Compounds as csf1r inhibitors

Abstract

This invention discloses pyrazolopyridine or pyrazolopyrimidine compounds or salts thereof with colony-stimulating factor-1 receptor (CSF1R) inhibitory activity, their medical uses for treating, preventing, and / or diagnosing CSF1R-related diseases, and methods for preparing said compounds or salts thereof. The provided invention includes a compound or salt thereof represented by formula [I], its medical uses, and its preparation method, wherein R... 1 It is hydrogen, etc.; R 21 and R 22 It is hydrogen, or R 21 and R 22 Together with the adjacent heterocyclic ring, it forms a bridging double ring; R 3 It is optionally controlled by one or more R 32 Replaced -L 31 -R 31 Or optionally by one or more R 32 Replacement R 31 L 31 It is -C(=O)- etc.; R 31 It is C 1‑6 Alkyl groups, etc.; R 32 Each is independently a halogen, etc.; and X is a CR. 1 Or N.

Description

Technical Field

[0001] This invention relates to pyrazolopyridine or pyrazolopyrimidine compounds and their salts. The invention also relates to the medical use of pyrazolopyridine or pyrazolopyrimidine compounds or their salts for the treatment, prevention, and / or diagnosis of diseases associated with colony-stimulating factor-1 receptor (CSF1R). Methods for preparing said compounds or their salts are also provided. Background Technology

[0002] Macrophage colony-stimulating factor-1 receptor (CSF1R) is a member of the class III receptor tyrosine kinase family, which also includes FMS-like tyrosine kinase 3 (FLT-3), tyrosine protein kinase KIT (KIT), and platelet-derived growth factor receptor (PDGFR) α and β. CSF1R is primarily expressed in macrophage lineages, including monocytes, tissue macrophages, dendritic cells, Kupffer cells, osteoclasts, and microglia. In the brain, CSF1R binding to CSF-1 or IL-34 activates signal transduction pathways such as the PI3K / AKT / NF-κB, PKC / NF-κB, and ROS / RAS / RAF / MAPK pathways, leading to differentiation, survival, proliferation, adhesion, and migration of monocyte / macrophage lineage cells.

[0003] The phenotypes of mice lacking functional CSF1R and ligands include osteosclerosis, reduced numbers of macrophages and microglia, and reduced production of inflammatory cytokines, indicating multiple functions of CSF1R signaling.

[0004] CSF1R signaling can also lead to the abnormal expression of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are involved in the exacerbation of various types of cancer, bone disorders, and inflammatory diseases.

[0005] Reference List

[0006] Non-patent literature

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[0008] [NPL 2] Lv Qi et al., (Z)-1-(3-((1H-pyrrolo-2-yl)methylene)-2-oxoindoline-6-yl)-3-(iso Discovery of (Z)-1-(3-((1H-Pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)-3-(isoxazol-3-yl)urea Derivatives as Novel and Orally Highly Effective CSF-1R Inhibitors for Potential Colorectal Cancer Immunotherapy. J Med Chem. 1c01184 (2021).

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[0011] [NPL 5] Uesato N, et al., Pharmacological Properties of JTE-952, an Orally Available and Selective Colony Stimulating Factor 1 Receptor Kinase Inhibitor. Biological and Pharmaceutical Bulletin 43, 325-333 (2020)

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[0020] [NPL 14] Sosna, J. et al., Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in a 5XFAD mouse model of Alzheimer's disease. Molecular neurodegeneration 13, 11 (2018).

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[0029] [NPL 23] Beckmann, N. et al., Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945. Actaneuropathologica communications 6, 9 (2018).

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[0032] [NPL 26] Wang Y. et al., Early posttraumatic CSF1R inhibition via PLX3397 leads to time- and sex-dependent effects on inflammation and neuronal maintenance after traumatic brain injury in mice. Brain Behav Immun. S0889-1591(22)00338-5 (2022).

[0033] [NPL 27] Rebecca J. H et al., Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. Journal of Neuroscience 10, 2402-19 (2020)

[0034] [NPL 28] Oh SJ et al., Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model. Mol ImagingBiol 22(4):1031-1042 (2020).

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[0036] [NPL 30] Sawicki CM et al., Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress. Journal of Neuroscience 39, 1139-1149 (2019).

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[0040] [NPL 34] Zhou Y. et al., CSF1 / CSF1R-mediated crosstalk between choroidal endothelial cells and macrophages promotes choroidal neovascularization. Invest Ophthalmol Vis Sci 62(3): 37 (2021) Summary of the Invention

[0041] Technical issues

[0042] One object of the present invention is to provide novel pyrazolopyridine or pyrazolopyrimidine compounds or salts thereof for the treatment, prevention and / or diagnosis of diseases associated with CSF1R.

[0043] Another object of the present invention is to provide a medicine having a broad therapeutic spectrum associated with CSF1R inhibition.

[0044] Solution to the problem

[0045] As a result of a detailed study aimed at solving the aforementioned problems, the inventors successfully synthesized new pyrazolopyridine and / or pyrazolopyrimidine compounds.

[0046] A compound or a salt thereof represented by formula [I] is provided: [Chemical Formula 1]

[0047] in

[0048] R 1 It is hydrogen, halogen, -CN, optionally dilated by one or more R 12 Replacement -L 11 -R 11 Or optionally by one or more R 12 Replacement -R 11 ; L 11 It is -C 1-3 alkylene-, -C 1-3 Alkylene -C(=O)-, -O-, -OC 1-3 Alkylene-, -OC 1-3 Alkylenes -O-, -OCH2C(=O)O-, -C(=O-, -C(=O)NH- or -NH-C(=O-); R 11 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirocyclic groups; R 12 Each is an independent halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-8 cycloalkyl, optionally with one or more C 1-6 Alkyl-substituted saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirochetal groups; R 21 and R 22 It is hydrogen, or R 21 and R 22 Together with the adjacent heterocyclic rings, they form a bridging double ring; R 3 It is optionally controlled by one or more R 32 Replacement -L 31 -R 31 Or optionally by one or more R 32 Replacement R 31 ; L 31 Yes -C(=O)-, -C(=O)O-, -C(=O)OC 1-3 Alkylene-, -C(=O)-C 1-3 Alkylene -O-, -C(=O)-C 1-3 Alkylene-OC 1-3 Alkylene- or -C(=O)NH-C 1-3 alkylene-; R 31 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, or e) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spiroheterocyclic groups; R 32 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; X is CR1 Or N; and key: [Chemical Formula 2]

[0049] It is either a single bond or a double bond.

[0050] Also provided are pharmaceutical compositions comprising a compound of formula [I] or a salt thereof and a pharmaceutically acceptable carrier or excipient.

[0051] Also provided are therapeutic, preventive and / or diagnostic agents of compounds of formula [I] or salts thereof for the treatment of diseases caused by CSF1R.

[0052] Methods for treating, preventing, and / or diagnosing diseases caused by CSF1R are also provided, the methods comprising administering an effective amount of a compound of formula [I] or a salt thereof to a person in need.

[0053] Compounds of formula [I] or salts thereof are also provided for the treatment, prevention and / or diagnosis of diseases caused by CSF1R.

[0054] Also provided is the use of compounds of formula [I] or salts thereof in the manufacture of medicaments for the treatment, prevention and / or diagnosis of diseases caused by CSF1R.

[0055] Methods for preparing compounds of formula [I] or salts thereof and novel intermediates used in the preparation of compounds of formula [I] or salts thereof are also provided. Detailed Implementation

[0056] The phrases and terms used in this specification are described in detail below.

[0057] In this specification, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. It is preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0058] In this specification, the term "C" 1-6 Alkyl groups are those having 1 to 6 carbon atoms (C6H ...7H6H6H6 1-6 ( ) straight-chain or branched alkyl groups, specific examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, etc. "C 1-6 "alkyl" also includes C with deuterium atoms that have replaced 1 to 3 hydrogen atoms. 1-6 Alkyl groups, specific examples of which include methyl-d1, methyl-d2, methyl-d3, ethyl-d5, etc.

[0059] In this specification, the term "C" 1-6 "Haloalkyl" refers to an alkyl group having 1 to 4 halogens, preferably 1 to 3 halogens, and having 1 to 6 carbon atoms (C6H6O). 1-6Straight-chain or branched alkyl groups, specific examples of which include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl, etc.

[0060] In this specification, the term "C" 1-3 "alkylene" refers to compounds with 1 to 3 carbon atoms (C60, C ... 1-3 ( ) straight-chain or branched alkylene groups. Specific examples include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, etc. "C 1-3 "Alkylene" also includes C atoms in which one to three hydrogen atoms are replaced by deuterium atoms. 1-3 Alkylene.

[0061] In this specification, the term "C" 1-6 "alkylene" refers to compounds with 1 to 6 carbon atoms (C6N-6 ... 1-6 ( ) straight-chain or branched alkylene groups. Specific examples include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, 2,2-dimethylethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, etc. "C 1-6 "alkylene" also includes C atoms in which 1 to 6 hydrogen atoms are replaced by deuterium atoms. 1-6 Alkylene.

[0062] In this specification, the term "C" 3-8 "Cycloalkyl" refers to saturated or partially unsaturated carbocyclic groups having 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0063] In this specification, the term "saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirocyclic group" comprises at least one heteroatom selected from nitrogen, oxygen, and sulfur atoms, and may be partially unsaturated. Heterocyclic groups include bridged heterocyclic groups. Specific examples include saturated or unsaturated 4- to 6-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms as cyclic heteroatoms; saturated or unsaturated 4- to 6-membered monocyclic heterocyclic groups containing 1 oxygen atom as a cyclic heteroatom; saturated or unsaturated 5- to 6-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms; unsaturated 5-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms; saturated or unsaturated 7- to 9-membered bicyclic heterocyclic groups containing 2 to 3 nitrogen atoms as cyclic heteroatoms; and bicyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1... A 7- to 9-membered bicyclic heterocyclic group with one oxygen atom as a saturated or unsaturated cyclic heteroatom; a 9-membered bicyclic heterocyclic group with one nitrogen atom, one oxygen atom, and one sulfur atom as saturated or unsaturated cyclic heteroatom; a 6- to 10-membered bicyclic heterocyclic group with one oxygen atom as a saturated or unsaturated cyclic heteroatom; a 7-membered spirocyclic heterocyclic group with one to two nitrogen atoms as cyclic heteroatom; a 7- to 8-membered spirocyclic heterocyclic group with one nitrogen atom and one oxygen atom as cyclic heteroatom; and a 6- to 10-membered spirocyclic heterocyclic group with two nitrogen atoms as cyclic heteroatom.

[0064] In this specification, saturated or unsaturated 4- to 6-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms as cyclic heteroatoms specifically include aziridine, piperidinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrazinyl, pyrazoleyl, pyrrolidinyl, imidazolyl, pyrazolylyl, and piperazinyl.

[0065] In this specification, saturated or unsaturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom specifically include oxocyclic butyl, pyranyl, furanyl, tetrahydropyranyl, and tetrahydrofuranyl.

[0066] In this specification, saturated or unsaturated 5- to 6-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms specifically include: azole, isotonic azole, diazole and morpholine.

[0067] In this specification, unsaturated 5-membered monocyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms specifically include thiazolyl, thiazolinyl (dihydrothiazolyl), thiadiazolyl, isothiazolyl, and thiazolylalkyl.

[0068] In this specification, saturated or unsaturated 7- to 9-membered bicyclic heterocyclic groups containing 2 to 3 nitrogen atoms as cyclic heteroatoms specifically include pyrrolidine-pyrrolidinyl, benzimidazolyl, dihydrobenzimidazolyl, indazole, indazolinyl (dihydroindazole), benzotriazolyl, imidazopyridyl, imidazopyrazinyl, tetrahydroimidazopyrazinyl, pyrazolpyridyl, tetrahydropyridindoleyl, benzozazazolyl, tetrahydrobenzozazazolyl, pyrrolopyrrolidinyl, and hexahydropyrrolopyrrolidinyl.

[0069] In this specification, saturated or unsaturated 7- to 9-membered bicyclic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms specifically include benzo[a]. azole group, dihydrobenzo azole, oxazabicycloheptyl, tetrahydrofuranopyrrole, benzo[] diazole group, benzo[a] azole, benzo[ Azine, dihydrobenzo Azine, dihydroimidazole Azine, dihydropyrazole Azine, furanopyridyl, furanopyrrole, benzo[a]oxazolidinyl and tetrahydrobenzo[a]oxazolidinyl.

[0070] In this specification, the saturated or unsaturated 9-membered bicyclic heterocyclic groups containing one nitrogen atom, one oxygen atom, and one sulfur atom as cyclic heteroatoms specifically include pyrano[4,3-d]thiazolyl and dihydropyrano[4,3-d]thiazolyl.

[0071] In this specification, saturated or unsaturated 6- to 10-membered bicyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom specifically include 2-oxabicyclo[2.1.1]hexyl.

[0072] In this specification, saturated 7-membered spiroheterocyclic groups containing 1 to 2 nitrogen atoms as cyclic heteroatoms specifically include 2-azaspiro[3.3]heptyl and 2,6-diazaspiro[3.3]heptyl.

[0073] In this specification, saturated 7- to 8-membered spirocyclic groups containing one nitrogen atom and one oxygen atom as cyclic heteroatoms specifically include 2-oxa-6-azaspiro[3.3]heptyl and oxaazaspirooctyl.

[0074] In this specification, saturated 6- to 10-membered spirocyclic groups containing two nitrogen atoms as cyclic heteroatoms specifically include 2,6-diazaspiro[3.3]heptyl.

[0075] In this specification, R is used. 21 R 22Bridged bicyclic rings formed with adjacent heterocyclic groups include 7- to 8-membered bicyclic rings, specific examples of which include azirbicyclo octane, preferably azirbicyclo[3.2.1]octane.

[0076] As used in this article, the term "C" 1-18 "alkylsulfonyl" is a group having 1 to 18 carbon atoms (C20-C40). 1-18 ) is a straight-chain or branched alkyl sulfonyl group, specific examples of which include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, etc.

[0077] As used herein, the term "lower alkylsulfonyloxy" refers to a substance having 1 to 6 carbon atoms (C6H6O2). 1-6 ) is a straight-chain or branched alkyl sulfonyloxy group, specific examples of which include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, etc.

[0078] As used herein, the term "arylsulfonyloxy" refers to benzenesulfonyloxy, naphthalenesulfonyloxy, etc., which are optionally substituted on a benzene or naphthalene ring with 1 to 3 groups selected from the group consisting of 1 to 6 carbon atoms (C6, C ... 1-6 Straight-chain or branched alkyl groups having 1 to 6 carbon atoms (C 1-6 The benzenesulfonyloxy group can be a straight-chain or branched alkoxy group, a nitro group, or a halogen. Specific examples of benzenesulfonyloxy groups optionally having substituents include benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, 2-methylbenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-methoxybenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 3-chlorobenzenesulfonyloxy, etc. Specific examples of naphthalenesulfonyloxy groups include α-naphthalenesulfonyloxy, β-naphthalenesulfonyloxy, etc.

[0079] As used herein, the term "aralkylsulfonyloxy" refers to an alkylsulfonyloxy group substituted with a phenyl group having 1 to 6 carbon atoms (C6H ... 1-6 A straight-chain or branched alkylsulfonyloxy group, optionally substituted on the benzene ring by 1 to 3 groups selected from the group having 1 to 6 carbon atoms (C 1-6 Straight-chain or branched alkyl groups having 1 to 6 carbon atoms (C 1-6 Straight-chain or branched alkoxy groups, nitro groups, and halogens; or naphthyl-substituted groups having 1 to 6 carbon atoms (C... 1-6Alkyl sulfonyl oxy groups, such as straight-chain or branched-chain alkyl sulfonyl oxy groups, are substituted with phenyl groups. Specific examples of phenyl-substituted alkyl sulfonyl oxy groups include benzylsulfonyl oxy, 2-phenylethylsulfonyl oxy, 4-phenylbutylsulfonyl oxy, 4-methylbenzylsulfonyl oxy, 2-methylbenzylsulfonyl oxy, 4-nitrobenzylsulfonyl oxy, 4-methoxybenzylsulfonyl oxy, 3-chlorobenzylsulfonyl oxy, etc. Specific examples of naphthyl-substituted alkyl sulfonyl oxy groups include α-naphthylmethylsulfonyl oxy, β-naphthylmethylsulfonyl oxy, etc.

[0080] Specific examples of the term "perhalogenated alkyl sulfonyloxy" used in this article include trifluoromethanesulfonyloxy, etc.

[0081] Specific examples of the term "sulfonyl" as used in this article include dimethylsulfonyl, diethylsulfonyl, dipropylsulfonyl, di-(2-cyanoethyl)sulfonyl, di-(2-nitroethyl)sulfonyl, di-(aminoethyl)sulfonyl, di-(2-methylaminoethyl)sulfonyl, di-(2-dimethylaminoethyl)sulfonyl, di-(2-hydroxyethyl)sulfonyl, di-(3-hydroxypropyl)sulfonyl, di-(2-methoxyethyl)sulfonyl, di-(2-carbamoylethyl)sulfonyl, di-(2-carboxyethyl)sulfonyl, di-(2-methoxycarbonylethyl)sulfonyl, diphenylsulfonyl, etc.

[0082] In this specification, the term "solvent" can refer to an inert solvent used in the reactions described herein, examples of which include water, ether (e.g., diethyl ether), and other solvents. Alkanes, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons, halogenated hydrocarbons (e.g., dichloromethane, trichloromethane, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), alcohols (e.g., methanol, ethanol, and isopropanol), esters, ketones, amides, nitriles, sulfoxides, and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphonic acid triamide, and acetonitrile). These solvents may be used alone or as mixtures of any two or more in optional proportions. Examples of "hydrocarbons" herein include, for example, aliphatic hydrocarbons such as hexane and pentane; alicyclic hydrocarbons such as cyclopentane and cyclohexane; and aromatic hydrocarbons such as benzene and toluene. Examples of "alcohols" herein include, for example, methanol, ethanol, 2-propanol, propanol, and tert-butanol. Examples of "ether" in this article include, for example, chain ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, and diphenyl ether; and cyclic ethers such as 1,4-di(2,3-diethyl) ethers. Alkanes and tetrahydrofurans. Examples of "ester" in this document include, for example, ethyl acetate and ethyl propionate. Examples of "ketone" in this document include acetone, methyl ethyl ketone, and methyl isobutyl ketone. Examples of "amide" in this document include N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone. Examples of "nitrile" in this document include, for example, acetonitrile and propionitrile. Examples of "sulfoxide" in this document include, for example, dimethyl sulfoxide.

[0083] In this specification, the term "catalyst" used in reduction reactions is not particularly limited to the examples used herein, but specific examples include palladium on carbon (Pd / C), platinum on carbon (Pt / C), platinum oxide (PtO2), etc.

[0084] In this specification, the term "halogenating agent" is not specifically limited to the examples used herein, but includes fluorinating agents, chlorinating agents, brominating agents, and iodizing agents, such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichlorophosphoric acid, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, sodium iodide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, etc.

[0085] In this specification, the term "acid" is not specifically limited to the examples used herein, but includes inorganic acids, organic acids, etc. Examples of "inorganic acids" include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. Examples of "organic acids" include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. These acids may be used alone or as a mixture of any two or more of them.

[0086] In this specification, the term "alkali" is not specifically limited to the examples used herein, but includes inorganic alkalis, organic alkalis, etc. Examples of "inorganic alkalis" include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, and barium hydroxide), alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, and barium carbonate), alkali metal carboxylates (e.g., sodium acetate, potassium acetate, and sodium butyrate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, and cesium phosphate), alkaline earth metal phosphates (e.g., magnesium phosphate and calcium phosphate), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide), alkali metal hydrides (e.g., sodium hydride, potassium hydride, and cesium hydride), etc. Examples of "organic bases" include aromatic amines (e.g., pyridine and dimethylpyridine), trialkylamines (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine (DIPEA)), cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, tetramethylethylenediamine, tetramethylpropylenediamine, methylpyridine, 1 ,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dialkylamines (e.g., diethylamine and diisopropylamine), metal amides (e.g., lithium diisopropylamino and lithium hexamethyldisilamide), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium phenoxide), etc. These bases can be used alone or as a mixture of any two or more of them. The organic bases used herein are preferably DMAP or TEA.

[0087] In this specification, the term "palladium catalyst" is not specifically limited to the examples used herein, but includes tetravalent palladium catalysts such as sodium hexachloropalladium(IV) tetrahydrate and potassium hexachloropalladium(IV) tetrahydrate; and divalent palladium catalysts such as [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloromethane adduct (PdCl2(dppf)). DCM), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos PdG3), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetone, bis(benzonitrile)palladium(II) dichloride, bis(acetonitrile)palladium(II) dichloride, bis(triphenylphosphine)palladium(II) dichloride, tetraaminopalladium(II) dichloride, (cyclooctyl-1,5-diene)palladium(II) dichloride and trifluoroacetate (II); and zero-valent palladium catalysts, such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium(0)-trichloromethane complex and tetra(triphenylphosphine)palladium(0) (Pd(PPh3)4). These palladium compounds can be used alone or as a mixture of any two or more of them.

[0088] In this specification, the term "leaving group" is not particularly limited to the examples used herein, but includes halogens (e.g., fluorine, chlorine, bromine, and iodine), C 1-18 Alkyl sulfonyl, alkyl sulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, and trifluoromethanesulfonyloxy), phenoxy (e.g., 4-nitrophenoxy), aryl sulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkyl sulfonyloxy, perhaloalkyl sulfonyloxy, sulfonyl, toluenesulfonyloxy, nitrophenyl carbonate, imidazole carbonate, etc.

[0089] The various substituents of the compound represented by chemical formula [I] (also referred to herein as "compound [I]") are described below.

[0090] In one embodiment of compound [I], R 1 It is hydrogen, halogen, -CN, or optionally surrounded by one or more R 12 Replacement -L 11 -R 11 Preferably, R 1 It can be optionally controlled by one or more R 12 Replacement -L 11 -R 11 .

[0091] In another embodiment of compound [I], R 1 It is hydrogen, halogen, cyano, C 1-6 Alkyl group, optionally with one or more deuterium, OH or C atoms. 1-6 Alkyl-O-substituted C 1-6 Alkyl-O-,C 1-6 Alkyl-OC(=O)CH2O-, C1-6 Halogenated alkyl-O-,C 1-6 Halogenated alkyl-OC 1-6 alkylene-, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, optionally coated with halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-O-,C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-NH-C(=O)-, optionally halogenated azaheptacyclic butyl, optionally oxocyclic butyl-C 1-6 Alkylene-O-, aziridine-O- optionally substituted with oxetane, piperidinyl optionally substituted with oxetane, morpholinyl, morpholinyl-C 1-6 Alkylene, morpholino-C 1-6 alkylene-O-,morpholinyl-C(=O)-C 1-6 Alkylene, optionally C 1-6 Alkyl-substituted pyrazolyl group, C 1-6 Deuterated alkyl, C 1-6 Alkyl-OC 1-6 Alkylene, C 3-8 cycloalkyl, optionally C 1-6 Halogenated alkyl-substituted thiazolyl or optionally C 1-6 Alkyl-substituted diazaspiroheptyl, optionally C 1-6 Alkyl-substituted thiadiazole group, optionally halogenated or C 1-6 Alkyl-substituted oxehericyclic butyl-C 1-6 Alkylene-O-, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazo[1,2-a]pyrazinyl, dihydroimidazo[2,1-c][1,4] Azine group, dihydropyrano[4,3-d]thiazolyl group, dihydropyrazolo[5,1-c][1,4] Azine, hexahydropyrrolo[3,4-c]pyrrol, tetrahydrofurano[3,4-c]pyrrol, 2-oxabicyclo[2.1.1]hexyl-C 1-6 Alkylene-O-, optionally halogenated 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl-C(=O)-, or optionally halogenated 2-azaspiro[3.3]heptyl-C 1-6 Alkylene-O-.

[0092] In yet another embodiment of compound [I], R 1It is hydrogen, fluorine, chlorine, cyano, isopropyl, methoxy, methoxy-d3, difluoromethoxy, ethoxy, 2-methoxyethoxy, 2-methoxy-2-oxoethoxy, 2,2-difluoroethoxy, 2-(difluoromethoxy)ethoxy, 2-(trifluoromethoxy)ethoxy, 2-hydroxy-2-methylpropoxy, 2-methoxy-2-methylpropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, cyclopropyl, cyclopropoxy, cyclopropylmethoxy, cyclopropane carbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluoro... Cyclopropyl)methoxy, 2-(3,3-difluorocyclobutyl)ethoxy, (2,2-difluoro-1-methylcyclopropyl)methoxy, (1-(difluoromethyl)cyclopropyl)methoxy, (1-(trifluoromethyl)cyclopropyl)methoxy, aziridine-1-yl, 3,3-difluoroaziridine-1-yl, (1-(oxacyclobutane-3-yl)aziridine-3-yl)oxy, (1-(oxacyclobutane-3-yl)aziridine-3-yl)methoxy, 1-methyl-1H-pyrazol-4-yl, 1-(methyl-d3)-1H-pyrazol-4-yl, 1-(2-methoxyethyl) 1,3,5-trimethyl-1H-pyrazole-4-yl, 1-cyclopropyl-1H-pyrazole-4-yl, 1-cyclopropyl-3,5-dimethyl-1H-pyrazole-4-yl, 3,5-dimethyl-1-(methyl-d3)-1H-pyrazole-4-yl, 1-(oxetane-3-yl)piperidin-4-yl, (1-methylpiperidin-4-yl)oxy, (oxetane-3-yl)methoxy, (3-fluorooxetane-3-yl)methoxy, (3-methyloxetane-3-yl)methoxy, morpholinyl, morpholinylmethyl, 2-morpholinyl- 2-Oxoethyl, 2-morpholinylethoxy, 2-morpholinylethyl, thiazolyl-4-yl, thiazolyl-5-yl, (trifluoromethyl)thiazolyl-4-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, 5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4] Azine-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4] Azine-2-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl, ((1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl)methoxy, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl, 6,6-difluoro-2-azaspiro[3.3]hept-2-yl, 2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy, or 2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)thiazolyl. Preferably, R 1 It can be 2-methoxyethoxy, cyclopropoxy, (1-methylpiperidin-4-yl)oxy or 2,2-difluoroethoxy.

[0093] In one embodiment of compound [I], L 11 It is methylene, ethylene, methylene-C(=O)-, -O-, -O-methylene, -O-ethylene, -O-ethylene-O-, -OCH2C(=O)O-, -C(=O)-, -C(=O)NH- or -NH-C(=O)-.

[0094] In another embodiment of compound [I], L 11 It is -O-, -O-ethylidene, -O-ethylidene-O-, -C(=O)NH-, or -NH-C(=O)-. Preferably, L 11 It can be -O- or -O-ethylene-O-.

[0095] In one embodiment of compound [I], R 11 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl or saturated 4 to 6 membered monocyclic heterocyclic groups.

[0096] In another embodiment of compound [I], R 11 It is methyl, methyl-d3, ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, aziridine, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, thiadiazolyl, tetrahydroimidazopyridyl, dihydroimidazopyridyl Azine, dihydropyrazole Azine, dihydropyranothiazolyl, hexahydropyrrolopyrrol, tetrahydrofuranopyrrol, oxabicyclohexyl, azaspiroheptyl or oxozazispiroheptyl.

[0097] In yet another embodiment of compound [I], R11 It is methyl, methyl-d3, ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, aziridine-1-yl, aziridine-3-yl, 1H-pyrazol-4-yl, piperidin-4-yl, oxacyclobutane-3-yl, pyrimidin-2-yl, morpholino, thiazolyl-4-yl, thiazolyl-5-yl 1,2,4-Thiadiazol-5-yl, 1,3,4-Thiadiazol-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4] Azine-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4] Azine-2-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl, (1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl or 2-azaspiro[3.3]hept-2-yl.

[0098] In another embodiment of compound [I], R 11 It is methyl, cyclopropyl, difluoroethyl, pyrazolyl, tetrahydrofuranyl, thiazolyl, piperidinyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranopyrrolithyl, hexahydropyrrolithyl, azaspiroheptyl or oxazaspiroheptyl.

[0099] In one embodiment of compound [I], R 12 It is a halogen, -OH, C that is optionally substituted with one or more deuteriums. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy-C 1-6 Alkyl, C 3-8 cycloalkyl, optionally C 1-6 Alkyl-substituted saturated 6- to 10-membered spiroheterocyclic groups containing two nitrogen atoms as cyclic heteroatoms. Preferably, R 12 It can be halogen, or C optionally substituted with one or more deuteriums. 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0100] In another embodiment of compound [I], R 12It is fluorine, methyl, methyl-d3, difluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -OH, oxecyclobutyl, or diazaspiroheptyl optionally substituted with methyl.

[0101] In yet another embodiment of compound [I], R 12 It is fluorine, methyl, methyl-d3, or cyclopropyl.

[0102] In one embodiment of compound [I], R 3 It is optionally controlled by one or more R 32 Replacement -L 31 -R 31 .

[0103] In another embodiment of compound [I], R 3 It is C 1-6 Halogenated alkyl group -OC(=O)-, optionally coated with halogen, C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-OC(=O)-, optionally C 1-6 Alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-OC(=O)-, benzyloxy, optionally C 1-6 Alkyl-substituted phenyl-CH2OCH2-C(=O)-, optionally C 1-6 Alkyl-substituted phenoxy-C 1-6 alkylene-C(=O)-, phenyl-C 1-3 Alkylene-NH-C(=O)-, optionally halogenated or C 1-6 Haloalkyl-substituted azaheterobutylene-C(=O)-, optionally C 1-6 Alkyl-substituted azole-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted Diazole group, optionally C 3-8 Cycloalkyl-substituted Diazolyl-OC(=O)-, optionally C 1-6 Halogenated alkyl-substituted thiazolyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted pyrimidinyl, tetrahydrofuranyl-C 1-6 Alkylene-OC(=O)-, oxazabicycloheptyl-C(=O)-, or oxazaspirooctyl-C(=O)-.

[0104] In one embodiment of compound [I], L 31It is -C(=O)-, -C(=O)O-, or -C(=O)OC. 1-3 Alkylene-. Preferably, L 31 It can be -C(=O)-, -C(=O)O-, or -C(=O)O-methylene-.

[0105] In one embodiment of compound [I], R 31 It is methyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azole group, thiazolyl group, Diazole, pyrimidinyl, tetrahydrofuranyl, azacyclobutane, diazaspirooctyl, oxazaspirooctyl, or oxazatricyclooctane. Preferably, R 31 It can be tert-butyl, cyclopropyl, Azolyl, thiazolyl, or aziridine-butane. More preferably, R 31 It can be cyclopropyl, Azolyl, thiazolyl, or aziridine-butane. More preferably, R 31 It can be cyclopropyl, Azolium or thiazole.

[0106] In another embodiment of compound [I], R 31 It is methyl, cyclopropyl, cyclobutyl, cyclohexyl or phenyl.

[0107] In one embodiment of compound [I], R 32 It is fluorine, methyl, ethyl, cyclopropyl, difluoromethyl, or trifluoromethyl.

[0108] In one embodiment of compound [I], X is CH or N.

[0109] In this specification, the options and preferred embodiments presented for different features of the compounds, methods and compositions of the present invention include all possible combinations of options and preferred embodiments for these different features, provided that they are consistent combinations.

[0110] The method for preparing compound [I] is described below. Compound [I] can be prepared based on, but is not limited to, the methods described in the general synthesis and examples below. Unless otherwise specified, the reaction temperature may optionally be adjusted according to the reactants, solvents and other conditions used in the reactions herein.

[0111] Alkylation, hydrolysis, amination, esterification, amidation, etherification, nucleophilic substitution, addition, oxidation, and reduction reactions in general synthesis can be carried out using any known method. Examples of such methods include those described in *Experimental Chemistry* (5th edition, edited by the Chemical Society of Japan and Maruzen); *Organic Functional Group Preparations* (2nd edition, Academic, 1989); *Comprehensive Organic Transformations* (VCH, 1989); and *Greene's Protective Groups in Organic Synthesis* (4th edition, 2006) by PGM Wuts and TW Greene.

[0112] In addition to the definitions above, examples of condensing agents used in this document include, for example: T3P; HATU; DCC; N-cyclohexyl-N'-morpholinylethyl carbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or its hydrochloride salt; N,N'-carbonylbis(2-methylimidazolium); pentylene-N-cyclohexylimide; diphenylenone-N-cyclohexylimide; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphoric acid; phosphorus trichloride; diphenyl azidophosphite; thionyl chloride; oxalyl chloride; alkyl halogenated formates, such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisyl Azoxylonium salt; 2-ethyl-5-(m-sulfophenyl)isocyanate The inner salt of azole hydroxide; benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and the so-called Wilsmayer reagent prepared by the reaction of DMF with thionyl chloride, phosgene, trichloromethyl chloroformate or phosphorus oxychloride.

[0113] In addition to condensing agents, condensation accelerators may also be added. Examples of condensation accelerators used in this article include, for example, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt).

[0114] Examples of “hydroxyl protecting group” as used herein include, but are not limited to, any hydroxyl protecting group used in the field of synthetic organic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); formyl; alkyl (alkenyl)carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, neopentanoyl). Valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propynyl, methacryloyl, crotonyl, isocrotonyl, (E)-2-methyl-2-butenoyl); aromatic acryloyl groups (e.g., benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluyl, 4-anisyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4-phenylbenzoyl); alkoxycarbonyl groups (e.g. Methoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 9-fluorenylmethoxycarbonyl); tetrahydro(thio)pyranyl (furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, tert-butyl dimethylsilyl, methyl diisopropylsilyl, methyl... Di-tert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyl diisopropylsilyl); alkoxymethyl groups (e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl); alkoxyethyl groups (e.g., 1-ethoxyethyl, 1-(isopropoxy)ethyl); haloethyl groups (e.g., 2,2,2-trichloroethyl);Arylalkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthraylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); alkenyloxycarbonyl groups (e.g., vinyloxycarbonyl, allyloxycarbonyl); and aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl).

[0115] Examples of “carboxyl protecting group” as used herein include, but are not limited to, any carboxyl protecting group used in the field of synthetic organic chemistry, and include, for example, “alkyl group”, “alkenyl group”, “alkynyl group”, “aralkyl group” and “silyl group”, and similar groups, as listed in the examples of “hydroxyl protecting group” above.

[0116] Examples of “amino protecting groups” as used herein include, but are not limited to, any amino protecting groups used in the field of synthetic organic chemistry, and include, for example, “alkyl (alkenyl) carbonyl groups,” “aromatic acyl groups,” “alkoxy carbonyl groups,” “silyl groups,” “aralkyl groups,” “alkenyloxy carbonyl groups,” and “aranekoxy carbonyl groups,” and similar groups, as listed in the “hydroxyl protecting groups” section above.

[0117] In this paper, the reaction temperature for each step in the general synthesis is typically in the range of -80°C to 150°C. The reaction time for each step is typically in the range of 0.1 to 200 hours.

[0118] General Synthesis 1

[0119] [Chemical Formula 3]

[0120] In the above scheme, Y 1 These are leaving groups, such as halogens (e.g., chlorine and bromine) and phenoxy groups (e.g., 4-nitrophenoxy groups), and other symbols as defined above for compound [I].

[0121] Compound [I] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [II] can be prepared by reacting a leaving group (Y) in an inert solvent in the presence of a base. 1 The compound [III] reacts with the compound to give compound [I].

[0122] Any of the bases mentioned above can be used in this reaction, and the bases preferred in this document include organic bases (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)).

[0123] Any of the solvents mentioned above can be used for this reaction, and the solvents preferred herein include inert solvents such as halogenated hydrocarbons (e.g., chloroform and dichloroform), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkane and tetrahydrofuran), amides (e.g., N,N-dimethylformamide), and nitriles (e.g., acetonitrile).

[0124] General Synthesis 2

[0125] [Chemical Formula 4]

[0126] In the above scheme, Y 1 These are leaving groups, such as halogens (e.g., chlorine and bromine) and phenoxy groups (e.g., 4-nitrophenoxy groups), protecting groups include alkyl (alkenyl) carbonyl groups, aryl groups and alkoxy carbonyl groups (e.g., tert-butoxy carbonyl), and other symbols as defined above for compound [I].

[0127] Compound [I] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [IV] can be deprotected in an inert solvent in the presence of an acid, and then reacted in an inert solvent in the presence of a base with a leaving group (Y). 1 Compound [III] was treated to obtain compound [I].

[0128] The intermediate compound obtained after the first step can be purified before proceeding to the second step, or it can be used in the second step without purification.

[0129] Any of the above-mentioned acids can be used in the first step, and the acids preferred in this document include inorganic acids (e.g., hydrochloric acid, sulfuric acid, and hydrobromic acid) and organic acids (acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid).

[0130] Any of the solvents mentioned above can be used in the first step, and solvents preferred herein include halogenated hydrocarbons (e.g., chloroform and dichloromethane), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkanes and tetrahydrofurans) and alcohols (e.g., methanol, ethanol and 2-propanol).

[0131] The base and inert solvent used in the second step can be selected from those bases and inert solvents described in General Synthesis 1.

[0132] General Synthesis 3

[0133] [Chemical Formula 5]

[0134] In the above scheme, the symbols are as defined above for compound [I].

[0135] Compound [I] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [I] can be prepared by reacting compound [II] with compound [V] in an inert solvent in the presence of a base.

[0136] Any of the condensing agents mentioned above can be used in this reaction, and the preferred condensing agents used herein include HATU, WSC, or hydrochloride.

[0137] Any of the bases mentioned above can be used in this reaction, and the bases preferred to be used herein include organic bases (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)).

[0138] Any of the solvents mentioned above can be used for this reaction, and preferred solvents used herein include halogenated hydrocarbons (e.g., chloroform and dichloroform), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkane and tetrahydrofuran), amides (e.g., N,N-dimethylformamide), and nitriles (e.g., acetonitrile).

[0139] General Synthesis 4

[0140] [Chemical Formula 6]

[0141] In the above scheme, Y 2 It is a leaving group, such as a phenoxy group (e.g., 4-nitrophenoxy group), and other symbols are as defined above for compound [I].

[0142] Compound [Ia] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [Ia] can be prepared by reacting compound [VI] with compound [Va] in an inert solvent in the presence of a base.

[0143] Any of the bases mentioned above can be used in this reaction, and the bases preferred in this document include alkali metal hydrides (e.g., sodium hydride and potassium hydride) and metal alkoxides (e.g., sodium tert-butoxide and potassium tert-butoxide).

[0144] Any of the solvents mentioned above can be used for this reaction, and solvents preferred herein include ethers (e.g., diethers). Alkane and tetrahydrofuran) and amide (e.g., N,N-dimethylformamide).

[0145] General synthesis 5

[0146] [Chemical Formula 7]

[0147] In the above scheme, the symbols are as defined above for compound [I].

[0148] Compound [Ib] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [Ib] can be prepared by reacting compound [VII] with compound [VIII] in an inert solvent in the presence of a base.

[0149] Any of the condensing agents mentioned above can be used in this reaction, and the preferred condensing agents used herein include reagents (e.g., HATU, WSC, or hydrochloride).

[0150] Any of the bases mentioned above can be used in this reaction, and the bases preferred to be used herein include organic bases (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)).

[0151] Any of the solvents mentioned above can be used for this reaction, and preferred solvents used herein include halogenated hydrocarbons (e.g., chloroform and dichloroform), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkane and tetrahydrofuran), amides (e.g., N,N-dimethylformamide), and nitriles (e.g., acetonitrile).

[0152] General Synthesis 6

[0153] [Chemical Formula 8]

[0154] In the above scheme, Y 3 These are leaving groups, such as halogens (e.g., chlorine and bromine) and alkylsulfonyloxy groups (e.g., trifluoromethylsulfonyloxy), and other symbols as defined above for compound [I].

[0155] Compound [I] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, compound [I] can be prepared by the Suzuki coupling reaction of borate ester compound [IX] with compound [X] having a leaving group in an inert solvent in the presence of a base and a palladium catalyst.

[0156] In this paper, compounds in which the boronic acid ester moiety of compound [IX] can be replaced by compounds in which boric acid can be substituted.

[0157] Any of the bases mentioned above can be used in this reaction, and the bases preferred to be used herein include alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate) and alkali metal phosphates (e.g., sodium phosphate and potassium phosphate).

[0158] Any of the palladium catalysts mentioned above can be used for this reaction, and the preferred palladium catalysts used herein include PdCl2(dppf). DCM, XPhos Pd G3, palladium(II) acetate, Pd2(dba)3 and Pd(PPh3)4.

[0159] Any of the solvents mentioned above can be used for this reaction, and the solvents preferred herein include ethers (e.g., dimethoxyethane, 1,4-dimethoxyethane, etc.). Alkane and tetrahydrofuran).

[0160] General Synthesis 7

[0161] [Chemical Formula 9]

[0162] In the above scheme, Y 4 X is a leaving group, such as a halogen (e.g., chlorine and bromine) and an alkylsulfonyloxy group (e.g., trifluoromethylsulfonyloxy) or a hydroxy protecting group such as an alkyl group (e.g., methyl) and an aralkyl group (e.g., benzyl), and X is as defined above for compound [I].

[0163] The intermediate [Va] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, the intermediate [Va] can be prepared by reacting compound [XI] with a halogenating agent in an inert solvent with or without a base.

[0164] Any halogenating agent can be used for this reaction, and the preferred halogenating agents used herein include N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide.

[0165] Any of the bases mentioned above can be used in this reaction, and the bases preferred to be used herein include alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate).

[0166] Any of the solvents mentioned above can be used for this reaction, and solvents preferred herein include amides (e.g., N,N-dimethylformamide) and nitriles (e.g., acetonitrile).

[0167] General Synthesis 8

[0168] [Chemical Formula 10]

[0169] In the above scheme, Y 5 and Y 6 These are leaving groups, such as halogens (e.g., chlorine and bromine) and alkylsulfonyloxy groups (e.g., trifluoromethylsulfonyloxy), and other symbols as defined above for compound [I].

[0170] Intermediate [XIII] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, intermediate [XIII] can be prepared by reacting compound [XII] with R in an inert solvent in the presence of a base. 1 It is produced by -H reaction.

[0171] Any of the bases mentioned above can be used in this reaction, and the bases preferred in this document include metal alkoxides (e.g., sodium tert-butoxide and potassium tert-butoxide) and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate and cesium carbonate).

[0172] Any of the palladium catalysts mentioned above can be used for this reaction, and palladium catalysts preferred in this paper include palladium(II) acetate and Pd2(dba)3.

[0173] Any of the solvents mentioned above can be used in this reaction, and the solvents preferred herein include aromatic hydrocarbons such as benzene and toluene, and ethers (e.g., diethyl ether). Alkanes and tetrahydrofurans) and alcohols (e.g., tert-butanol).

[0174] General Synthesis 9

[0175] [Chemical Formula 11]

[0176] In the above scheme, the protecting groups include alkyl (alkenyl) carbonyl groups, aryl groups, and alkoxy carbonyl groups, and the symbols are as defined above.

[0177] Intermediate [XV] can be prepared via the reaction indicated by the above synthetic scheme. Specifically, intermediate [XV] can be prepared by reacting a base and a palladium catalyst in an inert solvent to form a leaving group Y. 6 It is prepared by the Suzuki coupling reaction of compound [XIII] with borate compound [XIV].

[0178] In this paper, compounds in which the boronic ester moiety of compound [XIV] can be replaced by boric acid.

[0179] Any of the bases mentioned above can be used in this reaction, and the bases preferred to be used herein include alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate) and alkali metal phosphates (e.g., sodium phosphate and potassium phosphate).

[0180] Any of the palladium catalysts mentioned above can be used for this reaction, and the preferred palladium catalysts used herein include PdCl2(dppf). DCM, XPhos Pd G3, palladium(II) acetate, Pd2(dba)3 and Pd(PPh3)4.

[0181] Any of the solvents mentioned above can be used in this reaction, and the solvents preferred herein include ethers, with or without water (e.g., dimethoxyethane, 1,4-dimethoxyethane, etc.). Alkane and tetrahydrofuran).

[0182] General synthesis 10

[0183] [Chemical Formula 12]

[0184] In the above scheme, the protection base and various symbols are defined as above.

[0185] The intermediate [XVb] can be produced by the reaction indicated by the above synthetic scheme. Specifically, the intermediate [XVb] can be produced by adding hydrogen gas to compound [XVa] in an inert solvent in the presence of a catalyst.

[0186] Any of the catalysts mentioned above can be used for this reaction, and the preferred catalysts used herein include palladium on carbon (Pd / C), platinum on carbon (Pt / C), and platinum oxide (PtO2).

[0187] Any of the solvents mentioned above can be used for this reaction, and solvents preferred herein include ethers (e.g., diethers). Alkanes and tetrahydrofurans), alcohols (e.g., methanol, ethanol and 2-propanol), and esters (e.g., ethyl acetate).

[0188] General Synthesis 11

[0189] [Chemical Formula 13]

[0190] In the above scheme, the protecting groups include alkyl (alkenyl) carbonyl groups, aryl groups, and alkoxy carbonyl groups, and the symbols are as defined above.

[0191] Intermediate [IIa] can be prepared by the reaction indicated by the above synthetic scheme. Specifically, intermediate [IIa] can be prepared by deprotecting compound [XV] in an inert solvent in the presence of an acid.

[0192] Any of the above-mentioned acids can be used in this reaction, and the acids preferred in this document include inorganic acids (e.g., hydrochloric acid, sulfuric acid, and hydrobromic acid) and organic acids (acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid).

[0193] Any of the solvents mentioned above can be used for this reaction, and preferred solvents used herein include halogenated hydrocarbons (e.g., chloroform and dichloroform), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkanes and tetrahydrofurans) and alcohols (e.g., methanol, ethanol and 2-propanol).

[0194] General synthesis 12

[0195] [Chemical Formula 14]

[0196] In the above scheme, R 31 As defined above for compound [I].

[0197] Intermediate [XVIII] can be prepared according to any reaction indicated by the above synthetic scheme. For example, intermediate [XVIII] can be prepared by reacting compound [XVI] or [XVI'] with compound [XVII] in an inert solvent in the presence of an amine.

[0198] Any of the bases listed above as organic bases can be used in this reaction, and the amines preferred in this document include organic bases such as trimethylamine and N,N-diisopropylethylamine (DIPEA)

[0199] Any of the solvents mentioned above can be used for this reaction, and the preferred solvents used herein include halogenated hydrocarbons (e.g., chloroform and dichloroform), ethers (e.g., dichloromethane), and dichloroalkyl ethers. Alkanes and tetrahydrofurans) and nitriles (e.g., acetonitrile).

[0200] In each reaction of the above synthetic scheme, the reaction product may be used in the next reaction as a dissolved product or as a crude product, but it can also be separated from the reaction mixture by conventional methods and easily purified by conventional separation techniques. Examples of conventional separation techniques include recrystallization, distillation, and chromatography.

[0201] Any starting compound, intermediate compound, and product compound in each of the above steps, as well as compound [I], include its geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by conventional optical resolution methods. They can also be prepared from raw material compounds with suitable optical activity.

[0202] Compound [I] can be prepared according to any of the above-described synthetic schemes or similar methods.

[0203] Unless otherwise specified, any starting compound used to manufacture compound [I] is commercially available or can be produced by known methods or similar methods.

[0204] Any starting and product compounds in each of the above steps may be used in the form of their appropriate salts. Examples of such salts include those similar to those listed below for compound [I].

[0205] When any compound or commercially available compound obtained in any step of this document is in its free form, it can be converted into the corresponding salt by known methods. When any compound or commercially available compound obtained in any step of this document is in its salt form, it can be converted into the corresponding free form or other salt by known methods.

[0206] Compound [I] may also exist as any pharmaceutically acceptable salt thereof, and in some embodiments, depending on the substituents present in compound [I], compound [I] may form an acid addition salt or a salt with a base. Examples of “acid” in this document include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, etc. Examples of “base” in this document include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tri(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, methylpyridine, and choline; and ammonium salts, etc. Compound [I] can also form salts with amino acids such as lysine, arginine, aspartic acid, and glutamic acid.

[0207] This invention also covers various hydrates, solvates and polymorphs of compound [I] and its salts.

[0208] Compound [I] also includes compounds in which one or more isotopic atoms replace any one or more atoms in any proportion. Examples of isotopic atoms include deuterium ( 2 H or D), tritium ( 3 H) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 35 S, 36 Cl、 37 Cl、 18 F, 123 I, 125 I etc.

[0209] One embodiment of the present invention includes a prodrug of a pharmaceutically acceptable compound [I]. Any group of compound [I] can be modified, including any reactive functional group of compound [I], such as -OH, -COOH, amino, etc., thereby providing a prodrug of compound [I]. These functional groups can be modified with any group suitably selected from hydroxyl protecting groups, carboxyl protecting groups, and amino protecting groups.

[0210] Compound [I] or its salts may be in a pharmaceutically acceptable eutectic form. As used herein, a eutectic refers to a crystalline substance composed of two or more independent substances, each possessing different physical properties at room temperature, such as structure, melting point, and heat of fusion. Eutectic and eutectic salts can be suitably prepared by well-known co-crystallization methods.

[0211] Compound [I] or its salts may exhibit CSF1R inhibitory activity in mammals, leading to a reduction in macrophages, microglia, and osteoclasts. Compared to at least any other kinase adjacent to CSF1R, such as FLT3, cKit, PDGFR including PDGFRα and PDGFRβ, and Trk including TrkC, compound [I] or its salts may preferably exhibit highly selective inhibitory activity against CSF1R, thereby reducing the risk of any undesirable effects or side effects, including the risk of unintended inhibition of tyrosine kinases other than CSF1R following administration of compound [I] or its salts. In some embodiments, compound [I] or its salts may prevent or reduce microglial activation or proliferation (i.e., microglial hyperplasia) by inhibiting CSF1R specifically expressed in microglia, thereby enhancing central immune regulation. Compound [I] or its salts may be beneficial for the treatment of cancer, autoimmune diseases such as rheumatoid arthritis, muscular dystrophy, and asthma. Compound [I] or its salts may also be beneficial in the treatment of neurological disorders such as Alzheimer's disease (AD), tau disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, and skeletal diseases.

[0212] Compound [I] or its salts may also be effective in the treatment, prevention and / or diagnosis of any two or more of the above-mentioned diseases.

[0213] Furthermore, compound [I] or its salts can be used as active pharmaceutical ingredients and, for example, exhibit minimal side effects, the desired tolerability, the desired stability (storage stability, metabolic stability, etc.). Compound [I] or its salts can also be used as preventive and / or therapeutic agents for the various diseases described herein by inhibiting CSF1R.

[0214] In one embodiment, compound [I] or a salt thereof can be used as a positron emission tomography (PET) tracer, preferably a PET imaging agent, for in vitro, ex vivo, in vivo, or clinical trial testing and diagnostic imaging of humans and / or non-humans. Using positron emission isotopes such as... 11 C 18 F, 15 O and 13 N is used as a substitute in PET studies to examine target occupancy. For example, using... 11 C or 18 F-labeled compounds can be used as PET tracers.

[0215] In one embodiment, a medical preparation (also referred to herein as a "pharmaceutical composition") comprising compound [I] or a salt thereof as an active ingredient is provided.

[0216] Depending on the therapeutic purpose, the medical preparations described in this article may be selected from a variety of forms, and examples of medical preparations include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.). Tablets include coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, bilayer tablets, and multilayer tablets.

[0217] Compound [I] or its salts can be combined with pharmaceutically acceptable carriers to formulate any form of medical preparation. Examples of carriers include common substances used in medical preparation components, including excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorbents such as sodium lauryl sulfate; wetting agents such as glycerin and starch; adsorbents such as colloidal silica; and lubricants such as magnesium stearate and polyethylene glycol; diluents; fillers; extenders; surfactants, etc.

[0218] Pharmaceutically acceptable carriers used in formulations of tablets specifically include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorbents such as sodium lauryl sulfate; wetting agents such as glycerin and starch; adsorbents such as colloidal silica; and lubricants such as magnesium stearate and polyethylene glycol.

[0219] Pharmaceutically acceptable carriers used in the formulation of pills specifically include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as kelp polysaccharides.

[0220] Pharmaceutically acceptable diluents used to formulate liquids, emulsions, or suspensions specifically include water. Formulations may also contain any conventional solubilizers and / or buffers, as well as colorants, preservatives, flavorings, and sweeteners, and may contain other pharmaceuticals as needed.

[0221] Pharmaceutically acceptable carriers used in the formulation of suppositories include cocoa butter, etc.

[0222] The injection can be formulated as a liquid, emulsion, or suspension. In one embodiment, the injection is preferably sterile and also preferably isotonic with blood. The isotonic injection may contain sufficient amounts of sodium chloride and a sedative, and may optionally contain other drugs.

[0223] The amount of compound [I] or its salt contained in the medical preparation (also referred to herein as the “effective amount”) may be, but is not limited to, any amount conventionally used in the art, and preferably includes any amount from 1% to 70% of the medical preparation.

[0224] The route of administration for a medical preparation can be chosen based on the dosage form, the age and sex of the patient to be administered, the disease state, and other conditions. For example, if the medical preparation is in the form of tablets, pills, liquids, suspensions, emulsions, granules, or capsules, it can be administered orally. If it is in injectable form, the medical preparation can be administered intravenously alone or as a mixture with conventional alternative fluids such as glucose and amino acids. As needed, the medical preparation can be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally. If it is in suppository form, the medical preparation can be administered rectally.

[0225] The dosage of the compound [I] or its salt to be administered may be any dosage selected based on the route of administration, the age and sex of the patient to be administered, the severity of the disease, and other conditions, including 0.01 to 100 mg / kg body weight / day, preferably 0.1 to 50 mg / kg body weight / day. The dosage may be administered once or in several divided doses.

[0226] Compound [I] or a salt thereof may be used in combination with at least one therapeutic or preventative medicine or standard care agent, which may be referred to herein as a combination medicine, for one of the aforementioned diseases. When compound [I] or a salt thereof is used in combination with a combination medicine, compound [I] or a salt thereof and the medicine may be administered simultaneously or at the same time, separately or sequentially at approximately the same time, or separately or sequentially at appropriate intervals. Compound [I] or a salt thereof and the combination medicine may be formulated as separate formulations or mixed and formulated as a single formulation.

[0227] All publicly available information from the references cited in this specification is incorporated herein by reference in its entirety.

[0228] The invention will be further described with reference to the following items: Project 1-1. A compound or a salt thereof represented by formula [I]: [Chemical Formula 15]

[0229] in

[0230] R 1 It is hydrogen, halogen, -CN, optionally dilated by one or more R 12 Replacement -L 11 -R 11 Or optionally by one or more R 12 Replacement -R 11 ; L 11 It is -C 1-3 alkylene-, -C 1-3 Alkylene -C(=O)-, -O-, -OC 1-3 Alkylene-, -OC 1-3 Alkylenes -O-, -OCH2C(=O)O-, -C(=O-, -C(=O)NH- or -NH-C(=O-); R 11 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, or d) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirocyclic groups; R 12 Each is an independent halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-8 cycloalkyl, optionally with one or more C 1-6 Alkyl-substituted saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirochetal groups; R 21 and R 22 It is hydrogen, or R 21 and R 22 Together with the adjacent heterocyclic rings, they form a bridging double ring; R 3 It is optionally controlled by one or more R 32 Replacement -L 31 -R 31 Or optionally by one or more R32 Replacement R 31 ; L 31 Yes -C(=O)-, -C(=O)O-, -C(=O)OC 1-3 Alkylene-, -C(=O)-C 1-3 Alkylene -O-, -C(=O)-C 1-3 Alkylene-OC 1-3 Alkylene- or -C(=O)NH-C 1-3 alkylene-; R 31 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, or e) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spiroheterocyclic groups; R 32 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; X is CR 1 Or N; and key: [Chemical Formula 16]

[0231] Is it a single bond or a double bond? The condition is when R 1 When it is not hydrogen, there is only one R other than hydrogen. 1 exist.

[0232] Item 1-2. The compound or salt thereof according to Item 1-1, wherein the portion is represented by the following formula: [Chemical Formula 17]

[0233] It is any of the following structures: [Chemical Formula 18]

[0234] The condition is R 1 It is a halogen, -CN, optionally dilated by one or more R 12 Replacement -L 11 -R 11 Or optionally by one or more R 12 Replacement -R 11.

[0235] Item 1-3. The compound or salt thereof as described in Item 1-1 or 1-2, wherein R 3 It is not -C(=O)O-tert-butyl.

[0236] Items 1-4. The compound or salt thereof according to any one of Items 1-1 to 1-3, wherein R 11 yes

[0237] a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d1) A saturated or unsaturated 4- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms. d2) Saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom. d3) A saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. d4) An unsaturated 5-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms. d5) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 2 to 3 nitrogen atoms as cyclic heteroatoms. d6) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. d7) A saturated or unsaturated 9-membered bicyclic heterocyclic group containing one nitrogen atom, one oxygen atom, and one sulfur atom as cyclic heteroatoms. d8) A saturated or unsaturated 6- to 10-membered bicyclic heterocyclic group containing one oxygen atom as a cyclic heteroatom. d9) A saturated 7-membered spirocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms, or d10) is a saturated 7- to 8-membered spirocyclic group containing one nitrogen atom and one oxygen atom as cyclic heteroatoms.

[0238] Items 1-5. The compound or salt thereof according to any one of Items 1-1 to 1-3, wherein R 11 yes: a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, or d) Saturated 4 to 10-membered monocyclic, bicyclic, or spirocyclic groups.

[0239] Items 1-6. The compound or salt thereof according to any one of Items 1-1 to 1-3, wherein R 11 yes: a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl, or c) C 3-8 Cycloalkyl.

[0240] Items 1-7. The compound or salt thereof according to any one of Items 1-1 to 1-6, wherein R 12 Each is independently a halogen, -OH, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-8 Cycloalkyl groups, saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom, or optionally C-shaped groups. 1-6 Alkyl-substituted saturated 6- to 10-membered spiroheterocyclic groups containing two nitrogen atoms as cyclic heteroatoms.

[0241] Items 1-8. The compound or salt thereof according to any one of Items 1-1 to 1-7, wherein

[0242] L 11 It is methylene, ethylene, methylene-C(=O)-, -O-, -O-methylene, -O-ethylene, -O-ethylene-O-, -OCH2C(=O)O-, -C(=O)-, -C(=O)NH- or -NH-C(=O)-. R 11 The following are methyl, methyl-d3, ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, aziridine, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, thiadiazolyl, tetrahydroimidazo[1,2-a]pyridinyl, and dihydroimidazo[2,1-c][1,4]. Azine group, dihydropyrazolo[5,1-c][1,4] Azine, dihydropyrano[4,3-d]thiazolyl, hexahydropyrrolo[3,4-c]pyrryl, tetrahydrofurano[3,4-c]pyrryl, 2-oxabicyclo[2.1.1]hexyl, 2-azaspiro[3.3]heptyl or 2-oxa-6-azaspiro[3.3]heptyl, and R 12Each is independently fluorine, methyl, methyl-d3, difluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -OH, oxacyclobutyl or optionally methyl-substituted 2,6-diazaspiro[3.3]heptyl.

[0243] Items 1-9. The compound or salt thereof according to any one of Items 1-1 to 1-8, wherein R 1 It is hydrogen, halogen, cyano, C 1-6 Alkyl group, optionally with one or more deuterium, OH or C atoms. 1-6 alkyl-O-substituted C 1-6 Alkyl-O-,C 1-6 Alkyl-OC(=O)CH2O-, C 1-6 Halogenated alkyl-O-,C 1-6 Halogenated alkyl-OC 1-6 alkylene-, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, optionally coated with halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-O-,C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-NH-C(=O)-, optionally halogenated azaheptacyclic butyl, optionally oxocyclic butyl-C 1-6 Alkylene-O-, aziridine-O- optionally substituted with oxetane, piperidinyl optionally substituted with oxetane, morpholinyl, morpholinyl-C 1-6 Alkylene, morpholino-C 1-6 alkylene-O-,morpholinyl-C(=O)-C 1-6 Alkylene, optionally C 1-6 Alkyl-substituted pyrazolyl group, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkylene, optionally C 1-6 Halogenated alkyl-substituted thiazolyl or optionally C 1-6 Alkyl-substituted diazaspiroheptyl, optionally C 1-6 Alkyl-substituted thiadiazole group, optionally halogenated or C 1-6 Alkyl-substituted oxehericyclic butyl-C 1-6 Alkylene-O-, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazo[1,2-a]pyrazinyl, dihydroimidazo[2,1-c][1,4] Azine group, dihydropyrano[4,3-d]thiazolyl group, dihydropyrazolo[5,1-c][1,4] Azine, hexahydropyrrolo[3,4-c]pyrrol, tetrahydrofurano[3,4-c]pyrrol, 2-oxabicyclo[2.1.1]hexyl-C 1-6 Alkylene-O-, optionally halogenated 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl-C(=O)-, or optionally halogenated 2-azaspiro[3.3]heptyl-C 1-6 Alkylene-O-.

[0244] Item 1-10. A compound or a salt thereof according to any one of Items 1-1 to 1-9, wherein R 1 It is hydrogen, halogen, cyano, C 1-6 Alkyl group, optionally with one or more deuterium, OH or C atoms. 1-6 alkyl-O-substituted C 1-6 Alkyl-O-,C 1-6 Alkyl-OC(=O)CH2O-, C 1-6 Halogenated alkyl-O-,C 1-6 Halogenated alkyl-OC 1-6 alkylene-, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, optionally coated with halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-O-,C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-NH-C(=O)-, optionally halogenated azaheptacyclic butyl, optionally oxocyclic butyl-C 1-6 Alkylene-O-, optionally substituted with oxobutyryl-, morpholino-C 1-6 Alkylene, morpholino-C 1-6 alkylene-O-,morpholinyl-C(=O)-C 1-6 Alkylene, C substituted with one or more deuterium atoms 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkylene, optionally coated with halogen or C 1-6 Alkyl-substituted oxehericyclic butyl-C 1-6 Alkylene-O-,2-oxabicyclo[2.1.1]hexyl-C 1-6 Alkylene-O-, 2-oxa-6-azaspiro[3.3]heptyl-C(=O)-, or optionally halogen-substituted 2-azaspiro[3.3]heptyl-C 1-6 Alkylene-O-.

[0245] Item 1-11. A compound or a salt thereof according to any one of Items 1-1 to 1-10, wherein R 1 It is hydrogen, halogen, cyano, C 1-6 Alkyl group, optionally with one or more deuterium, OH or C atoms. 1-6 alkyl-O-substituted C 1-6 Alkyl-O-,C 1-6 Alkyl-OC(=O)CH2O-, C 1-6 Halogenated alkyl-O-,C 1-6 Halogenated alkyl-OC 1-6 alkylene-, C 3-8 cycloalkyl-O-, optionally coated with halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-O-,C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-NH-C(=O)-, optionally halogenated azaheptacyclic butyl, optionally oxocyclic butyl-C 1-6 Alkylene-O-, optionally substituted with oxobutyryl-, morpholino-C 1-6 Alkylene, morpholino-C 1-6 alkylene-O-,morpholinyl-C(=O)-C 1-6 Alkylene, C substituted with one or more deuterium atoms 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkylene, optionally coated with halogen or C 1-6 Alkyl-substituted oxehericyclic butyl-C 1-6 Alkylene-O-,2-oxabicyclo[2.1.1]hexyl-C 1-6 Alkylene-O-, 2-oxa-6-azaspiro[3.3]heptyl-C(=O)-, or optionally halogen-substituted 2-azaspiro[3.3]heptyl-C 1-6 Alkylene-O-.

[0246] Item 1-12. A compound or a salt thereof according to any one of Items 1-1 to 1-11, wherein R 1It is hydrogen, fluorine, chlorine, cyano, isopropyl, methoxy, methoxy-d3, difluoromethoxy, ethoxy, 2-methoxyethoxy, 2-methoxy-2-oxoethoxy, 2,2-difluoroethoxy, 2-(difluoromethoxy)ethoxy, 2-(trifluoromethoxy)ethoxy, 2-hydroxy-2-methylpropoxy, 2-methoxy-2-methylpropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, cyclopropyl, cyclopropoxy, cyclopropylmethoxy, cyclopropane carbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluoro... Cyclopropyl)methoxy, 2-(3,3-difluorocyclobutyl)ethoxy, (2,2-difluoro-1-methylcyclopropyl)methoxy, (1-(difluoromethyl)cyclopropyl)methoxy, (1-(trifluoromethyl)cyclopropyl)methoxy, aziridine-1-yl, 3,3-difluoroaziridine-1-yl, (1-(oxacyclobutane-3-yl)aziridine-3-yl)oxy, (1-(oxacyclobutane-3-yl)aziridine-3-yl)methoxy, 1-methyl-1H-pyrazol-4-yl, 1-(methyl-d3)-1H-pyrazol-4-yl, 1-(2-methoxyethyl) 1,3,5-trimethyl-1H-pyrazole-4-yl, 1-cyclopropyl-1H-pyrazole-4-yl, 1-cyclopropyl-3,5-dimethyl-1H-pyrazole-4-yl, 3,5-dimethyl-1-(methyl-d3)-1H-pyrazole-4-yl, 1-(oxetane-3-yl)piperidin-4-yl, (1-methylpiperidin-4-yl)oxy, (oxetane-3-yl)methoxy, (3-fluorooxetane-3-yl)methoxy, (3-methyloxetane-3-yl)methoxy, morpholinyl, morpholinylmethyl, 2-morpholinyl- 2-Oxoethyl, 2-morpholinylethoxy, 2-morpholinylethyl, thiazolyl-4-yl, thiazolyl-5-yl, (trifluoromethyl)thiazolyl-4-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, 5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4] Azine-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4] Azine-2-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl, ((1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl)methoxy, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl, 6,6-difluoro-2-azaspiro[3.3]hept-2-yl, 2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy or 2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)thiazolyl-5-yl.

[0247] Item 1-13. A compound or a salt thereof according to any one of Items 1-1 to 1-12, wherein R 1 It is hydrogen, fluorine, chlorine, cyano, isopropyl, methoxy, methoxy-d3, difluoromethoxy, ethoxy, 2-methoxyethoxy, 2-methoxy-2-oxoethoxy, 2,2-difluoroethoxy, 2-(difluoromethoxy)ethoxy, 2-(trifluoromethoxy)ethoxy, 2-hydroxy-2-methylpropoxy, 2-methoxy-2-methylpropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, cyclopropyl, cyclopropoxy, cyclopropylmethoxy, cyclopropane carbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropyl)methoxy, 2-(3,3-difluorocyclobutyl)ethoxy, (2,2-difluoro-1-methylcyclopropyl)methoxy, (1-(difluoromethyl)cyclopropyl)methoxy Oxygen, (1-(trifluoromethyl)cyclopropyl)methoxy, (1-(oxetane-3-yl)azacyclobutane-3-yl)oxy, (1-(oxetane-3-yl)azacyclobutane-3-yl)methoxy, (1-methylpiperidin-4-yl)oxy, (oxetane-3-yl)methoxy, (3-fluorooxetane-3-yl)methoxy, (3-methyloxetane) Butane-3-yl)methoxy, morpholinylmethyl, 2-morpholinyl-2-oxoethyl, 2-morpholinylethoxy, 2-morpholinylethyl, ((1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl)methoxy, 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl or 2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy.

[0248] Item 1-14. A compound or a salt thereof according to any one of Items 1-1 to 1-13, wherein R 1It contains hydrogen, fluorine, chlorine, cyano, isopropyl, methoxy, methoxy-d3, difluoromethoxy, ethoxy, 2-methoxyethoxy, 2-methoxy-2-oxoethoxy, 2,2-difluoroethoxy, 2-(difluoromethoxy)ethoxy, 2-(trifluoromethoxy)ethoxy, 2-hydroxy-2-methylpropoxy, 2-methoxy-2-methylpropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, cyclopropoxy, cyclopropylmethoxy, cyclopropane carbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropyl)methoxy, 2-(3,3-difluorocyclobutyl)ethoxy, (2,2-difluoro-1-methylcyclopropyl)methoxy, and (1-(difluoromethyl)cyclopropyl)methoxy. (1-(trifluoromethyl)cyclopropyl)methoxy, (1-(oxetane-3-yl)azacyclobutane-3-yl)oxy, (1-(oxetane-3-yl)azacyclobutane-3-yl)methoxy, (1-methylpiperidin-4-yl)oxy, (oxetane-3-yl)methoxy, (3-fluorooxetane-3-yl)methoxy, (3-methyloxetane-3-yl)methoxy Alkyl-3-yl)methoxy, morpholinylmethyl, 2-morpholinyl-2-oxoethyl, 2-morpholinylethoxy, 2-morpholinylethyl, ((1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl)methoxy, 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl or 2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy.

[0249] Item 1-15. A compound or a salt thereof according to any one of Items 1-1 to 1-14, wherein R 1 It is hydrogen, halogen, -CN, or optionally surrounded by one or more R 12 Replacement -L 11 -R 11 .

[0250] Item 1-16. A compound or a salt thereof according to any one of Items 1-1 to 1-15, wherein L 11 It is -O-, -O-ethylidene, -O-ethylidene-O-, -C(=O)NH- or -NH-C(=O)-; R 11 It is methyl, cyclopropyl, difluoroethyl, pyrazolyl, tetrahydrofuranyl, thiazolyl, piperidinyl, tetrahydropyranyl, morpholinyl, tetrahydrofuranopyrroleyl, hexahydropyrroleopyrroleyl, azaspiroheptyl, or oxazaspiroheptyl; and R 12 Each can be fluorine, methyl, methyl-d3, or cyclopropyl.

[0251] Item 1-17. A compound or a salt thereof according to any one of Items 1-1 to 1-16, provided that R1 It is optionally controlled by one or more R 12 Replacement -R 11 At that time, R 11 It is C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0252] Item 1-18. A compound or a salt thereof according to any one of Items 1-1 to 1-17, provided that R 1 It is optionally controlled by one or more R 12 Replacement -R 11 At that time, R 11 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0253] Item 1-19. A compound or a salt thereof according to any one of Items 1-1 to 1-18, wherein R 21 and R 22 It is hydrogen.

[0254] Item 1-20. A compound or a salt thereof according to any one of Items 1-1 to 1-19, wherein R 31 yes

[0255] a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, e1) A saturated or unsaturated 4- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms. e2) Saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom. e3) A saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. e4) An unsaturated 5-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms. e5) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms, or e6) A saturated 7- to 8-membered spirocyclic group containing one nitrogen atom and one oxygen atom as cyclic heteroatoms.

[0256] Item 1-21. A compound or a salt thereof according to any one of Items 1-1 to 1-19, wherein R 31 yes: a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, or e) Saturated 4 to 10-membered monocyclic, bicyclic, or spirocyclic groups.

[0257] Item 1-22. A compound or a salt thereof according to any one of Items 1-1 to 1-21, wherein R 31 yes: a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, or d) Phenyl.

[0258] Item 1-23. A compound or a salt thereof according to any one of Items 1-1 to 1-22, wherein R 31 yes: a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl, or c) C 3-8 Cycloalkyl.

[0259] Item 1-24. A compound or a salt thereof according to any one of Items 1-1 to 1-23, wherein

[0260] L 31 It is -C(=O)-, -C(=O)O-, -C(=O)O-methylene-, -C(=O)O-ethylidene-, -C(=O)-ethylidene-O-, -C(=O)-methylene-O-methylene- or -C(=O)NH-ethylidene-. R 31 It is methyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azole group, thiazolyl group, Diazolyl, pyrimidinyl, tetrahydrofuranyl, aziridine, or 6-oxa-1-azaspiro[3.4]octyl, and R 32 Each of them is independently fluorine, methyl, ethyl, cyclopropyl, difluoromethyl, or trifluoromethyl.

[0261] Item 1-25. A compound or a salt thereof according to any one of Items 1-1 to 1-24, wherein

[0262] L31 It is -C(=O)-, -C(=O)O-, or -C(=O)O-methylene-. R 31 It is methyl, tert-butyl, cyclopropyl, Azolyl, thiazolyl, or aziridine; preferably cyclopropyl, Azolyl, thiazolyl, or aziridine, R 32 Each is fluorine independently, and X is CH or N.

[0263] Item 1-26. A compound or a salt thereof according to any one of Items 1-1 to 1-25, wherein R 3 It is C 1-6 Halogenated alkyl group -OC(=O)-, optionally halogenated or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-OC(=O)-, optionally C 1-6 Alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted phenyl-CH2OCH2-C(=O)-, optionally C 1-6 Alkyl-substituted phenoxy-C 1-6 alkylene-C(=O)-, phenyl-C 1-3 Alkylene-NH-C(=O)-, optionally halogenated or C 1-6 Haloalkyl-substituted azaheterocyclic butyl-C(=O)-, optionally C 1-6 Alkyl-substituted azole-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl or C 3-8 Cycloalkyl-substituted Diazole group, optionally covered with C 1-6 Halogenated alkyl-substituted thiazolyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted pyrimidinyl, tetrahydrofuranyl-C 1-6 Alkylene-OC(=O)-, 3-oxa-6-azabicyclo[3.1.1]heptyl-C(=O)- or 6-oxa-1-azaspiro[3.4]octyl-C(=O)-.

[0264] Item 1-27. A compound or a salt thereof according to any one of Items 1-1 to 1-26, wherein R 3 It is C 1-6 Halogenated alkyl group -OC(=O)-, optionally halogenated or C1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-OC(=O)-, optionally C 1-6 Alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted phenyl-CH2OCH2-C(=O)-, optionally C 1-6 Alkyl-substituted phenoxy-C 1-6 alkylene-C(=O)-, phenyl-C 1-3 Alkylene-NH-C(=O)-, optionally halogenated or C 1-6 Haloalkyl-substituted azaheterocyclic butyl-C(=O)-, optionally C 1-6 Alkyl-substituted azole-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Halogenated alkyl-substituted thiazolyl-C 1-6 Alkylene-OC(=O)-, Tetrahydrofuranyl-C 1-6 Alkylene-OC(=O)-, 3-oxa-6-azabicyclo[3.1.1]heptyl-C(=O)- or 6-oxa-1-azaspiro[3.4]octyl-C(=O)-.

[0265] Item 1-28. A compound or a salt thereof according to any one of Items 1-1 to 1-27, wherein R 3 It is 5-ethylpyrimidin-2-yl, 5-methyl-1,2,4- Diazol-3-yl, 3-cyclopropyl-1,2,4- Diazol-5-yl, (2-(difluoromethyl)azacyclobutane-1-yl)carbonyl, (3,3-difluoroazacyclobutane-1-yl)carbonyl, (3-oxa-6-azabicyclo[3.1.1]hept-6-yl)carbonyl, 6-oxa-1-azaspiro[3.4]oct-1-ylcarbonyl, azacyclobutane-1-ylcarbonyl, 2-(p-tolyloxy)ethylcarbonyl, 2-phenoxyethylcarbonyl, ((2-methylbenzyl)oxy)methylcarbonyl, phenylethyl 1,1,1-trifluoro-2-methylprop-2-oxycarbonyl, 1-fluoro-2-methylprop-2-oxycarbonyl, cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, (1-methylcyclopropyl)methoxycarbonyl, 3,3-difluorocyclobutoxycarbonyl, (1R,3R)-3-(trifluoromethyl)cyclobutoxycarbonyl, (1S,3S)-3-(trifluoromethyl)cyclobutoxycarbonyl, 4,4-difluorocyclohexyloxycarbonyl, benzyloxycarbonyl azole-4-ylmethoxycarbonyl, 1-( (zol-4-yl)ethoxycarbonyl, (2-methyl) (2-(thiazol-4-yl)methoxycarbonyl, 2-(thiazol-4-yl)ethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, (2-(trifluoromethyl)thiazol-4-yl)methoxycarbonyl or (tetrahydrofuran-2-yl)methoxycarbonyl.

[0266] Item 1-29. A compound or a salt thereof according to any one of Items 1-1 to 1-28, wherein R 3 It is (2-(difluoromethyl)azacyclobutane-1-yl)carbonyl, (3,3-difluoroazacyclobutane-1-yl)carbonyl, (3-oxa-6-azabicyclo[3.1.1]hept-6-yl)carbonyl, 6-oxa-1-azaspiro[3.4]oct-1-ylcarbonyl, azacyclobutane-1-ylcarbonyl, 2-(p-tolyloxy)ethylcarbonyl, 2-phenoxyethylcarbonyl, ((2-methylbenzyl)oxy)methylcarbonyl, phenylethylamino Formicyl, 1,1,1-trifluoro-2-methylprop-2-oxycarbonyl, 1-fluoro-2-methylprop-2-oxycarbonyl, cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, (1-methylcyclopropyl)methoxycarbonyl, 3,3-difluorocyclobutoxycarbonyl, (1R,3R)-3-(trifluoromethyl)cyclobutoxycarbonyl, (1S,3S)-3-(trifluoromethyl)cyclobutoxycarbonyl, 4,4-difluorocyclohexyloxycarbonyl, benzyloxycarbonyl azole-4-ylmethoxycarbonyl, 1-( (zol-4-yl)ethoxycarbonyl, (2-methyl) (2-(thiazol-4-yl)methoxycarbonyl, 2-(thiazol-4-yl)ethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, (2-(trifluoromethyl)thiazol-4-yl)methoxycarbonyl or (tetrahydrofuran-2-yl)methoxycarbonyl.

[0267] Item 1-30. A compound or a salt thereof according to any one of Items 1-1 to 1-29, provided that R 3 It is optionally controlled by one or more R 32 Replacement R 31 At that time, R 31 It is C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 Cycloalkyl.

[0268] Item 1-31. A compound or a salt thereof according to any one of Items 1-1 to 1-30, wherein R 3 It is optionally controlled by one or more R 32 Replacement -L 31 -R 31 .

[0269] Item 1-32. A compound or a salt thereof according to any one of Items 1-1 to 1-31, wherein the compound of formula [I] is

[0270] [Chemical Formula 19] .

[0271] Item 1-33. A compound or a salt thereof according to any one of Items 1-1 to 1-32, wherein the compound of formula [I] is

[0272] [Chemical Formula 20] .

[0273] Item 1-34. A compound or a salt thereof according to any one of Items 1-1 to 1-33, wherein the compound of formula [I] is

[0274] [Chemical Formula 21] .

[0275] Item 1-35. A compound or a salt thereof according to any one of Items 1-1 to 1-33, wherein the compound of formula [I] is

[0276] [Chemical Formula 22] .

[0277] Item 1-36. A compound or a salt thereof according to any one of Items 1-1 to 1-33, wherein the compound of formula [I] is

[0278] [Chemical Formula 23] .

[0279] Item 1-37. A compound or a salt thereof according to any one of Items 1-1 to 1-33, wherein the compound of formula [I] is

[0280] [Chemical Formula 24] .

[0281] Item 1-38. A compound or a salt thereof according to any one of Items 1-1 to 1-33, wherein the compound of formula [I] is

[0282] [Chemical Formula 25] .

[0283] Item 1-39. A compound or a salt thereof as described in any one of Items 1-1 to 1-32, wherein X is CH.

[0284] Item 1-40. A compound or a salt thereof as described in any one of Items 1-1 to 1-32, wherein X is N.

[0285] Item 1-41. A compound or a salt thereof according to any one of Items 1-1 to 1-32, wherein the following bonds are present: [Chemical Formula 26]

[0286] It is a single key.

[0287] Item 1-42. A compound or a salt thereof according to any one of Items 1-1 to 1-32, wherein the following bonds are present: [Chemical Formula 27]

[0288] It is a double bond.

[0289] Item 1-43. A compound or a salt thereof according to any one of Items 1-1 to 1-42, wherein R 1 It is optionally controlled by one or more R 12 Replacement -L 11 -R 11 L 11 It is -O- or -O-ethylene-O-; R 11 It is C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, or saturated 4- to 6-membered monocyclic heterocyclic groups; and R 12 It is a halogen, C that is optionally replaced by one or more deuteriums. 1-6 Alkyl, or C 1-6 Halogenated alkyl groups.

[0290] Item 1-44. A compound or a salt thereof according to any one of Items 1-1 to 1-43, wherein R 1 It is 2-methoxyethoxy, cyclopropoxy, (1-methylpiperidin-4-yl)oxy, 2,2-difluoroethoxy, 1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 6,6-difluoro-2-azaspiro[3.3]hept-2-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, thiazolyl-5-yl, or 1-methyl-1H-pyrazol-4-yl.

[0291] Item 1-45. A compound or a salt thereof according to any one of Items 1-1 to 1-44, wherein R 1It is 2-methoxyethoxy, cyclopropoxy, (1-methylpiperidin-4-yl)oxy or 2,2-difluoroethoxy.

[0292] Item 1-46. A compound or a salt thereof according to any one of Items 1-1 to 1-45, wherein R 1 It is hydrogen, halogen, -CN, or optionally surrounded by one or more R 12 Replacement -L 11 -R 11 .

[0293] Item 1-47. A compound or a salt thereof according to any one of Items 1-1 to 1-46, wherein R 3 It is cyclopropoxycarbonyl, (1-fluoromethyl-2-methylprop-2-yl)oxycarbonyl, Azol-4-ylmethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, or 3,3-difluoroazacyclobutane-1-ylcarbonyl.

[0294] Item 1-48. The compound or a salt thereof according to Item 1-1, wherein said compound is selected from the following compounds: [Chemical Formula 28] .

[0295] Item 1-49. The compound according to Item 1-1, wherein the compound is selected from the following compounds: [Chemical Formula 29] .

[0296] Item 1-50. The compound or a salt thereof according to Item 1-1, wherein said compound is selected from the following compounds: [Chemical Formula 30] .

[0297] Item 1-51. The compound according to Item 1-1, wherein the compound is selected from the following compounds: [Chemical Formula 31] .

[0298] Items 1-52. The compounds according to Item 1-1, wherein the compounds are selected from the compounds of Examples 1 to 152 as shown in Table 3.

[0299] Item 2. A pharmaceutical composition comprising a compound or a salt thereof as an active ingredient according to any one of Items 1-1 to 1-52, and a pharmaceutically acceptable carrier or excipient.

[0300] Item 3-1. A pharmaceutical agent for the treatment, prevention and / or diagnosis of diseases caused by CSF1R, said agent comprising a compound or a salt thereof as an active ingredient according to any one of Items 1-1 to 1-52.

[0301] Project 3-2. The agent according to Project 3-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy or asthma.

[0302] Project 3-3. The pharmaceutical agent according to Project 3-1 or 3-2, for use simultaneously, separately or sequentially in combination with at least one therapeutic or preventive medicine for diseases selected from: Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy or asthma.

[0303] Item 4-1. A method for treating, preventing, and / or diagnosing diseases caused by CSF1R, the method comprising administering to a person in need an effective amount of a compound or a salt thereof according to any one of Items 1-1 to 1-52.

[0304] Project 4-2. According to the method described in Project 4-1, the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

[0305] Project 4-3. The method according to Project 4-1 or 4-2, the method further comprising: administering at least one therapeutic or preventive medicine for a disease selected from: Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

[0306] Item 5-1. A compound or a salt thereof according to any one of Items 1-1 to 1-52, for the treatment, prevention and / or diagnosis of diseases caused by CSF1R.

[0307] Item 5-2. A compound or salt thereof used according to Item 5-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

[0308] Item 5-3. A compound or salt thereof for use according to Item 5-1 or 5-2, wherein the compound or salt thereof is administered simultaneously, separately or sequentially in combination with at least one therapeutic or preventive medicine for a disease selected from: Alzheimer's disease (AD), tau disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy or asthma.

[0309] Item 6-1. Use of the compound or salt thereof described in any one of Items 1-1 to 1-52 in the manufacture of a medicament for the treatment, prevention and / or diagnosis of diseases caused by CSF1R.

[0310] Project 6-2. According to the use described in Project 6-1, the diseases caused by CSF1R are selected from Alzheimer's disease (AD), tau disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

[0311] Item 6-3. According to the use described in Item 6-1 or 6-2, the drug is administered simultaneously, separately or sequentially in combination with at least one therapeutic or preventive drug for a disease selected from: Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infections (such as viral, bacterial and parasitic infections), cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy or asthma.

[0312] Project 7. A method for preparing compounds of formula [I] as described herein, or salts thereof.

[0313] Project 8-1. An intermediate compound in a method for preparing a compound of formula [I] as described herein or a salt thereof.

[0314] Item 8-2. The compound or its salt as described in Item 8-1, represented by any one of the compounds of formula [II], [IV], [VI], [VII] and [IX]: [Chemical Formula 32]

[0315] Where R x It is a protecting group selected from alkyl (alkenyl) carbonyl groups, aryl groups, and alkoxy carbonyl groups, Y 2 It is a leaving group selected from phenoxy groups including 4-nitrophenoxy, n is 0 or 1, and other symbols are as defined in item 1-1.

[0316] Item 8-3. The compound or a salt thereof according to Item 8-1, wherein the compound is selected from the compounds of Reference Examples 1 to 244 as shown in Table 2.

[0317] Example

[0318] The present invention will be described in more detail with reference to the following test examples, reference examples and embodiments, which should not be regarded as limiting, and the embodiments may be modified without departing from the scope of the invention.

[0319] The following abbreviations may be used in this article.

[0320] [Table 1-1]

[0321] [Table 1-2]

[0322] [Table 1-3]

[0323] In the following embodiments, "room temperature (RT)" generally refers to about 10°C to about 35°C. Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios. Unless otherwise specified, % refers to wt%.

[0324] 1 H-NMR (proton nuclear magnetic resonance spectroscopy) is measured by Fourier transform NMR (any one of the following: Bruker AVANCE III 400 (400 MHz), Bruker AVANCE III HD (400 MHz), or Bruker AVANCE III HD (500 MHz)).

[0325] Mass spectrometry (MS) was performed using LC / MS (any of the following: ACQUITY UPLC H-Class, Agilent 1290 Infinity II / 6130, or Shimadzu Nexera / LCMS-2020). ESI was used as the ionization method. Data indicate actual measurements (found). Typically, a molecular ion peak ([M+H]) is observed. + [MH] - (etc.). In the case of salt, molecular ion peaks or fragment ion peaks in their free form are usually observed.

[0326] Chiral separation was performed using supercritical fluid chromatography (SFC).

[0327] In silica gel column chromatography, when the environment is considered alkaline, silica gel bound with aminopropylsilane is used.

[0328] The absolute configuration of the compound was determined by known X-ray crystal structure analysis (e.g., Basic Course for Chemists 12, X-ray Crystal Structure Analysis, 1st edition, 1999, by Shigeru Ohba and Shigenobu Yano), or estimated according to the empirical rule of Shi's asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401; Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0329] Reference example

[0330] Reference Example 1. 4-Nitrophenyl ( Synthesis of azole-4-ylmethyl)carbonate

[0331] At 0°C, under nitrogen atmosphere, 4-(hydroxymethyl)-1,3- Bis(4-nitrophenyl) carbonate (29.45 g) and TEA (21 mL) were added to a DCM (200 mL) solution of azole (10 g). After stirring at 0 °C for 5 min, the mixture was stirred at room temperature under nitrogen for 3 h, and then concentrated. AcOEt and 10% K2CO3 aqueous solution were added to the residue. The mixture was stirred at room temperature for 5–10 min. The organic layer was separated and then concentrated. The residue was milled overnight in IPE (150 mL) at room temperature. The solid was collected by filtration and washed with IPE to obtain the target compound (22.19 g).

[0332] Refer to Example 2. (1R,5S)-3-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)-8-aza Synthesis of bicyclic [3.2.1]octane-8-carboxylic acid tert-butyl ester

[0333] At 40 °C, a mixture of (1S,5R)-3-(6-(benzyloxy)pyrazolo[1,5-a]pyridin-3-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid tert-butyl ester (336 mg) and Pd / C (200 mg) in EtOAc / EtOH (6 mL) (1 / 1) was stirred for 2 h. The mixture was stored overnight under nitrogen. At 40 °C, the mixture was stirred for 1 h under hydrogen. The reaction mixture was filtered through a Celite filter. The filtrate was concentrated to obtain the intermediate compound (289 mg).

[0334] 2,2-Difluoroethyltrifluoromethanesulfonate (200 mg) and K₂CO₃ (161 mg) were added to a DMF (4 mL) solution of the intermediate compound (289 mg) at room temperature. The mixture was stirred for 3 h. The reaction mixture was diluted with water and extracted with AcOEt. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (231 mg) as a diastereomer mixture (dr 7:3).

[0335] Refer to Example 4. (1R,5S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-8-nitrogen Synthesis of heterobicyclo[3.2.1]oct-2-en-8-carboxylic acid tert-butyl ester

[0336] LDA (6.66 mL) was slowly added to a THF (25 mL) solution of (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2 g) at -78 °C, and the reaction mixture was stirred for 10 min. A THF (15 mL) solution of N-phenyltrifluoromethanesulfonylimide (3.49 g) was added. The reaction mixture was stirred at -78 °C for 30 min and heated to room temperature for 5 h. A saturated aqueous solution of NH4Cl was added, and extraction was performed with AcOEt. The organic layer was washed with brine and concentrated. The residue was purified by column chromatography (Si, hexane / AcOEt = 95 / 5-80 / 20) to give the desired yellow oil. Trifluoromethanesulfonate, bis(pinacol)diboron (2.71 g), and PdCl2 (dppf) were added under nitrogen at 80 °C. DCM (0.725 g), dppf (0.492 g), and AcOK (2.61 g) were used in two... The mixture in alkyl (50 mL) was stirred for 2 h. The mixture was diluted with AcOEt and H2O, and extracted with AcOEt. The organic layer was concentrated. The residue was purified twice by silica gel column chromatography (hexane / AcOEt and hexane / DCM / AcOEt) to obtain the target compound (1136 mg).

[0337] Refer to Example 5. Synthesis of 3-(piperidin-4-yl)-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridine

[0338] TFA (267 μL) was added to a mixture of tert-butyl 4-(5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylate (66.9 mg) in DCM (2 mL) at 0 °C. The mixture was stirred at room temperature for 3 h, and then H2O was added. A 2 N NaOH aqueous solution was added to the mixture at 0 °C for alkalization. The mixture was extracted with DCM, and the organic layer was concentrated to obtain the target compound (47.8 mg).

[0339] Refer to Example 6. 4-(5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert- Synthesis of butyl ester

[0340] 10% Pd / C (wet, NX type) (116 mg) was added to a mixture of 4-(5-(3,6-dihydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (138.5 mg) in EtOH / AcOEt (1 / 1) (5 mL) under nitrogen atmosphere. Hydrogen was used instead of nitrogen. The mixture was stirred at 40 °C for 1 h. The mixture was stirred at 50 °C for 0.5 h. The mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was stirred under hydrogen atmosphere at 50 °C for more than 1.5 h (total time 2 h). The mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by aminosilica gel column chromatography (hexane / AcOEt) to obtain the target compound (66.9 mg).

[0341] Refer to Example 7. 4-(5-(3,6-dihydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydro Synthesis of tert-butyl pyridine-1(2H)-formate

[0342] PdCl2 (dppf) was added to a mixture of 232.6 mg of 4-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in DME / H2O (10 / 1) (5 mL) at room temperature. DCM (50.2 mg), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (258 mg), and K3PO4 (392 mg). The mixture was stirred overnight at 80 °C under nitrogen. H2O was added to the mixture, and then the mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by amino silica gel column chromatography (hexane / AcOEt) to obtain the target compound (138.5 mg).

[0343] Refer to Example 8. 4-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester Synthesis

[0344] To a mixture of 5-bromo-3-iodopyrazolo[1,5-a]pyridine (796.1 mg) and Pd(Ph3P)4 (142 mg) in DME / H2O (10 / 1) (20 mL), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (915 mg) and K3PO4 (1570 mg) were added. The mixture was stirred overnight under nitrogen at 80 °C. H2O was added to the reaction mixture at 0 °C, and the mixture was then extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (442 mg).

[0345] Refer to Example 10. Synthesis of tert-butyl 4-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0346] K₂CO₃ (53.2 mg) and iodomethane (17.98 μL) were added to a mixture of 61.1 mg of 4-(5-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate in DMF (1 mL) at 0 °C. The mixture was stirred at room temperature for 8 h. H₂O was added to the mixture at 0 °C, and the mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by aminosilica gel column chromatography (hexane / AcOEt) to obtain the target compound (46.4 mg).

[0347] Refer to Example 13. Synthesis of 5-(benzyloxy)-3-bromopyrazolo[1,5-a]pyridine

[0348] NBS (241 mg) was added to an 8 mL solution of 5-(benzyloxy)pyrazolo[1,5-a]pyridine (252.6 mg) in DMF at 0 °C. The mixture was stirred for 2 h at room temperature. H₂O (200 mL) was added to the mixture at 0 °C to form a precipitate. The mixture was filtered and the precipitate was collected. The precipitate was washed with H₂O to obtain the target compound (285 mg).

[0349] Refer to Example 15. Synthesis of tert-butyl 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0350] At room temperature, under nitrogen atmosphere, 10% Pd-C (12.82 g) (wetted with water) was added to a mixture of 24.67 g of 4-(6-(benzyloxy)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (AcOEt / EtOH (800 ml) 1 / 1). Hydrogen was used instead of nitrogen. The mixture was stirred at 30 °C for 2.5 h.

[0351] The mixture was filtered through Celite, and the Celite was washed with AcOEt and DCM to obtain a filtrate. The filtrate was concentrated and dried. The residue was ground in hexane / AcOEt (1 / 1) (200 mL) at room temperature. The solid was collected, washed with hexane, and dried to obtain the target compound (16.60 g).

[0352] Refer to Example 16. 4-(6-(benzyloxy)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-methyl Synthesis of tert-butyl ester

[0353] Under nitrogen atmosphere, 20 g of 6-(benzyloxy)-3-bromopyrazolo[1,5-a]pyridine and 3,6-dihydro-2 H 24.98 g of pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester was added to a suspension in DME / H2O (330 ml) (10 / 1) with K3PO4 (35.04 g) and PdCl2 (dppf). DCM (2.69 g). After degassing, the mixture was refluxed overnight under nitrogen. AcOEt and H2O were added. The mixture was stirred at room temperature and passed through Celite, and the Celite was then treated with AcOEt and H2O. Wash with alkane. Wash the organic layer with brine and concentrate. Purify the residue by alkaline silica gel chromatography (DCM / AcOEt) to obtain the target compound (24.67 g).

[0354] Refer to Example 17. Synthesis of 6-(benzyloxy)-3-bromopyrazolo[1,5-a]pyridine

[0355] NBS (12.14 g) was added to a mixture of 6-(benzyloxy)pyrazolo[1,5-a]pyridine (15.30 g) in DMF (220 ml) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C under nitrogen atmosphere for 2.5 h. H2O (-700 ml) was added. The mixture was then stirred at room temperature. The solid was collected, washed with H2O, and dried to obtain the target compound (20.02 g).

[0356] Refer to Example 19. Synthesis of 6-(2-methoxyethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine

[0357] TFA (6775 μL) was added to a mixture of 1650.9 mg of 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (1650.9 mg) in DCM (65 mL) at 0 °C. The mixture was stirred under nitrogen at room temperature for 2 h. H₂O was added to the mixture at 0 °C, followed by 2 N NaOH. The mixture was extracted with DCM. The organic layer was concentrated. The residue was suspended in IPE, and the solid was collected and dried to obtain the target compound (1.008 g).

[0358] Refer to Example 20. 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0359] Cs₂CO₃ (6.16 g) and sodium iodide (0.472 g) were added to a mixture of 2-bromoethyl methyl ether (1.184 ml) and 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (2 g) in MeCN (30 mL) at 0 °C. The mixture was stirred under nitrogen at 50 °C for 3 h. H₂O was added to the mixture at 0 °C. The mixture was extracted with DCM. The organic layer was collected and concentrated to obtain a crude material. The crude material was purified by alkaline silica gel chromatography (hexane / AcOEt). The material was suspended in IPE at reflux temperature. The solid was collected and dried to obtain the target compound (1.65 g).

[0360] Refer to Example 21. Synthesis of 6-(2,2-difluoroethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine

[0361] TFA (35 mL) was added to a solution of 16.85 g of tert-butyl 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (16.85 g) in DCM (200 mL) at 0 °C. The mixture was stirred and concentrated at room temperature. The residue was dissolved in DCM. A 5 N NaOH aqueous solution (60 mL) was added at 0 °C. The mixture was extracted with DCM. The organic layer was concentrated. The crude product was purified by NH-silica gel chromatography (AcOEt / MeOH) to obtain the target compound (10.91 g).

[0362] Refer to Example 22. 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0363] Under nitrogen atmosphere, a solution of tert-butyl K₂CO₃ (4.88 g) and a solution of 2,2-difluoroethyltrifluoromethanesulfonate (6.31 g) in DMF (70 mL) were added. The mixture was stirred at room temperature for 8 h. K₂CO₃ (665.8 mg) was added. 2,2-difluoroethyltrifluoromethanesulfonate (690.8 mg) was added. The mixture was stirred overnight under nitrogen atmosphere at room temperature. 2,2-difluoroethyltrifluoromethanesulfonate (385.3 mg) was added. The mixture was stirred under nitrogen atmosphere at room temperature for 1 h. H₂O (160 mL) was added. The solid was collected and dried, then ground and dried in an IPE to obtain the target compound (7.22 g).

[0364] Refer to Example 27. 4-(6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-methyl Synthesis of tert-butyl ester

[0365] Magnesium methyl bromide (0.3 mL) was added to a THF (10 mL) solution of 102.7 mg of 4-(6-(2-methoxy-2-oxoethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (102.7 mg) at 0 °C under nitrogen. The mixture was stirred for 30 min at 0 °C under nitrogen. A saturated aqueous solution of NH4Cl and AcOEt were added. The mixture was extracted with AcOEt. The organic layer was concentrated to obtain the target compound (102.2 mg).

[0366] Refer to Example 31. Synthesis of tert-butyl 4-(6-cyanopyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0367] Zn(CN)₂ (157 mg) and Pd(PPh₃)₄ (103 mg) were added to a mixture of 4-[6-(trifluoromethanesulfonyloxy)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylic acid tert-butyl ester (400 mg) in DMF (3 mL), and the mixture was stirred at 80 °C for 3 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃ and filtered. The solid was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (33 mg).

[0368] Refer to Example 34. Synthesis of (S)-(2,2-difluoro-1-methylcyclopropyl)methylmethanesulfonate

[0369] LAH (167 mg) was added to a mixture of (1S)-2,2-difluoro-1-methylcyclopropane-1-carboxylic acid (200 mg) in ether (5 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred for 18 h at room temperature. The mixture was quenched with H₂O (0.167 mL), 15% NaOH aqueous solution (0.167 mL), and H₂O (0.501 mL). The mixture was stirred for 30 min at room temperature. MgSO₄ was added to the mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure. MsCl (298 μL) and TEA (614 μL) were added to a mixture of crude product in DCM (5 mL) at 0 °C. The mixture was stirred for 3 h at room temperature. The mixture was quenched with H₂O, extracted with DCM, and the organic layer was concentrated to obtain the target compound (294 mg) (containing DCM). The crude product was used without any further purification.

[0370] Refer to Example 39. Synthesis of tert-butyl 4-(6-chloropyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0371] EtOH (10 mL) was added to a mixture of 4-(6-chloropyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (400 mg) and platinum oxide (IV) (54.4 mg) at room temperature. The mixture was stirred under hydrogen at 40 °C for 10 h. The crude product was filtered through a Celite filter and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (93 mg).

[0372] Refer to Example 45. 4-(6-(2,2-difluoropropoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0373] At 0 °C, under nitrogen atmosphere, 262 μL of bis(2-methoxyethyl)aminosulfur trifluoride was added to a DCM solution (5 mL) of 177 mg of pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (177 mg). The mixture was heated to room temperature and stirred for 7 h. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer was concentrated. The residue was purified by basic silica gel column chromatography (hexane / AcOEt) to obtain the target compound (165 mg).

[0374] Refer to Example 55. Synthesis of benzyl 3-((p-toluenesulfonyloxy)methyl)azacyclobutane-1-carboxylate.

[0375] TsCl (1292 mg) was added to a pyridine (4 mL) solution of 1-Cbz-azacyclobutane-3-ylmethanol (1000 mg) at 0 °C, and the solution was stirred at room temperature for 24 h. The solution was diluted with AcOEt and 1 M HCl. The organic layer was washed with 1 M HCl and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1.3 g).

[0376] Refer to Example 58. 4-(6-(2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy)pyrazolo[1,5-a] Synthesis of tert-butyl pyridin-3-yl)piperidine-1-carboxylate

[0377] Dess-Martin (748.3 mg) was added to a 20 mL solution of 4-(6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (202.5 mg) in DCM under nitrogen atmosphere at room temperature. The mixture was stirred for 55 min under nitrogen atmosphere at room temperature. Dess-Martin (108.4 mg) was added at room temperature. The mixture was stirred for 55 min under nitrogen atmosphere at room temperature. DCM and a saturated aqueous solution of Na2S2O3 were added at 0 °C. The aqueous layer was extracted with DCM and AcOEt. The combined organic layers were concentrated to obtain the intermediate compound. 6,6-difluoro-2-azaspiro[3.3]heptane hydrochloride (131.8 mg) and sodium triacetoxyborohydride (253.2 mg) were added to a 20 mL solution of the intermediate compound in DCE at room temperature. The mixture was stirred overnight at room temperature. H₂O, a saturated aqueous solution of NaHCO₃, and DCM were added at room temperature. The organic layer was separated and then concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (71.4 mg).

[0378] Referring to Example 59. 4-(6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester synthesis

[0379] LAH (30.9 mg) was added to a THF (15 mL) solution of 258.7 mg of 4-(6-(2-methoxy-2-oxoethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (258.7 mg) under nitrogen at 0 °C. The mixture was stirred at 0 °C for 10 min. Hexane and Na₂SO₄·10H₂O were added at 0 °C. The mixture was stirred at 0 °C under nitrogen for 10 min. Na₂SO₄·10H₂O was added at 0 °C. The mixture was then stirred under nitrogen at room temperature. The mixture was filtered through Celite and then concentrated. The residue was purified by silica gel chromatography (hexane / AcOEt) to obtain the target compound (202.5 mg).

[0380] Refer to Example 71. 4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-di Synthesis of tert-butyl hydropyridine-1(2H)-formate

[0381] At 80°C and under nitrogen atmosphere, 6-bromo-3-chloropyrazolo[1,5-a]pyridine (780 mg), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (920 mg), and PdCl2 (dppf) were added. The mixture of DCM (138 mg) and K3PO4 (2145 mg) in DME / H2O (15 mL) was stirred for 2 h. The mixture was diluted with H2O and AcOEt and filtered through Celite. The filtrate was extracted with AcOEt. The organic layer was concentrated to obtain the intermediate compound. The mixture of the intermediate compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (1.6 g), palladium(II) acetate (80 mg), SPhos (280 mg), and K3PO4 (1.4 g) in DME / H2O (30 mL) was stirred for 8 h at 80 °C under nitrogen. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (0.8 g), palladium(II) acetate (40 mg), S-Phos (140 mg), and K3PO4 (0.7 g) were added to the mixture at room temperature. The mixture was stirred at 80 °C under nitrogen for 16 h. The mixture was diluted with H2O and AcOEt, filtered through a Celite filter, and washed with AcOEt. The organic layer was concentrated. The residue was purified by basic silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1142 mg).

[0382] Refer to Example 72. Synthesis of 6-bromo-3-chloropyrazolo[1,5-a]pyridine

[0383] NCS (3660 mg) was added to a MeCN (80 mL) solution of 5400 mg 6-bromopyrazolo[1,5-a]pyridine at room temperature. The mixture was stirred overnight at room temperature. The mixture was heated to 50 °C and stirred for 8 h. The mixture was diluted with H2O (300 mL) and stirred for 1 h. The resulting precipitate was collected by filtration to obtain the target compound (6067 mg).

[0384] Refer to Example 77. Synthesis of tert-butyl 4-(6-cyclopropoxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0385] Cs₂CO₃ (205 mg) and cyclopropyl bromide (126 μl) were added to a mixture of 100 mg of tert-butyl 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate in NMP (1 mL) at room temperature. The mixture was stirred under microwave irradiation at 150 °C for 2 h. The mixture was diluted with H₂O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (40 mg).

[0386] Refer to Example 78. 4-(6-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1- Synthesis of tert-butyl formate

[0387] At 0 °C, under nitrogen, a DCE solution (10 mL) of tert-butyl 4-(6-(piperidin-4-yloxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylate (227.2 mg) was added with formaldehyde solution (47 μL) and sodium triacetoxyborohydride (227.4 mg). The mixture was stirred for 3.5 h at room temperature under nitrogen. AcOEt and a saturated aqueous solution of NaHCO3 were added at room temperature. The organic layer was separated and then concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (197.5 mg).

[0388] Refer to Example 79. 4-(6-(piperidin-4-yloxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0389] Pd / C (244.5 mg) (10%, NX type, wetted with water) was added to a solution of 4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy)piperidin-1-carboxylic acid benzyl ester (342.1 mg) in AcOEt (50 ml) at room temperature. The mixture was stirred under hydrogen at room temperature for 22 h. The reaction mixture was filtered through a Celite filter and the filtrate was concentrated. The residue was purified by alkaline silica gel chromatography (AcOEt / MeOH) to obtain the target compound (227.2 mg).

[0390] Refer to Example 80. 4-((3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)oxy Synthesis of benzyl piperidine-1-carboxylate

[0391] At room temperature, under nitrogen, a suspension of 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate tert-butyl ester (247.8 mg) in MeCN (10 ml) was supplemented with Cs₂CO₃ (454.8 mg) and a solution of 4-((methanesulfonyl)oxy)piperidine-1-carboxylate benzyl ester (625.4 mg) in MeCN (10 ml). The mixture was refluxed under nitrogen for 4 h 10 min. AcOEt and H₂O were added. The aqueous layer was extracted with AcOEt. The combined organic layers were concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain a mixture (496.9 mg) of the target compound and 4-((methanesulfonyl)oxy)piperidine-1-carboxylate. At room temperature, under nitrogen atmosphere, tert-butyl 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate (279.1 mg) and Cs₂CO₃ (664 mg) were added to a 20 ml solution of the mixture (496.9 mg). The mixture was refluxed overnight under nitrogen atmosphere. AcOEt was added at room temperature. The mixture was filtered through a Celite filter. The filtrate was concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the desired product (342.1 mg).

[0392] Refer to Example 84. 4-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-formic acid tert-butyl Ester Synthesis

[0393] At room temperature, under nitrogen atmosphere, the reaction mixture of 6-bromo-3-iodopyrazolo[1,5-a]pyridine (102.3 mg) and 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (120 mg) was subjected to a dihydropyridine reaction. PdCl2 (dppf) was added to an alkane / H2O (10 / 1) (22 mL) solution. DCM (22.2 mg) and K3PO4 (245.9 mg). Reflux the mixture overnight. Add H2O, AcOEt, and brine at room temperature. Concentrate the organic layer. Purify the residue by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (69.7 mg).

[0394] Refer to Example 85. 4-(6-(2-morpholinylethyl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1 Synthesis of (2H)-Benzyl formate

[0395] At 80°C and under nitrogen atmosphere, benzyl 4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (952 mg), (E)-2-ethoxyvinylboronic acid pinacol ester (0.586 mL), and PdCl2 (dppf) were added. A mixture of DCM (188 mg) and K3PO4 (1467 mg) in DME / H2O (10 mL) was stirred for 4 h. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography (Si, hexane / AcOEt) to give the intermediate compound (761 mg). HCl (1.5 mL) was added to a THF (15 mL) solution of the intermediate compound at room temperature. The mixture was stirred at 60 °C for 5 h. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was concentrated to obtain the intermediate compound. Morpholine (0.401 mL), AcOH (0.264 mL), and sodium triacetoxyborohydride (976 mg) were added to a DCM (20 mL) solution of the intermediate compound at room temperature. The mixture was stirred overnight. The mixture was diluted with a saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (195 mg).

[0396] Refer to Example 87. 2-Chloro-1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)ethyl-1-one Synthesis

[0397] TEA (60.3 μL) was added to a mixture of 50 mg of 6-methoxy-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine in THF (1 mL) at 0 °C, and chloroacetyl chloride (22.38 μL) / THF (1 mL) was added dropwise at 0 °C. The mixture was stirred under nitrogen at room temperature for 2 h. A saturated aqueous solution of NH4Cl was added to the mixture. The mixture was extracted with AcOEt. The organic layer was collected and concentrated to obtain the target compound (quantitative yield).

[0398] Refer to Example 89. 4-(6-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-methyl Synthesis of thiazolyl-4-methyl ester

[0399] A mixture of 4-(6-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (410 mg) and 10% Pd / C (220 mg) in AcOEt / EtOH (1 / 1) (10 mL) was stirred for 4 h at 50 °C under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was used directly for the next step without further purification. TEA (281 μL) and 4-nitrophenyl(thiazol-4-ylmethyl) carbonate (257 mg) were added to a DCM (8 mL) solution of the residue at room temperature. The mixture was stirred overnight. The mixture was concentrated and purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (128 mg).

[0400] Refer to Example 90. 4-(6-(2-methoxy-2-oxoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydro Synthesis of pyridine-1(2H)-benzyl formate

[0401] A mixture of 4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (871 mg), 1-(tert-butyldimethylsilyloxy)-1-methoxyethylene (2300 μL), zinc fluoride (654 mg), Pd2(dba)3 (193 mg), and tri-tert-butylphosphine tetrafluoroborate (306 mg) in DMF (18 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. 1-(tert-butyldimethylsilyloxy)-1-methoxyethylene (1.4 mL), zinc fluoride (218 mg), Pd2(dba)3 (96 mg), and tri-tert-butylphosphine tetrafluoroborate (122 mg) were added to the mixture at room temperature. The mixture was stirred at 90 °C for 5 h. The mixture was diluted with H2O and AcOEt and filtered through a Celite filter. The filtrate was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (410 mg).

[0402] Refer to Example 91. Synthesis of 6-(2-methoxyethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine

[0403] TFA (1 ml) was added to a solution of 193 mg tert-butyl 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (193 mg) in DCM (10 ml). The mixture was stirred for 2.5 h at room temperature. The mixture was concentrated and azeotropically treated with toluene under vacuum. DCM and a 1 N NaOH aqueous solution were added to the crude product (TFA salt). The aqueous layer was extracted with DCM. The combined organic layers were concentrated. The residue was purified by alkaline silica gel chromatography (AcOEt / MeOH) to obtain the target compound (128.7 mg).

[0404] Refer to Example 92. 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0405] At room temperature and under nitrogen, 10 mL of 2-bromoethyl methyl ether (124 μL) and Cs₂CO₃ (286 mg) were added to a DMF solution of 207.3 mg of 4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (207.3 mg). The mixture was stirred overnight at 60 °C. AcOEt and H₂O were added to the mixture at room temperature. The aqueous layer was extracted with AcOEt. The combined organic layers were concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt, then AcOEt / MeOH) to obtain the target compound (193 mg).

[0406] Refer to Example 93. Synthesis of tert-butyl 4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate.

[0407] At room temperature, a suspension of 10% Pd / C (523 mg) in EtOH (20 mL) was added to a suspension of 2.72 g of 4-(6-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.72 g) in EtOH (50 mL). The mixture was stirred at 50 °C under hydrogen atmosphere for 7 h. The reaction mixture was filtered through a Celite filter. The filtrate was concentrated to obtain a crude product (2.18 g). The same reaction was repeated to obtain the desired product (2.13 g).

[0408] Refer to Example 94. 4-(6-(benzyloxy)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-methyl Synthesis of tert-butyl ester

[0409] At room temperature, under argon atmosphere, Pd(OAc)₂ (0.302 g) and SPhos (0.828 g) were added to a DME / H₂O (10:1) (60 mL) solution of 6-(benzyloxy)-3-bromopyrazolo[1,5-a]pyrimidine (4.09 g), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (6.24 g), and K₃PO₄ (8.56 g). The mixture was stirred overnight at 80 °C. AcOEt and H₂O were added to the reaction mixture at room temperature. The mixture was filtered through a Celite filter. The organic layer was concentrated. The residue was purified by silica gel chromatography (heptane / AcOEt) to obtain the target compound (3.24 g).

[0410] Refer to Example 95. 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0411] Cs₂CO₃ (512 mg) and 1,1-difluoro-2-iodoethane (138 μL) were added to a DMF (4 mL) solution of 250 mg of 4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate. The mixture was stirred at 60 °C for 3 h. The mixture was diluted with H₂O, and the resulting precipitate was collected by filtration and dried to obtain the desired product (238 mg).

[0412] Refer to Example 101. 4-(6-hydroxypyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-formic acid tert- Synthesis of butyl ester

[0413] At 100°C and under argon atmosphere, tert-butyl 4-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (209 mg), KOH (146 mg), Pd2(dba)3 (25.3 mg), and Me4tButylXphos (26.6 mg) were subjected to argon atmosphere. The mixture in alkyl / H₂O (1:1) (6 mL) was stirred overnight. 1 N HCl (3 mL) was added at 0 °C. The mixture was extracted with AcOEt, and the organic layer was concentrated. The residue was purified by alkaline silica gel chromatography (heptane / AcOEt / MeOH) to obtain the target compound (96 mg).

[0414] Refer to Example 104. 4-(6-(6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl)pyrazolo[1,5-a]pyrazololyl Synthesis of tert-butyl pyridinium (-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0415] To a mixture of 2-(3-chloropyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydro-4H-pyrano[4,3-d]thiazole (56.3 mg), SPhos (15.84 mg), and Pd(OAc)2 (4.33 mg) in DME / H2O (10 / 1) (2 mL), 3,6-dihydro-2H-pyridin-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (119 mg) and K3PO4 (123 mg) were added. The mixture was stirred overnight under nitrogen at 90 °C. H2O was added to the mixture at 0 °C, and the mixture was extracted with DCM. The organic layer was concentrated, and the residue was then purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (29.7 mg).

[0416] Refer to Example 105. 2-(3-chloropyrazolo[1,5-a]pyridin-6-yl)-6,7-dihydro-4H-pyrano[4,3-d]thiazolyl Synthesis of azoles

[0417] 3-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxabort-2-yl)pyrazolo[1,5-a]pyridine (251 mg) in 1,4-di Xantphos (59.2 mg), Pd(OAc)₂ (22.95 mg), 2-bromo-6,7-dihydro-4H-pyrano[4,3-d]thiazole (150 mg), and K₂CO₃ (283 mg) were added to a mixture of alkyl:H₂O (10:1) (6 mL). The mixture was stirred overnight at 80 °C under nitrogen. H₂O was added to the mixture at 0 °C, and the mixture was extracted with DCM. The organic layer was concentrated, and the residue was then purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (56.3 mg).

[0418] Refer to Example 106. 3-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazolo Synthesis of [1,5-a]pyridine

[0419] At room temperature, PdCl2(dppf) DCM (0.037 g) in 1,4-di 6-Bromo-3-chloropyrazolo[1,5-a]pyridine (0.208 g), bis(pinacol)diboron (0.274 g), and AcOK (0.221 g) were added to the mixture in alkane (5 mL). The mixture was refluxed overnight under nitrogen. H2O was added to the mixture, and the mixture was extracted with DCM. The organic layer was concentrated, and the residue was diluted with IPE and filtered through Celite. The filtrate was concentrated to obtain the target compound.

[0420] Refer to Example 108. 4-(6-(cyclopropylcarbamoyl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid Synthesis of tert-butyl ester

[0421] DIPEA (73 μL), HATU (160 mg), and cyclopropylamine (36 μL) were added to a THF (2 mL) solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid (121 mg). The mixture was stirred for 3 h at room temperature. A saturated aqueous solution of NaHCO3 and AcOEt were added to the mixture. The organic layer was separated by a phase separator (Whatman, 1 PS filter paper) and the solvent was removed. The residue was purified by alkaline silica gel column chromatography (heptane / AcOEt) to obtain the target compound (85 mg).

[0422] Refer to Example 109. Synthesis of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylic acid become

[0423] A 5 M NaOH aqueous solution (0.5 mL) was added to a MeOH / THF (1 / 1) (10 mL) solution of methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (436 mg), and the mixture was stirred at 50 °C for 1 h. After cooling the reaction mixture at 0 °C, the reaction mixture was diluted with water and acidified with 6 M HCl. The mixture was extracted with AcOEt. The organic layer was concentrated to obtain the target compound (451 mg).

[0424] Refer to Example 111. 3-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrazolium Synthesis of methyl 6-pyridine carboxylate

[0425] A mixture of tert-butyl 4-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.88 g), TEA (3.18 mL), and XantPhos Pd G3 (181 mg) in DMF / MeOH (4 / 1) (50 mL) was stirred under a carbon monoxide atmosphere. The reaction mixture was stirred overnight at 70 °C. The reaction mixture was concentrated, water was added to the residue, and the mixture was then extracted with AcOEt. The organic layer was concentrated, and the residue was then purified by basic silica gel column chromatography (heptane / AcOEt) to obtain the target compound (2.29 g).

[0426] Refer to Example 114. Synthesis of tert-butyl 4-(6-formylpyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate.

[0427] IBX (285 mg) was added to a DMSO (4 mL) solution of 225 mg 4-(6-(hydroxymethyl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (225 mg) at room temperature. The mixture was stirred for 1 h at room temperature. A saturated aqueous solution of NaHCO3 was added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was then purified by silica gel chromatography (heptane / AcOEt) to obtain the target compound (170 mg).

[0428] Referring to Example 115. The synthesis of tert-butyl 4-(6-(hydroxymethyl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate. become

[0429] DIBAL (1 M, in toluene) (3.00 mL) was added to a THF (5 mL) solution of methyl 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyridine-6-carboxylate (0.359 g) at 0 °C. The mixture was stirred under argon at 0 °C for 30 min. Then, 1 N HCl was added at 0 °C. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (heptane / AcOEt / MeOH) to obtain the target compound (225 mg).

[0430] Refer to Example 127. 6-(1-Cyclopropyl-3,5-Dimethyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo Synthesis of [1,5-a]pyrimidine

[0431] TFA (1.5 mL) was added to a solution of 471 mg of tert-butyl piperidine-1-carboxylate (471 mg) in DCM (10 mL) at room temperature. The mixture was stirred for 2 h. The mixture was concentrated. The residue was purified by basic silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (237 mg).

[0432] Refer to Example 128. 4-(6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of tert-butyl 3-yl)piperidine-1-carboxylate

[0433] At 100°C and under nitrogen atmosphere, tert-butyl 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (828 mg), 4-bromo-1-cyclopropyl-3,5-dimethyl-1H-pyrazole (416 mg), Pd(OAc)2 (43.4 mg), Xantphos (224 mg), and K2CO3 (535 mg) were subjected to a nitrogen atmosphere in a nitrogen atmosphere. The mixture in hexane / H2O (10 / 1) (12 mL) was stirred overnight. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to obtain the desired product.

[0434] Refer to Example 129. 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyrazolo[1, Synthesis of tert-butyl 5-a]pyrimidin-3-yl)piperidine-1-carboxylate

[0435] At 80°C and under nitrogen atmosphere, tert-butyl 4-(6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (542.2 mg) and PdCl2 (dppf) were added. DCM (49.2 mg), AcOK (236 mg), and bis(pinacol) diborone (397 mg) in 1,4-di The mixture in alkane (6 mL) was stirred for 2 h. The reaction mixture was concentrated and diluted with AcOEt. The mixture was filtered through Celite and concentrated to obtain the desired product.

[0436] Refer to Example 130. 4-(6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine- Synthesis of tert-butyl 1-carboxylate

[0437] DIPEA (77 μL) and N-phenyltrifluoromethanesulfonamide (144 mg) were added to a THF (3 mL) solution of 117 mg of tert-butyl 4-(6-hydroxypyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (117 mg) at 0 °C. After stirring at 0 °C for 30 min, a saturated aqueous solution of NH4Cl was added at 0 °C. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (heptane / AcOEt) to obtain the target compound (75 mg).

[0438] Referring to Example 136. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine become

[0439] TFA (2 mL) was added to a 20 mL solution of 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (776 mg) in DCM. The mixture was stirred at room temperature for 2 h 25 min. The reaction mixture was concentrated. DCM and a 1 mol / L NaOH aqueous solution were added to the residue. The organic layer was concentrated to obtain the target compound (628.4 mg).

[0440] Refer to Example 137. 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-methyl Synthesis of tert-butyl ester

[0441] Pd / C (144.9 mg) (10%, NX type, wetted with water) was added to a suspension of tert-butyl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (992 mg) in EtOH (100 mL). The mixture was stirred at 50 °C under hydrogen for 6 h. The reaction mixture was filtered through a Celite filter and concentrated. The reaction was repeated. Pd / C (647.9 mg) was added to a suspension of the residue in EtOH (100 mL). The mixture was stirred at 50 °C under hydrogen for 2 h. The reaction mixture was filtered through a Celite filter and concentrated. The crude product was purified by NH-silica gel chromatography (hexane / AcOEt) to obtain the target compound (776.0 mg).

[0442] Refer to Example 138. 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydro Synthesis of tert-butyl pyridine-1(2H)-formate

[0443] At room temperature, under nitrogen atmosphere, the dimethylpyrazolidine (713.7 mg) of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine was reacted with... 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (1.67 g), K3PO4 (1.91 g), Pd(OAc)2 (64.7 mg), and SPhos (275.9 mg) were added to a 10 / 1 solution of hexane / H2O (33 mL). The mixture was refluxed overnight under nitrogen. H2O and AcOEt were added to the reaction mixture. The organic layer was concentrated. The residue was purified by alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (992 mg).

[0444] Refer to Example 139. Synthesis of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine

[0445] At room temperature, under nitrogen atmosphere, 6-bromo-3-chloropyrazolo[1,5-a]pyrimidine (773.1 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (889 mg) were subjected to dihydropyridine reaction. Add K3PO4 (2.05 g) and PdCl2 (dppf) to an alkane / H2O (33 mL) (10 / 1) solution. DCM (186.3 mg). Reflux the mixture overnight under nitrogen. Add H2O and AcOEt to the reaction mixture. Concentrate the organic layer. Grind the residue in IPE. Collect the solid to obtain the target compound (713.7 mg).

[0446] Refer to Example 142. 6-(1-Cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine synthesis

[0447] TFA (1 mL) was added to a 10 mL solution of 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (472 mg) in DCM at room temperature. The mixture was stirred for 5 h and concentrated (azeotropically with toluene). The residue was purified by basic silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (322 mg).

[0448] Refer to Example 143. 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1- Synthesis of tert-butyl formate

[0449] A mixture of tert-butyl 4-(6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylate (770 mg), cyclopropyl bromide (1.3 ml), and Cs₂CO₃ (3414 mg) in DMF (15 mL) was stirred for 3 h at 180 °C in a microwave oven. The mixture was diluted with H₂O, combined, and extracted with AcOEt. The aqueous layer was extracted with DCM. The organic layer was concentrated. The residue was purified by basic silica gel column chromatography (hexane / AcOEt / MeOH) to obtain the target compound (472 mg).

[0450] Refer to Example 144. 4-(6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0451] p-TsOH was added to a MeOH (20 mL) suspension of 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (697 mg, 1.544 mmol) at room temperature. H2O (587 mg, 3.09 mmol). The mixture was stirred for 3 h. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was concentrated. The residue was purified by basic silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (507 mg).

[0452] Refer to Example 145. Racemic 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- Synthesis of tert-butyl pyridin-3-yl)piperidine-1-carboxylate

[0453] A mixture of racemic 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.329 g) and 10% Pd / C (wet) (2 g) in EtOH (100 mL) was stirred for 12 h at 50 °C under hydrogen atmosphere. The mixture was diluted with AcOEt, filtered through Celite, and washed with AcOEt and DCM. The filtrate was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (2.08 g).

[0454] Refer to Example 146. Racemic 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- Synthesis of tert-butyl pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0455] At 80 °C and under nitrogen atmosphere, racemic 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-pyrazole (1500 mg), 3-chloro-6-bromo-pyrazolo[1,5-a]pyridine (1 g), and PdCl2 (dppf) were added. DCM (353 mg) and K3PO4 (2751 mg, 12.96 mmol) in 1,4-dioxanone The mixture in alkane / H2O (9 / 1) (30 mL) was stirred for 2 h. AcOE and Si silica gel were added to the mixture. The mixture was stirred for 2 h and filtered through Celite. The filtrate was concentrated to obtain the intermediate (2.5 g). The intermediate, 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (2 g), Pd(OAc)2 (145 mg), SPhos (355 mg), and K3PO4 (2.8 g) in DME / H2O (9 / 1) (50 mL) were stirred overnight at 80 °C under nitrogen. 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (1 g), Pd(OAc)2 (145 mg), SPhos (355 mg), and K3PO4 (1.8 g) were added to the mixture at room temperature. The mixture was stirred at 80 °C under nitrogen for 4 h. The reaction mixture was diluted with H₂O and AcOEt and filtered through Celite. The organic layer was concentrated. The Celite was washed with DCM. The filtrate was concentrated. The residues were combined and purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1.86 g).

[0456] Refer to Example 167. 6-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)-2-oxa-6-azaspiro [3.3] Synthesis of heptane

[0457] TFA (1.0 mL) was added to a DCM (4 mL) solution of 4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (334 mg), and the mixture was stirred at room temperature for 1 h. A 1 mol / L NaOH aqueous solution was added to the mixture at 0 °C for alkalization. The mixture was extracted with DCM. The organic layer was concentrated to obtain the target compound (243 mg).

[0458] Refer to Example 168. 4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-yl) Synthesis of tert-butyl piperidine-1-carboxylate

[0459] A mixture of tert-butyl 4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (792 mg) and Pd / C (5% w / w, wet, NX type, 231 mg) in EtOH (50 mL) was stirred for 7.5 h at 40 °C under hydrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by alkaline silica gel column chromatography (heptane / AcOEt) to obtain the target compound (378 mg).

[0460] Refer to Example 169. 4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-yl)- Synthesis of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate

[0461] To a mixture of 6-(3-chloropyrazolo[1,5-a]pyridin-6-yl)-2-oxa-6-azaspiro[3.3]heptane (2.81 g) in DME / H₂O (10:1) (55 mL), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (6.96 g), Pd(OAc)₂ (126 mg), SPhos (462 mg), and K₃PO₄ (7.17 g) were added. The mixture was stirred overnight at 90 °C under an argon atmosphere. The reaction mixture was cooled to room temperature, and AcOEt and H₂O were added. The mixture was filtered through a Celite filter. The organic layer was washed with brine and concentrated to obtain the target compound (3.36 g).

[0462] Referring to Example 170. 6-(3-chloropyrazolo[1,5-a]pyridin-6-yl)-2-oxa-6-azaspiro[3.3]heptane synthesis

[0463] A mixture of 2-oxa-6-azaspiro[3.3]heptane (4.0 g), 6-bromo-3-chloropyrazolo[1,5-a]pyridine (4.26 g), Pd(OAc)₂ (0.413 g), BINAP (1.719 g), and Cs₂CO₃ (17.99 g) in toluene (180 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was diluted with H₂O and AcOEt and filtered through Celite. The filtrate was extracted with AcOEt. The organic layer was concentrated. The residue was dissolved in DCM and stirred with NH-silica gel for 1 h. The mixture was filtered through Celite. The filtrate was concentrated. The residue was milled with AcOEt / IPE (=1 / 1, 30 mL) to obtain the target compound (3.48 g).

[0464] Refer to Example 171. 6-(1-Cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine synthesis

[0465] TFA (1.5 mL) was added to a 15 mL solution of 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (619 mg) in DCM at room temperature. The mixture was stirred for 2 h. The reaction mixture was concentrated and co-evaporated with toluene. The residue was purified by basic silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (435 mg).

[0466] Refer to Example 172. 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1- Synthesis of tert-butyl formate

[0467] A mixture of cyclopropyl bromide (1.2 mL), 4-(6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (734 mg), and Cs₂CO₃ (1947 mg) in DMF (10 mL) was stirred for 1 h at 180 °C in a microwave oven. The reaction mixture was diluted with H₂O and extracted with AcOEt. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (440 mg).

[0468] Refer to Example 173. 4-(6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid tert-butyl Ester Synthesis

[0469] p-Toluenesulfonic acid monohydrate (1053 mg) was added to a MeOH (50 mL) suspension of 1253 mg of 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (1253 mg). The mixture was stirred for 3 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was concentrated. The residue was ground with IPE (10 mL) to obtain the target compound (889 mg).

[0470] Refer to Example 174. Racemic 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- Synthesis of tert-butyl pyrimidin-3-yl)piperidine-1-carboxylate

[0471] At 80 °C and under nitrogen atmosphere, racemic 4-(6-((((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (1.5 g), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (1.667 g), and PdCl2 (dppf) were added. A mixture of DCM (0.136 g) and K3PO4 (2.121 g) in DME / H2O (9 / 1) (40 mL) was stirred for 4 h. The mixture was diluted with H2O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1.383 g).

[0472] Refer to Example 175. (3aR,6aS)-5-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)hexahydro-1H- Synthesis of furano[3,4-c]pyrrole

[0473] TFA (1 mL) was added to a DCM (10 mL) solution of 310 mg of 4-(6-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (310 mg) at 0 °C. The mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated. The residue was purified by alkaline silica gel chromatography (MeOH / DCM) to obtain the target compound (230 mg).

[0474] Refer to Example 176. 4-(6-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)pyrazolo Synthesis of [1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0475] 5% wet Pd / C (NX type) (232 mg) was added to a solution of tert-butyl 4-(6-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (518 mg) in EtOH (20 mL). The mixture was stirred under hydrogen at 60 °C for 3.5 h. The reaction mixture was allowed to cool to room temperature and filtered through a Celite filter and concentrated. The residue was purified by silica gel chromatography (heptane / AcOE) to obtain the target compound (310 mg).

[0476] Refer to Example 177. 4-(6-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)pyrazolo Synthesis of tert-butyl [1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0477] A mixture of (3aR,6aS)-5-(3-chloropyrazolo[1,5-a]pyridin-6-yl)hexahydro-1H-furano[3,4-c]pyrrole (389 mg), 6-dihydro-2H-pyridin-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (912 mg), Pd(OAc)2 (33.1 mg), SPhos (121 mg), and K3PO4 (939 mg) in DME / H2O (10:1) (22 mL) was stirred overnight at 90 °C under argon atmosphere. After cooling to room temperature, H2O and AcOEt were added to the reaction mixture. The mixture was filtered through a Celite filter. The organic layer was washed with brine and concentrated. The residue was purified by silica gel chromatography (heptane / AcOEt) to obtain the target compound (518 mg).

[0478] Refer to Example 178. (3aR,6aS)-5-(3-chloropyrazolo[1,5-a]pyridin-6-yl)hexahydro-1H-furano[3, Synthesis of 4-c]pyrrole

[0479] A mixture of cis-hexahydro-1H-furano[3,4-c]pyrrole (528 mg), 3-chloro-6-bromo-pyrazolo[1,5-a]pyridine (900 mg), Pd(OAc)₂ (52.4 mg), BINAP (218 mg), and Cs₂CO₃ (6.334 g) in toluene (20 mL) was stirred for 7 h at 100 °C under Ar atmosphere. After cooling to room temperature, H₂O and AcOEt were added to the reaction mixture. The organic layer was washed with brine and concentrated. The residue was purified by alkaline silica gel chromatography (heptane / AcOEt) to obtain the target compound (389 mg).

[0480] Refer to Example 180. 4-(6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine- Synthesis of 1-Cyclopropyl Formate

[0481] TFA (0.8 mL) was added to a DCM (12 mL) solution of 400 mg of 4-(6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (400 mg) at 0 °C. The mixture was stirred for 5 h at room temperature. The mixture was concentrated and co-evaporated with toluene to obtain an intermediate (TFA salt). TEA (0.743 mL) and cyclopropyl(4-nitrophenyl) carbonate (238 mg) were added to a DCM (12 mL) solution of the intermediate at room temperature. The mixture was stirred for 3 h. The mixture was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (364 mg).

[0482] Refer to Example 183. 6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3-(piperidin-4-yl)pyrazolo[1,5- a] Synthesis of pyridine

[0483] TFA (2 mL) was added to a DCM (10 mL) solution of 517 mg of 4-(6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (517 mg) at 0 °C. The mixture was stirred for 2 h at room temperature. After cooling to 0 °C, a 5 mol / L aqueous solution of NaOH was added. The aqueous layer was extracted with DCM. The organic layer was concentrated to obtain the target compound (414 mg).

[0484] Refer to Example 184. 4-(6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridine-3- Synthesis of tert-butyl piperidine-1-carboxylate

[0485] 5% Pd / C (304 mg) was added to a solution of 4-(6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (704 mg) in EtOH / DCM (1:1) (30 mL). The mixture was stirred at 40 °C for 1.5 h. After cooling, the reaction mixture was filtered through a Celite filter. The filtrate was concentrated. The residue was purified by alkaline silica gel chromatography (heptane / AcOEt) to obtain the target compound (517 mg).

[0486] Refer to Example 185. 4-(6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridine-3- Synthesis of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate

[0487] A mixture of 3-chloro-6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridine (509 mg), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (1110 mg), Pd(OAc)2 (20.14 mg), SPhos (73.7 mg), and K3PO4 (1142 mg) in DME / H2O (10:1) (20 mL) was stirred overnight at 90 °C under argon atmosphere. After cooling to room temperature, H2O and AcOEt were added. The mixture was filtered through a Celite filter. The organic layer was washed with brine and concentrated. The residue was purified twice by silica gel chromatography (first: basic silica gel, heptane / AcOEt; second: diol silica gel, heptane / AcOEt) to obtain the target compound (704 mg).

[0488] Referring to Example 186. 3-Chloro-6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridine synthesis

[0489] A mixture of 6,6-difluoro-2-azaspiro[3.3]heptane trifluoroacetate (0.927 g), 3-chloro-6-bromo-pyrazolo[1,5-a]pyridine (0.579 g), Pd(OAc)₂ (0.034 g), BINAP (0.140 g), and Cs₂CO₃ (3.67 g) in toluene (10 mL) was stirred for 24 h at 100 °C under argon atmosphere. After cooling, H₂O and AcOEt were added at room temperature. The mixture was filtered through a Celite filter. The organic layer was washed with brine and concentrated. The residue was purified by silica gel chromatography (heptane / AcOEt) to obtain the target compound (509 mg).

[0490] Refer to Example 194. Synthesis of tert-butyl 6-(5-bromothiazolyl-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[0491] At room temperature, under nitrogen atmosphere, DIPEA (1.5 mL) and 1,1-dimethyl ethyl 2,6-diazaspiro[3.3]heptane-2-carboxylic acid (978.7 mg) were added to a DMSO (15 mL) solution of 1,0684 g of 2,5-dibromothiazole. The mixture was stirred overnight under nitrogen atmosphere at 70 °C. AcOEt and H2O were added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (1.2328 g).

[0492] Refer to Example 213. Synthesis of 5-(pyrazolo[1,5-a]pyridin-6-yl)-1,2,4-thiadiazole

[0493] 6-bromopyrazolo[1,5-a]pyridine (500 mg), bis(pinacol)diboron (967 mg), potassium acetate (747 mg), and PdCl2 (dppf) were added at 100 °C under N2. DCM (104 mg) in 1,4-di The mixture in alkyl (10 ml) was stirred for 2 h. The mixture was diluted with AcOE and filtered. The filtrate was concentrated to give the intermediate borate ester. The intermediate borate ester, Pd(OAc)2 (57.0 mg), xantphos (147 mg), K2CO3 (701 mg), and 5-bromo-1,2,4-thiadiazole (279 μl) were stirred in alkyl (1,4-di) at 100 °C under nitrogen atmosphere. The mixture in hexane / H2O (10 ml) (9 / 1) was stirred for 2 h. AcOEt and Na2SO4 were added to the mixture. The mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (352 mg).

[0494] Refer to Example 216. Synthesis of 5-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)thiazole

[0495] TFA (1.5 mL) was added to a solution of 411 mg tert-butyl piperidine-1-carboxylate (411 mg) in DCM (12 mL) at 0 °C. The mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated and co-evaporated with DCM. The residue was cooled to 0 °C, alkalized by adding 1 mol / L NaOH aqueous solution, and extracted with DCM. The organic layer was concentrated and purified by alkaline silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (180 mg).

[0496] Refer to Example 217. 4-(6-(thiazolyl-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester synthesis

[0497] At 100 °C and under nitrogen atmosphere, tert-butyl 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (0.475 g), 5-bromo-1,3-thiazole (0.119 mL), Pd(OAc)2 (0.012 g), Xantphos (0.032 g), and K2CO3 (0.460 g) were subjected to a nitrogen atmosphere in a nitrogen atmosphere. The mixture in hexane / H₂O (6 / 1) (10 ml) was stirred for 2 h. The reaction mixture was diluted with AcOEt. Na₂SO₄ was added to the mixture. The mixture was filtered through a diatomaceous earth filter and washed with AcOEt. The filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (411 mg).

[0498] Refer to Example 222. 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylic acid tert-butyl ester synthesis

[0499] [Chemical Formula 33]

[0500] Step 1: Synthesis of 6-bromo-3-chloropyrazolo[1,5-a]pyridine.

[0501] A suspension of 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (5.0 g), N-chlorosuccinimide (4.2 g), and NaHCO3 (7.0 g) in DMF (70 mL) was stirred for 4 hours at 50 °C. The reaction was allowed to partition between AcOEt and brine. The organic layer was concentrated under vacuum to give the desired product (4.9 g), which was used in the next step without further purification.

[0502] 1 H NMR (400 MHz, DMSO-d6): 9.15 (dd, J = 1.6, 0.9 Hz, 1H), 8.20 (s,1H), 7.64 (dd, J = 9.4, 0.9 Hz, 1H), 7.48 (dd, J = 9.4, 1.6 Hz, 1H).

[0503] Step 2: Synthesis of 4-{3-chloropyrazolo[1,5-a]pyridin-6-yl}morpholine.

[0504] A suspension of 6-bromo-3-chloropyrazolo[1,5-a]pyridine (1.0 g), morpholine (0.38 mL), Pd2dba3 (210 mg), sodium tert-butoxide (630 mg), and DavePhos (130 mg) in toluene (20 mL) was stirred for 4 hours at 90 °C. Morpholine (0.1 mL) and Pd2dba3 (100 mg) were then added, and stirring was maintained overnight at the same temperature. The reaction mixture was filtered through a Celite filter, and the residue was partitioned between AcOEt and water. The organic layer was concentrated under vacuum, and the residue was recrystallized from acetone to give the desired product (522 mg).

[0505] LCMS: [M+H] + = 238

[0506] Step 3: Synthesis of tert-butyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid.

[0507] 4-{3-chloropyrazolo[1,5-a]pyridin-6-yl}morpholine (42 mg), {1-[(tert-butoxy)carbonyl]-1,2,3,6-tetrahydropyridin-4-yl}boronic acid (60 mg), Pd(OAc)2 (2 mg), SPhos (7 mg), and K3PO4 (75 mg) were mixed under reflux in a two-phase flow system. The suspension in alkyl (5 mL) and water (0.25 mL) was stirred for 4 hours. The reaction mixture was filtered through Celite. The filtrate was partitioned between AcOEt and water. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, AcOEt:MeOH) to give 40 mg of the desired product.

[0508] LCMS: [M+H] + = 385

[0509] Step 4: Synthesis of tert-butyl 4-[6-(morpholino-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate.

[0510] A suspension of 4-[6-(morpholino-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (40 mg) and Pd / C (10%, 20 mg) in THF (1 mL) and MeOH (1 mL) was stirred for 6 hours at room temperature under H2. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt) to give 5 mg of the desired product.

[0511] LCMS: [M+H] + = 387.

[0512] Refer to Example 224. Synthesis of 4-(3-chloropyrazolo[1,5-a]pyridin-6-yl)morpholine

[0513] At room temperature and under nitrogen, Pd2(dba)3 (115.9 mg), BrettPhos (199.2 mg), NaOtBu (377.3 mg), and morpholine (253 μL) were added to a toluene (20 mL) solution of 6-bromo-3-chloropyrazolo[1,5-a]pyridine (562.2 mg). The mixture was refluxed for 3 h 35 min. H2O and AcOEt were added at room temperature. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (317.8 mg).

[0514] Refer to Example 235. Synthesis of tert-butyl 4-(6-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate.

[0515] At room temperature, under argon, Pd(OAc)₂ (7.48 mg) and cataCXium(R) (23.88 mg) were added to a solution of 4-(6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (75 mg), potassium cyclopropyltrifluoroborate (49.3 mg), and Cs₂CO₃ (163 mg) in toluene / H₂O (10:1) (5 mL). The mixture was stirred at 130 °C under argon for 2 h. H₂O was added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (heptane / AcOEt) to obtain the target compound (43 mg).

[0516] Referring to Example 242. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine become

[0517] At room temperature, under nitrogen atmosphere, 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (635.7 mg) and 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (2.7 g) were reacted in a nitrogen atmosphere. Pd(OAc)₂ (123.9 mg), SPhos (490.2 mg), and K₃PO₄ (3.9 g) were added to a suspension in hexane / H₂O (33 mL) (10 / 1). The mixture was refluxed overnight under nitrogen. H₂O and AcOEt were added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the intermediate compound (1.2291 g). Pd / C (1.27 g) (10%, NX type, wetted with water) was added to a solution of the intermediate compound in EtOH (100 mL) at room temperature. The mixture was stirred under hydrogen at 50 °C for 2.5 h. The mixture was filtered through Celite and the filtrate was concentrated to obtain the intermediate compound. TFA (4 mL) was added to a solution of the intermediate compound in DCM (20 mL) at room temperature. The mixture was stirred at room temperature for 8 h 20 min. The mixture was concentrated. The residue was treated with 1 N NaOH aqueous solution. The mixture was extracted with AcOEt and DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (AcOEt / MeOH) to obtain the target compound (295.6 mg).

[0518] Refer to Example 244. 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-3,6-dihydro Synthesis of tert-butyl pyridine-1(2H)-formate

[0519] At room temperature, under nitrogen atmosphere, 6-bromo-3-iodopyrazolo[1,5-a]pyridine (1.2042 g) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1960 g) were reacted in a two-phase reaction. K3PO4 (1.24 g) and Pd(PPh3)4 (216 mg) were added to a solution in hexane / H2O (22 mL) (10 / 1). The mixture was stirred for 5 h 20 min at 50 °C to 100 °C. H2O and AcOEt were added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel and alkaline silica gel column chromatography (hexane / AcOEt) to obtain an intermediate compound (243.2 mg). The intermediate (243.2 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole (400.5 mg) were added to a solution in hexane / H2O (22 mL) (10 / 1). K3PO4 (798.6 mg) and PdCl2 (dppf) were added to a solution of alkane / H2O (11 mL) (10 / 1). DCM (45 mg). The mixture was refluxed for 4 h. H2O and AcOEt were added at room temperature. The mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) and alkaline silica gel chromatography (hexane / AcOEt) to obtain the target compound (113.3 mg).

[0520] The compounds in the reference examples were prepared in the same manner as any of the reference examples above. The structural formulas and physicochemical data of the compounds in Reference Examples 1 to 244 are shown in the table below.

[0521] [Table 2-1]

[0522] [Table 2-2]

[0523] [Table 2-3]

[0524] [Table 2-4]

[0525] [Table 2-5]

[0526] [Table 2-6]

[0527] [Table 2-7]

[0528] [Table 2-8]

[0529] [Table 2-9]

[0530] [Table 2-10]

[0531] [Table 2-11]

[0532] [Table 2-12]

[0533] [Table 2-13]

[0534] [Table 2-14]

[0535] [Table 2-15]

[0536] [Table 2-16]

[0537] [Table 2-17]

[0538] [Table 2-18]

[0539] [Table 2-19]

[0540] [Table 2-20]

[0541] [Table 2-21]

[0542] [Table 2-22]

[0543] [Table 2-23]

[0544] [Table 2-24]

[0545] [Table 2-25]

[0546] [Table 2-26]

[0547] [Table 2-27]

[0548] [Table 2-28]

[0549] [Table 2-29]

[0550] [Table 2-30]

[0551] [Table 2-31]

[0552] [Table 2-32]

[0553] [Table 2-33]

[0554] [Table 2-34]

[0555] Example

[0556] Example 3. 4-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid 4-Azazole methyl ester synthesis

[0557] 5-Methoxy-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (28.3 mg) / THF (2 mL) was prepared in a flask. 4-Nitrophenyl ( (48.5 mg) azole-4-ylmethyl carbonate. DIPEA (64.1 μL) was added to the mixture at 0 °C. The mixture was stirred for 3 h at room temperature. H₂O was added to the reaction mixture at 0 °C to stop the reaction. The mixture was extracted three times with DCM. The organic layer was collected and then evaporated to obtain the crude product. The crude material was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (40.8 mg).

[0558] Example 7. 4-(6-((1-(difluoromethyl)cyclopropyl)methoxy)pyrazolo[1,5-a]pyridin-3-yl)piperazine 1-Pyridine-carboxylic acid Synthesis of 4-azolyl methyl ester

[0559] TFA (954 μL) was added to a solution of 87 mg of tert-butyl piperidine-1-carboxylate (87 mg) in DCM (2 mL) at room temperature. The mixture was stirred for 1 h. The mixture was then concentrated.

[0560] Add TEA (288 μL) and 4-nitrophenyl (4-nitrophenyl) to a 2 mL solution of the residue at room temperature. (Azolium-4-ylmethyl)carbonate (65.4 mg). The mixture was stirred for 3 h at room temperature. The mixture was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (67 mg).

[0561] Example 47. 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid Synthesis of 4-azolyl methyl ester

[0562] A mixture of 6-(2-methoxyethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (30.8 mg) in a flask. 4-Nitrophenyl ( (44.3 mg) azole-4-ylmethyl carbonate. DIPEA (58.6 μl) was added to the mixture at 0 °C. The mixture was stirred for 3 h under nitrogen at room temperature. H₂O was added to the reaction mixture at 0 °C to stop the reaction. The mixture was extracted three times with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane: AcOEt) to obtain the target compound (38.8 mg).

[0563] Example 50. 1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)-3-(p-tolyl) Synthesis of oxyacetone

[0564] At room temperature, under nitrogen atmosphere, 3-(p-tolyl) Oxygen A mixture of propionic acid (18 mg), 6-methoxy-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (25 mg), HOBt hydrate (22.95 mg), and TEA (41.8 μl) in DMF (1.5 ml) was stirred for 3 hours. H2O was added to the reaction mixture at 0 °C. The mixture was extracted with DCM, and the organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (31.4 mg).

[0565] Example 51. 4-(6-Cyclopropoxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid Azoxyl-4-methyl Ester Synthesis

[0566] At room temperature, TFA (0.5 ml) was added to a solution of 4-(6-cyclopropyloxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (40 mg) in DCM (1.5 ml). The mixture was stirred at room temperature for 3 h. The mixture was concentrated to obtain a crude amine. TEA (0.156 ml) and 4-nitrophenyl ( (35.5 mg) azole-4-ylmethyl carbonate. The mixture was stirred for 18 h at room temperature. The mixture was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (38 mg).

[0567] Example 52. 4-(6-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1- Formic acid Synthesis of 4-azolyl methyl ester

[0568] TFA (1 ml) was added to a DCM (10 ml) solution of 83.5 mg of 4-(6-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester (83.5 mg) under RT. The mixture was stirred for 2 h at room temperature and then evaporated to obtain the intermediate compound TFA salt. TEA (0.3 ml) and 4-nitrophenyl ( (Azolium-4-ylmethyl) carbonate (73.9 mg). The mixture was stirred under nitrogen at room temperature for 2.5 h. AcOEt and H2O were added at room temperature. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt to AcOEt / MeOH) to obtain the target compound (35 mg).

[0569] Example 54. 4-(6-(2-morpholinylethyl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid thiazole- Synthesis of 4-methyl methyl ester

[0570] A mixture of 4-(6-(2-morpholinylethyl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester (195 mg) and 10% Pd / C (170 mg) in AcOEt / EtOH (1 / 1) (10 mL) was stirred for 1 h at 50 °C under hydrogen atmosphere. The reaction mixture was filtered through Celite. The filtrate was concentrated to obtain the intermediate compound. A solution of the intermediate compound, TEA (121 μL), and 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (139 mg) in DCM (10 mL) was stirred for 3 days at room temperature. The mixture was concentrated. The residue was purified by basic silica gel column chromatography (hexane / AcOEt) to obtain the target compound (108 mg).

[0571] Example 55. 1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)-2-((2-methyl) Synthesis of benzyl(oxy)ethyl-1-one

[0572] A mixture of 2-methylbenzyl alcohol (45.02 mg) and NaH (12.86 mg) in DMF (1.5 mL) was slightly sonicated and then stirred at room temperature for several hours. A solution of 2-chloro-1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)ethyl-1-one (37.8 mg) in DMF (0.5 mL) was added to the mixture at 0 °C. The mixture was stirred under nitrogen at room temperature. Then, sodium iodide (9.20 mg) was added to the mixture. The mixture was stirred overnight under nitrogen at 60 °C. A saturated aqueous solution of NH4Cl was added to the mixture at 0 °C. The mixture was extracted with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (18.1 mg).

[0573] Example 56. 4-(6-(2-morpholino-2-oxoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-methyl Synthesis of thiazolyl-4-methyl ester

[0574] HATU (36.9 mg), DIPEA (26.1 μl, 0.149 mmol), and morpholine (13.03 μl, 0.149 mmol) were added to a DMF (2 ml) solution of 30 mg of 2-(3-(1-((thiazol-4-ylmethoxy)carbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (30 mg) at room temperature. The mixture was stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO3 solution and H2O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography to obtain the target compound (13 mg).

[0575] Example 57. 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid thiocarboxylic acid Synthesis of 4-azolyl methyl ester

[0576] Under RT and nitrogen atmosphere, TEA (125 μL) and 4-nitrophenyl(thiazol-4-yl)pyrazolo[1,5-a]pyrimidine (82.5 mg) were added to a DCM (10 mL) solution. The mixture was stirred for 3.5 h under nitrogen atmosphere at room temperature. H2O was added at room temperature. The aqueous layer was extracted with AcOEt. The organic layer was concentrated. The residue was purified by amino silica gel column chromatography (hexane / AcOEt). The obtained product was milled in IPE at room temperature (a solid appeared). The solid was collected to obtain the target compound (92.1 mg).

[0577] Example 65. 4-(6-(morpholinylmethyl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid azole-4- Synthesis of methyl ester hydrochloride

[0578] Add DIPEA (36 μL) and 4-nitrophenyl to a THF (3 mL) solution of 4-((3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)methyl)morpholine (41 mg) Azoxyl-4-ylmethyl) carbonate (54 mg) was added, and the mixture was stirred for 30 min at room temperature. A saturated aqueous solution of NaHCO3 and AcOEt were added to the mixture. The organic layer was separated using a phase separator (Whatman, 1 PS filter paper) and the solvent was removed. The residue was purified by amino silica gel column chromatography (heptane:AcOEt). The obtained product was dissolved in AcOEt (3 mL), and 4 N HCl / AcOEt (22 μL) was added to the mixture. The reaction mixture was stirred for 30 min at room temperature. The precipitate was collected on a filter to obtain the target compound (20 mg).

[0579] Example 67. 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid Synthesis of 4-azolyl methyl ester

[0580] Add DIPEA (33 μL) and 4-nitrophenyl to a THF (3 mL) solution of 6-(2,2-difluoroethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (35 mg). (49 mg) azole-4-ylmethyl carbonate was added, and the mixture was stirred for 30 min at room temperature. A saturated aqueous solution of NaHCO3 and AcOEt were added to the mixture. The organic layer was separated using a phase separator (Whatman, 1 PS filter paper) and the solvent was removed. The residue was purified by alkaline silica gel column chromatography (heptane / AcOEt). The obtained solid was washed with diisopropyl ether and then collected on a filter to obtain the target compound (36 mg).

[0581] Example 68. 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-carboxylic acid thiocarboxylic acid Synthesis of 4-azolyl methyl ester

[0582] DIPEA (33 μL) and 4-nitrophenyl(thiazol-4-yl)pyrazolo[1,5-a]pyridine (35 mg) were added to a THF (3 mL) solution and stirred for 30 min at room temperature. A saturated aqueous solution of NaHCO3 and AcOEt were added to the mixture. The organic layer was separated using a phase separator (Whatman, 1 PS filter paper) and the solvent was removed. The residue was purified by alkaline silica gel column chromatography (heptane / AcOEt). The obtained solid was washed with diisopropyl ether and collected on a filter to obtain the target compound (43 mg).

[0583] Example 76. 4-(6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3- Piperidine-1-carboxylic acid Synthesis of 4-azolyl methyl ester

[0584] At room temperature, TEA (66.3 μL) and 4-nitrophenyl (4-nitrophenyl) were added to a DCM (5 mL) solution of 6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine (80 mg). Azolium-4-ylmethyl)carbonate (75 mg). The mixture was stirred for 3 h. The mixture was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (100 mg).

[0585] Example 82. (4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1- Synthesis of (3,3-difluoroazacyclobutane-1-yl) methyl ketone

[0586] DIPEA (80 μL) was added to a mixture of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (35 mg) and 4-nitrobenzene 3,3-difluorozacyclobutane-1-carboxylic acid (38.2 mg) in THF (2.5 mL). The mixture was stirred overnight under reflux at nitrogen. H₂O was added to the reaction mixture at 0 °C to stop the reaction. The mixture was extracted with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (44 mg).

[0587] Example 85. 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1- Formic acid Synthesis of 4-azole esters

[0588] Add 4-nitrophenyl to a DCM (5 ml) solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (50 mg) under RT. (47.3 mg) azole-4-ylmethyl carbonate. The mixture was stirred for 3 h. The mixture was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) and silica gel column chromatography (AcOEt / MeOH), and ground with hexane / AcOEt to obtain the target compound (46 mg).

[0589] Example 93. 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1- Synthesis of cyclopropyl formate

[0590] At room temperature, TEA (58.8 μl) and cyclopropyl (4-nitrophenyl) carbonate (56.4 mg) were added to a DCM (4 mL) solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine (65 mg). The mixture was stirred for 3 h. The mixture was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (60 mg).

[0591] Example 94. 4-(6-(tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)pyrazolo[1,5-a]pyridine- Synthesis of cyclopropyl 3-yl)piperidine-1-carboxylate

[0592] DIPEA (58.7 μl) and cyclopropyl (4-nitrophenyl) carbonate (75 mg) were added to a THF (5 mL) solution of 4-(6-((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate (70 mg). The mixture was stirred overnight at room temperature. A saturated aqueous solution of NaHCO3 was added. The reaction mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by alkaline silica gel chromatography (heptane / AcOEt / MeOH). The obtained solid was ground in IPE (5 mL). The solid was collected to obtain the target compound (53 mg).

[0593] Example 95. 4-(6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]) (azin-2-yl)pyrazolo[1,5-a] Synthesis of cyclopropyl pyrimidin-3-yl)piperidine-1-carboxylate

[0594] At 80°C and under nitrogen atmosphere, 173 mg of cyclopropyl 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid and 2-bromo-5,6-dihydro-8H-imidazo[2,1-c][1,4] were... Azine (50 mg), Pd(OAc)2 (15 mg), Xantphos (50 mg), and K2CO3 (180 mg) were used in a two-phase reaction. The mixture in alkane / H2O (6 / 1) (5 mL) was stirred for 3 h. The mixture was diluted with AcOEt. Na2SO4 was added to the mixture. The mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by column chromatography to obtain the target compound (10 mg).

[0595] Example 102. 4-(6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)pyrazolo[1,5-a]pyridine-3- Synthesis of 4-yl thiazolyl-1-piperidine-1-carboxylic acid ester

[0596] A mixture of 6-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine (50 mg) in THF (1.5 mL) was prepared in a flask. 4-Nitrophenyl(thiazol-4-ylmethyl) carbonate (54.8 mg) was added to the mixture at 0 °C. DIPEA (52.5 μL) was added to the mixture at 0 °C. The mixture was stirred under nitrogen at room temperature for 3 h. H₂O was added to the reaction mixture at 0 °C to stop the reaction. The mixture was extracted three times with DCM. The organic layer was collected and then evaporated to obtain the crude product. The crude product was purified by alkaline silica gel column chromatography (hexane / AcOEt) to obtain the target compound (65.1 mg).

[0597] Example 110. 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1- Synthesis of cyclopropyl formate

[0598] TFA (0.5 mL) was added to a DCM (5 mL) solution of 72 mg of 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (72 mg) at room temperature. The mixture was stirred for 3 h. The mixture was concentrated. The residue was co-evaporated with toluene (3 times) and dried under vacuum to give an intermediate. TEA (0.148 mL) and cyclopropyl(4-nitrophenyl) carbonate (51.3 mg) were added to a DCM (4 mL) solution of the intermediate at room temperature. The mixture was stirred for 3 h. The mixture was diluted with H2O and extracted with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOE) to obtain the target compound (65 mg).

[0599] Example 112. 4-(6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrazolo[1,5-a]pyridin-3-yl) Synthesis of piperidine-1-carboxylic acid cyclopropyl ester

[0600] DIPEA (71 μL) and cyclopropyl (4-nitrophenyl) carbonate (79 mg) were added to a THF (5 mL) solution of 6-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)-2-oxa-6-azaspiro[3.3]heptane (81 mg), and the mixture was stirred at room temperature for 5 h. A saturated aqueous solution of NaHCO3 and AcOEt were added to the mixture. The organic layer was separated by a phase separator (Whatman, 1 PS filter paper) and the solvent was removed. The crude product obtained was purified by alkaline silica gel column chromatography (heptane:AcOEt). The product was milled with IPE and collected on a filter to obtain the target compound (65 mg).

[0601] Example 113. 4-(6-(thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid (1-methyl) Synthesis of cyclopropyl methyl ester

[0602] 4-(6-(thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidin-1-carboxylic acid 4-nitrobenzene ester (70 mg) was placed in a flask. DMF (1 mL) was added to the flask to prepare a mixture. (1-methylcyclopropyl)methanol (25.2 μL) was added to the mixture at room temperature. KOtBu (26.2 mg) was added to the mixture at 0 °C. The mixture was then stirred for 3 h at room temperature under nitrogen. The flask was cooled at 0 °C, and H2O was added to the reaction mixture. The mixture was extracted with AcOEt. The combined organic layers were concentrated. The residue was purified by basic silica gel column chromatography (hexane:AcOEt:MeOH) to obtain the target compound (13.9 mg).

[0603] Example 117. 4-(6-(thiazol-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylic acid thiazol-4- Synthesis of methyl ester

[0604] TEA (58.6 μL) and 4-nitrophenyl(thiazol-4-ylmethyl) carbonate (70.7 mg) were added to a DCM (4 mL) solution of 60 mg of 5-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)thiazole (4 mL) at room temperature. The mixture was stirred for 3 h. The mixture was diluted with H2O and extracted with DCM. The organic layer was concentrated. The residue was purified by alkaline silica gel column chromatography (hexane / AcOEt) and ground with AcOEt to obtain the target compound (74 mg).

[0605] Example 138. 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-methyl Synthesis of 1-fluoro-2-methylprop-2-yl ester

[0606] Under RT and nitrogen atmosphere, 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine (98 mg) and TEA (242 μl) were added to a DCM (20 ml) solution of 1-(((1-fluoro-2-methylprop-2-yl)oxy)carbonyl)-3-methyl-1H-imidazol-3-onium iodide (244.1 mg). The mixture was stirred for 1 h 5 min at room temperature. H2O was added under RT. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4. The mixture was filtered and concentrated to give a crude product, which was purified by silica gel chromatography (hexane / AcOEt). The product was milled in IPE to obtain the target compound (75.1 mg).

[0607] Example 143. 4-{3-[1-(5-methyl-1,2,4- [diazol-3-yl)piperidin-4-yl]pyrazolo[1,5-a] Synthesis of pyridin-6-ylmorpholine.

[0608] [Chemical Formula 34]

[0609] At room temperature, tert-butyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate (909 mg) was dissolved in 4 N HCl in diethyl ether. Neutralize dialkyl (5 mL) The solution in alkane (5 mL) was stirred for 4 h. The reactants were concentrated to obtain an intermediate compound (910 mg). The intermediate compound (100 mg), 3-chloro-5-methyl-1,2,4- A solution of diazole (70 mg) and TEA (0.16 mL) in EtOH (1 mL) was stirred overnight. The reaction mixture was then partitioned between DCM and water. The organic layer was separated and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / AcOEt) to obtain the target compound (25 mg).

[0610] Example 144. 4-{3-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]pyrazolo[1,5-a]pyridin-6-yl} Synthesis of morpholine

[0611] [Chemical Formula 35]

[0612] A solution of 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride (100 mg), 2-chloro-5-ethylpyrimidine (48 mg), and triethylamine (0.16 mL) in EtOH (1 mL) was stirred overnight at 80 °C. The reaction mixture was then partitioned between DCM and water. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (25 mg).

[0613] LCMS: [M+H] + = 393.

[0614] Example 145. 4-[6-(morpholino-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidin-1-carboxylic acid (1,3-thiazolinone) Synthesis of (4-yl)-azolyl methyl ester

[0615] [Chemical Formula 36]

[0616] A solution of (1,3-thiazolyl-4-yl)methanol (32 mg), 4-nitrophenyl chloroformate (60 mg), and triethylamine (0.12 mL) in DCM (3 mL) was stirred for 2 hours at room temperature. Then, a solution of 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholinodihydrochloride (100 mg) and triethylamine (0.12 mL) in DCM (2 mL) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was partitioned between DCM and NaHCO3. The organic phase was washed with NaHCO3 and then concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (67 mg).

[0617] LCMS: [M+H] + = 393.

[0618] Example 146. 4-[6-(morpholino-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidin-1-carboxylic acid 1,1,1-tris Synthesis of fluoro-2-methylpropyl-2-yl ester

[0619] [Chemical Formula 37]

[0620] Step 1: Synthesis of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropyl-2-yl carbonate.

[0621] 4-Nitrophenyl chloroformate (1.9 g) was added to a solution of 1,1,1-trifluoro-2-methylprop-2-ol (1.0 g) and pyridine (1.3 mL) in DCM (20 mL), and the solution was stirred overnight at room temperature. The reaction was quenched with 1 M HCl and extracted with DCM. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, DCM: petroleum ether) to give the desired product (1.1 g).

[0622] 1 H NMR (400 MHz, DMSO-d6): 8.38-8.28 (m, 2H), 7.67-7.58 (m, 2H), 1.75 (s, 6H).

[0623] Step 2: Synthesis of 1,1,1-trifluoro-2-methylpropyl-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidin-1-carboxylic acid.

[0624] A solution of 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride (100 mg), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropyl-2-yl carbonate (82 mg), and triethylamine (0.16 mL) in DCM (3 mL) was stirred overnight at room temperature. The reaction mixture was then partitioned between DCM and NaHCO3. The organic phase was washed with NaHCO3 and then concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (65 mg).

[0625] LCMS: [M+H] + = 441.

[0626] Example 147. 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidin-1-carboxylic acid 1-fluoro-2- Synthesis of methylpropyl-2-yl ester

[0627] [Chemical Formula 38]

[0628] Step 1: Synthesis of 1-fluoro-2-methylpropyl-2-yl-4-nitrophenyl carbonate.

[0629] 4-Nitrophenyl chloroformate (654 mg) was added to a solution of 1-fluoro-2-methylprop-2-ol (250 mg) and pyridine (0.44 mL) in DCM (10 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between DCM and 1 M HCl, and the organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, DCM: petroleum ether) to give the desired product (202 mg).

[0630] 1 H NMR (400 MHz, DMSO-d6): 8.36-8.26 (m, 2H), 7.63-7.50 (m, 2H), 4.62 (s, 1H), 4.51 (s, 1H), 1.51 (d, J = 2.3 Hz, 6H).

[0631] Step 2: Synthesis of 1-fluoro-2-methylpropyl-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylic acid.

[0632] A solution of 1-fluoro-2-methylpropyl-2-yl-nitrophenyl carbonate (72 mg), 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride (100 mg) and triethylamine (0.16 mL) in DCM (3 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between DCM and NaHCO3, and the organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (53 mg).

[0633] LCMS: [M+H] + = 405.

[0634] Example 148. 4-{3-[1-(3-cyclopropyl-1,2,4- diazol-5-yl)piperidin-4-yl]pyrazolo[1,5-] Synthesis of pyridin-6-ylmorpholine

[0635] [Chemical Formula 39]

[0636] At 80°C, 100 mg of 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride and 5-chloro-3-cyclopropyl-1,2,4- A solution of diazole (48 mg) and triethylamine (0.16 mL) in EtOH (1 mL) was stirred overnight. The reaction mixture was partitioned between DCM and water, and the organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (23 mg).

[0637] LCMS: [M+H] + = 395.

[0638] Example 149. 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine-1-carboxylic acid 1,1,1-trifluoro-2- Synthesis of methylpropyl-2-yl ester

[0639] [Chemical Formula 40]

[0640] Step 1: Synthesis of tert-butyl 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}-1,2,3,6-tetrahydropyridine-1-carboxylate.

[0641] A suspension of 3-bromo-6-methoxypyrazolo[1,5-a]pyridine (600 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (860 mg), Pd(PPh3)4 (153 mg), and 1 M Na2CO3 (5.3 mL) in DME (17 mL) was stirred for 2 hours under reflux. The reaction mixture was partitioned between AcOEt and water, and the organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (744 mg).

[0642] LCMS: [M+H] + = 330.

[0643] Step 2: Synthesis of tert-butyl 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine-1-carboxylate.

[0644] At room temperature, a mixture of 700 mg of 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester and 150 mg of PtO2 in an AcOEt (12 mL) was stirred overnight under H2. The reaction mixture was filtered through a Celite filter and the solvent was removed under vacuum to give the desired product (618 mg).

[0645] LCMS: [M-tBu] + = 276.

[0646] Step 3: Synthesis of 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine hydrochloride.

[0647] In the second 4 M HCl (6 mL) in alkyl groups was added to tert-butyl 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine-1-carboxylate (618 mg) The mixture was placed in a 6 mL solution of alkane and stirred for 4 hours at room temperature. The reactants were then concentrated under vacuum to give the desired product (520 mg).

[0648] LCMS: [M+H] + = 232

[0649] Step 4: Synthesis of 1,1,1-trifluoro-2-methylpropyl-2-yl 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine-1-carboxylic acid.

[0650] A solution of 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine hydrochloride (100 mg), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropyl-2-yl carbonate (121 mg), and triethylamine (0.2 mL) in DCM (2 mL) was stirred overnight at room temperature. The reaction mixture was then partitioned between DCM and NaHCO3. The organic phase was washed with NaHCO3 and then concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (42 mg).

[0651] LCMS: [M+H] + = 386.

[0652] Example 150. 1-Fluoro-2-methyl 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine-1-carboxylic acid Synthesis of propionic 2-methyl ester

[0653] [Chemical Formula 41]

[0654] A solution of 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine hydrochloride (100 mg), 1-fluoro-2-methylpropyl-2-yl-4-nitrophenyl carbonate (106 mg), and triethylamine (0.2 mL) in DCM (2 mL) was stirred overnight at room temperature. The reaction mixture was then partitioned between DCM and NaHCO3. The organic phase was washed with NaHCO3 and then concentrated under vacuum. The residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (41 mg).

[0655] LCMS: [M+H] + = 350.

[0656] Example 151. 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}-1-(5-methyl-1,2,4- diazole- Synthesis of 3-yl)piperidine

[0657] [Chemical Formula 42]

[0658] 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine hydrochloride (78 mg) and 3-chloro-5-methyl-1,2,4- A solution of diazole (52 mg) and triethylamine (0.16 mL) in EtOH (1 mL) was stirred overnight. The reaction mixture was then partitioned between DCM and water. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (7 mg).

[0659] LCMS: [M+H] + = 314.

[0660] Example 152. 5-Ethyl-2-(4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidin-1-yl)pyrimidine Synthesis

[0661] [Chemical Formula 43]

[0662] A solution of 4-{6-methoxypyrazolo[1,5-a]pyridin-3-yl}piperidine hydrochloride (100 mg), 2-chloro-5-ethylpyrimidine (64 mg), and triethylamine (0.2 mL) in EtOH (1 mL) was stirred overnight at 80 °C. The reaction mixture was then partitioned between DCM and water. The organic phase was concentrated under vacuum, and the residue was purified by column chromatography (SiO2, AcOEt: petroleum ether) to give the desired product (28 mg).

[0663] LCMS: [M+H] + = 338.

[0664] The compounds in the examples were prepared in the same manner as in any of the examples described above. The structural formulas and physicochemical data of the compounds in Examples 1 to 152 are shown in the table below.

[0665] [Table 3-1]

[0666] [Table 3-2]

[0667] [Table 3-3]

[0668] [Table 3-4]

[0669] [Table 3-5]

[0670] [Table 3-6]

[0671] [Table 3-7]

[0672] [Table 3-8]

[0673] [Table 3-9]

[0674] [Table 3-10]

[0675] [Table 3-11]

[0676] [Table 3-12]

[0677] [Table 3-13]

[0678] [Table 3-14]

[0679] [Table 3-15]

[0680] [Table 3-16]

[0681] [Table 3-17]

[0682] [Table 3-18]

[0683] [Table 3-19]

[0684] [Table 3-20]

[0685] [Table 3-21]

[0686] [Table 3-22]

[0687] [Table 3-23]

[0688] [Table 3-24]

[0689] [Table 3-25]

[0690] Bioactivity

[0691] Test Example 1: CSF1R kinase assay

[0692] The compounds of the examples were serially diluted in DMSO (semi-logarithmic gradient; 10 concentrations). Serial dilutions of the compounds were prepared using assay buffer (0.25 M EPPS pH 7.5, 50 mM MgCl2, 2.5 mM EGTA, 0.05% Briji-35) to achieve a 4-fold concentration in 4% (v / v) DMSO. Each compound concentration was added at 5 μL / well to a 384-well plate. 5 μL of ATP / peptide solution (0.372 mM ATP, 0.4 μM fluorescein-polyGT (PV3610, Life Technologies)) was added to all wells. 10 μL of CSF1R (PV3249, Life Technologies) dilution solution (0.28 nM) was added to the wells of each compound concentration and to the wells designated as 0% inhibition (containing no compound). Conversely, 10 μL of enzyme-free assay buffer was added to the wells designated as 100% inhibition (0% response control). Incubate the plate at 750 rpm for 80 min using an orbital shaker at room temperature. Add 20 μL of stop solution (20 mM EDTA, 2 nM Tb-PY20 (PV3528, Life Technologies) antibody diluted with TR-FRET dilution buffer (PV3574, Life Technologies)) to all wells. Incubate the plate at 750 rpm for 30 min using an orbital shaker at room temperature. Use an Infinite M1000 (Tecan) LanthaScreen. TM The assay pattern was read from the plate. Signal values ​​were calculated using 337 nm excitation light at an emission ratio of 520 nm / 490 nm. IC50 was calculated by fitting a nonlinear regression curve to plot the inhibition percentage against compound concentration using GraphPad Prism 7 software. 50 value.

[0693] The results are shown in the table below.

[0694] [Table 4]

[0695] Test Example 2: Assay of CSF1R phosphorylation in human CSF1R-overexpressing cells

[0696] The compounds from the examples were tested in H4 cells (H4 / hCSF1R) stably transfected with human CSF1R. H4 / hCSF1R cells were cultured in T150 flasks in DMEM medium supplemented with 10% FBS, 0.5 mg / mL genimycin (G418), 100 units / mL penicillin, and 100 μg / mL streptomycin, and passaged twice weekly. For experiments, cells were trypsinized, counted, and diluted with medium to 1.11 x 10⁻⁶ cells / mL. 5Cells / mL. Cells were seeded into 96-well plates at 180 μL per well (20,000 cells / well). The compound was serially diluted with DMSO to prepare an 8-point semi-logarithmic concentration series, then diluted 10-fold with culture medium to the final concentration. 20 μL of each concentration of the compound was added to the cells per well. The plates were briefly mixed using an orbital shaker and incubated for 1 hour at 37°C, 5% CO2, and 95% humidified atmosphere. Then, 22 μL of hCSF1 (300 ng / mL, #300-25, Peprotech) was added to each well. A 100% response control treated with hCSF1 (without the compound) and a 0% response control (without hCSF1) were prepared on each plate to calculate the percentage of inhibition and Z' value of the test compound. The plates were briefly mixed again and incubated for 15 min at 37°C, 5% CO2, and 95% humidified atmosphere. CSF1R phosphorylation was detected using an ELISA kit (PathScan® Phospho-CSF1R / M-CSF-R (panTyr) Sandwich ELISA Kit, 13491C, CST) according to the manufacturer's instructions. Culture medium was aspirated from each well, and cells were washed with 200 μl of ice-cold PBS. After adding 50 μl of lysis buffer containing phosphatase and protease inhibitors, the plate was incubated at 4°C for 20 minutes. 100 μL of sample diluent was added and mixed using a track-type shaker. 80 μL of cell lysate was transferred to an ELISA plate. The plate was sealed and stored overnight at 4°C. The next day, the lysate was removed, and the plate was washed four times with 200 μl of wash buffer. The remaining wash buffer was displaced, and 100 μl of detection antibody solution was added. The plate was incubated at 37°C for one hour. The antibody solution was removed, and the plate was washed four times with 200 μl of wash buffer. Add 100 μL of HRP-linked secondary antibody solution and incubate the plate at 37 °C for 30 min. Remove the antibody solution and wash the plate four times with 200 μL of wash buffer. Add 100 μL / well of TMB substrate and incubate the plate at room temperature for 10 min. Add 100 μL of stop solution to the plate and measure the absorbance at 450 nm using an Infinite M1000 (Tecan). Subtract the average background and normalize the results relative to the 100% response control. Calculate the IC50 by performing nonlinear regression curve fitting using GraphPad Prism 7 software to plot CSF1R phosphorylation against compound concentration. 50 value.

[0697] The results are shown in the table below.

[0698] [Table 5]

[0699] Test Example 3. Kinase assay for selectivity of receptor tyrosine kinases (RTKs)

[0700] Five commercially available RTKs (shown in the table below) were tested using the LabChip EZReader II and ProfilerPro Kinase Selectivity Assay Kit (PerkinElmer). Compounds were serially diluted in DMSO (semi-logarithmic gradient; 10 concentrations). 200 nL of each serially diluted compound was mixed with 10 μL of kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Briji-35) containing substrate (10 μM) and ATP (198 μM (CSF1R), 86 μM (FLT3, cKit, PDGFRβ, or TrkC)) to achieve a 2-fold concentration. Fluorescently labeled peptide substrates are shown in the table below. Each enzyme dilution (200 ng / mL) was added to all wells in 10 μL. The 0% inhibition control contained no inhibitor, while the 100% inhibition control contained no ATP. The plates were stirred on a plate shaker for a few seconds and incubated at room temperature for 60 min. Add 60 μL of stop buffer (100 mM HEPES pH 7.5, 40 mM EDTA, 1 mM DTT, 0.015% Briji-35, 0.13% LabChip Aspirate Chip Coating Reagent 3 (760050, PerkinElmer)) to all wells. Phosphorylated and unphosphorylated peptides were separated by electrophoresis and detected by their fluorescence. The percentage of substrate converted to product was determined using peak height. IsC was calculated by nonlinear regression curve fitting using GraphPad Prism 7 software to plot the percentage of inhibition against compound concentration. 50 The values ​​confirmed that the compound exhibited selective inhibitory activity against CSF1R compared to at least one tested kinase.

[0701] [Table 6]

[0702] Test Example 4. Pharmacokinetics / Pharmacodynamics

[0703] Male mice (C57BL / 6J, Jackson Laboratory, Japan, 8 weeks old) were orally administered the test compound using 5% gum arabic in water as a medium. Mice administered the medium alone served as negative controls. In each study, a control group and one or more test compound administration groups were prepared, but each group was administered only one concentration of one test compound. Blood was collected into heparin capillaries via posterior orbital puncture at 30 min, 1 h, 2 h, and 6 h post-administration. Blood was collected into heparin tubes via the posterior vena cava after anesthesia, and the brain was harvested 24 h post-administration. Blood was centrifuged at 1710 g for 10 min at 4°C to obtain plasma. The brain hemispheres were homogenized in 3 times their weight of saline using a PHYSCOTRON homogenizer (NS-360D, Microtec) for pharmacokinetic studies. Another brain hemisphere was immersed in an RNAlater (AM7021, Life Technologies) for gene expression assays.

[0704] Identification of compounds in mouse plasma and brain homogenates

[0705] Compounds in mouse plasma and brain homogenates were quantified using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS / MS). Standard solutions were prepared by dissolving the compounds in DMSO and diluting them with methanol. Calibration curve samples were prepared at concentrations ranging from 0.01 μg / mL to 10 μg / mL, while quality control samples were prepared at concentrations of 0.03 μg / mL, 5 μg / mL, and 8 μg / mL. An internal standard solution (spirocyclic piperidinone: 500 ng / mL) and methanol were added to each sample and mixed. The mixture was centrifuged at 6130 g for 10 min below 10 °C to obtain the supernatant. The supernatant was mixed with water / acetonitrile (1:1, v / v). HPLC and tandem mass spectrometry analysis were performed using a Prominence UFLC system (Shimadzu) and a switching valve (Valco Instruments). Chromatographic separation was achieved on an XBridge C18 (3.5 μm, 2.1 mm ID × 50 mm, Waters). A binary gradient was formed using a 10 mmol / L aqueous solution of ammonium acetate and acetonitrile at a flow rate of 0.55 mL / min. The ionization method was positive ion electrospray ionization. Multiple reaction monitoring (MRM) was employed, utilizing precursor and product ions from the analyte and internal standards. The peak area ratio of the analyte to the standard in the calibration curve was obtained. A quadratic regression equation (Y = aX) was calculated using the least squares method, employing the peak area ratio (Y) and the spike concentration (X). 2 +bX+c, weight: 1 / X 2The concentration of the analyte in the sample was determined by substituting the obtained peak area ratio into the above equation. A calibration curve was constructed using Analyst version 1.5.1 (AB Sciex), and peak areas and concentrations were determined. The average concentration and brain-to-plasma concentration ratio (Kp) at each time point were calculated using Microsoft Excel 2013 (Microsoft). Brain concentrations were corrected using a dilution factor (4-fold dilution) for the brain homogenate. Pharmacokinetic parameters (Cp) were calculated using a non-compartmental model with Phoenix® WinNonlin® 8.0 (Certara). max , t max , t 1 / 2,z AUC t and AUC ∞ ).

[0706] Quantitative analysis of microglia-related gene expression

[0707] RNA was extracted from each brain using the Maxwell® RSC simplyRNA Tissue Kit (AS1340, Promega), RNAdvance Tissue Kit (A32646, Beckman Coulter), or RNeasy Mini Kit (74106, Qiagen). RNA concentration and purity were assessed using a spectrophotometer (DropSense96, Trinean, or Nanodrop, Thermo Scientific). Equal volumes of RNA were reverse transcribed into cDNA using the Large Capacity RNA to cDNA Kit (4388950, Life Technologies) or the Large Capacity cDNA Reverse Transcription Kit (4368813, Life Technologies). Quantitative PCR was performed on a LightCycler 480 (Roche) or ViiA7 (Thermo Scientific) using TaqMan Rapid Universal PCR Premix (#4352042, Life Technologies) or TaqMan Rapid Advanced Premix (4444964, Life Technologies). Data were analyzed using the ΔΔCt method or fold change, calculated relative to a standard curve constructed from five points at a 1:2 dilution of the drug-treated animals. The GAPDH gene was used as an internal control. The percentage inhibition of the CD11b gene was calculated by setting the rate of decline in the absence of the drug to 0. Primers used in this study were: GAPDH gene (Mm99999915_g1, Life Technologies), CD11b gene (Mm00434455_m1, Life Technologies). All calculations were performed using Microsoft Excel 2013 (Microsoft Corporation).

[0708] Unless otherwise noted, the results of the test compounds administered at a dose of 30 mg / kg are shown in the table below.

[0709] [Table 7]

[0710] 20% to 40%: ++, 40% to 60%: +++, 60% to 100%: ++++ Results of a 100 mg / kg dose

[0711] Industrial applicability

[0712] Compounds of formula [I] or their salts may have CSF1R inhibitory activity and are intended for the treatment, prevention and / or diagnosis of CSF1R-related diseases.

Claims

1. A compound or a salt thereof represented by formula [I]: [Chemical Formula 1] in R 1 It is hydrogen, halogen, -CN, optionally dilated by one or more R 12 Replacement -L 11 -R 11 Or optionally by one or more R 12 Replacement -R 11 ; L 11 It is -C 1-3 alkylene-, -C 1-3 Alkylene -C(=O)-, -O-, -OC 1-3 Alkylene-, -OC 1-3 Alkylenes -O-, -OCH2C(=O)O-, -C(=O-, -C(=O)NH- or -NH-C(=O-); R 11 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, or d) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirocyclic groups; R 12 Each is an independent halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-8 cycloalkyl, optionally with one or more C 1-6 Alkyl-substituted saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spirochetal groups; R 21 and R 22 It is hydrogen, or R 21 and R 22 Together with the adjacent heterocyclic rings, they form a bridging double ring; R 3 It is optionally controlled by one or more R 32 Replacement -L 31 -R 31 Or optionally by one or more R 32 Replacement R 31 The condition is R. 3 It is not -C(=O)O-tert-butyl; L 31 Yes -C(=O)-, -C(=O)O-, -C(=O)OC 1-3 Alkylene-, -C(=O)-C 1-3 Alkylene -O-, -C(=O)-C 1-3 Alkylene-OC 1-3 Alkylene- or -C(=O)NH-C 1-3 alkylene-; R 31 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, or e) Saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spiroheterocyclic groups; R 32 Each is independently a halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-8 cycloalkyl; X is CR 1 Or N; key: [Chemical Formula 2] It is either a single bond or a double bond; and The part represented by the following formula: [Chemical Formula 3] It is any of the following structures: [Chemical Formula 4] The condition is R 1 It is a halogen, -CN, optionally dilated by one or more R 12 Replacement -L 11 -R 11 Or optionally by one or more R 12 Replacement -R 11 .

2. The compound or a salt thereof according to claim 1, wherein R 11 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d1) A saturated or unsaturated 4- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms. d2) Saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom. d3) A saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. d4) An unsaturated 5-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms. d5) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 2 to 3 nitrogen atoms as cyclic heteroatoms. d6) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. d7) A saturated or unsaturated 9-membered bicyclic heterocyclic group containing one nitrogen atom, one oxygen atom, and one sulfur atom as cyclic heteroatoms. d8) A saturated or unsaturated 6- to 10-membered bicyclic heterocyclic group containing one oxygen atom as a cyclic heteroatom. d9) A saturated 7-membered spirocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms, or d10) is a saturated 7- to 8-membered spirocyclic group containing one nitrogen atom and one oxygen atom as cyclic heteroatoms.

3. The compound or a salt thereof according to claim 1 or 2, wherein R 12 Each is independently a halogen, -OH, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OC 1-6 Alkyl, C 3-8 Cycloalkyl groups, saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom, or optionally C-shaped groups. 1-6 Alkyl-substituted saturated 6- to 10-membered spiroheterocyclic groups containing two nitrogen atoms as cyclic heteroatoms.

4. The compound or a salt thereof according to any one of claims 1 to 3, wherein L 11 It is methylene, ethylene, methylene-C(=O)-, -O-, -O-methylene, -O-ethylene, -O-ethylene-O-, -OCH2C(=O)O-, -C(=O)-, -C(=O)NH- or -NH-C(=O)-. R 11 The following are methyl, methyl-d3, ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, aziridine, piperidinyl, morpholinyl, pyrazolyl, thiazolyl, thiadiazolyl, tetrahydroimidazo[1,2-a]pyridinyl, and dihydroimidazo[2,1-c][1,4]. Azine group, dihydropyrazolo[5,1-c][1,4] Azine, dihydropyrano[4,3-d]thiazolyl, hexahydropyrrolo[3,4-c]pyrryl, tetrahydrofurano[3,4-c]pyrryl, 2-oxabicyclo[2.1.1]hexyl, 2-azaspiro[3.3]heptyl or 2-oxa-6-azaspiro[3.3]heptyl, and R 12 Each is independently fluorine, methyl, methyl-d3, difluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -OH, oxacyclobutyl or optionally methyl-substituted 2,6-diazaspiro[3.3]heptyl.

5. The compound or a salt thereof according to any one of claims 1 to 4, wherein R 1 It is hydrogen, halogen, cyano, C 1-6 Alkyl group, optionally with one or more deuterium, OH or C atoms. 1-6 alkyl-O-substituted C 1-6 Alkyl-O-,C 1-6 Alkyl-OC(=O)CH2O-, C 1-6 Halogenated alkyl-O-,C 1-6 Halogenated alkyl-OC 1-6 alkylene-, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, optionally coated with halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-O-,C 3-8 Cycloalkyl-C(=O)-, C 3-8 Cycloalkyl-NH-C(=O)-, optionally halogenated azaheptacyclic butyl, optionally oxocyclic butyl-C 1-6 Alkylene-O-, aziridine-O- optionally substituted with oxetane, piperidinyl optionally substituted with oxetane, morpholinyl, morpholinyl-C 1-6 Alkylene, morpholino-C 1-6 alkylene-O-,morpholinyl-C(=O)-C 1-6 Alkylene, optionally C 1-6 Alkyl-substituted pyrazolyl group, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkylene, optionally C 1-6 Halogenated alkyl-substituted thiazolyl or optionally C 1-6 Alkyl-substituted diazaspiroheptyl, optionally C 1-6 Alkyl-substituted thiadiazole group, optionally halogenated or C 1-6 Alkyl-substituted oxehericyclic butyl-C 1-6 Alkylene-O-, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroimidazo[1,2-a]pyrazinyl, dihydroimidazo[2,1-c][1,4] Azine group, dihydropyrano[4,3-d]thiazolyl group, dihydropyrazolo[5,1-c][1,4] Azine, hexahydropyrrolo[3,4-c]pyrrol, tetrahydrofurano[3,4-c]pyrrol, 2-oxabicyclo[2.1.1]hexyl-C 1-6 Alkylene-O-, optionally halogenated 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl-C(=O)-, or optionally halogenated 2-azaspiro[3.3]heptyl-C 1-6 Alkylene-O-.

6. The compound or a salt thereof according to any one of claims 1 to 5, wherein R 1 It is hydrogen, fluorine, chlorine, cyano, isopropyl, methoxy, methoxy-d3, difluoromethoxy, ethoxy, 2-methoxyethoxy, 2-methoxy-2-oxoethoxy, 2,2-difluoroethoxy, 2-(difluoromethoxy)ethoxy, 2-(trifluoromethoxy)ethoxy, 2-hydroxy-2-methylpropoxy, 2-methoxy-2-methylpropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, cyclopropyl, cyclopropoxy, cyclopropylmethoxy, cyclopropane carbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluoro... Cyclopropyl)methoxy, 2-(3,3-difluorocyclobutyl)ethoxy, (2,2-difluoro-1-methylcyclopropyl)methoxy, (1-(difluoromethyl)cyclopropyl)methoxy, (1-(trifluoromethyl)cyclopropyl)methoxy, aziridine-1-yl, 3,3-difluoroaziridine-1-yl, (1-(oxacyclobutane-3-yl)aziridine-3-yl)oxy, (1-(oxacyclobutane-3-yl)aziridine-3-yl)methoxy, 1-methyl-1H-pyrazol-4-yl, 1-(methyl-d3)-1H-pyrazol-4-yl, 1-(2-methoxyethyl) 1,3,5-trimethyl-1H-pyrazole-4-yl, 1-cyclopropyl-1H-pyrazole-4-yl, 1-cyclopropyl-3,5-dimethyl-1H-pyrazole-4-yl, 3,5-dimethyl-1-(methyl-d3)-1H-pyrazole-4-yl, 1-(oxetane-3-yl)piperidin-4-yl, (1-methylpiperidin-4-yl)oxy, (oxetane-3-yl)methoxy, (3-fluorooxetane-3-yl)methoxy, (3-methyloxetane-3-yl)methoxy, morpholinyl, morpholinylmethyl, 2-morpholinyl- 2-Oxoethyl, 2-morpholinylethoxy, 2-morpholinylethyl, thiazolyl-4-yl, thiazolyl-5-yl, (trifluoromethyl)thiazolyl-4-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, 7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl, 5-methylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4] Azine-3-yl, 5,6-dihydro-8H-imidazo[2,1-c][1,4] Azine-2-yl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl-2-yl, ((1s,4s)-2-oxabicyclo[2.1.1]hex-1-yl)methoxy, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]heptane-6-carbonyl, 6,6-difluoro-2-azaspiro[3.3]hept-2-yl, 2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)ethoxy or 2-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)thiazolyl-5-yl.

7. The compound or a salt thereof according to any one of claims 1 to 6, wherein R 21 and R 22 It is hydrogen.

8. The compound or a salt thereof according to any one of claims 1 to 7, wherein R 31 yes a) C 1-6 alkyl, b) C 1-6 Halogenated alkyl groups, c) C 3-8 cycloalkyl, d) Phenyl, e1) A saturated or unsaturated 4- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms as cyclic heteroatoms. e2) Saturated 4- to 6-membered monocyclic heterocyclic groups containing one oxygen atom as a cyclic heteroatom. e3) A saturated or unsaturated 5- to 6-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms. e4) An unsaturated 5-membered monocyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom as cyclic heteroatoms. e5) A saturated or unsaturated 7- to 9-membered bicyclic heterocyclic group containing 1 to 2 nitrogen atoms and 1 oxygen atom as cyclic heteroatoms, or e6) A saturated 7- to 8-membered spirocyclic group containing one nitrogen atom and one oxygen atom as cyclic heteroatoms.

9. The compound or a salt thereof according to any one of claims 1 to 8, wherein L 31 It is -C(=O)-, -C(=O)O-, -C(=O)O-methylene-, -C(=O)O-ethylidene-, -C(=O)-ethylidene-O-, -C(=O)-methylene-O-methylene- or -C(=O)NH-ethylidene-. R 31 It is methyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, azole group, thiazolyl group, Diazolyl, pyrimidinyl, tetrahydrofuranyl, aziridine, or 6-oxa-1-azaspiro[3.4]octyl, and R 32 Each of them is independently fluorine, methyl, ethyl, cyclopropyl, difluoromethyl, or trifluoromethyl.

10. The compound or a salt thereof according to any one of claims 1 to 9, wherein R 3 It is C 1-6 Halogenated alkyl group -OC(=O)-, optionally halogenated or C 1-6 Halogenated alkyl-substituted C 3-8 cycloalkyl-OC(=O)-, optionally C 1-6 Alkyl-substituted C 3-8 cycloalkyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted phenyl-CH2OCH2-C(=O)-, optionally C 1-6 Alkyl-substituted phenoxy-C 1-6 alkylene-C(=O)-, phenyl-C 1-3 Alkylene-NH-C(=O)-, optionally halogenated or C 1-6 Haloalkyl-substituted azaheterocyclic butyl-C(=O)-, optionally C 1-6 Alkyl-substituted azole-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl or C 3-8 Cycloalkyl-substituted Diazole group, optionally covered with C 1-6 Halogenated alkyl-substituted thiazolyl-C 1-6 Alkylene-OC(=O)-, optionally with C 1-6 Alkyl-substituted pyrimidinyl, tetrahydrofuranyl-C 1-6 Alkylene-OC(=O)-, 3-oxa-6-azabicyclo[3.1.1]heptyl-C(=O)- or 6-oxa-1-azaspiro[3.4]octyl-C(=O)-.

11. The compound or a salt thereof according to any one of claims 1 to 10, wherein R 3 It is 5-ethylpyrimidin-2-yl, 5-methyl-1,2,4- Diazol-3-yl, 3-cyclopropyl-1,2,4- Diazol-5-yl, (2-(difluoromethyl)azacyclobutane-1-yl)carbonyl, (3,3-difluoroazacyclobutane-1-yl)carbonyl, (3-oxa-6-azabicyclo[3.1.1]hept-6-yl)carbonyl, 6-oxa-1-azaspiro[3.4]oct-1-ylcarbonyl, azacyclobutane-1-ylcarbonyl, 2-(p-tolyloxy)ethylcarbonyl, 2-phenoxyethylcarbonyl, ((2-methylbenzyl)oxy)methylcarbonyl, phenylethyl 1,1,1-trifluoro-2-methylprop-2-oxycarbonyl, 1-fluoro-2-methylprop-2-oxycarbonyl, cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, (1-methylcyclopropyl)methoxycarbonyl, 3,3-difluorocyclobutoxycarbonyl, (1R,3R)-3-(trifluoromethyl)cyclobutoxycarbonyl, (1S,3S)-3-(trifluoromethyl)cyclobutoxycarbonyl, 4,4-difluorocyclohexyloxycarbonyl, benzyloxycarbonyl azole-4-ylmethoxycarbonyl, 1-( (zol-4-yl)ethoxycarbonyl, (2-methyl) (2-(thiazol-4-yl)methoxycarbonyl, 2-(thiazol-4-yl)ethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, (2-(trifluoromethyl)thiazol-4-yl)methoxycarbonyl or (tetrahydrofuran-2-yl)methoxycarbonyl.

12. The compound or a salt thereof according to any one of claims 1 to 6 and 8 to 11, wherein the compound of formula [I] is [Chemical Formula 5] 。 13. The compound or a salt thereof according to any one of claims 1 to 12, wherein the compound of formula [I] is [Chemical Formula 6] 。 14. The compound or a salt thereof according to any one of claims 1 to 12, wherein the compound of formula [I] is [Chemical Formula 7] 。 15. The compound or a salt thereof according to any one of claims 1 to 6 and 8 to 12, wherein the compound of formula [I] is [Chemical Formula 8] 。 16. The compound or a salt thereof according to any one of claims 1 to 12, wherein the compound of formula [I] is [Chemical Formula 9] 。 17. The compound or a salt thereof according to any one of claims 1 to 12, wherein the compound of formula [I] is [Chemical Formula 10] 。 18. The compound or a salt thereof according to any one of claims 1 to 11, wherein X is CH.

19. The compound or a salt thereof according to any one of claims 1 to 11, wherein X is N.

20. The compound or a salt thereof according to any one of claims 1 to 11, wherein the bond is: [Chemical Formula 11] It is a single key.

21. The compound or a salt thereof according to any one of claims 1 to 11, wherein the bond is: [Chemical Formula 12] It is a double bond.

22. The compound or a salt thereof according to any one of claims 1 to 21, wherein R 1 It is 2-methoxyethoxy, cyclopropoxy, (1-methylpiperidin-4-yl)oxy, 2,2-difluoroethoxy, 1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl, 1-cyclopropyl-1H-pyrazol-4-yl, tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl, 6,6-difluoro-2-azaspiro[3.3]hept-2-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, thiazolyl-5-yl, or 1-methyl-1H-pyrazol-4-yl.

23. The compound or a salt thereof according to any one of claims 1 to 22, wherein R 3 It is cyclopropoxycarbonyl, (1-fluoromethyl-2-methylprop-2-yl)oxycarbonyl, Azol-4-ylmethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, or 3,3-difluoroazacyclobutane-1-ylcarbonyl.

24. The compound of claim 1 or a salt thereof, wherein the compound is selected from the group consisting of: [Chemical Formula 13] 。 25. The compound according to claim 1, wherein the compound is selected from the group consisting of: [Chemical Formula 14] 。 26. A pharmaceutical composition comprising a compound or a salt thereof as an active ingredient according to any one of claims 1-25, and a pharmaceutically acceptable carrier or excipient.

27. A therapeutic, preventive, and / or diagnostic agent for a disease caused by CSF1R, said agent comprising a compound or a salt thereof as an active ingredient according to any one of claims 1-25.

28. The pharmaceutical agent of claim 27, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prion disease, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infection, cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

29. A method for treating, preventing, and / or diagnosing a disease caused by CSF1R, the method comprising administering to a person in need an effective amount of the compound or a salt thereof according to any one of claims 1-25.

30. The method of claim 29, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infection, cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

31. A compound or a salt thereof according to any one of claims 1-25, for the treatment, prevention and / or diagnosis of diseases caused by CSF1R.

32. The compound or salt thereof used according to claim 31, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prion disease, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infection, cardiovascular disease such as post-myocardial infarction inflammation, bone disease, muscular dystrophy, or asthma.

33. Use of the compound or a salt thereof according to any one of claims 1-25 in the manufacture of a medicament for treating, preventing and / or diagnosing diseases caused by CSF1R.

34. The use according to claim 33, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tau proteinosis, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive impairment (HAND), prions, traumatic brain injury (TBI), Parkinson's disease, pain, spinal cord injury, Crohn's disease, radiation-induced pulmonary fibrosis, glaucoma, infection, cardiovascular diseases such as post-myocardial infarction inflammation, bone diseases, muscular dystrophy, or asthma.

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