Amide compounds and their use

Abstract

The present invention relates to a novel amide compound of formula (I), a pharmaceutical composition containing the same, a method for preparing the same and its use, wherein the definitions of each symbol are as described in the specification. [Formula 1] TIFF2023520211000166.tif53170.

Description

Technical Field

[0001] The present invention relates to novel amide compounds, pharmaceutical compositions containing the same, methods for producing the same, and uses thereof.

Background Art

[0002] Members of the type III tyrosine kinase receptor family include CSF-1R, PDGFRα, PDGFRβ, FLT3, and c-KIT. All members of this family are composed of an extracellular immunoglobulin-like domain, a transmembrane domain, a juxtamembrane domain, and a protein kinase domain, and the kinase domain is highly conserved (Nat Rev Cancer. 2012, 12(11):753-66). The phosphorylation signals mediated thereby are involved in the biological functions of many cells and play an important role in the development of diseases. Specifically, there are reports suggesting that mutations in the kinase domains of PDGFRα and c-KIT cause gastrointestinal tumors (J Pathol. 2011, 223(2): 251-261). Furthermore, FLT-3 internal tandem duplication (FLT3-ITD) has been found to be an important pathogenic factor in about 20% of patients with acute lymphoblastic leukemia (Biomark Insights. 2015, 10(Suppl 3):1-14).

[0003] CSF-1R, that is, CSF-1 receptor (colony-stimulating factor 1 receptor), is encoded by the oncogene c-fms. The human C-fms gene is located at 5q33.3 on chromosome 5, downstream of the β-type platelet-derived growth factor receptor (PDGF_Rβ) gene, and the two genes are linked end to end. Human CSF-1R is a single-chain transmembrane receptor tyrosine kinase, a transmembrane glycoprotein with a molecular weight of 150 Kd and composed of 972 amino acids. Human CSF-1R is composed of an extracellular region of 512 amino acids, a transmembrane region of 25 amino acids, and an intracellular cytoplasmic region of 435 amino acids. The extracellular region has 5 disulfide bonds and 11 possible glycosylation sites, and the intracellular region has a Gly-X-Gly-X-X-Gly motif. Lysine at position 616 is the ATP-binding site, and it is adjacent to a kinase insert region of 72 amino acids. This is presumed to have the function of recognizing specific substrates (Cold Spring Harb Perspect Biol. 2014, 6(6)).

[0004] CSF-1, also known as M-CSF (macrophage colony-stimulating factor), is encoded by the CSF-1 gene. CSF-1 exerts its biological effects by binding to its only cell surface receptor, CSF-1R. After binding to CSF-1, the conformation of CSF-1R changes and it forms dimers or polymers. After dimerization, the tyrosine kinase activity of the receptor is activated, and tyrosine at positions such as 544, 559, 699, 708, 723, 809, 923, etc. is phosphorylated, and then interacts with multiple intracellular signaling pathways such as Ras, MAPK, PI3K, JAK, etc., generating various biological effects in the cell (J Cell Biochem. 1988, 38(3):179-87).

[0005] The tumor microenvironment is a complex ecosystem that supports tumor development, growth, and metastasis. Macrophages are particularly abundant among immune cells that migrate to the tumor site and are present at all stages of tumor progression. Studies have shown that tumor-associated macrophages (TAMs) play an important role in tumor development, growth, and metastasis. In the case of primary tumors, macrophages stimulate angiogenesis, assist in extravasation, tumor cell survival, and continuous growth, thereby promoting tumor cell metastasis. TAMs also exert an immunosuppressive effect, preventing natural killer cells and T cells from attacking tumor cells (Immunity. 2014, 41(1):49-61). CSF-1R is expressed in macrophages, and macrophage survival and differentiation depend on the CSF-1 / CSF-1R signaling pathway. The CSF-1 / CSF-1R signaling pathway hinders tumor progression by regulating TAMs to suppress tumor invasiveness and proliferation. As a result, the CSF-1 / CSF-1R signaling pathway may be a target for cancer treatment. Overexpression of CSF-1 or CSF-1R is associated with poor tumor aggressiveness and prognosis. Studies have shown that applying a CSF-1R inhibitor affects the exchange of inflammatory factors between TAMs and glioma cells, significantly reducing the volume of glioblastoma and decreasing tumor invasiveness and proliferation (Nat Med. 2013, 19(10):1264-72). Furthermore, abnormal overexpression of CSF-1 is the main cause of tenosynovial giant cell tumor (a rare non-metastatic tumor associated with giant cell tumor of the tendon sheath and pigmented villonodular synovitis). Patients with tenosynovial giant cell tumor obtain obvious clinical benefits after using a CSF-1R inhibitor (N Engl J Med. 2015, 373(5):428-37).

[0006] In addition to tumors, the CSF-1R signaling pathway plays an important role in autoimmune and inflammatory diseases, including systemic lupus erythematosus, arthritis, atherosclerosis, and obesity (Arthritis Res Ther. 2016, 18:75; Nat Rev Immunol. 2008, 8(7):533-44; J Immunother Cancer. 2017, 5(1):53). Therefore, the development of CSF-1R inhibitors may also be used for the treatment of such diseases.

[0007] Currently, pexidartinib, an inhibitor of CSF-1R and c-KIT, has been approved by the FDA for sale as a therapeutic agent for tenosynovial giant cell tumors in adult patients. There is still a need to develop new type III tyrosine kinase receptor inhibitors, particularly CSF-1R inhibitors, for the treatment of diseases such as cancer, autoimmune diseases, or inflammatory diseases. The present invention addresses these needs.

Summary of the Invention

[0008] There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer, and tautomer:

Chemical formula

Chemical formula

Chemical formula

[0009] Also provided is a pharmaceutical composition comprising a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0010] Also provided is a method of inhibiting the activity of CSF-1R in vivo or in vitro, the method comprising contacting CSF-1R with at least one of at least one compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0011] Also provided is the use of a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof for inhibiting the activity of CSF-1R in vivo or in vitro.

[0012] Also provided is the use of a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the activity of CSF-1R in vivo or in vitro.

[0013] Also provided is a method of treating cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, obesity or obesity-related disease in a subject, the method comprising administering to a subject in need thereof an effective amount of at least one of at least one compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0014] Also provided is the use of a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the treatment of cancer, autoimmune diseases, inflammatory diseases, metabolic diseases, neurodegenerative diseases, obesity or obesity-related diseases in a subject.

[0015] Also provided is a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof for the treatment of cancer, autoimmune diseases, inflammatory diseases, metabolic diseases, neurodegenerative diseases, obesity or obesity-related diseases in a subject.

[0016] Also provided is the use of a compound of formula (I) of the present invention (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, autoimmune diseases, inflammatory diseases, metabolic diseases, neurodegenerative diseases, obesity or obesity-related diseases in a subject. Detailed Description of the Invention

[0017] Definition As used in this application, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0018] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -O(C 1-6 alkyl) means the attachment of C 1-6 alkyl to the remainder of the molecule via an oxygen atom. When the point of attachment of a substituent is well known to a person of ordinary skill in the art ("POSITA"), the "-" can be omitted (e.g., for halogen substituents).

[0019] As used herein, the term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon radical containing from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms, particularly preferably from 1 to 6 carbon atoms, and even more preferably from 1 to 4 carbon atoms. For example, "C 1-6"Alkyl" refers to an alkyl containing 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), i-propyl ("i-Pr"), n-butyl ("n-Bu"), i-butyl ("i-Bu"), s-butyl ("s-Bu"), and t-butyl ("t-Bu").

[0020] As used herein, the term "alkylene" refers to a straight-chain or branched-chain saturated divalent hydrocarbon radical containing 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, particularly preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. For example, "C 1-6 alkylene" refers to a straight-chain or branched-chain alkylene containing 1 to 6 carbon atoms, such as a straight-chain alkylene-(CH 2 ) n -, or a branched-chain alkylene, such as -CH 2 -CH(CH 3 )-CH 2 -, -CH(CH 3 )-CH 2 - and -CH(CH 3 )-CH 2 -CH 2 -, preferably straight-chain C 1-6 alkylene, more preferably -CH 2 - and -CH 2 -CH 2 -.

[0021] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon radical containing one or more, such as 1, 2, or 3 carbon-carbon double bonds (C=C) and 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms. For example, "C 2-6 alkenyl" refers to an alkenyl containing 2 to 6 carbon atoms. Examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, and 2-butenyl. The point of attachment of the alkenyl may or may not be on the double bond.

[0022] As used herein, the term "alkynyl" refers to a linear or branched unsaturated hydrocarbon radical containing one or more, for example, 1, 2 or 3 carbon-carbon triple bonds (C≡C) and 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. For example, "C 2-6 alkynyl" refers to an alkynyl containing 2 to 6 carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl. The point of attachment of the alkynyl may or may not be on the triple bond.

[0023] As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo, preferably fluoro, chloro and bromo, more preferably fluoro and chloro.

[0024] As used herein, the term "haloalkyl" refers to an alkyl radical as defined herein, in which one or more, for example, 1, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms. When the hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other. In one embodiment, the term "haloalkyl" as used herein refers to an alkyl radical as defined herein, in which 2 or more, for example, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, and the halogen atoms are the same as each other. In another embodiment, the term "haloalkyl" as used herein refers to an alkyl radical as defined herein, in which 2 or more hydrogen atoms, for example, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, and the halogen atoms are different from each other. Examples of haloalkyl include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CH(CF 3 ) 2 and the like.

[0025] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical having 3 to 12 ring carbon atoms (such as 3 to 8 ring carbon atoms, 5 to 7 ring carbon atoms, 4 to 7 ring carbon atoms, 5 to 6 ring carbon atoms or 3 to 6 ring carbon atoms, etc.); it may have one or more rings, such as 1, 2 or 3 rings, preferably 1 or 2 rings, etc. For example, "C 3-8 cycloalkyl" refers to a cycloalkyl containing 3 to 8 ring carbon atoms. Cycloalkyl can include fused rings, bridged rings, or spiro rings. The rings of cycloalkyl are saturated or have one or more, for example, 1 or 2 double bonds (i.e., partially unsaturated), but are not fully conjugated and are not aryl as defined herein. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptanyl, bicyclo[3.1.1]heptanyl, spiro[3.3]heptanyl, spiro[2.2]pentanyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[3.1.1]hept-2-ene. In one embodiment of the present invention, the ring of cycloalkyl is saturated.

[0026] As used herein, the terms "heterocyclyl" or "heterocycle" refer to saturated or partially unsaturated monocyclic, bicyclic, or tricyclic radicals containing 3 to 12 ring atoms (such as 3 to 8 ring atoms, 4 to 7 ring atoms, 5 to 7 ring atoms, 4 to 6 ring atoms, 3 to 6 ring atoms, or 5 to 6 ring atoms, etc.), containing one or more (such as 1, 2, or 3, preferably 1 or 2, etc.) ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Heterocycles include those in which N or S heteroatoms are optionally oxidized to various oxidation states. The point of attachment of heterocyclyl may be on an N heteroatom or on carbon. For example, "3- to 12-membered heterocyclyl" or "3- to 12-membered heterocycle" refers to a heterocyclyl having 3 to 12 ring atoms and containing at least one heteroatom selected from N, O, and S; "4- to 6-membered heterocyclyl" or "4- to 6-membered heterocycle" refers to a heterocyclyl having 4 to 6 ring atoms and having at least one heteroatom selected from N, O, and S; "5- to 6-membered heterocyclyl" or "5- to 6-membered heterocycle" refers to a heterocyclyl having 5 or 6 ring atoms and having at least one heteroatom selected from N, O, and S. The heterocycle or heterocyclyl may include fused rings, bridged rings, or spiro rings, with at least one ring containing at least one ring heteroatom independently selected from N, O, and S, the point of attachment thereof to the rest of the molecule being located on the ring containing the ring heteroatom, and the remaining rings not being "aryl" or "heteroaryl" as defined in the present invention. The rings of the heterocycle or heterocyclyl are saturated or have one or more, for example, 1 or 2 double bonds (i.e., are partially unsaturated), but are not fully conjugated and are not heteroaryl as defined herein. In one embodiment of the present invention, the rings of the heterocycle or heterocyclyl are saturated.Examples of heterocyclyl include, but are not limited to, 4- to 6-membered heterocyclyl or 5- to 6-membered heterocyclyl, such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, morpholinyl, thiomorpholinyl, piperidyl, piperazinyl, pyrazolidinyl, dihydrooxadiazolyl, and oxaspiro[3.3]heptanyl.

[0027] As used herein, the terms "aryl" or "aromatic ring" refer to a carbocyclic hydrocarbon radical of 6 to 14 carbon atoms consisting of at least one ring or one or more fused rings, with at least one ring being an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, and azulenyl, preferably phenyl and naphthyl.

[0028] As used herein, the terms "heteroaryl" or "heteroaromatic ring" refer to an aromatic hydrocarbyl having 5 to 12 ring atoms (such as 5 to 10 ring atoms, 5 to 6 ring atoms, or 6 ring atoms, etc.), containing one or more (such as 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2, etc.) ring heteroatoms independently selected from N, O, and S in the ring, and the remaining ring atoms being carbon atoms (i.e., 5- to 12-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 6-membered heteroaryl, 6-membered heteroaryl), and may have one or more rings such as 1, 2, or 3 rings, preferably 1 or 2 rings. For example, heteroaryl includes: A monocyclic aromatic hydrocarbyl having 5, 6, or 7 ring atoms (preferably 5 or 6 ring atoms, i.e., 5- to 6-membered heteroaryl), containing one or more, such as 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2 ring heteroatoms independently selected from N, O, and S (preferably N and O) in the ring, and the remaining ring atoms being carbon atoms; and having 8 to 12 ring atoms (preferably 9 or 10 ring atoms), at least one ring containing one, two, three or four or more, preferably one, two or three ring heteroatoms independently selected from N, O and S (preferably N), the remaining ring atoms being carbon atoms, at least one ring being an aromatic ring and its point of attachment to the remainder of the molecule being located on the aromatic ring, a bicyclic aromatic hydrocarbyl Examples include. For example, bicyclic heteroaryl includes a 5- to 6-membered heteroaryl ring fused to a 5- to 6-membered cycloalkyl ring.

[0029] When the total number of S and O atoms in the heteroaryl group exceeds 1, those S and O heteroatoms are not adjacent to each other.

[0030] Heteroaryl also includes those in which the N ring atom is in the form of an N-oxide, for example N-oxide pyridine.

[0031] Examples of heteroaryl include, but are not limited to, 5- to 6-membered heteroaryl such as pyridyl, N-oxidopyridyl, pyrazinyl, pyrimidyl, triazinyl (such as 1,3,5-triazinyl), pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (such as 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl (such as 1,2,3-triazolyl and 1,2,4-triazolyl), thienyl, furanyl, pyranyl, pyrrolyl, and pyridazinyl; bicyclic heteroaryl such as benzodioxolyl, benzoxazolyl, benzoisoxazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (such as imidazo[1,2-a]pyridyl), imidazopyridazinyl (such as imidazo[1,2-b]pyridazinyl), pyrrolopyridyl (such as 1H-pyrrolo[2,3-b]pyridyl), pyrrolopyrimidyl (such as pyrrolo[3,4-d]pyrimidyl), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridyl), pyrazolopyrimidyl (such as pyrazolo[1,5-a]pyrimidyl), triazolopyridyl (such as [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl), triazolopyridazinyl (such as [1,2,4]triazolo[4,3-b]pyridazinyl), tetrazolopyridyl (such as tetrazolo[1,5-a]pyridyl), benzofuranyl, benzimidazolinyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0032] As used herein, the term "hydroxyl" refers to an -OH group.

[0033] As used herein, the term "oxo" refers to a =O group.

[0034] The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the absence of them. For example, "optionally substituted alkyl" includes "unsubstituted alkyl" and "substituted alkyl" as defined herein. It is understood that with respect to any group that contains one or more substituents, POSITA does not intend that such group introduce any substitution or substitution pattern that is sterically impractical, chemically imprecise, synthetically infeasible, and / or inherently unstable.

[0035] As used herein, the term "substituted" or "substituted with..." means that one or more hydrogen atoms at the specified atom or group are replaced with one or more substituents selected from the group of specified substituents, provided that the normal valence of the specified atom is not exceeded. If the substituent is oxo (i.e., =O), then two hydrogens on an atom are replaced with oxo. Combinations of substituents and / or variables are permitted only if they result in a chemically precise and stable compound. A chemically precise and stable compound is meant to suggest a compound that is robust enough to survive sufficient separation from a reaction mixture and can be formulated into at least a practical preparation.

[0036] Unless otherwise noted, substituents are named on the core structure. For example, when (cycloalkyl)alkyl is listed as a possible substituent, it is to be understood that the point of attachment of this substituent to the core structure is on the alkyl portion.

[0037] As used herein, the term "substituted with one or more substituents" means that one or more hydrogens on the specified atom or group are independently substituted with one or more substituents selected from the specified groups. In some embodiments, "substituted with one or more substituents" means that the specified atom or group is substituted with 1, 2, 3, or 4 substituents independently selected from the specified groups.

[0038] It is understood by the POSITA that some of the compounds of formula (I) contain one or more chiral centers and can therefore exist in two or more stereoisomeric forms. Racemates, individual isomers, and mixtures enriched in one enantiomer of these isomers, as well as diastereomers when two chiral centers are present, and mixtures enriched in a particular diastereomer are within the scope of the present invention. It will be further understood by the POSITA that the present invention encompasses all individual stereoisomers (e.g., enantiomers), racemic mixtures or partially resolved mixtures of the compounds of formula (I), and, where appropriate, their individual tautomers.

[0039] The racemate may be used as it is, or may be separated into individual isomers. By separation, a stereochemically pure compound or a mixture rich in one or more isomers can be obtained. Methods for separating isomers are well known (see Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971), and physical methods such as chromatography using a chiral adsorbent can be mentioned. The individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can form diastereomeric salts with chiral acids such as individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc., the salts are fractionally crystallized, and then one or both of the separated bases are liberated, and optionally this process is repeated to chemically separate them from the mixture, and one or both are obtained in a form substantially free of the other, i.e., having an optical purity of >95%. Alternatively, the racemic compound can be covalently bonded to a chiral compound (auxiliary) to form a diastereomer, separated by chromatography or fractional crystallization, and then the chiral auxiliary is chemically removed to obtain a pure enantiomer.

[0040] As used herein, the term "tautomer" refers to a structural isomer of a compound produced by the rapid movement of an atom at two positions within a molecule. Tautomers readily interconvert with each other; for example, the enol form and the ketone form are typical tautomers. As another example, some compounds of the present invention may exist in the structure of formula (II) as shown in the following figure when R 2 is hydrogen, i.e., the compound of formula (II) can be a tautomer of the compound of formula (I) of the present invention; such tautomers are compounds of the present invention.

Chemical formula

[0041] The term "pharmaceutically acceptable salt" is intended to mean a salt of the free acid or free base of a compound of formula (I) that is non-toxic, biologically acceptable or biologically suitable for administration to a subject. For example, pharmaceutically acceptable salts include acid addition salts such as salts derived from inorganic acids and organic acids. Such inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid, etc.; such organic acids include p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. For example, see S. M. Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19 and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002 for extensive reference.

[0042] Furthermore, in the present specification, when the compound of the present invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, when the product is a free base, the acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be produced by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. A POSITA will recognize the various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts or base addition salts without undue experimentation.

[0043] The term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to capture solvent molecules in a fixed molar ratio in the solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates consist of one or more water molecules and water where H 2Formed by combination with one molecule of a substance that retains a molecular state as O, and such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0044] As used herein, the terms "group" and "radical" are synonymous and are intended to denote a functional group or a fragment of a molecule that can be attached to other fragments of the molecule.

[0045] The term "active ingredient" is used to denote a chemical substance having biological activity. In some embodiments, the "active ingredient" is a chemical substance having pharmaceutical utility. In the United States, whether in vivo or in vitro, the actual pharmaceutical efficacy can be confirmed by appropriate preclinical tests. However, higher standards than preclinical tests are required for drug activities that can be sufficiently tolerated by regulatory agencies (such as the US FDA). Whether such higher-standard drug activities can be successfully obtained is generally not reasonably predictable from the results of preclinical tests, but can be established through appropriate and effective randomized double-blind comparative clinical trials in humans.

[0046] For a disease or disorder, the terms "treat" or "treatment" refer to administering one or more pharmaceutical substances, particularly a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, to a subject having the disease or disorder, or having a sign of the disease or disorder, or having a predisposition to the disease or disorder, for the purpose of curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving or affecting the disease or disorder, or a sign of the disease or disorder, or a predisposition to the disease or disorder, in the context of achieving a therapeutic benefit. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is an autoimmune disease or an inflammatory disease.

[0047] The terms "process", "contact" and "react" mean, in the context of a chemical reaction, adding or mixing two or more reagents under suitable conditions to produce the indicated and / or desired product. It should be understood that the reaction to produce the indicated and / or desired product does not necessarily occur directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates produced in the mixture that ultimately lead to the formation of the indicated and / or desired product.

[0048] As used herein, the term "effective amount" refers to an amount or dosage of a compound of the present invention sufficient to generally provide a therapeutic benefit in a patient in need of treatment for a disease or disorder mediated by CSF-1R activity, or a disease or disorder at least in part mediated by CSF-1R. The effective amount or effective dosage of the active ingredient of the present disclosure can be determined by methods such as modeling, dose escalation studies, or clinical trials, and by considering factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease or disorder, the subject's previous or current ongoing treatment, the subject's health status and response to the drug, as well as the judgment of the attending physician. In the United States, it is generally difficult to predict the determination of an effective dosage from preclinical trials. In fact, the dosage is completely unpredictable. After the first use of a volume that is a randomized double-blind comparative clinical trial, new unpredictable dosing schedules occur.

[0049] Exemplary dosages are in the range of from about 0.001 to 100 mg / kg / day, or from about 0.01 to 35 mg / kg / day, or from about 0.1 to 10 mg / kg / day, etc., of the active agent per kg of the subject's body weight per day, in single or divided dosage units (e.g., BID, TID, QID). For a 70 kg human, exemplary ranges of appropriate dosages are from about 0.05 to about 7 g / day, or from about 0.2 to about 5 g / day. If improvement of the patient's disease or disorder is seen, the dosage can be adjusted for maintenance therapy. For example, the dosage or dosing frequency, or both, can be reduced to a level at which the desired therapeutic effect is maintained, depending on the symptoms. Of course, if the symptoms are alleviated to an appropriate level, treatment can be discontinued. However, if the symptoms recur, the patient may need intermittent treatment over a long period.

[0050] The term "inhibit" or "inhibiting" refers to a decrease in the baseline activity of a biological activity or process. The term "inhibition of CSF-1R activity" is the actual drug activity for the purposes of the present disclosure, and refers to a decrease in the activity of CSF-1R as a direct or indirect response to the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof as compared to the activity of CSF-1R in the absence of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof described herein. The decrease in activity may be due to a direct interaction between the compound of formula (I) and / or a pharmaceutically acceptable salt thereof described herein and CSF-1R, or may be due to an interaction between the compound of formula (I) and / or a pharmaceutically acceptable salt thereof described herein and one or more other factors that affect CSF-1R activity. For example, the presence of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof described herein may reduce CSF-1R activity by directly binding to CSF-1R, by directly or indirectly affecting other factors, or by directly or indirectly decreasing the amount of CSF-1R present in a cell or organism.

[0051] As used herein, the term "subject" means a mammal and a non-mammal. Mammals mean members of the mammalian class, including but not limited to humans; non-human primates such as chimpanzees and other apes, monkey species, etc.; farm animals such as cows, horses, sheep, goats and pigs; domestic animals such as rabbits, dogs and cats; experimental animals including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include but are not limited to birds, etc. The term "subject" does not indicate a particular age or gender. In some embodiments, the subject is a human.

[0052] Generally, the term "about" is used herein to modify a numerical value above or below the recited value by a variance of 20%.

[0053] Technical terms and scientific terms used in this specification but not specifically defined have the meanings generally understood by a POSITA to which this disclosure pertains.

[0054] A compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer:

Chemical formula

Chemical formula

Chemical formula

[0055] In some embodiments of the compound of formula (I), X is N.

[0056] In some embodiments of the compound of formula (I), X is CR 5 .

[0057] In some embodiments of the compound of formula (I), R 5 is hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl).

[0058] In some embodiments of the compound of formula (I), X is CH.

[0059] In some embodiments of the compound of formula (I), Z 1 and Z 2 are each independently CR 6 .

[0060] In some embodiments of the compound of formula (I), Z 1 is N; Z 2 is CR 6 .

[0061] In some embodiments of the compound of formula (I), Z 1 is CR 6 ; Z 2 is N.

[0062] In some embodiments of the compound of formula (I), R 6 is hydrogen.

[0063] In some embodiments of the compound of formula (I), Z 1 and Z 2 are both CH.

[0064] In some embodiments of the compound of formula (I), Y 1 is CR 7 , Y 2 is CR 8 , Y 3 is CR 9 .

[0065] In some embodiments of the compound of formula (I), Y 1 is CR 7 , Y 2 is N, Y 3 is CR 9 .

[0066] In some embodiments of the compound of formula (I), Y 1 is N, Y 2 is CR 8 , Y 3 is CR 9 .

[0067] In some embodiments of the compound of formula (I), Y 1 is CR 7 and Y 2 is CR 8 and Y 3 is N.

[0068] In some embodiments of the compound of formula (I), L is O or CH 2 and.

[0069] In some embodiments of the compound of formula (I), L is O.

[0070] In some embodiments of the compound of formula (I), R 7 is selected from hydrogen, C 1-6 alkyl or -O(C 1-6 alkyl).

[0071] In some embodiments of the compound of formula (I), R 7 is hydrogen.

[0072] In some embodiments of the compound of formula (I), R 8 is selected from hydrogen, halogen or C 1-6 alkyl.

[0073] In some embodiments of the compound of formula (I), R 8 is selected from hydrogen, fluoro or methyl.

[0074] In some embodiments of the compound of formula (I), R 9 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 or C 3-6 cycloalkyl.

[0075] In some embodiments of the compound of formula (I), R 9 is hydrogen or methyl.

[0076] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is CR 8 ; Y 3 is CR 9 ; R 7 and R 8 are each independently selected from hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 9 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 is.

[0077] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is CR 8 ; Y 3 is CR 9 ; R 7 is hydrogen or -O(C 1-6 alkyl); R 8 is hydrogen, halogen or C 1-6 alkyl; R 9 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), -NH 2 , -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 is.

[0078] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y2 is CR 8 and Y 3 is CR 9 ; R 7 is hydrogen; R 8 is hydrogen or halogen; R 9 is hydrogen or C 1-6 alkyl.

[0079] In some embodiments of the compound of formula (I), Y 1 is CR 7 and Y 2 is CR 8 and Y 3 is CR 9 ; R 7 is hydrogen; R 8 is hydrogen or fluoro; R 9 is hydrogen or methyl.

[0080] In some embodiments of the compound of formula (I), Y 1 is CR 7 and Y 2 is CR 8 and Y 3 is CR 9 ; R 7 , R 8 and R 9 are hydrogen.

[0081] In some embodiments of the compound of formula (I), Y 1 is CR 7 and Y 2 is N, and Y 3 is CR 9 ; R 7 is hydrogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 9 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl.

[0082] In some embodiments of the compound of formula (I), Y 1 is CR7 is CR, Y 2 is N, Y 3 is CR 9 ; R 7 is hydrogen or C 1-6 alkyl; R 9 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.

[0083] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is N, Y 3 is CR 9 ; R 7 is hydrogen; R 9 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl.

[0084] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is N, Y 3 is CR 9 ; R 7 is hydrogen; R 9 is C 1-6 alkyl.

[0085] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is N, Y 3 is CR 9 ; R 7 is hydrogen; R 9 is methyl.

[0086] In some embodiments of the compound of formula (I), Y 1 is CR 7 ; Y 2 is N, Y 3 is CR 9 ; R 7 and R 9Both are hydrogen.

[0087] In some embodiments of the compound of formula (I), Y 1 is N, and Y 2 is CR 8 and Y 3 is CR 9 ; R 8 and R 9 are both hydrogen.

[0088] In some embodiments of the compound of formula (I), Y 1 is CR 7 and Y 2 is CR 8 and Y 3 is N; R 7 and R 8 are both hydrogen.

[0089] In some embodiments of the compound of formula (I), W is absent or NH.

[0090] In some embodiments of the compound of formula (I), W is absent.

[0091] In some embodiments of the compound of formula (I), W is NH.

[0092] In some embodiments of the compound of formula (I), R 1 is phenyl, 5- to 12-membered heteroaryl, 4- to 6-membered heterocyclyl or C 3-8 cycloalkyl, each of which is halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -NH 2 , -(C 1-6 alkylene) n -NH(C 1-6 alkyl), -(C 1-6 alkylene) n -N(C 1-6 alkyl) 2 or -(C 1-6(alkylene) n is optionally substituted with one or more groups selected from -OH.

[0093] In some embodiments of the compound of formula (I), R 1 is phenyl, 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl or C 3-8 cycloalkyl, each of which is halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 (alkylene) n -NH 2 -, -(C 1-6 (alkylene) n -NH(C 1-6 (alkyl)), -(C 1-6 (alkylene) n -N(C 1-6 (alkyl)) 2 or -(C 1-6 (alkylene) n -OH and is optionally substituted with one or more groups selected therefrom.

[0094] In some embodiments of the compound of formula (I), R 1 is phenyl, 5- to 6-membered monocyclic heteroaryl, 9- to 10-membered bicyclic heteroaryl, 4- to 6-membered heterocyclyl or C 3-8 cycloalkyl, each of which is halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 (alkylene) n -NH 2 (alkylene) 1-6 (alkylene) n -NH(C 1-6 (alkyl)), -(C 1-6 (alkylene) n -N(C 1-6 (alkyl)) 2 or -(C 1-6 (alkylene) n -OH and is optionally substituted with one or more groups selected therefrom.

[0095] In some embodiments of the compound of formula (I), R 1 is phenyl, pyrazolyl, pyrrolyl, furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazo[1,2-a]pyridyl, piperazinyl or cyclohexenyl, each of which is optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene) n -NH 2 -, -(C 1-6 alkylene) n -NH(C 1-6 alkyl), -(C 1-6 alkylene) n -N(C 1-6 alkyl) 2 or -(C 1-6 alkylene) n -OH.

[0096] In some embodiments of the compound of formula (I), R 1 is phenyl, pyrazolyl, pyrrolyl, furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazo[1,2-a]pyridyl, piperazinyl or cyclohexenyl, each of which is optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-NH 2 , -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 alkyl) 2 or -(C 1-6 alkylene)-OH.

[0097] In some embodiments of the compound of formula (I), R 1 is pyrazolyl or pyrrolyl, each of which is C 1-6 alkyl, C1-6 Haloalkyl, -(C 1-6 alkylene)-NH 2 、-(C 1-6 alkylene)-NH(C 1-6 alkyl)、-(C 1-6 alkylene)-N(C 1-6 alkyl) 2 or -(C 1-6 alkylene)-OH and is optionally substituted with one or more groups selected therefrom.

[0098] In some embodiments of the compound of formula (I), R 1 is pyrazolyl or pyrrolyl, each of which is methyl, ethyl, i-propyl, -CHF 2 、-CF 3 、-(CH 2 CH 2 )-NH 2 、-(CH 2 CH 2 )-NH(C 1-6 alkyl)、-(CH 2 CH 2 )-N(C 1-6 alkyl) 2 or -(CH 2 CH 2 )-OH and is optionally substituted with one or more groups selected therefrom.

[0099] In some embodiments of the compound of formula (I), R 1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more C 1-6 alkyl.

[0100] In some embodiments of the compound of formula (I), R 1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more methyls.

[0101] In some embodiments of the compound of formula (I), R 1 is

Chemical formula

[0102] In some embodiments of the compound of formula (I), R 1 is substituted with one or more methyls

Chemical formula

[0103] In some embodiments of the compound of formula (I), R 1 is phenyl optionally substituted with one or more halogens.

[0104] In some embodiments of the compound of formula (I), R 1 is phenyl optionally substituted with one or more Fs.

[0105] In some embodiments of the compound of formula (I), R 1 is furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazo[1,2-a]pyridyl, piperazinyl or cyclohexenyl, and each of these is optionally substituted with one or more C 1-6 alkyls.

[0106] In some embodiments of the compound of formula (I), R 1 is furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl or imidazo[1,2-a]pyridyl, and each of these is optionally substituted with one or more methyls.

[0107] In some embodiments of the compound of formula (I), R 1 is piperazinyl optionally substituted with one or more ethyls.

[0108] In some embodiments of the compound of formula (I), W is NH; R 1is pyrazolyl, pyridyl or thiazolyl, each of which is halogen, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-NH 2 、-(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-N(C 1-6 alkyl) 2 or -(C 1-6 alkylene)-OH and is optionally substituted with one or more groups selected from the group consisting of:

[0109] In some embodiments of the compounds of formula (I), W is NH; R 1 is pyrazolyl, pyridyl or thiazolyl, each of which is C 1-6 alkyl or C 1-6 haloalkyl and is optionally substituted with one or more groups selected from the group consisting of:

[0110] In some embodiments of the compounds of formula (I), W is NH; R 1 is pyrazolyl optionally substituted with one or more methyls.

[0111] In some embodiments of the compounds of formula (I), W is NH; R 1 is

Chemical formula

[0112] In some embodiments of the compounds of formula (I), W is absent; R 1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more methyls.

[0113] In some embodiments of the compounds of formula (I), W is absent; R 1 is

Chemical formula

[0114] In some embodiments of the compound of formula (I), W is absent; R 1 is substituted with one or more methyls

Chemical formula

[0115] In some embodiments of the compound of formula (I), R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, -(C 1-6 alkylene)-N(C 1-6 alkyl) 2 、-(C 1-6 alkylene)-O-(C 1-6 alkyl), -(C 1-6 alkylene)-OH, C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl.

[0116] In some embodiments of the compound of formula (I), R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, -(CH 2 CH 2 )-N(C 1-6 alkyl) 2 、-(CH 2 CH 2 )-O-(C 1-6 alkyl), -(CH 2 CH 2 )-OH, C 3-6 cycloalkyl or 4- to 6-membered heterocyclyl.

[0117] In some embodiments of the compound of formula (I), R 2 is hydrogen, C 1-6 alkyl, C2-6 Alkenyl, C 1-6 Haloalkyl, -(CH 2 CH 2 )-N(C 1-6 Alkyl) 2 、-(CH 2 CH 2 )-O-(C 1-6 Alkyl), -(CH 2 CH 2 )-OH, C 3-6 Cycloalkyl or oxetanyl.

[0118] In some embodiments of the compound of formula (I), R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, -(CH 2 CH 2 )-O-(C 1-6 Alkyl), -(CH 2 CH 2 )-OH, cyclopropyl, cyclobutyl or oxetanyl.

[0119] In some embodiments of the compound of formula (I), R 2 is C 1-6 Alkyl.

[0120] In some embodiments of the compound of formula (I), R 2 is methyl, ethyl or i-propyl.

[0121] In some embodiments of the compound of formula (I), R 2 is methyl.

[0122] In some embodiments of the compound of formula (I), R 2 is i-propyl.

[0123] In some embodiments of the compound of formula (I), R 3 and R 4 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl or -O(C 1-6selected from (alkyl).

[0124] In some embodiments of the compound of formula (I), R 3 and R 4 are each independently hydrogen, halogen, -CN, C 1-6 alkyl or -O(C 1-6 alkyl); when X is CH, at least one of R 3 and R 4 is hydrogen.

[0125] In some embodiments of the compound of formula (I), R 3 is hydrogen, halogen, -CN, C 1-6 alkyl or -O(C 1-6 alkyl); R 4 is hydrogen or C 1-6 alkyl.

[0126] In some embodiments of the compound of formula (I), both R 3 and R 4 are hydrogen.

[0127] In some embodiments of the compound of formula (I), X is CH; R 3 and R 4 are each independently selected from hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl), and at least one of R 3 and R 4 is hydrogen.

[0128] In some embodiments of the compound of formula (I), X is CH; R 3 is hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 4 is hydrogen.

[0129] In some embodiments of the compound of formula (I), n is 1.

[0130] In some embodiments of the compound of formula (I), Y 3 is CR 9 ; R 2 and R 9 together with the N and C atoms to which they are attached form pyridine or pyrrolidine.

[0131] In some embodiments of the compound of formula (I), Y 3 is CR 9 ; R 2 and R 9 together with the N and C atoms to which they are attached form pyridine.

[0132] In some embodiments of the compound of formula (I), Y 3 is CR 9 ; R 2 and R 9 together with the N and C atoms to which they are attached form pyrrolidine.

[0133] In some embodiments of the compound of formula (I),

Chemical formula

Chemical formula

[0134] In some embodiments of the compound of formula (I),

Chemical formula

Chemical formula

[0135] In some embodiments of the compound of formula (I), X is CR 5and Z 1 and Z 2 are each independently CR 6 and Y 1 is CR 7 and Y 2 is N or CR 8 and Y 3 is CR 9 and W is absent; R 1 is a 5- to 6-membered heteroaryl optionally substituted with one or more C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl), and at least one of R 3 and R 4 is hydrogen; R 9 is hydrogen or C 1-6 alkyl.

[0136] In some embodiments of the compound of formula (I), X is CH; Z 1 and Z 2 are both CH; Y 1 is CH; Y 2 is N or CH; Y 3 is CR 9 and W is absent; R 1 is a pyrazolyl optionally substituted with one or more C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 is hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 4 is hydrogen; R 9 is hydrogen or C 1-6 alkyl.

[0137] In some embodiments of the compound of formula (I), X is N; Z 1 and Z 2 are both CH; Y 1 is CH; Y 2 is N or CR 8 ; Y 3 is CR 9 ; W is absent; R 1 is pyrazolyl or pyrrolyl optionally substituted with one or more C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 is hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 4 is hydrogen; R 8 is hydrogen or halogen; R 9 is hydrogen or C 1-6 alkyl.

[0138] In some embodiments of the compound of formula (I), X is N; Z 1 and Z 2 are both CH; Y 1 is CH; Y 2 is N or CR 8 ; Y 3 is CR 9 ; W is absent; R 1 is pyrazolyl or pyrrolyl substituted with one or more methyls; R 2 is methyl or i-propyl; R 3 is hydrogen; R 4 is hydrogen; R 8 is hydrogen or F; R 9 is hydrogen or methyl.

[0139] In some embodiments of the compound of formula (I), X is N; Z 1 and Z 2 are both CH; Y 1 is CH; Y 2 is N or CR 8 ; Y 3is CR 9 ; W is NH; R 1 is pyrazolyl optionally substituted with one or more C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 is hydrogen, halogen, C 1-6 alkyl or -O(C 1-6 alkyl); R 4 is hydrogen; R 8 is hydrogen or halogen; R 9 is hydrogen or C 1-6 alkyl.

[0140] In some embodiments of the compounds of formula (I), X is N; Z 1 and Z 2 are both CH; Y 1 is CH; Y 2 is N or CR 8 ; Y 3 is CR 9 ; W is NH; R 1 is pyrazolyl substituted with one or more methyls; R 2 is methyl or i-propyl; R 3 is hydrogen; R 4 is hydrogen; R 8 is hydrogen or F; R 9 is hydrogen or methyl.

[0141] Also provided are the compounds of the examples selected from Compounds 1 - 135 numbered in the experimental section and / or their pharmaceutically acceptable salts.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0142] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, optionally comprising at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0143] In another aspect, there is provided a method of inhibiting the activity of CSF-1R in vivo or in vitro, comprising contacting CSF-1R with an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0144] In another aspect, there is provided a method of treating a disease mediated by CSF-1R or at least partially mediated by CSF-1R in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0145] In another aspect, there is provided a method of treating cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, obesity or obesity-related disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0146] In another aspect, there is provided a method for treating cancer, an autoimmune disease or an inflammatory disease in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof.

[0147] In another aspect, there is provided a method for treating a disease mediated by CSF-1R or at least in part by CSF-1R in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0148] In another aspect, there is provided a method for treating cancer, an autoimmune disease, an inflammatory disease, a metabolic disease, a neurodegenerative disease, obesity or an obesity-related disease in a subject, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0149] In another aspect, there is provided a method for treating cancer, an autoimmune disease or an inflammatory disease in a subject, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0150] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the treatment of a disease in a subject that is mediated by CSF-1R or at least in part by CSF-1R.

[0151] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the treatment of cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, obesity or obesity-related disease in a subject.

[0152] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the treatment of cancer, autoimmune disease or inflammatory disease in a subject.

[0153] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease in a subject that is mediated by CSF-1R or at least in part by CSF-1R.

[0154] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, autoimmune disease, inflammatory disease, metabolic disease, neurodegenerative disease, obesity or obesity-related disease in a subject.

[0155] In another aspect, provided is the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, autoimmune disease or inflammatory disease in a subject.

[0156] In another aspect, there is provided a combination comprising a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0157] In another aspect, there is provided a method of treating a disease mediated by CSF-1R, or at least in part by CSF-1R, in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent.

[0158] In another aspect, there is provided a method of treating cancer, an autoimmune disease or an inflammatory disease in a subject, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent.

[0159] In another aspect, there is provided the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, together with an additional therapeutic agent, in the manufacture of a combination medicament for treating a disease mediated by CSF-1R, or at least in part by CSF-1R, in a subject.

[0160] In another aspect, there is provided the use of a compound of formula (I) (e.g., any of the compounds of the examples described herein) and / or a pharmaceutically acceptable salt thereof, together with an additional therapeutic agent, in the manufacture of a combination medicament for treating cancer, an autoimmune disease or an inflammatory disease in a subject.

[0161] In some embodiments, the additional therapeutic agent is an anti-tumor agent.

[0162] In some embodiments, the anti-tumor agent is selected from a chemotherapeutic agent, an immune checkpoint inhibitor or agonist, and a targeted therapeutic agent.

[0163] In some embodiments, the disease mediated by CSF-1R, or at least in part by CSF-1R, is cancer, an autoimmune disease, an inflammatory disease, a metabolic disease, a neurodegenerative disease, obesity or an obesity-related disease.

[0164] In some embodiments, the disease mediated by CSF-1R, or at least in part by CSF-1R, is cancer, an autoimmune disease or an inflammatory disease.

[0165] In some embodiments, the cancer is a solid tumor or a hematological malignancy (such as leukemia, lymphoma or myeloma).

[0166] In some embodiments, the cancer is selected from ovarian cancer, lung cancer (including non-small cell lung cancer), brain tumor (including glioblastoma multiforme (GBM)), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma cancer, renal cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma or myeloma.

[0167] In some embodiments, the cancer is selected from ovarian cancer, lung cancer (including non-small cell lung cancer), brain tumor (including glioblastoma multiforme (GBM)), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma cancer, renal cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, acute myeloid leukemia (AML) (including relapsed AML or refractory AML), acute lymphoblastic leukemia (ALL), B-cell lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL) or multiple myeloma (MM).

[0168] In some embodiments, the autoimmune or inflammatory disease is selected from arthritis (including rheumatoid arthritis and collagen-induced arthritis), osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, autoimmune nephritis, Crohn's disease, asthma or chronic obstructive pulmonary disease.

[0169] In some embodiments, the metabolic disease is selected from osteoporosis, diabetes, diabetic ketoacidosis, hyperglycemia and hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, etc.

[0170] In some embodiments, the neurodegenerative disease is selected from Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, motor neuron disease (including amyotrophic lateral sclerosis (ALS)), hereditary motor and sensory neuropathy (CMT), etc.

[0171] In some embodiments, the obesity-related disease is selected from diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease and angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, etc.

[0172] General synthesis method of the disclosed embodiments The compound of formula (I) described herein and / or its pharmaceutically acceptable salt can be synthesized using commercially available materials by methods known in the art or disclosed in patent applications. The synthetic routes shown in Routes 1-3 illustrate the general synthetic methods of the compounds of the present invention.

[0173] Method 1:

Chemical formula

[0174] As shown in Route 1, under alkaline conditions (but not limited to, potassium carbonate, etc.), the compound represented by the molecular formula (1-1) and the compound represented by the molecular formula (1-2) are subjected to a substitution reaction, or the compound represented by the molecular formula (1-1’) and the compound represented by the molecular formula (1-2’) are subjected to a substitution reaction to obtain the compound represented by the molecular formula (1-3). The compound represented by the molecular formula (1-3) is subjected to a coupling reaction with the compound represented by the molecular formula (1-4) in the presence of a palladium reagent (but not limited to, Pd(dppf)Cl 2 etc.), or a substitution reaction with the compound represented by the molecular formula (1-4’) in the presence of a palladium reagent (but not limited to, Pd 2 (dba) 3 etc.) and a ligand (but not limited to, BINAP, etc.) to obtain the compound represented by the molecular formula (1-5); this is continuously subjected to a reduction reaction to obtain the compound represented by the molecular formula (1-6). The compound represented by the molecular formula (1-6) and the compound represented by the molecular formula (1-7) are subjected to a condensation reaction in the presence of a condensing agent (but not limited to, HATU, etc.) so that R 1 、R 2 、R 3 、R 4 、W, X, Y 1 、Y 2 、Y 3 、Z 1 and Z 2 are as defined in this specification; M is borate, boronic acid or alkyltin; X 1 is selected from Cl and Br; X 2 is a halogen selected from F and Cl to obtain the compound of formula (I).

[0175] Method 2:

Chemical formula

[0176] As shown in Route 2, the compound represented by the molecular formula (1-3) is subjected to a reduction reaction to obtain the compound represented by the molecular formula (1-8), and then this is subjected to a consecutive condensation reaction with the compound represented by the molecular formula (1-7) in the presence of a condensing agent (not limited to, e.g., HATU) to obtain the compound represented by the molecular formula (1-9). The compound represented by the molecular formula (1-9) is subjected to a coupling reaction with the compound represented by the molecular formula (1-4) in the presence of a palladium reagent (not limited to, e.g., Pd(dppf)Cl 2 etc.), or a substitution reaction with the compound represented by the molecular formula (1-4’) in the presence of a palladium reagent (not limited to, e.g., Pd 2 (dba) 3 etc.) and a ligand (not limited to, e.g., BINAP) to obtain a compound of formula (I) wherein R 1 , R 2 , R 3 , R 4 , W, X, Y 1 , Y 2 , Y 3 , Z 1 and Z 2 are as defined herein; M is a borate, boronic acid or alkyltin; X 1 is a halogen selected from Cl and Br

[0177] Method 3:

Chemical formula

[0178] As shown in Route 3, under alkaline conditions (not limited to, e.g., cesium carbonate), the compound represented by the molecular formula (1-1’) and the compound represented by the molecular formula (1-10) are subjected to a substitution reaction to obtain the compound represented by the molecular formula (1-8). The compound represented by the molecular formula (1-8) is subjected to a coupling reaction with the compound represented by the molecular formula (1-4) in the presence of a palladium reagent (not limited to, e.g., Pd(dppf)Cl 2 ), or a substitution reaction with the compound represented by the molecular formula (1-4’) in the presence of a palladium reagent (not limited to, e.g., Pd 2 (dba) 3In the presence of a transition metal catalyst (such as Pd(PPh₃)₄, etc.) and a ligand (such as BINAP, etc.), the compound represented by the molecular formula (1-4’) is subjected to a substitution reaction to obtain a compound represented by the molecular formula (1-6). The compound represented by the molecular formula (1-6) and the compound represented by the molecular formula (1-7) are subjected to a condensation reaction in the presence of a condensing agent (such as HATU, etc.) to obtain R 1 R 2 R 3 R 4 R, W, X, Y 1 Y 2 Y 3 Z 1 and Z 2 are as defined herein; M is borate, boronic acid or alkyltin; X 1 is a halogen selected from Cl and Br; X 2 is a halogen selected from F and Cl to obtain a compound of formula (I).

[0179] The substituents of the compound thus obtained can be further modified to obtain other desired compounds. Synthetic chemical transformations are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and their subsequent editions.

[0180] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods before use.

[0181] Pharmaceutical composition and utility The compounds of formula (I) described herein (e.g., any of the compounds of the examples described herein) and / or their pharmaceutically acceptable salts are used, alone or in combination with one or more additional active ingredients, for formulating pharmaceutical compositions. The pharmaceutical compositions comprise: (a) an effective amount of a compound of formula (I) described herein and / or its pharmaceutically acceptable salt, and optionally additional active ingredients; and (b) a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0182] A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredients of the composition (and in some embodiments can stabilize the active ingredients) and is not harmful to the subject to be treated. For example, solubilizing agents such as cyclodextrin (which forms a specific and more soluble complex with the compound of formula (I) described herein and / or its pharmaceutically acceptable salt) can be utilized as pharmaceutical excipients for the delivery of the active ingredient. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&CYelloW #10. Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

[0183] Pharmaceutical compositions comprising a compound of formula (I) described herein (e.g., any of the compounds of the examples described herein) and / or its pharmaceutically acceptable salt can be administered by various known methods such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0184] The pharmaceutical compositions described herein can be prepared in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, reconstitutable powders, liquid formulations or suppositories. In some embodiments, pharmaceutical compositions comprising a compound of formula (I) and / or a pharmaceutically acceptable salt thereof are formulated for intravenous infusion, topical administration or oral administration.

[0185] Oral compositions can be in any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions and aqueous suspensions, dispersions and solutions. Carriers commonly used in tablets include lactose and corn starch. Lubricants such as magnesium stearate are also usually added to tablets. In the case of oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension or emulsion is administered orally, the active ingredient can be suspended or dissolved in an oil phase combined with an emulsifying or suspending agent. Optionally, certain sweetening, flavoring or coloring agents can be added.

[0186] In some embodiments, tablets can contain from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof. In some embodiments, capsules can contain from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg of the compound of formula (I) and / or a pharmaceutically acceptable salt thereof.

[0187] Sterile injectable compositions (e.g., aqueous suspensions or oily suspensions) can be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Sterile injectable intermediate media can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, e.g., a solution in 1,3 - butanediol. Pharmaceutically acceptable carriers and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Further, as a solvent or suspension medium, sterile fixed oils (e.g., synthetic monoglycerides or diglycerides) have been conventionally used. Fatty acids such as oleic acid and its glyceride derivatives, and natural pharmaceutically acceptable oils such as olive oil or castor oil can be used as injectable intermediate media, especially in polyoxyethylated forms. These oil solutions or suspensions can also contain diluents or dispersants of long-chain alcohols, or carboxymethyl cellulose or similar dispersants.

[0188] Inhalation compositions can be prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0189] Topical compositions can be formulated in the form of oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white soft paraffin), branched-chain fats and oils, animal fats, and high molecular weight alcohols (greater than C12). In some embodiments, the pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble. Optionally, emulsifying agents, stabilizers, wetting agents, and antioxidants, as well as agents imparting color or fragrance, can also be included. Further, transdermal penetration enhancers can be used in these topical formulations. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0190] The cream can be formulated from a mixture of mineral oil, self-emulsifying wax and water, and an active ingredient dissolved in a small amount of oil such as almond oil is mixed into this mixture. An example of such a cream contains, by weight, about 40 parts of water, about 20 parts of wax, about 40 parts of mineral oil and about 1 part of almond oil. The ointment can be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and cooling the mixture. An example of such an ointment contains about 30% by weight of almond oil and about 70% by weight of white soft paraffin.

[0191] Using appropriate in vitro assays, the utility of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts in the inhibition of CSF-1R activity can be evaluated. The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be further investigated for additional utility in the treatment of, for example, cancer, autoimmune diseases or inflammatory diseases by in vivo assays. For example, the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be administered to animals having cancer (e.g., mouse models) and their therapeutic effects can be evaluated. If the preclinical results are successful, the dosage range and route of administration for animals such as humans can be predicted.

[0192] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be shown to have sufficient preclinical utility worthy of clinical trials expected to demonstrate a beneficial therapeutic or prophylactic effect in subjects having cancer.

[0193] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell growth, a decrease in cell differentiation, an inappropriate ability to invade surrounding tissues, and / or an ability to establish new growth at ectopic sites. The term "cancer" includes, but is not limited to, solid tumors and hematological malignancies. The term "cancer" encompasses diseases of the skin, tissue, organ, bone, cartilage, blood, and blood vessels. The term "cancer" includes primary cancers and, further, metastatic cancers.

[0194] Non-limiting examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; colon cancer; breast cancer including metastatic breast cancer; prostate cancer including androgen-dependent and androgen-independent prostate cancer; testicular cancer; kidney cancer including, for example, metastatic renal cell carcinoma; urothelial cancer; liver cancer; hepatocellular carcinoma; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer including, for example, advanced epithelial cancer or primary peritoneal cancer; cervical cancer; endometrial cancer; gastrointestinal stromal tumor (GIST); gastric cancer; esophageal cancer; head and neck cancer including, for example, squamous cell carcinoma of the head and neck; skin cancer including, for example, melanoma and basal cell carcinoma; neuroendocrine cancer including metastatic neuroendocrine tumors; brain tumors including, for example, glioma, anaplastic oligodendroglioma, glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; sarcoma including, for example, Kaposi's sarcoma; adrenal cancer; mesothelioma; mesothelioma; choriocarcinoma; myosarcoma; connective tissue cancer; tenosynovial giant cell tumor; and thyroid cancer.

[0195] Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and blast phase CML (CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL); follicular lymphoma; mantle cell lymphoma (MCL); B-cell lymphoma; T-cell lymphoma; diffuse large B-cell lymphoma (DLBCL); multiple myeloma (MM); Waldenstrom macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEB-T); and myeloproliferative syndromes.

[0196] In some embodiments, solid tumors include ovarian cancer, lung cancer (including non-small cell lung cancer), glioblastoma (GBM), tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma cancer, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, and sarcoma.

[0197] In some embodiments, exemplary hematological malignancies include leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphoma, such as Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0198] The compounds of formula (I) and / or their pharmaceutically acceptable salts described herein can be used, for example, to achieve a beneficial therapeutic or prophylactic effect in a subject having cancer.

[0199] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be used, for example, to achieve beneficial therapeutic or prophylactic effects in a subject having an autoimmune disease or an inflammatory disease.

[0200] The term "autoimmune disease" refers to a disease or disorder that arises from, and / or against, an individual's own tissues or organs, and / or their co-segregation or expression, or a condition resulting therefrom. Examples of autoimmune diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), allergic rhinitis, lupus erythematosus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), collagen-induced arthritis, psoriasis, inflammatory bowel disease (including Crohn's disease), asthma, autoimmune nephritis, idiopathic thrombocytopenic purpura (ITP), and myeloproliferative diseases such as myelofibrosis and polycythemia vera / essential thrombocythemia (myelofibrosis after PV / ET).

[0201] The term "inflammatory disease" or "inflammatory disorder" refers to a pathological condition that causes inflammation, particularly due to neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic and local inflammation, inflammation associated with immunosuppression, graft-versus-host reactions, allergic diseases, inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel disease (IBD such as Crohn's disease and ulcerative colitis); ischemia-reperfusion injury including surgical tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery and abnormal vasoconstrictive responses of coronary vessels after percutaneous transluminal coronary angioplasty, stroke and surgical tissue reperfusion injury of abdominal aortic aneurysm; cerebral edema following stroke; head trauma, and hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behçet's disease; dermatomyositis; polymyositis; multiple sclerosis (MS); dermatitis; meningitis; encephalitis; uveitis; osteoarthritis; lupus nephritis; autoimmune diseases such as rheumatoid arthritis (RA), Sjogren's syndrome and vasculitis; diseases associated with leukapheresis; central nervous system (CNS) inflammatory diseases and multiple organ injury syndromes secondary to sepsis or trauma; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases including glomerulonephritis; anemia; sarcoidosis; immunopathological reactions to tissue / organ transplantation; and lung inflammations including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonia, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, etc. Without limitation, symptoms include preferably chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other joint diseases, multiple sclerosis (MS), asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behçet's disease, psoriasis, chronic pulmonary inflammatory diseases, graft-versus-host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and fever, as well as any condition and related conditions associated with inflammation.

[0202] The term "metabolic disease" refers to a disease or disorder caused by metabolic problems, including metabolic disorders and hypermetabolism. Examples of metabolic diseases include, but are not limited to, osteoporosis, diabetes, diabetic ketoacidosis, hyperglycemia and hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency, etc.

[0203] The term "neurodegenerative disease" refers to a degenerative disease or disorder of the nervous system caused by neurodegeneration and apoptosis. Examples of neurodegenerative diseases include, but are not limited to, Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, motor neuron disease (amyotrophic lateral sclerosis (ALS)), hereditary motor and sensory neuropathy (CMT), etc.

[0204] The term "obesity-related disease" refers to a disease or disorder related to, caused by, or resulting from obesity. Examples of obesity-related diseases include diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular disease (including atherosclerosis, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease and angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, etc.

[0205] Furthermore, the compounds of formula (I) described herein (e.g., any of the compounds of the examples described herein) and / or their pharmaceutically acceptable salts can be administered in combination with additional therapeutic agents for treating cancer, autoimmune diseases or inflammatory diseases. The additional therapeutic agents can be administered separately from the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts, or can be included together with such components in a pharmaceutical composition of the present disclosure, such as a fixed-dose combination drug. In some embodiments, the additional therapeutic agents are known or found to be effective in the treatment of diseases mediated by CSF-1R, or at least in part by CSF-1R, such as another CSF-1R inhibitor or a compound active against other targets associated with a particular disease. This combination enhances efficacy (e.g., by including in the combination a compound that enhances the potency or effectiveness of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts), reduces one or more side effects, or decreases the required dosage of the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts.

[0206] In some embodiments, the compounds of formula (I) described herein (e.g., any of the compounds of the examples described herein) and / or their pharmaceutically acceptable salts can be administered in combination with an anti-tumor agent. As used herein, the term "anti-tumor agent" refers to any agent administered to a subject suffering from cancer for the purpose of treating cancer, and includes, but is not limited to, radiation therapy agents, chemotherapy agents, immune checkpoint inhibitors or agonists, targeted therapy agents, and the like.

[0207] In some embodiments, the compounds of formula (I) described herein (e.g., any of the compounds of the examples described herein) and / or their pharmaceutically acceptable salts can be administered in combination with an immune checkpoint inhibitor or agonist, a targeted therapy agent or a chemotherapy agent.

[0208] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, such as anti-PD-1 antibodies like pembrolizumab, nivolumab, and PDR001 (spartalizumab); PD-L1 inhibitors, such as anti-PD-L1 antibodies like atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies like ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, and the like.

[0209] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin, and their analogs or metabolites, as well as doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, idarubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin, etc.); DNA intercalators and free radical generators such as bleomycin; nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, docetaxel, and related analogs; vincristine, vinblastine, and related analogs; thalidomide and related analogs (e.g., CC-5013 and CC-4047, etc.).

[0210] Non-limiting examples of target therapeutic agents include protein tyrosine kinase inhibitors (such as imatinib mesylate and gefitinib); proteasome inhibitors (such as bortezomib); NF-κB inhibitors including IκB kinase inhibitors; IDO inhibitors; A2AR inhibitors; BRAF inhibitors (such as dabrafenib); MEK inhibitors (such as trametinib); mTOR inhibitors (such as rapamycin); anti-CD40 antibodies (such as APX005M, RO7009789, etc.); anti-CD20 antibodies (such as rituximab, ibritumomab, tiuxetan, tositumomab, etc.), anti-Her2 monoclonal antibodies (such as trastuzumab, etc.), anti-EGFR antibodies (such as cetuximab, etc.) and anti-VEGF antibodies (such as bevacizumab, etc.) which bind to proteins overexpressed in cancer and downregulate cell replication; anti-angiogenic drugs such as lenalidomide; and other proteins or enzymes known to be upregulated, overexpressed or activated in cancer, the inhibition of which downregulates cell replication.

Example

[0211] The following examples are for illustrative purposes only and should in no way be construed as limiting. Although efforts have been made to ensure the accuracy of the numerical values used (e.g., amounts, temperatures, etc.), one of ordinary skill in the art (POSITA) should understand that some experimental errors and deviations need to be taken into account. Unless otherwise indicated, parts are by weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. All MS data were determined by an Agilent 6120 or an Agilent 1100. All NMR data were generated using a Varian 400MHZ NMR instrument. All reagents used in the present invention, except for the intermediates, are commercially available. All compound names, except for the reagents, were generated by Chemdraw18.0.

[0212] When an atom with a vacant valence exists in any of the structures disclosed herein, the remaining vacant valences are hydrogen atoms that are omitted for convenience.

[0213] In this application, if there is a contradiction between the name and the structure of a compound and both are given for the compound, unless the context indicates that the structure of the compound is incorrect and the name is correct, it shall follow the structure of the compound.

[0214] In the following examples, abbreviations are used. [Table 2]

[0215] Example 1 Preparation of intermediates Intermediate 1 5-Chloro-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid [Chemical Formula]

[0216] (A) Isopropyl 5-chloro-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate Under nitrogen, 5-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 1.15 mmol), 2-iodopropane (784 mg, 4.61 mmol), potassium carbonate (637 mg, 4.61 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at 80 °C for 5 hours. The reaction solution was concentrated, water (10 ml) was added to the residue and dissolved, adjusted to pH 2 with 1N HCl solution, then extracted with dichloromethane (50 ml × 3), the organic layers were combined and concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 110 mg of the title product as a white solid. MS (m / z): 258.1 [M+H] +

[0217] (B) 5-Chloro-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid Isopropyl 5-chloro-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylate (110 mg, 0.43 mmol), lithium hydroxide monohydrate (36 mg, 0.86 mmol), methanol (3 ml) and water (1 ml) were added to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, water (2 ml) was added to the residue and dissolved (adjusted to pH 4 with 1N HCl solution), and the precipitated solid was filtered, washed and dried to obtain 74 mg of the title product as a white solid. MS (m / z): 216.0 [M+H] +

[0218] Intermediate 2 4-Methyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid

Chemical formula

[0219] (A) Methyl 4-methyl-3-oxo-3,4-dihydropyrazine-2-carboxylate Under nitrogen, methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (250 mg, 1.6 mmol), iodomethane (461 mg, 2.4 mmol), potassium carbonate (448 mg, 3.2 mmol) and DMF (5 ml) were sequentially added to a reaction flask and reacted at 50 °C for 4 hours. The reaction solution was concentrated, water (10 ml) was added to the residue and dissolved (adjusted to pH 4 with 1N HCl solution), then extracted with dichloromethane (50 ml × 3), the organic layers were combined and concentrated, and the obtained crude product was used as it was in the next step.

[0220] (B) 4-Methyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid Methyl 4-methyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (155 mg, 0.92 mmol), lithium hydroxide monohydrate (77 mg, 1.84 mmol), methanol (4 ml) and water (1 ml) were added to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution (adjusted to pH 4 with 1N HCl solution) was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 83 mg of the title product as a white solid. MS (m / z): 155.1 [M+H] +

[0221] Intermediate 3 4-Isopropyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid [Chemical formula] (A) Methyl 4-isopropyl-3-oxo-3,4-dihydropyrazine-2-carboxylate Under nitrogen, methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (500 mg, 3.25 mmol), 2-iodopropane (827 mg, 4.87 mmol), potassium carbonate (1.4 g, 9.75 mmol) and DMF (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 50 °C for 4 hours. The reaction solution was concentrated, water (50 ml) was added to the residue and dissolved (adjusted to pH 3 with 1N HCl solution), then extracted with dichloromethane (50 ml × 3), the organic layers were combined and concentrated, and the residue was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 10:1, gradient elution) to obtain 263 mg of the title product as a colorless liquid. MS (m / z): 197.1 [M+H] +

[0222] (B) 4-Isopropyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid Methyl 4-isopropyl-3-oxo-3,4-dihydropyrazine-2-carboxylate (263 mg, 1.34 mmol), lithium hydroxide monohydrate (113 mg, 2.68 mmol), methanol (3 ml) and water (1 ml) were added to a reaction flask, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, water (5 ml) was added to the residue and dissolved (adjusted to pH 4 with 1N HCl solution), and the precipitated solid was filtered, washed and dried to obtain 200 mg of the title compound as a white solid. MS (m / z): 183.1 [M+H] +

[0223] Intermediate 4 2-Isopropyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

Chemical formula

[0224] (B) 2-Isopropyl-3-oxo-2,3-dihydropyridazine-4-carboxylic acid Isopropyl 2-isopropyl-3-oxo-2,3-dihydropyridazine-4-carboxylate (90 mg, 0.4 mmol), lithium hydroxide monohydrate (34 mg, 0.8 mmol), methanol (3 ml) and water (1 ml) were added to a reaction flask, and the mixture was reacted at room temperature for 1 hour. The reaction solution (adjusted to pH 4 with 1N HCl solution) was concentrated, and the obtained crude product was used as it was in the next step.

[0225] Intermediate 5 1-(Difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

Chem.

[0226] (B) 1-(Difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Methyl 1-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (146 mg, 0.72 mmol), lithium hydroxide monohydrate (60 mg, 1.44 mmol), methanol (2 ml) and water (0.5 ml) were added to a reaction flask and the mixture was reacted at room temperature for 30 minutes. The reaction solution (adjusted to pH 4 with 1N HCl solution) was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 84 mg of the title product as a white solid. MS (m / z): 190.1 [M+H] +

[0227] Intermediate 6 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid

Chem.

[0228] (A) Ethyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate 2-Aminopyridine (500 mg, 5.31 mmol) and diethyl 2-(ethoxymethylene)malonate (1.206 g, 5.58 mmol) were added to a reaction flask, and the mixture was heated to 130 °C and reacted for 40 minutes. Then acetic acid (25 ml) was added, and the reaction solution was further heated to reflux and reacted for 4 hours. The reaction solution was concentrated to obtain an oily substance, which was used directly in the next step without purification. MS (m / z): 219.0 [M+H] +

[0229] (B) 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid Ethyl 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1.16 g, 5.32 mmol), lithium hydroxide monohydrate (894 mg, 21.28 mmol), THF (20 ml), MeOH (8 ml) and water (8 ml) were added to a reaction flask, and the mixture was stirred at room temperature overnight (adjusted to pH 3.0 with 1N hydrochloric acid), a white solid was precipitated, filtered, and the solid was dried to obtain 828 mg of the title product. MS (m / z): 191.0 [M+H] +

[0230] Intermediate 7 5-Oxo-1,2,3,5-tetrahydroindolizine-6-carboxylic acid

Chemical formula

[0231] (B) 2-(3-((tert-Butyldimethylsilyl)oxy)propyl)-6-methoxypyridine 2-Bromo-6-methoxypyridine (4.83 g, 25.67 mmol) and dry THF (100 ml) were added to a reaction flask, the reaction solution was cooled to -78 °C, and 2.4 N n-BuLi (11.77 ml, 28.24 mmol) was added dropwise under nitrogen. The reaction was carried out for 30 minutes, then (3-bromopropoxy)(tert-butyl)dimethylsilane (6.5 g, 25.67 mmol) was slowly added dropwise, and the reaction was continued at -78 °C for 1 hour. Then the temperature was raised to room temperature and the reaction was carried out overnight. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a yellow oil. MS (m / z): 282.2 [M+H] +

[0232] (C) 3-(6-Methoxypyridin-2-yl)propan-1-ol The oil obtained in the above step (B) was dissolved in THF (80 ml), TBAF trihydrate (16.1 g, 51.34 mmol) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with water. The organic phase was dried and concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 1.2 g of the title product as a colorless liquid.

[0233] (D) 3-(6-Methoxypyridin-2-yl)propyl methanesulfonate 3-(6-Methoxypyridin-2-yl)propan-1-ol (1.0 g, 5.98 mmol), TEA (1.66 ml, 11.96 mmol) and DCM (50 ml) were added to a reaction flask, the reaction solution was cooled in an ice bath, and then MsCl (822 mg, 7.18 mmol) was added dropwise. The reaction was carried out for 30 minutes, washed with water, and the organic phase was dried and concentrated to obtain a colorless liquid. MS (m / z): 246.1 [M+H] +

[0234] (E) 2,3-Dihydroindolizin-5(1H)-one The crude product of 3-(6-methoxypyridin-2-yl)propyl methanesulfonate obtained in the above step (D) and acetonitrile (25 ml) were added to a reaction flask, and the reaction mixture was reacted under microwave at 125 °C for 15 minutes, then concentrated, and the residue was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 400 mg of the title product as a pale yellow oil. MS (m / z): 136.1 [M+H] +

[0235] (F)6-Bromo-2,3-dihydroindolizin-5(1H)-one 2,3-Dihydroindolizin-5(1H)-one (300 mg, 2.22 mmol), DMF (5.0 ml) and NBS (435 mg, 2.44 mmol) were added to a reaction flask, and the mixture was stirred overnight at room temperature. The reaction solution was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 120 mg of the pale yellow title product. MS (m / z): 214.0, 216.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J = 7.4 Hz, 1H), 6.12 (dt, J = 7.4, 1.2 Hz, 1H), 4.06 - 3.93 (m, 3H), 3.09 - 2.97 (m, 3H), 2.18 - 2.01 (m, 3H)

[0236] (G)5-Oxo-1,2,3,5-tetrahydroindolizine-6-carbonitrile 6-Bromo-2,3-dihydroindolizin-5(1H)-one (120 mg, 0.56 mmol), zinc cyanide (43 mg, 0.365 mmol), Pd(PPH 3 )4 (65 mg, 0.0561 mmol) and DMF (5.0 ml) were added to a reaction flask, and the mixture was heated to 100 °C with stirring overnight under nitrogen. The reaction solution was purified by flash column chromatography (H 2Purified by O / MeOH = 100:0 to 0:100, gradient elution) to obtain 60 mg of the white title product. MS (m / z): 161.1 [M+H] +

[0237] (H)5-Oxo-1,2,3,5-tetrahydroindolizine-6-carboxylic acid 5-Oxo-1,2,3,5-tetrahydroindolizine-6-carbonitrile (60 mg, 0.375 mmol) and an aqueous sodium hydroxide solution with a concentration of 2N (1.0 ml, 2.0 mmol) were added to a reaction flask. The mixture was heated to 100 °C, stirred overnight, then cooled to room temperature (adjusted to pH 3 with 1N hydrochloric acid), and filtered to obtain 60 mg of the white title product. MS (m / z): 180.1 [M+H] +

[0238] Intermediate 8 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

Chemical formula

[0239] (A)Methyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate In a reaction flask, uracil-5-carboxylic acid (1 g, 6.4 mmol) was dissolved in DMF (15 ml), and Cs 2 CO 3 (12.5 g, 38.4 mmol) and CH 3 I (4.6 g, 32 mmol) were sequentially added, and the reaction solution was reacted at 60 °C for 16 hours. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction product was concentrated to obtain 0.8 g of a khaki solid. MS (m / z): 199 [M+H] +

[0240] (B)1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid In a reaction flask, methyl 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (500 mg, 2.5 mmol) was dissolved in methanol (6 ml) and water (1.5 ml), NaOH (200 mg, 5 mmol) was added, and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was rotated to remove methanol, neutralized to pH = 3 with 1N hydrochloric acid, and the solid was precipitated, filtered, and dried to obtain 300 mg of a white solid. MS (m / z): 185 [M+H] +

[0241] Intermediate 9 1-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [Chemical formula]

[0242] (A)Diethyl 2-(2-nitrobenzylidene)malonate Under nitrogen, 2-nitrobenzaldehyde (2.0 g, 13.2 mmol), diethyl malonate (2.0 ml, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and acetic anhydride (5 ml) were sequentially added to a reaction flask, the mixture was heated to 80 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, then poured into ice water (100 ml) and extracted with ethyl acetate (100 ml). The organic phase was washed with saturated sodium bicarbonate (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 3.2 g of the title product as a pale yellow solid. MS (m / z): 294.1 [M+H] +

[0243] (B)Ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate Diethyl 2-(2-nitrobenzylidene)malonate (3.2 g, 10.9 mmol), ethanol (50 ml), and Raney-Ni (1.0 g) were sequentially added to a reaction flask. After replacing hydrogen with a hydrogen balloon, the reaction solution was stirred at room temperature overnight under normal pressure. Dichloromethane (30 ml) and methanol (30 ml) were added, and then the reaction solution was filtered. The filtrate was concentrated to obtain 2.87 g of the title product as a brown solid. MS (m / z): 218.1 [M+H] +

[0244] (C)1-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid Ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate (500 mg, 2.3 mmol), iodomethane (430 μl, 6.9 mmol), potassium carbonate (636 mg, 4.6 mmol), and DMF (5 ml) were sequentially added to a reaction flask. The mixture was stirred at room temperature overnight. An aqueous sodium hydroxide solution (2N, 4 ml) was added dropwise, and the reaction solution was stirred at room temperature for 4 hours. Water (100 ml) was added, and the pH was adjusted to 4 with concentrated hydrochloric acid. The reaction solution was filtered, and the solid was washed with water and dried to obtain 350 mg of the title product as a white solid. MS (m / z): 204.1 [M+H] +

[0245] Intermediate 10 5-Fluoro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

Chemical Structure

[0246] (A)Methyl 5-fluoro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate Under nitrogen, 5-fluoro-2-hydroxynicotinic acid (720 mg, 4.6 mmol), iodomethane (860 μl, 13.8 mmol), potassium carbonate (2.74 g, 19.8 mmol) and DMF (10 ml) were sequentially added to a reaction flask, and the mixture was heated to 50 °C and stirred overnight. The reaction solution was cooled to room temperature and purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 750 mg of the title product as a pale yellow solid. MS (m / z): 186.1 [M+H] +

[0247] (B)5-Fluoro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid Methyl 5-fluoro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (750 mg, 4.05 mmol), lithium hydroxide monohydrate (340 mg, 9.1 mmol) and methanol / water (15 ml / 5 ml) were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, then water (40 ml) (adjusted to pH 4 with aqueous hydrochloric acid (2N)) was added and filtered. The solid was dried to obtain 600 mg of the white title product. MS (m / z): 172.0 [M+H] +

[0248] Intermediate 11 2-Isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid

Chemical Structure

[0249] (A)Methyl 2-isopropyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate Under nitrogen, isopropamidine hydrochloride (1.23 g, 10 mmol), anhydrous methanol (20 ml) and sodium methoxide (504 mg, 10 mmol) were sequentially added to a reaction flask. The mixture was stirred for 30 minutes, then dimethyl 2-(methoxymethylene)malonate (1.74 g, 10 mmol) and sodium methoxide (504 mg, 10 mmol) were sequentially added under an ice bath. The reaction solution was slowly warmed to room temperature and then stirred overnight. The reaction solution was concentrated, and the sample was stirred with silica gel and then purified by flash column chromatography (dichloromethane:methanol = 100:0 to 90:10, gradient elution) to obtain 700 mg of the title product as a pale yellow solid. MS (m / z): 197.1 [M+H] +

[0250] (B)Methyl 2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate Under nitrogen, methyl 2-isopropyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (700 mg, 3.6 mmol), iodomethane (436 μl, 7 mmol), cesium carbonate (2.28 g, 7 mmol) and DMF (10 ml) were sequentially added to a reaction flask. The mixture was heated to 80 °C and stirred overnight. The reaction solution was cooled to room temperature and purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0 to 0:100, gradient elution) to obtain 250 mg of the title product as a white solid. MS (m / z): 211.1 [M+H] +

[0251] (C)2-Isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid Methyl 2-isopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (250 mg, 1.2 mmol), sodium hydroxide (96 mg, 2 mmol) and methanol / water (10 ml / 2 ml) were sequentially added to a reaction flask and stirred at room temperature for 2 hours. The pH was adjusted to 4 with 2N hydrochloric acid aqueous solution, and the reaction solution was concentrated. The residue was purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0 to 0:100, gradient elution) to obtain 180 mg of the white title product. MS (m / z): 197.1 [M+H]+

[0252] Intermediate 12 2-Cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid

Chem.

[0253] (A)Methyl 2-cyclopropyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate The title compound was prepared using cyclopropamidine hydrochloride and the corresponding reagents with reference to the preparation process of Intermediate 11(A). MS (m / z): 195.1 [M+H] +

[0254] (B)Methyl 2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 11(B). MS (m / z): 209.1 [M+H] +

[0255] (C)2-Cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid Methyl 2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (750 mg, 3.6 mmol), sodium hydroxide (288 mg, 7.2 mmol) and methanol / water (20 ml / 4 ml) were sequentially added to a reaction flask and stirred at room temperature for 2 hours. After concentrating the reaction solution, water (40 ml) (adjusted to pH 4 with aqueous hydrochloric acid solution (2N)) was added and filtered. The solid was dried to obtain 450 mg of the yellow title product. MS (m / z): 195.1 [M+H] +

[0256] Intermediate 13 5-Fluoro-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

Chem.

[0257] (A)5-Fluoro-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 1,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (500 mg, 3.38 mmol), the fluorine reagent Selectfluor (1.19 g, 3.38 mmol), and acetonitrile (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at room temperature for 15 hours under nitrogen. The reaction solution was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 133 mg of the title product as a white solid. MS (m / z): 166.7 [M+H] +

[0258] (B) 5-Fluoro-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-Fluoro-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (133 g, 0.80 mmol) and concentrated hydrochloric acid (2 ml) were sequentially added to a reaction flask, and the mixture was refluxed and reacted for 3 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 60 mg of the title product as a white solid. MS (m / z): 186.0 [M+H] +

[0259] Intermediate 14 1-Methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid

Chemical formula

[0260] (A) Methyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate Dimethyl 2-(methoxymethylene)malonate (0.87 g, 5.0 mmol), formamidine (0.22 g, 5.0 mmol), sodium methoxide (0.27 g, 5.0 mmol), and anhydrous methanol (10 ml) were sequentially added to a reaction flask, and the mixture was refluxed and reacted for 7 hours under nitrogen. The reaction solution was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 0.51 g of the title product as a white solid. MS (m / z): 155.1 [M+H]+

[0261] (B) Methyl 1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate Methyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate (0.51 g, 3.31 mmol), iodomethane (0.94 g, 6.62 mmol), potassium carbonate (0.69 g, 4.97 mmol) and DMSO (10 ml) were successively added to a reaction flask and reacted at 50 °C for 1 hour. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 0.44 g of the title product as a yellow solid. MS (m / z): 169.1 [M+H] +

[0262] (C) 1-Methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid Methyl 1-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (0.44 g, 2.61 mmol), lithium hydroxide monohydrate (0.22 g, 5.22 mmol), methanol (10 ml) and water (2 ml) were added to a reaction flask and the mixture was reacted at 50 °C for 1 hour. The reaction solution (adjusted to pH 3 - 4) was extracted with ethyl acetate, concentrated to obtain a crude product, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 0.37 g of the title product as a white solid. MS (m / z): 155.1 [M+H] +

[0263] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 14 under appropriate conditions recognized by a POSITA. [Table 3]

[0264] Intermediate 17 (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid [Chemical formula]

[0265] (A) 4,5-Dibromo-1H-1,2,3-triazole 1H-1,2,3-triazole (10.0 g, 145 mmol) and water (150 ml) were added to a reaction flask, the reaction solution was cooled in an ice bath, then liquid bromine (10 ml) was added dropwise. After the addition was complete, the reaction solution was warmed to room temperature and stirred overnight. The reaction mixture was filtered, the obtained solid was washed with water and dried to obtain 18.9 g of the title product.

[0266] (B) 4,5-Dibromo-2-methyl-2H-1,2,3-triazole 4,5-Dibromo-1H-1,2,3-triazole (18.9 g, 83.3 mmol), K 2 CO 3 (23.04 g, 166.7 mmol) and DMF (150 ml) were added to a reaction flask, the mixture was cooled to -10 °C, then iodomethane (23.67 g, 166.7 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred overnight. 500 ml of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 9.2 g of the product 4,5-dibromo-2-methyl-2H-1,2,3-triazole as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.16 (s, 3H). And isomer 4,5-dibromo-1-methyl-1H-1,2,3-triazole 4.66 g. MS (m / z): 239.9, 241.9, 243.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 4.06 (s, 3H)

[0267] (C) 4-Bromo-2-methyl-2H-1,2,3-triazole 4,5-Dibromo-2-methyl-2H-1,2,3-triazole (9.2 g, 38.19 mmol) and THF (150 ml) were added to a reaction flask. The reaction solution was cooled to -78 °C, and then 2.5 N n-butyllithium (19.0 ml, 45.83 mmol) was slowly added dropwise. After the addition was complete, the reaction solution was continuously stirred for 1 hour, 50 ml of water was added to quench it, and it was extracted 3 times with ethyl acetate. The organic phase was washed 3 times with saturated brine, dried and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 2.5 g of the liquid title product. MS (m / z): 162.0, 164.0 [M+H] +

[0268] (D) (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid 4-Bromo-2-methyl-2H-1,2,3-triazole (2.5 g, 15.43 mmol) and THF (50 ml) were added to a reaction flask. Under nitrogen, 1.3 N isopropylmagnesium chloride lithium chloride (14.2 ml, 18.52 mmol) was added dropwise. After the addition was complete, the reaction solution was continuously stirred for 2 hours, then the reaction solution was cooled to -20 °C, trimethyl borate was added, and it was continuously stirred for 1.5 hours. The temperature was raised to room temperature, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried and concentrated to obtain 1.02 g of the title product as a white solid. MS (m / z): 128.1 [M+H] +

[0269] Intermediate 18 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical Structure

[0270] (A) 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine 2-Chloro-4-hydroxypyridine (12.9 g, 0.1 mol), 5-fluoro-2-nitropyridine (14.2 g, 0.1 mol) and potassium carbonate (27.6 g, 0.2 mol) were dissolved in DMSO (130 ml), and the mixture was heated at 80 °C for 2 days. The reaction mixture was cooled to room temperature and diluted with water (100 ml) and ethyl acetate (200 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated to obtain the crude product, which was purified by flash column chromatography (elution with petroleum ether / ethyl acetate = 1:1) to give 10.8 g of the title product. MS (m / z): 251.9 [M+H] +

[0271] (B) 2-(1-Methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (10.8 g, 42.9 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.7 g, 52.0 mmol), Pd(dppf)Cl 2 (3.14 g, 4.3 mmol) and K 2 CO 3 (11.9 g, 86.0 mmol) were dissolved in a mixture of 1,4-dioxane (110 ml) and water (11 ml), and the mixture was heated to 80 °C under nitrogen and stirred for 5 hours. The reaction mixture was cooled to room temperature, quenched with water, concentrated to obtain the crude product, which was purified by flash column chromatography (gradient elution with petroleum ether / ethyl acetate = 100:0 to 0:100 and dichloromethane / methanol = 100:0 to 90:10) to give 8.2 g of the title product. MS (m / z): 298.0 [M+H] +

[0272] (C) 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine 2-(1-Methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (4.8 g, 16.1 mmol) and palladium carbon (1.0 g) were dissolved in methanol (50 ml), and the reaction solution was stirred at room temperature for 15 hours under hydrogen. The reaction product was filtered to remove palladium carbon, and the liquid was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 3.6 g of the title product. MS (m / z): 268.0 [M+H] +

[0273] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 18 under appropriate conditions recognized by a POSITA. [Table 4]

[0274] Intermediate 24 5-((2-(2-Methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine [Chemical formula]

[0275] (A) 2-Methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (200 mg, 0.79 mmol), 2-methyl-5-(tributylstannyl)thiazole (339 mg, 0.87 mmol), Pd(PPH 3 ) 4 (46 mg, 0.04 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C overnight. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 120 mg of the solid title product. MS (m / z): 315.1 [M+H] +

[0276] (B) 5-((2-(2-Methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine Under nitrogen, 2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (120 mg, 0.38 mmol), ammonium chloride (102 mg, 1.91 mmol), iron powder (85 mg, 1.52 mmol), ethanol (20 ml) and water (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at 90 °C for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 88 mg of the solid title product. MS (m / z): 285.1 [M+H] +

[0277] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 24 under appropriate conditions recognized by a POSITA.

Table 5

[0278] Intermediate 26 4-((6-Aminopyridin-3-yl)oxy)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

Chemical formula

[0279] (A) N-(1-Methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridin-2-amine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (150 mg, 0.6 mmol), 1-methyl-1H-pyrazol-4-amine hydrochloride (96 mg, 0.72 mmol), p-toluenesulfonic acid monohydrate (103 mg, 0.6 mmol) and isopropyl alcohol (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at 150 °C for 16 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 90 mg of the title product as a brown solid. MS (m / z): 313.1 [M+H] +

[0280] (B) 4-((6-Aminopyridin-3-yl)oxy)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 283.1 [M+H] +

[0281] Intermediate 27 4-((6-Aminopyridin-3-yl)oxy)-N-(pyridin-2-yl)pyridin-2-amine [Chemical formula]

[0282] (A) 4-((6-Nitropyridin-3-yl)oxy)-N-(pyridin-2-yl)pyridin-2-amine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.2 mmol), 2-aminopyridine (123 mg, 1.3 mmol), BINAP (150 mg, 0.24 mmol), Pd 2 (dba) 3 (69 mg, 0.12 mmol), cesium carbonate (782 mg, 2.4 mmol) and DMA (5 ml) were sequentially added to the reaction flask, and the mixture was reacted with microwave at 145 °C for 10 minutes. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 210 mg of the title product as a brown solid. MS (m / z): 310.1 [M+H] +

[0283] (B)4-((6-Aminopyridin-3-yl)oxy)-N-(pyridin-2-yl)pyridine-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 280.1 [M+H] +

[0284] Intermediate 28 5-((2-(Imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)oxy)pyridine-2-amine [Chemical formula]

[0285] (A)4-((6-Nitropyridin-3-yl)oxy)-[2,4'-bipyridine]-2'-amine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.2 mmol), (2-aminopyridin-4-yl)boronic acid (197 mg, 1.4 mmol), Pd(dppf)Cl 2 (98 mg, 0.12 mmol), 2 M potassium carbonate solution (1.5 ml) and 1,4-dioxane (6 ml) were sequentially added to a reaction flask, and the mixture was reacted at 90 °C overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 187 mg of the title product as a yellow solid. MS (m / z): 310.1 [M+H] +

[0286] (B)7-(4-((6-Nitropyridin-3-yl)oxy)pyridin-2-yl)imidazo[1,2-a]pyridine Under nitrogen, 4-((6-nitropyridin-3-yl)oxy)-[2,4’-bipyridine]-2’-amine (187 mg, 0.61 mmol), 40% aqueous chloroacetaldehyde solution (1 ml), potassium carbonate (84 mg, 0.61 mmol) and ethanol (5 ml) were sequentially added to a reaction flask, and the mixture was refluxed overnight to react. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 130 mg of the title product as a yellow solid. MS (m / z): 334.0 [M+H] +

[0287] (C)5-((2-(Imidazo[1,2-a]pyridin-7-yl)pyridin-4-yl)oxy)pyridine-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 304.1 [M+H] +

[0288] Intermediate 29 4-((6-Aminopyridin-3-yl)oxy)-N-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridine-2-amine

Chemical Structure

[0289] (A)1-(Difluoromethyl)-3-nitro-1H-pyrazole Under nitrogen, 3-nitro-1H-pyrazole (5 g, 44.2 mmol), sodium 2-chloro-2,2-difluoroacetate (8.1 g, 53.0 mmol), potassium carbonate (9.2 g, 66.3 mmol), 18-crown-6 (2.3 g, 8.8 mmol) and acetonitrile (20 ml) were sequentially added to a reaction flask, and the mixture was refluxed and reacted overnight. The reaction solution was filtered, the filtrate was concentrated, water (200 ml) was added to the residue and dissolved, and the solution was extracted with ethyl acetate (100 ml × 3). The combined organic layers were concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 - 0:100, gradient elution) to obtain 5 g of the title product as a yellow oil. MS (m / z): 164.1 [M+H] +

[0290] (B)1-(Difluoromethyl)-1H-pyrazol-3-amine 1-(Difluoromethyl)-3-nitro-1H-pyrazole (5 g, 30.7 mmol), Pd / C (500 mg) and methanol (15 ml) were sequentially added to a reaction flask, and the mixture was reacted overnight at room temperature under hydrogen. The reaction solution was filtered, and the filtrate was concentrated to obtain 4 g of the crude product as a yellow oil. MS (m / z): 134.0 [M+H] +

[0291] (C)N-(1-(Difluoromethyl)-1H-pyrazol-3-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine-2-amine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (500 mg, 2.59 mmol), 1-(difluoromethyl)-1H-pyrazol-3-amine (345 mg, 1.3 mmol), XantPhos (231 mg, 0.40 mmol), Pd 2 (dba) 3(183 mg, 0.20 mmol), cesium carbonate (1.3 g, 3.88 mmol) and 1,4-dioxane (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 600 mg of the solid title product. MS (m / z): 349.0 [M+H] +

[0292] (D)4-((6-Aminopyridin-3-yl)oxy)-N-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyridine-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 319.0 [M+H] +

[0293] Intermediate 30 5-((2-(1-Methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridine-2-amine [Chemical formula]

[0294] (A)2-(1-Methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.19 mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (663 mg, 1.79 mmol), Pd(PPH 3 ) 4 (137 mg, 0.119 mmol) and DMF (5.0 ml) were added to a reaction flask. Under nitrogen, the mixture was heated to 100 °C, stirred for 3 hours, and after cooling, the reaction solution was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 220 mg of the title product as a white solid. MS (m / z): 298.1 [M+H] +

[0295] (B)5-((2-(1-Methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridine-2-amine 2-(1-Methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (220 mg, 0.74 mmol), Pd / C (30 mg) and methanol (15.0 ml) were added to a reaction flask, and the mixture was stirred overnight under a hydrogen pressure, filtered, and the filtrate was concentrated to obtain 152 mg of the title product as a yellow oil. MS (m / z): 268.1 [M+H] +

[0296] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 30 under appropriate conditions recognized by a POSITA.

Table 6

[0297] Intermediate 32 5-((2-(1H-1,2,4-Triazol-1-yl)pyridin-4-yl)oxy)pyridine-2-amine

Chemical formula

[0298] (A)4-((6-Nitropyridin-3-yl)oxy)-2-(1H-1,2,4-triazol-1-yl)pyridine 2-Chloropyridin-4-ol (500 mg, 3.86 mmol), 1H-1,2,4-triazole (400 mg, 5.79 mmol), Cs 2 CO 3 (4.71 mg, 14.48 mmol), CuI (73 mg, 0.386 mmol) and DMF (20.0 ml) were added to a sealed tube, and the mixture was heated to 130 °C under nitrogen and stirred for 2 days. After cooling, 5-fluoro-2-nitropyridine (1.1 g, 7.72 mmol) was added, and the reaction solution was heated to 100 °C and stirred overnight, filtered, and the filtrate was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 396 mg of the title product as a pale yellow solid. MS (m / z): 285.1 [M+H] +

[0299] (B)5-((2-(1H-1,2,4-triazol-1-yl)pyridin-4-yl)oxy)pyridine-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 255.1 [M+H] +

[0300] Intermediate 33 5-((2-(4-Methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridine-2-amine

Chemical formula

[0301] (A)2-(4-Methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (500 mg, 2.0 mmol), 4-methyl-1H-imidazole (490 mg, 5.97 mmol), Pd 2 (dba) 3 (36.5 mg, 0.04 mmol), Me 4 tBuXPhos (38 mg, 0.08 mmol), K 3 PO 4 (845 mg, 3.98 mmol), dioxane (4.0 ml) and toluene (20.0 ml) were added to a sealed tube, and the mixture was heated to 120 °C under nitrogen and stirred overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 280 mg of the title product as a pale yellow solid. MS (m / z): 298.1 [M+H] +

[0302] (B)5-((2-(4-Methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 268.1[M+H] +

[0303] Intermediate 34 5-([2,3'-Bipyridin]-4-yloxy)pyridin-2-amine

Chemical formula

[0304] (A)4-((6-Nitropyridin-3-yl)oxy)-2,3'-bipyridine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (500 mg, 0.2 mmol), pyridin-3-ylboronic acid (367 mg, 0.3 mmol), Na 2 CO 3 (640 mg, 6.0 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (163 mg, 0.02 mmol), dioxane (25.0 ml) and water (3.0 ml) were added to a reaction flask, the mixture was heated to 100 °C and stirred overnight, after cooling, the reaction solution was concentrated, and the residue was purified by flash column chromatography (H 2 O / MeOH = 100:0~0:100, gradient elution) to obtain 441 mg of the title product as a yellow solid. MS (m / z): 295.0 [M+H] +

[0305] (B)5-([2,3'-Bipyridin]-4-yloxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 265.1 [M+H] +

[0306] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 34 under appropriate conditions recognized by a POSITA.

Table 7

[0307] Intermediate 35 4-((6-Aminopyridin-3-yl)oxy)-N-(6-methylpyridin-2-yl)pyridin-2-amine

Chemical formula

[0308] (A)6-Methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyridin-2-amine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (500 mg, 2.0 mmol), 6-methylpyridin-2-amine (432 mg, 4.0 mmol), Pd 2 (dba) 3 (183 mg, 0.2 mmol), Xantphos (231 mg, 0.4 mmol), Cs 2 CO 3 (1.63 g, 5.0 mmol) and dioxane (50.0 ml) were added to a sealed tube. Under nitrogen, the mixture was heated to 100 °C and stirred for 4 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution) to obtain 550 mg of the product as a pale yellow solid. MS (m / z): 324.1 [M+H] +

[0309] (B)4-((6-Aminopyridin-3-yl)oxy)-N-(6-methylpyridin-2-yl)pyridin-2-amine The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 294.1 [M+H] +

[0310] Intermediate 36 5-((2-(1H-Pyrazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0311] (A)2-(1H-Pyrazol-1-yl)pyridin-4-ol 2-Chloro-4-hydroxypyridine (500 mg, 3.9 mmol), pyrazole (527 mg, 7.8 mmol), Cs 2 CO 3(2.5 g, 7.8 mmol), CuI (76 mg, 0.4 mmol) and DMF (10 ml) were sequentially added to a sealed tube and reacted at 130 °C for 12 h. The reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 - 50:50, gradient elution) to obtain 300 mg of the title product as a yellow solid. MS (m / z): 162 [M+H] +

[0312] (B)4-((6-Nitropyridin-3-yl)oxy)-2-(1H-pyrazol-1-yl)pyridine 2-(1H-Pyrazol-1-yl)pyridin-4-ol (250 mg, 1.6 mmol), 5-fluoro-2-nitropyridine (220 mg, 1.6 mmol), K 2 CO 3 (321 mg, 2.4 mmol) and DMF (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C for 12 h. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction product was concentrated to obtain 250 mg of a pale yellow solid. MS (m / z): 284 [M+H] +

[0313] (C)5-((2-(1H-Pyrazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagent with reference to the preparation process of Intermediate 24(B). MS (m / z): 254 [M+H] +

[0314] Intermediate 37 5-((2-(1-Ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0315] (A)2-(1-Ethyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.2 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (398 mg, 1.8 mmol), Pd(PPH 3 ) 4 (138 mg, 0.12 mmol), Cs 2 CO 3 (779 mg, 2.4 mmol), dioxane (8 ml) and water (2 ml) were successively added to the reaction flask, and the mixture was reacted at 100 °C for 3 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 50:50, gradient elution) to obtain 300 mg of the title product as a yellow solid. MS (m / z): 312 [M+H] +

[0316] (B)5-((2-(1-Ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 282 [M+H] +

[0317] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 37 under appropriate conditions recognized by a POSITA.

Table 8

[0318] Intermediate 39 5-([2,4'-Bipyridin]-4-yloxy)pyridin-2-amine

Chemical formula

[0319] (A)4-((6-Nitropyridin-3-yl)oxy)-2,4'-bipyridine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.2 mmol), 4-pyridineboronic acid (220 mg, 1.8 mmol), Pd(PPH 3 ) 4 (138 mg, 0.12 mmol), Cs 2 CO 3 (779 mg, 2.4 mmol), dioxane (8 ml) and water (2 ml) were successively added to a reaction flask, and the mixture was reacted at 100 °C for 3 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 300 mg of the title product as a yellow solid. MS (m / z): 295 [M+H] +

[0320] (B)5-([2,4'-Bipyridin]-4-yloxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 265 [M+H] +

[0321] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 39 under appropriate conditions recognized by a POSITA.

Table 9

[0322] Intermediate 42 4-((6-Aminopyridin-3-yl)oxy)-N-(1-methyl-1H-pyrazol-3-yl)pyridin-2-amine

Chemical formula

[0323] (A)N-(1-Methyl-1H-pyrazol-3-yl)-4-((6-nitropyridin-3-yl)oxy)pyridin-2-amine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (400 mg, 1.6 mmol), 1-methyl-1H-pyrazol-3-amine (309 mg, 3.2 mmol), Pd 2 (dba)3 (145 mg, 0.16 mmol), Xantphos (184 mg, 0.32 mmol), Cs 2 CO 3 (779 mg, 2.4 mmol) and dioxane (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C for 16 hours. The reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 200 mg of the title product as a yellow solid. MS (m / z): 313 [M+H] +

[0324] (B)4-((6-Aminopyridin-3-yl)oxy)-N-(1-methyl-1H-pyrazol-3-yl)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24 (B). MS (m / z): 283 [M+H] +

[0325] The following intermediates were prepared using the corresponding intermediates and reagents with reference to the preparation process of Intermediate 42 under appropriate conditions recognized by a POSITA.

Table 10

[0326] Intermediate 45 5-((2-(1-(Difluoromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0327] (A) 1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.1 mmol), sodium 2-chloro-2,2-difluoroacetate (0.94 g, 6.2 mmol), 18-crown-6 (0.27 g, 1.02 mmol) and acetonitrile (20 ml) were sequentially added to a reaction flask, and the mixture was reacted at 85 °C for 20 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction product was concentrated to obtain 900 mg of a crude product, which was used as such in the next step. MS (m / z): 245 [M+H] +

[0328] (B) 2-(1-(Difluoromethyl)-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 37(A). MS (m / z): 334 [M+H] +

[0329] (C) 5-((2-(1-(Difluoromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 304 [M+H] +

[0330] Intermediate 46 2-Chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline

Chemical Structure

[0331] (A) 2-Chloro-4-(3-chloro-4-nitrophenoxy)pyridine 2-Chloro-4-hydroxypyridine (294 mg, 2.28 mmol), 2-chloro-4-fluoro-1-nitrobenzene (400 mg, 2.28 mmol), K 2 CO 3(473 mg, 3.42 mmol) and DMF (8 ml) were sequentially added to a reaction flask, and the mixture was reacted at 80 °C for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction product was concentrated to obtain 500 mg of the title product as a yellow solid. MS (m / z): 285 [M+H] +

[0332] (B) 4-(3-chloro-4-nitrophenoxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 37(A). MS (m / z): 331 [M+H] +

[0333] (C) 2-Chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 301 [M+H] +

[0334] Intermediate 47 5-((2-(1-(2-(Dimethylamino)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0335] (A) 4-((6-nitropyridin-3-yl)oxy)-2-(1H-pyrazol-4-yl)pyridine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (1.0 g, 4.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.55 g, 8.0 mmol), Pd(dppf)Cl 2 (0.29 g, 0.4 mmol) and K 2 CO 3(0.83 g, 6.0 mmol) was dissolved in a mixture of 1,4-dioxane (16 ml) and water (4 ml), and the mixture was heated to 80 °C under nitrogen and reacted overnight. The reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 90:10, gradient elution) to obtain 0.57 g of the title product. MS (m / z): 284.1 [M+H] +

[0336] (B) N,N-Dimethyl-2-(4-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine 4-((6-Nitropyridin-3-yl)oxy)-2-(1H-pyrazol-4-yl)pyridine (100 mg, 0.35 mmol), 2-chloro-N,N-dimethylethyl-1-amine (72 mg, 0.70 mmol) and cesium carbonate (170 mg, 0.52 mmol) were dissolved in acetonitrile (10 ml), and the mixture was stirred at 80 °C for 5 hours. The reaction product was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 88 mg of the title product. MS (m / z): 355.1 [M+H] +

[0337] (C) 5-((2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine N,N-Dimethyl-2-(4-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethan-1-amine (88 mg, 0.25 mmol) and palladium on carbon (10 mg) were dissolved in methanol (10 ml), and the mixture was stirred at room temperature for 5 hours under hydrogen. The reaction solution was filtered to remove palladium on carbon, and the liquid was concentrated to obtain 67 mg of the crude product of the title compound. MS (m / z): 325.2[M+H] +

[0338] Intermediate 48 5-((2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical Structure

[0339] (A) 4-((6-aminopyridin-3-yl)oxy)picolinitrile 4-Chloropyridinecarbonitrile (1.38 g, 10.0 mmol), 6-aminopyridin-3-ol (1.1 g, 10.0 mmol), potassium t-butoxide (1.12 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) were dissolved in DMSO (20 ml), and the mixture was stirred at 80 °C for 15 h. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, concentrated to obtain a crude product, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 1.12 g of the title product. MS (m / z): 213.0 [M+H] +

[0340] (B) 4-((6-aminopyridin-3-yl)oxy)-N’-methylpicolinimidohydrazide 4-((6-Aminopyridin-3-yl)oxy)picolinitrile (1.12 g, 5.28 mmol) and methylhydrazine (1.21 g, 26.4 mmol) were dissolved in ethanol (20 ml), and the mixture was reacted at room temperature for 15 h. The reaction solution was concentrated to obtain a crude product, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 430 mg of the title product. MS (m / z): 259.1 [M+H] +

[0341] (C) 5-((2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)pyridin-2-amine 4-((6-Aminopyridin-3-yl)oxy)-N'-methylpicolinimidohydrazide (258 mg, 1.0 mmol) was dissolved in formic acid (5 ml), and refluxed for 4 h. The reaction solution was concentrated to obtain a crude product, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 88 mg of the title product. MS (m / z): 269.1 [M+H] +

[0342] Intermediate 49 N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-5-methylthiazol-2-amine

Chemical Structure

[0343] (A) 5-Methyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole-2-amine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (300 mg, 1.20 mmol), 5-methylthiazol-2-amine (200 mg, 1.80 mmol), Pd 2 (dba) 3 (100 mg, 0.12 mmol), Xantphos (60 mg, 0.12 mmol) and potassium carbonate (331 mg, 2.40 mmol) were dissolved in dioxane (15 ml), and the mixture was stirred at 90 °C for 6 hours to react. The reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 90:10, gradient elution) to obtain 370 mg of the title product. MS (m / z): 330.1 [M+H] +

[0344] (B) N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-5-methylthiazole-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 300.0 [M+H] +

[0345] Intermediate 50 3-Fluoro-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical Structure

[0346] (A) 5-((2-Chloropyridin-4-yl)oxy)-3-fluoropyridin-2-amine 6-Amino-5-fluoropyridin-3-ol (1.70 g, 13.3 mmol), 2-chloro-4-fluoropyridine (1.74 g, 13.3 mmol) and cesium carbonate (6.50 g, 20.0 mmol) were dissolved in DMSO (50 ml), and the mixture was stirred at 90 °C for 2 hours to react. The reaction product was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 1.41 g of the title product. MS (m / z): 240.1 [M+H] +

[0347] (B) 3-Fluoro-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 30(A). MS (m / z): 286.0 [M+H] +

[0348] Intermediate 51 3-Fluoro-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0349] The title compound was prepared using 5-((2-chloropyridin-4-yl)oxy)-3-fluoropyridin-2-amine and the corresponding reagents with reference to the preparation process of Intermediate 18(B). MS (m / z): 286.0 [M+H] +

[0350] Intermediate 52 2-Amino-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)nicotinonitrile

Chemical formula

[0351] (A) 2-Amino-5-((2-chloropyridin-4-yl)oxy)nicotinonitrile The title compound was prepared using 6-amino-5-cyanopyridin-3-ol and the corresponding reagents with reference to the preparation process of Intermediate 50(A). MS (m / z): 247.1 [M+H]+

[0352] (B) 2-Amino-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)nicotinonitrile 2-Amino-5-((2-chloropyridin-4-yl)oxy)nicotinonitrile (150 mg, 0.61 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (253 mg, 1.22 mmol), Pd(dppf)Cl 2 (43 mg, 0.06 mmol) and sodium carbonate (95 mg, 0.92 mmol) were dissolved in dioxane (5 ml) and water (1 ml), and the mixture was reacted at 80 °C for 5 hours under nitrogen. The reaction product was concentrated to obtain a crude product, which was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 93 mg of the title product. MS (m / z): 293.0 [M+H] +

[0353] Intermediate 53 5-((2-(2-Methylthiazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine

Chemical formula

[0354] (A) 2-(1-Ethoxyvinyl)-4-((6-nitropyridin-3-yl)oxy)pyridine Under nitrogen, 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (252 mg, 1.0 mmol), tributyl(1-ethoxyvinyl)stannane (722 mg, 2.0 mmol) and Pd(PPH 3 ) 4 (58 mg, 0.05 mmol) were dissolved in 10 ml of DMF, and the reaction solution was heated at 100 °C for 15 hours. The reaction solution was cooled to room temperature, 20 ml of water and 50 ml of ethyl acetate were added. The reaction solution was extracted and concentrated, and the crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain the title product (162 mg) as a yellow solid. MS (m / z): 288.0 [M+H] +

[0355] (B) 2-Bromo-1-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)ethan-1-one In a reaction flask, 2-(1-ethoxyvinyl)-4-((6-nitropyridin-3-yl)oxy)pyridine (162 mg, 0.564 mmol) and NBS (100 mg, 0.564 mmol) were dissolved in a mixed solvent of tetrahydrofuran (10 ml) and water (1 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, and then the crude product was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (136 mg) as a yellow solid. MS (m / z): 338.0 [M+H] +

[0356] (C) 2-Methyl-4-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole In a reaction flask, 2-bromo-1-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)ethan-1-one (136 mg, 0.402 mmol) and thioacetamide (151 mg, 2.01 mmol) were dissolved in 5 ml of ethanol, and the reaction solution was heated and refluxed for 1 hour. The reaction solution was concentrated, and then the crude product was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (98 mg) as a yellow solid. MS (m / z): 315.0 [M+H] +

[0357] (D) 5-((2-(2-Methylthiazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Intermediate 24(B). MS (m / z): 285.0 [M+H] +

[0358] Example 2 Preparation of Compound 1-135 Compound 1 6-(Dimethylamino)-1-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0359] (A) 6-Chloro-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine-2-amine (500 mg, 1.87 mmol), 6-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (487 mg, 2.81 mmol), HATU (1.07 g, 2.81 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and then TEA (0.76 ml, 5.61 mmol) was added. The mixture was reacted overnight at room temperature. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 320 mg of the title product as a brown solid. MS (m / z): 423.1 [M+H] +

[0360] (B)6-(Dimethylamino)-1-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 6-chloro-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (70 mg, 0.17 mmol), 2-bromopropane (41 mg, 0.33 mmol), potassium carbonate (69 mg, 0.50 mmol) and DMF (3 ml) were added to a reaction flask, and the mixture was reacted overnight at 80 °C. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) and p-TLC plate (dichloromethane / methanol = 15:1) to obtain 12 mg of the title product as a yellow solid. MS (m / z): 474.2 [M+H] + 11H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.35 (s, 1H), 8.27 (d, J = 2.9 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.72 (dd, J = 9.0, 2.9 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 5.7, 2.3 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.53 - 5.41 (m, 1H), 3.82 (s, 3H), 3.09 (s, 6H), 1.44 (d, J = 6.2 Hz, 6H).

[0361] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 1 under appropriate conditions recognized by a person of ordinary skill in the art (POSITA). [Table 11]

[0362] Compound 2 6-(Dimethylamino)-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical formula]

[0363] Under nitrogen, 6-chloro-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.24 mmol), iodomethane (30 μl, 0.47 mmol), potassium carbonate (100 mg, 0.72 mmol) and DMF (4 ml) were added to a reaction flask, and the mixture was reacted at 80 °C overnight. Then, dimethylamine hydrochloride (38 mg, 0.47 mmol) was added, and the mixture was reacted at room temperature overnight. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) and p-TLC plate (dichloromethane / methanol = 15:1) to obtain 16 mg of the title product as a pale yellow solid. MS (m / z): 446.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.36 (dd, J = 7.4, 4.3 Hz, 2H), 8.29 (d, J = 8.5 Hz, 1H), 8.25 (m, 2H), 7.95 (d, J = 0.6 Hz, 1H), 7.71 (dd, J = 9.0, 2.9 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 6.16 (d, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.49 (s, 3H), 2.87 (s, 6H)

[0364] Compound 3 6-Methoxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0365] (A)6-Chloro-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 6-chloro-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (320 mg, 0.76 mmol), iodomethane (71 μl, 1.14 mmol), potassium carbonate (540 mg, 1.42 mmol) and DMF (5 ml) were added to a reaction flask, and the mixture was reacted at 80 °C overnight. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 130 mg of the title product as a brown solid. MS (m / z): 437.1 [M+H] +

[0366] (B)6-Methoxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 6-chloro-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 0.07 mmol) and 7M ammonia methanol solution (3 ml) were added to a reaction flask, the tube was sealed, and the mixture was reacted at 80 °C for 2 hours. Then, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) and p-TLC plate (dichloromethane / methanol = 15:1) to obtain 3 mg of the title product as a yellow solid. MS (m / z): 433.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.38 - 8.33 (m, 2H), 8.29 - 8.20 (m, 2H), 7.95 (d, J = 0.5 Hz, 1H), 7.72 (dd, J = 9.0, 2.9 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 6.25 (d, J = 8.7 Hz, 1H), 4.04 (s, 3H), 3.82 (s, 3H), 3.45 (s, 3H).

[0367] Compound 4 N-(3-Fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0368] (A)5-((2-Bromopyridin-4-yl)oxy)-3-fluoropyridin-2-amine Under nitrogen, 6-amino-5-fluoropyridin-3-ol (1.28 g, 10 mmol), 2-bromo-4-fluoropyridine (1.76 g, 10 mmol), cesium carbonate (4.9 g, 15 mmol) and DMSO (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 80 °C for 2 hours. The reaction solution was cooled to room temperature and added to water (100 ml) with stirring, extracted with ethyl acetate (100 ml × 3), the organic layers were combined and concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 2.7 g of the title product as a yellow solid. MS (m / z): 285.9 [M+H] +

[0369] (B)N-(5-((2-Bromopyridin-4-yl)oxy)-3-fluoropyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 5-((2-Bromopyridin-4-yl)oxy)-3-fluoropyridin-2-amine (200 mg, 0.70 mmol), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (118 mg, 0.77 mmol), HATU (322 mg, 0.85 mmol), TEA (148 μl, 1.05 mmol) and DMF (6 ml) were sequentially added to a reaction flask, and the mixture was reacted at 45 °C overnight. The reaction solution was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) to obtain 133 mg of the title product as a brown solid. MS (m / z): 419.0 [M+H] +

[0370] (C)N-(3-Fluoro-5-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-bromopyridin-4-yl)oxy)-3-fluoropyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (133 mg, 0.32 mmol), 1-methyl-1H-pyrazol-4-amine (37 mg, 0.38 mmol), XantPhos (37 mg, 0.064 mmol), Pd 2 (dba) 3 (29 mg, 0.032 mmol), cesium carbonate (261 mg, 0.8 mmol) and 1,4-dioxane (10 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) and p-TLC plate (dichloromethane / methanol / formic acid = 10:1:0.1) to obtain 15 mg of the title product as a yellow solid. MS (m / z): 436.1[M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.83 (s, 1H), 8.46 (dd, J = 7.3, 2.1 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 6.5, 2.1 Hz, 1H), 8.16 (s, 2H), 8.05 (d, J = 5.8 Hz, 1H), 7.94 (dd, J = 10.5, 2.4 Hz, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 6.66 - 6.58 (m, 1H), 6.39 (dd, J = 5.8, 2.2 Hz, 1H), 6.12 (d, J = 2.1 Hz, 1H), 3.78 (s, 3H), 3.65 (s, 3H).

[0371] Compound 5 1,2-Dimethyl-N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0372] (A)5-((6-Chloropyrimidin-4-yl)oxy)pyridin-2-amine Under nitrogen, 4,6-dichloropyrimidine (530 mg, 3.56 mmol), 6-aminopyridin-3-ol (390 mg, 3.56 mmol), potassium t-butoxide (800 mg, 7.12 mmol) and DMSO (18 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C overnight. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 494 mg of the solid title product. MS (m / z): 233.0 [M+H] +

[0373] (B) 5-((6-(1-Methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine Under nitrogen, 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (300 mg, 1.35 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (336 mg, 1.62 mmol), Pd(dppf)Cl 2 (110 mg, 0.135 mmol), cesium carbonate (660 mg, 2.03 mmol), water (2 ml) and 1,4-dioxane (8 ml) were sequentially added to a reaction flask, and the mixture was reacted at 50 °C overnight. The reaction solution was concentrated, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 160 mg of the solid title product. MS (m / z): 269.1 [M+H] +

[0374] (C) 1,2-Dimethyl-N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide The title compound was prepared using the corresponding intermediate and reagent with reference to the preparation process of Compound 1(A). MS (m / z): 419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.76 (s, 1H), 8.65 (d, J = 0.7 Hz, 1H), 8.49 (s, 1H), 8.38 - 8.27 (m, 2H), 8.18 (s, 1H), 7.82 (dd, J = 8.9, 2.8 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 2.65 (s, 3H).

[0375] Compound 6 1-Isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0376] (B) N-(5-((2-Chloropyrimidin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of compound 1(A). MS (m / z): 386.0, 388.0 [M+H] +

[0377] (C) 1-Isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide N-(5-((2-Chloropyrimidin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65 mg, 0.311 mmol), Na 2 CO 3 (83 mg, 0.78 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (22 mg, 0.026 mmol), dioxane (25.0 ml) and water (3.0 ml) were added to a reaction flask, the mixture was heated to 100 °C and stirred overnight. After cooling, the reaction solution was purified by flash column chromatography (H 2 O / MeOH = 100:0 - 0:100, gradient elution) to obtain 40 mg of the title product as a white solid. MS (m / z): 432.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.70-8.56 (m, 1H), 8.55-8.44 (m, 1H), 8.44 - 8.31 (m, 2H), 8.24 (s, 1H), 8.11 (s, 1H), 7.93-7.72 (m, 2H), 7.00-6.82 (m, 1H), 6.79-6.56 (m, 1H), 5.35-5.11 (m, 1H), 3.83 (s, 3H), 1.37 (d, J = 5.3 Hz, 6H).

[0378] Compound 7 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0379] (A) 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine 5-((2-Chloropyrimidin-4-yl)oxy)pyridin-2-amine (1.9 g, 8.56 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.18 g, 9.41 mmol), Na 2 2 3 (2.72 g, 25.68 mmol), Pd(dppf)Cl 2 2 2 2 2 (1.05 g, 1.284 mmol), dioxane (25.0 ml) and water (3.0 ml) were added to a reaction flask, the mixture was heated to 100 °C and stirred for 4 h, after cooling, the reaction solution was concentrated, and purified by flash column chromatography (H 2 2O / MeOH = 100:0~0:100, gradient elution) to obtain 1.72 g of the title product as a yellow solid. MS (m / z): 269.1 [M+H] +

[0380] (B) 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 1(A). MS (m / z): 419.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.75 (s, 1H), 8.62 (d, J = 6.2 Hz, 1H), 8.40 - 8.31 (m, 2H), 8.11 (s, 1H), 7.89 - 7.76 (m, 1H), 7.81 (s, 1H), 6.90 (d, J = 5.3 Hz, 1H), 3.83 (s, 3H), 3.58 (s, 3H), 2.64 (s, 3H).

[0381] Compound 8 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0382] 5 - ((2 - (1 - Methyl - 1H - pyrazol - 4 - yl)pyridin - 4 - yl)oxy)pyridin - 2 - amine (158 mg, 0.59 mmol), 1,2 - dimethyl - 6 - oxo - 1,6 - dihydropyrimidine - 5 - carboxylic acid (100 mg, 0.59 mmol), HATU (224 mg, 0.59 mmol), triethylamine (178 mg, 1.77 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was heated to 40 °C and reacted for 15 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) to obtain 22 mg of the product as a pale yellow solid. MS (m / z): 418.1[M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.73 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.29 (d, J = 2.6 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.76 (dd, J = 9.0, 2.6 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 6.71 (dd, J = 5.5, 2.2 Hz, 1H), 3.83 (s, 3H), 3.57 (s, 3H), 2.62 (s, 3H).

[0383] The following compound was prepared using the corresponding intermediate and reagent with reference to the preparation process of Compound 8 under appropriate conditions recognized by a person of ordinary skill in the art. [Table 12]

[0384] Compound 9 N-(5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical formula]

[0385] Under nitrogen, 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (100 mg, 0.37 mmol), 2-hydroxynicotinic acid (78 mg, 0.56 mmol), HATU (213 mg, 0.56 mmol), dichloromethane (20 ml) and TEA (155 μl, 1.1 mmol) were sequentially added to a reaction flask. The mixture was stirred at room temperature overnight, water (5 ml) was added, and then it was concentrated. The residue was purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0 to 0:100, gradient elution) and p-TLC plate to obtain 45 mg of the title product as a white solid. MS (m / z): 389.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 12.69 (s, 1H), 8.52 (dd, J = 7.2, 2.2 Hz, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.38 (s, 1H), 8.31 (d, J = 2.9 Hz, 1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.86 (dd, J = 6.2, 2.2 Hz, 1H), 7.77 (dd, J = 9.0, 2.9 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 6.60 (dd, J = 7.1, 6.3 Hz, 1H), 3.85 (s, 3H).

[0386] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 9 under appropriate conditions recognized by a POSITA. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5] [Table 13-6] [Table 13-7] [Table 13-8] [Table 13-9]

Table 13-10

Table 13-11

Table 13-12

Table 13-13

Table 13-14

Table 13-15

Table 13-16

Table 13-17

Table 13-18

[0387] Compound 79 4-Methoxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0388] (A) 4-Methoxy-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (100 mg, 0.37 mmol), 2-hydroxy-4-methoxynicotinic acid (76 mg, 0.45 mmol), HATU (213 mg, 0.56 mmol), DMF (5 ml) and TEA (155 μl, 1.1 mmol) were sequentially added to a reaction flask, and the mixture was heated to 40 °C and stirred overnight. The reaction solution was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0~0:100, gradient elution) to obtain 80 mg of the title product as a white solid. MS (m / z): 419.2 [M+H] +

[0389] (B) 4-Methoxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 4-methoxy-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (80 mg, 0.2 mmol), iodomethane (74 mg, 0.52 mmol), potassium carbonate (72 mg, 0.52 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 1 hour to react completely. The reaction solution was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0~0:100, gradient elution) and p-TLC plate to obtain 60 mg of the title product as a white solid. MS (m / z): 433.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.38 (d, J = 5.7 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 8.26 (d, J = 2.9 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.72 (dd, J = 9.0, 2.9 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 5.7, 2.4 Hz, 1H), 6.42 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H).

[0390] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 79 under appropriate conditions recognized by a person of ordinary skill in the art (POSITA). [Table 14]

[0391] Compound 81 1-(2-(Dimethylamino)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical Structure]

[0392] Under nitrogen, N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (80 mg, 0.21 mmol), 2-bromo-N,N-dimethylethyl-1-amine hydrochloride (144 mg, 0.63 mmol), cesium carbonate (267 mg, 0.82 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was heated to 80 °C and stirred overnight. The reaction solution was cooled to room temperature and then purified by flash column chromatography (water (0.5% ammonia):methanol = 100:0 to 0:100, gradient elution) to obtain 50 mg of the title product as a white solid. MS (m / z): 460.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.50 (dd, J = 7.4, 2.2 Hz, 1H), 8.40 (s, 1H), 8.38 (d, J = 3.7 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J = 6.5, 2.2 Hz, 1H), 7.98 (d, J = 0.5 Hz, 1H), 7.77 (dd, J = 9.0, 2.9 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 6.66 - 6.59 (m, 1H), 4.19 (t, J = 6.1 Hz, 2H), 3.85 (s, 3H), 2.59 (t, J = 6.1 Hz, 2H), 2.20 (s, 6H).

[0393] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 81 under appropriate conditions recognized by a POSITA.

Table 15-1

Table 15-2

Table 15-3

[0394] Compound 92 1-Isopropyl-N-(3-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0395] (A) N-(5-Bromo-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of compound 79(A). MS (m / z): 366.0 [M+H] +

[0396] (B) (6-(1-Isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide)-5-methoxypyridin-3-yl)boronic acid Under nitrogen, N-(5-bromo-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (360 mg, 1.0 mmol), pinacol borate (508 mg, 2 mmol), potassium acetate (294 mg, 3 mmol), dioxane (10 ml) and Pd(dppf)Cl 2 (73 mg, 0.1 mmol) were sequentially added to a reaction flask, and the mixture was refluxed and stirred overnight. The reaction solution was cooled to room temperature and then concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 330 mg of the title product as a white solid. MS (m / z): 332.1 [M+H] +

[0397] (C) N-(5-Hydroxy-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, (6-(1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide)-5-methoxypyridin-3-yl)boronic acid (330 mg, 1.0 mmol) and tetrahydrofuran (20 ml) were sequentially added to a reaction flask, and 1 N aqueous sodium hydroxide solution (2 ml) and 30% hydrogen peroxide (567 mg, 5 mmol) were sequentially added dropwise. The mixture was stirred at room temperature for 30 minutes. After adjusting the pH to 4 with 1 N aqueous hydrochloric acid solution, saturated aqueous sodium thiosulfate solution (1 ml) was added dropwise, and the reaction solution was concentrated. The residue was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 240 mg of the title product as a pale yellow solid. MS (m / z): 304.1 [M+H] +

[0398] (D) N-(5-((2-Chloropyridin-4-yl)oxy)-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-hydroxy-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (240 mg, 0.8 mmol), 2-chloro-4-fluoropyridine (126 mg, 0.96 mmol), potassium t-butoxide (135 mg, 1.2 mmol) and DMSO (6 ml) were sequentially added to a reaction flask. The mixture was heated to 90 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, then water (40 ml) was added, stirred for 30 minutes, and then filtered. The solid was washed with water and dried to obtain 180 mg of the title product as a brown solid. MS (m / z): 415.1 [M+H] +

[0399] (E) 1-Isopropyl-N-(3-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)-3-methoxypyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (90 mg, 0.22 mmol), 1-methyl-4-pyrazolepinacol borate (69 mg, 0.33 mmol), potassium carbonate (59 mg, 0.43 mmol), dioxane / water (10 ml / 2 ml) and Pd(dppf)Cl 2(15 mg, 0.02 mmol) was sequentially added to a reaction flask, and the mixture was refluxed and stirred overnight. The reaction solution was cooled to room temperature and then concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 - 0:100, gradient elution) to obtain 70 mg of the title product as a white solid. MS (m / z): 461.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.43 (dd, J = 7.2, 1.9 Hz, 1H), 8.40 (d, J = 5.7 Hz, 1H), 8.29 (s, 1H), 8.22 (dd, J = 6.7, 2.0 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.76 (dd, J = 5.7, 2.3 Hz, 1H), 6.70 - 6.59 (m, 1H), 5.35 - 5.18 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H).

[0400] Compound 93 1-Isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0401] (A) 3-((2-Bromopyridin-4-yl)oxy)-2-methyl-6-nitropyridine Under nitrogen, 2-methyl-6-nitropyridin-3-ol (616 mg, 4 mmol), 2-bromo-4-fluoropyridine (739 mg, 4.2 mmol), cesium carbonate (1.95 g, 6 mmol) and DMF (15 ml) were sequentially added to a reaction flask, and the mixture was heated to 90 °C and stirred for 6 hours. The reaction solution was cooled to room temperature, then water (80 ml) was added, stirred for 30 minutes, and then filtered. The solid was washed with water and dried to obtain 460 mg of the title product as a brown solid. MS (m / z): 310.0 [M+H] +

[0402] (B) 2-Methyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Compound 92(E). MS (m / z): 312.1 [M+H] +

[0403] (C) 6-Methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine 2-Methyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (250 mg, 0.8 mmol), methanol (20 ml) and palladium carbon (100 mg) were sequentially added to a reaction flask. After replacing hydrogen with a hydrogen balloon, the reaction solution was stirred at normal pressure and room temperature overnight. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0 to 0:100, gradient elution) to obtain 180 mg of the title product as a brown solid. MS (m / z): 282.1 [M+H] +

[0404] (D) 1-Isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Compound 79(A). MS (m / z): 445.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.49 (dd, J = 7.2, 2.0 Hz, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.32 - 8.17 (m, 3H), 7.98 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 6.74 - 6.58 (m, 2H), 5.30 - 5.14 (m, 1H), 3.85 (s, 3H), 2.30 (s, 3H), 1.40 (d, J = 6.8 Hz, 6H)

[0405] Compound 94 N-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0406] (A) N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (850 mg, 3.84 mmol), 2-hydroxynicotinic acid (640 mg, 4.6 mmol), HATU (2.2 g, 5.8 mmol), DMF (12 ml) and TEA (1.3 ml, 9.6 mmol) were sequentially added to a reaction flask, and the mixture was heated to 40 °C and stirred overnight. The reaction solution was cooled to room temperature, then water (80 ml) was added and stirred for 2 hours, and then filtered. The solid was washed with water and dried to obtain 900 mg of the title product as a pale yellow solid. MS (m / z): 343.0 [M+H] +

[0407] (B) N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (900 mg, 2.6 mmol), iodomethane (479 μl, 7.7 mmol), potassium carbonate (1.06 g, 7.7 mmol) and DMF (10 ml) were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 1 hour to react completely. Water (80 ml) was added, and the reaction solution was stirred for 1 hour and then filtered. The solid was washed with water and dried to obtain 800 mg of the title product as a pale yellow solid. MS (m / z): 357.0 [M+H] +

[0408] (C) N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.28 mmol), 4-pyrazolepinacol borate (82 mg, 0.42 mmol), potassium carbonate (77 mg, 0.56 mmol), dioxane / water (10 ml / 2 ml) and Pd(dppf)Cl 2 (21 mg, 0.03 mmol) were sequentially added to a reaction flask, and the mixture was refluxed and stirred for 2 hours. The reaction solution was cooled to room temperature, then concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 80 mg of the title product as a pale yellow solid. MS (m / z): 389.1 [M+H] +

[0409] (D) N-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine β-carboxamide (80 mg, 0.21 mmol), 2-bromoethyl acetate (167 mg, 1 mmol), cesium carbonate (326 mg, 1 mmol) and DMF (5 ml) were sequentially added to a reaction flask, and the mixture was heated to 80 °C and stirred overnight. The reaction solution was cooled to room temperature, then 2N aqueous sodium hydroxide solution (2 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 40 mg of the title product as a white solid. MS (m / z): 433.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.50 (dd, J = 7.3, 1.9 Hz, 1H), 8.43 - 8.35 (m, 2H), 8.35 - 8.25 (m, 2H), 8.20 (dd, J = 6.4, 1.9 Hz, 1H), 8.01 (s, 1H), 7.77 (dd, J = 9.0, 2.8 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 5.6, 2.3 Hz, 1H), 6.67 - 6.57 (m, 1H), 4.94 (t, J = 5.2 Hz, 1H), 4.15 (t, J = 5.5 Hz, 2H), 3.80 - 3.69 (m, 2H), 3.64 (s, 3H).

[0410] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process (Steps A - C) of Compound 94 under appropriate conditions recognized by a POSITA.

Table 16

[0411] Compound 95 N-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0412] (A) N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 94(A). MS (m / z): 385.1 [M+H] +

[0413] (B) N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 94(C). MS (m / z): 417.1 [M+H] +

[0414] (C) N-(5-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 94(D). MS (m / z): 461.2[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.50 (dd, J = 7.3, 2.1 Hz, 1H), 8.40 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 2.9 Hz, 1H), 8.29 (s, 1H), 8.26 (dd, J = 6.7, 2.1 Hz, 1H), 8.01 (s, 1H), 7.77 (dd, J = 9.0, 2.9 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 5.7, 2.4 Hz, 1H), 6.72 - 6.66 (m, 1H), 5.30 - 5.18 (m, 1H), 4.93 (t, J = 5.3 Hz, 1H), 4.15 (t, J = 5.6 Hz, 2H), 3.79 - 3.70 (m, 2H), 1.39 (d, J = 6.8 Hz, 6H).

[0415] Compound 96 1-Isopropyl-N-(5-((2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0416] Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (50 mg, 0.13 mmol), 1-methyl-1H-pyrazol-4-amine (38 mg, 0.39 mmol), BINAP (8 mg, 0.013 mmol), sodium tert-butoxide (25 mg, 0.26 mmol), dioxane (10 ml) and Pd 2 (dba) 3 (12 mg, 0.013 mmol) were sequentially added to a reaction flask, and the mixture was refluxed and stirred for 2 h. The reaction solution was cooled to room temperature and then concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0~0:100, gradient elution) and p-TLC plate to obtain 25 mg of the title product as a pale yellow solid. MS (m / z): 446.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.78 (s, 1H), 8.49 (dd, J = 7.3, 2.1 Hz, 1H), 8.38 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.25 (dd, J = 6.7, 2.1 Hz, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.76 (dd, J = 9.0, 2.9 Hz, 1H), 7.32 (s, 1H), 6.73 - 6.64 (m, 1H), 6.34 (dd, J = 5.8, 2.2 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 5.29 - 5.18 (m, 1H), 3.77 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H).

[0417] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 96 under appropriate conditions recognized by a POSITA.

Table 17

[0418] Compound 98 N-(5-((2-(4-ethylpiperazin-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0419] N-(5-((2-Chloropyridin-4-yl)oxy)pyridin-2-yl)-1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (50 mg, 0.13 mmol), 1-ethylpiperazine (74 mg, 0.65 mmol) and NMP (4.0 ml) were added to a microwave tube and reacted under microwave at 160 °C for 1.5 h. The reaction solution was subjected to flash column chromatography (H 2Purified by gradient elution (O / MeOH = 100:0 to 0:100), 25 mg of the title product was obtained as a yellow solid. MS (m / z): 463.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.44 (s, 1H), 8.39 - 8.26 (m, 1H), 8.26 - 8.11 (m, 2H), 7.97 (s, 1H), 7.78 - 7.56 (m, 1H), 6.75 - 6.54 (m, 1H), 6.31 (s, 1H), 6.17 (s, 1H), 5.19 (s, 1H), 3.36 - 3.30 (m, 4H), 2.41 - 2.20 (m, 6H), 1.35 (s, 6H), 0.97 (s, 3H).

[0420] Compound 99 1-Methyl-N-(5-((2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical formula

[0421] N-(5-((2-Chloropyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (120 mg, 0.336 mmol), (2-Methyl-2H-1,2,3-triazol-4-yl)boronic acid (85 mg, 0.673 mmol), Na 2 CO 3 (106 mg, 1.008 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (27 mg, 0.0336 mmol), dioxane (23.0 ml) and water (3.0 ml) were added to the reaction flask, the mixture was heated to 110 °C and stirred overnight, after cooling, the reaction solution was purified by flash column chromatography (H 2 O / MeOH = 100:0 to 0:100, gradient elution), 65 mg of the title product was obtained as a white solid. MS (m / z): 404.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H), 8.48 (dd, J = 7.4, 2.2 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 8.34 (d, J = 2.9 Hz, 1H), 8.20 - 8.15 (m, 2H), 7.81 (dd, J = 9.0, 2.9 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 5.7, 2.5 Hz, 1H), 6.64 - 6.55 (m, 1H), 4.15 (s, 3H), 3.61 (s, 3H).

[0422] The following compounds were prepared using the corresponding intermediates and reagents under appropriate conditions recognized by a POSITA with reference to the preparation process of Compound 99. [Table 18 - 1] [Table 18 - 2]

[0423] Compound 104 1-Cyclopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical Structure]

[0424] N-(5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (100 mg, 0.26 mmol), cyclopropylboronic acid (66 mg, 0.78 mmol), 2,2'-bipyridine (8 mg, 0.05 mmol), copper(II) acetate (55 mg, 0.30 mmol), triethylamine (53 mg, 0.52 mmol), molecular sieve (200 mg) and 1,2-dichloroethane (10 ml) were successively added to a reaction flask, and the mixture was reacted at 70 °C for 24 h under oxygen. The reaction solution was filtered, and the filtrate was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) to obtain 10.1 mg of the title product as a yellow solid. MS (m / z): 429.2 [M+H] + . 1 H NMR (400 MHz, a mixed solution of CD 3 OD and CDCl 3 ) δ 8.54 (dd, J = 7.3, 2.1 Hz, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 5.8 Hz, 1H), 8.19 (d, J = 2.9 Hz, 1H), 8.02 (s, 1H), 7.93 - 7.85 (m, 2H), 7.60 (dd, J = 9.0, 2.9 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 5.8, 2.4 Hz, 1H), 6.55 (t, J = 7.0 Hz, 1H), 3.90 (s, 3H), 3.49 - 3.38 (m, 1H), 1.22 - 1.13 (m, 2H), 0.99 - 0.95 (m, 2H).

[0425] Compound 105 6-Amino-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0426] 6-Chloro-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (80 mg, 0.18 mmol), ammonium chloride (46 mg, 0.90 mmol), potassium carbonate (50 mg, 0.36 mmol) and DMSO (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at room temperature for 15 h. The reaction solution was filtered, and the filtrate was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) to obtain 6.3 mg of the title product as a yellow solid. MS (m / z): 418.1[M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.36 - 8.33 (m, 2H), 8.24 (s, 1H), 8.20 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.76 - 7.61 (m, 3H), 7.21 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 5.6, 2.3 Hz, 1H), 5.81 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.39 (s, 3H).

[0427] Compound 106 1-Methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical formula

[0428] 6-Chloro-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (80 mg, 0.18 mmol) and methylamine alcohol solution (5 ml) were sequentially added to a reaction flask, and the mixture was reacted at 80 °C for 2 hours. The reaction solution was filtered, and the filtrate was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 23.0 mg of the title product as a yellow solid. MS (m / z): 432.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.40 - 8.30 (m, 2H), 8.24 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.95 (s, 1H), 7.68 - 7.65 (m, 2H), 7.21 (d, J = 2.3 Hz, 1H), 6.68 (dd, J = 5.6, 2.2 Hz, 1H), 5.80 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.41 (s, 3H), 2.85 (s, 3H).

[0429] Compound 107 1-Methyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chemical Structure

[0430] (A) N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide The title compound was prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 79(A). MS (m / z): 343.0 [M+H] +

[0431] (B) N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (387 mg, 1.13 mmol), iodomethane (241 mg, 1.70 mmol), potassium carbonate (312 mg, 2.26 mmol) and DMSO (5 ml) were sequentially added to a reaction flask and reacted at 60 °C for 1 hour. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 203 mg of the title product as a yellow solid. MS (m / z): 356.7 [M+H] +

[0432] (C) 1-Methyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide Under nitrogen, N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (130 mg, 0.37 mmol), 1-methyl-4-(tributylstannyl)-1H-imidazole (208 mg, 0.56 mmol), Pd(PPH 3 ) 4 (13 mg, 0.01 mmol) and DMF (5 ml) were sequentially added to a reaction flask and the mixture was reacted at 100 °C for 2 hours. The reaction solution was concentrated and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 64.5 mg of the title product as a yellow solid. MS (m / z): 403.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.47 (d, J = 6.9 Hz, 1H), 8.39 - 8.35 (m, 2H), 8.30 (s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.25 (s, 1H), 6.81 (s, 1H), 6.61 - 6.57 (m, 1H), 3.66 (s, 3H), 3.61 (s, 3H).

[0433] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 107 under appropriate conditions recognized by a person of ordinary skill in the art. [Table 19]

[0434] Compound 109 N-(5-((2-(1-(2-Aminoethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [Chemical Formula]

[0435] (A) tert-Butyl (2-(4-(4-((6-Nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate 4-((6-Nitropyridin-3-yl)oxy)-2-(1H-pyrazol-4-yl)pyridine (350 mg, 1.24 mmol), tert-butyl (2-bromoethyl)carbamate (415 mg, 1.85 mmol), cesium carbonate (601 mg, 1.85 mmol) and acetonitrile (20 ml) were successively added to a reaction flask, and the mixture was reacted at 80 °C for 5 hours. The reaction solution was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 0:100, gradient elution) to obtain 362 mg of the title product as a yellow solid. MS (m / z): 427.2 [M+H] +

[0436] (B) tert-Butyl (2-(4-(4-((6-Aminopyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (2-(4-(4-((6-Nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamic acid tert-butyl (110 mg, 0.26 mmol) and palladium on carbon (11 mg) were dissolved in methanol (10 ml), and the mixture was stirred at room temperature under hydrogen for 5 hours. The reaction solution was filtered to remove palladium on carbon, the filtrate was concentrated, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 93 mg of the title product. MS (m / z): 397.2 [M+H] +

[0437] (C) tert-Butyl (2-(4-(4-((6-(1,2-Dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide)pyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (2-(4-(4-((6-Aminopyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamic acid tert-butyl (93 mg, 0.23 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (35 mg, 0.23 mmol), HATU (86 mg, 0.23 mmol), triethylamine (70 mg, 0.69 mmol) and DMF (4 ml) were successively added to a reaction flask, and the mixture was reacted at 45 °C for 15 h. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 37 mg of the title product as a yellow solid. MS (m / z): 547.2 [M+H] +

[0438] (D) N-(5-((2-(1-(2-Aminoethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide In a reaction flask, (2-(4-(4-((6-(1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamido)pyridin-3-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethyl)carbamic acid tert-butyl (37 mg, 0.07 mmol) was dissolved in concentrated hydrochloric acid (1 ml) and methanol (5 ml), the mixture was reacted at room temperature for 30 min, the reaction solution was concentrated at 50 °C, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 7 mg of the title product as a yellow solid. MS (m / z): 447.1 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.71 (s, 1H), 8.58 (d, J = 6.5 Hz, 1H), 8.49 - 8.45 (m, 2H), 8.35 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.36 (d, J = 6.0 Hz, 1H), 4.62 - 4.57 (m, 2H), 3.77 (s, 3H), 3.53 - 3.48 (m, 2H), 2.90 - 2.67 (m, 3H).

[0439] The following compound was prepared using the corresponding intermediate and reagent with reference to the preparation process of Compound 109 under appropriate conditions recognized by a person of ordinary skill in the art (POSITA). [Table 20]

[0440] Compound 111 1,2-Dimethyl-N-(5-((2-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide [Chemical formula]

[0441] (A) N-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-((6-nitropyridin-3-yl)oxy)pyridin-2-amine 2-Chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (500 mg, 2.0 mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (540 mg, 3.0 mmol), Pd 2 (dba) 3(186 mg, 0.2 mmol), Xantphos (116 mg, 0.2 mmol), potassium carbonate (420 mg, 3.0 mmol) and dioxane (20 ml) were sequentially added to a reaction flask, and the mixture was reacted at 100 °C for 15 h under nitrogen. The reaction solution was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 0:100, gradient elution) to obtain 320 mg of the title product as a yellow solid. MS (m / z): 397.0 [M+H] +

[0442] (B) 4-((6-Aminopyridin-3-yl)oxy)-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyridin-2-amine N-(5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine-2-amine (320 mg, 0.81 mmol), iron powder (168 mg, 3.24 mmol) and ammonium chloride (214 mg, 4.05 mmol) were dissolved in ethanol (8 ml) and water (2 ml), and the mixture was refluxed for 1 h to react. The reaction solution was filtered to remove iron powder, the filtrate was concentrated, and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain 227 mg of the title product. MS (m / z): 367.1 [M+H] +

[0443] (C) 1,2-Dimethyl-N-(5-((2-((5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Compound 1 (A). MS (m / z): 517.2 [M+H] +

[0444] (D) 1,2-Dimethyl-N-(5-((2-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Compound 109 (D). MS (m / z): 433.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.09 (s, 1H), 8.73 (s, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.99 (d, J = 5.7 Hz, 1H), 7.73 (dd, J = 9.0, 2.9 Hz, 1H), 6.88 (s, 1H), 6.35 - 6.28 (m, 1H), 5.93 (s, 1H), 3.57 (s, 3H), 2.63 (s, 3H), 2.13 (s, 3H).

[0445] The following compound was prepared using the corresponding intermediate and reagent with reference to the preparation process of Compound 111 under appropriate conditions recognized by a person of ordinary skill in the art. [Table 21]

[0446] Compound 113 N-(5-((2-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide [Chemical formula]

[0447] (A) 2-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine 4-((6-Nitropyridin-3-yl)oxy)-2-(1H-pyrazol-4-yl)pyridine (100 mg, 0.35 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (101 mg, 0.42 mmol) and cesium carbonate (172 mg, 0.53 mmol) were dissolved in acetonitrile (10 ml), and the mixture was stirred at 80 °C for 5 hours. The reaction solution was concentrated to obtain a crude product, which was purified by flash column chromatography (dichloromethane / methanol = 100:0 to 90:10, gradient elution) to obtain 139 mg of the title product. MS (m / z): 442.2 [M+H] +

[0448] (B) 5-((2-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine The title compound was prepared using the corresponding intermediate and reagents with reference to the preparation process of Compound 111(B). MS (m / z): 412.2 [M+H] +

[0449] (C) N-(5-((2-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (83 mg, 0.20 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (34 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), triethylamine (60 mg, 0.60 mmol) and DMF (3 ml) were sequentially added to a reaction flask, and the mixture was reacted at 40 °C for 15 h. The reaction solution was purified by flash column chromatography (water / methanol = 100:0~0:100, gradient elution) to obtain 23.3 mg of the title product as a yellow solid. MS (m / z): 448.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.74 (s, 1H), 8.43 - 8.22 (m, 4H), 8.00 (s, 1H), 7.79 - 7.75 (m, 1H), 7.29 - 7.25 (m, 1H), 6.75 - 6.72 (m, 1H), 4.93 (s, 1H), 4.17 - 4.14 (m, 2H), 3.77 - 3.72 (m, 2H), 3.59 (s, 3H), 2.64 (s, 3H).

[0450] Compound 117 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrrol-3-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chemical Structure

[0451] (A) 2-Bromo-4-((6-nitropyridin-3-yl)oxy)pyridine 2-Bromo-4-hydroxypyridine (5.22 g, 30 mmol), 5-fluoro-2-nitropyridine (4.263 g, 30 mmol), and potassium carbonate (4.975 g, 36 mmol) were dissolved in DMF (40 ml), and the mixture was heated at 90 °C for 4 h. The reaction was cooled to room temperature and quenched with water (200 ml). The reaction solution was filtered, and the solid was collected to obtain 8.1 g of the title product. MS (m / z): 296.0, 298.0 [M+H] +

[0452] (B) 5-((2-Bromopyridin-4-yl)oxy)pyridin-2-amine 2-Bromo-4-((6-nitropyridin-3-yl)oxy)pyridine (5 g, 16.89 mmol), iron powder (3.773 g, 67.56 mmol), ammonium chloride (4.517 g, 84.45 mmol), ethanol (60 ml), and water (15 ml) were sequentially added to a reaction flask, and the mixture was heated to reflux for 1 h. The reaction solution was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 4.3 g of the title product. MS (m / z): 266.0, 268.0 [M+H] +

[0453] (C) 5-((2-(1-methyl-1H-pyrrol-3-yl)pyridin-4-yl)oxy)pyridin-2-amine 5-((2-Bromopyridin-4-yl)oxy)pyridin-2-amine (532 mg, 2.0 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (414 mg, 2.0 mmol), Pd(dppf)Cl 2 (73 mg, 0.1 mmol), K 2 CO 3 (552 mg, 4.0 mmol), dioxane (20 ml), and water (4 ml) were sequentially added to a reaction flask, and the mixture was heated to 100 °C under nitrogen for 15 h. The reaction solution was concentrated and then purified by flash column chromatography (petroleum ether / ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 410 mg of the title product. MS (m / z): 267.1 [M+H] +

[0454] (D) 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrrol-3-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-Methyl-1H-pyrrol-3-yl)pyridin-4-yl)oxy)pyridin-2-amine (410 mg, 1.54 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (388 mg, 2.31 mmol), HATU (878 mg, 2.31 mmol), DMAP (282 mg, 2.31 mmol) and DMF (3 ml) were sequentially added to a reaction flask, the mixture was heated to 40 °C and reacted for 15 hours. The reaction solution was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution), and the obtained crude product was further purified by flash column chromatography (dichloromethane / methanol = 100:0 to 70:30, gradient elution) to obtain the title product (180 mg). MS (m / z): 417.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.73 (s, 1H), 8.35 - 8.25 (m, 3H), 7.74 (dd, J = 9.1, 2.9 Hz, 1H), 7.34 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.72-6.67 (m, 1H), 6.61 (dd, J = 5.7, 2.4 Hz, 1H), 6.53-6.48 (m, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 2.62 (s, 3H).

[0455] The following compounds were prepared using the corresponding intermediates and reagents with reference to the preparation process of Compound 117 (D) under appropriate conditions recognized by a POSITA.

Table 22

[0456] Compound 123 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methyl)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide [Chemistry]

[0457] (A) 2-(1-Methyl-1H-pyrazol-4-yl)isonicotinaldehyde Under nitrogen, 2-chloroisonicotinaldehyde (1 g, 7.1 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1.8 g, 8.5 mmol), cesium carbonate (1.95 g, 14.2 mmol), dioxane / water (20 ml / 2 ml) and Pd(dppf)Cl 2 (512 mg, 0.7 mmol) were sequentially added to a reaction flask, and the mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, then concentrated, and the residue was purified by flash column chromatography (water (0.5% formic acid): methanol = 100:0 to 0:100, gradient elution) to obtain 1 g of the title product as a brown solid. MS (m / z): 220.1 [M+MeOH+H] +

[0458] (B) (2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)methanol Under nitrogen, 2-(1-methyl-1H-pyrazol-4-yl)isonicotinaldehyde (1 g, 5.3 mmol) and methanol (20 ml) were added to a reaction flask, then sodium borohydride (1 g, 26.5 mmol) was slowly added batchwise, and the mixture was stirred at room temperature for 1 hour to complete the reaction. Water (2 ml) was slowly added dropwise to quench the reaction, concentrated, and the residue was purified by flash column chromatography (water: methanol = 100:0 to 0:100, gradient elution) to obtain 800 mg of the title product as a pale yellow solid. MS (m / z): 190.1 [M+H] +

[0459] (C) 4-(Bromomethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine Under nitrogen, (2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methanol (800 mg, 4.2 mmol), carbon tetrabromide (2.1 g, 6.3 mmol) and dichloromethane (30 ml) were sequentially added to a reaction flask, and then triphenylphosphine (1.7 g, 6.3 mmol) was added batchwise. The mixture was stirred at room temperature for 1 hour to react completely. The reaction solution was concentrated, and then the residue was purified by flash column chromatography (dichloromethane:methanol = 100:0 to 90:10, gradient elution) to obtain 1.06 g of the title product as a pale yellow solid. MS (m / z): 252.0 [M+H] +

[0460] (D) 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)methyl)pyridin-2-amine Under nitrogen, 4-(bromomethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (200 mg, 0.79 mmol), 2-aminopyridine-5-boronic acid pinacol ester (262 mg, 1.2 mmol), tripotassium phosphate (503 mg, 2.4 mmol), dioxane / water (10 ml / 2 ml) and Pd(dppf)Cl 2 (58 mg, 0.08 mmol) were sequentially added to a reaction flask, and the mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, then concentrated, and the residue was purified by flash column chromatography (water:methanol = 100:0 to 0:100, gradient elution) and flash column chromatography (dichloromethane:methanol = 100:0 to 90:10, gradient elution) to obtain 50 mg of the title product as a white solid. MS (m / z): 266.1 [M+H] +

[0461] (E) 1,2-Dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methyl)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Under nitrogen, 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methyl)pyridin-2-amine (50 mg, 0.19 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (64 mg, 0.38 mmol), HATU (144 mg, 0.38 mmol), DMF (5 ml) and DMAP (116 mg, 0.95 mmol) were sequentially added to a reaction flask. The mixture was heated to 40 °C and stirred for 2 days. Water (2 ml) was added, and then the reaction solution was purified by flash column chromatography (water (0.5% formic acid):methanol = 100:0~0:100, gradient elution) to obtain 30 mg of the title product as a white solid. MS (m / z): 416.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.72 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.76 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (s, 1H), 7.04 (d, J = 4.9 Hz, 1H), 3.96 (s, 2H), 3.87 (s, 3H), 3.57 (s, 3H), 2.63 (s, 3H).

[0462] Compound 128 2-Methyl-1-(methyl-d3)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0463] (A) 2-Methyl-1-(methyl-d3)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile In a reaction flask, 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2702 mg, 20.0 mmol), iodomethane-d3 (3189 mg, 22.0 mmol), and potassium carbonate (4146 mg, 30.0 mmol) were dissolved in dimethyl sulfoxide (10 ml). The reaction mixture was stirred at room temperature for 15 hours and then purified by flash column chromatography (water:methanol = 100:0 to 0:100, gradient elution) to obtain the title product (2.05 g, yield 67.3%) as a white solid. MS (m / z): 153.0 [M+H] +

[0464] (B) 2-Methyl-1-(methyl-d3)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid In a reaction flask, 2-methyl-1-(methyl-d3)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2.05 g, 13.47 mmol) was dissolved in concentrated hydrochloric acid (10 ml), and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (1.6 g, yield 69.4%) as a white solid. MS (m / z): 172.0 [M+H] +

[0465] (C) 2-Methyl-1-(methyl-d3)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.92 g, 7.18 mmol), 2-Methyl-1-(methyl-d3)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (1.60 g, 9.34 mmol), HATU (3.55 g, 9.34 mmol), 4-dimethylaminopyridine (1.14 g, 9.34 mmol) and N,N-dimethylformamide (20 ml) were sequentially added to a reaction flask, and the mixture was reacted at room temperature and stirred for 15 hours. After completion of the reaction, water (2 ml) was added, then the reaction solution was concentrated, and the residue was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient) to obtain a white solid. The white solid was recrystallized from dichloromethane and methanol to obtain the title product (2.4 g, yield 79.5%) as a white solid. MS (m / z): 421.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.73 (d, J = 0.7 Hz, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.29 (d, J = 2.9 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.76 (dd, J = 9.0, 2.9 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.76 - 6.67 (m, 1H), 3.83 (s, 3H), 2.62 (s, 3H).

[0466] Compound 129 1,2-Dimethyl-N-(5-((2-(1-(methyl-d3)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chemical Structure

[0467] (A) 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole In a reaction flask, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (582 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (5 ml). Sodium hydride (132 mg, 3.3 mmol) was added to the reaction solution in batches at room temperature. Then, the reaction mixture was stirred at room temperature for 10 minutes. Subsequently, deuterated iodomethane (522 mg, 3.6 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 4 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were concentrated and purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (420 mg, yield 66%) as a white solid. MS (m / z): 212.1 [M+H] +

[0468] (B) 5-((2-(1-(methyl-d3)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine 1-(Methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (441 mg, 1.99 mmol), 5-((2-bromopyridin-4-yl)oxy)pyridin-2-amine (447 mg, 1.66 mmol), Pd(dppf)Cl 2 (124 mg, 0.17 mmol) and potassium carbonate (458 mg, 3.32 mmol) were added to a mixed solution of 1,4-dioxane (20 ml) and water (5 ml). The mixture was heated to reflux and stirred for 15 hours. The reaction mixture was cooled to room temperature, concentrated to obtain a crude product, and purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (370 mg, yield 82.5%) as a white solid. MS (m / z): 271.1[M+H] +

[0469] (C) 1,2-Dimethyl-N-(5-((2-(1-(methyl-d3)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-(Methyl-d3)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (135 mg, 0.5 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (126 mg, 0.75 mmol), HATU (285 mg, 0.75 mmol), 4-dimethylaminopyridine (92 mg, 0.75 mmol) and N,N-dimethylformamide (3 ml) were sequentially added to a reaction flask, and the reaction solution was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was quenched with 2 ml of water, concentrated to obtain a crude product, and purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (85 mg, yield 40.47%) as a white solid. MS (m / z): 421.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.72 (s, 1H), 8.42 - 8.27 (m, 3H), 8.24 (s, 1H), 7.95 (s, 1H), 7.76 (d, J = 6.7 Hz, 1H), 7.23 (s, 1H), 6.71 (d, J = 3.6 Hz, 1H), 3.56 (s, 3H), 2.61 (s, 3H).

[0470] Compound 130 N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chemical Structure

[0471] (A) 5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine In a reaction flask, 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (222 mg, 1.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 2.0 mmol), Pd(dppf)Cl 2(73 mg, 0.1 mmol) and potassium carbonate (276 mg, 2.0 mmol) were dissolved in a mixed solution of 1,4-dioxane (20 ml) and water (5 ml), and the mixture was heated to reflux and stirred for 15 h. The reaction mixture was cooled to room temperature, concentrated to obtain a crude product, and purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 - 0:100, gradient elution) to give the title product (120 mg, yield 47.4%) as a white solid. MS (m / z): 254.0 [M+H] +

[0472] (B) N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1H-Pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (120 mg, 0.47 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (128 mg, 0.76 mmol), HATU (289 mg, 0.76 mmol), 4-dimethylaminopyridine (93 mg, 0.76 mmol) and N,N-dimethylformamide (3 ml) were sequentially added to a reaction flask, and the reaction solution was heated at 45 °C for 15 h. After completion of the reaction, the reaction solution was quenched with 2 ml of water, concentrated to obtain a crude product, and purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 - 0:100, gradient elution) to give the title product (18 mg, yield 9.5%) as a white solid. MS (m / z): 404.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 12.99 (s, 1H), 11.85 (s, 1H), 8.73 (s, 1H), 8.37 (d, J = 5.7 Hz, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.03 (s, 1H), 7.76 (dd, J = 9.0, 2.9 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 5.7, 2.4 Hz, 1H), 3.57 (s, 3H), 2.63 (s, 3H).

[0473] Compound 131 2-Methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0474] (A) 2-Methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid In a reaction flask, 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (1.35 g, 10.0 mmol) was dissolved in concentrated hydrochloric acid (10 ml). The reaction solution was heated to reflux for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (1.1 g, yield 71.4%) as a white solid. MS (m / z): 155.0 [M+H] +

[0475] (B) 2-Methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (134 mg, 0.5 mmol), 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (123 mg, 0.8 mmol), HATU (304 mg, 0.8 mmol), 4-dimethylaminopyridine (98 mg, 0.8 mmol) and N,N-dimethylformamide (3 ml) were sequentially added to a reaction flask, and the reaction solution was heated at 45 °C for 15 hours. After completion of the reaction, the reaction solution was quenched with 2 ml of water, concentrated to obtain a crude product, and purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (130 mg, yield 64%) as a white solid. MS (m / z): 404.0 [M+H] + 11H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.71 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.75 (dd, J = 9.0, 2.9 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 5.7, 2.4 Hz, 1H), 3.83 (s, 3H), 2.40 (s, 3H).

[0476] Compound 132 2-(2-Hydroxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0477] 2-Methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (100 mg, 0.248 mmol), aqueous formaldehyde solution (1 ml) and ethanol (3 ml) were sequentially added to a microwave tube. The microwave tube was sealed, and the reaction solution was reacted at 140 °C for 1 hour in a microwave reactor. After completion of the reaction, the reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0~0:100, gradient elution) and further purified by preparative thin layer chromatography to obtain the title product (9 mg, yield 8.4%) as a white solid. MS (m / z): 434.0 [M+H] + 11H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.74 (s, 1H), 8.36 (dd, J = 9.9, 7.4 Hz, 2H), 8.28 (d, J = 2.9 Hz, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.75 (dd, J = 9.0, 2.9 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.72 (dd, J = 5.7, 2.4 Hz, 1H), 3.83 (s, 3H), 3.78 (t, J = 6.2 Hz, 2H), 2.80 (t, J = 6.2 Hz, 2H).

[0478] Compound 133 2-(Hydroxymethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0479] (A) 2-Methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid In a reaction flask, 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6.0 g, 44.4 mmol) was dissolved in concentrated hydrochloric acid (15 ml). The reaction solution was heated to reflux for 2 hours. The reaction solution was concentrated to dryness, and the crude product was used directly in the next step without purification (6.84 g, yield 100%). MS (m / z): 155.2 [M+H] +

[0480] (B) Ethyl 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate In a reaction flask, the acid intermediate 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (6.84 g, 44.4 mmol) prepared in the previous step was dissolved in ethanol (100 ml). Thionyl chloride (5 ml) was added dropwise to the mixture under an ice bath. After the addition was complete, the reaction solution was heated to reflux for 15 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (4.5 g, two-step reaction yield 55.6%) as a white solid. MS (m / z): 183.2 [M+H] +

[0481] (C) Ethyl 2-(chloromethyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate Ethyl 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (4500 mg, 24.7 mmol), N-chlorosuccinimide (3298 mg, 24.7 mmol) and dichloromethane (100 ml) were sequentially added to a reaction flask, and the mixture was heated to reflux for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water, concentrated to dryness, and the residue was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (1.7 g, yield 37.7%) as a white solid. MS (m / z): 217.0 [M+H] +

[0482] (D) 2-(Chloromethyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid In a reaction flask, ethyl 2-(chloromethyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.7 g, 7.85 mmol) was dissolved in concentrated hydrochloric acid (15 ml), and the reaction solution was heated to reflux for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (1.2 g, yield 81%) as a white solid. MS (m / z): 189.0 [M+H] +

[0483] (E) 2-(Chloromethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide 5-((2-(1-Methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1742 mg, 6.52 mmol), 2-(chloromethyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (1.23 g, 6.52 mmol), HATU (2.73 g, 7.17 mmol), 4-dimethylaminopyridine (876 mg, 7.17 mmol) and N,N-dimethylformamide (15 ml) were sequentially added to a reaction flask, and the reaction solution was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was quenched with 2 ml of water, concentrated, and the crude product was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (1.8 g, yield 63%) as a white solid. MS (m / z): 438.1 [M+H] +

[0484] (F) Methyl (5-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-6-oxo-1,6-dihydropyrimidin-2-yl)acetate 2-(Chloromethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (500 mg, 1.14 mmol), potassium acetate (500 mg, 5.1 mmol) and N,N-dimethylformamide (4 ml) were sequentially added to a reaction flask. The reaction solution was heated at 80 °C for 15 hours. After completion of the reaction, the reaction solution was cooled to room temperature and quenched with water (1 ml). The reaction solution was concentrated, and the crude product was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (290 mg, yield 55.1%) as a white solid. MS (m / z): 462.2 [M+H] +

[0485] (G) 2-(Hydroxymethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide Methyl (5 - ((5 - ((2 - (1 - methyl - 1H - pyrazol - 4 - yl)pyridin - 4 - yl)oxy)pyridin - 2 - yl)carbamoyl)-6 - oxo - 1,6 - dihydropyrimidin - 2 - yl)acetate (30 mg, 0.065 mmol), methanol (3 ml), and sodium methoxide (14 mg, 0.26 mmol) were sequentially added to a reaction flask, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the pH of the reaction solution was adjusted to about 5 with dilute hydrochloric acid (2 M). The reaction solution was concentrated, and the crude product was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (15 mg, yield 55.5 g). %) Obtained as a white solid. MS (m / z): 420.1[M + H] + 1 H NMR (400 MHz, DMSO - d6) δ 12.19 (s, 1H), 8.65 (s, 1H), 8.36 (d, J = 5.7 Hz, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.74 (dd, J = 9.0, 2.9 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 5.7, 2.4 Hz, 1H), 5.86 (s, 1H), 4.44 (s, 2H), 3.82 (s, 3H).

[0486] Compound 134 2-Hydroxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0487] (A) Methyl (1-methyl-5-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (Methyl (5-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (200 mg, 0.433 mmol), potassium carbonate (72 mg, 0.519 mmol), N,N-dimethylformamide (3 ml) and iodomethane (62 mg, 0.433 mmol) were sequentially added to a reaction flask. The reaction solution was continuously stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined and concentrated, and eluted by flash column chromatography (water / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (140 mg, yield 67.96%) as a white solid. MS (m / z): 476.1 [M+H] +

[0488] (B) 2-Hydroxy-1-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide (Methyl (1-methyl-5-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-6-oxo-1,6-dihydropyrimidin-2-yl)acetate (48 mg, 0.1 mmol), methanol (3 ml) and sodium methoxide (216 mg, 0.4 mmol) were sequentially added to a reaction flask, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the pH of the reaction solution was adjusted to about 5 with dilute hydrochloric acid (2M). The reaction solution was concentrated, and the crude product was purified by flash column chromatography (water (0.05% formic acid) / methanol = 100:0 to 0:100, gradient elution) to obtain the title product (10 mg, yield 23.8%) as a white solid. MS (m / z): 420.1 [M+H] + 11H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 8.9 Hz, 1H), 8.24 (s, 2H), 7.95 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 5.5, 2.0 Hz, 1H), 3.82 (s, 3H), 3.21 (s, 3H).

[0489] Compound 135 N-(5-((2-(3-Hydroxy-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide

Chem.

[0490] (A) 3-(Benzyloxy)-1-methyl-1H-pyrazole Under nitrogen, 1-methyl-1H-pyrazol-3-ol (4 g, 41 mmol), potassium carbonate (6.8 g, 49 mmol) and DMF (50 ml) were sequentially added to a reaction flask. Benzyl bromide (8.4 g, 49 mmol) was added dropwise in an ice bath. The mixture was warmed to room temperature and stirred for 1.5 h, then heated to 50 °C and stirred for an additional 4 h. The reaction solution was cooled to room temperature, water (100 ml) and ethyl acetate (150 ml) were added. After liquid separation, the organic phase was washed twice with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 4.7 g of the title product as a colorless oil. MS (m / z): 189.1 [M+H] +

[0491] (B) 3-(Benzyloxy)-4-iodo-1-methyl-1H-pyrazole Under nitrogen, 3-(benzyloxy)-1-methyl-1H-pyrazole (4.7 g, 25 mmol), acetonitrile (60 ml), cerium(IV) ammonium nitrate (8.22 g, 15 mmol) and elemental iodine (3.8 g, 15 mmol) were sequentially added to a reaction flask, and the mixture was stirred at room temperature for 2 hours. The reaction solution was cooled in an ice bath, then 5% sodium bisulfite (100 ml) was added dropwise, and the mixture was extracted with ethyl acetate (100 ml). The organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 5.1 g of the title product as a brown oil. MS (m / z): 315.0 [M+H] +

[0492] (C) 3-(Benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole Under nitrogen, 3-(benzyloxy)-4-iodo-1-methyl-1H-pyrazole (5.1 g, 16 mmol) and anhydrous tetrahydrofuran (80 ml) were sequentially added to a reaction flask, and the mixture was cooled to -10 °C in an ice-salt bath. Then, isopropylmagnesium chloride chloride (12 ml, 24 mmol) was added dropwise, and the reaction solution was warmed to 0 °C and stirred for 1.5 hours. Then, it was cooled again to -10 °C in an ice-salt bath, and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.95 g, 32 mmol) was added dropwise. Then, the reaction solution was slowly warmed to room temperature and stirred for 4 hours. Saturated ammonium chloride (100 ml) was added, and the reaction solution was extracted with ethyl acetate (100 ml). The organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100, gradient elution) to obtain 4.6 g of the title product as a colorless oil. MS (m / z): 315.2 [M+H] +

[0493] (D) 5-((2-(3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine Under nitrogen, 3-(benzyloxy)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.57 g, 5 mmol), 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (742 mg, 3.33 mmol), cesium carbonate (2.7 g, 8.3 mmol), tetrakis(triphenylphosphine)palladium (380 mg, 0.33 mmol) and DMF / H 2 O (18 ml / 6 ml) were sequentially added to a reaction flask, the mixture was heated to 90 °C and then stirred overnight. The reaction solution was cooled to room temperature and then concentrated, and the residue was purified by flash column chromatography (water (0.1% formic acid): acetonitrile = 100:0 to 0:100, gradient elution) to obtain 1.2 g of the title product as a pale yellow solid. MS (m / z): 374.2 [M+H] +

[0494] (E) 4-(4-((6-Aminopyridin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazol-3-ol 5-((2-(3-(Benzyloxy)-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.2 g, 3.33 mmol), methanol (60 ml), dichloromethane (6 ml) and palladium hydroxide (600 mg) were sequentially added to a reaction flask, and the mixture was stirred overnight at room temperature under hydrogen. The reaction solution was filtered, the filter cake was washed with methanol, the filtrates were combined and concentrated, and the residue was purified by flash column chromatography (dichloromethane: methanol = 100:0 to 90:10, gradient elution) to obtain 590 mg of the title product as a white solid. MS (m / z): 284.1 [M+H] +

[0495] (F) N-(5-((2-(3-Hydroxy-1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxamide Under nitrogen, 4-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1-methyl-1H-pyrazol-3-ol (283 mg, 1 mmol), 1,2-dimethyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (202 mg, 1.2 mmol), HATU (570 mg, 1.5 mmol), DMF (10 ml) and DMAP (183 mg, 1.5 mmol) were sequentially added to a reaction flask. The mixture was heated to 40 °C and then stirred overnight. Water (2 ml) was added, and the reaction solution was purified by flash column chromatography (water (0.1% formic acid): acetonitrile = 100:0 to 0:100, gradient elution) and preparative thin-layer chromatography to obtain 75 mg of the title product as a white solid. MS (m / z): 434.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.96 (s, 1H), 8.76 (s, 1H), 8.45 - 8.28 (m, 3H), 8.07 (s, 1H), 7.81 (dd, J = 9.0, 2.9 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 5.8, 2.5 Hz, 1H), 3.65 (s, 3H), 3.59 (s, 3H), 2.65 (s, 3H).

[0496] Example 3 Measurement of CSF1R kinase activity at the molecular level 1. Reagents and materials: Z-LYTE™ TyR1 Peptide Substrate: Invitrogen, PV3190; 5× Kinase Buffer: Invitrogen, PV3189; 10 mM ATP: Invitrogen, PV3227; Developing Reagent B: Invitrogen, PV3295; Developing Buffer: Invitrogen, P3127; Stop Solution: Invitrogen, P3094; Recombinant Human CSF1R Kinase: Invitrogen, PR4598A; 384-well plate, black: Corning, 3575; Envision: Perkin Elmer.

[0497] 2. Preparation of reaction solution 1) 1.33× Kinase Buffer: 5× Kinase Buffer was diluted with ddH 2 O to 1.33× Kinase Buffer. 2) 4-fold Dilution of Test Compounds: Test compounds were serially diluted to 4-fold of the reaction concentration, keeping the DMSO concentration at 8%. The final concentrations of the compounds during the reaction were set as: 1 μM, 0.33 μM, 0.11 μM, 0.037 μM, 0.012 μM, 0.004 μM, 0.0014 μM, 0.00046 μM, and the final concentration of DMSO was 2%. 3) Mixture of Kinase / Peptide Substrate: In 1.33× Kinase Buffer, the kinase and Z-LYTE™ TyR1 peptide substrate were diluted to 0.12 μg / mL and 4 μM respectively to prepare the kinase / peptide substrate mixture. The mixture was gently mixed with a pipette. 4) Phosphorylated Peptide Substrate Solution (PP Solution): 0.4 μL of Z-LYTE™ TyR1 phosphorylated peptide substrate was added to 99.6 μL of 1.33× Kinase Buffer. 5) ATP Solution: 10 mM ATP was diluted to 760 μM with 1.33× Kinase Buffer to prepare the ATP solution. 6) Developing Solution: Developing Reagent B was diluted with Developing Buffer at a ratio of 1:200.

[0498] 3. Method 1) Kinase Reaction (10 μL System) 2.5 μL of the 4× test compound was added to each reaction well of the 384-well plate, and the corresponding amount of 8% DMSO was added to the control wells. The plate was left standing on ice. 5 μL of the kinase / peptide substrate mixture, 2.5 μL of the kinase buffer, and the ATP solution were sequentially added to each well. Three control groups were set up: group C1 contained only the kinase buffer, group C2 contained the mixture of kinase / peptide substrate, kinase buffer, and ATP, and group C3 contained 5 μL of the PP solution. After adding the reaction components, the 384-well plate was sealed and incubated in the dark at 25 - 30 °C for 1 hour.

[0499] 2) Development reaction 5 μL of the developing solution was added to each well, sealed, and further incubated in the dark at 25 - 30 °C for 1 hour.

[0500] 3) Reaction termination and plate reading 5 μL of the stop solution was added to each well. The coumarin value (excitation at 400 nm, emission at 445 nm) and the fluorescein value (excitation at 400 nm, emission at 520 nm) were measured respectively.

[0501] 4. Data analysis % Phosphorylation rate = 100% - 100% × [ER × C3 520nm - C3 445nm] / [(C1 445nm - C3 445nm) + ER × (C3 520nm - C1 520nNm)] [where ER (emission ratio): coumarin emission reading (445 nm) / fluorescein emission reading (520 nm); C3 445nm: reading of 100% phosphorylated coumarin emission; C3 520nm: reading of 100% phosphorylated fluorescein emission; C1 445nm: reading of 0% phosphorylated coumarin emission; C1 520nm: reading of 0% phosphorylated fluorescein emission is.]. % Inhibition rate (IR) = [1 - % phosphorylation rate 試験試料 / 100% phosphorylation rate 対照 × 100% [Wherein, % phosphorylation rate 試験試料 : Phosphorylation rate of the test compound; 100% phosphorylation rate 対照 : Phosphorylation rate of the C3 control group is.].

[0502] 5. IC 50 value: Calculated using software XL-Fit (trademark) (version 5.3) provided by ID Business Solutions (Guildford, UK), additional software for Microsoft Excel.

[0503] 6. Test results

Table 23-1

Table 23-2

[0504] Example 4 Detection of CSF1R phosphorylation activity at the cellular level 1. Cell line THP-1 (ATCC), human acute monocytic leukemia cells. The cells were cultured in RPMI 1640 medium containing 10% FBS.

[0505] 2. Reagents and instruments · Human Phosphorylated-CSF1R ELISA Kit: R&D, #DYC3268-2; · RPMI 1640 culture medium: GIBCO, #10491; · Human M-CSF recombinant cytokine: R&D, #216-MC-500; · Cell lysis buffer: Cell Signal, #9803S; · 1×PBS buffer (1L): 8.0 g of NaCl, 0.2 g of KCl, 3.58 g of Na 2 HPO4 -12H 2 O, 0.24 g of KH 2 PO 4 was dissolved in 1 L of ddH 2 O and the pH was adjusted to 7.4; · Blocking solution: PBS buffer containing 1% BSA; · PBST washing solution: PBS buffer containing 0.05% Tween-20; · Chromogenic substrate: R&D, #DY999; · 2N H 2 SO 4 ; · Microplate reader: Labsystems Multiskan K3: Thermo; Envision: Perkin Elmer; · ELISA plate: Corning, #9018; · Cell culture plate: Facol, #353027.

[0506] 3. Cell treatment and preparation of lysis buffer THP-1 cells were resuspended in RPMI-1640 culture medium containing 2% FBS, and the culture was added to a 96-well plate at a density of 5×10 4 / well, 50 μL / well and cultured overnight in a 5% CO 2 and 37 °C cell incubator. Test compounds were diluted to 3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.014 μM, 0.005 μM and 0.002 μM in serum-free RPMI-1640 medium, and the DMSO concentration was 5%. 5 μL of the diluted compound was added to 50 μL of the cell culture system, and the mixture was cultured in a 5% CO 2 , 37 °C cell incubator for 60 minutes, 300 Ng / mL of M-CSF was added to the cells, the mixture was stimulated in a 37 °C cell incubator for 1 minute, 50 μL of cell lysis buffer was added, and the mixture was stored in a -80 °C refrigerator.

[0507] 4. ELISA detection procedure 100 μL of p-CSF1R capture antibody diluted to 0.8 μg / mL with PBS was added to each well of an ELISA plate, and the plate was coated overnight at room temperature on a shaker. The culture was washed with PBST, then blocking solution was added and incubated for 2 hours at room temperature. The culture was washed with PBST, 90 μL of cell lysis buffer was added, and the mixture was incubated for 2 hours at 25 °C on a shaker. The plate was washed 3 times with PBST, 100 μL of anti-p-tyrosine-HRP detection antibody diluted with 0.1% PBS-BSA diluent was added, and the mixture was incubated for 2 hours at 25 °C on a shaker. The plate was washed with PBST wash solution, 100 μL of chromogenic substrate was added, and the mixture was incubated for 10 - 20 minutes at room temperature. 50 μL of 2N H 2 SO 4 was added to stop the reaction. The optical density signal (450 / 570 Nm) of each well was detected using a Labsystems Multiskan K3 or Envision.

[0508] 5. Data analysis

Number

[0509] 6. IC 50 calculation: Obtained using XL-Fit5.3 software.

[0510] 7. Test results

Table 24-1

Table 24-2

[0511] Example 5 Cell proliferation experiment 1. Cell line Ba / F3 BCR-FMS-11 Primary mouse B lymphocytes that stably express the BCR-FMS fusion gene. The cells were cultured in RPMI 1640 medium containing 10% FBS.

[0512] 2. Reagents and instruments · CCK-8 kit: Dojindo, #CK04; · Envision: Perkin Elmer; · Cell culture plates: Facol, #353027.

[0513] 3. Experimental procedure A cell line Ba / F3 that stably expresses BCR-FMS by introducing the BCR-FMS fusion gene into Ba / F3 cells and proliferates in a CSF-1R-dependent manner BCR-FMS-11 was screened. Ba / F3 BCR-FMS-11 The cell proliferation experiment was completed using the cell counting kit CCK-8 in a 96-well plate. Ba / F3 cells at 5000 / well were inoculated into the 96-well plate at 100 μL / well. After 24 hours, the test compound was diluted to 10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.12 μM, 0.037 μM, 0.012 μM, and 0.004 μM, and the concentration of DMSO was maintained at 5%. 10 μL of the compound dilutions at the above 8 concentrations were added to the culture cell wells. The cultures were incubated in a cell incubator at 37 °C and 5% CO BCR-FMS-11 for 72 hours. 10 μL of the CCK-8 detection reagent for cell counting was added to each well and incubated in the cell incubator at 37 °C and 5% CO 2 for an additional 1 hour. The optical density absorption value at 450 nm of each well was detected using the Envision instrument of Perkin Elmer. 2

[0514] 4. Data analysis

Number

[0515] 5. IC 50 calculation: Obtained using XL-Fit5.3 software.

[0516] 6. Test results

Table 25-1

Table 25-2

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer: 【Chemical 1】 [wherein, X is N or CR ５ wherein; Z １ and Z ２ are each independently N or CR ６ ; Y １ is N or CR ７ ; Y ２ is N or CR ８ ; Y ３ is N or CR ９ ; L is O or CH ２ and; W is absent or is NH; R １ is phenyl, 5- to 12-membered heteroaryl, 4- to 6-membered heterocyclyl or C ３－８ cycloalkyl, each of which is optionally substituted with one or more groups selected from halogen, C １－６ alkyl, C １－６ haloalkyl, -(C １－６ alkylene) ｎ -NH ２ , -(C １－６ alkylene) ｎ -NH(C １－６ alkyl), -(C １－６ alkylene) ｎ -N(C １－６ alkyl) ２ or -(C １－６ alkylene) ｎ -OH; R ２ is hydrogen, C １－６ alkyl, C ２－６ alkenyl, C １－６ haloalkyl, -(C １－６ alkylene)-N(C １－６ alkyl) ２ , -(C １－６ alkylene)-O-(C １－６ alkyl), -(C １－６ alkylene)-OH, C ３－８ cycloalkyl or 4- to 6-membered heterocyclyl; R ３ 、R ４ 、R ５ 、R ６ 、R ７ and R ８ are each independently selected from hydrogen, halogen, -CN, C １－６ alkyl or -O(C １－６ alkyl); R ９ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, -O(C １－６ alkyl), -OH, -(C １－６ alkylene)-OH, -NH ２ , -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ or C ３－８ cycloalkyl; n is 0 or 1; or Y ３ is CR ９ when it is ２ and R ９ together with the N and C atoms to which they are attached form a 5- or 6-membered heteroaromatic ring or a 5- or 6-membered heterocyclic ring; or Y ２ is CR ８ and Y ３ is CR ９ when it is, R ８ and R ９ together with the C atom to which they are attached form a benzene ring; or ​ is 【Chemical Formula 3】 and in the formula, R １０ is hydrogen or C １－６ alkyl; However, when X is CH, Z １ is not N.].

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein X is N.

3. X is CR ５ wherein; R ５ is hydrogen or -O(C １－６ alkyl), the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

4. Z １ and Z ２ are each independently CR ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein each is independently CR

5. Z １ and Z ２ The compound according to claim 4, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein both are CH.

6. Y １ is CR ７ and Y ２ is CR ８ and Y ３ is CR ９ and; R ７ and R ８ are each independently: hydrogen, halogen, C １－６ alkyl or -O(C １－６ alkyl) and R ９ is hydrogen, C １－６ alkyl, C １－６ haloalkyl, -O(C １－６ alkyl), -NH ２ , -NH(C １－６ alkyl) or -N(C １－６ alkyl) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R7 is hydrogen or -O(C1-6 alkyl), R8 is hydrogen, halogen or C1-6 alkyl, and R9 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, -O(C1-6 alkyl), -NH2, -NH(C1-6 alkyl) or -N(C1-6 alkyl)2.

8. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R7 is hydrogen, R8 is selected from hydrogen or fluorine, and R9 is hydrogen or methyl.

9. Y １ is CR ７ and Y ２ is N, and Y ３ is CR ９ and; R ７ is hydrogen, C １－６ alkyl or -O(C １－６ alkyl); R ９ is hydrogen, C １－６ alkyl, C １－６ haloalkyl or C ３－６ cycloalkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof.

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R7 is hydrogen; and R9 is hydrogen, C1-6 alkyl or C3-6 cycloalkyl.

11. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R7 is hydrogen; and R9 is hydrogen or methyl.

12.

13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein L is O.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein W is absent.

14. R １ is phenyl, pyrazolyl, pyrrolyl, furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazo[1,2-a]pyridyl, piperazinyl or cyclohexenyl, each of which is optionally substituted with one or more groups selected from halogen, C １－６ alkyl, C １－６ haloalkyl, -(C １－６ alkylene) ｎ -NH ２ , -(C １－６ alkylene) ｎ -NH(C １－６ alkyl), -(C １－６ alkylene) ｎ -N(C １－６ alkyl) ２ or -(C １－６ alkylene) ｎ -OH, and the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more groups selected from C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkylene)-NH2, -(C1-6 alkylene)-NH(C1-6 alkyl), -(C1-6 alkylene)-N(C1-6 alkyl)2 or -(C1-6 alkylene)-OH.

16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more C1-6 alkyls.

17. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R1 is pyrazolyl or pyrrolyl, each of which is optionally substituted with one or more methyls.

18. R １ The compound according to claim 14, or a pharmaceutically acceptable salt thereof, and / or a deuterated acid salt, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R is phenyl optionally substituted with one or more halogens.

19. R １ is furanyl, thienyl, pyridyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, imidazo[1,2-a]pyridyl, piperazinyl or cyclohexenyl, each of which is optionally substituted with one or more C １－６ alkyl, the compound according to claim 14 or a pharmaceutically acceptable salt thereof, and / or its deuterated acid salt, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

20. W is NH; R １ is pyrazolyl, pyridyl or thiazolyl, each of which is halogen, C １－６ alkyl, C １－６ haloalkyl, -(C １－６ alkylene)-NH ２ ,-(C １－６ alkylene)-NH(C １－６ alkyl),-(C １－６ alkylene)-N(C １－６ alkyl) ２ or -(C １－６ alkylene)-OH and is optionally substituted with one or more groups selected therefrom, a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R1 is pyrazolyl, pyridyl or thiazolyl, each of which is optionally substituted with one or more groups selected from C1-6 alkyl or C1-6 haloalkyl.

22. R ２ is C １－６ alkyl, C ２－６ alkenyl, -(CH ２ CH ２ )-O-(C １－６ alkyl), -(CH ２ CH ２ )-OH, C ３－６ cycloalkyl or oxetanyl, the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer, wherein R2 is C1-6 alkyl.

24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R2 is methyl, ethyl or i-propyl.

25. R ３ and R ４ each independently is hydrogen, halogen, -CN, C １－６ alkyl or -O(C １－６ alkyl); when X is CH, at least one of R ３ and R ４ is hydrogen, the compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

26. The compound according to claim 25, or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R3 is hydrogen, halogen, -CN, C1-6 alkyl or -O(C1-6 alkyl); and R4 is hydrogen or C1-6 alkyl.

27. Y ３ is CR ９ in the case where R ２ and R ９ together with the N and C atoms to which they are attached form pyridine or pyrrolidine, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

28. 【Chemical Formula 4】 is ​ and R １０ is C １－６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof, wherein R is C alkyl.

29. X is CR ５ and; Z １ and Z ２ are each independently CR ６ and; Y １ is CR ７ and; Y ２ is N or CR ８ and; Y ３ is CR ９ and; W is absent; R １ is a 5- to 6-membered heteroaryl optionally substituted with one or more C １－６ alkyl; R ２ is C １－６ alkyl; R ３ , R ４ , R ５ , R ６ , R ７ and R ８ are each independently hydrogen, halogen, C １－６ alkyl or -O(C １－６ alkyl) selected from; at least one of R ３ and R ４ is hydrogen; R ９ is hydrogen or C １－６ alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and / or its deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer.

30. X is CH; Z １ and Z ２ are both CH; Y １ is CH; Y ２ is N or CH; Y ３ is CR ９ ; W is absent; R １ is pyrazolyl optionally substituted with one or more C １－６ alkyl; R ２ is C １－６ alkyl; R ３ is hydrogen, halogen, C １－６ alkyl or -O(C １－６ alkyl); R ４ is hydrogen; R ９ is hydrogen or C １－６ alkyl, the compound according to claim 29 or a pharmaceutically acceptable salt thereof, and / or a deuteride, solvate, racemic mixture, enantiomer, diastereomer and tautomer thereof.

31.

30. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】

32.

31. A pharmaceutical composition comprising the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, optionally comprising a pharmaceutically acceptable excipient.

33.

32. Use of the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease in a subject.

34.

33. Use according to claim 33, wherein the disease is cancer, an autoimmune disease, an inflammatory disease, a metabolic disease, a neurodegenerative disease, obesity or an obesity-related disease.

35. Use according to claim 34, wherein the cancer is selected from solid tumors or hematological malignancies; and the autoimmune disease or inflammatory disease is selected from arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, autoimmune nephritis, Crohn's disease, asthma and chronic obstructive pulmonary disease.

36. Use according to claim 34, wherein the cancer is selected from ovarian cancer, lung cancer, brain tumor, tenosynovial giant cell tumor, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelioma, renal cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial cancer, bladder cancer, endometrial cancer, choriocarcinoma, adrenal cancer, sarcoma, leukemia, lymphoma and myeloma.

37. Use according to claim 34, wherein the cancer is selected from non-small cell lung cancer and glioblastoma (GBM).

38. Use according to claim 35, wherein the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis and collagen-induced arthritis.

39. A combination comprising the compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent.

40. The combination according to claim 39, wherein the additional therapeutic agent is an anti-tumor agent.

41. The combination according to claim 40, wherein the anti-tumor agent is selected from chemotherapeutic agents, immune checkpoint inhibitors and agonists, and targeted therapeutic agents.

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