), 8.14 (s, 1H), 8.04-8.03 (d, 1H), 3.81 (s, 8H), 2.06-1.96 (m, 4H), 1.79 (s, 8H). LCMS: 84.1%, m / z = 508.2 (M+1) + . HPLC: 97.6%.

[0177] [Example 11] (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0178] [ka] Step 1: Preparation of (S)-tert-butyl 3-((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate A solution of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (300 mg, 1.0563 mmol), (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (237 mg, 1.267 mmol), and potassium carbonate (292 mg, 2.112 mmol) in DMF (2 mL) was heated at 100° C. for 2 h. The reaction was quenched with ice water, and the solid was filtered. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (350 mg, 76.25%). LCMS: m / z: 435.4 (M+1) + . Step 2: Preparation of (S)-tert-butyl 3-((6-amino-2-morpholinoxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate Using the same reaction conditions as described in Step 5 of Example 1, (S)-tert-butyl 3-((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate (350 mg, 0.806 mmol) was reduced with zinc dust (422 mg, 6.451 mmol) and ammonium chloride (691 mg, 12.903 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (240 mg, 71.8%). LCMS: m / z: 405.2 (M+1) + . Step 3: Preparation of (S)-tert-butyl 3-((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate Using the same reaction conditions as described in Step 6 of Example 1, (S)-tert-butyl 3-((6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate (115 mg, 0.284 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (70 mg, 0.341 mmol) using EDCI.HCl (82 mg, 0.426 mmol), HOBt (58 mg, 0.426 mmol), DIPEA (0.199 mL, 1.138 mmol) in DMF (2 mL) to afford the title compound (100 mg, 59.52%). LCMS: m / z: 591.4 (M+1) + . Step 4: Preparation of (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, (S)-tert-butyl 3-((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate (100 mg, 0.169 mmol) was deprotected using methanolic HCl (5 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (9 mg, 10.84%). 1 HNMR (CDCl3, 400MHz): δ 9.91 (s, 1H), 8.78 (s, 1H), 8.74-8.73 (d, 1H), 8.45 (s, 1H), 7.82 (s, 1H), 7.76-7.74 (d, 1H), 4.50 (s, 1H), 4.04-4.03 (d, 4H), 3.30-3.00 (m, 7H), 2.70 (s, 3H), 2.40-1.80 (m, 4H), 1.00-0.08 (m, 1H). LCMS: 100%, m / z = 491.3 (M+1) + .

[0179] [Example 12] 6'-Amino-N-(2-morpholinoxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide

[0180] [ka] Step 1: Preparation of 3-amino-6-chloropyridin-2-ol Using the same reaction conditions as described in Step 5 of Example 1, 6-chloro-3-nitropyridin-2-ol (1.0 g, 5.747 mmol) was reduced with zinc dust (3.0 g, 45.977 mmol) and ammonium chloride (4.92 g, 91.952 mmol) in THF / methanol / HO (20 m / 4 mL / 2 mL) to give the crude product, which was purified by 60-120 silica gel column chromatography using 10% methanol in DCM as the eluent to give the title compound (500 mg, 60.97%). 1 HNMR (DMSO-d6, 300MHz): δ 6.84-6.81 (d, 1H), 6.55-6.52 (d, 1H). LCMS: m / z: 145.0(M+1) + . Step 2: Preparation of 5-chlorooxazolo[5,4-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 3-amino-6-chloropyridin-2-ol (900 mg, 6.25 mmol) was cyclized using potassium ethyl xanthate (1.1 g, 6.875 mmol) in pyridine (8 mL) to give the title compound (1.0 g, 86.2%). LCMS: m / z: 185.0 (M-1). + . Step 3: Preparation of 5-chloro-2-morpholinooxazolo[5,4-b]pyridine A mixture of 5-chlorooxazolo[5,4-b]pyridine-2-thiol (550 mg, 2.956 mmol) and morpholine (5 mL) was heated at 110° C. overnight. The solvent was evaporated. The resulting crude material was purified by 60-120 silica gel column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (200 mg, 28.5%). LCMS: m / z: 240.0 (M+1) + . Step 4: Preparation of 6'-amino-N-(2-morpholinoxazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide A sealed tube was charged with 5-chloro-2-morpholinooxazolo[5,4-b]pyridine (76 mg, 0.316 mmol), tert-butyl (6-carbamoyl-[2,3'-bipyridin]-6'-yl)carbamate (100 mg, 0.316 mmol) (Intermediate 2), and cesium carbonate (257 mg, 0.79 mmol) in toluene (5 mL) and purged with argon for 10 minutes. X-Phos (15 mg, 0.32 mmol) was added and heated at 110 °C overnight. The solvent was evaporated. The crude product was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as the eluent. The crude product was further purified by preparative HPLC to give the title compound (11 mg, 10.0%). 1 HNMR (CDCl3, 300MHz): δ 8.81 (s, 1H), 8.25-8.24 (d, 1H), 8.10 (s, 1H), 7.80-7.75 (m, 3H), 7.50-7.44 (m, 1H), 7.25 (s, 1H), 3.77-3.62 (m, 8H). LCMS: 72.3%, m / z = 418.2 (M+1) + .HPLC: 96.1%.

[0181] [Example 13] 6'-Amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide

[0182] [ka] Step-1: Synthesis of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione Using the same reaction conditions as described in Step 1 of Example 1, 4,6-dichloropyridin-3-amine (1.3 g, 7 mmol) was cyclized using potassium ethylxanthate (2.55 g, 15 mmol) in DMF (25 mL) at 150° C. for 8 hours to afford the title compound (1.3 g, 86.6%) as a light brown solid. 1 HNMR (400 MHz, DMSO-d6): δ 14.2-14.0 (b, 1H), 8.274 (s, 1H), 7.931 (s, 1H); LCMS: 100%, m / z = 201.3 (M+1) + . Step-2: Synthesis of 4-(6-chlorothiazolo[4,5-c]pyridin-2-yl)morpholine To a suspension of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione (0.3 g, 1.16 mmol) in DCM (4 mL) was added oxalyl chloride (0.2 mL, 2.38 mmol) and DMF (1.5 mL) at 0 °C. The resulting mixture was slowly warmed to room temperature and stirred there for 1 h. The reaction mixture was cooled to 0 °C again, and triethylamine (0.66 mL, 4.76 mmol) and morpholine (0.13 mL, 1.75 mmol) were added. The reaction mixture was stirred at room temperature for 1 h, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc / n-hexane 3:7) to afford the title compound (0.14 g, 39.6%) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.04 (s, 1H), 3.74-3.72 (m, 4H), 3.61-3.59 (m, 4H); LCMS: m / z = 256.1 (M+1) + . Step-3: Synthesis of 6'-amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide Using the same reaction conditions as described in Step 4 of Example 12, 4-(6-chlorothiazolo[4,5-c]pyridin-2-yl)morpholine (0.081 g, 0.32 mmol) was coupled with tert-butyl (6-carbamoyl-[2,3'-bipyridin]-6'-yl)carbamate (Intermediate 2) (0.1 g, 0.32 mmol) using cesium carbonate (0.21 g, 0.64 mmol), Xantphos (0.028 g, 0.047 mmol), and Pd(dba) (0.015 mg, 0.015 mmol) in toluene:dioxane (2:2 mL) to give the crude product, which was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent. The resulting crude product was further purified by preparative HPLC to give the title compound (0.01 g, 6%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.88 (d, 1H), 8.85 (dd, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.22-8.13 (m, 4 H), 7.09 (d, 1H), 3.73 (t, 4H), 3.58 (t, 4H). LCMS: 100%, m / z = 434.2 (M+1) + .

[0183] [Example 14] 6'-Amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide

[0184] [ka] Step 1: Preparation of 5-chlorothiazolo[5,4-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 2,6-dichloropyridin-3-amine (5 g, 30 mmol) was cyclized using potassium ethylxanthate (9.81 g, 61 mmol) in NMP (40 mL) at 150° C. overnight to give the title compound (5.5 g, 92%). 1 HNMR (DMSO-d6, 300MHz): δ 14.10 (bs, 1H), 7.66-7.62 (d, 1H), 7.53-7.48 (d, 1H). LCMS: m / z: 202.9 (M+1) + . Step 2: Preparation of 4-(5-chlorothiazolo[5,4-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 4, morpholine (40 mL) was used to replace 5-chlorothiazolo[5,4-b]pyridine-2-thiol (5.5 g, 27.22 mmol) to give the title compound (4 g, 58%). 1 HNMR (DMSO-d6, 300MHz): δ 7.83-7.80 (d, 1H), 7.42-7.39 (d, 1H), 3.75-3.71 (m, 4H), 3.61-3.58 (m, 4H). LCMS: m / z: 256.0(M+1) + . Step 3: Preparation of 6'-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide Using the same reaction conditions as described in Step 4 of Example 12, 6'-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3'-bipyridine]-6-carboxamide (200 mg, 0.632 mmol) was coupled with tert-butyl (6-carbamoyl-[2,3'-bipyridin]-6'-yl)carbamate (Intermediate 2) (177 mg, 0.692 mmol) using cesium carbonate (514 mg, 1.582 mmol), X-Phos (30 mg, 0.063 mmol), and Pd(dba) (28 mg, 0.031 mmol) in toluene (5 mL) to give the crude product. The crude product was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent. The resulting crude product was further purified by preparative HPLC to give the title compound (13 mg, 5%). 1 HNMR (DMSO-d6, 300MHz): δ 10.06 (s, 1H), 9.17-9.16 (d, 1H), 8.64-8.60 (m, 1H), 8.39 (s, 1H), 8.15-8.13 (d, 1H), 8.04-7.99 (t, 1H), 7.93-7.91 (d, 1H), 7.80-7.69 (m, 4H), 3.75-3.72 (t, 4H), 3.55-3.52 (t, 4H). LCMS: 96.5%, m / z = 434.4 (M+1) + . HPLC: 95.1%.

[0185] [Example 15] 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0186] [ka] Step 1: Preparation of thiazolo[4,5-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 3-bromopyridin-2-amine (5 gr, 28 mmol) was cyclized using potassium ethylxanthate (9.24 gr, 57 mmol) in NMP (40 mL) at 150° C. overnight to give the title compound (4.2 gr, 88%). 1 HNMR (DMSO-d6, 300MHz): δ 8.37-8.35 (m, 1H), 8.15-8.12 (m, 1H), 7.32-7.28 (q, 1H) LCMS: m / z: 169.1(M+1) + . Step 2: Preparation of 4-(thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 4, morpholine (20 mL) was used to displace thiazolo[4,5-b]pyridine-2-thiol (4.2 g, 25 mmol) at 110° C. to give the title compound (3 g, 55%). 1 HNMR (DMSO-d6, 300MHz): δ 8.32-8.30 (dd, 1H), 8.22-8.18 (dd, 1H), 7.07-7.03 (q, 1H), 3.76-3.72 (m, 4H), 3.62-3.59 (m, 4H). LCMS: m / z: 222.3 (M+1) + . Step 3: Preparation of 4-(6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 4 of Example 1, 4-(thiazolo[4,5-b]pyridin-2-yl)morpholine (2.5 g, 11.3 mmol) was nitrated using acetic acid (5 mL) and fuming nitric acid (10 mL) at 100° C. overnight to give the title compound (1.5 g, 50%). 1 HNMR (DMSO-d6, 300MHz): δ 9.15-9.09 (m, 2H), 3.70-3.60 (bs, 8H). Step 4: Preparation of 2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (500 mg, 1.879 mmol) was reduced with zinc dust (977 mg, 15.03 mmol) and ammonium chloride (812 mg, 15.03 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (430 mg, 97%). 1 HNMR (DMSO-d6, 300MHz): δ 7.75-7.74 (d, 1H), 7.36-7.35 (d, 1H), 5.10-5.05 (bs, 2H), 3.73-3.70 (m, 4H), 3.48-3.34 (m, 4H). LCMS: m / z: 237.4 (M+1) + . Step 5: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholinothiazolo[4,5-b]pyridin-6-amine (110 mg, 0.466 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (95 mg, 0.466 mmol) using EDCI.HCl (133 mg, 0.699 mmol), HOBt (94 mg, 0.69 mmol), DIPEA (0.2 mL, 1.165 mmol) in DMF (2 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent. The crude product was further purified by preparative HPLC to give the title compound (28 mg, 15%). 1 HNMR (DMSO-d6, 300MHz): δ 10.45 (s, 1H), 9.01 (s, 1H), 8.70-8.63 (d, 1H), 8.65-8.62 (dd, 2H), 7.89 (s, 1H), 7.80-7.75 (d, 1H), 3.77-3.72 (t, 4H), 3.62-3.60 (t, 4H), 2.60 (s, 3H). LCMS: 100%, m / z = 423.2 (M+1) + . HPLC: 96.9%.

[0187] [Example 16] 6'-Amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide

[0188] [ka] Step 1: Preparation of 6-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 15) (320 mg, 1.35 mmol) was coupled with 6-bromopicolinic acid (356 mg, 1.76 mmol) using EDCI.HCl (698 mg, 5.4 mmol), HOBt (239 mg, 1.76 mmol), DIPEA (338 mL, 1.76 mmol) in DMF (5 mL) to give the title compound (250 mg, 43.9%). LCMS: m / z: 421.6 (M+1). + . Step 2: Preparation of tert-butyl (6-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3'-bipyridin]-6'-yl)carbamate Using the same reaction conditions as described in Step 7 of Example 1, 6-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (250 mg, 0.59 mmol) was coupled with tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (151 mg, 0.71 mmol) (Intermediate 1) using sodium carbonate (188 mg, 1.77 mmol) and Pd(PPh)Cl (22 mg, 0.029 mmol) in 1,2-dimethoxyethane (8 mL) to give the crude product. The resulting crude was purified by Combiflash using 0.2-2.0% methanol in chloroform as the eluent to give the title compound (120 mg, 37.8%). LCMS: m / z: 534.2(M+1) + . Step 3: Preparation of 6'-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3'-bipyridine]-6-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (6-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate (120 mg, 0.22 mmol) was deprotected using TFA (12 mL) to give the title compound (80 mg, 82%). 1 HNMR (DMSO-d6, 300MHz): δ 10.65 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H), 8.45-8.42 (d, 1H), 8.08-7.95 (m, 3H), 6.59-6.56 (d, 1H), 6.38 (s, 2H), 3.76-3.74 (t, 4H), 3.63-3.62 (t, 4H). LCMS: 98.9%, m / z = 434.1 (M+1) + . HPLC: 95.9%.

[0189] [Example 17] N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

[0190] [ka] Using the same reaction conditions as described in Step 7 of Example 1, 6-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 1 of Example 16) (200 mg, 0.477 mmol) was coupled with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111 mg, 0.572 mmol) using sodium carbonate (151 mg, 1.431 mmol) and Pd(PPh)Cl in 1,2-dimethoxyethane (5 mL) to give the crude product. The crude product was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent. It was further purified by preparative HPLC to give the title compound (14 mg, 8%). 1 HNMR (DMSO-d6, 400MHz): δ 13.2 (s, 1H), 10.60 (s, 1H), 8.70-8.60 (m, 3H), 8.40 (s, 1H), 8.02-7.91 (m, 3H), 3.76-3.74 (t, 4H), 3.62-3.60 (t, 4H). LCMS: 100%, m / z = 408.1 (M+1) + . HPLC: 97.9%.

[0191] [Example 18] 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide

[0192] [ka] Step 1: tert-butyl ((1-(3-fluoro-5-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 15) (60 mg, 0.254 mmol) was coupled with 3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid (Intermediate 5) (98 mg, 0.279 mmol) using EDCI.HCl (72 mg, 0.381 mmol), HOBt (52 mg, 0.381 mmol), DIPEA (98 mg, 0.762 mmol) in DMF (5 mL) to afford the title compound (130 mg, 90.2%). LCMS: m / z: 571.2 (M+1) + . Step 2: 3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl ((1-(3-fluoro-5-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate (130 mg, 0.228 mmol) was deprotected using methanolic HCl (4.7 mL) to give the crude compound. The resulting crude was purified by preparative HPLC to give the title compound (55 mg, 47.8%). 1 HNMR (DMSO-d6, 3 00MHz): δ 10.74 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 7.96 (s, 3H), 7.41 (s, 1H), 7.14-7.01 (m, 2H), 3.69-3.68 (m, 6H), 2.83-2.73 (m, 5H), 2.27 (s, 1H), 1.85-1.81 (m, 4H), 1.30-1.23 (m, 3H). LCMS: 100%, m / z = 471.5(M+1) + . HPLC: 97.9%.

[0193] [Example 19] 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide

[0194] [ka] Step 1: Preparation of tert-butyl ((1-(4-fluoro-2-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 15) (100 mg, 0.423 mmol) was coupled with 2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoic acid (Intermediate 6) (164 mg, 0.466 mmol) using EDCI.HCl (121 mg, 0.65 mmol), HOBt (85 mg, 0.635 mmol), TEA (0.3 mL, 1.694 mmol) in DMF (4 mL) to provide the title compound (50 mg, 21%). LCMS: m / z: 571.3 (M+1) + . Step 2: Preparation of 2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide hydrochloride Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl ((1-(4-fluoro-2-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate (50 mg, 0.087 mmol) was deprotected using methanolic HCl (4.7 mL) to give the title compound (40 mg, 90%). 1 HNMR (DMSO-d6, 300MHz): δ 11.93 (s, 1H), 8.87-8.86 (d, 1H), 8.70-8.69 (d, 1H), 8.20-7.98 (m, 3H), 7.65-7.61 (m, 1H), 7.49-7.43 (m, 2H), 3.77-3.75 (t, 4H), 3.75-3.67 (t, 4H), 3.22-3.19 (m, 2H), 2.82-2.72 (m, 4H), 1.89-1.85 (m, 3H), 1.40-1.36 (m, 2H). LCMS: 100%, m / z = 471.3 (M+1) + . HPLC: 96.8%.

[0195] [Example 20] 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0196] [ka] Step 1: Preparation of 5-chlorothiazolo[4,5-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 3-bromo-6-chloropyridin-2-amine (1.8 g, 8.653 mmol) was cyclized using potassium ethylxanthate (2.35 g, 14.71 mmol) in NMP (5 mL) at 165° C. overnight to give the crude product (2.0 g). LCMS: m / z: 202.9 (M+1) + . Step 2: Preparation of 5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 1, 5-chlorothiazolo[4,5-b]pyridine-2-thiol (2 g, 9.850 mmol) was methylated using potassium carbonate (2.71 g, 19.7 mmol) and methyl iodide (2.1 g, 14.775 mmol) in ethyl acetate (10 mL) to give the crude product, which was purified by 60-120 silica gel column chromatography using 20% ​​ethyl acetate in hexane as the eluent to give the title compound (500 mg, 23.8%). 1 HNMR (CDCl3, 300MHz): δ 8.02-8.00 (d, 1H), 7.37-7.24 (m, 2H), 2.85 (s, 3H). Step 3: Preparation of 4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 3 of Example 1, using morpholine (1 mL) and THF (1 mL) and substituting 5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (500 mg, 2.314 mmol), the title compound (450 mg, 76.2%) was obtained. 1 HNMR (CDCl3, 400MHz): δ 7.82-7.80 (d, 1H), 7.04-7.01 (d, 1H), 3.84-3.83 (m, 4H), 3.75-3.71 (m, 4H). LCMS: m / z: 256.0 (M+1) + . Step 4: Preparation of 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Potassium nitrate (266 mg, 2.64 mmol) was added to a solution of 4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)morpholine (450 mg, 1.764 mmol) in concentrated sulfuric acid (5 mL) and stirred at room temperature overnight. Ice water was added to the reaction mixture, and the solid was filtered to give the title compound (450 mg, 86.0%). 1HNMR (DMSO-d6, 400MHz): δ 9.06 (s, 1H), 3.75 (s, 8H). LCMS: m / z: 301.0 (M+1) + Step 5: Preparation of 4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 6, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (450 mg, 1.50 mmol) using piperidine (0.5 mL) in THF (5 mL) at 75° C. for 2 hours, the title compound (450 mg, 85.7%) was obtained. LCMS: m / z: 350.1 (M+1). + . Step 6: Preparation of 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine (400 mg, 1.142 mmol) was reduced with zinc dust (600 mg, 9.136 mmol) and ammonium chloride (1.0 g, 18.272 mmol) in THF / methanol / HO (10 / 2 mL / 1 mL) to give the crude product (400 mg). LCMS: m / z: 320.25 (M+1). + . Step 7: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg, 0.313 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (64 mg, 0.313 mmol) using EDCI.HCl (90 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), DIPEA (101 mg, 0.782 mmol) in DMF (5 mL) to give a crude product. The crude product was purified by preparative HPLC to give the title compound (40 mg, 47.5%). 1 HNMR (DMSO-d6, 400MHz): δ 9.80 (s, 1H), 9.21 (s, 1H), 8.90-8.88 (m, 2H), 8.19 (s, 1H), 8.07-8.06 (m, 1H), 3.73-3.72 (t, 4H), 3.60-3.58 (t, 4H), 3.03-2.90 (t, 4H), 2.66 (s, 3H), 1.88-1.79 (t, 4H), 1.65-1.58 (m, 2H). LCMS: 90.4%, m / z = 506.3 (M+1) + . HPLC: 92.6%.

[0197] [Example 21] N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

[0198] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (100 mg, 0.313 mmol) was coupled with 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (Intermediate 3) (90 mg, 0.313 mmol) using EDCI.HCl (90 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), DIPEA (101 mg, 0.782 mmol) in DMF (5 mL) to give the crude coupled product. Using the same reaction conditions as described in Step 8 of Example 1, the crude product was deprotected using methanolic HCl (5 mL) to give the crude compound. The resulting crude product was purified by preparative HPLC to give the title compound (30 mg, 43.5%). 1 HNMR (DMSO-d6, 400MHz): δ 10.80 (s, 1H), 9.05 (s, 1H), 8.39 (s, 2H), 8.05-7.98 (m, 3H), 3.73-3.58 (m, 8H), 2.99-2.90 (m, 4H), 1.75-1.68 (m, 4H), 1.54-1.48 (m, 2H). LCMS: 85.0%, m / z = 491.3 (M+1) + . HPLC: 95.7%.

[0199] [Example 22] N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

[0200] [ka] Step 1: Preparation of 5-chloro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (450 mg, 2.314 mmol) was substituted using piperidine (1 mL) and THF (mL) at 75° C. for 2 hours to give the crude product (500 mg). LCMS: m / z: 254.0 (M+1). + . Step 2: Preparation of 5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine Potassium nitrate (71 mg, 2.657 mmol) was added to a solution of 5-chloro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (450 mg, 1.771 mmol) in concentrated sulfuric acid (5 mL) and stirred at room temperature overnight. Ice water was added to the reaction mixture, and the solid was filtered to give the title compound (400 mg, 75.5%). LCMS: m / z: 299.0 (M+1) + . Step 3: Preparation of 6-nitro-2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 6, 5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (400 mg, 1.337 mmol) was substituted using piperidine (2.0 mL) in THF (5 mL) at 75° C. for 30 minutes to give the crude product (400 mg). LCMS: m / z: 348.1 (M+1). + . Step 4: Preparation of 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 6-nitro-2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridine (400 mg, 1.149 mmol) was reduced with zinc dust (597 mg, 9.192 mmol) and ammonium chloride (974 mg, 18.384 mmol) in THF (10 mL) to give the crude product (320 mg). LCMS: m / z: 318.1 (M+1). + . Step 5: Preparation of N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg, 0.315 mmol) was coupled with 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid (Intermediate 3) (77 mg, 0.378 mmol) using EDCI.HCl (90 mg, 0.472 mmol), HOBt (63 mg, 0.472 mmol), DIPEA (101 mg, 0.787 mmol) in DMF (5 mL) to give the crude product (140 mg). LCMS: m / z: 573.3 (M+1). + . Step 6: Preparation of N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 8 of Example 1, N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide (140 mg, 0.244) was deprotected using methanolic HCl (5 mL) to give the crude compound. The resulting crude was purified by preparative HPLC to give the title compound (40 mg, 32.3%). 1 HNMR (CD3OD, 400MHz): δ 8.94 (s, 1H), 8.74 (s, 2H), 8.17-8.03 (m, 3H), 3.90-3.82 (m, 4H), 3.33-3.32 (m, 4H), 1.90-1.83 (m, 10H), 1.69-1.68 (m, 2H). LCMS: 99.0%, m / z = 489.5 (M+1) + . HPLC: 96.2%.

[0201] [Example 23] N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0202] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 22) (100 mg, 0.315 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (77 mg, 0.378 mmol) using EDCI.HCl (90 mg, 0.472 mmol), HOBt (63 mg, 0.472 mmol), DIPEA (101 mg, 0.787 mmol) in DMF (5 mL) to give the crude product. The crude product was purified by preparative HPLC to give the title compound (45 mg, 26.5%). 1 HNMR (CD3OD, 400MHz): δ 9.00 (s, 1H), 8.96-8.94 (d, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.52-8.50 (d, 1H), 3.90-3.81 (m, 4H), 3.50-3.41 (m, 4H), 2.94 (s, 3H), 1.89-1.75 (m, 12H). LCMS: 80.0%, m / z = 504.2 (M+1) + . HPLC: 98.4%.

[0203] [Example 24] N-(2,5-dimorpholinoxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0204] [ka] Step 1: Preparation of 2,5-dimorpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 4, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (175 mg, 0.6147 mmol) was heated with morpholine (2 mL) at 110° C. for 3 hours. The solvent was distilled to give the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (190 mg, 92.23%). 1 HNMR (CDCl3, 300MHz): δ 8.14 (s, 1H), 3.84-3.81 (m, 12H), 3.49-3.45 (m, 4H). LCMS: m / z = 336.0 (M+1) + . Step 2: Preparation of 2,5-dimorpholinoxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 2,5-dimorpholino-6-nitrooxazolo[4,5-b]pyridine (190 mg, 0.5666 mmol) was reduced with zinc dust (297 mg, 4.5329 mmol) and ammonium chloride (485 mg, 9.0659 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (150 mg, 86.70%). 1 HNMR (CDCl3, 400MHz): δ 6.97 (s, 1H), 3.87-3.66 (m, 14H), 3.12-3.10 (t, 4H). LCMS: m / z = 306.1 (M+1) + . Step 3: Preparation of N-(2,5-dimorpholinoxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 6 of Example 1, 2,5-dimorpholinooxazolo[4,5-b]pyridin-6-amine (70 mg, 0.229 mmol) was coupled with 2-(pyridin-4-yl)oxazole-4-carboxylic acid (56 mg, 0.275 mmol) using EDCI.HCl (66 mg, 0.343 mmol), HOBt (47 mg, 0.343 mmol), DIPEA (0.16 mL, 0.917 mmol) in DMF (2 mL) to give the crude product, which was then treated with methanolic HCl to give the title compound (61 mg, 50.41%). 1 HNMR (CD3OD, 400MHz): δ 8.90-8.88 (m, 2H), 8.7 (s, 1H), 8.6 (s, 1H), 8.5 (d, 1H), 3.99-3.95 (t, 4H), 3.84-3.83 (t, 4H), 3.78-3.76 (t, 4H), 3.20-3.18 (t, 4H), 2.92 (s, 3H). LCMS: m / z = 492.0 (M+1) + . HPLC: 95.10%.

[0205] [Example 25] N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0206] [ka] Step 1: Preparation of 5-(4-methylpiperazin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 4, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (175 mg, 0.6147 mmol) was heated with N-methylpiperazine (185 mg, 1.844 mmol) at 75° C. for 3 hours. The solvent was distilled to give the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 5% methanol in DCM as the eluent to give the title compound (200 mg, 93.45%). m / z = 349.3 (M+1). + . Step 2: Preparation of 5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(4-methylpiperazin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (200 mg, 0.5747 mmol) was reduced with zinc dust (301 mg, 4.5977 mmol) and ammonium chloride (492 mg, 9.1954 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (150 mg, 81.96%). LCMS: m / z = 319.4 (M+1). + . Step 3: Preparation of N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (70 mg, 0.2198 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (54 mg, 0.2638 mmol) using EDCI.HCl (64 mg, 0.3298 mmol), HOBt (45 mg, 0.3298 mmol), DIPEA (0.145 mL, 0.8794 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC and treated with methanolic HCl to give the title compound (50 mg, 42.01%). 1 HNMR (CD3OD, 400MHz): δ 8.91 (m, 2H), 8.70 (s, 1H), 8.60-8.55 (m, 2H), 3.85-3.82 (t, 4H), 3.76-3.74 (t, 4H), 3.67-3.30 (m, 8H), 3.04 (s, 3H), 2.93 (s, 3H). m / z = 505.3 (M+1) + . HPLC: 97.92%.

[0207] [Example 26] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0208] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (70 mg, 0.2317 mmol) was coupled with 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 7) (62 mg, 0.2781 mmol) using EDCI.HCl (67 mg, 0.3476 mmol), HOBt (47 mg, 0.3476 mmol), DIPEA (0.162 mL, 0.9271 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (10 mg, 8.54%). 1 HNMR (DMSO-d6, 400MHz): δ 9.77 (s, 1H), 8.84 (s, 1H), 8.85-8.84 (d, 1H), 8.60 (s, 1H), 8.27-8.24 (dd, 1H), 7.10-7.07 (d, 1H), 3.95 (s, 3H), 3.62-3.60 (t, 4H), 2.94-2.91 (t, 4H), 1.90 (s, 4H), 1.77-1.50 (s, 8H). LCMS: m / z = 504.2 (M+1) + . HPLC: 97.23%.

[0209] [Example 27] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide

[0210] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (70 mg, 0.2317 mmol) was coupled with 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 8) (57 mg, 0.2781 mmol) using EDCI.HCl (67 mg, 0.3476 mmol), HOBt (47 mg, 0.3476 mmol), DIPEA (0.162 mL, 0.9271 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (50 mg, 44.24%). 1 HNMR (DMSO-d6, 400MHz): δ 9.79 (s, 1H), 9.02 (s, 1H), 8.639-8.631 (d, 2H), 8.33-8.30 (d, 1H), 7.50-7.45 (m, 1H), 3.61-3.60 (m, 4H), 2.97 (s, 3H), 2.90-2.88 (t, 4H), 1.80-1.70 (m, 4H), 1.61-1.50 (m, 8H). LCMS: m / z = 488.2 (M+1) + . HPLC: 97.55%.

[0211] [Example 28] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazole-4-carboxamide

[0212] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (70 mg, 0.232 mmol) was coupled with 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 9) (48 mg, 0.232 mmol) using EDCI.HCl (67 mg, 0.348 mmol), HOBt (47 mg, 0.348 mmol), DIPEA (75 mg, 0.581 mmol) in DMF (2 mL) to provide the title compound (75 mg, 66.3%). 1 HNMR (DMSO-d6, 400MHz): δ 12.4 (s, 1H), 9.80 (s, 1H), 8.87 (s, 1H), 8.61 (s, 1H), 8.22-8.20 (d, 1H), 7.70-7.69 (d, 1H), 6.45-6.42 (t, 1H), 3.62 (s, 4H), 2.90-2.89 (m, 4H), 1.90-1.77 (m, 4H), 1.69-1.55 (m, 8H). LCMS: m / z = 490.1 (M+1) + . HPLC: 90.22%.

[0213] [Example 29] 2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0214] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.232 mmol) was coupled with 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 9) (48 mg, 0.232 mmol) using EDCI.HCl (67 mg, 0.348 mmol), HOBt (47 mg, 0.348 mmol), DIPEA (75 mg, 0.581 mmol) in DMF (2 mL) to provide the title compound (65 mg, 57.5%). 1 HNMR (DMSO-d6, 400MHz): δ 12.30 (s, 1H), 9.80 (s, 1H), 8.88 (s, 1H), 8.65 (s, 1H), 8.24-8.13 (d, 1H), 7.70-7.64 (d, 1H), 6.50-6.30 (t, 1H), 3.73-3.72 (m, 4H), 3.63-3.62 (m, 4H), 2.90-2.89 (m, 4H), 1.90-1.76 (m, 4H), 1.64-1.54 (m, 2H). LCMS: m / z = 492.0 (M+1) + . HPLC: 90.53%.

[0215] [Example 30] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazole-4-carboxamide

[0216] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (75 mg, 0.247 mmol) was coupled with 2-(2-hydroxypyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 10) (61 mg, 0.297 mmol) using EDCI.HCl (70 mg, 0.371 mmol), HOBt (50 mg, 0.371 mmol), DIPEA (0.2 mL, 0.99 mmol) in DMF (4 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (25 mg, 21%). 1 HNMR (DMSO-d6, 400MHz): δ 12.30 (s, 1H), 9.90 (s, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 8.14-8.02 (d, 1H), 7.98-7.88 (d, 1H), 6.68-6.53 (d, 1H), 3.64-3.52 (m, 4H), 2.94-2.92 (t, 4H), 1.84-1.73 (m, 4H), 1.70-1.54 (m, 8H). LCMS: m / z = 490.2 (M+1) + . HPLC: 93.74%.

[0217] [Example 31] 2-(2-Methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0218] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.230 mmol) was coupled with 2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 11) (57 mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346 mmol), DIPEA (0.161 mL, 0.929 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (7 mg, 6.03%). 1 HNMR (CDCl3, 400MHz): δ 10.0 (s, 1H), 8.76 (s, 1H), 8.38-8.33 (d, 2H), 7.51 (s, 1H), 7.38 (s, 1H), 5.34 (s, 1H), 4.10 (s, 3H), 3.80-3.70 (d, 8H), 3.05 (s, 4H), 1.89-1.82 (m, 4H), 1.65-1.63 (bs, 2H). LCMS: m / z = 506.2 (M+1) + . HPLC: 95.81%.

[0219] [Example 32] 2-(2-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0220] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.230 mmol) was coupled with 2-(2-methoxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 8) (57 mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346 mmol), DIPEA (0.161 mL, 0.929 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (7 mg, 6.03%). 1 HNMR (DMSO-d6, 400MHz): δ 9.91 (s, 1H), 9.11 (s, 1H), 8.78-8.77 (d, 1H), 8.65-8.62 (m, 2H), 7.76-7.75 (t, 1H), 3.73-3.61 (m, 8H), 3.08 (s, 3H), 2.94-2.75 (m, 4H), 1.76-1.65 (m, 4H), 1.60-1.55 (m, 2H). LCMS: m / z = 490.2 (M+1) + . HPLC: 96.28%.

[0221] [Example 33] 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0222] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (54 mg, 0.265 mmol) was coupled with 2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 12) (80 mg, 0.265 mmol) using EDCI.HCl (77 mg, 0.397 mmol), HOBt (38 mg, 0.278 mmol), DIPEA (0.12 mL, 0.927 mmol) in DMF (5 mL) to provide the title compound (121 mg, 93%). 1 HNMR (DMSO-d6, 300MHz): δ 9.90 (s, 1H), 9.10 (s, 1H), 8.75-8.60 (m, 3H), 7.95-7.86 (d, 1H), 3.80-3.52 (m, 8H), 2.95-2.85 (m, 4H), 2.80 (s, 3H), 1.80-1.68 (m, 4H), 1.66-1.50 (m, 2H). LCMS: m / z = 490.4 (M+1) + . HPLC: 95.93%.

[0223] [Example 34] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide

[0224] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (54 mg, 0.265 mmol) was coupled with 2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 12) (80 mg, 0.265 mmol) using EDCI.HCl (77 mg, 0.397 mmol), HOBt (38 mg, 0.278 mmol), DIPEA (0.12 mL, 0.927 mmol) in DMF (5 mL) to provide the title compound (117 mg, 91%). 1 HNMR (DMSO-d6, 300MHz): δ 9.90 (s, 1H), 9.05 (s, 1H), 8.77 (s, 1H), 8.68-8.60 (m, 2H), 7.90-7.85 (d, 1H),3.70-3.60 (m, 4H), 2.95-2.85 (m, 4H), 2.80 (s, 3H), 1.80-1.70 (m, 4H), 1.68-1.50 (m, 8H). LCMS: 98.99%, m / z = 488.4 (M+1) + . HPLC: 97.00%.

[0225] [Example 35] 2-(6-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0226] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.230 mmol) was coupled with 2-(6-methylpyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 13) (57 mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346 mmol), DIPEA (0.201 mL, 1.153 mmol) in DMF (2 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (30 mg, 24.79%). 1 HNMR (DMSO-d6, 400MHz): δ 9.85 (s, 1H), 9.147-9.142 (d, 1H), 9.04 (s, 1H), 8.64 (s, 1H), 8.37-8.35 (dd, 1H), 7.64-7.62 (d, 1H), 3.74-3.72 (m, 4H), 3.64-3.62 (m, 4H), 3.15-2.90 (m, 4H), 2.62 (s, 3H), 1.90-1.75 (m, 4H), 1.70-1.55 (m, 2H). LCMS: 98.39%, m / z = 490.0 (M+1) + . HPLC: 95.97%.

[0227] [Example 36] 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

[0228] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (80 mg, 0.2640 mmol) was coupled with 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (Intermediate 4) (65 mg, 0.3168 mmol) using EDCI.HCl (76 mg, 0.3960 mmol), HOBt (38 mg, 0.2772 mmol), DIPEA (0.103 mg, 0.7920 mmol) in DMF (4 mL) to provide the title compound (75 mg, 58.59%). 1 HNMR (DMSO-d6, 400MHz): δ 10.9 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.10-7.90 (m, 3H), 4.00 (s, 3H), 3.80-3.70 (m, 4H), 3.69-3.60 (m, 4H), 3.0 (s, 4H), 1.80 (s, 4H), 1.55 (s, 2H). LCMS: 100%, m / z = 489.3 (M+1) + . HPLC: 96.26%.

[0229] [Example 37] N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide

[0230] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 4) (80 mg, 0.265 mmol) was coupled with 2-(2-methylpyridin-5-yl)oxazole-5-carboxylic acid (Intermediate 13) (60 mg, 0.292 mmol) using EDCI.HCl (77 mg, 0.398 mmol), HOBt (38 mg, 0.279 mmol), DIPEA (0.102 mg, 0.797 mmol) in DMF (4 mL) to provide the title compound (90 mg, 69.7%). 1 HNMR (DMSO-d6, 400MHz): δ 9.83 (s, 1H), 9.11 (s, 1H), 9.00 (s, 1H), 8.61 (s, 1H), 8.27-8.25 (dd, 1H), 7.54-7.52 (d, 1H), 3.63 (s, 4H), 2.94-2.93 (t, 4H), 2.58 (s, 3H), 1.82 (s, 4H), 1.63 (s, 8H). LCMS: 98.89%, m / z = 488.2 (M+1) + . HPLC: 98.54%.

[0231] [Example 38] (S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0232] [ka] Step 1: Preparation of tert-butyl (S)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate A round-bottom flask was charged with 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (the product of Step 5 of Example 2) (157 mg, 0.555 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (125 mg, 0.555 mmol), potassium carbonate (238 mg, 1.722 mmol), and DMF (5 mL) and stirred overnight at room temperature. Ice water was added, and the solid was filtered and dried under vacuum to give the crude product, which was used directly in the next step. LCMS: m / z = 435.2 (M+1) + . HPLC: 80.36%. Step 2: Preparation of tert-butyl (S)-(1-(6-amino-2-morpholinoxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate The crude tert-butyl (S)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate obtained above was dissolved in methanol (30 mL), 10% Pd / C (25 mg) was added, and the mixture was stirred under a hydrogen balloon for 2 hours. The reaction mass was filtered through Celite® and concentrated to give the title compound (71 mg, 32%). LCMS: m / z = 405.2 (M+1) + .HPLC:79.86%. Step 3: Preparation of tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, tert-butyl (S)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (70 mg, 0.341 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (115 mg, 0.284 mmol) using EDCI.HCl (98 mg, 0.512 mmol), HOBt (46 mg, 0.341 mmol), DIPEA (0.148 mg, 1.1384 mmol) in DMF (4 mL) to provide the title compound (152 mg, 91%). LCMS: m / z = 591.6 (M+1) + . HPLC: 86.43%. Step 4: Preparation of (S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (150 mg, 0.2542 mmol) was deprotected using methanolic HCl (5 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (58 mg, 97%). 1 HNMR (CD3OD, 400MHz): δ 8.97 (s, 1H), 8.93-8.91 (d, 1H), 8.64 (s, 1H), 8.56-8.55 (d, 1H), 8.02 (s, 1H), 4.02-3.67 (m, 13H), 2.90 (s, 3H), 2.50-2.40 (m, 1H), 2.25-2.05 (m, 1H). LCMS: 96.74%, m / z = 491.4 (M+1) + . HPLC: 95.27%.

[0233] [Example 39] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0234] [ka] Step 1: Preparation of (S)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (291 mg, 2.112 mmol) and DMF (5 mL), and substituting (S)-pyrrolidin-3-ol (61 mg, 0.704 mmol) for 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (200 mg, 0.704 mmol) to give the title product (195 mg, 82%). LCMS: m / z = 335.9 (M+1). + . Step 2: Preparation of (S)-1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 2 of Example 38, (S)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (194 mg, 0.579 mmol) was reduced using 10% Pd / C (50 mg) in methanol (40 mL) to give the title compound (162 mg, 92%). LCMS: m / z = 306.1 (M+1). + . Step 3: Preparation of (S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (160 mg, 0.526 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (108 mg, 0.526 mmol) using EDCI.HCl (151 mg, 0.789 mmol), HOBt (75 mg, 0.5523 mmol), DIPEA (0.272 mg, 2.104 mmol) in DMF (5 mL) to provide the title compound (45 mg, 17%). 1 HNMR (CD3OD, 400MHz): δ 8.70 (s, 1H), 8.64-8.63 (d, 1H), 8.02 (s, 1H), 7.94-7.93 (d, 1H), 7.87 (s, 1H), 4.49-4.45 (m, 1H), 3.84-3.71 (m, 10H), 3.70-3.47 (m, 2H), 2.67 (s, 3H), 2.13-2.10 (m, 1H), 2.00-1.80 (m, 1H). LCMS: 100%, m / z = 492.2 (M+1) + . HPLC: 97.90%.

[0235] [Example 40] (R)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0236] [ka] Step 1: Preparation of tert-butyl (R)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (183 mg, 1.33 mmol) and DMF (5 mL), 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (126 mg, 0.444 mmol) was replaced with tert-butyl (R)-pyrrolidin-3-ylcarbamate (100 mg, 0.444 mmol) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (127 mg, 66%). LCMS: m / z = 435.2 (M+1). + . Step 2: Preparation of tert-butyl (R)-(1-(6-amino-2-morpholinoxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 2 of Example 38, (R)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (126 mg, 0.290 mmol) was reduced using 10% Pd / C (25 mg) in methanol (20 mL) to give the title compound (102 mg, 87%). LCMS: m / z = 405.3 (M+1). + . Step 3: Preparation of tert-butyl (R)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, tert-butyl (R)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (100 mg, 0.2475 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (51 mg, 0.2475 mmol) using EDCI.HCl (72 mg, 0.3712 mmol), HOBt (35 mg, 0.2599 mmol), DIPEA (0.128 mg, 0.990 mmol) in DMF (5 mL) to give the title compound (73 mg, 51%). LCMS: m / z = 591.1 (M+1). + . Step 4: Preparation of (R)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (R)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (73 mg, 0.123 mmol) was deprotected using methanolic HCl (5 mL) to afford the title compound (32 mg, 53%). 1 HNMR (CD3OD, 400MHz): δ 9.72 (s, 1H), 8.65-8.63 (d, 1H), 8.01 (s, 1H), 7.93-7.90 (t, 2H), 3.84-3.81 (t, 4H), 3.70-3.64 (m, 7H), 3.60-3.50 (m, 2H), 2.67 (s, 3H), 2.30-2.20 (m, 1H), 1.90-1.80 (m, 1H). LCMS: 96.75%, m / z = 491.2 (M+1) + . HPLC: 95.80%.

[0237] [Example 41] (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0238] [ka] Step 1: Preparation of (R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (291 mg, 2.112 mmol) and DMF (5 mL), substituting (R)-pyrrolidin-3-ol (61 mg, 0.704 mmol) for 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (200 mg, 0.704 mmol) to give the title product (231 mg, 98.7%). LCMS: m / z = 336.1 (M+1). + . Step 2: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine To a solution of (R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (230 mg, 0.698 mmol) in DMF (5 mL), TBDMS chloride (124 mg, 0.822 mmol) and imidazole (116 mg, 1.70 mmol) were added and stirred at room temperature overnight. The reaction mass was quenched with water and extracted with ethyl acetate to obtain the crude product. The obtained crude was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to obtain the title compound (310 mg, 99%). LCMS: m / z = 450.3 (M+1) + . Step 3: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (308 mg, 0.685 mmol) was reduced using 10% Pd / C (30 mg) in methanol (20 mL) to give the title compound (235 mg, 81%). LCMS: m / z = 420.2 (M+1). + . Step 4: Preparation of (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (234 mg, 0.5587 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (114 mg, 0.5584 mmol) using EDCI.HCl (180 mg, 0.840 mmol), HOBt (81 mg, 0.5863 mmol), DIPEA (0.290 mg, 2.237 mmol) in DMF (5 mL) to give the title compound (167 mg, 50%). LCMS: m / z = 606.2 (M+1). + . Step 5: Preparation of (R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions described in Step 8 of Example 1, (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (167 mg, 0.276 mmol) was deprotected using methanolic HCl (5 mL) to provide the title compound (106 mg, 78%). 1 HNMR (DMSO-d6, 300MHz): δ 9.82 (s, 1H), 8.96 (s, 1H), 8.68-8.67 (d, 1H), 7.86 (s, 1H), 7.80-7.77 (d, 1H), 7.66 (s, 1H), 4.86 (s, 1H), 4.27 (s, 1H), 3.72-3.6.0 (m, 11H), 3.25-3.21 (m, 1H), 2.58 (s, 3H), 1.89-1.78 (m, 2H). LCMS: 98.95%, m / z = 492.2 (M+1) + . HPLC: 95.08%.

[0239] [Example 42] (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0240] [ka] Step 1: Preparation of tert-butyl (S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (100 mg, 0.3296 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 14) (147 mg, 0.4944 mmol) using EDCI.HCl (95 mg, 0.4944 mmol), HOBt (67 mg, 0.4944 mmol), DIPEA (0.23 mL, 1.3185 mmol) in DMF (2 mL) to provide the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (130 mg, 67.7%). LCMS: m / z = 583.5 (M+1) + . Step 2: Preparation of (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate (130 mg, 4.482 mmol) was deprotected using TFA (5 mL) and DCM (5 mL) to afford the title compound (73 mg, 68.22%). 1 HNMR (CDCl3, 400MHz): δ 9.90 (s, 1H), 8.77 (s, 1H), 7.82 (s, 1H), 3.81-3.73 (m, 10H), 3.69-3.59 (m, 1H), 3.38-3.28 (m, 1H), 3.02 (s, 4H), 2.30-2.15 (m, 1H), 1.82 (m, 5H), 1.70-1.60 (m, 3H). LCMS: 99.52%, m / z = 483.2 (M+1) +. HPLC: 98.70%.

[0241] [Example 43] (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

[0242] [ka] Step 1: Preparation of 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (400 mg, 1.3245 mmol) was coupled with 6-bromopicolinic acid (321 mg, 1.5894 mmol) using EDCI.HCl (321 mg, 1.9867 mmol), HOBt (268 mg, 1.9867 mmol), DIPEA (683 mg, 5.2980 mmol) in DMF (20 mL) to provide the title compound (487 mg, 75%). 1 HNMR (CDCl3, 400MHz): δ 10.86 (s, 1H), 8.82 (s, 1H), 8.24-8.22 (d, 1H), 7.80-7.86 (t, 1H), 7.67-7.65 (d, 1H), 3.83-3.73 (m, 8H), 3.06-3.03 (t, 4H), 1.90-1.88 (m, 4H), 1.70-1.60 (m, 2H). LCMS: m / z = 489.1 (M+2) + . HPLC: 97.69%. Step 2: Preparation of (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide A mixture of 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide (130 mg, 0.2269 mmol), (S)-pyrrolidin-3-ol (35 mg, 0.4 mmol), and sodium carbonate (85 mg, 0.8 mmol) in DMF (2 mL) was heated at 140° C. for 12 h. The reaction was quenched with ice water, filtered, and purified by 60-120 silica gel column chromatography using 1% methanol in DCM as eluent to give the title compound (80 mg, 60.79%). 1 HNMR (CDCl3, 400MHz): δ 10.66 (s, 1H), 8.83 (s, 1H), 7.64-7.62 (t, 1H), 7.58-7.56 (d, 1H), 6.58-6.56 (d, 1H), 3.83-3.79 (m, 4H), 3.76-3.72 (m, 7H), 3.04-3.03 (m, 4H), 2.30-2.10 (m, 2H), 1.77-1.72 (m, 4H), 1.61-1.57 (m, 3H). LCMS: 96.72%, m / z = 494.2 (M+1) + . HPLC: 98.60%.

[0243] [Example 44] (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

[0244] [ka] Step 1: Preparation of tert-butyl (S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 2 of Example 6) (100 mg, 0.2053 mmol) with tert-butyl (S)-pyrrolidin-3-ylcarbamate (57 mg, 0.3080 mmol) using sodium carbonate (65 mg, 0.6160 mmol) in DMF (2 mL) at 140° C. for 12 hours, the title compound (60 mg, 49.34%) was obtained. Step 2: Preparation of (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (60 mg, 0.1013 mmol) was deprotected using TFA (2 mL) and DCM (2 mL) to afford the title compound (30 mg, 60.16%). 1 HNMR (CDCl3, 400MHz): δ 10.70 (s, 1H), 8.84 (s, 1H), 7.65-7.61 (t, 1H), 7.57-7.55 (d, 1H), 6.56-6.54 (d, 1H), 3.87-3.63 (m, 9H), 3.39-3.37 (m, 1H), 3.04-3.01 (t, 4H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 1H), 1.771-1.76 (m, 5H), 1.60-1.56 (m, 3H). LCMS: 98.72%, m / z = 493.3 (M+1) + . HPLC: 97.84%.

[0245] [Example 45] (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0246] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (100 mg, 0.3296 mmol) was coupled with (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 15) (124 mg, 0.3955 mmol) using EDCI.HCl (95 mg, 0.4944 mmol), HOBt (67 mg, 0.4944 mmol), DIPEA (0.23 mL, 1.3185 mmol) in DMF (2 mL) to provide the crude product. Using the same reaction conditions as described in Step 8 of Example 1, the crude product was deprotected using methanolic HCl (5 mL) to give the title compound (128 mg, 80.5%). 1 HNMR (CDCl3, 300MHz): δ 9.78 (s, 1H), 8.76 (s, 1H), 7.82 (s, 1H), 4.70-4.60 (m, 1H), 3.82-3.56 (m, 12H), 3.03-3.00 (t, 4H), 2.19-2.11 (m, 2H), 1.81-1.78 (m, 6H). LCMS: 95.04%, m / z = 484.2 (M+1) + . HPLC: 95.55%.

[0247] [Example 46] (S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide

[0248] [ka] Using the same reaction conditions as described in Example 45, 5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 7 of Example 2) (100 mg, 0.384 mmol) was coupled with (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 15) (145 mg, 0.4615 mmol) using EDCI.HCl (110 mg, 0.5769 mmol), HOBt (78 mg, 0.5769 mmol), DIPEA (0.268 mL, 1.5384 mmol) in DMF (2 mL), followed by deprotection using methanolic HCl (5 mL) to give the title compound (56 mg, 50.4%). 1 HNMR (CDCl3, 300MHz): δ 9.17 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H), 4.70-4.60 (m, 1H), 3.82-3.56 (m, 12H), 2.13-2.03 (m, 3H), 1.86-1.84 (d, 1H), 1.16-1.13 (m, 2H), 1.04-1.00 (m, 2H). LCMS: 93.32%, m / z = 440.8 (M+1) + . HPLC: 95.51%.

[0249] [Example 47] (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0250] [ka] Using the same reaction conditions as described in Example 45, 5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 7 of Example 2) (100 mg, 0.384 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 14) (137 mg, 0.4615 mmol) using EDCI.HCl (110 mg, 0.5769 mmol), HOBt (78 mg, 0.5769 mmol), DIPEA (0.268 mL, 1.5384 mmol) in DMF (2 mL), followed by deprotection using TFA (5 mL) and DCM (5 mL) to afford the title compound (27 mg, 18.49%). 1 HNMR (CDCl3, 400MHz): δ 9.17 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 3.82-3.72 (m, 10H), 3.61-3.59 (m, 1H), 3.29-3.26 (m, 1H), 2.30-2.18 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.78 (m, 1H), 1.16-1.15 (m, 2H), 1.04-1.00 (m, 2H). LCMS: 100%, m / z = 440.2 (M+1) + . HPLC: 98.06%.

[0251] [Example 48] 2-(2-Methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride

[0252] [ka] Step 1: Preparation of 5-chloro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, using pyrrolidine (2 mL) and THF (5 mL) at 75° C. for 2 hours, substituting 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (250 mg), gave the title compound (250 mg). 1 HNMR (CDCl3, 400MHz): δ 7.35-7.33 (d, 1H), 6.89-6.87 (d, 1H), 3.70-3.60 (m, 4H), 2.10-2.00 (m, 4H). LCMS: m / z = 224.1 (M+1) + . Step 2: Preparation of 5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions described in Step 4 of Example 20, 5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (250 mg, 1.121 mmol) was nitrated using potassium nitrate (226 mg, 2.242 mmol) and concentrated sulfuric acid (3 mL) at room temperature for 24 hours to afford the crude title compound (180 mg, 60%). Step 3: Preparation of 6-nitro-5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 6, piperidine (57 mg) in THF (3 mL) was used to replace 5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (180 mg, 0.6716 mmol) at room temperature for 12 hours to give the title compound (150 mg, 70.7%). LCMS: m / z = 318.45 (M+1). + . Step 4: Preparation of 5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 6-nitro-5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (150 mg, 0.4731 mmol) was reduced with zinc dust (247 mg, 3.7854 mmol) and ammonium chloride (404 mg, 7.5696 mmol) in THF / methanol / HO (5 m / 1 mL / 0.5 mL) to give the crude title product (152 mg). LCMS: m / z = 288.2 (M+1). + . Step 5: Preparation of 2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 6 of Example 1, 5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (150 mg, 0.5226 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (127 mg, 0.6271 mmol) using EDCI.HCl (149 mg, 0.7839 mmol), HOBt (108 mg, 0.7839 mmol), DIPEA (0.18 mL, 1.0452 mmol) in DMF (2 mL) to give a crude product. The crude product was purified by preparative HPLC and treated with methanolic HCl to give the title compound (38 mg, 14.28%). 1 HNMR (CDCl3, 400MHz): δ 13.4-12.8 (bs, 1H), 11.80 (s, 1H), 9.19 (s, 1H), 8.74 (s, 1H), 8.47-8.42 (m, 2H), 7.93 (s, 1H), 3.74 (s, 4H), 3.65 (s, 4H), 3.08 (s, 3H), 2.48 (s, 2H), 2.12 (s, 4H), 1.99 (s, 2H), 1.90-1.70 (m, 2H). LCMS: 100%, m / z = 474.2 (M+1) + . HPLC: 97.93%.

[0253] [Example 49] N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride

[0254] [ka] Step 1: Preparation of 5-chloro-2-(2,6-dimethylmorpholino)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, substituting 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of Step 3 of Example 2) (250 mg, 1.25 mmol) using 2,6-dimethylmorpholine (2 mL) and THF (5 mL) at 75° C. for 2 hours, the title compound (251 mg) was obtained. 1 HNMR (CDCl3, 400MHz): δ 7.38-7.36 (d, 1H), 6.94-6.92 (d, 1H), 4.17-4.14 (d, 2H), 3.75-3.68 (m, 2H), 2.90-2.84 (t, 2H), 1.27-1.26 (d, 6H). LCMS: m / z = 268.0 (M+1) + . Step 2: Preparation of 5-chloro-2-(2,6-dimethylmorpholino)-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 4 of Example 20, 5-chloro-2-(2,6-dimethylmorpholino)oxazolo[4,5-b]pyridine (250 mg, 0.9363 mmol) was nitrated using potassium nitrate (189 mg, 1.8726 mmol) and concentrated sulfuric acid (3 mL) at room temperature for 24 hours to give the title compound (150 mg, 51.3%). LCMS: m / z = 313.0 (M+1). + . Step 3: Preparation of 2-(2,6-dimethylmorpholino)-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 6, substituting 5-chloro-2-(2,6-dimethylmorpholino)-6-nitrooxazolo[4,5-b]pyridine (150 mg, 0.1602 mmol) using piperidine (45 mg) in THF (3 mL) at room temperature for 12 hours, the title compound (152 mg, 86.2%) was obtained. LCMS: m / z = 362.4 (M+1) + . Step 4: Preparation of 2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 2-(2,6-dimethylmorpholino)-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine (152 mg, 0.4143 mmol) was reduced with zinc dust (216 mg, 3.3147 mmol) and ammonium chloride (353 mg, 6.6288 mmol) in THF / methanol / HO (5 mL / 1 mL / 0.5 mL) to give the crude title compound (160 mg). 1 HNMR (CDCl3, 400MHz): δ 6.96 (s, 1H), 4.11-4.07 (dd, 2H), 3.74-3.70 (m, 2H), 3.02-3.01 (m, 4H), 2.83-2.77 (t, 2H), 1.76-1.68 (m, 4H), 1.64-1.56 (m, 2H), 1.26-1.24 (d, 6H). LCMS: m / z = 332.2 (M+1) + . Step 5: Preparation of N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 6 of Example 1, 2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (152 mg, 0.6024 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (147 mg, 0.7228 mmol) using EDCI.HCl (172 mg, 0.9036 mmol), HOBt (125 mg, 0.9036 mmol), DIPEA (0.2 mL, 1.2048 mmol) in DMF (2 mL) to give a crude product. The crude product was purified by preparative HPLC and treated with methanolic HCl to give the title compound (80 mg). 1 HNMR (CDCl3, 400MHz): δ 13.15-12.90 (bs, 1H), 11.90 (s, 1H), 9.18 (s, 1H), 8.74 (s, 1H), 8.46-8.42 (d, 1H), 7.96 (s, 1H), 4.21-4.18 (m, 2H), 3.76-3.60 (m, 6H), 3.08 (s, 3H), 2.99-2.92 (t, 2H), 2.60-2.41 (m, 2H), 2.08-1.90 (m, 2H), 1.60-1.80 (m, 2H), 1.29-1.27 (d, 6H). LCMS: 100%, m / z = 518.5 (M+1) + . HPLC: 98.81%.

[0255] [Example 50] N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide hydrochloride

[0256] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 22) (70 mg, 0.220 mmol) was coupled with 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (Intermediate 4) (53 mg, 0.264 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), DIPEA (78 mg, 0.66 mmol) in DMF (5 mL) to give the crude product. The crude product was purified by preparative HPLC and treated with methanolic HCl to give the title compound (25 mg, 21.2%). 1 HNMR (CD3OD, 300MHz): δ 9.01 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 8.10-8.01 (m, 2H), 7.92-7.89 (dd, 1H), 4.01 (s, 3H), 3.80 (s, 4H), 3.39-3.30 (m, 4H), 1.82 (s, 10H), 1.69-1.67 (d, 2H). LCMS: 98.92%, m / z = 503.3 (M+1) + . HPLC: 98.03%.

[0257] [Example 51] 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

[0258] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.313 mmol) was coupled with 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (Intermediate 4) (53 mg, 0.262 mmol) using EDCI.HCl (62 mg, 0.327 mmol), HOBt (45 mg, 0.327 mmol), DIPEA (85 mg, 0.654 mmol) in DMF (5 mL) to give a crude coupling product. The resulting crude product was purified by preparative HPLC to give the title compound (35 mg, 30%). 1 HNMR (CD3OD, 300MHz): δ 8.96 (bs, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.11-8.01 (m, 2H), 7.94-7.91 (d, 1H), 4.02 (s, 3H), 3.88-3.82 (m, 8H), 3.55-3.21 (m, 4H), 1.87 (s, 4H), 1.80-1.60 (m, 2H). LCMS: 82.87%, m / z = 505.2 (M+1) + . HPLC: 97.63%.

[0259] [Example 52] N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide hydrochloride

[0260] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 22) (70 mg, 0.220 mmol) was coupled with 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 8) (50 mg, 0.242 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to give the crude product. The crude product was purified by preparative HPLC and treated with methanolic HCl to give the title compound (30 mg, 27.2%). 1 HNMR (CD3OD, 400MHz): δ 9.21-9.19 (d, 2H), 8.91-8.88 (m, 3H), 8.80 (bs, 1H), 8.15-8.11 (t, 2H), 3.78 (s, 8H), 3.18 (s, 3H), 1.80 (s, 8H), 1.71-1.70 (m, 4H). LCMS: 85.44%, m / z = 504.2 (M+1) + . HPLC: 98.54%.

[0261] [Example 53] N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0262] [ka] Step 1: Preparation of (2R,6S)-4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine Using the same reaction conditions as described in Step 3 of Example 1, substituting 5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (product of Step 2 of Example 20) (170 mg, 0.784 mmol) using (2R,6S)-2,6-dimethylmorpholine (1 mL) and THF (2 mL) at 75° C. for 16 hours, the crude title compound (260 mg) was obtained. LCMS: m / z = 284.1 (M+1). + . Step 2: Preparation of (2R,6S)-4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine Using the same reaction conditions as described in Step 4 of Example 20, (2R,6S)-4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine (260 mg, 0.916 mmol) was nitrated using potassium nitrate (277 mg, 2.74 mmol) and concentrated sulfuric acid (5 mL) at room temperature for 2 days to give the crude title compound (120 mg). LCMS: m / z = 328.9 (M+1). + . Step 3: Preparation of (2R,6S)-2,6-dimethyl-4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 6, (2R,6S)-4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine (120 mg, 0.365 mmol) was replaced with piperidine (0.5 mL) in THF (2 mL) at room temperature for 30 minutes to give the title compound (190 mg). m / z = 378.0 (M+1). + . Step 4: Preparation of 2-((2R,6S)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, (2R,6S)-2,6-dimethyl-4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine (190 mg, 0.503 mmol) was reduced with zinc dust (260 mg, 4.026 mmol) and ammonium chloride (430 mg, 8.04 mmol) in THF / methanol / HO (3 mL / 0.8 mL / 0.3 mL) to give the crude product (170 mg). LCMS: m / z = 348.2 (M+1). + . Step 5: Preparation of N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Step 6 of Example 1, 2-((2R,6S)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (85 mg, 0.244 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (60 mg, 0.293 mmol) using EDCI.HCl (70 mg, 0.366 mmol), HOBt (50 mg, 0.366 mmol), DIPEA (0.94 mg, 0.732 mmol) in DMF (2 mL) to give the crude product. The crude product was purified by preparative HPLC and treated with methanolic HCl to give the title compound (25 mg, 19.20%). 1 HNMR (CD3OD, 300MHz): δ 9.05 (s, 1H), 8.90-8.85 (d, 1H), 8.70 (s, 1H), 8.60 (s, 1H), 8.58-8.45 (d, 1H), 4.06-3.97 (m, 2H), 3.85-3.79 (m, 2H), 3.49 (s, 4H), 3.21-3.05 (t, 2H), 2.93 (s, 3H), 1.89 (s, 4H), 1.76 (s, 2H), 1.29-1.21 (d, 6H). LCMS: 98.99%, m / z = 534.3 (M+1)+ . HPLC: 96.10%.

[0263] [Example 54] 2-(2-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0264] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.219 mmol) was coupled with 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 8) (45 mg, 0.219 mmol) using EDCI.HCl (63 mg, 0.329 mmol), HOBt (45 mg, 0.329 mmol), DIPEA (71 mg, 0.548 mmol) in DMF (5 mL) to obtain the crude title compound. The resulting crude product was purified by preparative HPLC to obtain the title compound (35 mg, 30%). 1 HNMR (DMSO-d6, 400MHz): δ 9.70 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.82-8.74 (d, 1H), 8.68-8.62 (d, 1H), 7.83-7.72 (t, 1H), 3.74-3.72 (m, 4H), 3.59-3.57 (m, 4H), 3.08 (s, 3H), 2.99 (s, 4H), 1.74 (s, 4H), 1.65-1.52 (m, 2H). LCMS: 88.8%, m / z = 506.2 (M+1) + . HPLC: 97.66%.

[0265] [Example 55] 2-(2-Hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0266] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.219 mmol) was coupled with 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 9) (45 mg, 0.219 mmol) using EDCI.HCl (63 mg, 0.329 mmol), HOBt (45 mg, 0.329 mmol), DIPEA (71 mg, 0.548 mmol) in DMF (5 mL) to obtain the crude title compound. The resulting crude product was purified by preparative HPLC to obtain the title compound (35 mg, 31.5%). 1 HNMR (DMSO-d6, 400MHz): δ 12.40 (s, 1H), 9.62 (s, 1H), 8.97 (s, 1H), 8.89 (s, 1H), 8.23-8.21 (dd, 1H), 7.73-7.62 (m, 1H), 3.75-3.73 (m, 4H), 3.58-3.56 (m, 4H), 2.99-2.96 (, 4H), 1.80 (s, 4H), 1.68-1.53 ​​(m, 2H). LCMS: 100%, m / z = 508.0 (M+1) + . HPLC: 96.21%.

[0267] [Example 56] N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide

[0268] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 22) (70 mg, 0.220 mmol) was coupled with 2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 11) (53 mg, 0.242 mmol) using EDCI.HCl (57 mg, 0.30 mmol), HOBt (41 mg, 0.30 mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to give the crude product. The crude product was purified by preparative HPLC to give the title compound (13 mg, 11%). 1 HNMR (CDCl3, 300MHz): δ 9.84 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H), 8.34-8.33 (d, 1H), 7.52-7.50 (dd, 1H), 7.38 (s, 1H), 4.01 (s, 3H), 3.66 (s, 4H), 3.12-3.09 (t, 4H), 1.88 (s, 4H), 1.69 (s, 8H). LCMS: 100%, m / z = 520.0 (M+1) + . HPLC: 94.16%.

[0269] [Example 57] 2-(6-Methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0270] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (540 mg, 1.692 mmol) was coupled with 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 7) (442 mg, 2.031 mmol) using EDCI.HCl (484 mg, 25.39 mmol), HOBt (228 mg, 1.692 mmol), DIPEA (1.3 g, 6.771 mmol) in DMF (5 mL) to provide the title compound (400 mg, 45%). 1 HNMR (DMSO-d6, 400MHz): δ 9.65 (s, 1H), 8.98-8.97 (d, 2H), 8.87 (s, 1H), 8.35-8.30 (dd, 1H), 7.117.09 (d, 1H), 3.96 (s, 3H), 3.75-3.73 (m, 4H), 3.59-3.58 (m, 4H), 3.10-3.00 (t, 4H), 1.82 (s, 4H), 1.20-1.10 (m, 2H). LCMS: 95.26%, m / z = 522.2 (M+1) + . HPLC: 95.37%.

[0271] [Example 58] 2-(2-Methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0272] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.22 mmol) was coupled with 2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 11) (53 mg, 0.242 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to provide the title compound (25 mg, 21%). 1 HNMR (CD3OD, 300MHz): δ 8.99 (s, 1H), 8.59 (s, 1H), 8.35-8.30 (d, 1H), 7.60-7.52 (d, 1H), 7.42 (s, 1H), 3.99 (s, 3H), 3.84-3.81 (t, 4H), 3.67-3.64 (t, 4H), 3.11-3.08 (t, 4H), 1.90-1.85 (m, 4H), 1.80-1.70 (m, 2H). LCMS: 88.28%, m / z = 522.2 (M+1) + . HPLC: 91.56%.

[0273] [Example 59] (S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0274] [ka] Step 1: Preparation of (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol Using the same reaction conditions as described in Step 2 of Example 43, using sodium carbonate (265 mg, 2.4940 mmol) in DMF (2 mL) at 140° C. for 4 hours, and using (S)-piperidin-3-ol hydrochloride (137 mg, 0.9976 mmol) substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (250 mg, 1.50 mmol) to afford the title compound (190 mg, 62.70%). LCMS: m / z = 366.1 (M+1). + . Step 2: Preparation of (S)-4-(5-(3-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine DAST (0.17 mL, 1.3013 mmol) was added to a cooled (-78 °C) solution of (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (190 mg, 0.5205 mmol) in DCM (5 mL). The reaction was stirred at -78 °C for 30 minutes and then quenched with ice water. The compound was extracted with DCM and purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (100 mg, 52.35%). LCMS: m / z = 368.1 (M+1) + . Step 3: Preparation of (S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, (S)-4-(5-(3-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (100 mg, 0.2724 mmol) was reduced with zinc dust (143 mg, 2.1798 mmol) and ammonium chloride (233 mg, 4.3596 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the crude product (100 mg). LCMS: m / z = 338.1 (M+1). + . Step 4: Preparation of (S)—N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in step 6 of example 1, (S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg, 0.2724 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (84 mg, 0.4087 mmol) using EDCI.HCl (79 mg, 0.4087 mmol), HOBt (56 mg, 0.4087 mmol), DIPEA (0.19 mL, 1.0899 mmol) in DMF (2 mL) to obtain crude product. The obtained crude product was purified by preparative HPLC to obtain the title compound (26 mg, 18.30%). 1 HNMR (CDCl3, 400MHz): δ 9.94 (s, 1H), 9.09 (s, 1H), 8.69-8.68 (d, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.76-7.75 (d, 1H), 5.04-4.92 LCMS: 97.00%, m / z = 524.1 (M+1) + . HPLC: 95.24%.

[0275] [Example 60] 2-(6-Methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0276] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.22 mmol) was coupled with 2-(2-methylpyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 13) (54 mg, 0.264 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (40 mg, 0.33 mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to provide the title compound (30 mg, 26%). 1 HNMR (CD3OD, 400MHz): δ 9.36 (s, 1H), 9.08-9.05 (dd, 1H), 8.85 (s, 1H), 8.70 (s, 1H), 8.15-8.13 (d, 1H), 3.85-3.83 (t, 8H), 3.50-3.48 (m, 4H), 2.88 (s, 3H), 1.85 (s, 4H), 1.80-1.70 (m, 2H). LCMS: 98.51%, m / z = 506.2 (M+1) + . HPLC: 94.43%.

[0277] [Example 61] 2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0278] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (80 mg, 0.25 mmol) was coupled with 2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 12) (61 mg, 0.3 mmol) using EDCI.HCl (72 mg, 0.376 mmol), HOBt (36 mg, 0.263 mmol), DIPEA (97 mg, 0.75 mmol) in DMF (3.4 mL) to provide the title compound (29 mg, 23%). 1 HNMR (DMSO-d6, 400MHz): δ 9.70 (s, 1H), 9.09 (s, 1H), 8.99 (s, 1H), 8.71 (s, 1H), 8.65-8.64 (d, 1H), 7.92-7.91 (d, 1H), 3.73-3.72 (m, 4H), 3.65-3.55 (m, 4H), 2.96-2.95 (m, 4H), 2.78 (s, 3H), 1.76 (s, 4H), 1.59 (s, 2H). LCMS: 99.47%, m / z = 506.2 (M+1) + . HPLC: 98.79%.

[0279] [Example 62] (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

[0280] [ka] Step 1: Preparation of 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (35 mg, 0.994 mmol) was coupled with 6-bromopicolinic acid (301 mg, 1.49 mmol) using EDCI.HCl (285 mg, 1.49 mmol), HOBt (141 mg, 1.04 mmol), DIPEA (384 mg, 2.98 mmol) in DMF (10 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (220 mg, 40%). LCMS: m / z = 503.0 (M). + . Step 2: Preparation of tert-butyl (S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide (70 mg, 0.139 mmol) with tert-butyl (S)-pyrrolidin-3-ylcarbamate (39 mg, 0.209 mmol) using sodium carbonate (59 mg, 0.556 mmol) in DMF (3 mL) at 140° C. for 4 hours, the title compound (40 mg, 46.5%) was obtained. Step 3: Preparation of (S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (65 mg, 9.3655) was deprotected using TFA (2 mL) and DCM (8 mL) to give the title compound (45 mg, 83.3%). 1 HNMR (CDCl3, 400MHz): δ 10.58 (s, 1H), 9.11 (s, 1H), 7.65-7.55 (m, 2H), 6.57-6.55 (d, 1H), 3.87-3.77 (m, 6H), 3.68-3.3.63 (m, 5H), 3.38-3.37 (m, 1H), 3.10-3.07 (t, 4H), 2.28-2.25 (m, 1H), 1.90-1.87 (m, 1H), 1.77 (s, 4H), 1.57-1.55 (m, 3H). LCMS: 100%, m / z = 509.1 (M+1) + . HPLC: 95.95%.

[0281] [Example 63] (S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

[0282] [ka] Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 1 of Example 63) (70 mg, 0.139 mmol) with (S)-pyrrolidin-3-ol (19 mg, 0.208 mmol) using sodium carbonate (59 mg, 0.556 mmol) in DMF (3 mL) at 140° C. for 12 hours, the title compound (50 mg, 71.4%) was obtained. 1HNMR (DMSO-d6, 400MHz): δ 10.45 (s, 1H), 9.05 (s, 1H), 7.74-7.70 (t, 1H), 7.38-7.37 (d, 1H), 6.75-6.74 (d, 1H), 5.06-5.05 (d, 1H), 4.44 (s, 1H), 3.75-3.72 (m, 4H), 3.64-3.56 (m, 7H), 2.94-2.93 (d, 4H), 2.09-2.07 (m, 1H), 1.98-1.95 (m, 1H), 1.72 (s, 4H), 1.57 (s, 2H). LCMS: 94.83%, m / z = 510.2 (M+1) + . HPLC: 95.34%.

[0283] [Example 64] (S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

[0284] [ka] Step 1: Preparation of 6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 6 of Example 1, 2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 22) (300 mg, 0.946 mmol) was coupled with 6-bromopicolinic acid (286 mg, 1.419 mmol) using EDCI.HCl (270 mg, 1.419 mmol), HOBt (191 mg, 1.419 mmol), DIPEA (370 mg, 2.838 mmol) in DMF (5 mL) to provide the title compound (350 mg, 73.83%). 1HNMR (CDCl3, 300MHz): δ 10.7 (s, 1H), 9.06 (s, 1H), 8.24-8.21 (d, 1H), 7.80-7.75 (t, 1H), 7.67-7.64 (d, 1H), 3.65 (s, 4H), 3.12-3.08 (t, 4H), 1.95-1.85 (m, 4H), 1.69 (s, 8H). LCMS: m / z = 503.1 (M+2) + . Step 2: Preparation of tert-butyl (S)-(1-(6-((2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide (100 mg, 0.2 mmol) with tert-butyl (S)-pyrrolidin-3-ylcarbamate (56 mg, 0.3 mmol) using sodium carbonate (64 mg, 0.6 mmol) in DMF (2 mL) at 100° C. for 4 hours, yielded the title compound (120 mg, 100%). LCMS: m / z = 607.3 (M+1). + . Step 3: Preparation of (S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(6-((2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (120 mg, 0.197 mmol) was deprotected using TFA (1 mL) and DCM (1 mL) to give the crude product, which was purified by preparative HPLC to give the title compound (65 mg, 65%). 1HNMR (CDCl3, 300MHz): δ 10.53 (s, 1H), 9.05 (s, 1H), 7.65-7.54 (m, 2H), 6.55-6.53 (d, 1H), 3.84-3.73 (m, 3H), 3.64 (s, 6H), 3.50-3.35 (m, 1H), 3.08-3.04 (t, 4H), 2.31-2.25 (m, 1H), 2.10-1.85 (m, 1H), 1.80-1.60 (m, 11H). LCMS: 92.92%, m / z = 507.2 (M+1) + . HPLC: 96.92%.

[0285] [Example 65] (S)—N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

[0286] [ka] Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 1 of Example 65) (70 mg, 0.14 mmol) with (S)-pyrrolidin-3-ol (20 mg, 0.209 mmol) using sodium carbonate (45 mg, 0.42 mmol) in DMF (2 mL) at 100° C. for 4 hours, the title compound (60 mg, 84.5%) was obtained. 1HNMR (CDCl3, 400MHz): δ 10.57 (s, 1H), 9.06 (s, 1H), 7.66-7.62 (t, 1H), 7.59-7.57 (d, 1H), 6.58-6.56 (d, 1H), 4.68 (s, 1H), 3.79-3.74 (m, 4H), 3.65 (s, 4H), 3.09-3.07 (m, 4H), 2.24-2.12 (m, 2H), 1.77-1.76 (m, 4H), 1.69 (s, 6H), 1.61-1.56 (m, 3H). LCMS: 99.49%, m / z = 508.2 (M+1) + . HPLC: 99.62%.

[0287] [Example 66] (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0288] [ka] Step 1: Preparation of tert-butyl (S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (100 mg, 0.3134 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 14) (140 mg, 0.4702 mmol) using EDCI.HCl (91 mg, 0.4702 mmol), HOBt (64 mg, 0.4702 mmol), DIPEA (0.218 mL, 1.2539 mmol) in DMF (2 mL) to provide the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (170 mg, 90.9%). LCMS: m / z = 599.3 (M+1) + . HPLC: 88.43%. Step 2: Preparation of (S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate (170 mg, 0.2839 mmol) was deprotected using TFA (5 mL) and DCM (5 mL) to afford the title compound (69 mg, 48.93%). 1 HNMR (CDCl3, 400MHz): δ 9.07 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H), 3.82-3.68 (m, 11H), 3.30-3.28 (m, 1H), 3.15-3.03 (m, 4H), 2.30-2.20 (m, 1H), 1.90-1.80 (m, 5H), 1.62-1.55 (m, 3H). LCMS: 98.35%, m / z = 499.2 (M+1)+ . HPLC: 97.34%.

[0289] [Example 67] (S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0290] [ka] Step 1: Preparation of tert-butyl (S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 1 of Example 38, potassium carbonate (207 mg, 1.5 mmol) and DMF (5 mL) was used to replace 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (150 mg, 0.5 mmol) with tert-butyl (S)-pyrrolidin-3-ylcarbamate (93 mg, 0.5 mmol) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (195 mg, 87%). LCMS: m / z = 451.3 (M+1). + . Step 2: Preparation of tert-butyl tert-butyl (S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 2 of Example 38, tert-butyl (S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (194 mg, 0.431 mmol) was reduced with zinc dust (224 mg, 3.448 mmol) and ammonium chloride (366 mg, 6.8977 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (171 mg, 94%). LCMS: m / z = 421.2 (M+1). + . Step 3: Preparation of tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, tert-butyl (S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (83 mg, 0.4047 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (170 mg, 0.4047 mmol) using EDCI.HCl (117 mg, 0.6155 mmol), HOBt (58 mg, 0.4293 mmol), DIPEA (209 mg, 1.624 mmol) in DMF (5 mL) to afford the title compound (162 mg, 66%). LCMS: m / z = 607.2 (M+1). + . HPLC: 95.47%. Step 4: Preparation of (S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate (161 mg, 0.2656 mmol) was deprotected using methanolic HCl (5 mL) to provide the title compound (83 mg, 62%). 1 HNMR (CDCl3, 300MHz): δ 8.97 (s, 1H), 8.69-8.68 (d, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.84-3.80 LCMS: 100%, m / z = 507.1 (M+1) + . HPLC: 97.85%.

[0291] [Example 68] (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0292] [ka] Step 1: Preparation of 4-(5-cyclopropyl-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 7 of Example 1, 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (500 mg, 1.666 mmol) was coupled with cyclopropylboronic acid (286 mg, 3.333 mmol) using potassium phosphate (882 mg, 4.165 mmol), Pd(OAc) (57 mg, 0.254 mmol), and tricyclohexylphosphine (70 mg, 0.254 mmol) in toluene:water (10 mL / 1 mL) to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (400 mg, 80%). LCMS: m / z = 306.9 (M+1). + . Step 2: Preparation of 5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(5-cyclopropyl-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (400 mg, 1.307 mmol) was reduced with zinc dust (680 mg, 10.457 mmol) and ammonium chloride (1.13 g, 20.916 mmol) in THF (10 mL) to give the title compound (350 mg, 100%). LCMS: m / z = 277.1 (M+1). + . Step 3: Preparation of tert-butyl (S)-(1-(4-((5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate Using the same reaction conditions as described in Step 6 of Example 1, 5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg, 0.362 mmol) was coupled with (S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 14) (129 mg, 0.434 mmol) using EDCI.HCl (102 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol), DIPEA (0.280 mL, 2.16 mmol) in DMF (5 mL) to afford the title compound (180 mg, 85.1%). LCMS: m / z = 556.2 (M+1). + . Step 4: Preparation of (S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, tert-butyl (S)-(1-(4-((5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate (180 mg, 0.324 mmol) was deprotected using TFA (1 mL) and DCM (0.5 mL) to give the crude product. The resulting crude product was purified by preparative HPLC to give the title compound (60 mg, 40.8%). 1 HNMR (CDCl3, 300MHz): δ 9.20 (s, 1H), 8.72 (s, 1H), 7.83 (s, 1H), 3.83-3.56 (m, 12H), 3.28-3.25 (m, 1H), 2.22-2.18 (m, 1H), 2.10-2.03 (m, 1H), 1.88-1.77 (m, 1H), 1.33-1.21 (m, 2H), 1.07-1.00 (m, 2H). LCMS: 98.66%, m / z = 456.2 (M+1) + . HPLC: 95.53%.

[0293] [Example 69] N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0294] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 69) (100 mg, 0.362 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (110 mg, 0.54 mmol) using EDCI.HCl (102 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol), DIPEA (280 mg, 2.16 mmol) in DMF (5 mL) to provide the title compound (45 mg, 26.94%). 1 HNMR (CDCl3, 400MHz): δ 9.30 (s, 1H), 8.75-8.57 (m, 2H), 8.48 (s, 1H), 7.85 (s, 1H), 7.75-7.72 (d, 1H), 3.90-3.80 (t, 4H), 3.78-3.70 (t, 4H), 2.75 (s, 3H), 2.25-2.15 (m, 1H), 1.35-1.25 (m, 2H), 1.15-1.05 (m, 2H). LCMS: 98.37%, m / z = 463.1 (M+1) + . HPLC: 97.74%.

[0295] [Example 70] (S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0296] [ka] Using the same reaction conditions as described in Example 45, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (90 mg, 0.281 mmol) was coupled with (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 15) (105 mg, 0.3375 mmol) using EDCI.HCl (81 mg, 0.4218 mmol), HOBt (57 mg, 0.4218 mmol), DIPEA (145 mg, 1.125 mmol) in DMF (2 mL), followed by deprotection using methanolic HCl (2 mL) to provide the title compound (63 mg, 84%). 1 HNMR (CDCl3, 400MHz): δ 9.75 (s, 1H), 9.07 (s, 1H), 7.85 (s, 1H), 4.67 (bs, 1H), 3.843.59 (m, 12H), 3.12-3.09 (t, 4H), 2.30-2.10 (m, 2H), 1.85 (s, 4H), 1.63-1.59 (m, 3H). LCMS: 100%, m / z = 500.3 (M+1) + . HPLC: 97.36%.

[0297] [Example 71] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0298] [ka] Step 1: Preparation of (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (207 mg, 1.5 mmol) and DMF (2 mL), substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (150 mg, 0.5 mmol) with (S)-pyrrolidin-3-ol (43 mg, 0.5 mmol) gave the title product (171 mg, 97%). LCMS: m / z = 352.1 (M+1). + . Step 2: Preparation of (S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 2 of Example 38, (S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (167 mg, 0.475 mmol) was reduced with zinc dust (247 mg, 3.806 mmol) and ammonium chloride (403 mg, 7.6 mmol) in THF (10 mL) to give the title compound (147 mg, 96.7%). LCMS: m / z = 322.1 (M+1). + . Step 3: Preparation of (S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (146 mg, 0.6074 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (124 mg, 0.6074 mmol) using EDCI.HCl (175 mg, 0.911 mmol), HOBt (82 mg, 0.6074 mmol), DIPEA (354 mg, 2.429 mmol) in DMF (5 mL) to obtain a crude product. The resulting crude product was purified by preparative HPLC to obtain the title compound (30 mg, 10%). 1HNMR (CDCl3, 400MHz): δ 9.17 (s, 1H), 8.71-8.70 (d, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 7.76-7.75 (d, 1H), 4.60 (bs, 1H), 3.86-3.83 (t, 4H), 3.76-3.68 (m, 6H), 3.60-3.54 (m, 3H), 2.69 (s, 3H), 2.26-2.24 (m, 1H), 2.10-2.01 (m, 1H). LCMS: 100%, m / z = 508.4 (M+1) + . HPLC: 98.23%.

[0299] [Example 72] (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

[0300] [ka] Step 1: Preparation of 6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide Using the same reaction conditions as described in Example 45, 5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 69) (220 mg, 0.797 mmol) was coupled with 6-bromopicolinic acid (193 mg, 0.956 mmol) using EDCI.HCl (228 mg, 1.19 mmol), HOBt (112 mg, 0.836 mmol), DIPEA (308 mg, 2.39 mmol) in DMF (10 mL) to provide the title compound (200 mg, 54.64%). LCMS: m / z = 460.0 (M+1) + . Step 2: Preparation of (S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide Using the same reaction conditions as described in Step 2 of Example 43, substituting 6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (100 mg, 0.217 mmol) with (S)-pyrrolidin-3-ol (40 mg, 0.325 mmol) using sodium carbonate (92 mg, 0.868 mmol) in DMF (2 mL) at 100° C. for 4 hours, gave the title compound (55 mg, 54.45%). 1 HNMR (DMSO-d6, 400MHz): δ 10.41 (s, 1H), 8.60 (s, 1H), 7.71-7.67 (t, 1H), 7.32-7.30 (d, 1H), 6.72-6.70 (d, 1H), 5.00-4.99 (d, LCMS: 100%, m / z = 467.2 (M+1) + . HPLC: 95.50%.

[0301] [Example 73] (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide

[0302] [ka] Using the same reaction conditions as described in Example 45, 5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 69) (80 mg, 0.289 mmol) was coupled with (S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylic acid (Intermediate 15) (90 mg, 0.289 mmol) using EDCI.HCl (83 mg, 0.433 mmol), HOBt (59 mg, 0.433 mmol), DIPEA (149 mg, 1.156 mmol) in DMF (5 mL), followed by deprotection using methanolic HCl (5 mL) to give the title compound (40 mg, 44.4%). 1 HNMR (CDCl3, 300MHz): δ 9.19 (s, 1H), 8.71 (s, 1H), 7.84 (s, 1H), 4.65 (s, 1H), 3.83-3.74 (t, 4H), 3.71-3.60 (m, 9H), 2.10-2.08 (m, 3H), 1.21-1.19 (m, 2H), 1.06-1.02 (m, 2H). LCMS: 97.34%, m / z = 457.4 (M+1). HPLC: 95.05%.

[0303] [Example 74] (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide

[0304] [ka] Step 1: Preparation of N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 7 of Example 1, 6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 1 of Example 73) (100 mg, 0.217 mmol) was coupled with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (79 mg, 0.282 mmol) using sodium carbonate (69 mg, 0.651 mmol) and Pd(PPh)Cl (8 mg, 0.108 mmol) in 1,2-dimethoxyethane / water (5 / 1 mL) to provide the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 30% ethyl acetate in hexane as the eluent to give the title compound (100 mg, 86.9%). LCMS: m / z = 531.7 (M+1) + Step 2: Preparation of N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride Using the same reaction conditions as described in Step 8 of Example 1, N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide (100 mg, 0.188 mmol) was deprotected using methanolic HCl (8 mL) to give the title compound (90 mg, 94.7%). LCMS: m / z = 447.7 (M+1). + . Step 3: Preparation of (S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide Using the same reaction conditions as described in Step 2 of Example 43, N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride (90 mg, 0.201 mmol) was replaced with (S)-2-methyloxirane (24 mg, 0.402 mmol) using sodium carbonate (107 mg, 1.00 mmol) in DMF (2 mL) at 140° C. for 4 hours to give the crude product. The resulting crude product was purified by preparative HPLC to give the title compound (35 mg, 34.6%). 1 HNMR (DMSO-d6, 400MHz): δ 10.8 (s, 1H), 8.61 (s, 1H), 8.31-8.30 (d, 2H), 8.00-7.98 (m, 1H), 7.93-7.89 (m, 2H), 5.02-5.01 (d, 1H), 4.05-4.02 (m, 3H), 3.75 (s, 4H), 3.61 (s, 4H) 2.33-2.23(m, 1H), 1.08-1.07 (d, 3H), 0.99-0.95 (m, 4H). LCMS: m / z = 505.7 (M+1) + . HPLC: 98.67%.

[0305] [Example 75] (S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0306] [ka] Step 1: Preparation of N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions as described in Example 45, 6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (product of Step 1 of Example 73) (100 mg, 0.362 mmol) was coupled with 2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylic acid (Intermediate 16) (95 mg, 0.362 mmol) using EDCI.HCl (103 mg, 0.543 mmol), HOBt (73 mg, 0.543 mmol), DIPEA (187 mg, 1.448 mmol) in DMF (5 mL), followed by deprotection using methanol / methanolic HCl (1 / 5 mL) to give the title compound (145 mg, 85.1%). LCMS: m / z = 437.7 (M+1) + . Step 2: Preparation of (S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 2 of Example 43, N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide hydrochloride (145 mg, 0.306 mmol) was replaced with (S)-2-methyloxirane (35 mg, 0.613 mmol) using sodium carbonate (162 mg, 1.53 mmol) in DMF (2 mL) at 100° C. for 14 hours to give the crude product. The resulting crude product was purified by preparative HPLC to give the title compound (50 mg, 21.2%). 1HNMR (CDCl3, 400MHz): δ 9.18 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H), 8.05-8.03 (d, 2H), 4.28-4.25 (d, 3H), 3.83-3.81 (m, 4H), 3.70-3.69 (m, 4H), 2.22-2.15 (m, 2H), 1.28-1.27 (m, 4H) 1.11-1.09 (d, 2H). LCMS: 98.69%, m / z = 496.2 (M+1) + . HPLC: 97.79%.

[0307] [Example 76] N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0308] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (230 mg, 1.666 mmol) and DMF (5 mL), substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (125 mg, 0.4166 mmol) with pyrrolidin-3-ol hydrochloride (54 mg, 0.437 mmol) to give the title product (102 mg, 70%). LCMS: m / z = 351.8 (M+1). + . Step 2: Preparation of 4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (100 mg, 0.2857 mmol) was protected using TBDMS chloride (52 mg, 0.3428 mmol) and imidazole (43 mg, 0.712 mmol) in DMF (5 mL) at room temperature for 14 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (111 mg, 84%). LCMS: m / z = 465.7 (M+1). + . Step 3: Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol) and ammonium chloride (200 mg, 3.7816 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (101 mg, 99%). LCMS: m / z = 436.2 (M+1). + . Step 4: Preparation of N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (60 mg, 0.2727 mmol) was coupled with 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 7) (100 mg, 0.2298 mmol) using EDCI.HCl (80 mg, 0.4108 mmol), HOBt (39 mg, 0.2865 mmol), DIPEA (142 mg, 1.095 mmol) in DMF (5 mL) to afford the title compound (103 mg, 70%). LCMS: m / z = 637.6 (M+1). + . Step 5: Preparation of N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide TBAF (0.3 mL) was added to a stirred solution of N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide (100 mg, 0.1569 mmol) in THF (5 mL) and stirred at room temperature for 1 hour. The reaction mass was diluted with saturated ammonium chloride solution and the solid was filtered and sucked dry to give the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (35 mg, 43%). 1HNMR (CDCl3, 400MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s, 3H), 3.84-3.53 (m, 9H) 2.50-2.49 (d, 1H), 2.31-2.21 (m, 2H), 2.09-2.01 (m, 2H). LCMS: 100%, m / z = 524.3 (M+1) + . HPLC: 97.99%.

[0309] [Example 77] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0310] [ka] Step 1: Preparation of (S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (product of Step 1 of Example 72) (100 mg, 0.2857 mmol) was protected using TBDMS chloride (52 mg, 0.3428 mmol) and imidazole (43 mg, 0.712 mmol) in DMF (5 mL) at room temperature for 14 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (113 mg, 85%). LCMS: m / z = 465.7 (M+1). + . Step 2: Preparation of (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, (S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol) and ammonium chloride (200 mg, 3.7816 mmol) in THF / methanol / HO (20 mL / 2 mL / 1 mL) to give the title compound (100 mg, 98%). LCMS: m / z = 436.3 (M+1). + . Step 3: Preparation of (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (60 mg, 0.2727 mmol) was coupled with 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 7) (100 mg, 0.2298 mmol) using EDCI.HCl (80 mg, 0.4108 mmol), HOBt (39 mg, 0.2865 mmol), DIPEA (142 mg, 1.095 mmol) in DMF (5 mL) to afford the title compound (102 mg, 70%). LCMS: m / z = 637.6 (M+1). + . Step 4: Preparation of (S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide. TBAF (0.3 mL) was added to a stirred solution of (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide (100 mg, 0.1569 mmol) in THF (5 mL) and stirred at room temperature for 1 hour. The reaction mass was diluted with saturated ammonium chloride solution and the solid was filtered and dried by suction to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (15 mg, 18%). 1 HNMR (CDCl3, 400MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s, 3H), 3.83-3.81 (m, 4H),3.76-3.69 (m, 4H), 3.68-3.51 (m, 4H), 2.47-2.46 (d, 1H), 2.27-2.21 (m, 1H), 2.04-2.02 (m, 1H). LCMS: 100%, m / z = 524.1 (M+1) + . HPLC: 99.55%.

[0311] [Example 78] (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0312] [ka] Step 1: Preparation of (R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (230 mg, 1.666 mmol) and DMF (5 mL), substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (125 mg, 0.4166 mmol) with (R)-pyrrolidin-3-ol (38 mg, 0.437 mmol) to give the title product (101 mg, 70%). LCMS: m / z = 351.8 (M+1). + . Step 2: Preparation of (R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, (R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (100 mg, 0.2857 mmol) was protected using TBDMS chloride (52 mg, 0.3428 mmol) and imidazole (43 mg, 0.712 mmol) in DMF (5 mL) at room temperature for 14 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 40% ethyl acetate in hexane as the eluent to give the title compound (115 mg, 85.5%). LCMS: m / z = 465.7 (M+1). + . Step 3: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, (R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol) and ammonium chloride (200 mg, 3.7816 mmol) in THF / methanol / HO (20 mL / 2 mL / 1 mL) to give the title compound (100 mg, 98%). LCMS: m / z = 436.5 (M+1). + . Step 4: Preparation of (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (60 mg, 0.2727 mmol) was coupled with 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (Intermediate 7) (100 mg, 0.2298 mmol) using EDCI.HCl (79 mg, 0.4108 mmol), HOBt (39 mg, 0.2865 mmol), DIPEA (141 mg, 1.095 mmol) in DMF (5 mL) to afford the title compound (110 mg, 75%). LCMS: m / z = 637.6 (M+1). + . Step 5: Preparation of (R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide. TBAF (0.3 mL) was added to a stirred solution of (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide (100 mg, 0.1569 mmol) in THF (5 mL) and stirred at room temperature for 1 hour. The reaction mass was diluted with saturated ammonium chloride solution and the solid was filtered and dried by suction to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (45 mg, 55%). 1 HNMR (CDCl3, 400MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 8.22-8.20 (dd, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s, 3H), 3.84-3.81 (m, 4H),3.76-3.63 (m, 4H), 3.61-3.48 (m, 4H), 2.50-2.49 (d, 1H), 2.44-2.22 (m, 1H), 2.04-2.03 (m, 1H). LCMS: 100%, m / z = 524.1 (M+1) + . HPLC: 98.62%.

[0313] [Example 79] (S)—N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

[0314] [ka] Step 1: Preparation of 4-(5-(azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 38, using sodium carbonate (283 mg, 2.664 mmol) and DMF (5 mL), substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.666 mmol) with azetidine (76 mg, 1.333 mmol) to give the title product (150 mg, 71.4%). LCMS: m / z = 322.1 (M+1). + . Step 2: Preparation of 5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(5-(azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (150 mg, 0.465 mmol) was reduced with zinc dust (243 mg, 3.726 mmol) and ammonium chloride (402 mg, 7.440 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (150 mg, crude). LCMS: m / z = 292.1 (M+1). + . Step 3: Preparation of N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-bromopicolinamide Using the same reaction conditions as described in Example 45, 5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (80 mg, 0.2373 mmol) was coupled with 6-bromopicolinic acid (83 mg, 0.410 mmol) using EDCI.HCl (80 mg, 0.41 mmol), HOBt (55 mg, 0.410 mmol), DIPEA (141 mg, 1.092 mmol) in DMF (5 mL) to give the title compound (130 mg, 100%). LCMS: m / z = 477.1 (M+2). + . Step 4: Preparation of (S)—N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide Using the same reaction conditions as described in Step 2 of Example 43, substituting N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-bromopicolinamide (100 mg, 0.210 mmol) with (S)-pyrrolidin-3-ol hydrochloride (40 mg, 0.315 mmol) using sodium carbonate (90 mg, 0.840 mmol) in DMF (2 mL) at 100° C. for 14 hours, the title compound (35 mg, 35%) was obtained. 1 HNMR (CDCl3, 300MHz): δ 9.79 (s, 1H), 8.59 (s, 1H), 7.66-7.60 (m, 1H), 7.55-7.53 (d, 1H), 6.59-6.56 (d, 1H), 4.71 (s, 1H), 4.26-4.12 (m, 4H), 3.83-3.76 (m, 4H), 3.74-3.65 (m, 8H),2.32-2.19 (m, 4H). LCMS: 97.98%, m / z = 482.2 (M+1) + . HPLC: 97.38%.

[0315] [Example 80] N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0316] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)azetidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.6666 mmol) with azetidin-3-ol hydrochloride (109 mg, 1.0 mmol) using sodium carbonate (212 mg, 3.0 mmol) and DMF (2 mL) at 80° C. for 1 hour, yielded the title product (160 mg, 71.11%). LCMS: m / z = 338.1 (M+1). + . Step 2: Preparation of 4-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)azetidin-3-ol (160 mg, 0.4742 mmol) was protected using TBDMS chloride (86 mg, 0.5691 mmol), imidazole (113 mg, 1.658 mmol), and DAMP (64 mg, 0.5217 mmol) in DMF (5 mL) at room temperature for 1 hour to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (210 mg, 98.59%). LCMS: m / z = 452.2 (M+1). + . Step 3: Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (210 mg, 0.4656 mmol) was reduced with zinc dust (244 mg, 3.725 mmol) and ammonium chloride (399 mg, 7.4501 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (180 mg, 91.83%). LCMS: m / z = 422.2 (M+1). + . Step 4: Preparation of N-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (180 mg, 0.4275 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (131 mg, 0.6413 mmol) using EDCI.HCl (123 mg, 0.6413 mmol), HOBt (87 mg, 0.6413 mmol), DIPEA (0.297 mL, 1.7102 mmol) in DMF (2 mL) to provide the title compound (150 mg, 57.91%). Step 5: Preparation of N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide TBAF (1 M in THF) (0.5 mL) was added to a stirred solution of N-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (150 mg, 0.2467 mmol) in THF (20 mL) and stirred at room temperature for 1 hour. The reaction mass was diluted with saturated ammonium chloride solution and the solid was filtered and dried to give the crude product. The resulting crude was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (35 mg, 28.92%). 1 HNMR (DMSO-d6, 300MHz): δ 9.71 (s, 1H), 8.96 (s,1H), 8.68-8.66 (d, 1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.77-7.75 (d, 1H), 5.51-5.49 (d, 1H), 4.48-4.42 (m, 1H), 4.19-4.14 (t, 2H),3.76-3.70(m, 6H), 3.56-3.54 (m, 4H), 2.57 (s, 3H). LCMS: 100%, m / z = 494.1 (M+1) + . HPLC: 98.83%.

[0317] [Example 81] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

[0318] [ka] Step 1: Preparation of (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Compound 78) (90 mg, 0.206 mmol) was coupled with 5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid (Intermediate 17) (54 mg, 0.248 mmol) using EDCI.HCl (59 mg, 0.309 mmol), HOBt (42 mg, 0.309 mmol), DIPEA (106 mg, 0.824 mmol) in DMF (5 mL) to give the title compound (120 mg, crude). LCMS: m / z = 637.2 (M+1). + . Step 2: Preparation of (S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide (120 mg, 0.188 mmol) was deprotected using methanolic HCl / methanol (5 / 1 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (45 mg, 45.4%). 1HNMR (CDCl3, 400MHz): δ 8.66 (s, 1H), 8.54-8.53 (d, 1H), 8.38 (s, 1H), 7.70-7.69 (d, 1H), 7.489-7.480 (d, 1H), 7.38 (s, 1H), 7.34-7.32 (s, 1H), 4.59 (s, 1H), 3.83-3.81 (m, 4H),3.69-3.67(m, 4H), 3.64-3.61 (m, 1H), 3.53-3.50 (m, 3H), 2.62 (s, 3H), 229-2.19 (m, 1H), 2.18-1.90 (m, 1H). LCMS: 99.27%, m / z = 523.1 (M+1) + . HPLC: 96.58%.

[0319] [Example 82] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0320] [ka] Step 1: Preparation of (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Compound 78) (90 mg, 0.206 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (50 mg, 0.248 mmol) using EDCI.HCl (59 mg, 0.309 mmol), HOBt (42 mg, 0.309 mmol), DIPEA (106 mg, 0.824 mmol) in DMF (5 mL) to give the title compound (130 mg, crude). Step 2: Preparation of (S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide (130 mg, 0.209 mmol) was deprotected using methanolic HCl / methanol (5 / 1 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (50 mg, 47.16%). 1 HNMR (CDCl3, 300MHz): δ 8.72 (s, 2H), 8.57-8.55 (d, 1H), 7.51 (s, 1H), 7.44-7.42 (d, 1H), 7.36-7.34 (d, 1H), 7.00-6.99 (d, 1H), 4.62 (s, 1H), 3.84-3.75 (m, 4H), 3.75-3.65 (m, 6H),3.55-3.43(m, 2H), 2.63 (s, 3H), 2.42-2.39 (m, 1H), 2.26-2.21 (m, 1H), 2.06-1.99 (m, 1H). LCMS: 97.85%, m / z = 507.2 (M+1) +. HPLC: 99.02%.

[0321] [Example 83] (S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0322] [ka] Step 1: Preparation of (S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (product of Step 1 of Example 59) (210 mg, 0.575 mmol) was protected using TBDMS chloride (108 mg, 0.719 mmol), imidazole (98 mg, 1.438 mmol), and DMAP (88 mg, 0.719 mmol) in DMF (5 mL) at room temperature for 14 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (177 mg, 64%). LCMS: m / z = 480.3 (M+1). + . Step 2: Preparation of (S)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, (S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (175 mg, 0.3645 mmol) was reduced with zinc dust (190 mg, 2.916 mmol) and ammonium chloride (312 mg, 5.833 mmol) in THF / methanol / water (20 / 10 / 5 mL) to give the title compound (162 mg, 98.7%). LCMS: m / z = 450.2 (M+1). + . Step 3: Preparation of (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (S)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (160 mg, 0.355 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (91 mg, 0.444 mmol) using HATU (202 mg, 0.532 mmol) and DIPEA (183 mg, 1.42 mmol) in DMF (5 mL) to afford the title compound (198 mg, 88%). LCMS: m / z = 634.3 (M-1). + . Step 4: Preparation of (S)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, (S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (197 mg, 0.3102 mmol) was deprotected using methanolic HCl / methanol (5 / 5 mL) to give the title compound (138 mg, 85.7%). 1 HNMR (CDCl3, 300MHz): δ 9.78 (s, 1H), 9.05 (s, 1H), 8.71-8.69 (d, 1H), 8.41 (s, 1H), 7.86 (s, 1H), 7.77-7.75 (d, 1H), 4.19-4.12 (m, 1H), 3.84-3.81 (m, 4H), 3.71-3.67 (m, 4H),3.33-3.32 (m, 1H), 3.24-3.13 (m, 4H), 2.68 (s, 3H), 2.21-2.00 (m, 1H), 1.86-1.83 (m, 3H). LCMS: 98.40%, m / z = 522.2 (M+1) + . HPLC: 98.37%.

[0323] [Example 84] N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0324] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol Using the same reaction conditions as described in Step 1 of Example 38, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.6666 mmol) with piperidin-4-ol (68 mg, 0.666 mmol) using potassium carbonate (311 mg, 2.66 mmol) and DMF (5 mL) at room temperature for 14 hours, gave the title product (211 mg, 87%). LCMS: m / z = 366.1 (M+1). + . Step 2: Preparation of 4-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (210 mg, 0.575 mmol) was protected using TBDMS chloride (108 mg, 0.7191 mmol), imidazole (98 mg, 1.438 mmol), and DMAP (88 mg, 0.719 mmol) in DMF (5 mL) at room temperature for 1 hour to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 1% methanol in DCM as the eluent to give the title compound (216 mg, 78.2%). LCMS: m / z = 480.2 (M+1). + . Step 3: Preparation of 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (215 mg, 0.448 mmol) was reduced with zinc dust (233 mg, 3.583 mmol) and ammonium chloride (387 mg, 7.16 mmol) in THF / methanol / HO (20 mL / 5 mL / 2 mL) to give the title compound (161 mg, 80%). LCMS: m / z = 450.2 (M+1). + . Step 4: Preparation of N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (160 mg, 0.355 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (91 mg, 0.444 mmol) using HATU (202 mg, 0.532 mmol) and DIPEA (0.183 mg, 1.42 mmol) in DMF (5 mL) to afford the title compound (192 mg, 68%). LCMS: m / z = 634.3 (M-1). + . Step 5: Preparation of N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (191 mg, 0.3 mmol) was deprotected using methanolic HCl / methanol (5 / 5 mL) to give the title compound (130 mg, 83.3%). 1 HNMR (CDCl3, 300MHz): δ 9.87 (s, 1H), 9.05 (s, 1H), 8.70-8.68 (d, 1H), 8.40 (s, 1H), 7.85 (s, 1H), 7.75-7.73 (d, 1H), 3.99-3.93 (m, 1H), 3.84-3.81 (m, 4H), 3.70-3.67 (m, 4H),3.35-3.30 (m, 2H), 3.11-3.08 (m, 2H), 2.68 (s, 3H), 2.22-2.15 (m, 2H), 2.13-1.97 (m, 2H), 1.69-1.68 (m, 1H). LCMS: 94.22%, m / z = 522.2 (M+1) + . HPLC: 97.51%.

[0325] [Example 85] (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0326] [ka] Step 1: Preparation of (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 79) (150 mg, 0.34 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (85 mg, 0.413 mmol) using HATU (196 mg, 0.517 mmol) and DIPEA (177 mg, 1.37 mmol) in DMF (8 mL) to afford the title compound (120 mg, 52.1%). LCMS: m / z = 622.3 (M+1). + . Step 2: Preparation of (R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (120 mg, 0.1759 mmol) was deprotected using methanolic HCl / methanol (5 / 5 mL) to give the title compound (77 mg, 65%). 1 HNMR (DMSO-d6, 400MHz): δ 9.99 (s, 1H), 8.96 (s, 1H), 8.69-8.68 (d, 1H), 7.86 (s, 2H), 7.78-7.76 (d, 1H), 4.48 (s, 1H), 4.27 (s, 1H), 3.74-3.72 (m, 4H), 3.64-3.52 (m, 6H),2.59 (s, 3H), 2.09 (s, 1H), 1.89-1.87 (m, 1H), 1.84-1.77 (m, 1H). LCMS: 97.25%, m / z = 508.2 (M+1) + . HPLC: 95.18%.

[0327] [Example 86] N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0328] [ka] Step 1: Preparation of N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 85) (150 mg, 0.334 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (68 mg, 0.334 mmol) using HATU (190 mg, 0.501 mmol) and DIPEA (172 mg, 1.336 mmol) in DMF (5 mL) to afford the title compound (165 mg, 77.8%). LCMS: m / z = 633.3 (M-1). + . Step 2: Preparation of N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide (160 mg, 0.252 mmol) was deprotected using methanolic HCl / methanol (5 / 5 mL) to give the title compound (107 mg, 81.6%). 1HNMR (DMSO-d6, 300MHz): δ 9.61 (s, 1H), 8.58 (s, 1H), 8.55-8.53 (d, 1H), 7.74 (s, 1H), 7.68-7.67 (d, 1H), 7.45-7.44 (d, 2H), 4.74 LCMS: 99.09%, m / z = 521.2 (M+1) + . HPLC: 95.12%.

[0329] [Example 87] N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0330] [ka] Step 1: Preparation of 5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 38, substituting 5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (product of Step 2 of Example 22) (250 mg, 0.8389 mmol) with azetidine hydrochloride (117 mg, 1.2583 mmol) using sodium carbonate (267 mg, 2.5167 mmol) and DMF (5 mL) at room temperature overnight, gave the title product (170 mg, 63.43%). LCMS: m / z = 320.1 (M+1). + . Step 2: Preparation of 5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (170 mg, 0.5329 mmol) was reduced with zinc dust (228 mg, 4.2633 mmol) and ammonium chloride (558 mg, 8.5266 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (140 mg, 90.9%). LCMS: m / z = 290.1 ​​(M+1). + . Step 3: Preparation of N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (140 mg, 0.4844 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (119 mg, 0.5813 mmol) using HATU (294 mg, 0.6297 mmol) and DIPEA (0.338 mL, 1.9377 mmol) in DMF (3 mL) to provide the title compound (96 mg, 41.73%). 1 HNMR (CDCl3, 400MHz): δ 8.70-8.69 (d, 1H), 8.55 (s, 1H), 8.38-8.36 (d, 2H), 7.81 (s, 1H), 7.78-7.76 (d, 1H), 4.24-4.20 (t, 4H), 3.65 (s, 4H), 2.69 (s, 3H), 2.40-2.33 (m, 2H),1.69(s, 6H). LCMS: 100%, m / z = 476.1 (M+1) + . HPLC: 97.70%.

[0331] [Example 88] 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0332] [ka] Step 1: Preparation of 6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 38, substituting 5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (product of Step 2 of Example 22) (250 mg, 0.8389 mmol) with pyrrolidine (90 mg, 1.2583 mmol) using sodium carbonate (178 mg, 1.6778 mmol) and DMF (5 mL) at room temperature overnight, gave the title product (200 mg, 71.42%). LCMS: m / z = 334.1 (M+1). + . Step 2: Preparation of 2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine (200 mg, 0.5998 mmol) was reduced with zinc dust (257 mg, 4.7988 mmol) and ammonium chloride (628 mg, 9.5977 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (140 mg, 76.92%). LCMS: m / z = 304.1 (M+1). + . Step 3: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg, 0.3300 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.3960 mmol) using HATU (163 mg, 0.4290 mmol) and DIPEA (0.23 mL, 1.3201 mmol) in DMF (3 mL) to provide the title compound (59 mg, 36.64%). 1 HNMR (CDCl3, 300MHz): δ 8.95 (s, 1H), 8.69-8.68 (d, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.75-3.65 (m, 4H), 3.55-3.49 (m, 4H), 2.67 (s, 3H), 1.99-1.94(m, 4H), 1.69 (s, 6H). LCMS: 98.26%, m / z = 490.1 (M+1) + . HPLC: 97.87%.

[0333] [Example 89] 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0334] [ka] Step 1: Preparation of 4-(6-nitro-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 38, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.666 mmol) with pyrrolidine (71 mg, 0.999 mmol) using potassium carbonate (275 mg, 1.998 mmol) and DMF (5 mL) at room temperature overnight, gave the title product (200 mg, 89.68%). LCMS: m / z = 336.0 (M+1). + . Step 2: Preparation of 2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(6-nitro-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine (200 mg, 0.597 mmol) was reduced with zinc dust (310 mg, 4.776 mmol) and ammonium chloride (515 mg, 9.552 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (200 mg, crude). LCMS: m / z = 306.1 (M+1). + . Step 3: 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg, 0.327 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (80 mg, 0.393 mmol) using HATU (186 mg, 0.490 mmol) and DIPEA (169 mg, 1.3081 mmol) in DMF (5 mL) to afford the title compound (90 mg, 56.2%). 1HNMR (CDCl3, 300MHz): δ 8.94 (s, 1H), 8.70-8.68 (d, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.83-3.80 (m, 4H), 3.70-3.65 (m, 4H), 3.56-3.52 (m, 4H),2.68(s, 3H), 2.00-1.95 (m, 4H). LCMS: 100%, m / z = 492.1 (M+1) + . HPLC: 97.29%.

[0335] [Example 90] 5-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide

[0336] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (150 mg, 0.468 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (114 mg, 0.562 mmol) using HATU (267 mg, 0.702 mmol) and DIPEA (241 mg, 1.872 mmol) in DMF (5 mL) to provide the title compound (60 mg, 25.4%). 1HNMR (CDCl3, 400MHz): δ 9.08 (s, 1H), 8.58-8.57 (d, 1H), 7.58 (s, 1H), 7.44-7.42 (d, 1H), 7.35-7.34 (d, 1H), 7.02-7.01 (d, 1H), 3.84-3.82 (m, 4H), 3.71-3.68 (m, 4H), 3.13-3.10 (m, 4H),2.64(s, 3H), 1.99-1.86 (m, 4H), 1.69 (s, 2H). LCMS: 100%, m / z = 505.3 (M+1) + . HPLC: 95.52%.

[0337] [Example 91] N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0338] [ka] Step 1: Preparation of 4-(5-(azepan-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 1 of Example 38, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (250 mg, 0.8333 mmol) with azepane (165 mg, 1.6666 mmol) using sodium carbonate (221 mg, 2.0833 mmol) and DMF (4 mL) at 80° C. for 2 hours, gave the title product (200 mg, 66.22%). LCMS: m / z = 364.0 (M+1). + . Step 2: Preparation of 5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, 4-(5-(azepan-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (200 mg, 0.550 mmol) was reduced with zinc dust (236 mg, 4.407 mmol) and ammonium chloride (577 mg, 8.8154 mmol) in THF / methanol / HO (10 mL / 2 mL / 2 mL) to afford the title compound (100 mg, 52.93). LCMS: m / z = 334.3 (M+1). + . Step 3: Preparation of N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg, 0.300 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (74 mg, 0.360 mmol) using HATU (149 mg, 0.390 mmol) and DIPEA (0.21 mL, 1.2012 mmol) in DMF (5 mL) to afford the title compound (84 mg, 53.84%). 1 HNMR (CDCl3, 300MHz): δ 9.85 (s, 1H), 9.07 (s, 1H), 8.69-8.67 (d, 1H), 8.40 (s, 1H), 7.83 (s, 1H), 7.72-7.71 (d, 1H), 3.84-3.81 (m, 4H), 3.70-3.67 (m, 4H), 3.39-3.32 (m, 4H),2.67(s, 3H), 1.93 (s, 8H). LCMS: 89.19%, m / z = 520.2 (M+1) + . HPLC: 95.29%.

[0339] [Example 92] 2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride

[0340] [ka] Using the same reaction conditions as described in Example 45, 2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of Step 6 of Example 20) (70 mg, 0.2191 mmol) was coupled with 2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 19) (74 mg, 0.2410 mmol) using HATU (108 mg, 0.2848 mmol) and DIPEA (0.153 mL, 0.8765 mmol) in DMF (2 mL), followed by deprotection using methanolic HCl / DCM (2 / 5 mL) to give the crude product, which was then purified by preparative HPLC and treated with methanolic HCl to give the title compound (47 mg, 52.80%). 1 HNMR (DMSO-d6, 400MHz): δ 9.61 (s, 1H), 9.19 (s, 1H), 8.91 (s, 1H), 8.49-8.41 (m, 2H), 8.21-8.19 (d, 1H), 7.53 (s, 1H), 7.30-7.28 LCMS: 93.04%, m / z = 507.2 (M+1) + . HPLC: 98.15%.

[0341] [Example 93] N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0342] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 80) (100 mg, 0.344 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (105 mg, 0.517 mmol) using HATU (196 mg, 0.517 mmol) and DIPEA (177 mg, 1.376 mmol) in DMF (5 mL) to provide the title compound (40 mg, 25.0%). 1 HNMR (CDCl3, 300MHz): δ 8.71-8.69 (d, 1H), 8.57 (s, 1H), 8.42-8.39 (d, 2H), 7.81 (s, 1H), 7.75-7.73 (d, 1H), 4.26-4.21 (t, 4H), 3.84-3.80 (m, 4H), 3.69-3.66 (m, 4H), 2.69 (s, 3H),2.39-2.34(m, 2H). LCMS: 94.95%, m / z = 478.1 (M+1) + . HPLC: 98.37%.

[0343] [Example 94] (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0344] [ka] Step 1: Preparation of (R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol Using the same reaction conditions as described in Step 2 of Example 43, using potassium carbonate (552 mg, 4 mmol) in DMF (5 mL) at room temperature for 14 hours, and using (R)-piperidin-3-ol hydrochloride (218 mg, 1.6 mmol) to substitute 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (400 mg, 1.333 mmol) to give the title compound (420 mg, 86.4%). LCMS: m / z = 365.3 (M+1). + . Step 2: Preparation of (R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 41, (R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (420 mg, 0.903 mmol) was protected using TBDMS chloride (110 mg, 0.903 mmol), imidazole (92 mg, 1.354 mmol), and DMAP (204 mg, 1.354 mmol) in DMF / DCM (10 mL / 2 mL) at room temperature for 0.5 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (520 mg, 94.5%). LCMS: m / z = 480.2 (M+1). + . Step 3: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 2 of Example 38, (R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (520 mg, 0.898 mmol) was reduced with zinc dust (467 mg, 7.184 mmol) and ammonium chloride (776 mg, 14.368 mmol) in THF / water (20 / 5 mL) to give the title compound (500 mg, crude). LCMS: m / z = 450.0 (M+1). + . Step 4: Preparation of (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (120 mg, 0.266 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.399 mmol) using HATU (152 mg, 0.399 mmol) and DIPEA (137 mg, 1.064 mmol) in DMF (3 mL) to give the crude title compound (200 mg). LCMS: m / z = 636.2 (M+1). + . Step 5: Preparation of (R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 5 of Example 77, (R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (200 mg, 0.314 mmol) was deprotected using TBAF / THF (2 / 5 mL) to give the crude product. The resulting crude was purified by prep plate using 5% methanol in DCM as the eluent to give the title compound (50 mg, 30.4%). 1 HNMR (CDCl3, 400MHz): δ 9.92 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.69-7.67 (d, 1H), 4.15 (s, 1H), 3.84-3.82 (m, 4H), 3.71-3.69 (m, 4H),3.39-3.36(m, 1H), 3.34-3.31 (m, 3H), 3.12-3.05 (m, 1H), 2.68 (s, 3H), 2.20-2.10 (m, 1H), 1.90-1.60 (m, 3H). LCMS: 97.74%, m / z = 522.2 (M+1) + . HPLC: 98.12%.

[0345] [Example 95] (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0346] [ka] Using the same reaction conditions as described in Example 45, (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 95) (100 mg, 0.209 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (51 mg, 0.250 mmol) using HATU (120 mg, 0.315 mmol) and DIPEA (108 mg, 0.840 mmol) in DMF (5 mL), followed by deprotection using TBAF / THF (1 / 2 mL) to give the crude product, which was then purified by prep plate using 5% methanol in DCM as the eluent to give the title compound (50 mg, 59.5%). 1 HNMR (CDCl3, 300MHz): δ 9.33 (s, 1H), 9.09 (s, 1H), 8.57-8.56 (d, 1H), 7.59 (s, 1H), 7.45-7.44 (d, 1H), 7.37-7.35 (d, 1H), 7.00-6.99 (d, 1H), 4.13 (s, 1H), 3.84-3.81 (m, 4H),3.71-3.69(m, 4H), 3.36-3.11 (m, 1H), 3.19-3.10 (m, 3H), 2.64 (s, 3H), 2.39 (s, 1H) 2.17-2.11 (m, 1H), 1.99-1.90 (m, 1H), 1.80-1.77 (m, 2H). LCMS: 93.43%, m / z = 521.4 (M+1) + . HPLC: 95.34%.

[0347] [Example 96] (S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

[0348] [ka] Using the same reaction conditions as described in Step 2 of Example 43, N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide (Example 21) (200 mg, 0.380 mmol) was replaced with (S)-2-methyloxirane (34 mg, 0.570 mmol) using sodium carbonate (201 mg, 1.900 mmol) in DMF (5 mL) at 100° C. for 14 hours to give the crude product. The resulting crude was purified by preparative plate chromatography using 5% methanol in DCM as the eluent to give the title compound (50 mg, 24.5%). 1 HNMR (DMSO-d6, 300MHz): δ 10.59 (s, 1H), 9.03 (s, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 8.04-8.01 (m, 1H), 7.97-7.96 (m, 2H), 5.02 (s, 1H), 4.06-4.04 (m, 3H), 3.72-3.70 (m, 4H),3.58-3.55 (m, 4H), 3.02-2.89 (m, 4H), 1.78-1.73 (m, 4H), 1.61-1.55 (m, 2H), 1.11-1.04 (m, 3H). LCMS: 92.56%, m / z = 549.3 (M+1) + . HPLC: 96.98%.

[0349] [Example 97] N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0350] [ka] Step 1: Preparation of 4-(5-(4-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 2 of Example 59, 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (product of Step 1 of Example 85) (450 mg, 1.3846 mmol) was fluorinated using DAST (0.3 mL, 2.353 mmol) in DCM (10 mL) at −78° C. for 30 minutes. The resulting crude material was purified by 60-120 silica gel column chromatography using 50% ethyl acetate in hexane as the eluent to give the crude title compound (360 mg). LCMS: m / z = 368.0 (M+1). + . Step 2: Preparation of 5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(5-(4-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (360 mg, 0.9809 mmol) was reduced with zinc dust (510 mg, 0.7847 mmol) and ammonium chloride (423 mg, 0.7847 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the crude product (240 mg). LCMS: m / z = 338.3 (M+1). + . Step 3: Preparation of N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (120 mg, 0.3560 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (86 mg, 0.4272 mmol) using HATU (202 mg, 0.5341 mmol) and DIPEA (0.3 mL, 1.424 mmol) in DMF (5 mL) to give a crude product. The crude product was purified by preparative HPLC to give the title compound (75 mg, 40%). 1 HNMR (DMSO-d6, 400MHz): δ 9.85 (s, 1H), 8.55-8.53 (d, 2H), 7.77 (s, 1H), 7.69-7.68 (d, 1H), 7.46 (s, 2H), 4.95-4.79 (m, 1H), 3.75-3.73 (m, 4H), 3.60-3.58 (m, 4H), 3.28-3.27 (m, 2H),3.06-3.02(m, 2H), 2.53 (s, 3H), 2.06-2.02 (m, 2H), 1.92-1.90 (m, 2H). LCMS: 100%, m / z = 523.2 (M+1) + . HPLC: 97.39%.

[0351] [Example 98] N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0352] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 2 of 98) (120 mg, 0.3560 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (87 mg, 0.4272 mmol) using HATU (202 mg, 0.5341 mmol) and DIPEA (183 mg, 1.024 mmol) in DMF (5 mL) to give the crude product. The crude product was purified by preparative HPLC to give the title compound (30 mg, 20%). 1 HNMR (DMSO-d6, 400MHz): δ 9.72 (s, 1H), 9.25 (s, 1H), 8.91-8.89(m, 2H), 8.24 (s, 1H), 8.14-8.12 (d, 1H), 5.08-4.91 (m, 1H), 3.7-3.73 (m, 4H), 3.60-3.58 (m, 4H),3.27-3.23 (m, 2H), 3.16 (s, 1H), 3.06-3.03 (m, 2H), 2.76 (s, 2H), 2.25-2.15 (m, 2H), 2.10-2.02 (m, 2H). LCMS: 99.32%, m / z = 524.0 (M+1) + . HPLC: 98.71%.

[0353] [Example 99] N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0354] [ka] Step 1: Preparation of 4-(5-(1-methyl-1H-pyrazol-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 7 of Example 1, 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.66 mmol) was coupled with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 0.99 mmol) using sodium iodide (200 mg, 1.33 mmol), potassium carbonate (220 mg, 1.99 mmol), and Pd(dppf)Cl (48 mg, 0.066 mmol) in 1,2-dimethoxyethane / water (0.5 / 0.2 mL) to give the title compound (150 mg, %). LCMS: m / z = 346.9 (M+1). + . Step 2: Preparation of 5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(5-(1-methyl-1H-pyrazol-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (150 mg, 0.43 mmol) was reduced with zinc dust (220 mg, 3.4 mmol) and ammonium chloride (360 mg, 6.9 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) (2 mL) to give the crude product (100 mg). LCMS: m / z = 317.3 (M+1). + . Step 3: Preparation of N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg, 0.316 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (77 mg, 0.38 mmol) using HATU (156 mg, 0.41 mmol) and DIPEA (122 mg, 0.94 mmol) in DMF (5 mL) to provide the title compound (40 mg, %). 1 HNMR (DMSO-d6, 400MHz): δ 10.1 (s, 1H), 9.05 (s, 1H), 8.71-8.70 (d, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.80-7.79 (d, 1H), 3.87 (s, 3H),3.82-3.76(m, 4H), 3.69-3.64 (m, 4H), 2.60 (s, 3H). LCMS: 97.70%, m / z = 503.2 (M+1) + . HPLC: 96.20%.

[0355] [Example 100] N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0356] [ka] Step 1: Preparation of 4-(5-(3-fluorophenyl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 7 of Example 1, 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (250 mg, 0.83 mmol) was coupled with 3-fluorophenylboronic acid (173 mg, 1.25 mmol) using sodium iodide (375 mg, 2.5 mmol), potassium carbonate (517 mg, 3.7 mmol), and Pd(dppf)Cl (61 mg, 0.1056 mmol) in 1,2-dimethoxyethane / water (0.5 / 0.2 mL) to afford the title compound (200 mg, %). LCMS: m / z = 361.2 (M+1). + . Step 2: Preparation of 5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(5-(3-fluorophenyl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (360 mg, 0.9809 mmol) was reduced with zinc dust (510 mg, 0.7847 mmol) and ammonium chloride (423 mg, 0.7847 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the crude product (240 mg). LCMS: m / z = 330.9 (M+1). + . Step 3: Preparation of N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (120 mg, 0.36 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (89 mg, 0.43 mmol) using HATU (180 mg, 0.47 mmol) and DIPEA (190 mg, 1.45 mmol) in DMF (5 mL) to give the title compound (50 mg). 1HNMR (DMSO-d6, 400MHz): δ 10.10 (s, 1H), 8.94 (s, 1H), 8.68-8.67 (d, 1H), 8.51 (s, 1H), 7.79 (s, 1H), 7.71-7.70 (d, 1H), 7.53-7.48 (m, 2H), 7.27-7.24 (t, 1H), 3.77-3.75 (m, 4H),3.70-3.66(m, 4H), 2.54 (s, 3H). LCMS: 97.4%, m / z = 517.0 (M+1) + . HPLC: 98.80%.

[0357] [Example 101] N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0358] [ka] Using the same reaction conditions as described in Example 45, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 85) (200 mg, 0.445 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (135 mg, 0.668 mmol) using HATU (253 mg, 0.668 mmol) and DIPEA (230 mg, 1.780 mmol) in DMF (5 mL), followed by deprotection using methanol / methanolic HCl (1 / 5 mL) to give the crude product, which was then purified by preparative HPLC to give the title compound (50 mg, 30.4%). 1HNMR (CDCl3, 400MHz): δ 9.33 (s, 1H), 9.10 (s, 1H), 8.58-8.57 (d, 1H), 7.60 (s, 1H), 7.46-7.45 (d, 1H), 7.37-7.36 (d, 1H), 7.01-7.00 (d, 1H), 4.13 (s, 1H), 3.85-3.82 (m, 4H),3.71-3.69(m, 4H), 3.35-3.33 (m, 1H), 3.20-3.10 (m, 3H), 2.65 (s, 3H), 2.35 (s, 1H), 2.14-2.12 (m, 1H), 1.97-1.91 m, 1H), 1.79-1.77 (m, 2H). LCMS: 99.89%, m / z = 521.20 (M+1) + . HPLC: 97.27%.

[0359] [Example 102] N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0360] [ka] Using the same reaction conditions as described in Step 6 of Example 1, (S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 4 of Example 59) (200 mg, 0.593 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (180 mg, 0.890 mmol) using HATU (338 mg, 0.890 mmol) and DIPEA (305 mg, 2.372 mmol) in DMF (5 mL) to give a crude product. The crude product was purified by preparative HPLC to give the title compound (40 mg, 12.9%). 1HNMR (CDCl3, 300MHz): δ 9.51 (s, 1H), 9.14 (s, 1H), 8.56-8.54 (d, 1H), 7.65 (s, 1H), 7.48-7.46 (d, 1H), 7.35-7.34 (d, 1H), 7.00-6.99 (d, 1H), 5.05-4.90 (m, 1H), 3.85-3.81 (m, 4H), 3.71-3.68 (m, 4H), 3.49-3.44 (m, 2H), 3.23-3.08 (m, 2H), 2.63 (s, 3H), 2.20-2.17 (m, 2H), 1.79-1.75 (m, 2H). LCMS: 98.09%, m / z = 523.0 (M+1) + . HPLC: 99.18%.

[0361] [Example 103] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0362] [ka] Using the same reaction conditions as described in Example 45, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 39) (130 mg, 0.3090 mmol) was coupled with 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 7) (80 mg, 0.3636 mmol) using EDCI.HCl (105 mg, 0.5454 mmol), HOBt (52 mg, 0.3817 mmol), DIPEA (188 mg, 1.454 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using 1 M TBAF / THF in THF (0.3 / 5 mL) to give the title compound (59 mg, 33%). 1HNMR (CDCl3, 300MHz): δ 9.46 (s, 1H), 8.89-8.88 (d, 1H), 8.55 (s, 1H), 8.32 (s, 1H), 8.23-8.19 (dd, 1H), 6.88-6.85 (dd, 1H), 4.55 (m, 1H), 4.02 (s, 1H), 3.83-3.80 (m, 4H),3.75-3.72(m, 4H), 3.50-3.48 (m, 4H), 2.85 (s, 1H), 2.26-2.22 (m, 1H), 2.05-2.01 (m, 1H). LCMS: 100%, m / z = 508.1 (M+1) + . HPLC: 98.32%.

[0363] [Example 104] N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0364] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (183 mg, 1.320 mmol) and DMF (5 mL), substituting 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (250 mg, 0.880 mmol) with pyrrolidin-3-ol (108 mg, 0.880 mmol) to give the title product (210 mg, 72.41%). LCMS: m / z = 335.8 (M+1). + . Step 2: Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (150 mg, 0.447 mmol) was protected using TBDMS chloride (102 mg, 0.6716 mmol), imidazole (60 mg, 0.8955 mmol), and DMAP (10 mg, 0.089 mmol) in DMF (5 mL) at room temperature for 2 hours to give the crude product. The resulting crude material was purified by 60-120 silica gel column chromatography using ethyl acetate in hexane as the eluent to give the title compound (160 mg, 80%). LCMS: m / z = 449.8 (M+1). + . Step 3: Preparation of 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (160 mg, 0.3555 mmol) was reduced with zinc dust (0.1859 mg, 2.8444 mmol) and ammonium chloride (304 mg, 5.688 mmol) in THF / methanol / HO (5 mL / 2 mL / 1 mL) to give the title product (90 mg, 60.44%). LCMS: m / z = 420.5 (M+1). + . Step 4: Preparation of N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Example 45, 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (80 mg, 0.190 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (42 mg, 0.229 mmol) using EDCI.HCl (54 mg, 0.286 mmol), HOBt (38 mg, 0.2863 mmol), DIPEA (99 mg, 0.7637 mmol) in DMF (3 mL) to give the coupled product, followed by deprotection using TBAF / THF (0.173 / 5 mL) to give the title compound (30 mg, 53.57%). 1 HNMR (CDCl3, 400MHz): δ 9.46 (s, 1H), 8.69-8.68 (d, 1H), 8.52 (s, 1H), 8.40 (s, 1H), 7.81 (s, 1H), 7.74-7.70 (d, 1H), 4.57 (s, 1H), 3.82-3.81 (m, 4H), 3.75-3.74 (m, 4H),3.61-3.59(m, 1H), 3.57-3.46 (m, 1H), 3.42-3.33 (m, 1H), 2.80-2.78 (d, 1H), 2.68 (s, 1H), 2.27-2.24 (m, 2H), 2.05-2.02 (m, 2H), 1.03-0.99 (m, 1H). LCMS: 100%, m / z = 492.1 (M+1) + . HPLC: 98.80%.

[0365] [Example 105] (R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0366] [ka] Using the same reaction conditions as described in step Example 45, (R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of step 3 of Example 41) (57 mg, 0.1357 mmol) was coupled with 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 7) (35 mg, 0.1628 mmol) using EDCI.HCl (38 mg, 0.2035 mmol), HOBt (27 mg, 0.2035 mmol), DIPEA (70 mg, 0.542 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using TBAF / THF (0.144 / 5 mL) to give the title compound (10 mg, 20.44%). 1 HNMR (CDCl3, 400MHz): δ 9.47 (s, 1H), 8.89 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.56-4.45 LCMS: 94.67%, m / z = 507.7 (M+1) + . HPLC: 97.15%.

[0367] [Example 106] N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

[0368] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 105) (90 mg, 0.2142 mmol) was coupled with 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (Intermediate 7) (56 mg, 0.2571 mmol) using EDCI.HCl (62 mg, 0.3214 mmol), HOBt (43 mg, 0.3214 mmol), DIPEA (110 mg, 0.8571 mmol) in DMF (3 mL) to give the coupled product, followed by deprotection using TBAF / THF (0.144 / 5 mL) to give the title compound (15 mg, 31.25%). 1 HNMR (CDCl3, 400MHz): δ 9.47 (s, 1H), 8.89 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.56 (s, 1H), 4.02 (s, 3H), 3.83-3.81 (m, 4H),3.75-3.73(m, 4H), 3.55-3.45 (m, 4H), 2.94-2.93 (d, 1H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 1H). LCMS: 98.15%, m / z = 507.7 (M+1) + . HPLC: 98.95%.

[0369] [Example 107] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0370] [ka] Using the same reaction conditions as described in Example 45, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinoxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 39) (109 mg, 0.261 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (53 mg, 0.261 mmol) using EDCI.HCl (75 mg, 0.3916 mmol), HOBt (37 mg, 0.2741 mmol), DIPEA (135 mg, 1.046 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using TBAF / THF (1 / 5 mL) to give the title compound (26 mg, 41.2%). 1 HNMR (CD3OD, 400MHz): δ 8.49-8.47 (d, 1H), 7.85 (s, 1H), 7.74-7.72 (d, 1H), 7.70 (s, 1H), 7.40-7.39 (d, 1H), 7.33-7.32 (d, 1H), 4.45 (s, 1H), 3.83-3.77 (m, 4H), 3.74-3.69 (m, 4H),3.49-3.47(m, 1H), 3.42-3.40 (m, 1H), 3.21-3.16 (m, 1H), 2.61 (s, 3H), 2.09-2.07 (m, 1H), 1.89-1.86 (m, 1H), 1.88-1.72 (m, 1H), 1.43-1.37 (m, 1H). LCMS: 100%, m / z = 491.2 (M+1) + . HPLC: 97.91%.

[0371] [Example 108] (S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

[0372] [ka] Using the same reaction conditions as described in Example 45, (S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 39) (109 mg, 0.261 mmol) was coupled with 5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid (Intermediate 17) (57 mg, 0.261 mmol) using EDCI.HCl (75 mg, 0.3916 mmol), HOBt (37 mg, 0.2741 mmol), DIPEA (135 mg, 1.046 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using TBAF / THF (1 / 5 mL) to give the title compound (55 mg, 66%). 1 HNMR (CD3OD, 400MHz): δ 8.46-8.45 (d, 1H), 7.93-7.92 (d, 1H), 7.76-7.75 (d, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.57-7.56 (d, 1H), 4.43 (s, 1H), 3.83-3.75 (m, 4H), 3.72-3.68 (m, 6H),3.51-3.50 (m, 1H), 3.42-3.36 (m, 1H), 2.60 (s, 3H), 2.07-2.05 (m, 1H), 1.93-1.92 (m, 1H). LCMS: 92.94%, m / z = 507.2 (M+1) + . HPLC: 96.09%.

[0373] [Example 109] N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0374] [ka] Step 1: Preparation of 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, piperidine (8 mL) and THF (30 mL) were used to substitute 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of Step 3 of Example 2) (3 g) to give the title compound (3 g, 90%). LCMS: m / z = 238.1 (M+1) + . Step 2: Preparation of 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 4 of Example 20, 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (4 g, 168 mmol) was nitrated using potassium nitrate (3.4 g, 337 mmol) and concentrated sulfuric acid (20 mL) at room temperature for 3 hours to give the crude title compound (4 g). LCMS: m / z = 283.0 (M+1). + . Step 3: Preparation of 5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (391 mg, 2.836 mmol) and THF (5 mL), substituting 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (400 mg, 1.418 mmol) with azetidine hydrochloride (161 mg, 1.7021 mmol) to give the crude product (300 mg). LCMS: m / z = 304.3 (M+1). + . Step 4: Preparation of 5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (300 mg, 0.990 mmol) was reduced with zinc dust (514 mg, 7.92 mmol) and ammonium chloride (427 mg, 7.92 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the crude product (200 mg). LCMS: m / z = 274.1 (M+1). + . Step 5: Preparation of N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100 mg, 0.366 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (90 mg, 0.439 mmol) using HATU (208 mg, 0.549 mmol) and DIPEA (0.3 mL, 1.465 mmol) in DMF (5 mL) to provide the title compound (60 mg, 36%). 1 HNMR (DMSO-d6, 400MHz): δ 9.81 (s, 1H), 8.97 (s, 1H), 8.69-8.68 (d, 1H), 7.86 (s, 1H), 7.78-7.77 (d, 1H), 7.60 (s, 1H), 3.97-3.93 (t, 4H), 3.65-3.60 (m, 4H), 2.59 (s, 3H),2.20-2.17(t, 2H), 1.62 (s, 6H). LCMS: 97.60%, m / z = 460.1 (M+1) + . HPLC: 96.38%.

[0375] [Example 110] N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0376] [ka] Step 1: Preparation of 5-(azetidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (200 mg, 0.701 mmol) was replaced with azetidine (81 mg, 0.140 mmol) and THF (5 mL) at room temperature for 2 hours to give the title compound (160 mg, 73.39%). LCMS: m / z = 306.1 (M+1). + . Step 2: Preparation of 5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(azetidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (160 mg, 0.5245 mmol) was reduced with zinc dust (274 mg, 4.196 mmol) and ammonium chloride (448 mg, 8.393 mmol) in THF / methanol / HO (8 mL / 2 mL / 1 mL) to give the title product (138 mg, 95.83%). LCMS: m / z = 274.1 (M-1). + . Step 3: Preparation of N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (150 mg, 0.5454 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (166 mg, 0.818 mmol) using EDCI.HCl (156 mg, 0.818 mmol), HOBt (110 mg, 0.818 mmol) and DIPEA (282 mg, 2.1818 mmol) in DMF (5 mL) to provide the title compound (20 mg, 8.0%). 1 HNMR (CDCl3, 400MHz): δ 8.70-8.69 (d, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.75-7.74 (d, 1H), 4.19-4.15 (t, 4H), 3.82-3.81 (m, 4H), 3.74-3.73 (m, 4H),2.69(s, 3H), 2.37-2.33 (t, 2H). LCMS: 83.88%, m / z = 462.1 (M+1) + . HPLC: 95.19%.

[0377] [Example 111] 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0378] [ka] Step 1: Preparation of 6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 38, substituting 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (product of Step 2 of Example 110) (400 mg, 1.418 mmol) with pyrrolidine (120 mg, 1.7021 mmol) in THF (10 mL) gave the crude product (300 mg). LCMS: m / z = 318.2 (M+1). + . Step 2: Preparation of 2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (300 mg, 0.946 mmol) was reduced with zinc dust (492 mg, 7.57 mmol) and ammonium chloride (409 mg, 7.57 mmol) in THF / methanol / HO (5 mL / 2 mL / 1 mL) to give the crude product (200 mg). LCMS: m / z = 288.1 (M+1). + . Step 3: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100 mg, 0.348 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (80 mg, 0.418 mmol) using HATU (198 mg, 0.522 mmol) and DIPEA (0.3 mL, 1.393 mmol) in DMF (5 mL) to provide the title compound (140 mg, 86%). 1HNMR (DMSO-d6, 400MHz): δ 9.80 (s, 1H), 8.97 (s, 1H), 8.69-8.68 (d, 1H), 7.85 (s, 1H), 7.77-7.76 (d, 1H), 7.66 (s, 1H), 3.61-3.60 (m, 4H), 3.39-3.34 (m, 4H), 2.59 (s, 3H), 1.83(s, 4H), 1.62 (s, 6H). LCMS: 97.7%, m / z = 474.2 (M+1) + . HPLC: 95.05%.

[0379] [Example 112] 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0380] [ka] Step 1: Preparation of 2-morpholino-6-nitro-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (200 mg, 0.701 mmol) was replaced with pyrrolidine (100 mg, 0.7403 mmol) and THF (5 mL) at room temperature for 2 hours to give the title compound (160 mg, 71.11%). LCMS: m / z = 320.1 (M+1). + . Step 2: Preparation of 2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 2-morpholino-6-nitro-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (160 mg, 0.5015 mmol) was reduced with zinc dust (262 mg, 0.4012 mmol) and ammonium chloride (430 mg, 8.0250 mmol) in THF / methanol / HO (5 mL / 2 mL / 1 mL) to give the title product (130 mg, 92.85%). Step 3: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (148 mg, 0.5172 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (158 mg, 0.7758 mmol) using EDCI.HCl (148 mg, 0.7758 mmol), HOBt (104 mg, 0.7758 mmol) and DIPEA (267 mg, 2.0689 mmol) in DMF (5 mL) to provide the title compound (80 mg, 33.05%). 1 HNMR (DMSO-d6, 400MHz): δ 9.82 (s, 1H), 8.96 (s, 1H), 8.69-8.68 (s, 1H), 7.85 (s, 1H), 7.77-7.76 (d, 1H), 7.69 (s, 1H), 3.73-3.72 (m, 4H), 3.69-3.68 (m,4H), 3.62-3.59 (m, 4H), 2.59 (s, 3H),1.84-1.81 (m, 4H). LCMS: 98.97%, m / z = 476.2 (M+1) + . HPLC: 99.34%.

[0381] [Example 113] 5-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide

[0382] [ka] Using the same reaction conditions as described in Step 6 of Example 1, 2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of Step 2 of Example 6) (70 mg, 0.3448 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) using HATU (196 mg, 0.5172 mmol), DIPEA (134 mg, 1.034 mmol) in DMF (5 mL) to give the crude product. The resulting crude product was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as the eluent to give the title compound (46 mg, 29.8%). 1 HNMR (CDCl3, 400MHz): δ 9.85 (s, 1H), 8.79 (s, 1H), 8.58-8.56 (d, 1H), 7.59 (s, 1H), 7.44-7.43 (d, 1H), 7.34-7.33 (d, 1H), 7.02-7.01 (d, 1H), 3.84-3.81 (m, 4H), 3.76-3.74 (m, 4H),3.07-3.04(t, 4H), 2.64 (s, 3H), 1.88-1.85 (m, 4H), 1.69 (s, 2H). LCMS: 100%, m / z = 489.2 (M+1) + . HPLC: 98.98%.

[0383] [Example 114] N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinoxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0384] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (250 mg, 0.8802 mmol) was replaced with piperidin-4-ol (178 mg, 1.760 mmol) and THF (10 mL) at room temperature for 2 hours to give the title compound (300 mg, 97.71%). LCMS: m / z = 350.1 (M+1). + . Step 2: Preparation of 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (300 mg, 0.859 mmol) was protected using TBDMS chloride (194 mg, 1.289 mmol) and imidazole (117 mg, 1.7191 mmol) and DMAP (21 mg, 1.719 mmol) in DMF (5 mL) at room temperature for 2 hours to give the title compound (300 mg, 76%). LCMS: m / z = 464.2 (M+1). + . Step 3: Preparation of 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (300 mg, 0.6479 mmol) was reduced with zinc dust (330 mg, 5.183 mmol) and ammonium chloride (554 mg, 10.367 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title product (150 mg, 53.57%). LCMS: m / z = 434.2 (M+1). + . Step 4: Preparation of N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Example 45, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (150 mg, 0.346 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (84 mg, 0.415 mmol) using HATU (171 mg, 0.4503 mmol) and DIPEA (178 mg, 1.385 mmol) in DMF (3 mL) to give the coupled product, followed by deprotection using TBAF / THF (63 mg / 5 mL) to give the title compound (40 mg, 50%). 1 HNMR (DMSO-d6, 400MHz): δ 9.62 (s, 1H), 8.55-8.54 (d, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.68-7.67 (d, 1H), 7.48-7.45 (d, 2H), 4.80-4.79 (d, 1H), 3.73-3.63 (m, 8H), 3.20-3.17 (m, 3H),2.86-2.81(t, 2H), 2.56 (s, 3H), 1.91 (s, 2H), 1.67-1.65 (m, 2H). LCMS: 100%, m / z = 505.2 (M+1) +. HPLC: 96.82%.

[0385] [Example 115] (R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

[0386] [ka] Step 1: Preparation of (R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (250 mg, 0.8802 mmol) was replaced with (R)-piperidin-3-ol (121 mg, 1.88 mmol) and THF (10 mL) at room temperature for 2 hours to give the title compound (230 mg, 74.91%). LCMS: m / z = 350.1 (M+1). + . Step 2: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 41, (R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (230 mg, 0.659 mmol) was protected using TBDMS chloride (149 mg, 0.9885 mmol) and imidazole (89 mg, 1.318 mmol) and DMAP (16 mg, 0.1318 mmol) in DMF (5 mL) at room temperature for 2 hours to give the title compound (300 mg, 99.5%). LCMS: m / z = 464.2 (M+1). + . Step 3: Preparation of (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (300 mg, 0.6479 mmol) was reduced with zinc dust (330 mg, 5.183 mmol) and ammonium chloride (554 mg, 10.367 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title product (150 mg, 53.57%). LCMS: m / z = 434.2 (M+1). + . Step 4: Preparation of (R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide Using the same reaction conditions as described in Example 45, (R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (150 mg, 0.346 mmol) was coupled with 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (Intermediate 18) (84 mg, 0.415 mmol) using HATU (171 mg, 0.4503 mmol) and DIPEA (178 mg, 1.385 mmol) in DMF (3 mL) to give the coupled product, followed by deprotection using TBAF / THF (63 mg / 5 mL) to give the title compound (32 mg, 30.18%). 1HNMR (DMSO-d6, 400MHz): δ +.85 (s, 1H), 8.55-8.54 (d, 1H), 8.42 (s, 1H), 7.81 (s, 1H), 7.70-7.68 (d, 1H), 7.48-7.46 (m, 2H), 4.92-4.91 (d, 1H), 3.83 (s, 1H), 3.74-3.64 (m, 4H),3.64-3.62(m, 4H), 3.17-3.15 (m, 1H), 3.02-2.99(m, 1H), 2.83-2.79 (m, 1H), 2.73-2.70 (m, 1H), 2.55 (s,3H), 1.90-1.84 (m, 2H), 1.66-1.64 (m, 1H), 1.45-1.43 (m, 1H). LCMS: 98.47%, m / z = 505.2 (M+1) + . HPLC: 98.78%.

[0387] [Example 116] N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0388] [ka] Step 1: Preparation of 5-(furan-3-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 7 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (300 mg, 1.0563 mmol) was coupled with furan-3-boronic acid (177 mg, 1.5845 mmol) using sodium iodide (237 mg, 1.5843 mmol) and Pd(dppf)Cl (86 mg, 0.1056 mmol) in 1,2-dimethoxyethane / water (5 / 1 mL) to give the crude title compound (170 mg). LCMS: m / z = 317.1 (M+1). + . Step 2: Preparation of 5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions described in Step 5 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (170 mg, 0.5379 mmol) was reduced with zinc dust (281 mg, 4.303 mmol) and ammonium chloride (460 mg, 8.607 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to afford the title product (130 mg, 43.33%). Step 3: Preparation of N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (100 mg, 0.3496 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (106 mg, 0.5244 mmol) using HATU (172 mg, 0.4545 mmol) and DIPEA (180 mg) in DMF (5 mL) to provide the title compound (70 mg, 42.42%). 1 HNMR (DMSO-d6, 400MHz): δ 10.19 (s, 1H), 9.02 (s, 1H), 8.71-8.69 (d, 1H), 8.14 (s, 1H), 7.94-7.87 (d, 2H), 7.79-7.75 (m, 2H), 7.01 (s, 1H), 3.76-3.65 (m, 8H), 2.60 (s, 3H). LCMS: 100%, m / z = 473.1 (M+1) + . HPLC: 95.76%.

[0389] [Example 117] N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0390] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol Using the same reaction conditions as described in Step 3 of Example 1, 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of Step 5 of Example 2) (300 mg, 1.056 mmol) was replaced with piperidin-3-ol (211 mg, 2.110 mmol) and THF (5 mL) at room temperature for 14 hours to give the title compound (298 mg, 81%). LCMS: m / z = 350.3 (M+1). + . Step 2: Preparation of 5-(3-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 59, 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (270 mg, 0.7736 mmol) was fluorinated using DAST (218 mg, 1.353 mmol) in DCM (20 mL) at −78° C. for 1 hour to give the title compound (240 mg, 88.4%). Step 3: Preparation of 5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(3-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (230 mg, 0.6552 mmol) was reduced with zinc dust (340 mg, 5.24 mmol) and ammonium chloride (555 mg, 10.48 mmol) in THF / water (20 / 5 mL) to give the title compound (145 mg, 69%). Step 4: Preparation of N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (120 mg, 0.3738 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (95 mg, 0.4672 mmol) using HATU (213 mg, 0.5605 mmol) and DIPEA (193 mg) in DMF (5 mL) to give the crude compound, which was then purified by preparative TLC using 3.5% methanol in chloroform to give the title compound (81 mg, 34%). 1 HNMR (DMSO-d6, 300MHz): δ 9.86 (s, 1H), 9.05 (s, 1H), 8.70-8.68 (d, 1H), 8.62 (s, 1H), 7.85 (s, 1H), 7.75-7.74 (d, 1H), 5.10-4.90 LCMS: 100%, m / z = 508.0 (M+1) + . HPLC: 99.27%.

[0391] [Example 118] N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0392] [ka] Using the same reaction conditions as described in Example 45, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 115) (140 mg, 0.3233 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (66 mg, 0.3233 mmol) using HATU (185 mg, 0.4868 mmol) and DIPEA (167 mg, 1.295 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using methanol / MeOH.HCl (5 / 5 mL) to give the title compound (127 mg, 88%). 1 HNMR (DMSO-d6, 300MHz): δ 9.90 (s, 1H), 9.00 (s, 1H), 8.66-8.64 (d, 1H), 8.58 (s, 1H), 7.83 (s, 1H), 7.74-7.72 (d, 1H), 4.90 (s, 1H), 3.71-3.70 (m, 5H), 3.61-3.59 (d, 4H), 3.12-3.08 (m, 2H), 2.85-2.78 (t, 2H), 2.57 (s, 3H), 1.99-1.96 (m, 2H),1.79-1.76 (m, 2H). LCMS: 100%, m / z = 506.1 (M+1) + . HPLC: 98.00%.

[0393] [Example 119] N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0394] [ka] Step 1: Preparation of 5-(4-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 59, 1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (product of Step 1 of Example 115) (200 mg, 0.5730 mmol) was fluorinated using DAST (161 mg, 1.002 mmol) in DCM (20 mL) at −78° C. for 1 hour to give the title compound (191 mg, 95%). LCMS: m / z = 352.1 (M+1). + . Step 2: Preparation of 5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 5-(4-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (190 mg, 0.5413 mmol) was reduced with zinc dust (281 mg, 4.33 mmol) and ammonium chloride (460 mg, 8.66 mmol) in THF / water (20 / 5 mL) to give the title product (90 mg, 52%). Step 3: Preparation of N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (85 mg, 0.2647 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (67 mg, 0.328 mmol) using HATU (149 mg, 0.394 mmol) and DIPEA (135 mg, 1.050 mmol) in DMF (5 mL) to obtain the crude compound, which was then purified by preparative TLC using 3.5% methanol in chloroform to obtain the title compound (81 mg, 34%). 1HNMR (CDCl3, 300MHz): δ 10.00 (s, 1H), 8.76 (s, 1H), 8.70-8.69 (d, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.71-7.69 (dd, 1H), 5.00-4.70 LCMS: 100%, m / z = 508.3 (M+1) + . HPLC: 90.17%.

[0395] [Example 120] (S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride

[0396] [ka] Step 1: Preparation of tert-butyl (S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (276 mg, 1.99 mmol) and THF (10 mL), 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.66 mol) was replaced with tert-butyl (S)-piperidin-3-ylcarbamate (199 mg, 0.99 mmol) to give the crude product, which was carried on directly to the next step. Step 2: Preparation of tert-butyl (S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate Using the same reaction conditions as described in Step 5 of Example 1, crude tert-butyl (S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate was reduced with zinc dust (338 mg, 5.1724 mmol) and ammonium chloride (553 mg, 10.344 mmol) in THF / methanol / HO (10 mL / 2 mL / 1 mL) to give the title compound (180 mg, 64.48%). LCMS: m / z = 435.4 (M+1). + . Step 3: Preparation of tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate Using reaction conditions similar to those described in Step 6 of Example 1, tert-butyl (S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate (450 mg, 0.464 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (296 mg, 1.4547 mmol) using HATU (479 mg, 1.2607 mmol) and DIPEA (501 mg, 3.8793 mmol) in DMF (5 mL) to afford the title compound (400 mg, 66.66%). LCMS: m / z = 621.4 (M+1). + . Step 4: Preparation of (S)—N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride Using the same reaction conditions described in Step 8 of Example 1, tert-butyl (S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate (400 mg, 0.6451 mmol) was deprotected using methanolic HCl / methanol (5 / 5 mL) to provide the title compound (100 mg, 94.33%). 1 HNMR (DMSO-d6, 400MHz): δ 9.71 (s, 1H), 9.24 (s, 1H), 8.85-8.83 (d, 1H), 8.75 (s, 1H), 8.26 (s, 2H), 8.13 (s, 1H), 8.05-8.03 (d, 1H), 3.75-3.73 (m, 5H), 3.42-3.39 (m, 4H), 3.16-3.04 (m, 3H), 2.90-2.80 (m, 2H), 2.72 (s, 3H), 2.04-1.90 (m, 3H), 1.79-1.69 (m, 2H). LCMS: 86.06%, m / z = 521.4 (M+1) + . HPLC: 98.61%.

[0397] [Example 121] 2-(2-Methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0398] [ka] Step 1: Preparation of 4-(6-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 7 of Example 1, 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (250 mg, 0.833 mmol) was coupled with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (579 mg, 2.083 mmol) using sodium iodide (375 mg, 2.5 mmol), potassium carbonate (345 mg, 2.5 mmol), and Pd(dppf)Cl (304 mg, 0.4166 mmol) in 1,2-dimethoxyethane / water (5 / 1 mL) to provide the title compound (150 mg, 43.35%). LCMS: m / z = 417.15 (M+1) + . Step 2: Preparation of 2-morpholino-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(6-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine (150 mg, 0.360 mmol) was reduced with zinc dust (188 mg, 2.8846 mmol) and ammonium chloride (308 mg, 5.769 mmol) in THF / water (5 / 1 mL) to give the crude product (110 mg, 79.23%). LCMS: m / z = 387.2 (M+1). + . Step 3: Preparation of 2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Example 45, 2-morpholino-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-amine (130 mg, 0.336 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (103 mg, 0.505 mmol) using HATU (166 mg, 0.4378 mmol) and DIPEA (174 mg, 1.347 mmol) in DMF (5 mL) to give the coupled product, followed by deprotection using methanol / MeOH HCl (2 / 5 mL) to give the title compound (75 mg, 67.56%). 1 HNMR (DMSO-d6, 400MHz): δ 13.0 (s, 1H), 10.18 (s, 1H), 9.02 (s, 1H), 8.69-8.68 (d, 1H), 8.31 (s, 1H), 8.20-8.00 (bs, 2H), 7.87 (s, 1H), 7.79-7.78 (d, 1H), 3.76-3.64 (m, 8H), 2.60 (s, 3H). LCMS: 100%, m / z = 489.3 (M+1) + . HPLC: 95.64%.

[0399] [Example 122] N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0400] [ka] Step 1: Preparation of 4-(5-(6-fluoropyridin-3-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine Using the same reaction conditions as described in Step 7 of Example 1, 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (200 mg, 0.666 mmol) was coupled with (6-fluoropyridin-3-yl)boronic acid (234 mg, 1.66 mmol) using sodium iodide (299 mg, 1.99 mmol), potassium carbonate (276 mg, 1.99 mmol), and Pd(dppf)Cl (243 mg, 0.333 mmol) in 1,2-dimethoxyethane / water (5 / 1 mL) to provide the title compound (152 mg, 63.33%). Step 2: Preparation of 5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine Using the same reaction conditions as described in Step 5 of Example 1, 4-(5-(6-fluoropyridin-3-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (152 mg, 0.4210 mmol) was reduced with zinc dust (220 mg, 3.368 mmol) and ammonium chloride (360 mg, 6.736 mmol) in THF / water (5 / 1 mL) to give the crude product (150 mg). LCMS: m / z = 331.9 (M+1). + . Step 3: Preparation of N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using reaction conditions similar to those described in Step 6 of Example 1, crude 5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (150 mg, 0.4531 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (138 mg, 6.797 mmol) using HATU (223 mg, 0.589 mmol) and DIPEA (234 mg, 1.812 mmol) in DMF (5 mL) to provide the title compound (110 mg, 47%). 1HNMR (DMSO-d6, 400MHz): δ 10.4 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H), 8.68-8.66 (d, 1H), 8.589-8.582 (d, 1H), 8.427 (s, 1H), 8.00-7.98 (d, 1H), 7.82 (s, 1H), 7.74-7.73 (d, 1H),3.76-3.75 (t, 4H), 3.67-3.66 (t, 4H), 2.58 (s, 3H). LCMS: 79.07%, m / z = 518.3 (M+1) + . HPLC: 95.64%.

[0401] [Example 123] N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0402] [ka] Step 1: Preparation of 8-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol Using the same reaction conditions as described in Step 1 of Example 38, substituting 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (300 mg, 1 mmol) with 8-azabicyclo[3.2.1]octan-3-ol hydrochloride (195 mg, 1.2 mmol) using potassium carbonate (552 mg, 4 mmol) and DMF (5 mL), gave the title product (360 mg, 92.3%). LCMS: m / z = 392.1 (M+1). + . Step 2: Preparation of 8-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol Using the same reaction conditions as described in Step 2 of Example 38, 8-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol (350 mg, 0.8951 mmol) was reduced with zinc dust (468 mg, 7.161 mmol) and ammonium chloride (766 mg, 14.321 mmol) in THF / water (10 / 2 mL) to give the title compound (280 mg, 86.68%). LCMS: m / z = 362.1 (M+1). + . Step 3: Preparation of N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 6 of Example 1, 8-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol (100 mg, 0.2770 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (85 mg, 0.4155 mmol) using HATU (136 mg, 0.3601 mmol) and DIPEA (143 mg, 1.108 mmol) in DMF (5 mL) to afford the title compound (120 mg, 79.47%). 1 HNMR (DMSO-d6, 400MHz): δ 9.52 (s, 1H), 9.08 (s, 1H), 8.78 (s, 1H), 8.71-8.70 (d, 1H), 7.81 (s, 1H), 7.73-7.72 (s, 1H), 4.568-4.563 (d, 1H), 4.10 (s, 1H), 4.03 (s, 2H), 3.74-3.72 (t, 4H), 3.58-3.55 (m, 4H), 2.59 (s, 3H), 2.42-2.39 (m, 2H), 2.20-2.18 (m, 2H), 1.94-1.93 (m, 2H), 1.83-1.80 (m, 2H). LCMS: 100%, m / z = 548.5 (M+1) +. HPLC: 95.67%.

[0403] [Example 124] N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0404] [ka] Step 1: Preparation of 6-bromo-5-chlorothiazolo[4,5-b]pyridine-2-thiol Using the same reaction conditions as described in Step 1 of Example 1, 3,5-dibromo-6-chloropyridin-2-amine (3 g, 10.489 mmol) was cyclized using potassium ethylxanthate (3 g, 18.881 mmol) in DMF (50 mL) at 155° C. for 3 hours to give the title product (2.95 g, 100%). LCMS: m / z = 280.8 (M-1). + . Step 2: Preparation of 6-bromo-5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 1, 6-bromo-5-chlorothiazolo[4,5-b]pyridine-2-thiol (3 g, 10.676 mmol) was methylated using potassium carbonate (2.94 g, 21.352 mmol) and methyl iodide (2.29 g, 16.014 mmol) in ethyl acetate (100 mL) to give the title compound (3.16 g, 100%). LCMS: m / z = 296.7 (M+1). + . Step 3: Preparation of 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-chlorothiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 38, replacing 6-bromo-5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (500 mg, 1.689 mmol) with 3-(benzyloxy)piperidine hydrochloride (322 mg, 1.689 mmol) using potassium carbonate (932 mg, 6.756 mmol) and THF (5 mL) at 85° C. for 14 hours, the crude product was obtained. The crude product was purified by using 60-120 silica gel column chromatography, and the compound was eluted with 30% ethyl acetate in hexane as the eluent to give the title compound (280 mg, 37.8%). LCMS: m / z = 438.2 (M). + . Step 4: Preparation of 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 1 of Example 6, 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-chlorothiazolo[4,5-b]pyridine (280 mg, 0.639 mmol) was substituted using piperidine (1 mL) in THF (1 mL) at 125° C. for 14 hours to give the crude product (280 mg). LCMS: m / z = 489.1 (M+2). + . Step 5: Preparation of N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide To a solution of 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine (50 mg, 0.102 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (31 mg, 0.154 mmol) (Intermediate 23) and potassium phosphate (65 mg, 0.306 mmol) in 1,4-dioxane (4 mL), copper iodide (2 mg, 0.01 mmol) and trans-N1,N2-dimethylcyclohexane-1,2-diamine (5 mg, 0.030 mmol) were added and heated at 110 °C for 14 h. The solvent was evaporated and purified by 60-120 silica gel column chromatography using 5% methanol in DCM as eluent to give the title compound (40 mg, 64.5%). LCMS: m / z = 610.3 (M+1) + . Step 6: Preparation of N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using reaction conditions similar to those described in Step 8 of Example 1, N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (200 mg, 0.328 mmol) was deprotected using TFA (5 mL) and toluene (1 mL) at 110° C. for 14 hours to give the crude product, which was purified by preparative HPLC to give the title compound (50 mg, 29.4%). 1HNMR (CDCl3, 300MHz): δ 9.90 (s, 1H), 9.00 (s, 1H), 8.70-8.69 (d, 1H), 8.39 (s, 1H), 7.83 (s, 1H), 7.74-7.25 (s, 1H), 4.05-3.94 (m, 2H), 3.85-3.70 (m, 1H), 3.53-3.51 (m, 2H), 3.14-3.10 (t, 4H), 2.67 (s, 3H), 1.92-1.58 (m, 11H). LCMS: 96.10%, m / z = 520.4 (M+1) + . HPLC: 97.47%.

[0405] [Example 125] 2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0406] [ka] Using the same reaction conditions as described in Example 45, 5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of Step 3 of Example 85) (155 mg, 0.3452 mmol) was coupled with 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid (Intermediate 20) (106 mg, 0.4315 mmol) using HATU (197 mg, 0.5188 mmol) and DIPEA (179 mg, 1.3835 mmol) in DMF (5 mL) to give the crude compound, followed by deprotection using TBAF / THF (1 / 10 mL) to give the title compound (42 mg, 46%). 1HNMR (CDCl3, 300MHz): δ 9.10 (s, 1H), 8.60 (s, 1H), 8.32-8.31 (d, 1H), 7.42-7.41 (d, 1H), 7.33-7.32 (d, 1H), 7.07-7.06 (d, 1H), 3.18 (s, 4H), 3.69-3.67 (m, 4H), 3.30-3.26 (m, 2H), 3.09-3.01 (t, 2H), 2.26 (s, 3H), 2.19-2.16 (m, 2H), 2.00-1.87 (m, 4H). LCMS: 96.40%, m / z = 564.4 (M+1) + . HPLC: 96.95%.

[0407] [Example 126] N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0408] [ka] Step 1: Preparation of 1-(2-(3-(benzyloxy)piperidin-1-yl)-6-bromothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol Using the same reaction conditions as described in Step 1 of Example 38, using potassium carbonate (126 mg, 0.912 mmol) and DMF (5 mL) at 150° C. for 5 hours, 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine (product of Step 3 of Example 125) (200 mg, 0.456 mmol) was replaced with 4-hydroxypiperidine (56 mg, 0.547 mmol) to give the crude product (250 mg). LCMS: m / z = 505.3 (M+2). + . Step 2: Preparation of 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridine Using the same reaction conditions as described in Step 2 of Example 41, 1-(2-(3-(benzyloxy)piperidin-1-yl)-6-bromothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (250 mg, 0.496 mmol) was protected using TBDMS chloride (149 mg, 0.992 mmol), imidazole (50 mg, 0.744 mmol) and DMAP (60 mg, 0.496 mmol) in DMF (5 mL) at room temperature for 2 hours to give the crude product (306 mg). Step 3: Preparation of N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 5 of Example 125, potassium phosphate (314 mg, 1.485 mmol), copper iodide (10 mg, 0.049 mmol) and trans-N1,N2-dimethylcyclohexane-1,2-diamine (21 mg, 0.148 mmol) in 1,4-dioxane (5 mL) at 110° C. for 14 hours, 2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(4-((tert- (butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridine (306 mg, 0.495 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (120 mg, 0.595 mmol) (Intermediate 23) and purified by 60-120 silica gel column chromatography using 2% methanol in DCM as eluent to give the title compound (300 mg, 84.2%). Step 4: Preparation of N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using the same reaction conditions as described in Step 8 of Example 1, N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (150 mg, 0.202 mmol) was deprotected using methanolic HCl / methanol (1 / 1 mL) to give the crude compound (120 mg). LCMS: m / z = 626.4 (M+1). + . Step 5: Preparation of N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide Using reaction conditions similar to those described in Step 8 of Example 1, N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (120 mg, 0.191 mmol) was deprotected using TFA (5 mL) and toluene (1 mL) at 110° C. for 1 hour to give the crude product, which was purified by preparative HPLC to give the title compound (40 mg, 39.2%). 1HNMR (DMSO-d6, 400MHz): δ 9.76(s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.70-8.69 (d, 1H), 7.89 (s, 1H), 7.79-7.77 (d, 1H), 5.09-5.08 (d, 1H), 4.90-4.89 (d, 1H), 3.88-3.86 (m, 1H), 3.73-3.62 (m, 3H), 3.21-3.11 (m, 4H), 2.89-2.86 (t, 2H), 2.67 (s, 3H), 2.02-1.99 (m, 2H), 1.90-1.77 (m, 4H), 1.53-1.23 (m, 2H). LCMS: 81.88%, m / z = 536.3 (M+1) + . HPLC: 98.31%.

[0409] [Example 127] 2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

[0410] [ka] Step 1: Preparation of 1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol Using the same reaction conditions as described in Step 2 of Example 43, using potassium carbonate (691 mg, 4.99 mmol) in DMF (5 mL) at room temperature for 2 hours, piperidin-3-ol (202 mg, 1.99 mmol) was used to replace 4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product of Step 4 of Example 20) (500 mg, 1.66 mol) to give the title compound (...

Claims

【Request Item 1】 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, IRAK4-mediated inflammatory disorders include conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, systemic lupus erythematosus, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, colitis, enteritis, enterocolitis, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, myelitis, polyneuropathy, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, and chronic hypersensitivity Pneumonitis, primary biliary cirrhosis, uveitis, Sjögren's syndrome, interstitial pulmonary fibrosis, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephrosis, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, and Naphylaxis, fibrositis, gastritis, gastroenteritis, rhinosinusitis, silica-induced disease, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, cataracts, myositis in conjunction with systemic sclerosis, inclusion body myositis, thyroiditis, Addison's disease, lichen planus, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, cystitis, dacryoadenitis, dermatitis, encephalitis, endocarditis, endometritis, epicondylitis, epididymitis, fasciitis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, Interstitial lung disease, laryngitis, mastitis, meningitis, myocarditis, myositis, oophoritis, orchitis, osteitis, otitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa acquisita, psoriasis, cryopyrin-associated periodic syndromes (CAPS), rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis, psoriatic arthritis,selected from acute and chronic gout, chronic gouty arthritis, osteoarthritis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease; Pharmaceutical compositions.

2. The compound is 【Chemistry 2】 The pharmaceutical composition of claim 1, wherein

3. The compound is 【Transformation 3】 2. The pharmaceutical composition of claim 1, wherein the compound is a pharmaceutically acceptable salt of

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is systemic lupus erythematosus.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is autoimmune inflammatory bowel disease.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is ulcerative colitis.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is Crohn's disease.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is irritable bowel syndrome.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is colitis.

10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is enteritis.

11. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is enterocolitis.

12. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is alcoholic liver disease.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is chronic active hepatitis.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is hepatitis.

15. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is rheumatoid arthritis.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is juvenile rheumatoid arthritis.

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is systemic juvenile idiopathic arthritis.

18. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is psoriatic arthritis.

19. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is acute and chronic gout.

20. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is chronic gouty arthritis.

21. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is osteoarthritis.

22. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is multiple sclerosis.

23. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is myelitis.

24. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is polyneuropathy.

25. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is Alzheimer's disease.

26. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is Parkinson's disease.

27. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is amyotrophic lateral sclerosis.

28. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IRAK4-mediated inflammatory disorder is Huntington's disease.

Images