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WO2025089370A1 - Composés utilisés en tant qu'inhibiteurs de csf1r - Google Patents

Composés utilisés en tant qu'inhibiteurs de csf1r Download PDF

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WO2025089370A1
WO2025089370A1 PCT/JP2024/038053 JP2024038053W WO2025089370A1 WO 2025089370 A1 WO2025089370 A1 WO 2025089370A1 JP 2024038053 W JP2024038053 W JP 2024038053W WO 2025089370 A1 WO2025089370 A1 WO 2025089370A1
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salt
optionally substituted
alkyl
mixture
compound
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Masaki Suzuki
Valerio Berdini
Yohei Yuki
Emiliano TAMANINI
Masatoshi Iida
Louise Marie Walsh
Hidenori Someya
James Daniel OSBORNE
Hideto Fujiwara
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrazolopyridine or pyrazolopyrimidine compounds and salts thereof.
  • the present invention also relates to medical use of pyrazolopyridine or pyrazolopyrimidine compounds or salts thereof for treating, preventing, and/or diagnosing diseases associated with colony-stimulating factor-1 receptor (CSF1R). Methods of preparing said compounds or salts thereof are also provided.
  • CSF1R colony-stimulating factor-1 receptor
  • Macrophage colony-stimulating factor-1 receptor is a member of 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) ⁇ and ⁇ .
  • CSF1R is primarily expressed in macrophage lineages including monocytes, tissue macrophages, dendritic cells, Kupffer cells, osteoclasts, and microglia.
  • CSF1R binding CSF-1 or IL-34 in the brain activates signal transduction pathways, such as PI3K/AKT/NF- ⁇ B, PKC/NF- ⁇ B, and ROS/RAS/RAF/MAPK pathways, resulting in the differentiation, survival, proliferation, adhesion, and migration of monocyte/macrophage lineage cells.
  • signal transduction pathways such as PI3K/AKT/NF- ⁇ B, PKC/NF- ⁇ B, and ROS/RAS/RAF/MAPK pathways, resulting in the differentiation, survival, proliferation, adhesion, and migration of monocyte/macrophage lineage cells.
  • mice lacking functional CSF1R and ligands includes osteopetrosis, reduced numbers of macrophage and microglia and reduced inflammatory cytokine production, which indicates the diverse functions of CSF1R signaling.
  • CSF1R signaling may also lead to aberrant expression of proinflammatory cytokines, including tumor necrosis factor- ⁇ (TNF- ⁇ ) and interleukin-6 (IL-6), which are involved in the exacerbation of various types of cancer, bone disorders, and inflammatory diseases.
  • proinflammatory cytokines including tumor necrosis factor- ⁇ (TNF- ⁇ ) and interleukin-6 (IL-6), which are involved in the exacerbation of various types of cancer, bone disorders, and inflammatory diseases.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-6 interleukin-6
  • 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) [NPL 31] Yan X, Maixner DW, Li F3 Weng HR. Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors. Journal f Neurochemistry 140, 963-976 (2017) [NPL 32] Poulen G. et al. Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates. Theranostics 11(18):8640-8659 (2021).
  • R 1 is hydrogen, halogen, -CN, -L 11 -R 11 optionally substituted with one or more R 12 , or -R 11 optionally substituted with one or more R 12 ;
  • R 11 is a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, d) a saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spiro heterocyclyl;
  • R 12 is each independently halogen
  • compositions comprising a compound of Formula [I], or a salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • halogen is fluorine, chlorine, bromine, or iodine. It is preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.
  • C 1-6 alkyl is a linear or a branched alkyl having 1 to 6 carbon atoms (C 1-6 ), and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, and the like.
  • C 1-6 alkyl also includes C 1-6 alkyl having deuterium atoms substituted for 1 to 3 hydrogen atoms, and specific examples include methyl-d 1 , methyl-d 2 , methyl-d 3 , ethyl-d 5 , and the like.
  • C 1-6 haloalkyl is a linear or a branched alkyl having 1 to 6 carbon atoms (C 1-6 ) with 1 to 4 halogens, preferably 1 to 3 halogens, and specific examples thereof include fluoromethyl, chloromethyl, bromomethyl, iodemethyl, 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-dibromohexy
  • C 1-3 alkylene is a linear or a branched alkylene having 1 to 3 carbon atoms (C 1-3 ). Specific examples thereof include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, and the like. “C 1-3 alkylene” also includes C 1-3 alkylene in which 1 to 3 hydrogen atoms are replaced with deuterium atoms.
  • C 1-6 alkylene is a linear or a branched alkylene having 1 to 6 carbon atoms (C 1-6 ). Specific examples thereof include methylene, ethylene, 1-methylethylene, 2-methylethylene, trimethylene, methylmethylene, ethylmethylene, dimethylmethylene, 2,2-dimethylethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, and the like. “C 1-6 alkylene” also includes C 1-6 alkylene in which 1 to 6 hydrogen atoms are substituted with deuterium atoms.
  • C 3-8 cycloalkyl is a saturated or partially unsaturated carbocyclyl having 3 to 8 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, and the like.
  • saturated or unsaturated 4- to 10-membered monocyclic, bicyclic, or spiro heterocyclyl comprises at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur atoms and may be partially unsaturated.
  • the heterocyclyl includes a bridged heterocyclyl.
  • Specific examples include a saturated or unsaturated 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms as a ring-constituting heteroatom, a saturated or unsaturated 4- to 6-membered monocyclic heterocyclyl containing 1 oxygen atom as ring-constituting heteroatom, a saturated or unsaturated 5- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 oxygen atom as ring-constituting heteroatom, an unsaturated 5-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 sulfur atom as ring-constituting heteroatom, a saturated or unsaturated 7- to 9-membered bicyclic heterocyclyl containing 2 to 3 nitrogen atoms as ring-constituting heteroatom, a saturated or unsaturated 7- to 9-membered bicyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 oxygen atom as ring-
  • a saturated or unsaturated 5- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atom and 1 oxygen atom as a ring-constituting heteroatom specifically includes oxazole, isoxazole, oxadiazole, and morpholine.
  • an unsaturated 5-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 sulfur atom as a ring-constituting heteroatom specifically includes thiazolyl, thiazolinyl (dihydrothiazolyl), thiadiazolyl, isothiazolyl, and thiazolidinyl.
  • a saturated or unsaturated 7- to 9-membered bicyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 oxygen atom as a ring-constituting heteroatom specifically includes benzoxazolyl, dihydrobenzoxazolyl, oxaazabicycloheptanyl, tetrahydrofuropyrrolyl, benzoxadiazolyl, benzoisoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, dihydroimidazooxazinyl, dihydropyrazolooxazinyl, furopyridinyl, furopyrrolyl, benzoxazepinyl, and tetrahydrobenzoxazepinyl.
  • a saturated or unsaturated 9-membered bicyclic heterocyclyl containing 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom as a ring-constituting heteroatom specifically includes pyrano[4,3-d]thiazolyl, and dihydropyrano[4,3-d]thiazolyl.
  • a saturated or unsaturated 6- to 10-membered bicyclic heterocyclyl containing 1 oxygen atom as a ring-constituting heteroatom specifically includes 2-oxabicyclo[2.1.1]hexanyl.
  • a saturated 7-membered spiro heterocyclyl containing 1 to 2 nitrogen atoms as a ring-constituting heteroatom specifically includes 2-azaspiro[3.3]heptanyl and 2,6-diazaspiro[3.3]heptanyl.
  • a saturated 7- to 8-membered spiro heterocyclyl containing 1 nitrogen atom and 1 oxygen atom as a ring-constituting heteroatom specifically includes 2-oxa-6-azaspiro[3.3]heptanyl and oxaazaspirooctanyl.
  • C 1-18 alkanesulfonyl is a linear or branched alkanesulfonyl having 1 to 18 carbon atoms (C 1-18 ), and specific examples thereof include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.
  • lower alkanesulfonyloxy is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ), and specific examples thereof include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.
  • aralkylsulfonyloxy is a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) that is substituted with phenyl optionally substituted with 1 to 3 groups selected from the group consisting of a linear or branched alkyl having 1 to 6 carbon atoms (C 1-6 ), a linear or branched alkoxy having 1 to 6 carbon atoms (C 1-6 ), nitro, and halogen on the benzene ring; or a linear or branched alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) that is substituted with naphthyl, and the like.
  • alkanesulfonyloxy substituted with phenyl include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, and the like.
  • sulfonio examples include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di-(2-cyanoethyl)sulfonio, di-(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di-(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(
  • solvent may be an inert solvent in a reaction described herein, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), hydrocarbons, halogenated hydrocarbons (e.g., methylene chloride, chloroform, 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 (DMF), N-methylpyrroli
  • solvents may be used alone or as a mixture of any two or more of them with optional ratios.
  • hydrocarbons 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.
  • alcohols include, for example, methanol, ethanol, 2-propanol, propanol, and tert-butanol.
  • ethers herein include, for example, chained ethers such as diethyl ether, diisopropyl ether, dibutyl ether, dimethoxyethane, and diphenyl ether; and circular ethers such as 1,4-dioxane and tetrahydrofuran.
  • esters herein include, for example, ethyl acetate and ethyl propionate.
  • ketones herein include, for example, acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • amides herein include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone.
  • nitriles herein include, for example, acetonitrile and propionitrile.
  • sulfoxides herein include, for example, dimethyl sulfoxide.
  • catalyst to be used in reduction reactions is not particularly limited to examples used herein, but specific examples thereof include palladium on carbon (Pd/C), platinum on carbon (Pt/C), platinum oxide (PtO 2 ), and the like.
  • halogenating agent is not particularly limited to examples used herein, but specific examples thereof include fluorinating agents, chlorinating agents, brominating agents, and iodinating 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, and the like.
  • fluorinating agents such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychlor
  • the term “acid” is not particularly limited to examples used herein, but includes an inorganic acid, an organic acid, and the like.
  • examples of the “inorganic acid” include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like.
  • examples of the “organic acid” 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, and the like. These acids may be used alone or as a mixture of any two or more of them.
  • the term “base” is not particularly limited to examples used herein, but includes an inorganic base, an organic base, and the like.
  • the “inorganic base” 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 hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, and ce
  • organic base examples include aromatic amines (e.g., pyridine and lutidine), trialkylamines (e.g., trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine (DIPEA)), cyclohexyldimethylamine, 4-dimethylaminopyridine (DMAP), N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorphiline, tetramethylethylenediamine, tetramethylpropylenediamine, picoline, 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), dialkylamine (e.g., diethylamine and diisopropylamine), metal
  • palladium catalyst is not particularly limited to examples used herein, and examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladium (IV) acid tetrahydrate and potassium hexachloropalladium (IV) acid; divalent palladium catalysts such as [1,1’-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane adduct (PdCl 2 (dppf) ⁇ DCM), (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium (II) methanesulfonate (XPhos Pd G3), palladium (II) chloride, palladium (II) bromide, palladium (II) acetate, palladium (II) a
  • the term “leaving group” is not particularly limited to examples used herein, and examples thereof include halogen (e.g., fluorine, chlorine, bromine, and iodine), C 1-18 alkylsulfonyl, alkylsulfonyloxy (e.g., methylsulfonyloxy, ethylsulfonyloxy, and trifluoromethylsulfonyloxy), phenyloxy (e.g., 4-nitrophenyloxy), arylsulfonyloxy (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, and 4-nitrobenzenesulfonyloxy), aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulf
  • R 1 is hydrogen, fluoro, chloro, cyano, isopropyl, methoxy, methoxy-d 3 , 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, cyclopropanecarbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropyl)methoxy, 2-(3,3-difluorocycl
  • L 11 may be -O- or -O-ethylene-O-.
  • R 11 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or a saturated 4- to 6-membered monocyclic heterocyclyl.
  • R 11 is methyl, methyl-d 3 , ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofrunyl, tetrahydropyranyl, azetizinyl, piperidinyl, morpholino, pyrazolyl, thiazolyl, thiadiazolyl, tetrahydroimidazopyridinyl, dihydroimidazooxazinyl, dihydropyrazolooxazinyl, dihydropyranothiazolyl, hexahydropyrropyrolyl, tetrahydrofuropyrrolyl, oxabicyclohexanyl, azas
  • R 11 is methyl, methyl-d 3 , ethyl, propyl, isopropyl, isobutyl, difluoromethyl, trifluoromethyl, difluoroethyl, difluoropropyl, trifluoropropyl, cyclopropyl, cyclobutyl, azetidin-1-yl, azetidin-3-yl, 1H-pyrazol-4-yl, piperidin-4-yl, oxetan-3-yl, pyrimidin-2-yl, morpholino, thiazol-4-yl, thiazol-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
  • R 11 is methyl, cyclopropyl, difluoroethyl, pyrazolyl, tetrahydrofuranyl, thiazolyl, piperidinyl, tetrahydropyranyl, morpholino, tetrahydrofuropyrrolyl, hexahydropyrrolopyrrolyl, azaspiroheptanyl, or oxaazaspiroheptanyl.
  • R 12 is halogen, -OH, C 1-6 alkyl optionally substituted with one or more deuteriums, C 1-6 haloalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl, a saturated 6- to 10-membered spiro heterocyclyl containing 2 nitrogen atoms as ring-constituting heteroatom optionally substituted with C 1-6 alkyl.
  • R 12 may be halogen, C 1-6 alkyl optionally substituted with one or more deuteriums, or C 1-6 haloalkyl.
  • R 12 is fluoro, methyl, mehyl-d 3 , difluoromethyl, trifluoromethyl, methoxyethyl, cyclopropyl, -OH, oxetanyl, or diazaspiroheptanyl optionally substituted with methyl.
  • R 12 is fluoro, methyl, mehyl-d 3 , or cyclopropyl.
  • R 3 is -L 31 -R 31 optionally substituted with one or more R 32 .
  • R 31 is methyl, tert-butyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, oxazolyl, thiazolyl, oxadiazole, pyrimidinyl, tetrahydrofuranyl, azetidinyl, diazaspirooctanyl, oxaazaspirooctanyl, or oxaazatricyclooctane.
  • R 31 may be tert-butyl, cyclopropyl, oxazolyl, thiazolyl, or azetidinyl.
  • R 31 may be cyclopropyl, oxazolyl, thiazolyl, or azetidinyl. Still more preferably, R 31 may be cyclopropyl, oxazolyl, or thiazolyl.
  • R 31 is methyl, cyclopropyl, cyclobutyl, cyclohexyl, or phenyl.
  • R 32 is fluoro, methyl, ethyl, cyclopropyl, difluoromethyl, or trifluoromethyl.
  • Compound [I] may be manufactured, but is not limited thereto, based on the methods described in the General syntheses and Examples below. Unless otherwise specified, reaction temperatures may be optionally adjusted depending on reactants, solvents, and other conditions used in each reaction herein.
  • An alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, and the like in the General syntheses may be performed in accordance with any known methods. Examples of such methods include the methods described in Experimental Chemistry (Fifth Edition, edited by The Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations Second Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers, Inc., 1989; and P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis (Fourth Edition, 2006), and the like.
  • examples of a condensation agent used herein include, for example: T3P; HATU; DCC; N-cyclohexyl-N’-morpholinoethylcarbodiimide; N-cyclohexyl-N’-(4-diethylaminocyclohexyl)carbodiimide; N,N’-diethylcarbodiimide; N,N’-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or a hydrochloride salt thereof; N,N’-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate;
  • a condensation accelerator may be added.
  • a condensation accelerator used herein 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).
  • Examples of a "protecting group of hydroxy” used herein include, but not limited to, any protecting groups of hydroxy 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., ethenyl, 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, pivaloyl, valeryl, isovaleryl, chloroacet
  • Examples of a “protecting group of carboxy” used herein include, but not limited to, any protecting groups of carboxy used in the field of synthetic organic chemistry, and include, for example, the “alkyl groups”, “alkenyl groups”, “alkynyl groups”, “aralkyl groups”, and “silyl groups” as above listed in the examples of the "protecting group of hydroxy” and similar groups thereof.
  • Examples of a “protecting group of amino” used herein include, but not limited to, any protecting groups of amino used in the field of synthetic organic chemistry, and include, for example, the “alkyl (alkenyl) carbonyl groups", “arylcarbonyl groups”, “alkoxycarbonyl groups”, “silyl groups”, “aralkyl groups”, “alkenyloxycarbonyl groups”, and “aralkyloxycarbonyl groups” as above listed in the "protecting group of hydroxy” and similar groups thereof.
  • the reaction temperature in each step in the General syntheses herein typically ranges from -80 to 150°C.
  • the reaction time in each step typically ranges from 0.1 to 200 hours.
  • Y 1 is a leaving group such as, halogens (e.g. chlorine and bromine), and phenyloxy groups (e.g. 4-nitro-phenyloxy group) and the other symbols are as defined for Compound [I] above.
  • halogens e.g. chlorine and bromine
  • phenyloxy groups e.g. 4-nitro-phenyloxy group
  • Compound [I] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, compound [II] may be reacted with compound [III] having a leaving group (Y 1 ) in the presence of a base in an inert solvent to give Compound [I].
  • a base preferably used herein includes organic bases (e.g. trimethylamine, triethylamine and N,N-diisopropylethylamine (DIPEA)).
  • DIPEA N,N-diisopropylethylamine
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes inert solvents such as halohydrocarbons (e.g. chloroform and dichloromethane), ethers (e.g. dioxane, and tetrahydrofuran), amides (e.g. N,N-dimethylformamide) and nitriles (e.g. acetonitrile).
  • Y 1 is a leaving group such as, halogen (e.g. chlorine and bromine), and phenyloxy groups (e.g. 4-nitrophenyloxy group), the protecting group includes alkyl (alkenyl) carbonyl groups, arylcarbonyl groups and alkoxycarbonyl groups (e.g. tert-butoxycarbonyl), and the other symbols are as defined for Compound [I] above.
  • halogen e.g. chlorine and bromine
  • phenyloxy groups e.g. 4-nitrophenyloxy group
  • the protecting group includes alkyl (alkenyl) carbonyl groups, arylcarbonyl groups and alkoxycarbonyl groups (e.g. tert-butoxycarbonyl), and the other symbols are as defined for Compound [I] above.
  • Compound [I] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, compound [IV] may be de-protected in the presence of an acid in an inert solvent, followed by treatment with compound [III] having a leaving group (Y 1 ) in the presence of a base in an inert solvent, to give Compound [I].
  • An intermediate compound obtained after the first step may be purified before moving to the second step or be used to the second step without purification. Any acids that are described above may be used in the first step, and the acid preferably used herein includes inorganic acids (e.g. hydrochloric acid, sulfuric acid and hydrobromic acid) and organic acids (acetic acid, trifluoroacetic acid and p-toluenesulfonic acid).
  • any solvents that are described above may be used in the first step, and the solvent preferably used herein includes as halogenated hydrocarbons (e.g. chloroform and dichloromethane), ethers (e.g. dioxane and tetrahydrofuran), and alcohols (e.g. methanol, ethanol and 2-propanol).
  • halogenated hydrocarbons e.g. chloroform and dichloromethane
  • ethers e.g. dioxane and tetrahydrofuran
  • alcohols e.g. methanol, ethanol and 2-propanol
  • Compound [I] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, Compound [I] may be manufactured by reacting compound [II] with compound [V] in an inert solvent in the presence of a base. Any condensation agents that are described above may be used in this reaction, and the condensation agents preferably used herein includes HATU, WSC or a hydrochloride salt. Any bases that are described above may be used in this reaction, and the base preferably used herein includes as an organic base (e.g. trimethylamine, triethylamine and N,N-diisopropylethylamine (DIPEA)).
  • DIPEA diisopropylethylamine
  • any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes as halogenated hydrocarbons (e.g. chloroform and dichloromethane), ethers (e.g. dioxane and tetrahydrofuran), amides (e.g. N,N-dimethylformamide), and nitriles (e.g. acetonitrile).
  • halogenated hydrocarbons e.g. chloroform and dichloromethane
  • ethers e.g. dioxane and tetrahydrofuran
  • amides e.g. N,N-dimethylformamide
  • nitriles e.g. acetonitrile
  • Y 2 is a leaving group such as phenyloxy groups (e.g. 4-nitrophenyloxy group), and the other symbols are as defined for Compound [I] above.
  • Compound [Ia] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, compound [Ia] may be manufactured by reacting compound [VI] with compound [Va] in an inert solvent in the presence of a base.
  • a base preferably used herein includes alkali metal hydrides (e.g. sodium hydride, and potassium hydride), and metal alkoxides (e.g sodium tert-butoxide, and potassium tert-butoxide).
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes ethers (e.g. dioxane and tetrahydrofuran), and amides (e.g. N,N-dimethylformamide),
  • Compound [Ib] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, compound [Ib] may be manufactured by reacting compound [VII] with compound [VIII] in an inert solvent in the presence of a base. Any condensation agents that are described above may be used in this reaction, and the agents preferably used herein includes agents (e.g. HATU, WSC or a hydrochloride salt). Any bases that are described above may be used in this reaction, and the base preferably used herein includes as an organic base (e.g. trimethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)).
  • DIPEA N,N-diisopropylethylamine
  • any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes as halogenated hydrocarbons (e.g. chloroform, and dichloromethane), ethers (e.g. dioxane and tetrahydrofuran), amides (e.g. N,N-dimethylformamide) and nitriles (e.g. acetonitrile).
  • halogenated hydrocarbons e.g. chloroform, and dichloromethane
  • ethers e.g. dioxane and tetrahydrofuran
  • amides e.g. N,N-dimethylformamide
  • nitriles e.g. acetonitrile
  • Y 3 is a leaving group such as halogen (e.g. chlorine and bromine) and alkylsulfonyloxy groups (e.g. trifluoromethylsulfonyloxy), and the other symbols are as defined for Compound [I] above.
  • halogen e.g. chlorine and bromine
  • alkylsulfonyloxy groups e.g. trifluoromethylsulfonyloxy
  • Compound [I] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, compound [I] may be manufactured by Suzuki coupling reaction of a boronic acid ester compound [IX] with compound [X] having a leaving group in an inert solvent in the presence of a base and a palladium catalyst. Instead of compound [IX], a compound where the boronic acid ester moiety of compound [IX] may be replaced with boronic acid may be used herein. Any bases that are described above may be used in this reaction, and the base preferably used herein includes alkali metal carbonates (e.g. sodium carbonate, potassium carbonate and cesium carbonate) and alkali metal phosphates (e.g. sodium phosphate and potassium phosphate).
  • alkali metal carbonates e.g. sodium carbonate, potassium carbonate and cesium carbonate
  • alkali metal phosphates e.g. sodium phosphate and potassium phosphate
  • any palladium catalysts that are described above may be used in this reaction, and the palladium catalyst preferably used herein includes PdCl 2 (dppf) ⁇ DCM, XPhos Pd G3, palladium (II) acetate, Pd 2 (dba) 3 and Pd(PPh 3 ) 4 .
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes ethers (e.g. dimethoxyethane, 1,4-dioxane and tetrahydrofuran).
  • Y 4 is a leaving group such as halogen (e.g. chlorine and bromine) and alkylsulfonyloxy groups (e.g. trifluoromethylsulfonyloxy) or a protecting group of hydroxy such as alkyl groups (e.g. methyl) and aralkyl groups (e.g. benzyl), and X is as defined for Compound [I] above.
  • halogen e.g. chlorine and bromine
  • alkylsulfonyloxy groups e.g. trifluoromethylsulfonyloxy
  • a protecting group of hydroxy such as alkyl groups (e.g. methyl) and aralkyl groups (e.g. benzyl)
  • X is as defined for Compound [I] above.
  • Intermediate [Va] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, intermediate [Va] may be manufactured by reacting compound [XI] with a halogenating agent in an inert solvent in the presence or absence of a base. Any known halogenating agents may be used in this reaction, and the halogenating agent preferably used herein includes N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide. Any bases that are described above may be used in this reaction, and the base preferably used herein includes alkali metal carbonates (e.g. sodium carbonate, potassium carbonate and cesium carbonate). Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes amides (e.g. N,N-dimethylformamide) and nitriles (e.g. acetonitrile).
  • amides e.g. N,N-dimethylformamide
  • nitriles e.
  • Y 5 and Y 6 are a leaving group such as halogen (e.g. chlorine and bromine) and alkylsulfonyloxy groups (e.g. trifluoromethylsulfonyloxy), and the other symbols are as defined for Compound [I] above.
  • halogen e.g. chlorine and bromine
  • alkylsulfonyloxy groups e.g. trifluoromethylsulfonyloxy
  • Intermediate [XIII] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, intermediate [XIII] may be manufactured by reacting compound [XII] with R 1 -H in an inert solvent in the presence of a base. Any bases that are described above may be used in this reaction, and the base preferably used herein includes metal alkoxides (e.g sodium tert-butoxide, and potassium tert-butoxide) and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate). Any palladium catalysts that are described above may be used in this reaction, and the palladium catalyst preferably used herein includes palladium (II) acetate and Pd 2 (dba) 3 .
  • a base preferably used herein includes metal alkoxides (e.g sodium tert-butoxide, and potassium tert-butoxide) and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate).
  • any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes aromatic hydrocarbons such as benzene and toluene, ethers (e.g. dioxane and tetrahydrofuran) and alcohols (e.g. tert-butanol).
  • aromatic hydrocarbons such as benzene and toluene
  • ethers e.g. dioxane and tetrahydrofuran
  • alcohols e.g. tert-butanol
  • the protecting group includes alkyl (alkenyl) carbonyl groups, arylcarbonyl groups and alkoxycarbonyl groups, and each symbol is as defined above.
  • Intermediate [XV] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, intermediate [XV] may be manufactured by Suzuki coupling reaction of compound [XIII] having a leaving group Y 6 with a boronic acid ester compound [XIV] in an inert solvent in the presence of a base and a palladium catalyst. Instead of compound [XIV], a compound where the boronic acid ester moiety of compound [XIV] may be replaced with boronic acid may be used herein. Any bases that are described above may be used in this reaction, and the base preferably used herein includes alkali metal carbonates (e.g. sodium carbonate, potassium carbonate and cesium carbonate) and alkali metal phosphates (e.g.
  • alkali metal carbonates e.g. sodium carbonate, potassium carbonate and cesium carbonate
  • alkali metal phosphates e.g.
  • any palladium catalysts that are described above may be used in this reaction, and the palladium catalyst preferably used herein includes PdCl 2 (dppf) ⁇ DCM, XPhos Pd G3, palladium (II) acetate, Pd 2 (dba) 3 and Pd(PPh 3 ) 4 .
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes ethers (e.g. dimethoxyethane, 1,4-dioxane and tetrahydrofuran) with or without water.
  • Intermediate [XVb] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, intermediate [XVb] may be manufactured by addition of hydrogen to compound [XVa] in an inert solvent in presence of a catalyst. Any catalysts that are described above may be used in this reaction, and the catalyst preferably used herein includes palladium on carbon (Pd/C), platinum on carbon (Pt/C), platinum oxide (PtO 2 ). Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes ethers (e.g. dioxane and tetrahydrofuran), alcohols (e.g. methanol, ethanol and 2-propanol) and esters (e.g. ethyl acetate).
  • ethers e.g. dioxane and tetrahydrofuran
  • alcohols e.g. methanol, ethanol and 2-propanol
  • esters e.g. ethyl acetate
  • the protecting group includes alkyl (alkenyl) carbonyl groups, arylcarbonyl groups and alkoxycarbonyl groups and each symbol are as defined above.
  • Intermediate [IIa] may be manufactured by the reaction indicated by the above synthetic scheme. Specifically, intermediate [IIa] may be manufactured by de-protection of the compound [XV] in an inert solvent in presence of an acid.
  • Any acids that are described above may be used in this reaction, and the acid preferably used herein includes inorganic acids (e.g. hydrochloric acid, sulfuric acid and hydrobromic acid) and organic acids (acetic acid, trifluoroacetic acid and p-toluenesulfonic acid).
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includes as halogenated hydrocarbons (e.g. chloroform and dichloromethane), ethers (e.g. dioxane and tetrahydrofuran), and alcohols (e.g. methanol, ethanol and 2-propanol).
  • R 31 is as defined for Compound [I] above.
  • Intermediate [XVIII] may be manufactured according to any of the reactions indicated by the above synthetic scheme.
  • intermediate [XVIII] may be manufactured by reacting compound [XVI] or [XVI'] with compound [XVII] in an inert solvent in the presence of an amine.
  • Any bases that are listed above as the organic base may be used in this reaction, and the amine preferably used herein includes as an organic base (e.g. trimethylamine, and N,N-diisopropylethylamine (DIPEA)).
  • DIPEA N,N-diisopropylethylamine
  • Any solvents that are described above may be used in this reaction, and the solvent preferably used herein includess halohydrocarbons (e.g. chloroform, and dichloromethane), ethers (e.g. dioxane and tetrahydrofuran), and nitriles (e.g. acetonitrile).
  • reaction product may be used in the next reaction either as is in the form dissolved in the reaction solution or as a crude product, but it may also be isolated from the reaction mixture by ordinary methods and easily purified by ordinary separation techniques. Examples of ordinary separation techniques include recrystallization, distillation, and chromatography.
  • Any starting compounds, intermediate compounds, and product compounds in each of the above steps and Compound [I] include geometric isomers, stereoisomers, optical isomers, and tautomers thereof. Respective isomers may be separated by ordinary optical resolution methods. They may also be manufactured from raw material compounds having suitable optical activity.
  • Compound [I] may be manufactured according to any of the above synthetic schemes, or analogous methods thereof.
  • any starting compounds used in the manufacture of Compound [I] are commercially available, or may be produced by known methods or analogous methods thereof.
  • Any starting compounds and product compounds in each step above may be used in the form of appropriate salts thereof.
  • Examples of such salts include salts similar to those listed for salts of Compound [I] below.
  • any compounds obtained in each step or commercially available compounds used herein are in the free form, they may be converted to corresponding salts by known methods.
  • any compounds obtained in each step or commercially available compounds used herein are in the salt form, they may be converted to corresponding free forms or into other salts by known methods.
  • Compound [I] may also exist as any pharmaceutically acceptable salts thereof, and in some embodiments, Compound [I] may form an acid addition salt or a salt with a base depending on substituent(s) that are present in Compound [I].
  • Examples of the "acid” herein 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, and the like.
  • base examples 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, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, and choline; and ammonium salts, and the like.
  • Compound [I] may also form a salt with an amino acid such as lysine, arginine, aspartic acid, glutamic acid, and the like.
  • the present invention also encompasses various hydrates, solvates, and crystal polymorphs of Compound [I] and salts thereof.
  • Compound [I] also includes compounds in which one or more isotope atoms have been substituted for any one or more atoms in any proportions.
  • isotope 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, and the like.
  • One embodiment of the present invention includes pharmaceutically acceptable prodrugs of Compound [I].
  • Compound [I] may be modified on any group(s) including any reactive functional groups of Compound [I] such as -OH, -COOH, amino, and the like, so as to provide prodrugs of Compound [I].
  • These functional groups may be modified with any group(s) selected appropriately from the protecting groups of hydroxy, carboxy, and amino.
  • Compound [I], or a salt thereof may be in the form of a pharmaceutically acceptable co-crystal.
  • the co-crystal herein means a crystalline substance composed of two or more independent substances each having different physical properties at room temperature, such as structures, melting points, heat of fusion, and the like.
  • Co-crystals and co-crystal salts may be manufactured appropriately by well-known co-crystallization methods.
  • Compound [I], or a salt thereof may show CSF1R inhibitory activity in mammals, which leads to reduction of macrophage, microglia, and osteoclast.
  • Compound [I], or a salt thereof may preferably show highly selective CSF1R inhibitory activity compared to at least any one of other kinases adjacent to CSF1R such as FLT3, cKit, PDGFR including PDGFR ⁇ and PDGFR ⁇ , and Trk including TrkC, so as to reduce any risks of undesired actions or side effects, including those caused by unexpected inhibition of tyrosine kinases in addition to CSF1R, upon administration of Compound [I], or a salt thereof.
  • Compound [I], or a salt thereof may prevent or reduce activation or proliferation of microglia (i.e., microgliosis) by inhibiting CSF1R particularly expressed in microglia, so that central immunomodulatory function can be reinforced.
  • Compound [I], or a salt thereof may be beneficial to treat cancers, autoimmune diseases such as rheumatoid arthritis, muscular dystrophy, and asthma.
  • Compound [I], or a salt thereof, may also be beneficial to treat neurological diseases such as Alzheimer’s disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, traumatic brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, and bone diseases.
  • neurological diseases such as Alzheimer’s disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, traumatic brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post my
  • Compound [I], or a salt thereof may also be effective in the treatment, prevention, and/or diagnosis of any two or more diseases described above. Moreover, Compound [I], or a salt thereof, may be useful as active ingredients in pharmaceuticals, and for example may show few side effects, desirable tolerability, desirable stability (storage stability, metabolic stability, etc.), and the like. Compound [I], or a salt thereof, may also be useful for preventative and/or therapeutic agents for various diseases described herein by inhibiting CSF1R.
  • Compound [I], or a salt thereof may be useful as a Positron Emission Topography (PET) tracer, preferably a PET imaging agent, that may be useful for in vitro, exo vivo, in vivo, or clinical trial tests and diagnostic imaging in humans and/or non-humans.
  • PET Positron Emission Topography
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N, can be useful in PET studies for examining target occupancy.
  • compounds labeled with 11 C or 18 F may be used for a PET tracer.
  • a medical preparation (herein also referred to as a "pharmaceutical composition") comprising Compound [I] or a salt thereof as an active ingredient is provided.
  • a medical preparation herein may be selected from various forms depending on therapeutic objectives, and examples of the medical preparation include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), and the like. Tablets include coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayered tablets.
  • Compound [I], or a salt thereof, may be combined with a pharmaceutically acceptable carrier to be formulated into any forms of a medical preparation.
  • the carrier include commonly used substances for a component of a medical preparation, including excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol; diluents; fillers; bulking agents; surfactants; and the like.
  • Pharmaceutically acceptable carriers to be used in formulating into a tablet specifically include excipients such as lactose; binders such as polyvinylpyrrolidone; disintegrants such as starch; absorption aids such as sodium lauryl sulfate; humectants such as glycerin and starch; adsorbants such as colloidal silicic acid; and lubricants such as magnesium stearate and polyethylene glycol.
  • excipients such as lactose
  • binders such as polyvinylpyrrolidone
  • disintegrants such as starch
  • absorption aids such as sodium lauryl sulfate
  • humectants such as glycerin and starch
  • adsorbants such as colloidal silicic acid
  • lubricants such as magnesium stearate and polyethylene glycol.
  • Pharmaceutically acceptable carriers to be used in formulating into a pill specifically include excipients such as glucose; binders such as gum arabic powder; and disintegrants such as laminaran.
  • compositions to be used in formulating into a liquid, emulsion, or suspension specifically include water. Any ordinary solubilizing agents and/or buffers as well as colorants, preservatives, aromatics, flavorings, and sweeteners may also be comprised in the preparation, and other drugs may also be comprised as necessary.
  • Pharmaceutically acceptable carriers to be used in formulating into a suppository specifically include cocoa butter and the like.
  • An injection may be formulated into the form of a liquid, emulsion, or suspension.
  • the injection is preferably sterilized, and is also preferably isotonic with blood.
  • the isotonic injection may comprise a sufficient amount of sodium chloride and soothing agents, and may also optionally comprise other drugs.
  • the amount (herein also referred to as "effective amount") of Compound [I], or a salt thereof, comprised in a medical preparation may be, but is not limited thereto, any amounts conventionally used in the art, and preferably includes any amounts of 1% to 70% of the medical preparation.
  • a medical preparation may be administered orally if it is in the form of a tablet, pill, liquid, suspension, emulsion, granule, or capsule.
  • a medical preparation may be administered intravenously either alone or in a mixture with an ordinary replacement fluid such as glucose and amino acids if it is in the form of an injection.
  • a medical preparation may be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally as necessary.
  • a medical preparation may be administered rectally if it is in the form of a suppository.
  • the dose of Compound [I], or a salt thereof, to be administered may be any doses selected depending on administration routes, the age and sex of a patient to be administered, the severity of diseases, and other conditions, and includes 0.01 to 100 mg, preferably 0.1 to 50 mg, per 1 kg of body weight per day.
  • the dose may be administered once or separately in several times.
  • Compound [I], or a salt thereof may be used in combination with at least one therapeutic or preventive drug or standard-of-care agent, which may be referred to as a combined drug herein, useful for one of the above-mentioned diseases.
  • a combined drug useful for one of the above-mentioned diseases.
  • Compound [I], or a salt thereof is used in combination with a combined drug, Compound [I], or a salt thereof, and the drug may be administered simultaneously or at the same time, separately or sequentially at about the same time, or separately or sequentially at different times with a suitable interval in between.
  • Compound [I], or a salt thereof, and the combined drug may be formulated into separate preparations or mixed and formulated into a single preparation.
  • Item 1-2 The compound according to Item 1-1, or a salt thereof, wherein a moiety represented by the formula: is any one of the following structures: provided that R 1 is halogen, -CN, -L 11 -R 11 optionally substituted with one or more R 12 , or -R 11 optionally substituted with one or more R 12 .
  • Item 1-4 The compound according to any one of Items 1-1 to 1-3, or a salt thereof, wherein R 11 is a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, d1) a saturated or unsaturated 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms as ring-constituting heteroatom, d2) a saturated 4- to 6-membered monocyclic heterocyclyl containing 1 oxygen atom as ring-constituting heteroatom, d3) a saturated or unsaturated 5- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 oxygen atom as ring-constituting heteroatom, d4) an unsaturated 5-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 sulfur atom as ring-constituting heteroatom, d5) a saturated or unsaturated 7- to 9-
  • Item 1-5 The compound according to any one of Items 1-1 to 1-3, or a salt thereof, wherein R 11 is: a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, or d) a saturated 4- to 10-membered monocyclic, bicyclic, or spiro heterocyclyl.
  • Item 1-6 The compound according to any one of Items 1-1 to 1-3, or a salt thereof, wherein R 11 is: a) C 1-6 alkyl, b) C 1-6 haloalkyl, or c) C 3-8 cycloalkyl.
  • Item 1-7 The compound according to any one of Items 1-1 to 1-6, or a salt thereof, wherein R 12 is each independently halogen, -OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 3-8 cycloalkyl, a saturated 4- to 6-membered monocyclic heterocyclyl containing 1 oxygen atom as ring-constituting heteroatom, or a saturated 6- to 10-membered spiro heterocyclyl containing 2 nitrogen atoms as ring-constituting heteroatom optionally substituted with C 1-6 alkyl.
  • Item 1-12 The compound according to any one of Items 1-1 to 1-11, or a salt thereof, wherein R 1 is hydrogen, fluoro, chloro, cyano, isopropyl, methoxy, methoxy-d 3 , 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, cyclopropanecarbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropy
  • Item 1-13 The compound according to any one of Items 1-1 to 1-12, or a salt thereof, wherein R 1 is hydrogen, fluoro, chloro, cyano, isopropyl, methoxy, methoxy-d 3 , 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, cyclopropanecarbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropy
  • Item 1-14 The compound according to any one of Items 1-1 to 1-13, or a salt thereof, wherein R 1 is hydrogen, fluoro, chloro, cyano, isopropyl, methoxy, methoxy-d 3 , 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, cyclopropanecarbonyl, cyclopropylcarbamoyl, (1-fluorocyclopropyl)methoxy, (2,2-difluorocyclopropyl)methoxy, 2-
  • Item 1-15 The compound according to any one of Items 1-1 to 1-14, or a salt thereof, wherein R 1 is hydrogen, halogen, -CN, or -L 11 -R 11 optionally substituted with one or more R 12 .
  • Item 1-17 The compound according to any one of Items 1-1 to 1-16, or a salt thereof, provided that when R 1 is -R 11 optionally substituted with one or more R 12 , then R 11 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.
  • Item 1-18 The compound according to any one of Items 1-1 to 1-17, or a salt thereof, provided that when R 1 is -R 11 optionally substituted with one or more R 12 , then R 11 is C 1-6 alkyl or C 1-6 haloalkyl.
  • Item 1-19 The compound according to any one of Items 1-1 to 1-18, or a salt thereof, wherein R 21 and R 22 are hydrogen.
  • Item 1-20 The compound according to any one of Items 1-1 to 1-19, or a salt thereof, wherein R 31 is a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, d) phenyl, e1) a saturated or unsaturated 4- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms as ring-constituting heteroatom, e2) a saturated 4- to 6-membered monocyclic heterocyclyl containing 1 oxygen atom as ring-constituting heteroatom, e3) a saturated or unsaturated 5- to 6-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 oxygen atom as ring-constituting heteroatom, e4) an unsaturated 5-membered monocyclic heterocyclyl containing 1 to 2 nitrogen atoms and 1 sulfur atom as ring-constituting heteroatom, e5) a saturated or
  • Item 1-21 The compound according to any one of Items 1-1 to 1-19, or a salt thereof, wherein R 31 is: a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, d) phenyl, or e) a saturated 4- to 10-membered monocyclic, bicyclic, or spiro heterocyclyl.
  • Item 1-22 The compound according to any one of Items 1-1 to 1-21, or a salt thereof, wherein R 31 is: a) C 1-6 alkyl, b) C 1-6 haloalkyl, c) C 3-8 cycloalkyl, or d) phenyl.
  • Item 1-23 The compound according to any one of Items 1-1 to 1-22, or a salt thereof, wherein R 31 is: a) C 1-6 alkyl, b) C 1-6 haloalkyl, or c) C 3-8 cycloalkyl.
  • Item 1-28 The compound according to any one of Items 1-1 to 1-27, or a salt thereof, wherein R 3 is 5-ethylpyrimidin-2-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 3-cyclopropyl-1,2,4-oxadiazol-5-yl, (2-(difluoromethyl)azetidin-1-yl)carbonyl, (3,3-difluoroazetidin-1-yl)carbonyl, (3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)carbonyl, 6-oxa-1-azaspiro[3.4]octan-1-ylcarbonyl, azetidin-1-ylcarbonyl, 2-(p-tolyloxy)ethylcarbonyl, 2-phenoxyethylcarbonyl, ((2-methylbenzyl)oxy)methylcarbonyl, phenylethylcarbamoyl, 1,1,1-triflu
  • Item 1-29. The compound according to any one of Items 1-1 to 1-28, or a salt thereof, wherein R 3 is (2-(difluoromethyl)azetidin-1-yl)carbonyl, (3,3-difluoroazetidin-1-yl)carbonyl, (3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)carbonyl, 6-oxa-1-azaspiro[3.4]octan-1-ylcarbonyl, azetidin-1-ylcarbonyl, 2-(p-tolyloxy)ethylcarbonyl, 2-phenoxyethylcarbonyl, ((2-methylbenzyl)oxy)methylcarbonyl, phenylethylcarbamoyl, 1,1,1-trifluoro-2-methylpropan-2-yloxycarbonyl, 1-fluoro-2-methylpropan-2-yloxycarbonyl, cyclopropoxycarbonyl, cyclopropy
  • Item 1-30 The compound according to any one of Items 1-1 to 1-29, or a salt thereof, provided that when R 3 is R 31 optionally substituted with one or more R 32 , then R 31 is C 1-6 alkyl, C 1-6 haloalkyl, or C 3-8 cycloalkyl.
  • Item 1-3 The compound according to any one of Items 1-1 to 1-30, or a salt thereof, wherein R 3 is -L 31 -R 31 optionally substituted with one or more R 32 .
  • Item 1-32 The compound according to any one of Items 1-1 to 1-31, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-33 The compound according to any one of Items 1-1 to 1-32, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-34 The compound according to any one of Items 1-1 to 1-33, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-35 The compound according to any one of Items 1-1 to 1-33, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-36 The compound according to any one of Items 1-1 to 1-33, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-37 The compound according to any one of Items 1-1 to 1-33, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-38 The compound according to any one of Items 1-1 to 1-33, or a salt thereof, wherein the compound of Formula [I] is
  • Item 1-39 The compound according to any one of Items 1-1 to 1-32, or a salt thereof, wherein X is CH.
  • Item 1-40 The compound according to any one of Items 1-1 to 1-32, or a salt thereof, wherein X is N.
  • Item 1-4 The compound according to any one of Items 1-1 to 1-32, or a salt thereof, wherein the bond: is single bond.
  • Item 1-42 The compound according to any one of Items 1-1 to 1-32, or a salt thereof, wherein the bond: is double bond.
  • Item 1-43 The compound according to any one of Items 1-1 to 1-42, or a salt thereof, wherein R 1 is -L 11 -R 11 optionally substituted with one or more R 12 ; L 11 is -O- or -O-ethylene-O-; R 11 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or a saturated 4- to 6-membered monocyclic heterocyclyl; and R 12 is halogen, C 1-6 alkyl optionally substituted with one or more deuteriums, or C 1-6 haloalkyl.
  • Item 1-44 The compound according to any one of Items 1-1 to 1-43, or a salt thereof, wherein R 1 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-furo[3,4-c]pyrrol-5(3H)-yl, 6,6-difluoro-2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, thiazol-5-yl, or 1-methyl-1H-pyrazol-4-yl.
  • Item 1-45 The compound according to any one of Items 1-1 to 1-44, or a salt thereof, wherein R 1 is 2-methoxyethoxy, cyclopropoxy, (1-methylpiperidin-4-yl)oxy, or 2,2-difluoroethoxy.
  • Item 1-46 The compound according to any one of Items 1-1 to 1-45, or a salt thereof, wherein R 1 is hydrogen, halogen, -CN, or -L 11 -R 11 optionally substituted with one or more R 12 .
  • Item 1-47 The compound according to any one of Items 1-1 to 1-46, or a salt thereof, wherein R 3 is cyclopropoxycarbonyl, (1-fluoromethyl-2-methylpropan-2-yl)oxycarbonyl, oxazol-4-ylmethoxycarbonyl, thiazol-4-ylmethoxycarbonyl, or 3,3-difluoroazetidin-1-ylcarbonyl.
  • Item 1-48 The compound according to Item 1-1, or a salt thereof, wherein the compound is selected from the group consisting of the following compounds.
  • Item 1-49 The compound according to Item 1-1, wherein the compound is selected from the group consisting of the following compounds.
  • Item 1-50 The compound according to Item 1-1, or a salt thereof, wherein the compound is selected from the group consisting of the following compounds.
  • Item 1-51 The compound according to Item 1-1, wherein the compound is selected from the group consisting of the following compounds.
  • Item 1-52 The compound according to Item 1-1, wherein the compound is selected from the compounds of Examples 1 to 152 as shown in Table 3.
  • Item 2 A pharmaceutical composition comprising a compound according to any one of Items 1-1 to 1-52, or a salt thereof, as an active ingredient and a pharmaceutically acceptable carrier or excipient.
  • Item 3-1 A therapeutic, preventative, and/or diagnostic agent for a disease caused by CSF1R comprising a compound according to any one of Items 1-1 to 1-52, or a salt thereof, as an active ingredient.
  • Item 3-2 The agent according to Item 3-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation
  • Item 3-3 The agent according to Item 3-1 or 3-2, for use in simultaneous, separate, or sequential combination with at least one therapeutic or preventive drug for a disease selected from the group consisting of Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • tauopathies ALS
  • MS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI)
  • Parkinson’s disease pain, spinal cord injury, Crohn’s disease
  • Item 4-1 A method for treating, preventing, and/or diagnosing a disease caused by CSF1R, which comprises administering to a human in need thereof an effective amount of a compound according to any one of Items 1-1 to 1-52, or a salt thereof.
  • Item 4-2. The method according to Item 4-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation
  • Item 4-3 The method according to Item 4-1 or 4-2, the method further comprising: administering at least one therapeutic or preventive drug for a disease selected from the group consisting of Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • tauopathies ALS
  • MS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, gla
  • Item 5-1 A compound according to any one of Items 1-1 to 1-52, or a salt thereof, for use in the treatment, prevention, and/or diagnosis of a disease caused by CSF1R.
  • Item 5-2 The compound, or a salt thereof, for use according to Item 5-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial,
  • Item 5-3 The compound, or a salt thereof, for use according to Item 5-1 or 5-2, wherein the compound, or a salt thereof, is administered in simultaneous, separate, or sequential combination with at least one therapeutic or preventive drug for a disease selected from the group consisting of Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury
  • Item 6-1 Use of a compound according to any one of Items 1-1 to 1-52, or a salt thereof, in the manufacture of a medicament for treating, preventing, and/or diagnosing a disease caused by CSF1R.
  • Item 6-2 The use according to Item 6-1, wherein the disease caused by CSF1R is selected from Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation
  • Item 6-3 The use according to Item 6-1 or 6-2, wherein the medicament is administered in simultaneous, separate, or sequential combination with at least one therapeutic or preventive drug for a disease selected from the group consisting of Alzheimer's disease (AD), tauopathies, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), HIV-associated neurocognitive disorders (HAND), prion disease, trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis, glaucoma, infections (such as viral, bacterial, and parasitic), cardiovascular diseases such as inflammation post myocardial infarction, bone diseases, muscular dystrophy, or asthma.
  • AD Alzheimer's disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • HAND HIV-associated neurocognitive disorders
  • prion disease trauma brain injury (TBI), Parkinson’s disease, pain, spinal cord injury, Crohn’s disease, radiation-induced lung fibrosis,
  • Item 7 A process for preparing a compound of Formula [I], or a salt thereof, as described herein.
  • Item 8-2 The compound according to Item 8-1, or a salt thereof, represented by any one of the compounds of Formulae [II], [IV], [VI], [VII], and [IX]: wherein R x is a protecting group selected from alkyl (alkenyl) carbonyl groups, arylcarbonyl groups, and alkoxycarbonyl groups, Y 2 is a leaving group selected from phenyloxy groups including 4-nitrophenyloxy, n is 0 or 1, and the other symbols are as defined in Item 1-1.
  • R x is a protecting group selected from alkyl (alkenyl) carbonyl groups, arylcarbonyl groups, and alkoxycarbonyl groups
  • Y 2 is a leaving group selected from phenyloxy groups including 4-nitrophenyloxy
  • n is 0 or 1
  • the other symbols are as defined in Item 1-1.
  • Item 8-3 The compound according to Item 8-1, or a salt thereof, wherein the compound is selected from the compounds of Reference Examples 1 to 244 as shown in Table 2.
  • room temperature (RT) generally means about 10°C to about 35°C.
  • the ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified.
  • % means wt%, unless otherwise specified.
  • Mass spectrum was measured by LC/MS (either of ACQUITY UPLC H-Class, Agilent 1290 Infinity II/6130 or Shimadzu Nexera/LCMS-2020).
  • ESI method was used as an ionization method. The data indicate actual measured values (found).
  • molecular ion peaks [M+H] + , [M-H] - , etc.) were observed.
  • a molecular ion peak or fragment ion peak of free form was generally observed.
  • silica gel column chromatography when denoted as basic, aminopropylsilane-bound silica gel was used.
  • the absolute configuration of a compound was determined by known X-ray crystal structure analysis (e.g., “Basic Course for Chemists 12, X-ray Crystal Structure Analysis” written by Shigeru Ohba and Shigenobu Yano, 1st edition, 1999) or estimated from the empirical rule of Shi 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).
  • the mixture was stirred at 40°C for 1h.
  • the mixture was stirred at 50°C for 0.5 h.
  • the mixture was stirred under nitrogen at room temperature overnight.
  • the mixture was stirred at 50°C for more 1.5 h (total time was 2 h) under hydrogen.
  • the mixture was filtered through Celite, and the filtrate was concentrated.
  • the residue was purified by amino silica gel column chromatography (Hexane/AcOEt) to obtain the object compound (66.9 mg).
  • the mixture was extracted with DCM.
  • the organic layer was collected and concentrated to obtain the crude material.
  • the crude was purified by basic-silica gel chromatography (hexane/AcOEt).
  • the material was suspended in IPE at refluxing temperature. The solid was collected and dried to obtain the object compound (1.65 g).
  • the mixture was diluted with AcOEt, filtered through Celite and washed with AcOEt and DCM. The filtrate was concentrated. The residue was purified by basic-silica gel column chromatography (hexane/AcOEt) to obtain the object compound (2.08 g).
  • the mixture was stirred at 90 °C for overnight under an argon atmosphere.
  • the reaction mixture was cooled to room temperature, and AcOEt and H 2 O were added thereto.
  • the mixture was filtered through Celite.
  • the organic layer was washed with brine and concentrated to obtain the object compound (3.36 g).
  • the mixture was stirred at 60°C under hydrogen for 3.5 h.
  • the reaction mixture was allowed to cool to room temperature and filtered through Celite and concentrated.
  • the residue was purified by silica gel chromatography (heptane/AcOE) to obtain the object compound (310 mg).
  • the reaction mixture was diluted with AcOEt. To the mixture was added Na 2 SO 4 . The mixture was filtered through a pad of celite and washed with AcOEt. The filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt) to obtain the object compound (411 mg).
  • Step 2 synthesis of 4- ⁇ 3-chloropyrazolo[1,5-a]pyridin-6-yl ⁇ morpholine.
  • a suspension of 6-bromo-3-chloropyrazolo[1,5-a]pyridine (1.0 g), morpholine (0.38 mL), Pd 2 dba 3 (210 mg), sodium tert-butoxide (630 mg), DavePhos (130 mg) in toluene (20 mL) was stirred at 90°C for 4 hours. Further morpholine (0.1 mL) and Pd 2 dba 3 (100 mg) were added and stirring was maintained at the same temperature overnight. The reaction mixture was filtered through Celite and the residue was partitioned between AcOEt and water. The organic layer was concentrated in vacuo and the residue was recrystallised from acetone to give the desired product (522 mg).
  • LCMS: [M+H] + 238
  • Step 3 synthesis of tert-butyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate.
  • Step 4 synthesis of tert-butyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate.
  • the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo.
  • the residue was purified by column chromatography (SiO 2 , AcOEt) to give 5 mg of the desired product.
  • LCMS: [M+H] + 387.
  • the mixture was extracted with DCM three times.
  • the organic layer was collected, followed by the evaporation to obtain the crude product.
  • the crude material was purified by basic-silica gel column chromatography (hexane/AcOEt) to obtain the object compound (40.8 mg).
  • Example 47 Synthesis of oxazol-4-ylmethyl 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 4-Nitrophenyl(oxazol-4-ylmethyl)carbonate (44.3 mg) was added to the mixture at 0°C.
  • DIPEA 58.6 ⁇ l was added to the mixture at 0°C. The mixture was stirred at room temperature under nitrogen for 3 h.
  • Example 50 Synthesis of 1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)-3-(p-tolyloxy)propan-1-one
  • 3-(p-tolyloxy)propanoic acid 18 mg
  • 6-methoxy-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine 25 mg
  • HOBt hydrate 22.95 mg
  • TEA 41.8 ⁇ l
  • DMF 1.5 ml
  • H 2 O 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 basic-silica gel column chromatography (hexane/AcOEt) to obtain the object compound (31.4 mg).
  • Example 51 Synthesis of oxazol-4-ylmethyl 4-(6-cyclopropoxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • a solution of tert-butyl 4-(6-cyclopropyloxypyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate (40 mg) in DCM (1.5 ml) was added TFA (0.5 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was concentrated to give the crude amine.
  • Example 52 Synthesis of oxazol-4-ylmethyl 4-(6-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • a solution of tert-butyl 4-(6-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate 83.5 mg
  • TFA (1 ml) was added at RT.
  • the mixture was stirred at room temperature for 2 h and then evaporated to obtain the intermediate compound as TFA salt.
  • Example 54 Synthesis of thiazol-4-ylmethyl 4-(6-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • the reaction mixture was filtered through Celite. The filtrate was concentrated to obtain the intermediate compound.
  • Example 55 Synthesis of 1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)-2-((2-methylbenzyl)oxy)ethan-1-one
  • 2-methylbenzyl alcohol 45.02 mg
  • NaH (12.86 mg) in DMF 1.5 mL
  • 2-chloro-1-(4-(6-methoxypyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)ethan-1-one 37.8 mg
  • DMF 0.5 mL
  • Example 56 Synthesis of thiazol-4-ylmethyl 4-(6-(2-morpholino-2-oxoethyl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • 2-(3-(1-((thiazol-4-ylmethoxy)carbonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (30 mg) in DMF (2 ml) were added HATU (36.9 mg), DIPEA (26.1 ⁇ l, 0.149 mmol) and morpholine (13.03 ⁇ l, 0.149 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was diluted with sat. NaHCO 3 aq. and H 2 O and extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography to obtain the object compound (13 mg).
  • Example 57 Synthesis of thiazol-4-ylmethyl 4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • TEA 125 ⁇ L
  • 4-nitrophenyl (thiazol-4-ylmethyl) carbonate 131 mg
  • the mixture was stirred at room temperature under nitrogen for 3.5 h.
  • H 2 O was added at room temperature.
  • the water layer was extracted with AcOEt.
  • the organic layer was concentrated.
  • the residue was purified by amino silica gel column chromatography (hexane/AcOEt). The obtain product was triturated in IPE (solid appeared) at room temperature. The solid was collected to obtain the object compound (92.1 mg).
  • Example 65 Synthesis of oxazol-4-ylmethyl 4-(6-(morpholinomethyl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate hydrochloride
  • To a solution of 4-((3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)methyl)morpholine (41 mg) in THF (3 mL) were added DIPEA (36 ⁇ L) and 4-nitrophenyl(oxazol-4-ylmethyl)carbonate (54 mg), and the mixture was stirred at room temperature for 30 min. Sat. NaHCO 3 aq. and AcOEt were added to the mixture.
  • the organic layer was separated by phase separator (Whatman, filter paper 1PS), 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 4N HCl/AcOEt (22 ⁇ L) was added to the mixture.
  • the reaction mixture was stirred at room temperature for 30 min.
  • the precipitates were collected on a filter to obtain the object compound (20 mg).
  • Example 67 Synthesis of oxazol-4-ylmethyl 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 6-(2,2-difluoroethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine 35 mg
  • DIPEA 33 ⁇ L
  • 4-nitrophenyl(oxazol-4-ylmethyl)carbonate 49 mg
  • the organic layer was separated by phase separator (Whatman, filter paper 1PS), and the solvent was removed.
  • the residue was purified by basic-silica gel column chromatography (heptane/AcOEt). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to obtain the object compound (36 mg).
  • Example 68 Synthesis of thiazol-4-ylmethyl 4-(6-(2,2-difluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 6-(2,2-difluoroethoxy)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine 35 mg
  • DIPEA 33 ⁇ L
  • 4-nitrophenyl(thiazol-4-ylmethyl)carbonate 52 mg
  • the organic layer was separated by phase separator (Whatman, filter paper 1PS), and the solvent was removed.
  • the residue was purified by basic-silica gel column chromatography (heptane/AcOEt). The obtained solid was washed by trituration with diisopropyl ether, and then collected on a filter to obtain the object compound (43 mg).
  • Example 76 Synthesis of oxazol-4-ylmethyl 4-(6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • 6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine 80 mg
  • TEA 6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine (80 mg) in DCM (5 mL)
  • TEA 6-(1-cyclopropyl-3,5-dimethyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine
  • Example 82 Synthesis of (4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidin-1-yl)(3,3-difluoroazetidin-1-yl)methanone
  • 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine 35 mg
  • 4-nitrophenyl 3,3-difluoroazetidine-1-carboxylate 38.2 mg
  • DIPEA 80 ⁇ L
  • Example 85 Synthesis of oxazol-4-ylmethyl 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyridine 50 mg
  • 4-nitrophenyl(oxazol-4-ylmethyl)carbonate 47.3 mg
  • Example 93 Synthesis of cyclopropyl 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine 65 mg
  • TEA 58.8 ⁇ l
  • cyclopropyl(4-nitrophenyl)carbonate 56.4 mg
  • the mixture was stirred for 3 h.
  • the mixture was concentrated.
  • the residue was purified by basic-silica gel column chromatography (hexane/AcOEt) to obtain the object compound (60 mg).
  • Example 94 Synthesis of cyclopropyl 4-(6-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • tert-butyl 4-(6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate 70 mg
  • THF 5 ml
  • DIPEA 58.7 ⁇ l
  • cyclopropyl(4-nitrophenyl)carbonate 75 mg
  • Example 102 Synthesis of thiazol-4-ylmethyl 4-(6-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 4-nitrophenyl(thiazol-4-ylmethyl)carbonate 54.8 mg was added to the mixture at 0°C.
  • Example 110 Synthesis of cyclopropyl 4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • DCM DCM
  • TFA 0.5 mL
  • Example 112 Synthesis of cyclopropyl 4-(6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazolo[1,5-a]pyridin-3-yl)piperidine-1-carboxylate
  • 6-(3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl)-2-oxa-6-azaspiro[3.3]heptane 81 mg) in THF (5 mL) were added DIPEA (71 ⁇ L) and cyclopropyl (4-nitrophenyl) carbonate (79 mg), and the mixture was stirred at room temperature for 5 h. Sat. NaHCO 3 aq.
  • Example 113 Synthesis of (1-methylcyclopropyl)methyl-4-(6-(thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate 4-Nitrophenyl 4-(6-(thiazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate (70 mg) was placed in a flask. DMF (1 mL) was added to the flask to make the mixture. 1-methylcyclopropyl)methanol (25.2 ⁇ L) was added to the mixture at room temperature. KOtBu (26.2 mg) was added to the mixture at 0°C.
  • Example 117 Synthesis of thiazol-4-ylmethyl 4-(6-(thiazol-5-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • TEA 58.6 ⁇ L
  • 4-nitrophenyl(thiazol-4-ylmethyl)carbonate 70.7 mg
  • the mixture was stirred for 3 h.
  • the mixture was diluted with H 2 O and extracted with DCM.
  • the organic layer was concentrated.
  • the residue was purified by basic-silica gel column chromatography (hexane/AcOEt) and triturated with AcOEt to obtain the object compound (74 mg).
  • Example 138 Synthesis of 1-fluoro-2-methylpropan-2-yl 4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)piperidine-1-carboxylate
  • 1-(((1-fluoro-2-methylpropan-2-yl)oxy)carbonyl)-3-methyl-1H-imidazol-3-ium iodide 244.1 mg
  • 6-(1-methyl-1H-pyrazol-4-yl)-3-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine 98 mg
  • TEA ⁇ l
  • Example 143 Synthesis of 4- ⁇ 3-[1-(5-methyl-1,2,4-oxadiazol-3-yl)piperidin-4-yl]pyrazolo[1,5-a]pyridin-6-yl ⁇ morpholine.
  • a solution of tert-butyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate) (909 mg) in 4N HCl in dioxane (5 mL) and dioxane (5 mL) was stirred at room temperature for 4 h. The reaction was concentrated to obtain the intermediate compound (910 mg).
  • Example 145 Synthesis of (1,3-thiazol-4-yl)methyl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate
  • a solution of (1,3-thiazol-4-yl)methanol (32 mg), 4-nitrophenyl chloroformate (60 mg) and triethylamine (0.12 mL) in DCM (3 mL) was stirred at room temperature for 2 hours.
  • Example 146 Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate
  • Step 1 synthesis of 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate.
  • 4-Nitrophenyl chloroformate (1.9 g) was added to a solution of 1,1,1-trifluoro-2-methylpropan-2-ol (1.0 g) and pyridine (1.3 mL) in DCM (20 mL) and the solution was stirred at room temperature overnight. The reaction was quenched with 1M HCl and extracted with DCM.
  • Step 2 synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate.
  • a solution of 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride salt (100 mg), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate (82 mg) and triethylamine (0.16 mL) in DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and NaHCO 3 .
  • Example 147 Synthesis of 1-fluoro-2-methylpropan-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate
  • Step 1 synthesis of 1-fluoro-2-methylpropan-2-yl 4-nitrophenyl carbonate.
  • 4-Nitrophenyl chloroformate (654 mg) was added to a solution of 1-fluoro-2-methylpropan-2-ol (250 mg) and pyridine (0.44 mL) in DCM (10 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and 1M HCl and the organic phase was concentrated in vacuo.
  • Step 2 synthesis of 1-fluoro-2-methylpropan-2-yl 4-[6-(morpholin-4-yl)pyrazolo[1,5-a]pyridin-3-yl]piperidine-1-carboxylate.
  • a solution of 1-fluoro-2-methylpropan-2-yl 4-nitrophenyl carbonate (72 mg), 4-[3-(piperidin-4-yl)pyrazolo[1,5-a]pyridin-6-yl]morpholine dihydrochloride salt (100 mg) and triethylamine (0.16 mL) in DCM (3 mL) was stirred at room temperature overnight.
  • the reaction mixture was partitioned between DCM and NaHCO 3 and the organic phase was concentrated in vacuo.
  • the residue was purified by column chromatography (SiO 2 , AcOEt:petrol) to give the desired product (53 mg).
  • LCMS: [M+H] + 405.
  • Example 149 Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine-1-carboxylate Step 1: synthesis of tert-butyl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ -1,2,3,6-tetrahydropyridine-1-carboxylate.
  • Step 2 synthesis of tert-butyl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine-1-carboxylate.
  • a mixture of tert-butyl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ -1,2,3,6-tetrahydropyridine-1-carboxylate (700 mg) and PtO 2 (150 mg) in AcOEt (12 mL) was stirred under H 2 at room temperature overnight. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give the desired product (618 mg).
  • LCMS: [M-tBu] + 276.
  • Step 3 synthesis of 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine hydrochloride salt.
  • 4M HCl in dioxane (6 mL) was added to a solution of tert-butyl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine-1-carboxylate (618 mg) in dioxane (6 mL) and the resulting mixture was stirred at room temperature for 4 hours. The reaction was concentrated in vacuo to give the desired product (520 mg).
  • LCMS: [M+H] + 232
  • Step 4 synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine-1-carboxylate.
  • a solution of 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine hydrochloride salt (100 mg), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-yl carbonate (121 mg) and triethylamine (0.2 mL) in DCM (2 mL) was stirred at room temperature overnight.
  • the reaction mixture was partitioned between DCM and NaHCO 3 .
  • the organic phase was washed NaHCO 3 and then concentrated in vacuo.
  • the residue was purified by column chromatography (SiO 2 , AcOEt:petrol) to give the desired product (42 mg).
  • LCMS: [M+H] + 386.
  • Example 150 Synthesis of 1-fluoro-2-methylpropan-2-yl 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine-1-carboxylate
  • the reaction mixture was partitioned between DCM and NaHCO 3 .
  • the organic phase was washed with NaHCO 3 and then concentrated in vacuo.
  • the residue was purified by column chromatography (SiO 2 , AcOEt:petrol) to give the desired product (41 mg).
  • LCMS: [M+H] + 350.
  • Example 151 Synthesis of 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ -1-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine
  • a solution of 4- ⁇ 6-methoxypyrazolo[1,5-a]pyridin-3-yl ⁇ piperidine hydrochloride salt (78 mg), 3-chloro-5-methyl-1,2,4-oxadiazole (52 mg) and triethylamine (0.16 mL) in EtOH (1 mL) was stirred at 80°C overnight.
  • the reaction mixture was partitioned between DCM and water.
  • the organic phase was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , AcOEt:petrol) to give the desired product (7 mg).
  • LCMS: [M+H] + 314.
  • Example 1 CSF1R kinase assay Example Compounds were serially diluted (half log scale; 10 concentrations) in DMSO. Serially diluted compounds were prepared with the assay buffer (0.25 M EPPS pH7.5, 50 mM MgCl 2 , 2.5 mM EGTA, 0.05% Briji-35) to reach 4 times concentration in 4% (v/v) DMSO. Each compound concentration was added at 5 ⁇ L/well in a 384-wells plate. The ATP/peptide solution (0.372 mM ATP, 0.4 ⁇ M Fluorescein-polyGT (PV3610, Life Technologies)) was added at 5 ⁇ L in all wells.
  • the CSF1R (PV3249, Life Technologies) diluted solution (0.28 nM) was added at 10 ⁇ L in wells of each compound concentration and compound free control designated as 0% inhibition.
  • assay buffer without enzyme was added at 10 ⁇ L in wells of 0% response control designated as 100% inhibition.
  • the plates were incubated for 80 min at room temperature with orbital shaker at 750 rpm.
  • the stop solution (20 mM EDTA, 2 nM Tb-PY20 (PV3528, Life Technologies) antibody diluted with TR-FRET dilution buffer (PV3574, Life Technologies) was added at 20 ⁇ L in all wells. The plates were incubated for 30 min at room temperature with orbital shaker at 750 rpm.
  • the plates were read using LanthaScreen TM Assay Mode of Infinite M1000 (Tecan).
  • the value of signal is calculated with the ratio of 520 nm/490 nm emission using an excitation light at 337 nm.
  • the IC 50 value was calculated by plotting the percentage of inhibition against the concentration of compound in curve fitting of a non-linear regression using GraphPad Prism 7 software.
  • Test Example 2 CSF1R phosphorylation assay in human CSF1R overexpressing cell
  • H4/hCSF1R H4/hCSF1R cells
  • H4/hCSF1R cells were cultured in DMEM medium supplemented with 10%FBS, 0.5 mg/mL Geneticin (G418), 100 units/mL penicillin and 100 ⁇ g/mL streptomycin in T150 flask and split twice a week.
  • the cells were trypsinized, counted and diluted with culture medium to 1.11 x 10 5 cell/mL.
  • the cells were seeded into 96-well culture plate with 180 ⁇ L for each well (20,000 cells/well).
  • IC 50 value was calculated by plotting the percentage of inhibition for CSF1R phosphorylation against the concentration of a compound in curve fitting of a non-linear regression using GraphPad Prism 7 software.
  • Test Example 3 Kinase assay for selectivity within receptor type tyrosine kinases (RTKs)
  • RTKs receptor type tyrosine kinases
  • Five kinds of commercially available RTKs (as shown in the following table) were subjected to the tests using a LabChip EZReader II and ProfilerPro kinase selectivity assay kits (PerkinElmer). Compounds were serially diluted (half log scale; 10 concentrations) in DMSO.
  • kinase buffer 50 mM HEPES pH7.5, 10 mM MgCl 2 , 1 mM EGTA, 0.01% Briji-35
  • substrate 10 ⁇ M
  • ATP 198 ⁇ M (CSF1R), 86 ⁇ M (FLT3, cKit, PDGFR ⁇ , or TrkC)
  • the fluorescently-labelled peptide substrates were shown in the following table.
  • Each enzyme diluted solution 200 ng/mL was added at 10 ⁇ L in all wells. 0% inhibition controls contained no inhibitor and 100% inhibition controls contained no ATP.
  • the plates were mixed on a plate shaker for a few seconds and incubated for 60 min at room temperature.
  • the termination buffer 100 mM HEPES pH7.5, 40 mM EDTA, 1 mM DTT, 0.015% Briji-35, 0.13% LabChip Sipper Chip Coating Reagent 3 (760050, PerkinElmer)
  • the termination buffer 100 mM HEPES pH7.5, 40 mM EDTA, 1 mM DTT, 0.015% Briji-35, 0.13% LabChip Sipper Chip Coating Reagent 3 (760050, PerkinElmer)
  • Phosphorylated and unphosphorylated peptides were separated by electrophoresis and detected by those fluorescence. Percent conversion from substrate to product was determined using the peak heights.
  • the IsC50 value was calculated by plotting the percentage of inhibition against the concentration of compound in curve fitting of a non-linear regression using GraphPad Prism 7 software. Compounds were confirmed to show selective inhibitory activity against CSF1
  • Test Example 4 Pharmacokinetics/Pharmacodynamics Male Mice (C57BL/6J, The Jackson Laboratory Japan, eight weeks old) were orally administered with test compounds in 5% gum arabic in water as vehicle. Mice administered with vehicle only were used as a negative control. In each study, one control group and one or more test compound administered group(s) were prepared, but each group was only administered with one test compound at one concentration. Blood was collected via retro orbital puncture into heparin capillary at 30 minutes, 1 hour, 2 hours and 6 hours after dosing. After anesthetization, blood was collected through posterior vena cava into heparin tubes and brain was harvested at 24 hours after dosing.
  • the blood was centrifuged at 1,710 g for 10 minutes at 4°C to obtain plasma.
  • the half hemisphere of the brain was homogenized in 3-fold weight of saline by PHYSCOTRON homogenizer (NS-360D, Microtec) and subjected to pharmacokinetic study.
  • the other half hemisphere was soaked in RNAlater (AM7021, Life Technologies) for gene expression assay.
  • the compound in mouse plasma and brain homogenates was quantified with the high-performance liquid chromatographic-electrospray ionization tandem mass spectrometry method.
  • the compound was dissolved in DMSO and was diluted with methanol to prepare the standard solutions.
  • the concentrations of calibration curve samples were 0.01 to 10 ⁇ g/mL, and those of quality control samples were 0.03, 5, and 8 ⁇ g/mL.
  • the internal standard solution spikeperone: 500 ng/mL
  • methanol were added and mixed. The mixture was centrifuged at 6130 g for 10 minutes at 10°C or below to obtain the supernatant.
  • the mean of concentration at each time point, and the concentration ratio of brain to plasma (Kp) were calculated with Microsoft Excel 2013 (Microsoft Corp). Brain concentrations were corrected with dilution factor (4-time dilution) of brain homogenates. The pharmacokinetic parameters were calculated with the aid of non-compartmental model, Phoenix(R) WinNonlin(R) 8.0 (Certara LP).
  • RNA concentration and purity was assessed using spectrophotometer (DropSense96, Trinean or Nanodrop, Thermo Scientific). Equal amount of RNA was reverse transcribed to cDNA using High-Capacity RNA-to-cDNA Kit (4388950, Life Technologies) or High-Capacity cDNA Reverse Transcription Kit (4368813, Life Technologies).
  • Quantitative PCR was performed on LightCycler 480 (Roche) or ViiA7 (Thermo Scientific) using a TaqMan Fast Universal PCR Master Mix (#4352042, Life Technologies) or TaqMan Fast Advanced Master Mix (4444964, Life Technologies). Data was analyzed using ⁇ Ct method or fold change which was relatively calculated by standard curve that was made from 5-points 1:2 dilution of vehicle treated animals. GAPDH gene was used as an internal control for normalization. Percentage inhibition of CD11b gene was calculated by taking the rate of decrease in the absence of drug as 0%. The primers used in this study were the followings: GAPDH gene (Mm99999915_g1, Life Technologies), CD11b gene (Mm00434455_m1, Life Technologies). All calculation were performed with Microsoft Excel 2013 (Microsoft Corp).
  • Results of administration of the 30 mg/kg dose of test compounds are shown in the following table, unless otherwise noted.
  • a compound of Formula [I], or a salt thereof, may have CSF1R inhibitory activity and is expected to be useful for treating, preventing, and/or diagnosing diseases associated with CSF1R.

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Abstract

L'invention concerne des composés de pyrazolopyridine ou de pyrazolopyrimidine, ou des sels de ceux-ci, ayant une activité inhibitrice du récepteur du facteur 1 de stimulation des colonies (CSF1R), leur utilisation médicale pour le traitement, la prévention et/ou le diagnostic de maladies associées à CSF1R, et des procédés de préparation desdits composés, ou des sels de ceux-ci. L'invention concerne un composé représenté par la Formule [I], ou un sel de celui-ci, R1 étant de l'hydrogène, etc. ; R21 et R22 sont de l'hydrogène, ou R21 et R22 conjointement avec l'hétérocyclique adjacent forment un cycle bicyclique ponté ; R3 est -L31-R31 éventuellement substitué par un ou plusieurs R32, ou R31 éventuellement substitué par un ou plusieurs R32 ; L31 est -C(=O)-, etc. ; R31 est un alkyle en C1-6, etc. ; R32 est chacun indépendamment un halogène, etc. ; et X est CR1 ou N ; son utilisation médicale, et des procédés de préparation de celui-ci.
PCT/JP2024/038053 2023-10-26 2024-10-25 Composés utilisés en tant qu'inhibiteurs de csf1r Pending WO2025089370A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059502A1 (fr) * 1999-04-06 2000-10-12 Merck & Co., Inc. Pyrrolidines modulateurs de l'activite du recepteur de chimiokine
WO2007121484A2 (fr) * 2006-04-19 2007-10-25 Novartis Ag Composés à base de benzoxazole et de benzothiazole 6-0 substitués et procédés d'inhibition de signalisation csf-1r
WO2017015267A1 (fr) * 2015-07-20 2017-01-26 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
WO2021225798A1 (fr) * 2020-05-05 2021-11-11 Eli Lilly And Company Composés de {5-méthoxy-6-[(5-méthoxypyridin-2-yl)méthoxy]pyridin-3-yl}méthyl substitués en tant qu'inhibiteurs de csf-1r

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000059502A1 (fr) * 1999-04-06 2000-10-12 Merck & Co., Inc. Pyrrolidines modulateurs de l'activite du recepteur de chimiokine
WO2007121484A2 (fr) * 2006-04-19 2007-10-25 Novartis Ag Composés à base de benzoxazole et de benzothiazole 6-0 substitués et procédés d'inhibition de signalisation csf-1r
WO2017015267A1 (fr) * 2015-07-20 2017-01-26 Genzyme Corporation Inhibiteurs du récepteur de facteur-1 de stimulation de colonies (csf-1r)
WO2021225798A1 (fr) * 2020-05-05 2021-11-11 Eli Lilly And Company Composés de {5-méthoxy-6-[(5-méthoxypyridin-2-yl)méthoxy]pyridin-3-yl}méthyl substitués en tant qu'inhibiteurs de csf-1r

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Transformations", 1989, VCH PUBLISHERS, INC.
ASAI, H. ET AL.: "Depletion of microglia and inhibition of exosome synthesis halt tau propagation", NATURE NEUROSCIENCE, vol. 18, 2015, pages 1584
BABAEIJANDAGHI F. ET AL.: "Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics", SCI TRANSL MED, vol. 14, no. 651, 2022
BECKMANN, N. ET AL.: "Brain region-specific enhancement of remyelination and prevention of demyelination by the CSF1R kinase inhibitor BLZ945", ACTA NEU-ROPATHOLOGICA COMMUNICATIONS, vol. 6, 2018, pages 9
BORJINI, N.FERNANDEZ, M.GIARDINO, L.CALZA, L.: "Cytokine and chemokine alterations in tissue,CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis", JOURNAL OF NEUROINFLAMMATION, vol. 13, 2016, pages 291, XP055480357, DOI: 10.1186/s12974-016-0757-6
BRANDEN A.S: "PLX3397 treatment inhibits constitutive CSF1R-induced oncogenic ERK signaling, reduces tumor growth, and metastatic burden in os- teosarcoma", BONE, 2020, pages 115353
DAGHER, N. N. ET AL.: "Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice", JOURNAL OF NEUROINFLAMMATION, vol. 12, 2015, pages 139, XP021228327, DOI: 10.1186/s12974-015-0366-9
DEBBIE C SBRIAN RYOKO OMINA J BLISA M CNANCY PDYLAN D: "CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells", ONCOIMMUNOLOGY, vol. 2, 2013, pages 26968
GARCIA S ET AL.: "Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis", ARTHRITIS RESEARCH & THERAPY, vol. 18, 2016, pages 75
GERBER Y.N ET AL.: "CSF1R inhibition reduces microglia proliferation, promotes tissue preservation and improves motor recovery after spinal cord injury", FRONTIERS IN CELLULAR NEUROSCIENCE, vol. 12, 2018, pages 368
GERNGROSS, L.FISCHER, T.: "Evidence for cFMS signaling in HIV production by brain macrophages and microglia", JOURNAL OF NEUROVIROLOGY, vol. 21, 2015, pages 249 - 256
GOMEZ-NICOLA DFRANSEN NLSUZZI SPERRY VH: "Regulation of microglial proliferation during chronic neurodegeneration", JOURNAL OF NEUROSCIENCE, vol. 33, 2013, pages 2481 - 93, XP055292897, DOI: 10.1523/JNEUROSCI.4440-12.2013
GOWING, G.LALANCETTE-HEBERT, M.AUDET, J.-N.DEQUEN, F.JULIEN, J.-P.: "Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase", EXPERIMENTAL NEUROLOGY, vol. 220, 2009, pages 267 - 275, XP026762277, DOI: 10.1016/j.expneurol.2009.08.021
HAGAN N. ET AL.: "CSF1R signaling is a regulator of pathogenesis in progressive MS CSF1R signaling is a regulator of pathogenesis in progressive MS", CELL DEATH DIS, vol. 11, no. 10, 2020, pages 904
LODDER C. ET AL.: "CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia", ACTA NEUROPATHOL COMMUN, vol. 9, no. 1, 2021, pages 108, XP021292134, DOI: 10.1186/s40478-021-01204-8
LV QI: "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., 2021
MANCUSO, R. ET AL.: "CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice", BRAIN, 2019
MARTINEZ-MURIANA, A. ET AL.: "CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves", SCIENTIFIC REPORTS, vol. 6, 2016, pages 25663, XP055370399, DOI: 10.1038/srep25663
MOON H.G. ET AL.: "Colony-stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma", ALLERGY, vol. 75, no. 2, 2020, pages 357 - 369
NEAL ML ET AL.: "Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration", THE FASEB JOURNAL, vol. 34, 2020, pages 1679 - 1694
OH S.J. ET AL.: "Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model", MOL IMAGING BIOL, vol. 22, no. 4, 2020, pages 1031 - 1042, XP037186997, DOI: 10.1007/s11307-020-01485-w
OH SE JONG ET AL: "Evaluation of the Neuroprotective Effect of Microglial Depletion by CSF-1R Inhibition in a Parkinson's Animal Model", MOLECULAR IMAGING & BIOLOGY, ELSEVIER, BOSTON, vol. 22, no. 4, 21 February 2020 (2020-02-21), pages 1031 - 1042, XP037186997, ISSN: 1536-1632, [retrieved on 20200221], DOI: 10.1007/S11307-020-01485-W *
OLMOS-ALONSO, A. ET AL.: "Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology", BRAIN, vol. 139, 2016, pages 891 - 907, XP055289773, DOI: 10.1093/brain/awv379
P.G.M. WUTST.W. GREENE: "Greene's Protective Groups in Organic Synthesis", 2006
POULEN G. ET AL.: "Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates", THERANOSTICS, vol. 11, no. 18, 2021, pages 8640 - 8659
QIUJU XUN: "Small-Molecule CSF1R Inhibitors as Anticancer Agents", CURRENT MEDICINAL CHEMISTRY, vol. 27, no. 23, 1 July 2020 (2020-07-01), NL, pages 3944 - 3966, XP093152406, ISSN: 0929-8673, DOI: 10.2174/1573394715666190618121649 *
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, vol. 10, 2020, pages 2402 - 19
SAWICKI CM ET AL.: "Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress", JOURNAL OF NEUROSCIENCE, vol. 39, 2019, pages 1139 - 1149
SHIGERU OHBASHIGENOBU YANO, BASIC COURSE FOR CHEMISTS 12, X-RAY CRYSTAL STRUCTURE ANALYSIS, 1999
SMITH B.D ET AL.: "Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages", MOL CANCER THER, vol. 20, no. 11, 2021, pages 2098 - 2109, XP093171464, DOI: 10.1158/1535-7163.MCT-21-0361
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 5XFAD mouse model of Alzheimer's disease", MOLECULAR NEURODEGENERATION, vol. 13, 2018, pages 11
SPANGENBERG, E. E. ET AL.: "Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-(3 pathology", BRAIN, vol. 139, 2016, pages 1265 - 1281
TRIAS, E. ET AL.: "Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis", JOURNAL OF NEUROINFLAMMATION, vol. 13, 2016, pages 177
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, vol. 43, 2020, pages 325 - 333
WALDEMAR ADAMRAINER T. FELLCHANTU R. SAHA-MOLLERCONG-GUI ZHAO, TETRAHEDRON: ASYMMETRY, vol. 9, 1998, pages 397 - 401
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., vol. S0889-1591, no. 22, 2022, pages 00338 - 5
WIES MANCINI V.S.B ET AL.: "Microglial modulation through colony-stimulating factor-1 receptor inhibition attenuates demyelination", GLIA, vol. 67, no. 2, 2019, pages 291 - 308
XIANG C. ET AL.: "Interfering with alternatively activated macrophages by CSF-1R inhibition exerts therapeutic capacity on allergic airway inflammation", BIOCHEM PHARMACOL, vol. 198, 2022, pages 114952, XP086995362, DOI: 10.1016/j.bcp.2022.114952
YAN XMAIXNER DWLI F3WENG HR: "Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors", JOURNAL F NEUROCHEMISTRY, vol. 140, 2017, pages 963 - 976
YUANMING ZHUYONG TUHONGWU YUYIAN SHI, TETRAHEDRON LETT, vol. 29, 1988, pages 2437 - 2440
ZHOU Y. ET AL.: "CSF1/CSF1R-mediated Crosstalk Between Choroidal Vascular Endothelial Cells and Macrophages Promotes Choroidal Neovascularization", INVEST OPHTHALMOL VIS SCI, vol. 62, no. 3, 2021, pages 37

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