Heteroaromatic compounds and uses thereof

Abstract

The present application relates to heteroaromatic compounds and uses thereof. In particular, the present application relates to heteroaromatic compounds of formula (I), pharmaceutical compositions comprising them, and methods of their preparation and uses, wherein the variables are as defined in the specification.

Description

Technical Field

[0001] This invention relates to heterocyclic aromatic compounds, pharmaceutical compositions comprising them, and methods for their preparation and use. Background Technology

[0002] The type III tyrosine kinase receptor family includes CSF-1R, PDGFRα, PDGFRβ, FLT3, and c-KIT. All members of this family consist of an extracellular immunoglobulin-like domain, a transmembrane domain, a juxtamembrane domain, and a protein kinase domain, with the kinase domain being highly conserved (Nat Rev Cancer. 2012, 12(11):753-66). Their mediated phosphorylation signaling participates in numerous cellular biological functions and plays a crucial role in disease development. Among these, mutations in the PDGFRα and c-KIT kinase domains have been reported to lead to gastrointestinal tumors (J Pathol. 2011, 223(2):251-261). Furthermore, tandem duplication of FLT-3 (FLT3-ITD) has been identified as a key pathogenic factor in approximately 20% of patients with acute lymphoblastic leukemia (Biomark Insights. 2015, 10(Suppl 3):1-14).

[0003] CSF-1R, or CSF-1 receptor (Colony stimulating factor 1 receptor), is encoded by the oncogene c-fms. The human c-fms gene is located on chromosome 5, 5q33.3, downstream of the PDGF-Rβ gene, with the two linked end-to-end. Human CSF-1R is a single-chain, transmembrane receptor tyrosine kinase, a transmembrane glycoprotein composed of 972 amino acids with a molecular weight of 150 kDa. It consists of a 512-amino acid extracellular domain, a 25-amino acid transmembrane domain, and a 435-amino acid intracellular cytoplasmic domain. Its extracellular region has 5 disulfide bonds and 11 possible glycosylation sites, and its intracellular region has a Gly-X-Gly-XX-Gly motif. The lysine at position 616 is the ATP binding site. There is a 72-amino acid kinase insertion region on the flanking side of this site, which is speculated to have the function of recognizing specific substrates (ColdSpring 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 unique cell surface receptor, CSF-1R. After binding to CSF-1, CSF-1R undergoes a conformational change, forming a dimer or higher polymer. After dimerization, the tyrosine kinase activity of the receptor is activated, and tyrosine residues at positions 544, 559, 699, 708, 723, 809, and 923 are phosphorylated. Subsequently, these residues interact with multiple intracellular signaling pathways, such as Ras, MAPK, PI3K, and JAK, leading to 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 development. Studies have shown that tumor-associated macrophages (TAMs) play an important role in tumor development, growth, and metastasis. For primary tumors, macrophages can stimulate angiogenesis, assist in the extravasation, survival, and sustained growth of tumor cells, thereby promoting tumor cell metastasis. TAMs also play an immunosuppressive role, preventing natural killer cells and T cells from attacking tumor cells (Immunity. 2014, 41(1):49-61). CSF-1R is expressed in macrophages, and the survival and differentiation of macrophages depend on the CSF-1 / CSF-1R signaling pathway. The CSF-1 / CSF-1R signaling pathway intervenes in tumor progression by regulating TAMs, reducing tumor invasiveness and proliferation, so the CSF1 / CSF1R signaling pathway is a potential target for cancer therapy. Overexpression of CSF-1 or CSF-1R is associated with malignant invasiveness and poor prognosis in tumors. Studies have shown that the application of CSF-1R inhibitors can affect 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). In addition, abnormally high expression of CSF-1 is a major pathogenesis of tenosynovial giant cell tumor (a rare non-metastatic tumor of the tendon sheath that presents as a giant cell tumor and pigmented villonodular synovitis). Patients with tenosynovial giant cell tumor have shown significant clinical benefits after using CSF-1R inhibitors (N Engl J Med. 2015, 373(5): 428-37).

[0006] Besides 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 to treat these diseases.

[0007] Furthermore, a growing body of research indicates that neurological inflammation and abnormal activation of microglia are important pathogenic factors in related neurodegenerative diseases, particularly Alzheimer's disease (Neurobiol Aging. 2000, 21:383-421). Among these, the CSF-1R-mediated signaling pathway plays a dominant role in the activation and proliferation of microglia. Studies have shown that CSF-1R expression is significantly upregulated in tissue samples from Alzheimer's patients, accompanied by abnormal activation and proliferation of microglia (Brain Res. 1994, 639:171–4). Animal model studies have shown that blocking CSF-1R signaling can effectively inhibit microglia proliferation, thereby effectively improving disease progression in Alzheimer's disease model mice (Brain. 2016, 139:891-907). In other neurodegenerative disease models, such as amyotrophic lateral sclerosis (ALS), the therapeutic effect of targeting CSF-1R has also been preliminarily validated (Sci Rep. 2016, 6:25663). Currently, several CSF-1R inhibitor candidates are undergoing clinical trials related to neurodegenerative diseases.

[0008] There is a need for new CSF-1R inhibitors for the treatment of diseases such as cancer, autoimmune diseases, inflammatory diseases, or neurodegenerative diseases. This invention addresses these needs.

[0009] Invention Summary

[0010] This invention provides compounds of formula (I):

[0011]

[0012] Or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein:

[0013] R1 is selected from:

[0014] Selected from phenyl and 5-6-membered heteroaryl groups, each optionally substituted by one or more groups independently selected from: -CN, halogen, C 1-6 Alkyl, -O(C) 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN and -C 1-6 alkylene-OH;

[0015] R1' is selected from H, halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene groups -OH, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, and NR4R5; R4 and R5 are independently selected from H, halogen, -CN, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH and -O(C) 1-6 Alkyl groups; or R4, R5 and the N atom attached to them together form 4-8 membered heterocycles;

[0016] X is either O or CR6R7; R6 and R7 are independently selected from H, halogens, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene groups -OH, -O(C) 1-6 alkyl) and -O(C 1-6 (halogenated alkyl);

[0017] Y is either N or CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 1-6 Halogenated alkyl groups and -O(C) 1-6 (Halogenated alkyl);

[0018] R a and R b Selected independently from H, halogens, -CN, and C respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C1-6 alkylene groups -OH, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0019] n is 0, 1, 2, 3 or 4;

[0020] R2 is a phenyl or a 5-10 heteroaryl group, each optionally substituted by one or more groups independently selected from: -CN, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-8 Cycloalkyl, 4-8 membered heterocyclic and 5-6 membered heteroaryl; wherein, C as a substituent of R2 3-8 The cycloalkyl, 4-8-membered heterocyclic, or 5-6-membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: -CN, halogen, C 1-6 Alkyl, -O(C) 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN and -C 1-6 alkylene-OH;

[0021] Alternatively, when Y is CR3 and n is not 0, R3 and an R a The carbon atoms attached to them, along with the atoms between the carbon atoms, form 4-8 membered heterocycles.

[0022] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention (e.g., any of the examples herein) and / or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier).

[0023] The present invention also provides a method for inhibiting CSF-1R activity in vivo or in vitro, comprising contacting an effective amount of a compound of formula (I) of the present invention (e.g., any of the examples herein) and / or a pharmaceutically acceptable salt thereof with CSF-1R.

[0024] The present invention also provides a method for treating an individual with a disease mediated by or at least partially mediated by CSF-1R, comprising administering to the individual in need an effective amount of a compound of formula (I) of the present invention (e.g., any of the examples herein) and / or a pharmaceutically acceptable salt thereof.

[0025] The present invention also provides a method for treating an individual with an autoimmune disease, inflammatory disease, neurodegenerative disease, cancer, metabolic disease, obesity, or obesity-related disease, comprising administering to an individual in need an effective amount of a compound of formula (I) of the present invention (e.g., any of the examples herein) and / or a pharmaceutically acceptable salt thereof.

[0026] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., compounds of any of the embodiments herein) and / or pharmaceutically acceptable salts thereof in treating an individual with a disease mediated by or at least partially mediated by CSF-1R.

[0027] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., compounds of any of the embodiments herein) and / or pharmaceutically acceptable salts thereof in the treatment of individuals with autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cancer, metabolic diseases, obesity, or obesity-related diseases.

[0028] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., compounds of any of the embodiments herein) and / or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating an individual with a disease mediated by or at least partially mediated by CSF-1R.

[0029] The present invention also provides the use of compounds of formula (I) of the present invention (e.g., compounds of any of the embodiments herein) and / or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating an individual’s autoimmune disease, inflammatory disease, neurodegenerative disease, cancer, metabolic disease, obesity, or obesity-related disease. Invention Details

[0031] definition

[0032] The following words, phrases and symbols used in this application have the meanings described below, unless otherwise stated in the context.

[0033] A hyphen ("-") not between two letters or symbols indicates the connection site of a substituent. For example, -O(C 1-6 Alkyl groups are molecules in which carbon atoms are attached to the rest of the molecule via oxygen atoms. 1-6Alkyl groups. When the linking site of the substituent is well known to those skilled in the art, the "-" may be omitted, for example, halogen substituents.

[0034] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and even more preferably 1-4 (e.g., 1-3 or 1-2) carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("n-Pr"), isopropyl ("i-Pr"), n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), and tert-butyl ("t-Bu").

[0035] As used herein, the term "alkylene" refers to a straight-chain or branched saturated divalent hydrocarbon group containing 1-18 carbon atoms, preferably 1-10 carbon atoms, particularly preferably 1-6 carbon atoms, and even more preferably 1-4 carbon atoms (e.g., 1-3 or 1-2). For example, "C 1-6 "alkylene" refers to a straight-chain or branched alkylene chain having 1-6 carbon atoms, such as a straight-chain alkylene chain -(CH2). n -, where n is an integer from 1 to 6, such as -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, etc., or branched alkylene groups, such as -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-, -C(CH3)2-, etc.

[0036] As used herein, the term "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon double bonds (C=C), having 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms. For example, "C 2-6 "Alkenyl" refers to an alkenyl group containing 1, 2, or 3, preferably 1 or 2, carbon-carbon double bonds and having 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, and 2-butenyl. The alkenyl group may or may not be attached to a double bond.

[0037] As used herein, the term "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon group containing one or more, for example, 1, 2, or 3 carbon-carbon triple bonds (C≡C), having 2-10 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon atoms. For example, "C 2-6 "Alynyl" refers to an alkynyl group containing 1, 2, or 3, preferably 1 or 2, carbon-carbon triple bonds and having 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The alkynyl group may or may not be attached to a triple bond.

[0038] As used herein, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine, and more preferably fluorine and chlorine.

[0039] As used herein, the term "haloalkyl" or "haloalkyl" means an alkyl group as defined herein in which one or more hydrogen atoms, for example 1, 2, 3, 4, 5, or 6 hydrogen atoms, are replaced by halogen atoms, and when more than one hydrogen atom is replaced by a halogen atom, the halogen atoms may be the same as or different from each other. 1-6 A haloalkyl group is an alkyl group having 1 to 6 carbon atoms in which one or more hydrogen atoms, for example 1, 2, 3, 4, 5 or 6 hydrogen atoms, are replaced by halogen atoms. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH(CF3)2, etc.

[0040] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3-12 ring carbon atoms (e.g., 3-8 ring carbon atoms, 5-7 ring carbon atoms, 4-7 ring carbon atoms, 5-6 ring carbon atoms, or 3-6 ring carbon atoms); it may have one or more rings, such as 1, 2, or 3, preferably 1 or 2 rings. For example, "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3-8 ring carbon atoms. Cycloalkyl groups may include fused or bridged rings and spirocyclic rings. The ring of a cycloalkyl group may be saturated and may contain one or more double bonds, such as one or two (i.e., partially unsaturated), but it is not fully conjugated and is not an "aryl" group as defined in this invention. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptyl, bicyclo[3.1.1]heptyl, spiro[3.3]heptyl, spiro[2.2]pentyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and bicyclo[3.1.1]hept-2-ene. In one embodiment of the invention, the ring of the cycloalkyl group is saturated.

[0041] As used herein, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring having 3-12 ring atoms (e.g., 3-8, 4-8, 5-7, 4-6, 3-6, or 5-6 ring atoms), wherein the rings contain one or more (e.g., 1, 2, or 3, preferably 1 or 2) cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms. N and S may optionally be oxidized to various oxidation states, and the junction of the heterocyclic group may be on an N heteroatom or a carbon atom. For example, "3-12-membered heterocyclic group" or "3-12-membered heterocycle" indicates a heterocyclic group having 3-12 ring atoms containing at least one heteroatom selected from N, O, and S; "4-8-membered heterocyclic group" or "4-8-membered heterocycle" indicates a heterocyclic group having 4-8 ring atoms containing at least one heteroatom selected from N, O, and S. Heterocyclic rings or heterocyclic groups may include fused or bridged rings and spirocyclic rings. The ring of a heterocyclic ring or heterocyclic group may be saturated and may contain one or more double bonds, such as one or two double bonds (i.e., partially unsaturated), but it is not fully conjugated and is not a "heteroaryl" as defined in this invention. In one embodiment of the invention, the ring of the heterocyclic ring or heterocyclic group is saturated. Examples of heterocyclic groups include, but are not limited to: ethylene oxide, aziridinyl, oxetane, azirane, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxopent ... Alkyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazine, pyrazolyl, dihydro Diazolyl and oxazolo[3.3]heptyl.

[0042] As used herein, the term "aryl" or "aromatic ring" refers to a carbocyclic hydrocarbon group containing 6-14 carbon atoms, consisting of one or more fused rings, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulel, preferably phenyl and naphthyl, with phenyl being the most preferred.

[0043] As used herein, the term "heteroaryl" or "heteroary ring" refers to an aromatic hydrocarbon group (i.e., a 5-14-membered heteroaryl, 5-12-membered heteroaryl, 5-10-membered heteroaryl, 5-6-membered heteroaryl, or 6-membered heteroaryl) having 5-14 ring atoms (e.g., 5-12, 5-10, 5-6, or 6 ring atoms), wherein the ring comprises one or more (e.g., 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2) cyclic heteroatoms independently selected from N, O, and S, and the remaining ring atoms are carbon atoms; it may have one or more rings, such as 1, 2, or 3, preferably 1 or 2 rings, for example, the heteroaryl includes:

[0044] A monocyclic aromatic hydrocarbon group having 5, 6, or 7 ring atoms (preferably 5 or 6 ring atoms, i.e., 5-6 membered heteroaryl groups), wherein the ring contains one or more, for example 1, 2, 3, or 4, preferably 1, 2, or 3, more preferably 1 or 2 cyclic heteroatoms independently selected from N, O, and S (preferably N and O), and the remaining ring atoms are carbon atoms; and

[0045] A bicyclic aromatic hydrocarbon group having 8-12 ring atoms (preferably 9 or 10 ring atoms), wherein at least one ring contains one or more, for example 1, 2, 3 or 4, preferably 1, 2 or 3, cyclic heteroatoms independently selected from N, O and S (preferably N), and the remaining ring atoms are carbon atoms, wherein at least one ring is an aromatic ring. For example, a bicyclic heteroaryl group comprises a 5-6 membered heteroaryl ring fused to a 5-6 membered alkyl ring.

[0046] When the total number of S and O atoms in a heteroaryl group exceeds 1, these S and O heteroatoms are not adjacent to each other.

[0047] Heteroaryl groups also include those in which the N-ring atom is in the form of an N-oxide, such as N-pyridine oxide.

[0048] Examples of heteroaryl groups include, but are not limited to, 5-6 membered heteroaryl groups, such as pyridyl, N-pyridyl oxide, pyrazinyl, pyrimidinyl, triazine (e.g., 1,3,5-triazine), pyrazolyl, imidazoleyl, etc. azole group, iso azole group, Diazole groups (e.g., 1,2,4-) Diazolyl, 1,2,5- Diazole group and 1,3,4- Diazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl), thiophene, furanyl, pyranyl, pyrrolithyl, pyridazinyl, and bicyclic heteroaryl groups such as benzo[a]-dioxacyclopentenyl, benzo[a]-dioxacyclopentenyl, etc. azole group, benzo[a] Azolyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, imidazopyridyl (e.g., imidazo[1,2-a]pyridyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), pyrrolopyrimidinyl (e.g., pyrrolo[3,4-d]pyrimidinyl), pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl), pyrazolopyrimidinyl (e.g., pyrazolyl), [1,5-a]pyrimidinyl), triazolopyridyl (e.g., [1,2,4]triazolo[4,3-a]pyridyl and [1,2,4]triazolo[1,5-a]pyridyl), triazolopyridinyl (e.g., [1,2,4]triazolo[4,3-b]pyridinyl), tetraazolopyridyl (e.g., tetraazolo[1,5-a]pyridyl), benzofuranyl, benzimidazolinyl, indolyl, indazole, purinyl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0049] The term "hydroxyl group" as used in this article refers to the –OH group.

[0050] The term "oxo" as used in this article refers to the =O group.

[0051] The term "cyano" as used in this article refers to the -CN group.

[0052] As used herein, the terms “optional,” “optional,” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. For example, “optionally substituted alkyl” includes both “unsubstituted alkyl” and “substituted alkyl” as defined herein. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable.

[0053] As used herein, the terms “substituted” or “replaced by” mean that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, provided that the substitution does not exceed the normal valence of the given atom. When the substituent is oxo (i.e., =O), two hydrogen atoms on a single atom are replaced. Such combinations are permitted only if the combination of substituents and / or variables results in a chemically correct and stable compound. A chemically correct and stable compound means that the compound is stable enough to be isolated from the reaction mixture and subsequently formulated into an agent with at least practical utility.

[0054] Unless otherwise stated, substituents are named within the core structure. For example, it should be understood that when (cycloalkyl)alkyl is listed as a possible substituent, it indicates that the substituent is attached to the core structure at the alkyl moiety.

[0055] As used herein, the term "substituted by one or more groups" means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group. In some embodiments, "substituted by one or more groups" means that a given atom or group is replaced by 1, 2, 3 or 4 substituents independently selected from the given group.

[0056] Those skilled in the art will understand that some compounds of formula (I) may contain one or more chiral centers, and thus have two or more stereoisomers. Racemic mixtures of these isomers, mixtures of single isomers and enantiomer-enriched mixtures, and mixtures of diastereomers and specific diastereomer-enriched mixtures when there are two chiral centers are all within the scope of this invention. Those skilled in the art will also understand that this invention includes all single stereoisomers (e.g., enantiomers, such as (R) isomers or (S) isomers), racemic mixtures, or partially separated mixtures of compounds of formula (I), and, where appropriate, single tautomers thereof.

[0057] In some embodiments, the present invention provides compounds containing multiple stereoisomeric purities, i.e., enantiomeric or diastereomeric purities expressed in different "ee" or "de" values. In some embodiments, the compounds of formula (I) described herein have an enantiomeric purity of at least 60% ee (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these listed values). In some embodiments, the compounds of formula (I) described herein have an enantiomeric purity greater than 99.9% ee, reaching 100% ee. In some embodiments, the compounds of formula (I) described herein have a diastereomeric purity of at least 60% de (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% de, or any value between these listed values). In some embodiments, the compounds of formula (I) described herein have a diastereomeric purity greater than 99.9% de.

[0058] The term "enantiomer excess" or "ee" indicates the amount of one enantiomer relative to another. For a mixture of R and S enantiomers, the percentage of enantiomer excess is defined as |RS|*100, where R and S are the molar or weight fractions of their respective enantiomers in the mixture, and R+S=1. If the optical rotation of a chiral substance is known, the percentage of enantiomer excess is defined as ([a]obs / [a]max)*100, where [a]obs is the optical rotation of the enantiomer mixture, and [a]max is the optical rotation of the pure enantiomer.

[0059] The term "diasteresome excess" or "de" indicates the amount of one diastereomer relative to another, and is defined by analogy based on enantiomer excess. Therefore, for a mixture of diastereomers D1 and D2, the percentage of diastereomer excess is defined as |D1–D2|*100, where D1 and D2 are the molar or weight fractions of their respective diastereomers in the mixture, and D1+D2=1.

[0060] The determination of diastereomer excess and enantiomeric excess can be performed using a variety of analytical techniques (including nuclear magnetic resonance spectroscopy, chiral column chromatography and / or optical rotation determination) and according to conventional procedures familiar to those skilled in the art.

[0061] Racemic mixtures can be used in their original form or can be resolved into their individual isomers. Resolution yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for isomer separation are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyl tartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, and then freeing one or both of the resolved bases. Optionally, this process is repeated to obtain one or two isomers that substantially do not contain the other isomer, i.e., isomers with optical purity >95%. Alternatively, the racemic compound can be covalently attached to a chiral compound (auxiliary compound) to obtain diastereomers, which can be separated by chromatography or fractional crystallization. The chiral auxiliary compound can then be chemically removed to obtain pure enantiomers.

[0062] The term "tautomer" refers to a functional group isomer that occurs when an atom in a molecule rapidly moves between two positions. Tautomers can interconvert; for example, enols and ketos are typical tautomers.

[0063] "Pharmaceutical-acceptable salts" refer to salts of free acids or bases of formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to an individual. For example, pharmaceutically acceptable salts are acid addition salts, including, for example, addition salts derived from inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid, and such organic acids as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. For a general description of pharmaceutically acceptable salts, see, for example: SMBerge 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.

[0064] Furthermore, if the compound described herein is obtained as an acid addition salt, its free base form can be obtained by alkalizing the solution of the acid addition salt. Conversely, if the product is in the form of a free base, its acid addition salt, particularly a pharmaceutically acceptable acid addition salt, can be obtained by following the conventional procedure for preparing acid addition salts from basic compounds, by dissolving the free base in a suitable solvent and treating the solution with acid. Those skilled in the art can determine various synthetic methods for preparing non-toxic, pharmaceutically acceptable acid or base addition salts without extensive experimentation.

[0065] The term "solvate" refers to a solvation form containing stoichiometric or non-stoichiometric solvents. Some compounds have a tendency to engulf solvent molecules in a fixed molar ratio in the solid state, thus forming solvates. If the solvent is water, the formed solvate is a hydrate; when the solvent is ethanol, the formed solvate is an ethanolate. Hydrates are formed by one or more molecules of water with one molecule of the substance in which the water retains its H₂O molecular state; such combinations can form one or more hydrates, such as hemihydrates, monohydrates, and dihydrates.

[0066] The terms “group” and “base” used in this article are synonyms and are used to refer to functional groups or molecular segments that can be linked to other molecular segments.

[0067] The term "active ingredient" is used to refer to a biologically active chemical substance, such as a compound of formula (I) of the present invention (e.g., any of the examples herein) and / or a pharmaceutically acceptable salt thereof. In some embodiments, an "active ingredient" is a chemical substance having pharmaceutical use, the pharmaceutical activity of which can be determined by appropriate in vitro or in vivo testing (e.g., preclinical or clinical trials).

[0068] The term "treatment" or "disposition" refers to the administration of one or more pharmaceutical substances, particularly compounds of formula (I) or pharmaceutically acceptable salts thereof, to an individual suffering from, or having symptoms of, said disease or disorder, or being susceptible to said disease or disorder, in order to cure, heal, alleviate, reduce, alter, treat, improve, modify, or influence said disease or disorder, its symptoms, or the individual's susceptibility to said disease or disorder. In some embodiments, said disease or disorder is an autoimmune disease or an inflammatory disease. In some embodiments, said disease or disorder is a neurodegenerative disease.

[0069] When referring to chemical reactions, the terms “treatment,” “contact,” and “reaction” mean the addition or mixing of two or more reagents under appropriate conditions to produce the shown and / or desired product. It should be understood that the reaction producing the shown and / or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the shown and / or desired product.

[0070] As used herein, the term "effective amount" refers to an amount of the compound of the present invention that is generally sufficient to produce a beneficial therapeutic effect for a patient requiring treatment of a disease or disorder mediated or at least partially mediated by CSF-1R activity. The effective amount of the active ingredient in the present invention can be determined by conventional methods (e.g., modeling, dose-escalation studies, or clinical trials) in conjunction with conventional influencing factors (e.g., route of administration, pharmacokinetics of the drug component, severity of the disease or disorder, individual's prior or ongoing treatment, individual's health status and response to the drug, and the judgment of the attending physician).

[0071] Typical dosage ranges are from about 0.0001 to about 200 mg of active ingredient per kilogram of individual body weight per day, for example from about 0.001 to 100 mg / kg / day, or about 0.01 to 35 mg / kg / day, or about 0.1 to 10 mg / kg, taken once daily or in divided doses (e.g., twice daily, three times daily, four times daily). For a 70 kg person, an appropriate dosage range is exemplified as from about 0.05 to about 7 g / day, or about 0.2 to about 5 g / day.

[0072] The term “inhibition” refers to a reduction in the baseline activity of a biological activity. The term “inhibition of CSF-1R activity” refers to a reduction in CSF-1R activity resulting from a direct or indirect response to the presence of a compound of formula (I) and / or its pharmaceutically acceptable salt, relative to the absence of the compound of formula (I) and / or its pharmaceutically acceptable salt. The reduction in activity may be caused by the direct interaction of the compound of formula (I) and / or its pharmaceutically acceptable salt with CSF-1R, or by the interaction of the compound of formula (I) and / or its pharmaceutically acceptable salt with one or more other factors that affect CSF-1R activity. For example, the presence of the compound of formula (I) and / or its pharmaceutically acceptable salt may reduce CSF-1R activity by directly binding to CSF-1R, by directly or indirectly affecting another factor, or by directly or indirectly reducing the amount of CSF-1R present in cells or the body.

[0073] As used herein, the term "individual" refers to both mammals and non-mammals. Mammals include any member of the mammalian class, including but not limited to: humans; non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds. The term "individual" is not limited to a specific age or sex. In some implementations, an individual is a human being.

[0074] As used herein, the term "approximately" means approximately, around, roughly, or about. When the term "approximately" is used with a numerical range, it adjusts the range by extending the limits to be higher or lower than the given value. Generally, the term "approximately" is used herein to adjust a given value to be 20% higher or lower than that value.

[0075] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Detailed Implementation Plan

[0076] Implementation Scheme 1. Compound of Formula (I):

[0077]

[0078] Or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein:

[0079] R1 is selected from:

[0080] Selected from phenyl and 5-6-membered heteroaryl groups, each optionally substituted by one or more groups independently selected from: -CN, halogen, C 1-6 Alkyl, -O(C) 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN and -C 1-6 alkylene-OH;

[0081] R1' is selected from H, halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene groups -OH, -O(C) 1-6 alkyl), -O(C) 1-6 (halogenated alkyl), C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, and NR4R5; R4 and R5 are independently selected from H, halogen, -CN, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH and -O(C) 1-6 Alkyl groups; or R4, R5 and the N atom attached to them together form 4-8 membered heterocycles;

[0082] X is either O or CR6R7; R6 and R7 are independently selected from H, halogens, and C, respectively. 1-6 Alkyl, C 1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene groups -OH, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0083] Y is either N or CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 1-6 Halogenated alkyl groups and -O(C) 1-6 (Halogenated alkyl);

[0084] R a and R b Selected independently from H, halogens, -CN, and C respectively. 1-6 Alkyl, C1-6 Halogenated alkyl, -C 1-6 Alkylene-CN, -C 1-6 alkylene groups -OH, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0085] n is 0, 1, 2, 3 or 4;

[0086] R2 is a phenyl or a 5-10 heteroaryl group, each optionally substituted by one or more groups independently selected from: -CN, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-8 Cycloalkyl, 4-8 membered heterocyclic and 5-6 membered heteroaryl; wherein, C as a substituent of R2 3-8 The cycloalkyl, 4-8-membered heterocyclic, or 5-6-membered heteroaryl groups are each optionally substituted by one or more groups independently selected from the following: -CN, halogen, C 1-6 Alkyl, -O(C) 1-6 Alkyl), C 1-6 Haloalkyl, -O(C) 1-6 (halogenated alkyl), -C 1-6 Alkylene-CN and -C 1-6 alkylene-OH;

[0087] Alternatively, when Y is CR3 and n is not 0, R3 and an R a The carbon atoms attached to them, along with the atoms between the carbon atoms, form 4-8 membered heterocycles.

[0088] Implementation Scheme 2. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R1 is selected from:

[0089] Implementation Scheme 3. The compound according to Implementation Scheme 2, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R1' is selected from H, C 1-6 Alkyl, C 3-8Cycloalkyl and NR4R5; R4 and R5 are both H; or R4, R5 and the N atom attached to them together form a 4-8 membered heterocycle, preferably a 5 or 6 membered heterocycle containing 0, 1 or 2 heteroatoms independently selected from N, O or S in addition to the N atom attached to R4 and R5, more preferably a morpholine ring.

[0090] Implementation Scheme 4. The compound according to Implementation Scheme 3, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R1' is selected from H and C. 1-6 Alkyl group, preferably R1' selected from H and C 1-3 Alkyl group, more preferably R1' is selected from H and methyl.

[0091] Implementation Scheme 5. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R1 is selected from...

[0092] It is a 5-6 membered heteroaryl group, optionally substituted by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 alkylene-OH; preferably, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 alkylene-OH; more preferably, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl; more preferably, For a C 1-3 Alkyl-substituted pyrazolyl group; most preferably, It is 1-methyl-1H-pyrazole-4-yl.

[0093] Implementation Scheme 6. The compound according to any one of Implementation Schemes 1-5, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein X is O or CH2; preferably, X is O.

[0094] Implementation Scheme 7. A compound according to any one of Implementation Schemes 1-6, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein Y is N or CR3; R3 is selected from H, -CN, halogen, C 1-6 Alkyl, -O(C) 1-6alkyl) and -O(C 1-6 (Halogenated alkyl groups).

[0095] Implementation Scheme 8. The compound according to Implementation Scheme 7, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein Y is CR3, and R3 is selected from H, -CN, halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) or -O(C 1-6 (halogenated alkyl); preferably, R3 is -O(C) 1-6 Alkyl); more preferably, R3 is -O(C 1-3 alkyl).

[0096] Implementation Scheme 9. A compound according to any one of Implementation Schemes 1-8, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R a and R b All are H, and n is 0, 1, or 2; preferably, R a and R b All are H, and n is 1.

[0097] Implementation Scheme 10. A compound according to any one of Implementation Schemes 1-9, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R2 is a phenyl or a 5-6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-8 Cycloalkyl and 5-6-membered heteroaryl groups; wherein, C is a substituent for R2. 3-8 The cycloalkyl or 5-6-membered heteroaryl groups are optionally substituted with one or more halogens.

[0098] Implementation Scheme 11. The compound according to Implementation Scheme 10, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8The cycloalkyl group may optionally be replaced by one or more halogens.

[0099] Implementation Scheme 12. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-1a):

[0100]

[0101] in

[0102] R1' is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl and NR4R5; R4 and R5 are both H; or R4, R5 and the N atom attached to them together form a 4-8 membered heterocycle, preferably a 5 or 6 membered heterocycle containing 0, 1 or 2 heteroatoms independently selected from N, O or S in addition to the N atom attached to R4 and R5, more preferably a morpholine ring;

[0103] X is either O or CH2;

[0104] Y is either N or CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0105] R a and R b All are H;

[0106] n is 0, 1, or 2;

[0107] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-8 Cycloalkyl and 5-6-membered heteroaryl groups; wherein, C is a substituent for R2. 3-8 The cycloalkyl or 5-6-membered heteroaryl groups are optionally substituted with one or more halogens.

[0108] Implementation Scheme 13. The compound according to Implementation Scheme 12, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein,

[0109] R1' is selected from H and C. 1-6 alkyl;

[0110] X is O;

[0111] Y is CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0112] R a and R b All are H;

[0113] n is 1;

[0114] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group may optionally be replaced by one or more halogens.

[0115] Implementation Scheme 14. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-1b):

[0116]

[0117] in

[0118] R1' is selected from H and C. 1-6 alkyl;

[0119] X is O;

[0120] Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0121] R a and R b All are H;

[0122] n is 1 or 2;

[0123] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group may optionally be replaced by one or more halogens.

[0124] Implementation Scheme 15. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-1c):

[0125]

[0126] in

[0127] X is O;

[0128] Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0129] R a and R b All are H;

[0130] n is 1 or 2;

[0131] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group may optionally be replaced by one or more halogens.

[0132] Implementation Scheme 16. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-1d):

[0133]

[0134] in

[0135] X is O;

[0136] Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0137] R a and R b All are H;

[0138] n is 1 or 2;

[0139] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group may optionally be replaced by one or more halogens.

[0140] Implementation Scheme 17. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-1e):

[0141]

[0142] in

[0143] It is a 5-6 membered heteroaryl group, optionally substituted by one or more groups independently selected from the following: C 1-6 alkyl;

[0144] X is either O or CH2;

[0145] Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl);

[0146] R a and R b All are H;

[0147] n is 1 or 2;

[0148] R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group may optionally be replaced by one or more halogens.

[0149] Implementation Scheme 18. The compound according to Implementation Scheme 17, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl; preferably, For a C 1-3 Alkyl-substituted pyrazolyl group; more preferably, It is 1-methyl-1H-pyrazole-4-yl.

[0150] Implementation Scheme 19. The compound according to Implementation Scheme 1, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, when Y is CR3 and n is not 0, R3 and an R a The carbon atoms attached to them, along with the atoms between the carbon atoms, form 5-6 membered heterocycles.

[0151] Implementation Scheme 20. The compound according to Implementation Scheme 19, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has a structure of formula (I-2) or formula (I-3); preferably, the compound has a structure of formula (I-2):

[0152]

[0153] R1, R2, and X are as defined in Implementation Scheme 1.

[0154] Implementation Scheme 21. The compound according to Implementation Scheme 20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-2a):

[0155]

[0156] in

[0157] R1' is selected from H and C. 1-6 alkyl;

[0158] X is O;

[0159] R2 is a phenyl or a 5-6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group is optionally substituted with one or more halogens; preferably, R2 is phenyl or pyridyl, each optionally substituted with one or more groups independently selected from: -O(C 1-6 alkyl) and C 3-8 Cycloalkyl.

[0160] Implementation Scheme 22. The compound according to Implementation Scheme 20, or a pharmaceutically acceptable salt thereof, or a solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein the compound has the structure of formula (I-2b):

[0161]

[0162] in

[0163] It is a 5-6 membered heteroaryl group, optionally substituted by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 alkylene-OH; preferably, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 alkylene-OH; more preferably, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl; more preferably, For a C 1-3 Alkyl-substituted pyrazolyl group; most preferably, It is 1-methyl-1H-pyrazole-4-yl;

[0164] X is O;

[0165] R2 is a phenyl or a 5-6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-8 Cycloalkyl; wherein, C, as a substituent of R2 3-8 The cycloalkyl group is optionally substituted with one or more halogens; preferably, R2 is phenyl or pyridyl, each optionally substituted with one or more groups independently selected from: -O(C 1-6 alkyl) and C 3-8 Cycloalkyl; more preferably, R2 is pyridyl, which is optionally substituted by one or more groups independently selected from: -O(C 1-6 alkyl) and C 3-8 Cycloalkyl.

[0166] Implementation Scheme 23. A compound of formula (I) according to Implementation Scheme 1, selected from the following compounds or pharmaceutically acceptable salts thereof.

[0167]

[0168]

[0169]

[0170]

[0171] Implementation Scheme 24. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof described in any one of Implementation Schemes 1-23, and optionally comprising a pharmaceutically acceptable excipient.

[0172] Implementation Scheme 25. A method for inhibiting CSF-1R activity in vivo or in vitro, comprising contacting an effective amount of the compound of any one of Implementation Schemes 1-23 or a pharmaceutically acceptable salt thereof with CSF-1R.

[0173] Implementation Scheme 26. A method for treating an individual with a disease mediated or at least partially mediated by CSF-1R, comprising administering to the individual in need an effective amount of any one of Implementation Schemes 1-23 or a pharmaceutically acceptable salt thereof.

[0174] Implementation Scheme 27. The method described in Implementation Scheme 26, wherein: the disease is an autoimmune disease, an inflammatory disease, a neurodegenerative disease, cancer, a metabolic disease, obesity or an obesity-related disease.

[0175] Implementation Scheme 28. Use of any compound of embodiments 1-23 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an individual with a disease mediated by or at least partially mediated by CSF-1R.

[0176] Implementation Scheme 29. The use according to Implementation Scheme 28, wherein: the disease is an autoimmune disease, an inflammatory disease, a neurodegenerative disease, cancer, a metabolic disease, obesity or an obesity-related disease.

[0177] Implementation Scheme 30. According to the use described in Implementation Scheme 29, wherein: the autoimmune disease or inflammatory disease is selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and organ damage caused by chemotherapy drugs; the neurodegenerative disease is selected from Parkinson's disease (PD), multiple system atrophy, etc. Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary motor sensory neuropathy (CMT); the cancers mentioned are solid tumors or hematologic malignancies, such as ovarian cancer, lung cancer (including non-small cell lung cancer), brain tumors (including glioblastoma (GBM)), giant cell tumor of the tendinus sheath, gastrointestinal stromal tumors (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelial endometrial carcinoma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal carcinoma, sarcoma, leukemia, lymphoma, or myeloma.

[0178] Implementation Scheme 31. A pharmaceutical combination product comprising any one of the compounds described in Implementation Schemes 1-23 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

[0179] Implementation Scheme 32. The pharmaceutical combination product according to Implementation Scheme 31, wherein: the additional therapeutic agent is an anti-inflammatory agent or an antitumor agent; preferably, the antitumor agent is selected from radiotherapy agents, chemotherapy agents, immune checkpoint inhibitors or agonists, and targeted therapeutic agents.

[0180] In some implementations, the diseases mediated by CSF-1R or at least partially mediated by CSF-1R are autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cancer, metabolic diseases, obesity, or obesity-related diseases.

[0181] In some implementations, the disease mediated by CSF-1R or at least partially mediated by CSF-1R is an autoimmune disease, an inflammatory disease, or a neurodegenerative disease.

[0182] In some implementations, the autoimmune or inflammatory diseases are selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and organ damage caused by chemotherapy drugs.

[0183] In some implementations, the neurodegenerative diseases are selected from Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary motor sensory neuropathy (CMT).

[0184] General Synthesis Method

[0185] The compounds of formula (I) described herein and / or their pharmaceutically acceptable salts can be synthesized from commercially available starting materials, by methods known in the art, or by methods disclosed herein. The synthetic routes shown in routes 1-3 illustrate general synthetic methods for the compounds of the present invention.

[0186]

[0187] As shown in Route 1, under alkaline conditions (e.g., but not limited to NaH), the compound of formula (1-1) undergoes a substitution reaction with the compound of formula (1-2) to give the compound of formula (1-3). The compound of formula (1-3) is then catalyzed by a palladium reagent (e.g., but not limited to Pd(dppf)Cl2) to generate the compound of formula (1-4), which is further converted to the compound of formula (1-5) via an oxidation reaction (e.g., but not limited to using H2O2 as the oxidant). The compound of formula (1-5) undergoes a substitution reaction with the compound of formula (1-6) under alkaline conditions (e.g., but not limited to potassium carbonate) to give the compound of formula (I) (where X = O). Alternatively, the compound of formula (1-4) reacts with the compound of formula (1-7) under palladium reagent (e.g., but not limited to Pd(dppf)Cl2) catalyzed to give the compound of formula (I) (where X = CH2). Wherein, R1, R2, R... a R b Y and n are as defined in this paper.

[0188]

[0189] As shown in Route 2, under alkaline conditions (e.g., but not limited to cesium carbonate), the compound of formula (2-1) undergoes a substitution reaction with the compound of formula (2-2) to give the compound of formula (2-3). The compound of formula (2-3) undergoes a reduction reaction (e.g., but not limited to using iron as a reducing agent) to generate the compound of formula (2-4), which is then further converted to the compound of formula (2-5) under the action of sulfuric acid and sodium nitrite. The compound of formula (2-5) and the compound of formula (2-6) undergo a Mitsunobu reaction to give the compound of formula (I) (where X = O). Wherein, R1, R2, R... a R b Y and n are as defined in this paper.

[0190]

[0191] As shown in route 3, under alkaline conditions (e.g., but not limited to cesium carbonate), the compound of formula (3-1) undergoes a substitution reaction with the compound of formula (3-2) to give the compound of formula (3-3). The compound of formula (3-3) undergoes a reduction reaction (e.g., but not limited to using iron as a reducing agent) to generate the compound of formula (3-4), which further undergoes a ring-closure reaction (e.g., with...). A ring-closure reaction is carried out to produce a compound of formula (3-5). The compound of formula (3-5) undergoes a substitution reaction with the compound of formula (3-6) under basic conditions (e.g., but not limited to cesium carbonate) to give a compound of formula (I-1a) (where X = O). Wherein, R1', R2, R... a R b Y and n are as defined in this paper.

[0192] The substituents of the compounds obtained by the above methods can be further modified to obtain other desired compounds. For synthetic chemical transformation methods, see, for example: 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 subsequent editions.

[0193] Prior to use, the compounds of formula (I) described herein and / or their pharmaceutically acceptable salts may be purified by column chromatography, high performance liquid chromatography, crystallization or other suitable methods.

[0194] Pharmaceutical Compositions and Uses

[0195] Pharmaceutical compositions comprising compounds of formula (I) described herein (e.g., any of the examples herein) or pharmaceutically acceptable salts thereof may be administered in a variety of known manners, such as oral, parenteral, inhalation, or implantation. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intravertebral, intra-affective, and intracranial injections or infusions.

[0196] Orally administered compositions can be in any orally acceptable dosage form, including but not limited to: tablets, capsules, pills, powders, emulsions, and aqueous suspensions, dispersants, and solutions. Common tablet carriers include lactose and corn starch. Lubricants such as magnesium stearate are also frequently added to tablets. When administered orally in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspension or emulsion form, emulsifiers or suspending agents can be used to suspend or dissolve the active ingredient in the oil phase. If necessary, certain sweeteners, flavoring agents, or colorings may be added.

[0197] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in one tablet may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg. In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof in one capsule may be 1, 5, 10, 15, 20, 25, 50, 75, 80, 85, 90, 95, 100, 125, 150, 200, 250, 300, 400, and 500 mg.

[0198] Sterile injectable compositions (such as aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable intermediates can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Pharmaceutically acceptable carriers and solvents, particularly mannitol, water, Ringer's solution, and physiological saline, are commonly used. Furthermore, sterile, non-volatile oils, such as synthetic mono- or diglycerides, are often used as solvents or suspension media. Fatty acids, such as oleic acid and its glyceride derivatives, and natural, pharmaceutically acceptable oils, such as olive oil or castor oil (especially in their polyoxyethylated forms), are commonly used as injectable intermediates. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants.

[0199] Inhalation compositions can be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers that improve bioavailability, fluorocarbons and / or other solubilizers or dispersants known in the art, according to techniques well known in the pharmaceutical formulation field, or they can be prepared as solutions in saline.

[0200] Topical compositions can be formulated as oils, creams, lotions, ointments, etc. Suitable carriers for the compositions include vegetable or mineral oils, white petrolatum (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (i.e., alcohols with more than 12 carbon atoms). In some embodiments, pharmaceutically acceptable carriers are those in which the active ingredient can dissolve. If desired, the composition may also contain emulsifiers, stabilizers, wetting agents, and antioxidants, as well as substances that impart color or fragrance. Furthermore, transdermal penetration enhancers may be added to the topical formulation. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0201] Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, with an active ingredient dissolved in a small amount of oil, such as almond oil, incorporated therein. An example of a cream contains approximately 40 parts by weight of water, approximately 20 parts by weight of beeswax, approximately 40 parts by weight of mineral oil, and approximately 1 part by weight of almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm paraffin wax and then cooling the mixture. An example of an ointment contains approximately 30% by weight of almond oil and approximately 70% by weight of white paraffin wax.

[0202] A pharmaceutically acceptable carrier is one that is compatible with (and in some embodiments, stabilizes) the active ingredient in the composition and is harmless to the individual being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with compounds of formula (I) described herein and / or their pharmaceutically acceptable salts) can be used as pharmaceutical excipients to deliver the active ingredient. Other examples of carriers include colloidal silica, magnesium stearate, cellulose, sodium dodecyl sulfate, and pigments such as D&C Yellow #10.

[0203] Appropriate in vitro studies can be used to evaluate the practical use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof in inhibiting CSF-1R activity. Further in vivo studies can be conducted to investigate additional practical use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof in the treatment of autoimmune diseases, inflammatory diseases, neurodegenerative diseases, or cancer, etc. For example, compounds of formula (I) described herein or pharmaceutically acceptable salts thereof can be administered to animals (e.g., mouse models) with autoimmune or inflammatory diseases, and their therapeutic effects can then be evaluated. If the preclinical trial results are successful, the dosage range and route of administration in animals, such as humans, can also be predicted.

[0204] The compounds of formula (I) described herein, or their pharmaceutically acceptable salts, may be used to achieve beneficial therapeutic or preventative effects, for example, in individuals suffering from autoimmune or inflammatory diseases.

[0205] The term "autoimmune disease" refers to a disease or condition caused by damage to one's own tissues or organs due to an immune response to self-antigens. 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 (IBD), Crohn's disease, ulcerative colitis, asthma, autoimmune nephritis, idiopathic thrombocytopenic purpura (ITP), and myeloproliferative diseases, such as myelofibrosis and post-PV / ET myelofibrosis.

[0206] The term "inflammatory disease" or "inflammatory condition" refers to a pathological state that causes inflammation, especially due to neutrophil chemotaxis. Non-limiting examples of inflammatory diseases include systemic and local inflammation, immunosuppression-related inflammation, organ transplant rejection, allergic reactions, inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; reactions associated with inflammatory bowel diseases (IBD, such as Crohn's disease and ulcerative colitis); ischemia-reperfusion injury, including surgically induced tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, post-cardiac reperfusion and abnormal contractile responses of coronary vessels after percutaneous coronary angioplasty, tissue reperfusion injury after stroke and abdominal aortic aneurysm surgery; stroke-related cerebral edema; head trauma, 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) and Sjögren's syndrome. Syndrome; vasculitis; diseases involving leukocyte exudation; inflammatory diseases of the central nervous system (CNS) secondary to sepsis or trauma; multiple organ injury syndrome; alcoholic hepatitis; bacterial pneumonia; antigen-antibody complex-mediated diseases, including glomerulonephritis; septicemia; sarcoidosis; immunopathological reactions following tissue / organ transplantation; pulmonary inflammation, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, allergic pneumonia, idiopathic pulmonary fibrosis (IPF), and cystic fibrosis, etc. Preferred indications include, but are not limited to, 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 inflammatory lung disease, graft-versus-host disease, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and pyresis, and any disease associated with inflammation and related conditions.

[0207] In some implementations, the autoimmune or inflammatory diseases are selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, ischemia-reperfusion injury of solid organs, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and organ damage caused by chemotherapy drugs.

[0208] The compounds of formula (I) described herein, or their pharmaceutically acceptable salts, may be used to achieve beneficial therapeutic or preventative effects, for example, in individuals suffering from neurodegenerative diseases.

[0209] The term "neurodegenerative diseases" refers to neurodegenerative diseases or conditions caused by neuronal degeneration 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, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary motor-sensory neuropathy (CMT).

[0210] In some implementations, the neurodegenerative disease is selected from Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA).

[0211] The compounds of formula (I) described herein, or their pharmaceutically acceptable salts, may be used to achieve beneficial therapeutic or preventative effects, for example, in individuals with cancer.

[0212] As used herein, the term "cancer" refers to a cellular disorder characterized by uncontrolled or disordered cell proliferation, reduced cell differentiation, inappropriate invasion of surrounding tissues, and / or the ability to establish new growth sites in other locations. The term "cancer" includes, but is not limited to, solid tumors and hematologic malignancies. The term "cancer" includes cancers of the skin, tissues, organs, bones, cartilage, blood, and blood vessels. The term "cancer" includes both primary and metastatic cancers.

[0213] 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 non-androgen-dependent prostate cancer; testicular cancer; kidney cancer, including, for example, metastatic renal cell carcinoma; urothelial carcinoma; liver cancer; hepatocellular carcinoma; lung cancer, including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial carcinoma or primary peritoneal carcinoma; cervical cancer; endometrial cancer; and gastrointestinal stromal tumors (GIST). Cancers that can cause: gastric cancer; esophageal cancer; head and neck cancers, including, for example, squamous cell carcinoma of the head and neck; skin cancers, including, for example, melanoma and basal carcinoma; neuroendocrine carcinomas, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme and adult anaplastic astrocytoma; bone cancer; sarcomas, including, for example, Kaposi's sarcoma; adrenal carcinoma; mesothelioma; mesothelial endometrial carcinoma; choriocarcinoma; muscle cancer; connective tissue carcinoma; giant cell tumor of the tendon sheath; and thyroid cancer.

[0214] Non-limiting examples of hematologic malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast crisis (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); Waldenström macroglobulinemia; myelodysplastic syndromes (MDS), including refractory anemia (RA), ringed sideroblastic refractory anemia (RARS), excessive budding cell refractory anemia (RAEB), and excessive budding cell refractory anemia with acute transformation (RAEB-T); and myeloproliferative syndrome.

[0215] In some implementations, solid tumors include ovarian cancer, lung cancer (including non-small cell lung cancer), glioblastoma (GBM), giant cell tenosynovitis, gastrointestinal stromal tumors (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelial endometrial carcinoma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal carcinoma, and sarcoma.

[0216] In some implementations, typical hematologic malignancies include leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML); multiple myeloma (MM); and lymphomas 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).

[0217] The term "metabolic disease" refers to a disease or condition caused by metabolic problems, including metabolic disorders and hypermetabolism. Examples of metabolic diseases include, but are not limited to: osteoporosis, diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, protein-energy malnutrition, vitamin A deficiency, scurvy, and vitamin D deficiency.

[0218] The term "obesity-related diseases" refers to diseases or conditions that are associated with, caused by, or resulting from obesity. Examples of obesity-related diseases include, but are not limited to: diabetes, hypertension, insulin resistance syndrome, dyslipidemia, heart disease, cardiovascular diseases (including atherosclerosis, arrhythmias, irregular heart rhythms, myocardial infarction, congestive heart failure, coronary artery disease, angina pectoris), cerebral infarction, cerebral hemorrhage, osteoarthritis, metabolic syndrome, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis.

[0219] Furthermore, compounds of formula (I) described herein (e.g., compounds of any of the embodiments herein) or pharmaceutically acceptable salts thereof may be used in combination with additional therapeutic agents for the treatment of autoimmune diseases, inflammatory diseases, or cancer. These additional therapeutic agents may be administered separately from the compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, or may be included in a pharmaceutical composition, such as a fixed-dose combination drug, in accordance with this disclosure. In some embodiments, the additional therapeutic agents are those known or found to be effective in treating diseases mediated or at least partially mediated by CSF-1R, such as another CSF-1R inhibitor or a compound that effectively antagonizes another target associated with that particular disease. Combination therapy may be used to improve efficacy (e.g., by including a compound that enhances the potency or effectiveness of a compound of formula (I) described herein or pharmaceutically acceptable salts thereof in the combination therapy), reduce one or more side effects, or reduce the required dose of a compound of formula (I) described herein or pharmaceutically acceptable salts thereof.

[0220] In some embodiments, compounds of formula (I) described herein (e.g., any of the examples herein) or pharmaceutically acceptable salts thereof may be used in combination with anti-inflammatory agents.

[0221] Examples of anti-inflammatory agents include, but are not limited to, corticosteroids (such as fluticasone propionate, beclometasone dipropionate, mometasone furoate, triamcinolone acetonide, or budesonide), disease-modifying agents (such as antimalarial drugs, methotrexate, sulfasalazine, masalazine, azathioprine, 6-mercaptopurine, metronidazole, and D-penicillamine), and nonsteroidal anti-inflammatory drugs (such as acetaminophen, aspirin, sodium salicylate, cromoglycate sodium, magnesium salicylate, and choline magnesium trisalicylate). Trisalicylate, salsalate, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamic acid, meclofenamate sodium, mefenamic acid, nabumetone, oxaprozin, phenyl butylnitrone (PBN), sulindac or tolmetin, COX-2 inhibitors, and cytokine synthesis / release inhibitors (such as anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.).

[0222] In some embodiments, compounds of formula (I) described herein (e.g., compounds of any of the examples herein) or pharmaceutically acceptable salts thereof may be used in combination with an antitumor agent. As used herein, the term "antitumor agent" refers to any pharmaceutical agent administered to a subject suffering from cancer for the purpose of treating cancer, including but not limited to radiotherapy agents, chemotherapy agents, immune checkpoint inhibitors or agonists, targeted therapy agents, etc.

[0223] Non-limiting examples of immune checkpoint inhibitors or agonists include PD-1 inhibitors, such as anti-PD-1 antibodies, such as pembrolizumab, nivolumab, and spartalizumab; PD-L1 inhibitors, such as anti-PD-L1 antibodies, such as atezolizumab, durvalumab, and avelumab; CTLA-4 inhibitors, such as anti-CTLA-4 antibodies, such as ipilimumab; and BTLA inhibitors, LAG-3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, VISTA inhibitors, OX-40 agonists, etc.

[0224] Non-limiting examples of chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and its analogues or metabolites, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, mitoxantrone, demethoxydaunorubicin, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, nitrosourea mustard, cyclohexanenitrosourea, methylcyclohexanenitrosourea, streptozotocin, aminoimide, methotrexate, mitomycin C). (and cyclophosphamide); DNA intercalating agents (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalating agents and free radical generating agents such as bleomycin; nucleoside analogs (e.g., 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, azacitidine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea); paclitaxel, taxanes, and related analogs; vincristine, vinblastine, and related analogs; sedatives and related analogs (e.g., CC-5013 and CC-4047).

[0225] Non-limiting examples of targeted therapies include: protein tyrosine kinase inhibitors (e.g., imatinib mesylate and gefitinib); proteasome inhibitors (e.g., bortezomib); NF-κB inhibitors, including IκB kinase inhibitors; IDO inhibitors; A2AR inhibitors; BRAF inhibitors (e.g., dabrafenib); MEK inhibitors (e.g., trametinib); mTOR inhibitors (e.g., rapamycin); anti-CD40 antibodies (e.g., APX005M, RO7009789); and... Antibodies that bind to proteins overexpressed in cancer and thereby downregulate cell replication include anti-CD20 antibodies (such as rituximab, teimomab, and tosimob), anti-Her2 antibodies (such as trastuzumab), anti-EGFR antibodies (such as cetuximab), and anti-VEGF antibodies (such as bevacizumab); anti-angiogenic drugs, such as lenalidomide; and other protein or enzyme inhibitors known to be upregulated, overexpressed, or activated in cancer, and whose inhibition can downregulate cell replication.

[0226] Example

[0227] The following examples are illustrative of the invention and do not limit the invention in any way. The data given (e.g., quantities, temperatures, etc.) are intended to be accurate; however, those skilled in the art will understand that some experimental errors and biases may occur. Unless otherwise stated, all parts are by weight, temperatures are in Celsius, and pressures are at or near atmospheric pressure. All mass spectrometry data were obtained using Agilent 6120 and 1100. All nuclear magnetic resonance data were obtained using a Varian 400MHz NMR. Except for synthetic intermediates, all reagents used in this invention were commercially available. All compound names, except for reagents, were generated using Chemdraw 18.0. Rapid column chromatography was performed using conventional silica gel columns unless otherwise specified or contradicted by the context.

[0228] In any structural formula of this application, if there is a vacant valence on any atom, the vacant valence is actually for the sake of simplicity and is not specifically described as a hydrogen atom.

[0229] In this application, if both the name and structural formula of a compound are given, and the two are inconsistent, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct.

[0230] The following list of abbreviations is used in the examples below:

[0231]

[0232]

[0233]

[0234] Example 1

[0235] Preparation of intermediates

[0236] Intermediate 1: 5-Bromo-2-chloro-3-methylpyridine

[0237]

[0238] (A) 6-Chloro-5-methylpyridine-3-amine

[0239] In a reaction flask, 2-chloro-3-methyl-5-nitropyridine (2 g, 11.6 mmol), iron powder (2.6 g, 46.5 mmol), NH4Cl (3.13 g, 58 mmol), ethanol (40 mL), and water (10 mL) were added sequentially. The mixture was heated to 100 °C and stirred for 3 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1.5 g of the title product as a light brown solid. MS (m / z): 143.1 [M+H] +

[0240] (B) 5-Bromo-2-chloro-3-methylpyridine

[0241] In a reaction flask, 6-chloro-5-methylpyridin-3-amine (600 mg, 4.2 mmol), isoamyl nitrite (1.97 g, 16.9 mmol), CuBr (2.34 g, 16.9 mmol), and acetonitrile (20 mL) were added sequentially, and the mixture was heated to 70 °C and stirred overnight. The reaction solution was concentrated and purified by rapid column chromatography (eluting with petroleum ether:ethyl acetate = 4:1) to give 600 mg of the title product as a white solid. MS (m / z): 205.9 [M + Na] +

[0242] Intermediate 2: 7-hydroxy-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0243]

[0244] In a reaction flask, 3.3 g (30.0 mmol) of 6-aminopyridin-3-ol and ethyl (E)-3-ethoxy-2-methacrylate (9.5 g (60.0 mmol) were dissolved in acetic acid (50 mL), and the reaction mixture was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 4.56 g of the title product as a light brown solid. MS (m / z): 177.0 [M+H] +

[0245] The following intermediates were prepared using the same raw materials and reagents as intermediate 2, under conditions recognized by those skilled in the art.

[0246]

[0247] Intermediate 3: (4-Cyclopropyl-3-fluorophenyl)methanol

[0248]

[0249] In a reaction flask, 4-bromo-3-fluorobenzyl alcohol (580 mg, 2.83 mmol), cyclopropylboronic acid (730 mg, 8.49 mmol), palladium acetate (63 mg, 0.28 mmol), tricyclohexylphosphine (79 mg, 0.28 mmol), potassium phosphate (1200 mg, 5.66 mmol), toluene (40 mL), and water (5 mL) were added. The reaction mixture was heated under reflux for 15 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0–0:100 gradient elution) to give 266 mg of the title product as a white solid. MS (m / z): 149.1 [M-OH] +

[0250] Intermediate 4: 2-(3-(hydroxymethyl)phenyl)-2-methylpropionitrile

[0251]

[0252] (A) Methyl 3-(cyanomethyl)benzoate

[0253] In a reaction flask, methyl 3-(bromomethyl)benzoate (2290 mg, 10.0 mmol), sodium cyanide (735 mg, 15.0 mmol), DMF (5 mL), and water (0.5 mL) were added. The mixture was heated at 75 °C for 5 hours. After cooling to room temperature, the reaction mixture was extracted twice with water (50 mL) and ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1401 mg of the title product as a solid. MS (m / z): 176.1 [M+H] +

[0254] (B) Methyl 3-(2-cyanopropan-2-yl)benzoate

[0255] In a reaction flask, methyl 3-(cyanomethyl)benzoate (1401 mg, 8.0 mmol) was dissolved in DMSO (10 mL). Sodium hydride (960 mg, 24.0 mmol) was added in portions to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred at room temperature for 20 minutes. Then, methyl iodoform (3406 mg, 1.5 mL, 24.0 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 4 hours. After the reaction was complete, water (50 mL) and ethyl acetate (50 mL) were added, followed by extraction twice. The organic phases were combined, washed twice with saturated brine (30 mL), and concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100 gradient elution) to give 1260 mg of the pale yellow oil title product. MS (m / z): 204.1 [M+H] +

[0256] (C)2-(3-(hydroxymethyl)phenyl)-2-methylpropionitrile

[0257] In a reaction flask, methyl 3-(2-cyanopropane-2-yl)benzoate (610 mg, 3.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Borane dimethyl sulfide complex (2 M, 4.5 mL, 9.0 mmol) was added dropwise to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred for 15 hours. After the reaction was complete, methanol was slowly added dropwise under ice bath conditions to quench the reaction. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 370 mg of the pale yellow oil title product. MS (m / z): 158.1 [M-OH] +

[0258] Intermediate 5: (4-Cyclopropyl-2-fluorophenyl)methanol

[0259]

[0260] (A) Methyl 4-cyclopropyl-2-fluorobenzoate

[0261] In a reaction flask, methyl 4-bromo-2-fluorobenzoate (2330 mg, 10.0 mmol), cyclopropylboronic acid (2577 mg, 30.0 mmol), palladium acetate (224 mg, 1.0 mmol), tricyclohexylphosphine (280 mg, 1.0 mmol), potassium phosphate (4240 mg, 20.0 mmol), toluene (60 mL), and water (10 mL) were added. The reaction mixture was heated under reflux for 15 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1760 mg of the title product as a white solid. MS (m / z): 195.1 [M-OH] +

[0262] (B)(4-Cyclopropyl-2-fluorophenyl)methanol

[0263] In a reaction flask, methyl 4-cyclopropyl-2-fluorobenzoate (971 mg, 4.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). LiAlH4 (455 mg, 12.0 mmol) was added in portions to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred for 15 hours. After the reaction was complete, methanol was slowly added dropwise under ice bath conditions to quench the reaction. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 430 mg of the pale yellow oil title product. MS (m / z): 149.1 [M-OH] +

[0264] Intermediate 6: 2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-ol

[0265]

[0266] Under nitrogen protection, 2-chloropyridin-4-ol (388 mg, 3.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (1248 mg, 6.0 mmol), potassium carbonate (829 mg, 6.0 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), dioxane (20 mL), and water (5 mL) were added to a reaction flask. The reaction mixture was heated to reflux and stirred for 15 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 250 mg of the title product as a white solid. MS (m / z): 176.1 [M+H] +

[0267] Intermediate 7: 5-Fluoro-3-(Fluoromethoxy)-2-nitropyridine

[0268]

[0269] In a reaction flask, 5-fluoro-2-nitropyridine-3-ol (474 ​​mg, 3.0 mmol), bromofluoromethane (373 mg, 3.3 mmol), potassium carbonate (498 mg, 3.6 mmol), and DMF (3 mL) were added. The mixture was stirred at room temperature for 48 hours. After the reaction was complete, water (20 mL) was added, followed by extraction twice with ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 520 mg of the title product as a pale yellow solid. MS (m / z): 191.1 [M+H] +

[0270] Intermediate 8: 5-bromo-2-chloronicotinonitrile

[0271]

[0272] In a reaction flask, 1000 mg (5.05 mmol) of 2-amino-5-bromonicarnitrile was dissolved in 10 mL of concentrated hydrochloric acid. Sodium nitrite aqueous solution (418 mg, 6.06 mmol, dissolved in 3 mL of water) was added dropwise to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred for 15 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, and then 100 mL of water was slowly added to the reaction solution. The mixture was filtered, and the solid was washed with water and dried to give 900 mg of the title product. MS (m / z): 217.0, 219.0 [M+H] +

[0273] Intermediate 9: 2-(4-(hydroxymethyl)phenyl)-2-methylpropionitrile

[0274]

[0275] (A) Methyl 4-(2-cyanopropan-2-yl)benzoate

[0276] In a reaction flask, methyl 4-(cyanomethyl)benzoate (1752 mg, 10.0 mmol) was dissolved in DMF (30 mL). Sodium hydride (880 mg, 22.0 mmol) was then added to the reaction solution in portions. After the addition was complete, the reaction solution was stirred at room temperature for half an hour. Then, methyl iodoform (1.37 mL, 22.0 mmol) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for another 4 hours. After the reaction was complete, water (50 mL) and ethyl acetate (100 mL) were added. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1600 mg of the title product as a white solid. MS (m / z): 204.1 [M+H] +

[0277] (B)2-(4-(hydroxymethyl)phenyl)-2-methylpropionitrile

[0278] Under nitrogen protection, methyl 4-(2-cyanopropane-2-yl)benzoate (1600 mg, 7.87 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) in a reaction flask. DIBAL-H (10.5 mL, 15.7 mmol) was slowly added dropwise to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred under ice bath conditions for 2 hours. The reaction was quenched with saturated ammonium chloride after completion. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1050 mg of the title product as a white solid. MS (m / z + Na): 198.1 [M + H] +

[0279] The following intermediates were prepared using appropriate raw materials and reagents under conditions recognized by those skilled in the art, following the preparation process of intermediate step (B) 9.

[0280]

[0281] Intermediate 10: 2-(4-(hydroxymethyl)phenyl)propane-2-ol

[0282]

[0283] (A) Methyl 4-(hydroxymethyl)benzoate

[0284] In a reaction flask, methyl 4-formylbenzoate (1642 mg, 10.0 mmol) was dissolved in THF (50 mL). Sodium borohydride was added in portions to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched by adding water (5 mL) dropwise under ice bath conditions. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1600 mg of the title product as a white solid. MS (m / z): 189.1 [M+Na] +

[0285] (B)2-(4-(hydroxymethyl)phenyl)propane-2-ol

[0286] Under nitrogen protection, methyl 4-(hydroxymethyl)benzoate (1600 mg, 9.62 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) in a reaction flask. Methyl magnesium bromide (14.5 mL, 28.9 mmol) was slowly added dropwise to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred under ice bath conditions for 2 hours. The reaction was quenched with saturated ammonium chloride after completion. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1400 mg of the title product as a white solid. MS (m / z + Na): 189.1 [M + H] +

[0287] Intermediate 11: (4-(1H-pyrazol-1-yl)phenyl)methanol

[0288]

[0289] (A) Methyl 4-(1H-pyrazole-1-yl)benzoate

[0290] In a reaction flask, methyl 4-iodobenzoate (1048 mg, 4.0 mmol), pyrazole (544 mg, 8.0 mmol), cesium carbonate (1303 mg, 4.0 mmol), copper oxide (32 mg, 0.4 mmol), iron triacetylacetone (424 mg, 1.2 mmol), and DMF (10 mL) were added. The mixture was heated under reflux for 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then ethyl acetate (20 mL) was added. The mixture was filtered, and the resulting solid was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 557 mg of the title product as a solid. MS (m / z): 203.1 [M+H] +

[0291] (B)(4-(1H-pyrazole-1-yl)phenyl)methanol

[0292] In a reaction flask, methyl 4-(1H-pyrazol-1-yl)benzoate (557 mg, 2.76 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL). Lithium aluminum hydride (314 mg, 8.28 mmol) was added in portions to the reaction solution under ice bath conditions. After the addition was complete, the reaction solution was stirred for 15 hours. After the reaction was complete, methanol was slowly added dropwise under ice bath conditions to quench the reaction. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 390 mg of the title product. MS (m / z): 175.1 [M+H] +

[0293] Intermediate 12: (7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl) tert-butyl carbamate

[0294]

[0295] In a reaction flask, 3-bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (486 mg, 2.0 mmol), tert-butyl carbamate (468 mg, 4.0 mmol), Pd₂(dba)₃ (91 mg, 0.1 mmol), cesium carbonate (716 mg, 2.2 mmol), Xantphos (116 mg, 0.2 mmol), and dioxane (20 mL) were added. The reaction mixture was heated under reflux for 15 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 490 mg of the title product as a pale yellow solid. MS (m / z): 280.1 [M+H] +

[0296] Intermediate 13: 6-((5-methoxy-6-nitropyridin-3-yl)oxy)-3-methylquinazolin-4(3H)-one

[0297]

[0298] (A) Methyl 2-amino-5-((5-methoxy-6-nitropyridin-3-yl)oxy)benzoate

[0299] In a reaction flask, 5-fluoro-3-methoxy-2-nitropyridine (516 mg, 3.0 mmol), methyl 2-amino-5-hydroxybenzoate (502 mg, 3.0 mmol), potassium carbonate (829 mg, 6.0 mmol), and DMF (10 mL) were added. The mixture was heated at 80 °C for 4 hours. After cooling to room temperature, the reaction solution was extracted twice with water (50 mL) and ethyl acetate (50 mL). The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 900 mg of the title product as a pale yellow solid. MS (m / z): 320.0 [M+H] +

[0300] (B)6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin-4(3H)-one

[0301] In a reaction flask, methyl 2-amino-5-((5-methoxy-6-nitropyridin-3-yl)oxy)benzoate (900 mg, 2.82 mmol) was suspended in a mixed solvent of formic acid (5 mL) and formamide (5 mL). The reaction mixture was heated at 135 °C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and water (100 mL) and ethyl acetate (50 mL) were added. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 720 mg of the title product as a pale yellow solid. MS (m / z): 315.0 [M+H] +

[0302] (C)6-((5-methoxy-6-nitropyridin-3-yl)oxy)-3-methylquinazolin-4(3H)-one

[0303] In a reaction flask, 6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin-4(3H)-one (314 mg, 1.0 mmol), methyl iodide (170 mg, 1.2 mmol), potassium carbonate (138 mg, 1.0 mmol), and DMF (3 mL) were added. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (20 mL) and ethyl acetate (20 mL) were added for extraction twice. The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 300 mg of the title product as a pale yellow solid. MS (m / z): 329.0 [M+H] +

[0304] Intermediate 14: 9-((5-methoxy-6-nitropyridin-3-yl)oxy)-2,3-dihydroimidazo[1,2-c]quinazolin

[0305]

[0306] (A) 4-Chloro-6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin

[0307] In a reaction flask, 157 mg of 6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin-4(3H)-one (0.5 mmol) was suspended in phosphorus oxychloride (5 mL). The reaction mixture was heated under reflux for 2 hours. After the reaction was completed, the reaction mixture was concentrated to give 166 mg of the title product, which was directly used in the next step of the reaction. MS (m / z): 333.0 [M+H] +

[0308] (B)2-((6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin-4-yl)amino)ethane-1-ol

[0309] In a reaction flask, 166 mg (0.5 mmol) of 4-chloro-6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazoline, 153 mg (2.5 mmol), and 15 mL of dioxane were added. The reaction mixture was heated under reflux for 15 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 120 mg of the title product as a pale yellow solid. MS (m / z): 358.0 [M+H] +

[0310] (C)9-((5-methoxy-6-nitropyridin-3-yl)oxy)-2,3-dihydroimidazo[1,2-c]quinazolin

[0311] In a reaction flask, 120 mg (0.335 mmol) of 2-((6-((5-methoxy-6-nitropyridin-3-yl)oxy)quinazolin-4-yl)amino)ethane-1-ol) was dissolved in 15 mL of dichloromethane. A solution of 0.2 mL of thionyl chloride in 2 mL of dichloromethane was added dropwise to the reaction mixture under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with water, concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 90 mg of the title product as a pale yellow solid. MS (m / z): 340.1 [M+H] +

[0312] Intermediate 15: 7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one

[0313]

[0314] In a reaction flask under nitrogen protection, 1.12 g (10 mmol) of 5-fluoro-2-aminopyridine, 2.05 g (11 mmol) of 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, and 20 mL of dioxane were added sequentially, and the mixture was refluxed and stirred overnight. After cooling to room temperature, 60 mL of petroleum ether was added, and the mixture was stirred for 2 hours and filtered. The solid was washed with petroleum ether and dried, then 20 mL of diphenyl ether was added, and the mixture was heated under nitrogen protection and stirred under reflux for half an hour. After cooling to room temperature, 60 mL of petroleum ether was added, and the mixture was stirred for 2 hours and filtered. The solid was washed with petroleum ether and dried, and then purified by rapid column chromatography (dichloromethane:methanol = 100:0-90:10 gradient elution) to give 800 mg of the title product as a brown solid. MS (m / z): 165.0 [M+H] +

[0315] Intermediate 16: 4-(bromomethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine

[0316]

[0317] (A)(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methanol

[0318] In a reaction flask under nitrogen protection, (2-bromopyridin-4-yl)methanol (1.88 g, 10 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (2.5 g, 12 mmol), potassium carbonate (2.76 g, 20 mmol), Pd(PPh3)2Cl2 (702 mg, 1 mmol), and dioxane / water (30 mL / 6 mL) were added sequentially. The mixture was heated to 90 °C and stirred for 6 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) and rapid column chromatography (dichloromethane:methanol = 100:0-90:10 gradient elution) to give 1.5 g of the title product as a white solid. MS (m / z): 190.1 [M+H] +

[0319] (B) 4-(bromomethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine

[0320] In a reaction flask under nitrogen protection, 1.5 g (7.9 mmol) of (2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methanol, 3.94 g (11.9 mmol), and 50 mL of dichloromethane were added sequentially, followed by the addition of triphenylphosphine (3.1 g, 11.9 mmol) in portions, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0–0:100 gradient elution) and then by rapid column chromatography (water:methanol = 100:0–0:100 gradient elution) to give 1.0 g of the title product as a colorless oil. MS (m / z): 252.0 [M+H] +

[0321] Intermediate 17: 7-fluoro-3-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one

[0322]

[0323] In a reaction flask under nitrogen protection, 3-bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (140 mg, 0.58 mmol), morpholine (76 mg, 0.87 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), BINAP (68 mg, 0.11 mmol), t-BuONa (85 mg, 0.87 mmol), and toluene (8 mL) were added sequentially. The mixture was heated to 110 °C and stirred for 3 hours. After concentration, the reaction solution was purified by rapid column chromatography (dichloromethane:methanol = 100:0-20:1 gradient elution) to give 80 mg of the title product as a yellow solid. MS (m / z): 250.0 [M+H] +

[0324] Intermediate 18: 3-Cyclopropyl-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one

[0325]

[0326] In a reaction flask under nitrogen protection, 3-bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (200 mg, 0.83 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (208 mg, 1.24 mmol), Pd(OAc)₂ (18 mg, 0.08 mmol), tricyclohexylphosphine (45 mg, 0.16 mmol), potassium phosphate (530 mg, 2.48 mmol), toluene (8 mL), and water (1 mL) were added sequentially. The mixture was heated to 110 °C and stirred for 24 hours. After concentration, the reaction solution was purified by rapid column chromatography (eluting with petroleum ether:ethyl acetate = 1:1) to give 40 mg of the title product as a yellow solid. MS (m / z): 205.1 [M+H] +

[0327] Intermediate 19: 7-((6-bromopyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0328]

[0329] (A) 2-Bromo-5-((6-nitropyridin-3-yl)oxy)pyridine

[0330] In a reaction flask, 5-fluoro-2-nitropyridine (1.42 g, 10.0 mmol), 6-bromopyridin-3-ol (1.74 g, 10.0 mmol), potassium carbonate (2.76 g, 20.0 mmol), and DMF (20 mL) were added. The mixture was heated at 100 °C for 15 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 2.5 g of the title product as a yellow solid. MS (m / z): 296.0, 298.0 [M+H] +

[0331] (B) 5-((6-bromopyridin-3-yl)oxy)pyridin-2-amine

[0332] In a reaction flask, 2-bromo-5-((6-nitropyridin-3-yl)oxy)pyridine (2.5 g, 8.4 mmol), iron powder (1.88 g, 33.6 mmol), ammonium chloride (2.25 g, 42.0 mmol), ethanol (80 mL), and water (20 mL) were added. The reaction mixture was heated under reflux for 2 hours. After cooling to room temperature, the mixture was filtered. The solid was washed with methanol, and the filtrate was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 2.25 g of the title product as a pale yellow solid. MS (m / z): 266.0, 268.0 [M+H] +

[0333] (C)7-((6-bromopyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0334] In a reaction flask, 2.25 g (8.45 mmol) of 5-((6-bromopyridin-3-yl)oxy)pyridin-2-amine, 2.7 g (16.9 mmol) of (E)-3-ethoxy-2-methacrylate, and 20 mL of acetic acid were added. The reaction mixture was heated at 120 °C for 15 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 2.5 g of the title product as a pale yellow solid. MS (m / z): 332.0, 334.0 [M+H] +

[0335] Intermediate 20: 5-methoxy-6-((4-methoxybenzyl)oxy)pyridine-3-ol

[0336]

[0337] (A) 5-Bromo-3-methoxy-2-((4-methoxybenzyl)oxy)pyridine

[0338] In a reaction flask, 5-bromo-2-chloro-3-methoxypyridine (500 mg, 2.26 mmol), (4-methoxyphenyl)methanol (342 mg, 2.48 mmol), and DMF (10 mL) were added sequentially, followed by NaH (108 mg, 2.71 mmol). The mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 3:1) to give 600 mg of the title product as a white solid. MS (m / z): 346.0 [M+Na] +

[0339] (B) 3-Methoxy-2-((4-Methoxybenzyl)oxy)-5-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine

[0340] In a reaction flask under nitrogen protection, 5-bromo-3-methoxy-2-((4-methoxybenzyl)oxy)pyridine (500 mg, 1.54 mmol), Pin₂B₂ (588 mg, 2.32 mmol), Pd(dppf)Cl₂ (113 mg, 0.15 mmol), potassium acetate (455 mg, 4.64 mmol), and dioxane (15 mL) were added sequentially. The mixture was heated to 90 °C and stirred for 3 hours. After concentration, the reaction solution was purified by rapid column chromatography (petroleum ether:ethyl acetate = 5:1) to give 450 mg of the title product as a white solid. MS (m / z): 372.2 [M+Na] +

[0341] (C)5-Methoxy-6-((4-Methoxybenzyl)oxy)pyridine-3-ol

[0342] In a reaction flask, 3-methoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (371 mg, 1 mmol), NaOH (80 mg, 2 mmol), THF (5 mL), and water (1 mL) were added sequentially, followed by H₂O₂ (0.5 mL). The mixture was stirred at room temperature for 3 hours. An aqueous solution of Na₂S₂O₃ was added to the reaction mixture, and the mixture was extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 1:1) to give 200 mg of the title product as a white solid. MS (m / z): 284.1 [M+Na] +

[0343] The following intermediates were prepared using the same raw materials and reagents as intermediate 20, under conditions recognized by those skilled in the art.

[0344]

[0345]

[0346] Intermediate 29: 2-((4-cyclopropylbenzyl)oxy)pyrimidin-5-ol

[0347]

[0348] (A) 5-Bromo-2-((4-Cyclopropylbenzyl)oxy)pyrimidine

[0349] In a reaction flask, 5-bromo-2-chloropyrimidine (192 mg, 1 mmol), (4-cyclopropylphenyl)methanol (148 mg, 1 mmol), and DMF (5 mL) were added sequentially, followed by NaH (48 mg, 1.2 mmol). The mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with EA. The extract was washed with saturated brine and concentrated. The solution was purified by rapid column chromatography (petroleum ether:ethyl acetate = 2:1) to give 300 mg of the title product as a white solid. MS (m / z): 304.9 [M+1] +

[0350] (B)(2-((4-cyclopropylbenzyl)oxy)pyrimidin-5-yl)boronic acid

[0351] In a reaction flask under nitrogen protection, 5-bromo-2-((4-cyclopropylbenzyl)oxy)pyrimidine (220 mg, 0.72 mmol), Pin₂B₂ (275 mg, 1.08 mmol), Pd(dppf)Cl₂ (53 mg, 0.07 mmol), potassium acetate (212 mg, 2.17 mmol), and dioxane (8 mL) were added sequentially. The mixture was heated to 90 °C and stirred for 3 hours. The reaction solution was concentrated and purified by rapid column chromatography (petroleum ether:ethyl acetate = 1:1) to give 180 mg of the title product as a white solid. MS (m / z): 271.1 [M+1] +

[0352] (C)2-((4-Cyclopropylbenzyl)oxy)pyrimidin-5-ol

[0353] In a reaction flask, (2-((4-cyclopropylbenzyl)oxy)pyrimidin-5-yl)boronic acid (180 mg, 0.67 mmol), NaOH (60 mg, 1.33 mmol), THF (10 mL), and water (2 mL) were added sequentially, followed by H₂O₂ (1 mL). The mixture was stirred at room temperature for 3 hours. Na₂S₂O₃ aqueous solution was added to the reaction mixture, and the mixture was extracted with EA. The extract was washed with saturated brine and concentrated. The solution was purified by rapid column chromatography (petroleum ether:ethyl acetate = 1:1) to give 120 mg of the title product as a white solid. MS (m / z): 243.1 [M+1] +

[0354] The following intermediates were prepared using the same raw materials and reagents as intermediate 29, under conditions recognized by those skilled in the art.

[0355]

[0356] Intermediate 32: 7-((5-ethoxy-6-hydroxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidine

[0357] -4-keto

[0358]

[0359] (A) 3-ethoxy-5-fluoro-2-nitropyridine

[0360] In a reaction flask under nitrogen protection, 5-fluoro-2-nitropyridine-3-ol (1 g, 6.3 mmol), iodoethane (0.8 mL, 10 mmol), potassium carbonate (1.38 g, 10 mmol), and DMF (15 mL) were added sequentially. The mixture was heated to 50 °C and stirred overnight. After cooling to room temperature, water (60 mL) was added, and the mixture was stirred for 1 hour. The mixture was then filtered. The solid was washed with water and dried to give 850 mg of the title product as a brown solid. MS (m / z): 187.0 [M+H] +

[0361] (B) 7-((5-ethoxy-6-nitropyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0362] In a reaction flask under nitrogen protection, 3-ethoxy-5-fluoro-2-nitropyridine (850 mg, 4.6 mmol), 7-hydroxy-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (810 mg, 4.6 mmol), cesium carbonate (2.25 g, 6.9 mmol), and DMF (10 mL) were added sequentially. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, water (60 mL) and ethyl acetate (100 mL) were added, and the mixture was extracted twice. The organic phases were combined, washed twice with saturated brine (80 mL), and concentrated. The residue was purified by rapid column chromatography (dichloromethane:methanol = 100:0-90:10 gradient elution) to give 900 mg of the title product as a black solid. MS (m / z): 343.1 [M+H] +

[0363] In a reaction flask under nitrogen protection, 7-((5-ethoxy-6-nitropyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (900 mg, 2.6 mmol), iron powder (582 mg, 10.4 mmol), ammonium chloride (695 mg, 13 mmol), and ethanol / water (16 mL / 4 mL) were added sequentially, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the mixture was filtered, and the solid was washed with methanol. The filtrate was concentrated, and the residue was purified by rapid column chromatography (water (+0.05% formic acid):methanol = 100:0-0:100 gradient elution) to give 550 mg of the title product as a yellow solid. MS(m / z): 313.1 [M+H] +

[0364] (D)7-((5-ethoxy-6-hydroxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0365] In a reaction flask under nitrogen protection, 7-((6-amino-5-ethoxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (550 mg, 1.76 mmol), aqueous sulfuric acid solution (10 mL, 20% (by weight)), and sodium nitrite (242 mg, 3.5 mmol) were added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 500 mg of the title product as a yellow solid. MS (m / z): 314.1 [M+H] +

[0366] The following intermediates were prepared using the same raw materials and reagents as intermediate 32, under conditions recognized by those skilled in the art.

[0367]

[0368]

[0369] *: Intermediates 44 and 45 were prepared using intermediates 13 and 14 as raw materials, referring to steps (C) and (D) of intermediate 32.

[0370] Intermediate 48: 3-bromo-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one

[0371]

[0372] In a reaction flask, 7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (920 mg, 5.6 mmol), N-bromosuccinimide (998 mg, 5.6 mmol), and DMF (20 mL) were added, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) and ethyl acetate (40 mL) were added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100 gradient elution) to give 1.1 g of the title product as a white solid. MS (m / z): 244.0 [M+H] +

[0373] Intermediate 49: (3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid

[0374]

[0375] (A) 7-Bromo-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0376] In a reaction flask, 5-bromopyridin-2-amine (1.0 g, 5.78 mmol), ethyl 3-ethoxy-2-methacrylate (1.0 g, 6.36 mmol), and acetic acid (30 mL) were added, and the mixture was refluxed overnight. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0–0:100 gradient elution) to give 1.23 g of a white solid product. MS (m / z): 239.1 [M+H] +

[0377] (B)(3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid

[0378] In a reaction flask, 7-bromo-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (1.23 g, 5.14 mmol), Pin2B2 (1.96 g, 7.716 mmol), Pd(dppf)Cl2·CH2Cl2 (420 mg, 0.51 mmol), KOAc (1.51 g, 15.43 mmol), and dioxane (40.0 mL) were added. After stirring overnight at 100 °C, the reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 766 mg of a white solid product. MS (m / z): 205.1 [M+H] +

[0379] Intermediate 50: 4-Fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridine

[0380]

[0381] 2-Bromo-4-fluoropyridine (528 mg, 3.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (936 mg, 4.5 mmol), potassium carbonate (829 mg, 6.0 mmol), Pd(dppf)Cl2 (110 mg, 0.15 mmol), dioxane (20 mL), and water (5 mL) were added to a reaction flask. The reaction mixture was heated to reflux under nitrogen protection and stirred for 15 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 450 mg of the white solid title product. MS (m / z): 178.2 [M+H] +

[0382] Intermediate 51: 2-(4-(4-fluoropyridin-2-yl)-1H-pyrazol-1-yl)ethane-1-ol

[0383]

[0384] (A) 4-Fluoro-2-(1H-pyrazol-4-yl)pyridine

[0385] Following the preparation process of intermediate 50, the title product was prepared using the corresponding raw materials and reagents. MS (m / z): 164.2 [M+H] +

[0386] (B) 4-Fluoro-2-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridine

[0387] In a reaction flask, 4-fluoro-2-(1H-pyrazol-4-yl)pyridine (420 mg, 2.57 mmol) was dissolved in DMF (5 mL). Sodium hydride (113 mg, 2.82 mmol) was added to the reaction solution in portions. After the addition was complete, the reaction solution was stirred at room temperature for half an hour. Then, 2-(2-bromoethoxy)tetrahydro-2H-pyran (565 mg, 2.7 mmol) was dissolved in 2 mL of DMF and added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 630 mg of the title product, a pale yellow solid. MS (m / z): 292.2 [M+H] +

[0388] (C)2-(4-(4-fluoropyridin-2-yl)-1H-pyrazol-1-yl)ethane-1-ol

[0389] In a reaction flask, 630 mg (2.16 mmol) of 4-fluoro-2-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridine and 1 mL of hydrochloric acid were dissolved in 10 mL of methanol. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 400 mg of the title product, a pale yellow solid. MS (m / z): 208.2 [M+H] +

[0390] Intermediate 52: 3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridine-7-ol

[0391]

[0392] (A) 2-((5-bromo-2-hydroxypyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-one

[0393] 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-one (366 mg, 1.0 mmol), sodium acetate (820 mg, 10.0 mmol), and acetic acid (15 mL) were added to a 20 mL microwave-safe tube. The mixture was reacted in a microwave reactor at 160 °C for 4 hours. After the reaction, the solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 210 mg of a white solid mixture. MS (m / z): 348.0, 350.0 [M+H] +

[0394] (B) 5-Bromo-3-(2-(4-cyclopropylphenyl)-2-hydroxyethoxy)pyridine-2-ol

[0395] In a reaction flask, 2-((5-bromo-2-hydroxypyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-one (210 mg, 0.60 mmol) was dissolved in methanol (20 mL). Sodium borohydride (246 mg, 1.20 mmol) was added in portions under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 5-6 with dilute hydrochloric acid. The reaction mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 180 mg of the title product as a white solid. MS (m / z-H₂O): 332.2, 334.2 [M+H] +

[0396] (C)7-Bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridine

[0397] In a reaction flask, 5-bromo-3-(2-(4-cyclopropylphenyl)-2-hydroxyethoxy)pyridin-2-ol (180 mg, 0.51 mmol), triphenylphosphine (268 mg, 1.02 mmol), anhydrous tetrahydrofuran (20 mL), and diisopropyl azodicarbonate (206 mg, 1.02 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (2 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 130 mg of the title product as a white solid. MS (m / z): 332.2, 334.2 [M+H] +

[0398] (D)3-(4-Cyclopropylphenyl)-7-(4,4,5,5-Tetramethyl-1,3,2-dioxoboron-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0399] In a reaction flask under nitrogen protection, 7-bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridine (130 mg, 0.391 mmol), Pin2B2 (199 mg, 0.782 mmol), potassium acetate (77 mg, 0.782 mmol), Pd(dppf)Cl2 (24 mg, 0.04 mmol), and dioxane (30 mL) were added sequentially and stirred under reflux for 15 hours. After cooling to room temperature, the mixture was concentrated, and ethyl acetate (100 mL) was added and stirred for 1 hour. The mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was used directly in the next reaction. MS (m / z): 380.0 [M+H]+

[0400] (E)3-(4-Cyclopropylphenyl)-2,3-Dihydro-[1,4]dioxono[2,3-b]pyridine-7-ol

[0401] The crude product prepared in the previous step (148 mg, 0.39 mmol), THF (5 mL), and sodium hydroxide aqueous solution (31 mg dissolved in 2 mL of water) were added to the reaction flask. Hydrogen peroxide (1 mL, 30% wt) was added dropwise under ice bath conditions. After warming to room temperature, the mixture was stirred for 1 hour. After cooling in an ice bath, a saturated sodium thiosulfate aqueous solution was added dropwise. The mixture was stirred for 5 minutes, and the concentration was achieved after confirming the absence of peroxides using starch-potassium iodide paper. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100 gradient elution) to give 86 mg of the title product as a white solid. MS (m / z): 270.0 [M+H] +

[0402] Intermediate 53: 3-(6-cyclopropylpyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0403] (A) 1-(6-Cyclopropylpyridin-3-yl)ethane-1-one

[0404] In a reaction flask, 1-(6-bromopyridin-3-yl)ethane-1-one (8.0 g, 40.0 mmol), cyclopropylboronic acid (10.3 g, 120.0 mmol), palladium acetate (450 mg, 2.0 mmol), tricyclohexylphosphine (1.12 g, 4.0 mmol), potassium phosphate (17 g, 80.0 mmol), toluene (150 mL), and water (30 mL) were added. The reaction mixture was heated under reflux for 15 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 4.8 g of the title product as a white solid. MS (m / z): 162.2 [M+H] +

[0405] (B) 2-Bromo-1-(6-Cyclopropylpyridin-3-yl)ethane-1-one

[0406] 1-(6-cyclopropylpyridin-3-yl)ethane-1-one (3.22 g, 20.0 mmol) and hydrobromic acid-acetic acid solution (20 mL) were added to a reaction flask, and liquid bromine (3.2 g, 20.0 mmol) was added dropwise to the mixture at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was neutralized with saturated sodium bicarbonate, and the mixture was concentrated to dryness. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 4.3 g of a pale yellow oily product. MS (m / z): 240.0, 242.0 [M+H] +

[0407] (C)2-((5-bromo-2-fluoropyridin-3-yl)oxy)-1-(6-cyclopropylpyridin-3-yl)ethane-1-one

[0408] In a reaction flask, 5-bromo-2-fluoropyridin-3-ol (3436 mg, 17.9 mmol) was dissolved in DMF (50 mL). Sodium hydride (716 mg, 17.9 mmol) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for half an hour. Then, 2-bromo-1-(6-cyclopropylpyridin-3-yl)ethane-1-one (4300 mg, 17.9 mmol) was dissolved in 5 mL of DMF and added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (100 mL) and ethyl acetate (200 mL) were added twice for extraction. The organic phases were combined, washed twice with saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 4.65 g of the title product as a pale yellow solid. MS (m / z): 367.0, 369.0 [M+H] +

[0409] (D)2-((5-bromo-2-hydroxypyridin-3-yl)oxy)-1-(6-cyclopropylpyridin-3-yl)ethane-1-one

[0410] 2-((5-bromo-2-fluoropyridin-3-yl)oxy)-1-(6-cyclopropylpyridin-3-yl)ethane-1-one (4.65 g, 13.2 mmol), sodium acetate (10.82 g, 132.0 mmol), and acetic acid (100 mL) were added to a reaction flask. The mixture was heated at 140 °C for 10 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 3.1 g of a white solid mixture. MS (m / z): 349.0, 351.0 [M+H] +

[0411] (E)3-(6-Cyclopropylpyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0412] Following the preparation process of intermediate 52 steps (B)-(E), the title product was prepared using the appropriate raw materials and reagents. MS (m / z): 271.2 [M+H] +

[0413] The following intermediates were prepared using appropriate raw materials and reagents under conditions recognized by those skilled in the art, following the preparation process of intermediate 53 steps (C)-(E).

[0414]

[0415] Intermediate 55: 3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridin-7-ol

[0416]

[0417] (A) 1-(6-methoxypyridin-3-yl)ethane-1-one

[0418] In a reaction flask, 3.20 g (16.0 mmol) of 1-(6-bromopyridin-3-yl)ethane-1-one, 30 mL of methanol, and 1.70 g (32.0 mmol) of sodium methoxide were added. The mixture was refluxed and stirred for 3 hours under nitrogen protection, then cooled to room temperature. The reaction solution was concentrated, extracted twice with 30 mL of water and 50 mL of ethyl acetate. The combined organic phases were washed with 30 mL of saturated brine. After drying, the organic phase was filtered and concentrated to give 2.4 g of a pale yellow solid. MS (m / z): 152.1 [M+H] + .

[0419] (B) 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-one

[0420] Following the preparation procedures in steps (B) and (C) of intermediate 53, and using the appropriate raw materials and reagents, the title product was prepared. MS (m / z): 357.0 [M+H] + .

[0421] (C)2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-ol

[0422] In a reaction flask, 3.0 g (8.4 mmol) of 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-one and 45 mL of dry tetrahydrofuran were added. Under nitrogen protection, the mixture was cooled to -10 °C, and 159 mg (4.2 mmol) of sodium borohydride was added. The mixture was stirred for 2 hours while maintaining the temperature. The reaction solution was quenched dropwise with 5 mL of water, concentrated, and the residue was purified by rapid column chromatography (water:acetonitrile = 100:0–0:100 gradient elution) and then by rapid column chromatography (dichloromethane:methanol = 100:0–90:10 gradient elution) to give 1.8 g of a white solid. MS (m / z): 359.0 [M+H] + .

[0423] (D)7-Bromo-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridine

[0424] In a reaction flask, 1.80 g (7.5 mmol) of 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-ol and 60 mL of dry tetrahydrofuran were added. Under nitrogen protection, the mixture was cooled to -70 °C, and KHMDS (7.5 mL, 1 M tetrahydrofuran solution) was added dropwise. The temperature was slowly raised to -20 °C, and the mixture was stirred for 3 hours at a temperature maintained between -20 °C and 0 °C. The reaction solution was quenched with 50 mL of saturated ammonium chloride aqueous solution and extracted with 60 mL of ethyl acetate. The residue obtained after concentration of the organic phase was purified by rapid column chromatography (water (0.1% formic acid): acetonitrile = 100:0-0:100 gradient elution) and rapid column chromatography (dichloromethane: methanol = 100:0-90:10 gradient elution) to give 870 mg of a white solid. MS(m / z): 323.0 [M+H] + .

[0425] (E)3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0426] Following the preparation process of intermediate 52 in steps (D) and (E), the title product was prepared using the appropriate raw materials and reagents. MS (m / z): 261.2 [M+H] + .

[0427] Intermediate 56: (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridin-7-ol

[0428]

[0429] (A)(S)-2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-ol

[0430] Under nitrogen protection, triethylamine (1.1 mL, 8.0 mmol) was added dropwise to formic acid (0.75 mL, 20 mmol) while maintaining the temperature below 25°C. In a reaction flask, 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-one (1.50 g, 4.2 mmol), ethyl acetate (100 mL), and RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] (320 mg, 0.5 mmol, CAS: 192139-92-7) were added dropwise, followed by the above mixture of triethylamine and formic acid. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was washed sequentially with saturated ammonium chloride (60 mL), saturated sodium bicarbonate (60 mL), and saturated brine (60 mL). After concentrating the organic phase, the residue was purified by rapid column chromatography (water:acetonitrile = 100:0-0:100 gradient elution) to give 1.2 g of a brown solid. MS (m / z): 359.0 [M+H] + .

[0431] (B)(S)-7-bromo-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridine

[0432] In a reaction flask, (S)-2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(6-methoxypyridin-3-yl)ethane-1-ol (1.20 g, 3.3 mmol) and dry tetrahydrofuran (40 mL) were added. Under nitrogen protection, the mixture was cooled to -70 °C, and KHMDS (5 mL, 1 M tetrahydrofuran solution) was added dropwise. The temperature was slowly raised to -20 °C, and the mixture was stirred for 3 hours at a temperature maintained between -20 °C and 0 °C. The reaction solution was quenched with saturated ammonium chloride aqueous solution (40 mL), extracted with ethyl acetate (40 mL), and the organic phase was washed with saturated brine (40 mL). The residue obtained after concentration was purified by rapid column chromatography (water (0.1% formic acid): acetonitrile = 100:0-0:100 gradient elution) and chiral preparative HPLC to give 280 mg of white solid. MS (m / z): 323.0 [M+H] + HPLC conditions for chiral preparation: Column: ODH (2×25cm); Mobile phase: Acetonitrile / ethanol = 10:90 (0.1% ammonia); Flow rate: 15ml / min; Detector: UV 280nm.

[0433] (C)(S)-(3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridin-7-yl)boronic acid

[0434] In a reaction flask, (S)-7-bromo-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (280 mg, 0.87 mmol), Pin2B2 (442 mg, 1.74 mmol), Pd(dppf)Cl2 (64 mg, 0.09 mmol), potassium acetate (213 mg, 2.2 mmol), and dioxane (12 mL) were added, and the mixture was refluxed and stirred overnight under nitrogen protection. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by rapid column chromatography (elution gradient of water (0.1% formic acid):acetonitrile = 100:0-0:100) to give 250 mg of a brown solid product. MS (m / z): 289.2 [M+H] + .

[0435] (D)(S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0436] In a reaction flask, (S)-(3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxindo[2,3-b]pyridin-7-yl)boric acid (250 mg, 0.87 mmol) and methanol (12 mL) were added. Under ice bath conditions, an aqueous solution of sodium hydroxide (176 mg, 4.4 mmol) (3 mL) was added dropwise, followed by hydrogen peroxide (0.46 mL, 4.4 mmol). The mixture was stirred at room temperature for 4 hours. A saturated aqueous solution of sodium bisulfite (0.5 mL) was added dropwise to the reaction solution, and the mixture was concentrated. The residue was purified by rapid column chromatography (water:acetonitrile = 100:0-0:100 gradient elution) to give 200 mg of a gray solid. MS (m / z): 261.1 [M+H] + .

[0437] The following intermediates were prepared using the same raw materials and reagents as intermediate 56, under conditions recognized by those skilled in the art.

[0438]

[0439] Intermediate 58: 3-(5-cyclopropylpyridin-2-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0440]

[0441] (A) 1-(5-Cyclopropylpyridin-2-yl)ethane-1-one

[0442] In a reaction flask under nitrogen protection, 1-(5-bromopyridin-2-yl)ethane-1-one (3 g, 11.3 mmol), cyclopropylboronic acid (1.94 g, 22.6 mmol), Pd(OAc)₂ (253 mg, 1.13 mmol), tricyclohexylphosphine (633 mg, 2.26 mmol), potassium phosphate (7.2 g, 33.9 mmol), toluene (60 mL), and water (6 mL) were added sequentially. The mixture was heated to 110 °C and stirred for 16 hours. The residue obtained after concentration of the reaction solution was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give 1.3 g of product. MS (m / z): 162.1 [M+H] +

[0443] (B) 2-Bromo-1-(5-Cyclopropylpyridin-2-yl)ethane-1-one

[0444] In a reaction flask, 1.3 g (8.1 mmol) of 1-(5-cyclopropylpyridin-2-yl)ethane-1-one was dissolved in an acetic acid solution of hydrobromic acid (15 mL, 33% wt), followed by the addition of liquid bromine (1.78 g, 8.1 mmol). The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was neutralized with an aqueous sodium bicarbonate solution. The extract was then extracted and concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give 1.3 g of the product. MS (m / z): 240.0 [M+H] +

[0445] (C)2-((5-bromo-2-fluoropyridin-3-yl)oxy)-1-(5-cyclopropylpyridin-2-yl)ethane-1-one

[0446] In a reaction flask, 1.24 g (5.2 mmol) of 2-bromo-1-(5-cyclopropylpyridin-2-yl)ethane-1-one and 1 g (5.2 mmol) of 5-bromo-2-fluoropyridin-3-ol were dissolved in 15 mL of DMF, followed by the addition of sodium hydride (208 mg, 5.2 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was quenched with saturated ammonium chloride solution, extracted with EA, washed with brine, concentrated, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give 1.4 g of product. MS (m / z): 351.0 [M+H] +

[0447] (D)2-((5-bromo-2-hydroxypyridin-3-yl)oxy)-1-(5-cyclopropylpyridin-2-yl)ethane-1-one

[0448] In a sealed tube, 1.4 g (4 mmol) of 2-((5-bromo-2-fluoropyridin-3-yl)oxy)-1-(5-cyclopropylpyridin-2-yl)ethane-1-one, 3.28 g (40 mmol) of sodium acetate, and 10 mL of acetic acid were added sequentially, and the mixture was reacted at 140 °C for 16 h. The reaction solution was concentrated, neutralized with an aqueous sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1.2 g of product. MS (m / z): 349.0 [M+H] +

[0449] (E)5-Bromo-3-(2-(5-cyclopropylpyridin-2-yl)-2-hydroxyethoxy)pyridin-2-ol

[0450] In a reaction flask, (2-((5-bromo-2-hydroxypyridin-3-yl)oxy)-1-(5-cyclopropylpyridin-2-yl)ethane-1-one (1.2 g, 3.45 mmol), RuCl(p-isopropyltoluene)[(R,R)-Ts-DPEN] (109 mg, 0.17 mmol, CAS: 192139-92-7) and methanol (15 mL) were added. Under nitrogen protection, 1 mL of triethylamine / formic acid (molar ratio, 2:5) solution was added. After the addition was complete, the reaction was carried out overnight at 50 °C. The mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 800 mg of the product. MS (m / z): 351.0 [M+H] + .

[0451] (F)7-Bromo-3-(5-Cyclopropylpyridin-2-yl)-2,3-Dihydro-[1,4]dioxon[2,3-b]pyridine

[0452] In a reaction flask under nitrogen protection, 5-bromo-3-(2-(5-cyclopropylpyridin-2-yl)-2-hydroxyethoxy)pyridin-2-ol (850 mg, 2.43 mmol), tetrahydrofuran (15 mL), PPh3 (1.27 g, 4.86 mmol), and DIAD (981 mg, 4.86 mmol) were added sequentially, and the reaction was carried out at room temperature for 3 hours. The residue obtained after concentration was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give 700 mg of product. MS (m / z): 333.0 [M+H] +

[0453] (G)3-(5-Cyclopropylpyridin-2-yl)-7-(4,4,5,5-Tetramethyl-1,3,2-dioxoboron-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0454] In a reaction flask under nitrogen protection, 7-bromo-3-(5-cyclopropylpyridin-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (700 mg, 2.11 mmol), Pin2B2 (803 mg, 3.16 mmol), Pd(dppf)Cl2 (154 mg, 0.21 mmol), potassium acetate (620 mg, 6.33 mmol), and dioxane (10 mL) were added sequentially. The mixture was heated to 90 °C and stirred for 16 hours. The reaction solution was concentrated, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-50:50) to give 600 mg of a white solid product. MS (m / z): 381.2 [M+1] +

[0455] (H)3-(5-Cyclopropylpyridin-2-yl)-2,3-dihydro-[1,4]dioxon[2,3-b]pyridin-7-ol

[0456] In a reaction flask, 3-(5-cyclopropylpyridin-2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (600 mg, 1.58 mmol), sodium hydroxide (126 mg, 3.16 mmol), tetrahydrofuran (10 mL), and water (2 mL) were added sequentially. Then, 0.5 mL of H₂O₂ was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with an aqueous solution of Na₂S₂O₃ and ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100) to give 400 mg of a white solid product. MS (m / z): 271.1 [M+1] +

[0457] The following intermediates were prepared using the same raw materials and reagents as intermediate 58, under conditions recognized by those skilled in the art.

[0458]

[0459] Example 2

[0460] Preparation of Compounds 1-86

[0461] Compound 1

[0462] 7-((6-((4-methoxybenzyl)oxy)pyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0463]

[0464] In a reaction flask, 7-((6-bromopyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (332 mg, 1.0 mmol), 4-methoxybenzyl alcohol (276 mg, 2.0 mmol), cesium carbonate (652 mg, 2.0 mmol), potassium iodide (332 mg, 2.0 mmol), and DMF (10 mL) were added. The reaction mixture was heated under reflux for 24 hours. After the reaction was completed, water (2 mL) was added to quench the reaction, and the mixture was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) and preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give 13 mg of the title product as a white solid. MS (m / z): 390.0 [M+H] +

[0465] 1 H NMR (400MHz, DMSO-d6) δ8.30 (d, J=2.8Hz, 1H), 8.24 (d, J=0.9Hz, 1H), 8.17–8.14 (m, 1H), 7.84 (dd, J=9.7, 2.8Hz, 1H), 7.73–7.66 (m, 2H), 7.38 (dd, J=9.1, 2.5Hz, 2H), 6.94 (d, J=9.0Hz, 1H), 6.92 (d, J=2.0Hz, 1H), 6.91 (d, J=2.1Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H), 2.08 (s, 3H).

[0466] The following compounds were prepared using the same preparation process as compound 1, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0467]

[0468] Compound 5

[0469] 7-((6-((4-cyclopropylbenzyl)oxy)-5-ethoxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0470]

[0471] In a reaction flask under nitrogen protection, 7-((5-ethoxy-6-hydroxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.32 mmol), (4-cyclopropylphenyl)methanol (74 mg, 0.48 mmol), triphenylphosphine (131 mg, 0.48 mmol), THF (10 mL), and DIAD (100 mg, 0.48 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. The reaction was quenched with water (2 mL), and the mixture was concentrated. The residue was separated by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution). The product was further purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give 45 mg of the title product as a white solid. MS (m / z): 444.1 [M+H] +

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.36 (d, J=2.6Hz, 1H), 8.27 (s, 1H), 7.86 (dd, J=9.7, 2.7H z, 1H), 7.72 (d, J = 9.7Hz, 1H), 7.67 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.4Hz, 1H), 7.33 (d , J=8.0Hz, 2H), 7.08(d, J=8.1Hz, 2H), 5.31(s, 2H), 4.08–3.96(m, 2H), 2.11(s, 3H ), 1.98–1.85 (m, 1H), 1.29 (t, J=6.9Hz, 3H), 0.99–0.89 (m, 2H), 0.71–0.61 (m, 2H).

[0473] The following compounds were prepared using the same preparation process as compound 5, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] Compound 19

[0480] 7-((6-((4-chlorobenzyl)oxy)-5-methoxypyridin-3-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0481]

[0482] In a reaction flask, 7-fluoro-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (112 mg, 0.63 mmol), 6-((4-chlorobenzyl)oxy)-5-methoxypyridin-3-ol (168 mg, 0.63 mmol), cesium carbonate (205 mg, 0.63 mmol), and DMF (3 mL) were added. The mixture was heated at 120 °C for 2 hours. After cooling, the reaction solution was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 38 mg of the title product as a white solid. MS (m / z): 424.1 [M+H] +

[0483] 1 H NMR (400MHz, DMSO-d6) δ8.35 (d, J=2.7Hz, 1H), 8.24 (s, 1H), 7.83 (dd, J=9.7, 2.7Hz, 1H), 7.69 (d, J=9.7Hz, 1 H), 7.66 (d, J=2.4Hz, 1H), 7.49–7.40 (m, 4H), 7.38 (d, J=2.4Hz, 1H), 5.33 (s, 2H), 3.75 (s, 3H), 2.08 (s, 3H).

[0484] The following compounds were prepared using the same preparation process as compound 19, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492] Compound 45

[0493] 7-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0494]

[0495] (A) 1-(4-Cyclopropylphenyl)ethane-1-one

[0496] In a reaction flask, 1-(4-bromophenyl)ethane-1-one (1990 mg, 10.0 mmol), cyclopropylboronic acid (2577 mg, 30.0 mmol), palladium acetate (225 mg, 1.0 mmol), tricyclohexylphosphine (280 mg, 1.0 mmol), potassium phosphate (4243 mg, 20.0 mmol), toluene (40 mL), and water (5 mL) were added. The reaction mixture was heated under reflux for 15 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 1.3 g of the title product as a white solid. MS (m / z): 161.1 [M+H] +

[0497] (B) 2-Bromo-1-(4-cyclopropylphenyl)ethane-1-one

[0498] In a reaction flask, 1-(4-cyclopropylphenyl)ethane-1-one (800 mg, 5.0 mmol), N-bromosuccinimide (934 mg, 5.25 mmol), p-toluenesulfonic acid (172 mg, 1.0 mmol), and acetonitrile (30 mL) were added. The reaction mixture was heated under reflux for 5 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 810 mg of the title product as a pale yellow solid. MS (m / z): 239.0, 241.0 [M+H] +

[0499] (C)2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-one

[0500] In a reaction flask, 5-bromo-2-chloropyridin-3-ol (505 mg, 2.43 mmol) was dissolved in DMF (10 mL). Sodium hydride (107 mg, 2.67 mmol) was added to the reaction solution in portions. After the addition was complete, the reaction solution was stirred at room temperature for half an hour. Then, 2-bromo-1-(4-cyclopropylphenyl)ethane-1-one (580 mg, 2.43 mmol) was dissolved in 3 mL of DMF and added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, water (50 mL) and ethyl acetate (50 mL) were added, followed by extraction twice. The organic phases were combined, washed twice with saturated brine (30 mL), and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 780 mg of the title product as a pale yellow solid. MS (m / z): 366.0, 368.0 [M+H] +

[0501] (D)2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-ol

[0502] In a reaction flask, 780 mg (2.13 mmol) of 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-one was dissolved in 30 mL of methanol. Sodium borohydride (161 mg, 4.26 mmol) was added in portions under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 5-6 with dilute hydrochloric acid. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 680 mg of the title product as a white solid. MS (m / z): 268.0, 270.0 [M+H] +

[0503] (E)7-Bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxono[2,3-b]pyridine

[0504] In a reaction flask, 620 mg (1.68 mmol) of 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-ol was dissolved in 3 mL of DMF. Sodium hydride (74 mg, 1.85 mmol) was then added in portions to the reaction mixture. After the addition was complete, the reaction mixture was stirred at room temperature for 10 minutes, then at 60 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted twice with 50 mL of water and 50 mL of ethyl acetate. The organic phases were combined, washed twice with 30 mL of saturated brine, and concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 230 mg of the title product as a pale yellow solid. MS (m / z): 332.0, 334.0 [M+H]+

[0505] (F)3-(4-Cyclopropylphenyl)-2,3-Dihydro-[1,4]dioxono[2,3-b]pyridine-7-ol

[0506] In a reaction flask under nitrogen protection, 7-bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (230 mg, 0.692 mmol), Pin2B2 (352 mg, 1.38 mmol), potassium acetate (135 mg, 1.38 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol), dioxane (20 mL), and water (4 mL) were added sequentially. The reaction mixture was refluxed and stirred for 6 hours. After cooling to room temperature, the mixture was concentrated, and ethyl acetate (100 mL) was added and stirred for 1 hour. The mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated, and the residue was dissolved in THF (20 mL) and an aqueous solution of sodium hydroxide (56 mg sodium hydroxide dissolved in 2 mL of water). Hydrogen peroxide (1 mL, 30% by weight) was added dropwise under ice bath conditions, and the mixture was heated to room temperature and stirred for 1 hour. After cooling in an ice bath, a saturated sodium thiosulfate aqueous solution was added dropwise, and the mixture was stirred for 5 minutes. After confirming the absence of peroxides by starch-potassium iodide test paper, the solution was concentrated. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100 gradient elution) to give 80 mg of the title product as a white solid. MS (m / z): 270.0 [M+H] +

[0507] (G)5-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)pyridin-2-amine

[0508] In a reaction flask, 3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxinro[2,3-b]pyridin-7-ol (50 mg, 0.185 mmol), 5-fluoro-2-nitropyridine (27 mg, 0.185 mmol), potassium carbonate (26 mg, 0.185 mmol), and DMF (2 mL) were added. The reaction mixture was heated at 50 °C for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in 20 mL of 95% ethanol. Iron powder (42 mg, 0.742 mmol) and ammonium chloride (50 mg, 0.925 mmol) were then added. The reaction mixture was refluxed for 2 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 43 mg of the title product as a solid. MS (m / z): 362.1 [M+H] +

[0509] (H)7-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0510] In a microwave-safe tube, 5-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxinro[2,3-b]pyridin-7-yl)oxy)pyridine-2-amine (43 mg, 0.119 mmol), (E)-3-ethoxy-2-methacrylate (38 mg, 0.238 mmol), and acetic acid (3 mL) were added. The reaction was heated at 110 °C for 2 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) and preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give 13 mg of the title product as a white solid. MS (m / z): 428.1 [M+H] +

[0511] 1 H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 8.25 (s, 1H), 7.86-7.81 (m, 1H), 7.80 -7.76(m, 1H), 7.70(d, J=9.6Hz, 1H), 7.48-7.43(m, 1H), 7.39–7.29(m, 2H) , 7.15–7.07(m, 2H), 5.44-5.25(m, 1H), 4.57-4.40(m, 1H), 4.38-4.12(m, 1 H), 2.10 (s, 3H), 1.94-1.87 (m, 1H), 0.97-0.89 (m, 2H), 0.69-0.62 (m, 2H).

[0512] Compound 46

[0513] 2-((4-Cyclopropylbenzyl)oxy)-3-methoxy-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)methyl)pyridine

[0514]

[0515] Under nitrogen protection, 2-((4-cyclopropylbenzyl)oxy)-3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (prepared using the same raw materials and reagents as intermediate 20(B)) (2500 mg, 6.55 mmol) and 4-(bromomethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (1512 mg, 6.55 mmol) were added to the reaction flask. The reaction mixture was prepared by heating dioxane (40 mL) and water (5 mL) with potassium phosphate (2780 mg, 13.1 mmol), Pd(dppf)Cl2 (240 mg, 0.327 mmol), potassium phosphate (2780 mg, 13.1 mmol), Pd(dppf)Cl2 (240 mg, 0.327 mmol), potassium phosphate (2780 mg, 13.1 mmol), dioxane (40 mL), and refluxed for 15 hours. The reaction mixture was concentrated, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) and preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to give 185 mg of the title product as a white solid. MS (m / z): 427.2 [M+H] +

[0516] 1 H NMR (400MHz, DMSO-d6) δ8.34 (d, J=5.1Hz, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.61 (d, J=1.3Hz, 1H), 7.53 (s, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 7.20 (d, J=1.7Hz, 1H), 7.04-6.98 (m, 3H), 5.21 (s, 2H), 3.85 (s, 2H), 3.84 (s, 3H) , 3.70 (s, 3H), 1.91–1.79 (m, 1H), 0.92–0.85 (m, 2H), 0.64–0.57 (m, 2H).

[0517] Compound 47

[0518] 7-((5-methoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)methyl)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0519]

[0520] (A) 5-Methoxy-6-((4-Methoxybenzyl)oxy)nicotinaldehyde

[0521] In a reaction flask, 800 mg (2.47 mmol) of 5-bromo-3-methoxy-2-((4-methoxybenzyl)oxy)pyridine and 30 mL of dry THF were added. The reaction solution was cooled to -78 °C, and under nitrogen protection, 1.13 mL (2.71 mmol) of 2.4 M n-BuLi was added dropwise. After reacting for 20 min, 360 mg (4.94 mmol) of DMF was added dropwise, and the reaction was continued at -78 °C for 1 h. Then, the temperature was slowly raised to 0 °C, quenched with saturated ammonium chloride aqueous solution, extracted with EA, and the organic phase was dried and concentrated. The residue was purified by rapid column chromatography (PE / EA = 100:0-0:100 gradient elution) to give 280 mg of a white solid product. MS (m / z): 296.1 [M+Na] +

[0522] (B)(5-methoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)methanol

[0523] In a reaction flask, 5-methoxy-6-((4-methoxybenzyl)oxy)nicotinaldehyde (280 mg, 1.025 mmol), THF (10 mL), and methanol (10 mL) were added, followed by sodium borohydride (39 mg, 1.025 mmol). After stirring at room temperature for 30 minutes, the reaction solution was concentrated, water was added, and the mixture was extracted with EA. The organic phase was dried and concentrated, and the residue was purified by rapid column chromatography (PE / EA = 100:0-0:100 gradient elution) to give 268 mg of a white solid product. MS (m / z): 298.1 [M+Na] +

[0524] (C)5-(chloromethyl)-3-methoxy-2-((4-methoxybenzyl)oxy)pyridine

[0525] In a reaction flask, (5-methoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)methanol (90 mg, 0.327 mmol), DCM (20 mL), and TEA (0.136 mL, 0.981 mmol) were added, followed by dropwise addition of MsCl (45 mg, 0.393 mmol). After stirring at room temperature for 30 minutes, the mixture was washed with water, and the organic phase was dried and concentrated to give 110 mg of a colorless oily product.

[0526] (D)7-((5-methoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)methyl)-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0527] In a reaction flask, 5-(chloromethyl)-3-methoxy-2-((4-methoxybenzyl)oxy)pyridine (110 mg, 0.327 mmol), (3-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-7-yl)boronic acid (67 mg, 0.327 mmol), Na₂CO₃ (104 mg, 0.981 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (27 mg, 0.0327 mmol), dioxane (10.0 mL), and water (2.0 mL) were added. The mixture was heated to 60-80 °C under nitrogen protection and stirred for 30 minutes. After cooling, the reaction solution was concentrated and purified by rapid column chromatography (H₂O / MeOH = 100:0-0:100 gradient elution) to give 49 mg of a white solid product. MS (m / z): 418.2 [M+H] +

[0528] 1 H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 8.22 (s, 1H), 7.73 (dd, J=9.2, 2.0Hz, 1H), 7.67 (d, J=1.8Hz, 1H), 7.55 (d, J=9.2Hz, 1H), 7. 33(d, J=8.6Hz, 2H), 7.24(d, J=1.9Hz, 1H), 6.97–6.82(m, 2H), 5.21(s, 2H), 3.99(s, 2H), 3.71(s, 3H), 3.69(s, 3H), 2.10(s, 3H).

[0529] Compounds 48-51

[0530] (R / S)-3-(4-Cyclopropylphenyl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine and

[0531] (R / S)-2-(4-Cyclopropylphenyl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0532]

[0533] (A) 7-bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine and

[0534] 7-Bromo-2-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0535] In a reaction flask, 1.8 g (4.88 mmol) of 2-((5-bromo-2-chloropyridin-3-yl)oxy)-1-(4-cyclopropylphenyl)ethane-1-ol and bis(trimethylsilyl)amino potassium (1.07 g, 5.37 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). After the addition was complete, the reaction mixture was stirred at 60 °C for 4 hours. After the reaction was completed, the reaction mixture was concentrated. The residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 900 mg of a mixture of pale yellow solids containing the title product. MS (m / z): 332.0, 334.0 [M+H] +

[0536] (B) 3-(4-cyclopropylphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine and

[0537] 2-(4-Cyclopropylphenyl)-7-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0538] In a reaction flask under nitrogen protection, a mixture of 7-bromo-3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine and 7-bromo-2-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (900 mg, 2.71 mmol), Pin2B2 (1376 mg, 5.42 mmol), potassium acetate (532 mg, 5.42 mmol), Pd(dppf)Cl2 (99 mg, 0.135 mmol), and dioxane (30 mL) were added sequentially and stirred under reflux for 6 hours. After cooling to room temperature, the mixture was concentrated, and ethyl acetate (100 mL) was added and stirred for 1 hour. The mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was used directly in the next reaction. MS (m / z): 380.0 [M+H] +

[0539] (C)3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine-7-ol and

[0540] 2-(4-Cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine-7-ol

[0541] The crude product prepared in the previous step (1068 mg, 2.82 mmol), THF (30 mL), and sodium hydroxide aqueous solution (226 mg dissolved in 3 mL of water) were added to the reaction flask. Hydrogen peroxide (3 mL, 30% wt) was added dropwise under ice bath conditions. After warming to room temperature, the mixture was stirred for 1 hour. After cooling in an ice bath, a saturated sodium thiosulfate aqueous solution was added dropwise. The mixture was stirred for 5 minutes, and the concentration was achieved after confirming the absence of peroxides using starch-potassium iodide test paper. The residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 100:0-0:100 gradient elution) to give 480 mg of the title product mixture as a white solid. MS (m / z): 270.0 [M+H] +

[0542] (D)(R / S)-3-(4-cyclopropylphenyl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine and

[0543] (R / S)-2-(4-Cyclopropylphenyl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0544] In a reaction flask, a mixture of 3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine-7-ol and 2-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine-7-ol (300 mg, 1.11 mmol), 4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridine (196 mg, 1.11 mmol), and cesium carbonate (362 mg, 1.11 mmol) prepared in the previous step was dissolved in DMF (3 mL). The mixture was heated at 90 °C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 115 mg of a white solid mixture. The mixture was resolved by chiral HPLC to give two pairs of enantiomers. Chiral HPLC conditions: Column: IC (2×25cm); Mobile phase: Acetonitrile / ethanol = 10:90 (0.1% ammonia); Flow rate: 15ml / min; Detector: UV 254nm.

[0545] First eluent (compound 48, 10 mg, RT = 8.693 min), ee% = 100%, [M+H] +427.4. 1HNMR (400MHz, DMSO-d6) δ8.35 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.73 (dd, J= 2.6,0.8Hz,1H),7.39(d,J=2.6Hz,1H),7.35(d,J=8.2Hz,2H),7.21(d,J=2.4Hz,1H),7.13(d,J= 8.1Hz,2H),6.68–6.62(m,1H),5.39(dd,J=8.5,2.2Hz,1H),4.44(dd,J=11.6,2.3Hz,1H),4.12 (dd,J=11.5,8.7Hz,1H),3.83(s,3H),1.96–1.85(m,1H),0.98–0.89(m,2H),0.69–0.63(m,2H).

[0546] Second eluent (compound 49, 12 mg, RT = 9.317 min), ee% = 90%, [M+H) + 427.4. 1 HNMR(400MHz,DMSO-d6)δ8.34(d,J=5.7Hz,1H),8.25(s,1H),7.95(s,1H),7.72(d,J=2.6Hz,1 H),7.41(d,J=2.6Hz,1H),7.33(d,J=8.2Hz,2H),7.22(d,J=2.4Hz,1H),7.10(d,J=8.2Hz,2H), 6.65(dd,J=5.7,2.4Hz,1H),5.27(dd,J=8.5,2.2Hz,1H),4.55(dd,J=11.8,2.3Hz,1H),4.31( dd,J=11.8,8.6Hz,1H),3.83(s,3H),1.94–1.86(m,1H),0.96–0.89(m,2H),0.70–0.61(m,2H).

[0547] The third eluent (compound 50, 18 mg, RT = 10.392 min), ee% = 95%, [M+H] + 427.4. 1HNMR(400MHz,DMSO-d6)δ8.34(d,J=5.7Hz,1H),8.25(s,1H),7.95(s,1H),7.72(dd,J=2.6,0.4Hz ,1H),7.42–7.39(m,1H),7.33(d,J=8.2Hz,2H),7.22(d,J=2.4Hz,1H),7.10(d,J=8.2Hz,2H),6.6 5(dd,J=5.7,2.4Hz,1H),5.27(dd,J=8.5,2.2Hz,1H),4.55(dd,J=11.8,2.4Hz,1H),4.31(dd,J=1 1.8,8.6Hz,1H),3.83(s,3H),1.89(td,J=8.4,4.2Hz,1H),0.96–0.88(m,2H),0.70–0.61(m,2H).

[0548] Fourth elution buffer (compound 51, 18 mg, RT = 11.410 min), ee% = 90%, [M+H] + 427.4. 1 HNMR(400MHz,DMSO-d6)δ8.35(d,J=5.7Hz,1H),8.25(s,1H),7.95(s,1H),7.73(dd,J=2.5,0.5Hz ,1H),7.39(dd,J=2.5,0.4Hz,1H),7.35(d,J=8.2Hz,2H),7.21(d,J=2.4Hz,1H),7.13(d,J=8.2Hz ,2H),6.66(dd,J=5.5,2.2Hz,1H),5.39(dd,J=8.5,2.2Hz,1H),4.44(dd,J=11.6,2.4Hz,1H),4.1 2(dd,J=11.5,8.6Hz,1H),3.83(s,3H),1.96–1.85(m,1H),0.95–0.88(m,2H),0.70–0.61(m,2H).

[0549] Compound 52

[0550] 2-(4-(4-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)pyridin-2-yl)-1H-pyrazol-1-yl)ethane-1-ol

[0551]

[0552] In a reaction flask, 3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxinro[2,3-b]pyridin-7-ol (150 mg, 0.57 mmol), 2-(4-(4-fluoropyridin-2-yl)-1H-pyrazol-1-yl)ethane-1-ol (118 mg, 0.57 mmol), and cesium carbonate (186 mg, 0.57 mmol) were dissolved in DMF (3 mL). The mixture was heated at 90 °C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 6 mg of the title compound as a white solid. MS (m / z): 457.2 [M+H] +

[0553] 1 H NMR (400MHz, DMSO-d6) δ8.35(d,J=5.5Hz,1H),8.25(s,1H),7.97(s,1H),7.72(dd,J=4.3,2.5Hz,1H),7.40(d d,J=7.0,2.4Hz,1H),7.34(t,J=7.8Hz,2H),7.26–7.21(m,1H),7.12(t,J=8.9Hz,2H),6.69–6.62(m,1H),5.3 3(dd,J=45.8,7.6Hz,1H),4.90(s,1H),4.49(dd,J=45.8,9.7Hz,1H),4.36–4.14(m,1H),4.14–4.09(m,2H),3 .72(d,J=5.3Hz,2H),2.85(s,1H),2.69(s,1H),1.95–1.88(m,1H),0.96–0.91(m,2H),0.66(t,J=4.7Hz,2H).

[0554] Compounds 53-54

[0555] (R / S)-3-(6-Cyclopropylpyridin-3-yl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0556]

[0557] (A) 7-((2-bromopyridin-4-yl)oxy)-3-(6-cyclopropylpyridin-3-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0558] In a reaction flask, 3-(6-cyclopropylpyridin-3-yl)-2,3-dihydro-[1,4]dioxinro[2,3-b]pyridin-7-ol (210 mg, 0.777 mmol), 2-bromo-4-fluoropyridine (205 mg, 1.165 mmol), and cesium carbonate (379 mg, 1.165 mmol) were dissolved in DMF (3 mL). The mixture was heated at 90 °C for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 180 mg of the title product as a white solid. MS (m / z): 426.2, 428.2 [M+H] +

[0559] (B)(R / S)-3-(6-Cyclopropylpyridin-3-yl)-7-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine

[0560] Add 7-((2-bromopyridin-4-yl)oxy)-3-(6-cyclopropylpyridin-3-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridine (130 mg, 0.305 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-pyrazole (127 mg, 0.610 mmol), potassium carbonate (85 mg, 0.610 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), dioxane (20 mL), and water (4 mL) to a reaction flask. Heat the reaction mixture to reflux under nitrogen protection and stir for 5 hours. After the reaction was complete, the reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 130 mg of a white solid mixture. The mixture was resolved by chiral HPLC to give a pair of enantiomers. Chiral HPLC conditions: column: IC (2 × 25 cm); mobile phase: acetonitrile / ethanol = 5:95 (0.1% ammonia); flow rate: 18 mL / min; detector: UV 254 nm.

[0561] First eluent (compound 53, 52 mg, RT = 10.192 min), ee% = 95%, [M+H] + 428.2. 1HNMR (400MHz, DMSO-d6) δ8.51(d,J=2.0Hz,1H),8.35(d,J=5.7Hz,1H),8.25(s,1H),7.96( s,1H),7.75(dt,J=4.2,3.4Hz,2H),7.42(dd,J=2.5,0.6Hz,1H),7.36(d,J=8.1Hz,1H),7. 22(d,J=2.4Hz,1H),6.68–6.63(m,1H),5.47(dd,J=8.5,2.2Hz,1H),4.49(dd,J=11.7,2.3 Hz,1H),4.22(dd,J=11.5,8.6Hz,1H),3.83(s,3H),2.16–2.06(m,1H),0.98–0.88(m,4H).

[0562] Second eluent (compound 54, 50 mg, RT = 11.170 min), ee% = 100%, [M+H] + 428.2. 1 HNMR(400MHz,DMSO-d6)δ8.51(d,J=2.1Hz,1H),8.35(d,J=5.6Hz,1H),8.25(s,1H),7.96(s ,1H),7.78–7.69(m,2H),7.42(dd,J=2.6,0.8Hz,1H),7.36(d,J=8.1Hz,1H),7.22(d,J=2.3 Hz,1H),6.66(ddd,J=5.7,2.4,0.7Hz,1H),5.47(dd,J=8.5,2.2Hz,1H),4.49(dd,J=11.6,2 .2Hz,1H),4.21(dd,J=11.5,8.7Hz,1H),3.83(s,3H),2.15–2.05(m,1H),0.98–0.87(m,4H).

[0563] Compounds 55-56

[0564] (R / S)-7-((3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-4-one

[0565]

[0566] In a reaction flask, 3-(4-cyclopropylphenyl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-ol (80 mg, 0.297 mmol), 7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (49 mg, 0.297 mmol), and cesium carbonate (97 mg, 0.297 mmol) were dissolved in DMF (2 mL). The mixture was heated at 90 °C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by rapid column chromatography (water:methanol = 100:0-0:100 gradient elution) to give 120 mg of a white solid mixture. The mixture was resolved by chiral HPLC to give a pair of enantiomers. Chiral HPLC conditions: Column: IC (2×25cm); Mobile phase: Acetonitrile / ethanol = 5:95 (0.1% ammonia); Flow rate: 18ml / min; Detector: UV 254nm.

[0567] First eluent (compound 55, 52 mg, RT = 16.519 min), ee% = 100%, [M+H] + 414.2. 1 HNMR(400MHz,DMSO-d6)δ8.42(d,J=2.7Hz,1H),8.28(d,J=6.3Hz,1H),7.95(dd,J=9.6,2.8Hz, 1H),7.80(d,J=2.6Hz,1H),7.77(d,J=9.6Hz,1H),7.47(d,J=2.6Hz,1H),7.35(d,J=8.2Hz,2H), 7.12(d,J=8.3Hz,2H),6.37(d,J=6.3Hz,1H),5.40(dd,J=8.6,2.3Hz,1H),4.42(dd,J=11.6,2.5 Hz,1H),4.16(dd,J=11.6,8.6Hz,1H),1.95–1.85(m,1H),0.98–0.89(m,2H),0.69–0.62(m,2H).

[0568] Second eluent (compound 56, 50 mg, RT = 18.566 min), ee% = 90%, [M+H] + 414.2. 1HNMR(400MHz,DMSO-d6)δ8.42(d,J=2.7Hz,1H),8.28(d,J=6.3Hz,1H),7.95(dd,J=9.6,2.8Hz, 1H),7.80(d,J=2.6Hz,1H),7.77(d,J=9.6Hz,1H),7.47(d,J=2.6Hz,1H),7.35(d,J=8.2Hz,2H), 7.12(d,J=8.3Hz,2H),6.37(d,J=6.3Hz,1H),5.41(dd,J=8.6,2.3Hz,1H),4.42(dd,J=11.6,2.5 Hz,1H),4.16(dd,J=11.6,8.6Hz,1H),1.96–1.83(m,1H),0.96–0.90(m,2H),0.68–0.62(m,2H).

[0569] The following compounds were prepared using the same preparation process as compounds 55 and 56, with the corresponding intermediates and reagents, and under conditions generally recognized as suitable by those skilled in the art, referring to their chiral resolution conditions.

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] The chiral HPLC conditions for the enantiomers in the table are as follows (flow rate: 18 mL / min; detector: UV 254 nm):

[0578]

[0579]

[0580] Compound 83

[0581] (S)-7-((3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxin[2,3-b]pyridin-7-yl)oxy)-4H-pyrido[1,2-a]pyrimidin-4-one

[0582]

[0583] In a reaction flask, (S)-3-(6-methoxypyridin-3-yl)-2,3-dihydro-[1,4]dioxinro[2,3-b]pyridin-7-ol (60 mg, 0.23 mmol), 7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (45 mg, 0.28 mmol), cesium carbonate (112 mg, 0.35 mmol), and dry DMF (5 mL) were added. The mixture was heated to 90 °C and stirred for 4 hours under nitrogen protection. After cooling to room temperature, the reaction solution was purified by rapid column chromatography (water (0.1% formic acid): acetonitrile = 100:0-0:100 gradient elution), and purified again by rapid column chromatography (dichloromethane: methanol = 100:0-90:10 gradient elution). The product was then recrystallized from ethanol (30 mL) to give 50 mg of a white solid. MS (m / z): 405.1 [M+H] + .

[0584] 1 H NMR (400MHz, CDCl3) δ8.63 (s, J=2.5Hz, 1H), 8.28 (d, J=5.4Hz, 1H), 8.26 (d, J= 2.2Hz,1H),7.77(d,J=1.6Hz,1H),7.73–7.65(m,3H),7.10(d,J=1.6Hz,1H),6 .83(d,J=8.6Hz,1H),6.44(d,J=5.9Hz,1H),5.32(dd,J=9.2,7.1Hz,1H),4.38 (dd,J=11.7,1.7Hz,1H),4.11(dd,J=10.9,9.0Hz,1H),3.96(s,J=0.9Hz,3H).

[0585] The following compounds were prepared using the same preparation process as compound 83, with appropriate intermediates and reagents, under conditions deemed suitable by those skilled in the art.

[0586]

[0587]

[0588] Example 3

[0589] Determining CSF1R kinase activity at the molecular level

[0590] 1. Reagents and materials:

[0591] Z-LYTE TM Tyr 1 substrate peptide: Invitrogen, PV3190;

[0592] Z-LYTETM Tyr 1 phosphorylated substrate peptide: Invitrogen, PV3258;

[0593] 5X kinase buffer: Invitrogen, PV3189;

[0594] 10mM ATP: Invitrogen, PV3227;

[0595] Development reagent B: Invitrogen, PV3295;

[0596] Development buffer: Invitrogen, P3127;

[0597] Termination solution: Invitrogen, P3094;

[0598] Recombinant human CSF1R kinase: Invitrogen, PR4598A;

[0599] 384-hole blackboard: Corning, 3575;

[0600] Envision: Perkin Elmer.

[0601] 2. Preparation of reaction solution

[0602] 1) 1.33X Kinase Buffer: Dilute 5X kinase buffer to 1.33X with ddH2O.

[0603] 2) 4X dilution of the test compound: The test compound was serially diluted to a 4-fold reaction concentration while maintaining the DMSO concentration at 8%. The final reaction concentrations of the compounds were: 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014, and 0.00046 μM, with a final DMSO concentration of 2%.

[0604] 3) Kinase / substrate peptide mixture: In 1.33X kinase buffer, mix the kinase and Z-LYTE... TM The Tyr 1 substrate peptide was diluted to 0.12 μg / mL and 4 μM, respectively, to prepare kinase / substrate peptide mixtures. The mixtures were then gently mixed using a pipette.

[0605] 4) Phosphorylated substrate peptide solution (PP solution): Add 0.4 μL of Z-LYTE... TM Tyr1 phosphorylated substrate peptide was added to 99.6 μL of 1.33X kinase buffer.

[0606] 5) ATP solution: Dilute 10 mM ATP with 1.33X kinase buffer to 760 μM to prepare ATP solution.

[0607] 6) Development solution: Mix Development reagent B with Development buffer at a ratio of 1:1.

[0608] Dilute at a ratio of 200.

[0609] 3. Methods

[0610] 1) Kinase reaction (10μL system)

[0611] Add 2.5 μL of the 4X test compound to each well of a 384 plate, and add the corresponding volume of 8% DMSO to each control well. Place the plate on ice. Add 5 μL of the kinase / substrate peptide mixture, 2.5 μL of kinase buffer, and ATP solution to each well sequentially. Set up three control groups: group C1 contains only kinase buffer, group C2 contains the kinase / substrate peptide mixture, kinase buffer, and ATP, and group C3 contains 5 μL of PP solution. After adding the reaction components, seal the 384-well plate in the dark and incubate at 25–30 °C for 1 hour.

[0612] 2) Development response

[0613] Add 5 μL of Development solution to each well, seal the wells to protect them from light, and incubate at 25-30°C for 1 hour.

[0614] 3) Termination of reaction and plate reading

[0615] Add 5 μL of stop solution to each well. Measure the Coumarin value (excitation wavelength 400 nm, emission wavelength 445 nm) and Fluorescein value (excitation wavelength 400 nm, emission wavelength 520 nm).

[0616] 4. Data Analysis

[0617] % phosphorylation rate = 100% - 100% × [ER × C3 520nm – C3 445nm] / [(C1 445nm – C3 445nm) + ER × (C3 520nm – C1 520nm)]

[0618] in:

[0619] ER (Emission Ratio): Coumarin emission reading (445nm) / Fluorescein emission reading (520nm);

[0620] C3 445nm: Emission reading of 100% phosphorylated Coumarin;

[0621] C3 520nm: Emission reading of 100% phosphorylated Fluorescein;

[0622] C1 445nm: Emission reading of 0% phosphorylated Coumarin;

[0623] C1 520nm: Emission reading of 0% phosphorylated Fluorescein.

[0624] Inhibition rate % (IR) = [1 - % phosphorylation rate] 待测样品 / 100% phosphorylation rate 对照 ]×100%

[0625] in:

[0626] % phosphorylation rate 待测样品 Phosphorylation rate of the compound to be tested;

[0627] 100% phosphorylation rate 对照 Phosphorylation rate of C3 control group.

[0628] 5.IC 50 Value: XL-Fit software bundled with Microsoft Excel by ID Business Solutions (Guildford, UK) TM (Version 5.3) Calculation.

[0629] 6. Test Results

[0630]

[0631] Example 4

[0632] Detection of CSF1R phosphorylation activity at the cellular level

[0633] 1. Cell lines

[0634] THP-1 (ATCC) is a human acute monocytic leukemia cell line. These cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS).

[0635] 2. Reagents and Instruments

[0636] Human phosphorylated-CSF1R ELISA kit: R&D, #DYC3268-2;

[0637] • RPMI 1640 culture medium: GIBCO, #10491;

[0638] • Human M-CSF recombinant cytokine: R&D, #216-MC-500;

[0639] • Cell lysis buffer: Cell Signal, #9803S;

[0640] • 1XPBS buffer (1L): Dissolve 8.0g NaCl, 0.2g KCl, 3.58g Na2HPO4-12H2O, and 0.24g KH2PO4 in 1L dd H2O and adjust the pH to 7.4;

[0641] • Blocking solution: PBS buffer containing 1% bovine serum albumin (BSA);

[0642] • PBST washing buffer: PBS buffer containing 0.05% Tween-20;

[0643] • Developing substrate: R&D, #DY999;

[0644] ·2N H2SO4;

[0645] • Microplate reader: Labsystems Multiskan K3: Thermo; Envision: Perkin Elmer;

[0646] ·ELISA plate: Corning, #9018;

[0647] • Cell culture plate: Facol, #353027.

[0648] 3. Cell processing and lysis buffer preparation

[0649] THP-1 cells were resuspended in RPMI-1640 medium containing 2% FBS at a concentration of 5 × 10⁻⁶ cells / mL. 4 Add 50 μL of the compound to each well of a 96-well plate and incubate overnight at 37°C with 5% CO2. Dilute the compound to be tested with serum-free RPMI-1640 medium to 3, 1.1, 0.37, 0.12, 0.04, 0.014, 0.005, and 0.002 μM, with 5% DMSO. Add 5 μL of the diluted compound to 50 μL of cell culture medium and incubate for 60 min at 37°C with 5% CO2. Then add 300 ng / mL M-CSF to the cells and stimulate for 1 min at 37°C. Add 50 μL of cell lysis buffer and store at -80°C.

[0650] 4. ELISA testing steps

[0651] Add 100 μL / well of p-CSF1R capture antibody diluted to 0.8 μg / mL with PBS to the ELISA plate and coat overnight on a shaker at room temperature. After washing with PBST, add blocking buffer and incubate at room temperature for 2 h. Wash with PBST, add 90 μL of cell lysis buffer, and incubate on a shaker at 25°C for 2 h. Wash three times with PBST, add 100 μL of anti-p-tyrosine-HRP detection antibody diluted with 0.1% PBS-BSA, and incubate on a shaker at 25°C for 2 h. After washing with PBST, add 100 μL of chromogenic substrate and incubate at room temperature for 10–20 min. Stop the reaction by adding 50 μL of 2N H2SO4. Detect the optical density signal (450 / 570 nm) of each well using a Labsystems Multiskan K3 or Envision.

[0652] 5. Data Analysis

[0653]

[0654] in:

[0655] • Drug treatment well reading: Represents the optical density signal of the cell pore affected by the test compound.

[0656] • Background reading: Represents the optical density signal of a cell-free pore containing cell lysis buffer.

[0657] • Cell pore reading: Represents the optical density signal of cell pores that have not been treated with the compound.

[0658] 6.IC 50 Calculation: Obtained using XL-Fit 5.3 software.

[0659] 7. Test Results

[0660]

[0661] Example 5

[0662] Macrophage Viability Detection

[0663] 1. Reagents and Instruments

[0664] Ficoll-Paque PLUS cell separation medium: GE Healthcare, catalog number 17-1440-02;

[0665] Human Monocyte Isolation Kit II: Miltenyi, catalog number 130-091-153;

[0666] RoboSep buffer: Stemcell Technologies, catalog number 20104;

[0667] LS column: Miltenyi Biotec, part number 130-042-401;

[0668] Recombinant human macrophage colony-stimulating factor (rh M-CSF): R&D systems, catalog number 216-MC-025;

[0669] Recombinant mouse macrophage colony-stimulating factor (rm M-CSF): R&D systems, catalog number 416-ML-050;

[0670] 0.25% Trypsin-EDTA: GIBCO, Catalog No. 25200-072;

[0671] Penicillin / streptomycin: GIBCO, catalog number 15140122;

[0672] 2.0 Detection Kit: Promega, Catalog No. G9243;

[0673] 96-well plate (Biocoat Poly-D-Lysine 96-well plate): Corning, part number 356692.

[0674] Envision: PerkinElmer.

[0675] 2. Experimental Procedure

[0676] 1) Isolation of human monocyte-derived macrophages (hMDM)

[0677] Peripheral blood was collected from healthy volunteers and diluted with an equal volume of PBS.

[0678] Add 15 mL of ficoll to a 50 mL centrifuge tube, then add 20 mL of diluted blood and centrifuge at 400 g for 30 minutes.

[0679] • Collect the surface mononuclear cells, dilute with 4 times the volume of PBS, and then centrifuge at 400g for 10 minutes.

[0680] • The cells were washed with 50 mL of PBS and centrifuged twice at 200 g for 10 minutes each time to remove platelets.

[0681] • Use the Human Mononuclear Cell Isolation Kit II to isolate mononuclear cells according to the manufacturer's instructions.

[0682] • Wash the mononuclear cells once with PBS (centrifuge at 400g for 5 minutes) and resuspend them in RPMI 1640 medium, then supplement with 10% fetal bovine serum (FBS) and penicillin / streptomycin.

[0683] • Add 100 ng / mL rh M-CSF (final concentration) to the cells and incubate at 37°C and 5% CO2 for 6 days; change the culture medium every two days.

[0684] 2) Isolation of mouse bone marrow-derived macrophages (mBMDM)

[0685] C57BL / 6j mice were washed with 75% ethanol.

[0686] • Harvest the femur and tibia, and remove all muscle tissue from the bones.

[0687] • Using a 5mL syringe, flush the bone marrow cells into a 1.5mL centrifuge tube with 1mL of culture medium.

[0688] • Resuspend the fresh cells and wash with PBS.

[0689] Add 10 ng / mL rm M-CSF (final concentration) to the cells and incubate at 37°C and 5% CO2 for 6 days; change the culture medium every two days.

[0690] 3) CellTiter-Glo

[0691] hMDM or mBMDM cells were collected using 0.25% trypsin-EDTA.

[0692] • Seed 100 μL of hMDM or mBMDM cell suspension at 5000 cells / well in 96-well plates, and supplement with rh M-CSF (100 ng / mL) or rm M-CSF (10 ng / mL), respectively. Cells without rh M-CSF or rm M-CSF were used as background controls.

[0693] • Add 10 μL of serially diluted compound or 0.1% DMSO medium (as a control) to the plate and incubate at 37°C and 5% CO2 for 4 days.

[0694] • Cells were treated with 50 μL of CellTiter-Glo reagent on a track-type shaker for 10 minutes.

[0695] • Read the board's light emission signal value on Envision.

[0696] 3. Data Analysis

[0697]

[0698] ·compound lum : The luminescence signal value of cells treated with the compound;

[0699] ·cell lum : The luminescence signal value of cells treated with 0.1% DMSO;

[0700] ·background lum : The luminescence signal value of cells treated with 0.1% DMSO without the addition of rh M-CSF / rm M-CSF;

[0701] 4.IC 50 calculate

[0702] IC 50 The values ​​were calculated using XL-Fit 5.3 with model 205.

[0703] 5. Results

[0704] Based on the above experiments, the compounds of the present invention have a strong ability to inhibit macrophages derived from human monocytes or macrophages derived from mouse bone marrow.

Claims

1. Compounds of formula (I): Or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, enantiomer, diastereomer, or tautomer, wherein: R1 is selected from: It is a 5-membered heteroaryl group, which is optionally substituted by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 Alkylene-OH, wherein the 5-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, and the remaining cyclic atoms are carbon atoms; R1' is selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl groups and NR4R5; R4 and R5 are both H; or R4, R5 and the N atoms attached to them together form a 6-membered heterocycle, wherein the 6-membered heterocycle contains one or two cyclic heteroatoms independently selected from N and O, and the remaining cyclic atoms are carbon atoms; X is either O or CR6R7; R6 and R7 are each independently selected from H; Y is either N or CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b Selected independently from H and C respectively 1-6 alkyl; n is 0, 1, 2, 3 or 4; R2 is a phenyl or a 6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-6 cycloalkyl and 5-membered heteroaryl; among which, C as a substituent for R2 3-6 The cycloalkyl or 5-membered heteroaryl group is optionally substituted with one or more halogens; wherein the 5-membered heteroaryl or 6-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, and the remaining cyclic atoms are carbon atoms; Alternatively, when Y is CR3 and n is not 0, R3 and an R a The carbon atoms bonded to them, along with the atoms between the carbon atoms, form a 6-membered heterocycle, which contains two O-ring heteroatoms and the remaining ring atoms are carbon atoms.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R1 is selected from:

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R1' is selected from H and C. 1-6 alkyl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R1 is selected from It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 Alkylene-OH.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, enantiomer, diastereomer, or tautomer, wherein... It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 alkyl.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, enantiomer, diastereomer, or tautomer, wherein, X is either O or CH2.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, or a racemic mixture thereof, enantiomer, diastereomer or tautomer thereof, wherein X is O.

8. The compound according to any one of claims 1-5 and 7, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, Y is CR3, and R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) or -O(C 1-6 (Halogenated alkyl groups).

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R3 is -O(C) 1-6 alkyl).

10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R3 is -O(C) 1-3 alkyl).

11. The compound according to any one of claims 1-5, 7, and 9-10, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R a and R b All are H, and n is 0, 1 or 2.

12. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R a and R b All are H, and n is 1.

13. The compound according to any one of claims 1-5, 7, 9, 10 and 12, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer or tautomer thereof, wherein, R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

14. The compound according to claim 11, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-1a): in R1' is selected from H and C. 1-6 Alkyl, C 3-6 Cycloalkyl groups and NR4R5; R4 and R5 are both H; or R4, R5 and the N atoms attached to them together form a 6-membered heterocycle, wherein the heterocycle contains one O heteroatom in addition to the N atoms attached to R4 and R5, and the remaining ring atoms are carbon atoms; X is either O or CH2; Y is either N or CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 0, 1, or 2; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 alkynyl group, -O(C 1-6 Alkyl), -C 1-6 Alkylene-CN, -C 1-6 alkylene-OH, C 3-6 Cycloalkyl and 5-membered heteroaryl; wherein, C, as a substituent of R2, 3-6 The cycloalkyl or 5-membered heteroaryl group is optionally substituted with one or more halogens, and the 5-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, with the remaining cyclic atoms being carbon atoms.

16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R4 and R5 are both H; or R4, R5 and the N atoms attached to them together form a morpholine ring.

17. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R1' is selected from H and C. 1-6 alkyl; X is O; Y is CR3; R3 is selected from H, -CN, halogens, and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 1; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-1b): in R1' is selected from H and C. 1-6 alkyl; X is O; Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 1 or 2; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

19. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-1c): in X is O; Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 1 or 2; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-1d): in X is O; Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 1 or 2; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-1e): in It is a 5-membered heteroaryl group, which is optionally substituted by one or more groups independently selected from the following: C 1-6 Alkyl group, wherein the 5-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, and the remaining cyclic atoms are carbon atoms; X is either O or CH2; Y is CR3; R3 is selected from H and C. 1-6 Alkyl, -O(C) 1-6 alkyl) and -O(C 1-6 (Halogenated alkyl); R a and R b All are H; n is 1 or 2; R2 is a phenyl group, which is optionally substituted by one or more groups independently selected from the following: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

22. The compound according to claim 21, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 alkyl.

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, Y is CR3 and n is not 0, R3 and an R a The carbon atoms bonded to them, along with the atoms between the carbon atoms, form a 6-membered heterocycle, which contains two O-ring heteroatoms and the remaining ring atoms are carbon atoms.

24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-2) or formula (I-3): R1, R2 and X are defined as in claim 1.

25. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-2).

26. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-2a): in R1' is selected from H and C. 1-6 alkyl; X is O; R2 is a phenyl or a 6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein, C, as a substituent of R2 3-6 The cycloalkyl group is optionally substituted with one or more halogens; wherein the 6-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, and the remaining cyclic atoms are carbon atoms.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from: -O(C 1-6 alkyl) and C 3-6 Cycloalkyl.

28. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the structure of formula (I-2b): in It is a 5-membered heteroaryl group, which is optionally substituted by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 Alkylene-OH; wherein the 5-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, and the remaining cyclic atoms are carbon atoms; X is O; R2 is a phenyl or a 6-membered heteroaryl group, each optionally substituted by one or more groups independently selected from: halogen, C 1-6 Alkyl, -O(C) 1-6 alkyl) and C 3-6 Cycloalkyl; wherein the 6-membered heteroaryl group comprises one or two N-type cyclic heteroatoms, the remaining cyclic atoms are carbon atoms, and the C atoms acting as substituents for R2 are... 3-6 The cycloalkyl group may optionally be replaced by one or more halogens.

29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 Alkyl and -C 1-6 Alkylene-OH.

30. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, It is a pyrazolyl group, which is optionally replaced by one or more groups independently selected from the following: C 1-6 alkyl.

31. The compound according to any one of claims 28-30, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from the following: -O(C 1-6 alkyl) and C 3-6 Cycloalkyl.

32. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, or a racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R2 is a pyridyl group, which is optionally substituted by one or more groups independently selected from the following: -O(C 1-6 alkyl) and C 3-6 Cycloalkyl.

33. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein, R2 is a phenyl or pyridyl group, each optionally substituted by one or more groups independently selected from the following: -O(C 1-3 Alkyl) and cyclopropyl.

34. Selected from the following compounds or their pharmaceutically acceptable salts.

35. A pharmaceutical composition comprising a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, and optionally comprising a pharmaceutically acceptable excipient.

36. A method for inhibiting CSF-1R activity in vitro, comprising contacting an effective amount of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof with CSF-1R.

37. Use of the compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an individual with a disease mediated by or at least partially mediated by CSF-1R.

38. The use according to claim 37, wherein: The diseases mentioned are autoimmune diseases, inflammatory diseases, neurodegenerative diseases, cancer, or metabolic diseases.

39. The use according to claim 37, wherein the disease is obesity or an obesity-related disease.

40. The use according to claim 38, wherein: The autoimmune or inflammatory diseases mentioned are selected from rheumatoid arthritis, collagen-induced arthritis, osteoarthritis, pigmented villonodular synovitis (PVNS), systemic lupus erythematosus, multiple sclerosis, systemic scleroderma, autoimmune nephritis, inflammatory bowel disease, psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, Behçet's disease, idiopathic thrombocytopenic purpura, spondyloarthritis, systemic juvenile idiopathic arthritis (SoJIA), pancreatitis, and ischemia-reperfusion disorders of solid organs. Injuries, organ transplant rejection, sepsis, systemic inflammatory response syndrome, and organ damage caused by chemotherapy drugs; the neurodegenerative diseases mentioned are selected from Parkinson's disease (PD), multiple system atrophy, Alzheimer's disease (AD), frontotemporal dementia, Huntington's disease (HD), corticobasal degeneration, spinocerebellar ataxia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary motor sensory neuropathy (CMT); the cancer mentioned is a solid tumor or a hematologic malignancy.

41. The use according to claim 40, wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.

42. The use according to claim 40, wherein the cancer is selected from ovarian cancer, lung cancer, brain tumor, giant cell tumor of the tendon sheath, gastrointestinal stromal tumor (GIST), gastric cancer, esophageal cancer, colon cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, melanoma, mesothelioma, mesothelial endometrial carcinoma, kidney cancer, liver cancer, thyroid cancer, head and neck cancer, urothelial carcinoma, bladder cancer, endometrial cancer, choriocarcinoma, adrenal carcinoma, sarcoma, leukemia, lymphoma, or myeloma.

43. The use according to claim 42, wherein the lung cancer is non-small cell lung cancer.

44. The use according to claim 42, wherein the brain tumor is a glioblastoma (GBM).

45. A pharmaceutical combination product comprising a compound of any one of claims 1-34 or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent.

46. ​​The pharmaceutical combination product according to claim 45, wherein: The other therapeutic agents mentioned are anti-inflammatory agents or antitumor agents.

47. The pharmaceutical combination product of claim 46, wherein the antitumor agent is selected from radiotherapy agents, chemotherapy agents, immune checkpoint inhibitors or agonists, and targeted therapy agents.

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