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WO2024215070A1 - Pyrazolopyridine derivative compound, and use thereof - Google Patents

Pyrazolopyridine derivative compound, and use thereof Download PDF

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Publication number
WO2024215070A1
WO2024215070A1 PCT/KR2024/004758 KR2024004758W WO2024215070A1 WO 2024215070 A1 WO2024215070 A1 WO 2024215070A1 KR 2024004758 W KR2024004758 W KR 2024004758W WO 2024215070 A1 WO2024215070 A1 WO 2024215070A1
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Prior art keywords
cancer
alkyl
membered
ring
halo
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PCT/KR2024/004758
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French (fr)
Korean (ko)
Inventor
고이경
이윤호
이화
조서현
임혜림
이승주
최윤하
전국봉
이창주
황선아
마다훈
오세린
이수영
김대권
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보로노이 주식회사
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Publication of WO2024215070A1 publication Critical patent/WO2024215070A1/en

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  • the present invention relates to pyrazolopyridine derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to pyrazolopyridine derivative compounds having EGFR inhibitory activity.
  • Protein kinases act as molecular switches and are involved in signal transduction pathways, and the transition between the active and inactive states of target proteins by kinases within cells must be smoothly regulated. If the transition between the active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated or inactivated, leading to uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification, and/or overexpression of protein kinase genes causes the occurrence and progression of various tumors, and plays a critical role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.
  • Epidermal growth factor receptor a receptor tyrosine kinase of the ErbB family
  • NSCLC non-small cell lung carcinoma
  • breast cancer glioma, squamous cell carcinoma of the head and neck, colorectal cancer, rectal adenocarcinoma, head and neck cancer, gastric cancer, and prostate cancer
  • activation of the EGFR-tyrosine kinase causes sustained cell proliferation, invasion of surrounding tissues, distant metastasis, angiogenesis, and increased cell survival.
  • EGFR Del19/T790M or EGFR L858R/T790M double mutations occur, rendering existing treatments ineffective.
  • Osimertinib a third-generation EGFR-TKI target drug that shows high responsiveness to drug resistance due to EGFR T790M mutation, was developed, but it was also reported to develop drug resistance (Niederst MJ. et al., Clin Cancer Res, 2015, 21(17), 3924-3933).
  • EGFR C797S mutation has been suggested as one of the major mechanisms causing drug resistance to osimertinib, and approximately 40% of clinical trial patients were reported to have EGFR C797S mutation (Thress KS. et al., Nature Medicine, 2015, 21, 560-562).
  • the object of the present invention is to provide a novel structural pyrazolopyridine derivative, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for producing the pyrazolopyridine derivative compound.
  • Another object of the present invention is to provide a pharmaceutical use of the pyrazolopyridine derivative compound, and specifically, to provide a pharmaceutical composition for treating or preventing an EGFR-related disease, comprising the pyrazolopyridine derivative compound as an active ingredient.
  • Another object of the present invention is to provide a use for treating or preventing an EGFR-related disease using the pyrazolopyridine derivative compound or a method for treating or preventing an EGFR-related disease comprising a step of administering the compound.
  • the present invention provides a compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • X 1 is NR 1 or S
  • X 2 is N or NR 2 ;
  • R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
  • R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
  • L 1 is -NH-, -O-, or nothing (null);
  • L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null ⁇ wherein m is an integer from 1 to 6 ⁇ ;
  • W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ⁇ wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl) ⁇ ;
  • R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ⁇ wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo ⁇ ;
  • R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
  • V is -NH-, -O-, or nothing (null);
  • Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
  • R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  • the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • one or more H of the ring Z can be independently substituted with R Z1 and R Z2 ⁇ .
  • the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
  • the present invention provides a compound represented by the following chemical formula 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
  • R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
  • L 1 is -NH-, -O-, or nothing (null);
  • L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null ⁇ wherein m is an integer from 1 to 6 ⁇ ;
  • W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ⁇ wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl) ⁇ ;
  • R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ⁇ wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo ⁇ ;
  • R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
  • V is -NH- or nothing (null);
  • Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
  • R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  • the present invention provides a compound represented by the following chemical formula 3, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
  • L 1 is -NH-, -O-, or nothing (null);
  • L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null ⁇ wherein m is an integer from 1 to 6 ⁇ ;
  • W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ⁇ wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl) ⁇ ;
  • R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ⁇ wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo ⁇ ;
  • R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
  • Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
  • R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  • the present invention provides a compound represented by the following chemical formula 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
  • L 1 is -NH-, -O-, or nothing (null);
  • L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null ⁇ wherein m is an integer from 1 to 6 ⁇ ;
  • W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ⁇ wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl) ⁇ ;
  • R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ⁇ wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo ⁇ ;
  • R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
  • Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
  • R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  • the compound represented by the chemical formula 1, 2, 3, or 4 may be selected from the group consisting of compounds of Examples 1 to 100 listed in the table below.
  • a symbol for combining atoms and/or groups " " is a single bond, symbol " " means double bond, and the symbol " " means a single bond or a double bond.
  • the symbol may be omitted, and may be indicated when necessary, such as when specifying a bonding atom or bonding position.
  • the term "connected" between atoms may include not only cases where atoms are directly connected between atoms, but also cases where atoms are indirectly connected between atoms via another atom and/or group.
  • the other atom and/or group may be, but is not limited to, oxygen, sulfur, C 1-6 alkylamino, C 1-6 alkylene, and the like, and the atoms and/or groups may be substituted or unsubstituted.
  • substituteable and “substituted or unsubstituted” may mean that one or more hydrogen atoms are substituted or unsubstituted with another atom or substituent.
  • alkyl may mean a straight-chain or branched-chain acyclic, cyclic, or a saturated hydrocarbon group combined therewith.
  • C 1-6 alkyl may mean alkyl having 1 to 6 carbon atoms.
  • Examples of acyclic alkyl may include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, tert -butyl, isopentyl, and 2-methylpentyl.
  • alkylene a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene.”
  • ring alkyl may be used interchangeably with "cycloalkyl” herein.
  • Cycloalkyl may include unsaturated rings having one or more carbon-carbon double bonds in the ring, as long as the ring does not have aromaticity due to the presence of the double bond, and for example, cyclopentenyl may also be included in the category.
  • cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.
  • “3-7 membered cycloalkyl” may mean a cycloalkyl having 3 to 7 ring forming atoms.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Alkyl groups comprising acyclic and cyclic alkyls may include, but are not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, and cyclopropylethyl, for example.
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as heterocycloalkene.
  • heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.
  • 3--7 membered heterocycloalkyl may mean a heterocycloalkyl containing 3 to 7 ring forming atoms.
  • heterocycloalkyl examples include aziridine, azetedine, pyrrolidine, piperidine, N -methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4( 1H , 3H )-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, isoxazolidine, benzo[ d ]isoxazolidine, oxazinane, Including azabicyclo[2,
  • heterocycloalkyl may mean a double ring having a spiro ring, a bridged ring or a fused ring containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and may be saturated or partially unsaturated.
  • unsaturated it may be referred to as heterobicycloalkene.
  • heterocycle may mean a saturated, partially unsaturated, unsaturated, or aromatic ring containing at least one heteroatom selected from N, O, and S as ring forming atoms, and may be a single ring or multiple rings (bi- to tetra-rings).
  • the multiple ring heterocycle may be formed through a common single or double bond, formed by sharing two or more arranged atoms (bridged ring, fused ring), or formed through a common single atom (spiro ring).
  • alkenyl and “alkynyl” may mean a straight-chain or branched-chain acyclic, cyclic, or unsaturated hydrocarbon combined therewith.
  • C 1-6 alkenyl may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms and having one or more double bonds
  • C 1-6 alkynyl may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms and having one or more triple bonds.
  • alkoxy may mean an alkyl ether group, -(R'-OR"), wherein R' may be selected from the group consisting of a single bond and C 1-6 alkyl, and R" may be C 1-6 alkyl.
  • R' may be selected from the group consisting of a single bond and C 1-6 alkyl
  • R" may be C 1-6 alkyl.
  • alkyl is as defined above.
  • C 1-6 alkoxy can mean an alkoxy containing an alkyl of C 1-6 , i.e., -(OC 1-6 alkyl) or -(C 1-6 alkyl-OC 1-6 alkyl), examples of alkoxy include, but are not limited to, methoxy, ethoxy , n -propoxy , isopropoxy , n -butoxy, isobutoxy, sec -butoxy, and tert -butoxy .
  • alkylamino or “aminoalkyl” may mean -(NR'R"), wherein R' and R" may each be independently selected from the group consisting of hydrogen and C 1-6 alkyl, and the selected R' and R" may each independently be substituted or unsubstituted.
  • C 0-6 alkylamino may mean amino not containing alkyl (-NH 2 ) or amino containing C 1-6 alkyl, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 , and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, and ethylpropylamino.
  • hydroxyalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (-OH), and examples thereof include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, and tert -butyl independently substituted with -OH.
  • halo or “halogen” may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein.
  • haloalkyl include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, and tert -butyl, each independently substituted with one or more halogens, for example, F, Cl, Br, or I.
  • R' and R" may be independently substituted or unsubstituted.
  • R' and R" may each independently be substituted or unsubstituted.
  • cyanoalkyl may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (-CN).
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15.
  • Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like.
  • aryl a residue obtained by removing one hydrogen atom from the "arene” is referred to as "aryl.”
  • the aryl may be included in the category as long as it is a hydrocarbon ring having at least one ring in which electrons are delocalized by alternating single bonds and double bonds, i.e., conjugated ⁇ bonds.
  • C 6-12 aryl, C 6-10 aryl, etc. are possible, but are not limited thereto.
  • heteroarene may be a ring including at least one of O, N, P, Si, and S as a heteroatom.
  • the number of ring-forming atoms of the heteroarene may be 3 or more and 30 or less, 3 or more and 20 or less, or 3 or more and 15 or less.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • the polycyclic heteroarene may have, for example, a two-ring or three-ring structure.
  • heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, triazolopyrimidine, triazolopyrimidine, triazolopyrimidine, N -arylcarbazole, N -hetero
  • the heteroarene may also include a bicyclic heterocyclo-arene including an arene ring fused to a heterocycloalkyl ring and a heteroarene fused to a cycloalkyl ring.
  • a moiety having one hydrogen atom removed from the above “heteroarene” is referred to as a "heteroaryl”.
  • heterohydroarene may mean a polycyclic ring (bicyclic ring to tetracyclic ring) containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and at least one of the polycyclic rings may be a saturated or partially unsaturated ring, and at least another may have an aromatic ring.
  • a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as "heterohydroaryl”.
  • the “ring” may be a single ring or a multi-ring, and the multi-ring may be in the form of a spiro ring, a bridged ring, a fused ring, or the like.
  • stereoisomer means a compound having the same chemical formula or molecular formula but being sterically different.
  • stereoisomers include “enantiomers” and “diastereoisomers”, and diastereoisomers also include conformational isomers such as rotamers and cis/trans isomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention.
  • a solid bond ( ) is a wedge-shaped solid line combination that represents the absolute arrangement of the stereocenter. ) and wedge-shaped dotted line joints ( ) may be included.
  • tautomer refers to a compound that is one of structural isomers and has different structures and atomic arrangements but exists in an equilibrium state. Therefore, the compound of the present invention may include various tautomers. Typical tautomeric pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid in a heterocyclic ring (e.g., in the nucleobases guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. The following examples are included for illustrative purposes, and the present disclosure is not limited to the examples:
  • the compound represented by chemical formula 1, 2, 3, or 4 of the present invention may exist in the form of a "pharmaceutically acceptable salt". Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by chemical formula 1, 2, 3, or 4.
  • pharmaceutically acceptable salt of the present invention means any organic or inorganic acid addition salt of the compound represented by chemical formula 1, 2, 3, or 4, which has an effective effect that is relatively nontoxic and harmless to the patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by chemical formula 1, 2, 3, or 4 at a concentration.
  • the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid.
  • the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic
  • Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.
  • the above acid addition salt can be prepared by a conventional method, for example, by dissolving a derivative of chemical formula 1, 2, 3, or 4 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • the pharmaceutically acceptable salt may be a salt or metal salt obtained by using a base.
  • a metal salt an alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate.
  • the alkali metal salt sodium, potassium or calcium salts can be pharmaceutically suitable.
  • the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal with a suitable silver salt (e.g., silver nitrate), and can be prepared through a method for preparing a salt known in the art.
  • the present invention may include compounds represented by the chemical formulae 1, 2, 3, or 4 and pharmaceutically acceptable salts thereof, as well as isomers thereof, particularly stereoisomers, diastereoisomers, enantiomers or mixtures thereof.
  • the present invention provides the use of a compound represented by the following chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • the present invention provides pharmaceutical uses of compounds represented by chemical formula 1, 2, 3, or 4, tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • the compound represented by chemical formula 1, 2, 3, or 4 of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against EGFR.
  • the present invention provides an EGFR inhibitor comprising a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for inhibiting the activity of EGFR, comprising the step of treating a sample or cell with a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pyrazolopyridine derivative represented by the chemical formula 1, 2, 3, or 4 exhibits excellent inhibitory activity against EGFR kinase, and thus can be usefully used for the treatment or prevention of EGFR-related diseases, particularly, cancer.
  • the compound of the chemical formula 1, 2, 3, or 4 can inhibit EGFR mutant kinase, which is supported by the experimental examples described below.
  • the EGFR mutation may be, for example, EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/T790M/C797S, but is not limited thereto. Since the compound of chemical formula 1, 2, 3, or 4 of the present invention exhibits excellent inhibitory activity against EGFR mutations, it can be usefully used for the treatment or prevention of carcinomas induced by EGFR.
  • prevention means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the compound
  • treatment means any act of improving or beneficially changing the symptoms of the disease by administering the compound.
  • the cancer includes all cancers that can exhibit therapeutic and preventive efficacy due to inhibition of EGFR kinase activity, and may be solid cancer or blood cancer.
  • the type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater, bladder cancer,
  • the present invention provides a pharmaceutical composition for treating or preventing an EGFR-related disease, which contains as an active ingredient a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the EGFR-related disease may be cancer.
  • the type of cancer is as mentioned above.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same and/or similar efficacy in addition to the compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral or parenteral dosage forms.
  • a method for treating or preventing an EGFR-related disease comprising administering a therapeutically effective amount of a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the subject may be a mammal including a human.
  • the EGFR-related disease may be cancer.
  • the type of cancer is as mentioned above.
  • a “therapeutically effective amount” refers to an amount of a compound represented by Chemical Formula 1, 2, 3, or 4 that is effective in treating or preventing an EGFR-related disease.
  • a “therapeutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject type, severity, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration, excretion rate, duration of treatment, concurrently used drugs, or other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by considering all of the above factors, and it can be easily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used even at a dosage higher than the determined dosage.
  • the present invention provides the use of a compound represented by Chemical Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of an EGFR-related disease.
  • the compound represented by Chemical Formula 1, 2, 3, or 4 for use in the manufacture of a medicament may include a conventional, non-toxic, pharmaceutically acceptable additive incorporated into a formulation according to a conventional method.
  • the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable additive.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound represented by Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like.
  • the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.
  • the above pharmaceutical composition may be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).
  • oral administration e.g., tablets, pills, powders, capsules, syrups or emulsions
  • parenteral administration e.g., intramuscular, intravenous or subcutaneous injection.
  • the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, and the like.
  • solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like, into the composition.
  • liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.
  • preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc.
  • injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.
  • they may be prepared as a compound preparation with other active agents to have a synergistic effect of the active ingredients.
  • pyrazolopyridine derivative compounds of the present invention exhibit excellent inhibitory activity against kinases, particularly EGFR, and therefore can be usefully used for the treatment or prevention of EGFR-related diseases, and particularly can be usefully used as therapeutic agents for cancer.
  • a UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters and equipped with a mass QDa Detector manufactured by Waters were used.
  • Mobile phase A used water containing 0.1% formic acid
  • mobile phase B used acetonitrile containing 0.1% formic acid.
  • An ACCQPrep HP150 instrument from Teledyne was used.
  • An XTERRA ® Prep RP18 OBD TM (10 ⁇ m, 30 ⁇ 300 mm) column from Waters was used, and the column temperature was set to room temperature.
  • room temperature or ambient temperature refers to a temperature of about 5 to 40°C, for example, 10 to 30°C, and for another example, 20 to 27°C, and is not strictly limited to the above range.
  • Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.
  • Step 1 tert -butyl 9-(1-methoxy-2-methyl-1-oxopropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq) obtained was dissolved in tetrahydrofuran (0.25 M), and lithium aluminum hydride (2.5 M, 2.0 eq) dissolved in tetrahydrofuran under nitrogen was added at -40 °C, and the mixture was stirred for 2 h.
  • step 2 tert -butyl 9-(1-hydroxy-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.3 M), DAST (2.2 eq.) was slowly added at 0 °C, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC, the organic matter was extracted with a saturated sodium bicarbonate aqueous solution and dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow liquid was used in the next reaction without further purification (yield: 99%).
  • step 3 tert -Butyl 9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq) obtained was dissolved in dichloromethane (0.4 M), and a solution of hydrochloric acid (4 M, 6.6 eq) dissolved in 1,4-dioxane was added at 0 °C, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated, ethyl acetate was added, and the mixture was stirred at room temperature for 30 min.
  • step 1 benzyl 4-allylpiperazine-1-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.3 M), m-CPBA (purity: 85%, 1.0 eq.) was added at -30 °C, and the mixture was stirred at -30 °C for 1 hour. After confirming that the reactant was consumed using LC-MS, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure.
  • the concentrated mixture was dissolved in toluene (0.4 M) and stirred at 80 °C for 16 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (petroleum ether/ethyl acetate) to obtain the target compound as a colorless liquid (yield: 34%).
  • Benzyl 4-(allyloxy)piperazine-1-carboxylate (1.0 eq.) obtained in step 2 was dissolved in dichloromethane (0.1 M) and methanol (0.36 M), and the mixture was stirred at -78 °C for 30 minutes while adding ozone. After removing the remaining ozone by adding nitrogen, NaBH 4 (1.5 eq.) was added to the reaction mixture at -78 °C, and the temperature was gradually raised while stirring at room temperature for 2 hours. After confirming that the target compound was produced using LC-MS, saturated sodium bicarbonate was added to the reaction mixture, and the organic compound was extracted using dichloromethane. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 71%).
  • Benzyl 4-(2-hydroxyethoxy)piperazine-1-carboxylate (1.0 eq.) obtained in step 3 was dissolved in tetrahydrofuran (0.23 M), lithium aluminum hydride (3.0 eq.) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture at 0 °C, and then 15% sodium hydroxide aqueous solution was added. Sodium sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, filtered, and concentrated under reduced pressure.
  • 6-Bromo-2,4-dimethyl-pyridin-3-amine (1.0 eq) was dissolved in acetic acid (0.15 M), and sodium nitrite aqueous solution (2.0 M, 1.2 eq) was slowly added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 20 °C for 16 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure to remove acetic acid, and then diluted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added to the diluted mixture, and the organic matter was extracted.
  • step 1 5-bromo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.25 M), and then dihydropyran (5.0 equiv.) and p -toluenesulfonic acid (0.2 equiv.) were added. The reaction mixture was stirred at 70 °C for 6 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was diluted with water and ethyl acetate, and saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution were added to extract the organic matter.
  • step 3 4 M hydrochloric acid solution (18.8 equivalents) dissolved in 1,4-dioxane was added to 5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equivalent) obtained at 0 °C, and the mixture was stirred at room temperature for 12 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was filtered, and the filtered solid was dissolved in methanol/dichloromethane (1/3 v/v), and then stirred using a base resin until the pH became 7. After filtering the reaction mixture, it was concentrated under reduced pressure, and the target compound obtained as a brown solid was used in the next reaction without further purification (yield: 89%).
  • step 4 5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in dimethylformamide (0.4 M), N -iodosuccinimide (1.1 eq.) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted using dichloromethane and methanol. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. Ethyl acetate was added to the concentrated mixture to produce a solid, which was then filtered, and the target compound obtained as a gray solid was used in the next reaction without further purification (yield: 75%).
  • step 5 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and Boc 2 O (2.0 equiv.), triethylamine (2.0 equiv.), and N,N -dimethylpyridin-4-amine (0.5 equiv.) were added, and the mixture was stirred at room temperature for 30 min.
  • Compound Manufacturing Example 4 was manufactured using a method similar to Manufacturing Example 3.
  • step 1 of Manufacturing Example 3 5-bromo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in tetrahydrofuran (0.27 M), t-BuOK (3.0 eq.) and iodine (2.0 eq.) were added at 0 °C, and the mixture was stirred at room temperature for 6 hours. After confirming that the target compound was produced using LC-MS, a saturated sodium bisulfite aqueous solution was added to the reaction mixture at 0 °C, and the organic matter was extracted with ethyl acetate.
  • step 1 6-chloro-2-iodo-4-methylpyridin-3-amine (1.0 eq.) obtained was dissolved in dimethylformamide (0.2 M), potassium fluoride (2.0 eq.), copper(I) iodide (1.1 eq.), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.0 eq.) were added, and the mixture was stirred at 100 °C for 16 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified using MPLC (dichloromethane:methanol), and the target compound was obtained as an orange solid (yield: 40%, MS (ESI): m/z 211 [M+H] + ).
  • step 2 6-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (1.0 eq.) obtained was dissolved in 1,4-dioxane (0.2 M), and 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 eq.) and cesium carbonate (3.0 eq.) were added.
  • Pd(dppf)Cl 2 (0.1 eq.) was added to the reaction mixture under nitrogen, and the mixture was stirred at 130 °C for 10 min using a microwave apparatus.
  • the reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown liquid (yield: 90%, MS (ESI): m/z 284 [M+H] + ).
  • step 3 4'-methoxy-4-methyl-6-(trifluoromethyl)-[2,3'-bipyridin]-5-amine (1.0 eq.) obtained was dissolved in acetic acid (0.037 M), and then sodium nitrite aqueous solution (1.1 eq.) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown liquid (yield: 96%, MS (ESI): m/z 295 [M+H] + ).
  • step 4 5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in dimethylformamide (0.2 M), N -iodosuccinimide (1.3 eq.) was added, and the mixture was stirred at room temperature for 16 hours. After confirming that the target compound was produced using LC-MS, an aqueous sodium thiosulfate solution was added, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow liquid (yield: 44%, MS (ESI): m/z 421 [M+H] + ).
  • step 5 3-iodo-5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and DMAP (0.5 equiv.), Boc 2 O (2.0 equiv.), and triethylamine (2.0 equiv.) were added, and the mixture was stirred at room temperature for 1 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 20%, MS (ESI): m/z 521 [M+H] + ).
  • 6-Bromo-2,4-dimethylpyridin-3-amine (1.5 equiv) was dissolved in 1,4-dioxane/water (4/1 v/v, 0.1 M), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.0 equiv) and sodium carbonate (3.0 equiv) were added, and the mixture was degassed with nitrogen. Pd(amphos)Cl 2 (0.15 equiv) was added, and the mixture was stirred at 70 °C for 1 h.
  • N- (6-(5-methoxy-1-methyl-1 H -pyrazol-4-yl)-2,4-dimethylpyridin-3-yl)acetamide (1.0 equiv.) obtained in step 2 was dissolved in benzene (0.07 M), acetic anhydride (3.0 equiv.), potassium acetate (1.5 equiv.), and isopentyl nitrite (2.0 equiv.) were added, and the mixture was stirred at 80 °C for 16 hours, and the reaction mixture was concentrated under reduced pressure.
  • the reaction mixture was dissolved in water/ethanol (1/3 v/v, 0.07 M), lithium hydroxide (7.0 equiv.) was added, and the mixture was stirred at room temperature for 2 hours.
  • step 1 2,6-dichloro- N -methyl-3-nitropyridin-4-amine (1.0 eq), ammonium chloride (5.0 eq), and iron (5.0 eq) obtained were dissolved in water/ethanol (1/4 v/v, 0.35 M) and stirred at 90 °C for 2 hours.
  • iron was removed using celite, and the filtered filtrate was concentrated under reduced pressure to remove ethanol.
  • Water was added to the concentrated mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure.
  • the concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 75%, MS (ESI): m/z 192 [M+H] + ).
  • step 2 2,6-Dichloro- N 4 -methylpyridine-3,4-diamine (1.0 eq.) obtained was dissolved in tetrahydrofuran (0.5 M), di(1 H -imidazol-1-yl)methanethione (2.0 eq.) was added, and the mixture was stirred at 80 °C for 16 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 78%, MS (ESI): m / z 234 [M + H] + ).
  • step 3 4,6-dichloro-1-methyl-1 H -imidazo[4,5- c ]pyridine-2-thiol (1.0 eq.) obtained was dissolved in thionyl chloride (20.0 eq.), dimethylformamide (4.0 eq.) was slowly added at 0 °C, and the reaction mixture was stirred at 60 °C for 1 hour. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was slowly added to the concentrated mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated compound was purified by MPLC (dichloromethane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 66%, MS (ESI): m/z 236 [M+H] + ).
  • step 5 3-(4,6-dichloro-1-methyl-1 H -imidazo[4,5- c ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane (1.0 eq) obtained was dissolved in 1,3-dimethyl-2-imidazolidinone (0.23 M), 4,4-difluoropiperidine hydrochloride (1.0 eq) and sodium bicarbonate (10.0 eq) were added, and the mixture was stirred at 180 °C for 5 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with dichloromethane.
  • step 7 tert -butyl 3-(4-(4,4-difluoropiperidin-1-yl)-2-(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.2 M), trifluoroacetic acid (44.0 eq.) was added, and the mixture was stirred at room temperature for 1 hour.
  • the mixture was concentrated under reduced pressure.
  • the concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 25%, MS (ESI): m/z 717 [M+H] + ).
  • the mixture was filtered using Celite. Water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 36%, MS (ESI): m/z 297 [M+H] + ).
  • step 2 4,6-dichloro-1-methyl-2-(1-methylpiperidin-4-yl)-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained was added a 40% dimethylamine aqueous solution (50.0 eq.) and stirred at 80 °C for 1 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Magnesium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 51%, MS (ESI): m/z 308 [M+H] + ).
  • step 4 tert -butyl 3-(4-(dimethylamino)-1-methyl-2-(1-methylpiperidin-4-yl)-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 30 minutes. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated.
  • the concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 8%, MS (ESI): m/z 512 [M+H] + ).
  • Step 1 ( R )-6-chloro-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-1-methyl-4-(prop-1-en-2-yl)-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained was dissolved in ethanol (0.1 M), tris(triphenylphosphine)rhodium(I) chloride (0.2 eq.) was added, and the mixture was stirred at room temperature under hydrogen for 12 hours. After confirming the production of the target compound using LC-MS, the mixture was filtered using celite, and the obtained filtrate was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 60%, MS (ESI): m/z 334 [M+H] + ).
  • step 3 tert -butyl ( R )-3-(2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-4-isopropyl-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour.
  • the mixture was concentrated under reduced pressure.
  • the concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 10%, MS (ESI): m/z 538 [M+H] + ).
  • step 2 ( R )-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridin-3-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.2 M). Sodium hydride (3.0 equiv.) was added at 0 °C, and the mixture was stirred at 0 °C for 30 min.
  • Example 95 6-(5-((3 R ,4 S )-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-1 H -Pyrazolo[3,4- c ]pyridin-3-yl)-2-(( R )-hexahydropyrrolo[1,2- a ]Pyrazine-2(1 H )-Day)- N , N ,1-trimethyl-1 H -Imidazo[4,5- c ]Preparation of pyridin-4-amine
  • step 2 tert -butyl( R )-5-bromo-3-(4-(dimethylamino)-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.2 M), and then (3 R ,4 S )-3-fluoro-4-methoxypiperidine hydrochloride (1.5 equiv.) and sodium trimethylsilanolate (3.0 equiv.) were added.
  • the reaction mixture was degassed with nitrogen, and [(Cinnamyl)PdCl] 2 (0.2 equiv.) and Gphos (0.2 equiv.) were added, and the mixture was stirred at 110 °C for 10 min using a microwave apparatus. After confirming that the target compound was produced using LC-MS, the reaction mixture was filtered through Celite and washed with dichloromethane and methanol. The obtained filtrate was concentrated under reduced pressure, and then purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to obtain the target compound as a yellow solid (yield: 17%, MS (ESI): m/z 563 [M+H] + ).
  • Compound Example 96 was prepared in a similar manner to Example 95 above.
  • step 2 2,6-dichloro- N 4 -methylpyridine-3,4-diamine (1.0 eq.) and 1,1'-carbonyldiimidazole (1.3 eq.) obtained were dissolved in dichloroethane (0.3 M) and stirred at 50 °C for 15 h. After confirming that the target compound was produced using LC-MS, acetonitrile was added to the reaction mixture. The produced solid was filtered and washed with acetonitrile, and the target compound was obtained as a white solid (yield: 75%, MS (ESI): m / z 218 [M + H] + ).
  • step 3 4,6-dichloro-1-methyl-1,3-dihydro-2 H -imidazo[4,5- c ]pyridin-2-one (1.0 eq.) obtained was dissolved in dimethylformamide (0.4 M), sodium hydride (1.2 eq.) was added at -5 °C, the mixture was stirred for 10 minutes, methyl iodide (1.2 eq.) was added, and the mixture was stirred for 1 hour at -5 °C. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The combined organic layers were concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (dichloromethane: methanol) to obtain the target compound as a white solid (yield: 63%, MS (ESI): m/z 232 [M+H] + ).
  • step 5 6-chloro-1,3-dimethyl-4-morpholino-1,3-dihydro-2 H -imidazo[4,5- c ]pyridin-2-one (1.0 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.0 equiv.) and sodium carbonate (6.0 equiv.) were dissolved in water/dioxane (1/4 v/v, 0.1 M), and then Pd(amphos)Cl 2 (0.15 equiv.) was added at 80 ° C. under nitrogen, and stirred at 80 ° C.
  • step 6 tert -butyl 3-(1,3-dimethyl-4-morpholino-2-oxo-2,3-dihydro-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 15 h. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated.
  • the concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid): methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 3%, MS (ESI): m/z 487 [M+H] + ).
  • Example 97 The chemical structure, compound name, NMR, and LC-MS analysis results of Example 97 compound are summarized in Table 8 below.
  • Example 98 4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -Pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-2-(2-(((4-methylpiperazin-1-yl)oxy)ethoxy)-1 H -Imidazo[4,5- c ]pyridin-4-yl)morpholine and ⁇ Example 99> 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -Pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin)-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 H -Imidazo[4,5- c ]Preparation of pyridin-2-one
  • Step 1 6-chloro-1-methyl-4-morpholino-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained was dissolved in 1,4-dioxane (0.08 M), and bis(tributyltin) (1.8 equiv.), lithium chloride (6.0 equiv.), PCy 3 (0.2 equiv.), and Pd 2 (dba) 3 (0.1 equiv.) were added. After degassing with nitrogen, the mixture was stirred at 110 °C for 16 h under nitrogen. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated.
  • Step 2 1-methyl-4-morpholino-6-(tributylstannyl)-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained was dissolved in 1,4-dioxane (0.04 M). Then, compound 5 of Preparation Example 5, 5-bromo-3-iodo-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.), copper iodide (0.1 equiv.), and Pd(PPh 3 ) 4 (0.15 equiv.) were added.
  • Step 5 4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -Evacuation-2-days)-1 H -Pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-2-(2-((4-methylpiperazin-1-yl)oxy)ethoxy)-1 H -Imidazo[4,5- c ]pyridin-4-yl)morpholine and 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -Evacuation-2-days)-1 H -Pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 H -Imidazo[4,5- c ]Preparation of
  • Compound Example 100 was prepared in a similar manner to Examples 98 and 99 above.
  • Each cell was cultured using a medium (RPMI-1640) containing 10% fetal bovine serum (FBS), and 3,000 cells were seeded in a well plate (white clear bottom 96 well plate, Corning) 24 hours before treatment with compounds.
  • the compounds were diluted in dimethyl sulfoxide to a final concentration of 0.2 nM to 5 ⁇ M (3-fold dilution, total of 12 concentrations) and injected 1 ⁇ l each.
  • the cells were reacted in a CO2 incubator at 37 °C for 72 hours, and the luminescence intensity was measured using a reagent (Cell Titer-Glo luminescent cell-viability reagent, Promega) after storing at room temperature for 10 minutes.

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Abstract

The present invention relates to a pyrazolopyridine derivative, and a use thereof. The pyrazolopyridine derivative according to the present invention exhibits excellent inhibitory activity against EGFR, and thus can be effectively used as a therapeutic agent for the EGFR-related diseases.

Description

피라졸로피리딘 유도체 화합물 및 이의 용도 Pyrazolopyridine derivative compounds and uses thereof
본 발명은 피라졸로피리딘 유도체 화합물 및 이의 의약적 용도에 관한 것이다. 구체적으로, 본 발명은 EGFR 억제 활성을 갖는 피라졸로피리딘 유도체 화합물에 관한 것이다.The present invention relates to pyrazolopyridine derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to pyrazolopyridine derivative compounds having EGFR inhibitory activity.
단백질 키나아제는 분자 스위치로 작용하여 신호전달경로에 관여하는데, 세포 내에서 키나아제에 의한 표적 단백질의 활성과 비활성 상태 사이의 전환은 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전환이 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화하거나 비활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 특히, 단백질 키나아제 유전자의 변이, 증폭 및/또는 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행을 유발하거나 염증성 질환, 퇴행성 뇌질환, 자가면역 질환 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. Protein kinases act as molecular switches and are involved in signal transduction pathways, and the transition between the active and inactive states of target proteins by kinases within cells must be smoothly regulated. If the transition between the active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated or inactivated, leading to uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification, and/or overexpression of protein kinase genes causes the occurrence and progression of various tumors, and plays a critical role in the development of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.
ErbB 패밀리의 수용체 타이로신 키나아제(receptor tyrosine kinase)인 상피 성장 인자 수용체(epidermal growth factor receptor, EGFR)는 비소세포폐암종(NSCLC), 유방암, 신경교종, 두경부의 편평 세포 암종, 대장암, 곧창자 샘암종, 두경부암, 위암, 및 전립선암을 포함한 많은 상피세포 종양에서 비정상적으로 활성화되어 있고, 상기 EGFR-타이로신 키나아제의 활성화가 지속적인 세포 증식, 주변 조직에 대한 침범, 원격 전이, 혈관 형성을 일으키며 세포 생존을 증가시킴이 알려진 바 있다.Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase of the ErbB family, is abnormally activated in many epithelial tumors, including non-small cell lung carcinoma (NSCLC), breast cancer, glioma, squamous cell carcinoma of the head and neck, colorectal cancer, rectal adenocarcinoma, head and neck cancer, gastric cancer, and prostate cancer, and it is known that activation of the EGFR-tyrosine kinase causes sustained cell proliferation, invasion of surrounding tissues, distant metastasis, angiogenesis, and increased cell survival.
또한, EGFR 돌연변이인 EGFR Del19 또는 EGFR L858R이 비소세포폐암과 두경부암의 주요한 원인이라는 것이 알려져 있었고, 이들의 치료제인 이레사, 타세바가 개발되어 현재 임상에서 사용되고 있다. 하지만, 이러한 약물을 환자에 사용하였을 때 약물의 구조에 기반을 두는 EGFR 2차 돌연변이가 생기는 획득내성(acquired resistance)이 관찰되었고, 이것이 실제 약제내성의 주요 원인이라는 것도 밝혀졌다. EGFR 1세대 저해제를 평균 10개월 정도 사용하게 되면 EGFR 키나아제의 게이트키퍼(gatekeeper)에 위치한 T790M 돌연변이라는 획득내성이 발생하여 EGFR 1세대 저해제들이 약효를 내지 못하는 것이다. 즉, EGFR Del19/T790M 또는 EGFR L858R/T790M 이중돌연변이가 발생하여 기존 치료제가 약효를 나타내지 못하게 된다. EGFR T790M 변이에 따른 약물 저항성에 대해 높은 반응성을 나타내는 3세대 EGFR-TKI 표적 약물인 오시머티닙(Osimertinib)이 개발되었으나, 이로부터 역시 약물 저항성이 생기는 것으로 보고되었다(Niederst MJ. et al., Clin Cancer Res, 2015, 21(17), 3924-3933). EGFR C797S 변이는 오시머티닙에 대한 약물 내성을 야기하는 주요 메커니즘 중 하나로 제시되었으며, 임상 시험 환자 중 약 40 %가 EGFR C797S 변이를 가지는 것으로 보고되었다(Thress KS. et al., Nature Medicine, 2015, 21, 560-562).In addition, it was known that EGFR mutations, EGFR Del19 or EGFR L858R, are the main cause of non-small cell lung cancer and head and neck cancer, and their treatments, Iressa and Tarceva, were developed and are currently in clinical use. However, when these drugs were used in patients, acquired resistance was observed due to secondary EGFR mutations based on the structure of the drugs, and it was also revealed that this was the main cause of actual drug resistance. If first-generation EGFR inhibitors are used for an average of 10 months, acquired resistance called T790M mutation located in the gatekeeper of EGFR kinase occurs, causing first-generation EGFR inhibitors to become ineffective. In other words, EGFR Del19/T790M or EGFR L858R/T790M double mutations occur, rendering existing treatments ineffective. Osimertinib, a third-generation EGFR-TKI target drug that shows high responsiveness to drug resistance due to EGFR T790M mutation, was developed, but it was also reported to develop drug resistance (Niederst MJ. et al., Clin Cancer Res, 2015, 21(17), 3924-3933). EGFR C797S mutation has been suggested as one of the major mechanisms causing drug resistance to osimertinib, and approximately 40% of clinical trial patients were reported to have EGFR C797S mutation (Thress KS. et al., Nature Medicine, 2015, 21, 560-562).
따라서, 기존 약물에 대한 저항성을 극복하고 단일 약물을 통해 EGFR 활성(예컨대, EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/T790M/C797S)을 조절함으로써 EGFR 관련 질환의 치료에 유용하게 활용될 수 있는 신규 화합물에 대한 미충족된 수요가 증대되고 있다.Therefore, there is a growing unmet need for novel compounds that could be useful in the treatment of EGFR-related diseases by overcoming resistance to existing drugs and modulating EGFR activity (e.g., EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/T790M/C797S) through a single drug.
본 발명의 목적은 신규한 구조의 피라졸로피리딘 유도체, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공하는 것이다.The object of the present invention is to provide a novel structural pyrazolopyridine derivative, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 피라졸로피리딘 유도체 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing the pyrazolopyridine derivative compound.
본 발명의 다른 목적은 상기 피라졸로피리딘 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 피라졸로피리딘 유도체 화합물을 유효성분으로 포함하는 EGFR 관련 질환의 치료 또는 예방용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical use of the pyrazolopyridine derivative compound, and specifically, to provide a pharmaceutical composition for treating or preventing an EGFR-related disease, comprising the pyrazolopyridine derivative compound as an active ingredient.
본 발명의 또 다른 목적은 상기 피라졸로피리딘 유도체 화합물을 이용한 EGFR 관련 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 EGFR 관련 질환의 치료 또는 예방 방법을 제공하는 것이다.Another object of the present invention is to provide a use for treating or preventing an EGFR-related disease using the pyrazolopyridine derivative compound or a method for treating or preventing an EGFR-related disease comprising a step of administering the compound.
상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1, 2, 3, 또는 4로 표시되는 피라졸로피리딘 유도체 화합물들이 EGFR 돌연변이를 갖는 세포의 증식을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above purpose, the inventors of the present invention completed the present invention by confirming through research efforts that pyrazolopyridine derivative compounds represented by chemical formulas 1, 2, 3, or 4 mentioned below inhibit the proliferation of cells having EGFR mutations.
피라졸로피리딘 유도체 화합물Pyrazolopyridine derivative compounds
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
Figure PCTKR2024004758-appb-img-000001
Figure PCTKR2024004758-appb-img-000001
상기 화학식 1에서,In the above chemical formula 1,
Figure PCTKR2024004758-appb-img-000002
는 단일 결합 또는 이중 결합이고;
Figure PCTKR2024004758-appb-img-000002
is a single bond or a double bond;
X1은 NR1 또는 S이고;X 1 is NR 1 or S;
X2는 N 또는 NR2이고;X 2 is N or NR 2 ;
X3는 CR3 또는 C(=O)이고;X 3 is CR 3 or C(=O);
R1 및 R2는 각각 독립적으로 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo};
RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
V는 -NH-, -O-, 또는 아무것도 아니고(null);V is -NH-, -O-, or nothing (null);
고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 하기 범위일 수 있다:According to a specific example of the present invention, the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
상기
Figure PCTKR2024004758-appb-img-000003
는 Above
Figure PCTKR2024004758-appb-img-000003
Is
Figure PCTKR2024004758-appb-img-000004
,
Figure PCTKR2024004758-appb-img-000005
, 또는
Figure PCTKR2024004758-appb-img-000006
이다.
Figure PCTKR2024004758-appb-img-000004
,
Figure PCTKR2024004758-appb-img-000005
, or
Figure PCTKR2024004758-appb-img-000006
am.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 하기 범위일 수 있다:According to a specific example of the present invention, the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
상기 고리 Z는 The above ring Z is
Figure PCTKR2024004758-appb-img-000007
,
Figure PCTKR2024004758-appb-img-000008
,
Figure PCTKR2024004758-appb-img-000009
,
Figure PCTKR2024004758-appb-img-000010
,
Figure PCTKR2024004758-appb-img-000011
,
Figure PCTKR2024004758-appb-img-000012
,
Figure PCTKR2024004758-appb-img-000013
,
Figure PCTKR2024004758-appb-img-000014
,
Figure PCTKR2024004758-appb-img-000015
,
Figure PCTKR2024004758-appb-img-000016
,
Figure PCTKR2024004758-appb-img-000017
,
Figure PCTKR2024004758-appb-img-000018
,
Figure PCTKR2024004758-appb-img-000019
,
Figure PCTKR2024004758-appb-img-000020
,
Figure PCTKR2024004758-appb-img-000021
,
Figure PCTKR2024004758-appb-img-000022
,
Figure PCTKR2024004758-appb-img-000023
,
Figure PCTKR2024004758-appb-img-000024
,
Figure PCTKR2024004758-appb-img-000025
,
Figure PCTKR2024004758-appb-img-000026
,
Figure PCTKR2024004758-appb-img-000027
,
Figure PCTKR2024004758-appb-img-000028
,
Figure PCTKR2024004758-appb-img-000029
,
Figure PCTKR2024004758-appb-img-000030
,
Figure PCTKR2024004758-appb-img-000031
,
Figure PCTKR2024004758-appb-img-000032
,
Figure PCTKR2024004758-appb-img-000033
,
Figure PCTKR2024004758-appb-img-000034
, 또는
Figure PCTKR2024004758-appb-img-000035
이다 {여기서, 상기 고리 Z의 하나 이상의 H는 각각 독립적으로 RZ1 및 RZ2로 치환될 수 있음}.
Figure PCTKR2024004758-appb-img-000007
,
Figure PCTKR2024004758-appb-img-000008
,
Figure PCTKR2024004758-appb-img-000009
,
Figure PCTKR2024004758-appb-img-000010
,
Figure PCTKR2024004758-appb-img-000011
,
Figure PCTKR2024004758-appb-img-000012
,
Figure PCTKR2024004758-appb-img-000013
,
Figure PCTKR2024004758-appb-img-000014
,
Figure PCTKR2024004758-appb-img-000015
,
Figure PCTKR2024004758-appb-img-000016
,
Figure PCTKR2024004758-appb-img-000017
,
Figure PCTKR2024004758-appb-img-000018
,
Figure PCTKR2024004758-appb-img-000019
,
Figure PCTKR2024004758-appb-img-000020
,
Figure PCTKR2024004758-appb-img-000021
,
Figure PCTKR2024004758-appb-img-000022
,
Figure PCTKR2024004758-appb-img-000023
,
Figure PCTKR2024004758-appb-img-000024
,
Figure PCTKR2024004758-appb-img-000025
,
Figure PCTKR2024004758-appb-img-000026
,
Figure PCTKR2024004758-appb-img-000027
,
Figure PCTKR2024004758-appb-img-000028
,
Figure PCTKR2024004758-appb-img-000029
,
Figure PCTKR2024004758-appb-img-000030
,
Figure PCTKR2024004758-appb-img-000031
,
Figure PCTKR2024004758-appb-img-000032
,
Figure PCTKR2024004758-appb-img-000033
,
Figure PCTKR2024004758-appb-img-000034
, or
Figure PCTKR2024004758-appb-img-000035
{wherein, one or more H of the ring Z can be independently substituted with R Z1 and R Z2 }.
본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 하기 범위일 수 있다:According to a specific example of the present invention, the compound represented by the chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be in the following range:
상기 고리 W1은 The above ring W 1 is
Figure PCTKR2024004758-appb-img-000036
,
Figure PCTKR2024004758-appb-img-000037
,
Figure PCTKR2024004758-appb-img-000038
,
Figure PCTKR2024004758-appb-img-000039
,
Figure PCTKR2024004758-appb-img-000040
,
Figure PCTKR2024004758-appb-img-000041
,
Figure PCTKR2024004758-appb-img-000042
,
Figure PCTKR2024004758-appb-img-000043
,
Figure PCTKR2024004758-appb-img-000044
,
Figure PCTKR2024004758-appb-img-000045
,
Figure PCTKR2024004758-appb-img-000046
,
Figure PCTKR2024004758-appb-img-000047
,
Figure PCTKR2024004758-appb-img-000048
,
Figure PCTKR2024004758-appb-img-000049
,
Figure PCTKR2024004758-appb-img-000050
,
Figure PCTKR2024004758-appb-img-000051
,
Figure PCTKR2024004758-appb-img-000052
,
Figure PCTKR2024004758-appb-img-000053
,
Figure PCTKR2024004758-appb-img-000054
,
Figure PCTKR2024004758-appb-img-000055
,
Figure PCTKR2024004758-appb-img-000056
,
Figure PCTKR2024004758-appb-img-000057
,
Figure PCTKR2024004758-appb-img-000058
,
Figure PCTKR2024004758-appb-img-000059
,
Figure PCTKR2024004758-appb-img-000060
,
Figure PCTKR2024004758-appb-img-000061
,
Figure PCTKR2024004758-appb-img-000062
,
Figure PCTKR2024004758-appb-img-000063
,
Figure PCTKR2024004758-appb-img-000064
,
Figure PCTKR2024004758-appb-img-000065
,
Figure PCTKR2024004758-appb-img-000066
,
Figure PCTKR2024004758-appb-img-000067
,
Figure PCTKR2024004758-appb-img-000068
,
Figure PCTKR2024004758-appb-img-000069
,
Figure PCTKR2024004758-appb-img-000070
,
Figure PCTKR2024004758-appb-img-000071
,
Figure PCTKR2024004758-appb-img-000072
,
Figure PCTKR2024004758-appb-img-000073
,
Figure PCTKR2024004758-appb-img-000074
,
Figure PCTKR2024004758-appb-img-000075
,
Figure PCTKR2024004758-appb-img-000076
,
Figure PCTKR2024004758-appb-img-000077
,
Figure PCTKR2024004758-appb-img-000078
,
Figure PCTKR2024004758-appb-img-000079
,
Figure PCTKR2024004758-appb-img-000080
,
Figure PCTKR2024004758-appb-img-000081
,
Figure PCTKR2024004758-appb-img-000082
,
Figure PCTKR2024004758-appb-img-000083
,
Figure PCTKR2024004758-appb-img-000084
,
Figure PCTKR2024004758-appb-img-000085
,
Figure PCTKR2024004758-appb-img-000086
,
Figure PCTKR2024004758-appb-img-000087
,
Figure PCTKR2024004758-appb-img-000088
,
Figure PCTKR2024004758-appb-img-000089
,
Figure PCTKR2024004758-appb-img-000090
,
Figure PCTKR2024004758-appb-img-000091
,
Figure PCTKR2024004758-appb-img-000092
,
Figure PCTKR2024004758-appb-img-000093
,
Figure PCTKR2024004758-appb-img-000094
,
Figure PCTKR2024004758-appb-img-000095
,
Figure PCTKR2024004758-appb-img-000096
,
Figure PCTKR2024004758-appb-img-000097
,
Figure PCTKR2024004758-appb-img-000098
,
Figure PCTKR2024004758-appb-img-000099
,
Figure PCTKR2024004758-appb-img-000100
,
Figure PCTKR2024004758-appb-img-000101
, 또는
Figure PCTKR2024004758-appb-img-000102
이다 {여기서, 상기 고리 W1의 하나 이상의 H는 각각 독립적으로 RW로 치환될 수 있고; 상기 고리 W1의 -CH2-는 -C(=O)-로 치환될 수 있음}.
Figure PCTKR2024004758-appb-img-000036
,
Figure PCTKR2024004758-appb-img-000037
,
Figure PCTKR2024004758-appb-img-000038
,
Figure PCTKR2024004758-appb-img-000039
,
Figure PCTKR2024004758-appb-img-000040
,
Figure PCTKR2024004758-appb-img-000041
,
Figure PCTKR2024004758-appb-img-000042
,
Figure PCTKR2024004758-appb-img-000043
,
Figure PCTKR2024004758-appb-img-000044
,
Figure PCTKR2024004758-appb-img-000045
,
Figure PCTKR2024004758-appb-img-000046
,
Figure PCTKR2024004758-appb-img-000047
,
Figure PCTKR2024004758-appb-img-000048
,
Figure PCTKR2024004758-appb-img-000049
,
Figure PCTKR2024004758-appb-img-000050
,
Figure PCTKR2024004758-appb-img-000051
,
Figure PCTKR2024004758-appb-img-000052
,
Figure PCTKR2024004758-appb-img-000053
,
Figure PCTKR2024004758-appb-img-000054
,
Figure PCTKR2024004758-appb-img-000055
,
Figure PCTKR2024004758-appb-img-000056
,
Figure PCTKR2024004758-appb-img-000057
,
Figure PCTKR2024004758-appb-img-000058
,
Figure PCTKR2024004758-appb-img-000059
,
Figure PCTKR2024004758-appb-img-000060
,
Figure PCTKR2024004758-appb-img-000061
,
Figure PCTKR2024004758-appb-img-000062
,
Figure PCTKR2024004758-appb-img-000063
,
Figure PCTKR2024004758-appb-img-000064
,
Figure PCTKR2024004758-appb-img-000065
,
Figure PCTKR2024004758-appb-img-000066
,
Figure PCTKR2024004758-appb-img-000067
,
Figure PCTKR2024004758-appb-img-000068
,
Figure PCTKR2024004758-appb-img-000069
,
Figure PCTKR2024004758-appb-img-000070
,
Figure PCTKR2024004758-appb-img-000071
,
Figure PCTKR2024004758-appb-img-000072
,
Figure PCTKR2024004758-appb-img-000073
,
Figure PCTKR2024004758-appb-img-000074
,
Figure PCTKR2024004758-appb-img-000075
,
Figure PCTKR2024004758-appb-img-000076
,
Figure PCTKR2024004758-appb-img-000077
,
Figure PCTKR2024004758-appb-img-000078
,
Figure PCTKR2024004758-appb-img-000079
,
Figure PCTKR2024004758-appb-img-000080
,
Figure PCTKR2024004758-appb-img-000081
,
Figure PCTKR2024004758-appb-img-000082
,
Figure PCTKR2024004758-appb-img-000083
,
Figure PCTKR2024004758-appb-img-000084
,
Figure PCTKR2024004758-appb-img-000085
,
Figure PCTKR2024004758-appb-img-000086
,
Figure PCTKR2024004758-appb-img-000087
,
Figure PCTKR2024004758-appb-img-000088
,
Figure PCTKR2024004758-appb-img-000089
,
Figure PCTKR2024004758-appb-img-000090
,
Figure PCTKR2024004758-appb-img-000091
,
Figure PCTKR2024004758-appb-img-000092
,
Figure PCTKR2024004758-appb-img-000093
,
Figure PCTKR2024004758-appb-img-000094
,
Figure PCTKR2024004758-appb-img-000095
,
Figure PCTKR2024004758-appb-img-000096
,
Figure PCTKR2024004758-appb-img-000097
,
Figure PCTKR2024004758-appb-img-000098
,
Figure PCTKR2024004758-appb-img-000099
,
Figure PCTKR2024004758-appb-img-000100
,
Figure PCTKR2024004758-appb-img-000101
, or
Figure PCTKR2024004758-appb-img-000102
{wherein, one or more H of the ring W 1 may be independently substituted with R W ; and -CH 2 - of the ring W 1 may be substituted with -C(=O)-}.
또한, 본 발명은 하기 화학식 2로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:Furthermore, the present invention provides a compound represented by the following chemical formula 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 2][Chemical formula 2]
Figure PCTKR2024004758-appb-img-000103
Figure PCTKR2024004758-appb-img-000103
상기 화학식 2에서,In the above chemical formula 2,
R1은 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 is -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
V는 -NH- 또는 아무것도 아니고(null);V is -NH- or nothing (null);
고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
또한, 본 발명은 하기 화학식 3로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:Furthermore, the present invention provides a compound represented by the following chemical formula 3, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 3][Chemical Formula 3]
Figure PCTKR2024004758-appb-img-000104
Figure PCTKR2024004758-appb-img-000104
상기 화학식 3에서,In the above chemical formula 3,
R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein n is an integer from 0 to 6};
W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
또한, 본 발명은 하기 화학식 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:Furthermore, the present invention provides a compound represented by the following chemical formula 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 4][Chemical Formula 4]
Figure PCTKR2024004758-appb-img-000105
Figure PCTKR2024004758-appb-img-000105
상기 화학식 4에서,In the above chemical formula 4,
R1 및 R2는 각각 독립적으로 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
본 발명의 구체예에 따르면, 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물이 하기에 기재된 표에 나열된 실시예 1 내지 100 화합물로 이루어진 군으로부터 선택된 것일 수 있다.According to a specific example of the present invention, the compound represented by the chemical formula 1, 2, 3, or 4 may be selected from the group consisting of compounds of Examples 1 to 100 listed in the table below.
이하, 본 발명을 실시 형태로 예를 들어 상세히 설명한다. Hereinafter, the present invention will be described in detail by way of an example embodiment.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.The embodiments of the present invention can be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiments of the present invention are provided so that a person having average knowledge in the relevant technical field can more completely explain the present invention. Furthermore, throughout the specification, the term "including" a certain component does not exclude other components unless specifically stated to the contrary, but rather means that other components can be further included.
본 발명에 있어서, 원자 및/또는 기(group)를 결합하는 기호 "
Figure PCTKR2024004758-appb-img-000106
"는 단일 결합, 기호 "
Figure PCTKR2024004758-appb-img-000107
"는 이중 결합을 의미하고, 기호 "
Figure PCTKR2024004758-appb-img-000108
"는 단일 결합 또는 이중 결합을 의미한다. 상기 기호는 생략될 수 있으며, 결합 원자 또는 결합 위치를 특정하는 경우 등 필요한 경우 표시될 수도 있다. In the present invention, a symbol for combining atoms and/or groups "
Figure PCTKR2024004758-appb-img-000106
" is a single bond, symbol "
Figure PCTKR2024004758-appb-img-000107
" means double bond, and the symbol "
Figure PCTKR2024004758-appb-img-000108
" means a single bond or a double bond. The symbol may be omitted, and may be indicated when necessary, such as when specifying a bonding atom or bonding position.
본 발명에 있어서, 원자들 간 "연결되어"는 원자들 간 직접 연결되는 경우뿐만 아니라, 다른 원자 및/또는 기(group)가 매개되어 원자들 간 간접 연결되는 경우도 포함될 수 있다. 이 때, 다른 원자 및/또는 기(group)는 산소, 황, C1-6알킬아미노, 또는 C1-6알킬렌 등일 수 있고, 이에 제한되는 것이 아니며, 상기 원자 및/또는 기(group)는 치환되거나 비치환될 수 있다.In the present invention, the term "connected" between atoms may include not only cases where atoms are directly connected between atoms, but also cases where atoms are indirectly connected between atoms via another atom and/or group. In this case, the other atom and/or group may be, but is not limited to, oxygen, sulfur, C 1-6 alkylamino, C 1-6 alkylene, and the like, and the atoms and/or groups may be substituted or unsubstituted.
본 발명에 있어서, "치환될 수 있는" 및 "치환되거나 비치환된"은 다른 기재가 없는 한 하나 또는 복수의 수소 원자가 다른 원자 또는 치환기로 치환되거나 치환되지 않은 것을 의미할 수 있다. 상기 치환기는 할로겐(클로로(Cl), 아이오도(I), 브로모(Br), 플루오로(F)), C1-10알킬, C2-10알켄일, C2-10알킨일, 하이드록실, C1-10알콕시, 아미노, 나이트로, 싸이올(thiol), 싸이오에터, 이민, 사이아노, 포스핀(phosphine), 카복시, 카바모일(carbamoyl), 아세탈, 싸이오카보닐, 설폰일, 설폰아마이드(sulfonamide), 케톤, 알데하이드, 에스터, 아세틸, 아마이드, 옥소(=0), 할로알킬(예를 들어, 트라이플루오로메틸), 치환 아미노아실과 아미노알킬, 탄소고리 사이클로알킬로서 단일 고리이거나 융합 혹은 비융합 다중 고리(예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 또는 사이클로헥실), 혹은 헤테로사이클로알킬로서 단일 고리이거나 융합 또는 비융합된 다중 고리(예를 들어, 피롤리딘일, 피페리딘일, 피페라진일, 모폴린일, 또는 싸이아진일), 탄소고리, 헤테로고리, 단일고리, 융합 다중고리, 비융합 다중고리, 융합 다중고리 아릴 또는 비융합 다중고리 아릴(예를 들어, 페닐, 나프틸, 피롤릴(pyrrolyl), 인돌릴, 퓨란일, 싸이엔일, 이미다졸릴, 옥사졸릴, 아이소옥사졸릴(isoxazolyl), 싸이아졸릴, 트라이아졸릴, 테트라졸릴, 피라졸릴, 피리딘일, 퀴놀린일, 아이소퀴놀린일, 아크리딘일(acridinyl), 피라진일, 피리다진일, 피리미딘일, 벤즈이미다졸릴(benzimidazolyl), 벤조싸이엔일 또는 벤조퓨란일), 아미노(일급, 이급, 또는 삼급), 아릴, 아릴옥시, 및 아릴-알킬로 이루어진 군 중에서 선택되는 하나 이상일 수 있으며, 이에 제한되는 것은 아니다. 또한, 상기 예시된 치환기 각각은 다시 이들 치환기 군 중에서 선택된 치환기로 치환되거나 비치환될 수 있다.In the present invention, unless otherwise stated, “substituteable” and “substituted or unsubstituted” may mean that one or more hydrogen atoms are substituted or unsubstituted with another atom or substituent. The above substituents are halogen (chloro (Cl), iodo (I), bromo (Br), fluoro (F)), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hydroxyl, C 1-10 alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphine, carboxy, carbamoyl, acetal, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, amide, oxo (=0), haloalkyl (e.g., trifluoromethyl), substituted aminoacyl and aminoalkyl, carbon ring cycloalkyl which is monocyclic or fused or unfused multiple rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocycloalkyl which is monocyclic or fused or an unfused polycyclic ring (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), a carbocyclic ring, a heterocyclic ring, a monocyclic ring, a fused polycyclic ring, a non-fused polycyclic ring, a fused polycyclic aryl, or a non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl), amino (primary, secondary, or tertiary), It may be at least one selected from the group consisting of aryl, aryloxy, and aryl-alkyl, but is not limited thereto. In addition, each of the above-mentioned exemplified substituents may be substituted or unsubstituted with a substituent selected from these groups of substituents.
본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-6알킬"은 탄소 원자를 1 내지 6 개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬의 일 예로서, 메틸, 에틸, n-프로필, 아이소프로필, n-부틸, 2급(sec)-부틸, 아이소부틸, 3급(tert)-부틸, 아이소펜틸, 및 2-메틸펜틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 본 명세서에서 상기 "알킬"에서 수소 원자 하나를 제거한 잔기를 "알킬렌"으로 지칭한다.In the present invention, unless otherwise specified, "alkyl" may mean a straight-chain or branched-chain acyclic, cyclic, or a saturated hydrocarbon group combined therewith. For example, "C 1-6 alkyl" may mean alkyl having 1 to 6 carbon atoms. Examples of acyclic alkyl may include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, tert -butyl, isopentyl, and 2-methylpentyl. In the present specification, a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene."
본 발명에 있어서, 고리형(ring) 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있다. 사이클로알킬은 이중 결합의 존재로 인해 방향성을 갖지 않는 범위에서 고리 내에 하나 이상의 탄소-탄소 이중 결합을 가져 불포화된 고리를 포함할 수 있으며, 예를 들어 사이클로펜텐일 등도 범주에 포함될 수 있다. 달리 언급하지 않는 한, 사이클로알킬은 단일 고리이거나, 스피로(spiro) 고리, 다리(bridged) 고리, 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 예를 들어, "3-7원 사이클로알킬"은 고리를 형성하는 원자를 3 내지 7 개 포함하는 사이클로알킬을 의미할 수 있다. 사이클로알킬의 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 및 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 비고리형과 고리형 알킬이 결합된 알킬은, 예를 들어, 메틸사이클로프로필, 사이클로프로필메틸, 에틸사이클로프로필, 및 사이클로프로필에틸 등을 포함할 수 있으나, 이에 제한되지 않는다.In the present invention, ring alkyl may be used interchangeably with "cycloalkyl" herein. Cycloalkyl may include unsaturated rings having one or more carbon-carbon double bonds in the ring, as long as the ring does not have aromaticity due to the presence of the double bond, and for example, cyclopentenyl may also be included in the category. Unless otherwise stated, cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. For example, "3-7 membered cycloalkyl" may mean a cycloalkyl having 3 to 7 ring forming atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Alkyl groups comprising acyclic and cyclic alkyls may include, but are not limited to, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, and cyclopropylethyl, for example.
본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O, 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스피로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 예를 들어, "3-7원 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 7 개 포함하는 헤테로사이클로알킬을 의미할 수 있다. 헤테로사이클로알킬의 일 예로서, 아지리딘, 아제테딘, 피롤리딘, 피페리딘, N-메틸피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이마이드, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥세인, 모폴린, 싸이오모폴린, 싸이오모폴린-S-옥사이드, 싸이오모폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 아이소옥사졸리딘, 벤조[d]아이소옥사졸리딘, 옥사지네인, 아자바이사이클로[2,2,1]헵테인, 2-아자스피로[3.3]헵테인, 5-옥사-6-아자스피로[2.4]헵테인, (1R,5S)-3-아자바이사이클로[3.2.1]옥테인, (1S,4S)-2-아자바이사이클로[2.2.2]옥테인, 다이아자스피로[5.5]운데칸, 다이아자바이사이클로[2.2.1]헵탄, 2-아자스피로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1S,4S)-2-아자바이사이클로[2.2.2]옥탄, 및 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. For example, "3-7 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 7 ring forming atoms. Examples of heterocycloalkyl include aziridine, azetedine, pyrrolidine, piperidine, N -methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4( 1H , 3H )-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, isoxazolidine, benzo[ d ]isoxazolidine, oxazinane, Including azabicyclo[2,2,1]heptane, 2-azabicyclo[3.3]heptane, 5-oxa-6-azabicyclo[2.4]heptane, (1 R , 5 S )-3-azabicyclo[3.2.1]octane, (1 S , 4 S )-2-azabicyclo[2.2.2]octane, diazabicyclo[5.5]undecane, diazabicyclo[2.2.1]heptane, 2-azabicyclo[3.3]heptane, (1 R , 5 S )-3-azabicyclo[3.2.1]octane, (1 S , 4 S )-2-azabicyclo[2.2.2]octane, and (1 R , 4 R )-2-oxa-5-azabicyclo[2.2.2]octane. However, it is not limited to these.
본 발명에 있어서, "헤테로바이사이클로알킬"은 고리를 형성하는 원자로 N, O, 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리를 갖는 이중 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로바이사이클로알켄으로 지칭될 수 있다.In the present invention, "heterobicycloalkyl" may mean a double ring having a spiro ring, a bridged ring or a fused ring containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as heterobicycloalkene.
본 발명에 있어서, "헤테로고리"는 고리를 형성하는 원자로 N, O, 및 S 중 1개 이상의 헤테로 원자를 포함하는 포화, 부분 불포화, 불포화, 또는 방향족 고리를 의미할 수 있고, 단일 고리 또는 다중 고리(2환 내지 4환)일 수 있다. 다중 고리의 헤테로 고리는 공통적인 단일 또는 이중 결합을 통해 형성되거나, 2개 이상의 배열된 원자들을 공유하여 형성되거나(다리 고리, 융합 고리), 또는 공통적인 단일 원자를 통해 형성될 수 있다(스피로 고리). In the present invention, "heterocycle" may mean a saturated, partially unsaturated, unsaturated, or aromatic ring containing at least one heteroatom selected from N, O, and S as ring forming atoms, and may be a single ring or multiple rings (bi- to tetra-rings). The multiple ring heterocycle may be formed through a common single or double bond, formed by sharing two or more arranged atoms (bridged ring, fused ring), or formed through a common single atom (spiro ring).
본 발명에 있어서, "알케닐" 및 "알키닐"은 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 불포화 탄화수소를 의미할 수 있다. 예를 들어, "C1-6알케닐"은 하나 이상의 이중결합을 갖는 탄소 원자 1 내지 6 개의 불포화 탄화수소를 의미할 수 있고, "C1-6알키닐"은 하나 이상의 삼중결합을 갖는 탄소 원자 1 내지 6 개의 불포화 탄화수소를 의미할 수 있다.In the present invention, "alkenyl" and "alkynyl" may mean a straight-chain or branched-chain acyclic, cyclic, or unsaturated hydrocarbon combined therewith. For example, "C 1-6 alkenyl" may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms and having one or more double bonds, and "C 1-6 alkynyl" may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms and having one or more triple bonds.
본 발명에 있어서, "알콕시"는 알킬 에터기로 -(R'-O-R")을 의미할 수 있으며, 여기서 R'은 단일 결합 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있고, R"은 C1-6알킬일 수 있다. 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C1-6알콕시"는 C1-6의 알킬을 함유하는 알콕시, 즉, -(O-C1-6알킬) 또는 -(C1-6알킬-O-C1-6알킬)을 의미할 수 있으며, 알콕시의 일 예로서, 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 및 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" may mean an alkyl ether group, -(R'-OR"), wherein R' may be selected from the group consisting of a single bond and C 1-6 alkyl, and R" may be C 1-6 alkyl. Here, alkyl is as defined above. For example, "C 1-6 alkoxy" can mean an alkoxy containing an alkyl of C 1-6 , i.e., -(OC 1-6 alkyl) or -(C 1-6 alkyl-OC 1-6 alkyl), examples of alkoxy include, but are not limited to, methoxy, ethoxy , n -propoxy , isopropoxy , n -butoxy, isobutoxy, sec -butoxy, and tert -butoxy .
본 발명에 있어서, "알킬아미노" 또는 "아미노알킬"은 -(NR'R")을 의미할 수 있으며, 여기서 R' 및 R"은 각각 독립적으로 수소 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있고, 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. 또한, "C0-6알킬아미노"는 알킬을 함유하지 않는 아미노(-NH2) 또는 C1-6 알킬을 함유하는 아미노, 즉, -NH(C1-6알킬) 또는 -N(C1-6알킬)2을 의미할 수 있으며, 다이메틸아미노, 다이에틸아미노, 메틸에틸아미노, 메틸프로필아미노, 및 에틸프로필아미노를 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkylamino" or "aminoalkyl" may mean -(NR'R"), wherein R' and R" may each be independently selected from the group consisting of hydrogen and C 1-6 alkyl, and the selected R' and R" may each independently be substituted or unsubstituted. In addition, "C 0-6 alkylamino" may mean amino not containing alkyl (-NH 2 ) or amino containing C 1-6 alkyl, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2 , and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, and ethylpropylamino.
본 발명에 있어서, "하이드록시알킬"은 하이드록시(-OH)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있으며, 예를 들어 -OH로 독립적으로 치환된 메틸, 에틸, n-프로필, 아이소프로필, n-부틸, sec-부틸, 아이소부틸, 및 tert-부틸을 포함하나, 이에 한정되는 것은 아니다.본 발명에 있어서, "할로" 또는 "할로겐"은 F, Cl, Br, 또는 I일 수 있다.In the present invention, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (-OH), and examples thereof include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, and tert -butyl independently substituted with -OH. In the present invention, "halo" or "halogen" may be F, Cl, Br, or I.
본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, n-프로필, 아이소프로필, n-부틸, sec-부틸, 아이소부틸, 및 tert-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, n -propyl, isopropyl, n -butyl, sec -butyl, isobutyl, and tert -butyl, each independently substituted with one or more halogens, for example, F, Cl, Br, or I.
본 발명에 있어서, "알킬설폰일"은 -(R'-S(=O)2-R")을 의미할 수 있으며, 여기서 R'은 단일 결합 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있고, R"은 하이드록시 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있다. 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. 또한, "C0-6알킬설폰일"은 알킬을 함유하지 않는 설폰산기(-S(=O)2OH) 또는 C1-6알킬을 함유하는 설폰일기, 즉, -S(=O)2-(C1-6알킬) 또는 -(C1-6알킬)-S(=O)2-(C1-6알킬)을 의미할 수 있으며, 메틸설폰일, (메틸설폰일)메틸, (메틸설폰일)에틸, 에틸설폰일, (에틸설폰일)메틸, 및 (에틸설폰일)에틸을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkylsulfonyl" may mean -(R'-S(=O) 2 -R"), wherein R' may be selected from the group consisting of a single bond and C 1-6 alkyl, and R" may be selected from the group consisting of hydroxy and C 1-6 alkyl. The above selected R' and R" may be independently substituted or unsubstituted. In addition, "C 0-6 alkylsulfonyl" may mean a sulfonic acid group not containing alkyl (-S(=O) 2 OH) or a sulfonyl group containing C 1-6 alkyl, i.e., -S(=O) 2 -(C 1-6 alkyl) or -(C 1-6 alkyl)-S(=O) 2 -(C 1-6 alkyl), and may include, but are not limited to, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, ethylsulfonyl, (ethylsulfonyl)methyl, and (ethylsulfonyl)ethyl.
본 발명에 있어서, "알킬카보닐"은 -(R'-C(=O)-R")을 의미할 수 있으며, 여기서 R'은 단일 결합 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있고, R"은 수소 및 C1-6알킬로 이루어진 군 중에서 선택될 수 있다. 상기 선택된 R' 및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. 또한, "C0-6알킬카보닐"은 알킬을 함유하지 않는 알데하이드기(-C(=O)H) 또는 C1-6알킬을 함유하는 케톤기, 즉, -C(=O)-(C1-6알킬) 또는 -(C1-6알킬)-C(=O)-(C1-6알킬)을 의미할 수 있다.In the present invention, "alkylcarbonyl" may mean -(R'-C(=O)-R"), wherein R' may be selected from the group consisting of a single bond and C 1-6 alkyl, and R" may be selected from the group consisting of hydrogen and C 1-6 alkyl. The selected R' and R" may each independently be substituted or unsubstituted. In addition, "C 0-6 alkylcarbonyl" may mean an aldehyde group not containing alkyl (-C(=O)H) or a ketone group containing C 1-6 alkyl, i.e., -C(=O)-(C 1-6 alkyl) or -(C 1-6 alkyl)-C(=O)-(C 1-6 alkyl).
본 발명에 있어서, "사이아노알킬"은 사이아노(-CN)로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다.In the present invention, “cyanoalkyl” may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (-CN).
본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 바이벤젠, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다. 상기 아릴은 교대 배열된 단일 결합과 이중 결합, 즉 컨쥬게이션된 ð결합에 의해 전자가 비편재화된 고리를 적어도 하나 갖는 탄화수소 고리라면 범주에 포함될 수 있다. 고리를 구성하는 탄소의 개수에 따라 C6-12아릴, C6-10아릴 등이 가능하나, 이에 한정되지 않는다.In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quarterbenzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl." The aryl may be included in the category as long as it is a hydrocarbon ring having at least one ring in which electrons are delocalized by alternating single bonds and double bonds, i.e., conjugated ð bonds. Depending on the number of carbons forming the ring, C 6-12 aryl, C 6-10 aryl, etc. are possible, but are not limited thereto.
본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 고리일 수 있다. 헤테로아렌의 고리 형성 원자수는 3 이상 30 이하, 3 이상 20 이하, 또는 3 이상 15 이하일 수 있다. 헤테로아렌은 단환식 헤테로아렌 또는 다환식 헤테로아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 비피리딜, 트라이아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진, 피라졸로피리딘, 트라이아졸로피리딘, 트라이아졸로피리미딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤, 또는 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 발명의 일 실시 태양에서 헤테로아렌은 또한 헤테로사이클로알킬 고리에 융합된 아렌 고리 및 사이클로알킬 고리에 융합된 헤테로아렌을 포함하는 바이사이클릭 헤테로사이클로-아렌을 포함할 수 있다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" may be a ring including at least one of O, N, P, Si, and S as a heteroatom. The number of ring-forming atoms of the heteroarene may be 3 or more and 30 or less, 3 or more and 20 or less, or 3 or more and 15 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazino pyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine, pyrazolopyridine, triazolopyrimidine, triazolopyrimidine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, Examples thereof include, but are not limited to, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, or dibenzofuran. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene including an arene ring fused to a heterocycloalkyl ring and a heteroarene fused to a cycloalkyl ring. As used herein, a moiety having one hydrogen atom removed from the above "heteroarene" is referred to as a "heteroaryl".
본 발명에 있어서, "헤테로하이드로아렌"은 고리를 형성하는 원자로 N, O, 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 다중 고리(2환 내지 4환)를 의미할 수 있고, 상기 다중 고리 중 적어도 하나는 포화 또는 부분 불포화 고리이고, 적어도 다른 하나는 방향족 고리를 갖는 것일 수 있다. 본 명세서에서 상기 "헤테로하이드로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로하이드로아릴"로 지칭한다.In the present invention, "heterohydroarene" may mean a polycyclic ring (bicyclic ring to tetracyclic ring) containing 1 to 5 heteroatoms selected from N, O, and S as ring forming atoms, and at least one of the polycyclic rings may be a saturated or partially unsaturated ring, and at least another may have an aromatic ring. In the present specification, a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as "heterohydroaryl".
본 발명에 있어서, "고리(ring)"는 단일 고리이거나 다중 고리일 수 있고, 상기 다중 고리는 스피로(spiro) 고리, 다리(bridged) 고리, 또는 융합(fused) 고리 등의 형태일 수 있다.In the present invention, the “ring” may be a single ring or a multi-ring, and the multi-ring may be in the form of a spiro ring, a bridged ring, a fused ring, or the like.
본 발명에 있어서, "입체 이성질체(stereoisomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 화합물을 의미한다. 본 발명에서 입체 이성질체는 "광학 이성질체(enantiomer)" 및 "부분입체 이성질체(diasteromer)"를 포함하고, 또한 부분입체 이성질체는 회전이성질체(rotamer)와 같은 형태이성질체(conformational isomer) 및 시스(cis)/트랜스(trans) 이성질체를 포함하는데, 이들 각각의 이성질체, 라세미, 및 이들의 혼합물들 역시 본 발명의 범위에 포함된다. 예를 들어 본 발명의 화학식 1, 2, 3, 또는 4는 입체 화학구조가 특정되지 않기 때문에 화학식 1, 2, 3, 또는 4의 상기 입체 이성질체들을 포함할 수 있다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합(
Figure PCTKR2024004758-appb-img-000109
)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합(
Figure PCTKR2024004758-appb-img-000110
) 및 쐐기형 점선 결합(
Figure PCTKR2024004758-appb-img-000111
)을 포함할 수 있다.In the present invention, "stereoisomer" means a compound having the same chemical formula or molecular formula but being sterically different. In the present invention, stereoisomers include "enantiomers" and "diastereoisomers", and diastereoisomers also include conformational isomers such as rotamers and cis/trans isomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention. For example, since the stereochemical structure of chemical formula 1, 2, 3, or 4 of the present invention is not specified, it may include the stereoisomers of chemical formula 1, 2, 3, or 4. Unless otherwise specified, a solid bond (
Figure PCTKR2024004758-appb-img-000109
) is a wedge-shaped solid line combination that represents the absolute arrangement of the stereocenter.
Figure PCTKR2024004758-appb-img-000110
) and wedge-shaped dotted line joints (
Figure PCTKR2024004758-appb-img-000111
) may be included.
본 발명에 있어서, "호변 이성질체(tautomer)"는 구조 이성질체 중 하나로서 구조 및 원자 배열이 상이하지만 평형 상태로 존재하는 화합물을 지칭한다. 따라서, 본 발명의 화합물은 다양한 호변 이성질체를 포함할 수 있다. 통상적인 호변 이성질체 쌍은 케톤-에놀, 아마이드-나이트릴, 락탐-락팀, 헤테로사이클릭 고리에서 아마이드-이미드산 (예를 들어, 핵염기 구아닌, 티민, 및 시토신에서), 아민-엔아민 및 엔아민-엔아민을 포함한다. 하기 예는 예시적인 목적으로 포함되며, 본 개시는 예에 제한되지 않는다:In the present invention, "tautomer" refers to a compound that is one of structural isomers and has different structures and atomic arrangements but exists in an equilibrium state. Therefore, the compound of the present invention may include various tautomers. Typical tautomeric pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid in a heterocyclic ring (e.g., in the nucleobases guanine, thymine, and cytosine), amine-enamine, and enamine-enamine. The following examples are included for illustrative purposes, and the present disclosure is not limited to the examples:
Figure PCTKR2024004758-appb-img-000112
,
Figure PCTKR2024004758-appb-img-000113
,
Figure PCTKR2024004758-appb-img-000114
.
Figure PCTKR2024004758-appb-img-000112
,
Figure PCTKR2024004758-appb-img-000113
,
Figure PCTKR2024004758-appb-img-000114
.
일 예로, 본 발명의 상기 화학식 1, 2, 3, 또는 4에서,
Figure PCTKR2024004758-appb-img-000115
는
Figure PCTKR2024004758-appb-img-000116
또는
Figure PCTKR2024004758-appb-img-000117
로 호변이성질화될 수 있다.For example, in the chemical formula 1, 2, 3, or 4 of the present invention,
Figure PCTKR2024004758-appb-img-000115
Is
Figure PCTKR2024004758-appb-img-000116
or
Figure PCTKR2024004758-appb-img-000117
It can be transformed into a tautomer.
본 발명의 화학식 1, 2, 3, 또는 4로 표시되는 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 이에 본 발명의 화합물의 범주에는 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물의 약학적으로 허용가능한 염이 포함된다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1, 2, 3, 또는 4로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound represented by chemical formula 1, 2, 3, or 4 of the present invention may exist in the form of a "pharmaceutically acceptable salt". Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by chemical formula 1, 2, 3, or 4. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound represented by chemical formula 1, 2, 3, or 4, which has an effective effect that is relatively nontoxic and harmless to the patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by chemical formula 1, 2, 3, or 4 at a concentration.
특히, 상기 약학적으로 허용가능한 염은, 유리산(free acid)에 의해 형성된 산 부가염일 수 있다. 여기서, 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 아이오딘화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 다이카복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸다이오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트라이플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻을 수 있다. In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, and the like.
이러한 약학적으로 허용가능한 염의 종류로는 설페이트, 설파이트, 니트레이트, 포스페이트, 피로포스페이트, 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 아이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 벤조에이트, 프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, 글리콜레이트, 말레이트, 타트레이트, 만델레이트 등을 포함할 수 있다. Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.
상기 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1, 2, 3, 또는 4의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토나이트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The above acid addition salt can be prepared by a conventional method, for example, by dissolving a derivative of chemical formula 1, 2, 3, or 4 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.
또한, 상기 약학적으로 허용가능한 염은, 염기를 사용하여 얻어진 염 또는 금속염일 수 있다. 금속염의 일 예로서, 알칼리 금속 또는 알칼리 토금속 염은, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발 및 건조시켜 얻을 수 있다. 알칼리 금속염으로는 나트륨, 칼륨 또는 칼슘염이 제약상 적합할 수 있다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained by using a base. As an example of the metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As the alkali metal salt, sodium, potassium or calcium salts can be pharmaceutically suitable. In addition, the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal with a suitable silver salt (e.g., silver nitrate), and can be prepared through a method for preparing a salt known in the art.
나아가, 본 발명은 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물 및 이의 약학적으로 허용가능한 염 뿐만 아니라, 이들의 이성질체, 특히, 입체, 부분입체, 거울상 이성질체 또는 이들의 혼합물일 수 있다.Furthermore, the present invention may include compounds represented by the chemical formulae 1, 2, 3, or 4 and pharmaceutically acceptable salts thereof, as well as isomers thereof, particularly stereoisomers, diastereoisomers, enantiomers or mixtures thereof.
피라졸로피리딘 유도체 화합물의 용도Uses of Pyrazolopyridine Derivative Compounds
본 발명은 하기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다:The present invention provides the use of a compound represented by the following chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
Figure PCTKR2024004758-appb-img-000118
Figure PCTKR2024004758-appb-img-000118
[화학식 2][Chemical formula 2]
Figure PCTKR2024004758-appb-img-000119
Figure PCTKR2024004758-appb-img-000119
[화학식 3][Chemical Formula 3]
Figure PCTKR2024004758-appb-img-000120
Figure PCTKR2024004758-appb-img-000120
[화학식 4][Chemical Formula 4]
Figure PCTKR2024004758-appb-img-000121
Figure PCTKR2024004758-appb-img-000121
상기 화학식 1, 2, 3, 또는 4는 위에서 정의한 바와 같다.The above chemical formulas 1, 2, 3, or 4 are as defined above.
본 발명은 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 약학적 용도를 제공한다.The present invention provides pharmaceutical uses of compounds represented by chemical formula 1, 2, 3, or 4, tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof.
본 발명의 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 EGFR에 대하여 억제 활성을 나타낸다.The compound represented by chemical formula 1, 2, 3, or 4 of the present invention, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against EGFR.
따라서 본 발명은 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 포함하는 EGFR 억제제를 제공한다.Therefore, the present invention provides an EGFR inhibitor comprising a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
또한 본 발명은 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 검체나 세포에 처리하는 단계를 포함하는 EGFR의 활성을 억제하는 방법을 제공한다.The present invention also provides a method for inhibiting the activity of EGFR, comprising the step of treating a sample or cell with a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 일 구체예에 따르면, 상기 화학식 1, 2, 3, 또는 4로 표시되는 피라졸로피리딘 유도체는 EGFR 키나아제에 대해 우수한 억제 활성을 나타내므로, EGFR 관련 질환, 특히, 암에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. 구체적으로, 상기 화학식 1, 2, 3, 또는 4의 화합물은 EGFR 돌연변이 키나아제를 억제할 수 있으며, 이는 후술하는 실험예에 의해 뒷받침된다. 상기 EGFR 돌연변이는 예컨대, EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/T790M/C797S일 수 있으나, 이에 제한되지 않는다. 본 발명의 화학식 1, 2, 3, 또는 4의 화합물은 EGFR 돌연변이에 대한 우수한 억제 활성을 나타내므로, EGFR로 인해 유도되는 암종에 대하여 치료 또는 예방에 유용하게 사용될 수 있다.According to one specific example of the present invention, the pyrazolopyridine derivative represented by the chemical formula 1, 2, 3, or 4 exhibits excellent inhibitory activity against EGFR kinase, and thus can be usefully used for the treatment or prevention of EGFR-related diseases, particularly, cancer. Specifically, the compound of the chemical formula 1, 2, 3, or 4 can inhibit EGFR mutant kinase, which is supported by the experimental examples described below. The EGFR mutation may be, for example, EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR L858R/T790M/C797S, but is not limited thereto. Since the compound of chemical formula 1, 2, 3, or 4 of the present invention exhibits excellent inhibitory activity against EGFR mutations, it can be usefully used for the treatment or prevention of carcinomas induced by EGFR.
여기서 "예방"이란 상기 화합물의 투여로 상기 질환의 발생, 확산 및 재발을 억제시키거나 지연시키는 모든 행위를 의미하고, "치료"는 상기 화합물의 투여로 상기 질환의 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.Here, “prevention” means any act of inhibiting or delaying the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any act of improving or beneficially changing the symptoms of the disease by administering the compound.
본 발명에 있어서, 상기 암은 EGFR 키나아제 활성 억제로 인해 치료 및 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 암의 종류는 제한되지 않으나, 예를 들어, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 흑색종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 편평세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있다. 또한, 상기 암은 원발성 암뿐 아니라 전이성 암도 포함한다. In the present invention, the cancer includes all cancers that can exhibit therapeutic and preventive efficacy due to inhibition of EGFR kinase activity, and may be solid cancer or blood cancer. The type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, From the group consisting of renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, melanoma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. There may be more than one selected. In addition, the cancer includes not only primary cancer but also metastatic cancer.
본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는 EGFR 관련 질환의 치료 또는 예방용 약학적 조성물을 제공한다. 구체적으로, 상기 EGFR 관련 질환은 암일 수 있다. 상기 암의 종류는 위에서 언급한 바와 같다.According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing an EGFR-related disease, which contains as an active ingredient a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Specifically, the EGFR-related disease may be cancer. The type of cancer is as mentioned above.
본 발명의 상기 약학적 조성물은 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 및/또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다.The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same and/or similar efficacy in addition to the compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 약학적 조성물은, 임상 투여시에 이용될 수 있으며, 경구 또는 비경구의 여러 가지 제형으로 투여될 수 있도록 제조될 수 있다.The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral or parenteral dosage forms.
또한 본 발명의 일 구체예에 따르면, 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, EGFR 관련 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다. 구체적으로, 상기 EGFR 관련 질환은 암일 수 있다. 상기 암의 종류는 위에서 언급한 바와 같다.In addition, according to one specific example of the present invention, a method for treating or preventing an EGFR-related disease is provided, comprising administering a therapeutically effective amount of a compound represented by the chemical formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal including a human. Specifically, the EGFR-related disease may be cancer. The type of cancer is as mentioned above.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 EGFR 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류, 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로, 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소, 또는 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The term "therapeutically effective amount" as used in the present invention refers to an amount of a compound represented by Chemical Formula 1, 2, 3, or 4 that is effective in treating or preventing an EGFR-related disease. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject type, severity, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration, excretion rate, duration of treatment, concurrently used drugs, or other factors well known in the medical field.
본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별, 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it may be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by considering all of the above factors, and it can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used even at a dosage higher than the determined dosage.
본 발명의 일 구체예에 따르면, 본 발명은 EGFR 관련 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1, 2, 3, 또는 4로 표시되는 화합물은 통상적인 방법에 따라 제제에 배합되는 통상적이고 무독성인 약학적으로 허용가능한 첨가제를 포함할 수 있다. 이에 따라 본 발명은 상기 화학식 1, 2, 3, 또는 4의 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 포함하고 약학적으로 허용가능한 첨가제를 포함하는 약학적 조성물을 제공한다.According to one specific embodiment of the present invention, the present invention provides the use of a compound represented by Chemical Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of an EGFR-related disease. The compound represented by Chemical Formula 1, 2, 3, or 4 for use in the manufacture of a medicament may include a conventional, non-toxic, pharmaceutically acceptable additive incorporated into a formulation according to a conventional method. Accordingly, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable additive.
예를 들어, 상기 약학적 조성물은 약학적으로 허용되는 담체, 희석제, 또는 부형제를 추가로 포함할 수 있다. 일 구현예에 있어서, 본 발명은 화학식 1, 2, 3, 또는 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염 및 약학적으로 허용가능한 첨가제를 포함하는 약학적 조성물을 제공한다.For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Formula 1, 2, 3, or 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
상기 약학적 조성물에 사용되는 첨가제의 예는 감미제, 결합제, 용매, 용해 보조제, 습윤제, 유화제, 등장화제, 흡수제, 붕해제, 산화방지제, 보존제, 윤활제, 충전제, 향미제 등을 포함할 수 있다. 예를 들어, 상기 첨가제는 락토오스, 덱스트로스, 수크로스, 만니톨, 소르비톨, 셀룰로스, 글리신, 실리카, 활석, 스테아르산, 스테아린, 마그네슘 스테아레이트, 마그네슘 알루미노실리케이트, 전분, 젤라틴, 트라가칸트 검, 알긴산, 나트륨 알기네이트, 메틸셀룰로스, 나트륨 카복시메틸셀룰로스, 한천, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 에센스, 딸기 에센스, 바닐라 향 등을 포함할 수 있다.Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.
상기 약학적 조성물은 경구 투여(예컨대, 정제, 환제, 산제, 캡슐제, 시럽 또는 에멀젼) 또는 비경구 투여(예컨대, 근육내, 정맥내 또는 피하 주사)를 위한 다양한 제제 형태로 배합될 수 있다. The above pharmaceutical composition may be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).
예를 들어 상기 약학적 조성물은 경구 투여용 제제로 배합될 수 있으며, 이때 사용되는 첨가제로는 셀룰로스, 칼슘 실리케이트, 옥수수 전분, 락토오스, 수크로스, 덱스트로스, 칼슘 포스페이트, 스테아르산, 마그네슘 스테아레이트, 칼슘 스테아레이트, 젤라틴, 활석, 계면활성제, 현탁제, 유화제, 희석제 등이 포함될 수 있다. 구체적으로, 경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토즈, 젤라틴 등을 혼합하여 제형화될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제가 사용될 수 있다. 또한, 경구 투여를 위한 액상 제제로는 현탁제, 유제, 시럽제 등이 예시될 수 있으며, 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, and the like. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like, into the composition. In addition, a lubricant, such as magnesium stearate or talc, may be used in addition to simple excipients. In addition, liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.
또한, 비경구 투여를 위한 제제에는 멸균된 수용액제, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로골, 트윈61. 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 한편, 주사제에는 용해제, 등장화제, 현탁화제, 유화제, 안정화제, 방부제 등과 같은 종래의 첨가제가 포함될 수 있다. 또한, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.In addition, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives. In addition, they may be prepared as a compound preparation with other active agents to have a synergistic effect of the active ingredients.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable unless they are contradictory to each other.
본 발명의 피라졸로피리딘 유도체 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염은 키나아제, 특히 EGFR에 대한 우수한 억제 활성을 나타내므로 EGFR 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있고, 특히 암의 치료제로 유용하게 사용될 수 있다.The pyrazolopyridine derivative compounds of the present invention, tautomers thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against kinases, particularly EGFR, and therefore can be usefully used for the treatment or prevention of EGFR-related diseases, and particularly can be usefully used as therapeutic agents for cancer.
이하, 본 발명을 제조예, 실시예, 및 실험예에 의하여 상세히 설명한다. 단, 하기 제조예, 실시예, 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by means of manufacturing examples, examples, and experimental examples. However, the following manufacturing examples, examples, and experimental examples are only illustrative of the present invention, and the content of the present invention is not limited thereto.
<정제 및 분석 조건><Purification and analysis conditions>
본 발명의 제조예 및 실시예에서 합성된 화합물은 다음의 조건에 의해 정제하거나 또는 구조 분석을 실시하였다.The compounds synthesized in the manufacturing examples and examples of the present invention were purified or subjected to structural analysis under the following conditions.
분석용 LC-MS (ACQUITY UPLC H-Class Core System)Analytical LC-MS (ACQUITY UPLC H-Class Core System)
Waters사 제조 UPLC system (ACQUITY UPLC PDA Detector)에 Waters사 제조 mass QDa Detector가 장착된 장비를 사용하였다. Waters사의 ACQUITY UPLC® BEH C18 (1.7 ㎛, 2.1×50 mm) 컬럼을 사용하였고, 컬럼온도는 30 ℃로 하였다.A UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters and equipped with a mass QDa Detector manufactured by Waters were used. A Waters ACQUITY UPLC ® BEH C18 (1.7 ㎛, 2.1 × 50 mm) column was used, and the column temperature was 30 °C.
이동상 A는 0.1 % 포름산이 포함된 물, 이동상 B는 0.1 % 포름산이 포함된 아세토나이트릴을 사용하였다.Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.
Gradient condition (10-100 % B로 3분, 이동속도 = 0.6 ml/min)Gradient condition (10-100% B for 3 minutes, moving speed = 0.6 ml/min)
정제용 Preparative HPLC System (Preparative-Liquid chromatography UV spectrometry)Preparative HPLC System for purification (Preparative-Liquid chromatography UV spectrometry)
Teledyne사 제조 ACCQPrep HP150 장비를 사용하였다. Water사의 XTERRA® Prep RP18 OBDTM (10 ㎛, 30 Х 300 mm) 컬럼을 사용하였고, 컬럼 온도를 실온으로 하였다.An ACCQPrep HP150 instrument from Teledyne was used. An XTERRA ® Prep RP18 OBD TM (10 μm, 30 Х 300 mm) column from Waters was used, and the column temperature was set to room temperature.
Gradient condition (10-100 % B로 120분, 이동속도 = 42 ml/min)Gradient condition (10-100% B for 120 min, moving speed = 42 ml/min)
정제용 중압액체크로마토그래피 (Medium pressure liquid chromatography; MPLC)Medium pressure liquid chromatography (MPLC) for purification
Teledyne ISCO사의 CombiFlash Rf +UV를 사용하여 중압액체크로마토그래피를 수행하였다.Medium-pressure liquid chromatography was performed using a CombiFlash Rf +UV from Teledyne ISCO.
NMR 해석NMR interpretation
NMR 분석은 Bruker사 제조 NMR AVANCE NEO 400 MHz를 사용해서 수행하고, 데이터는 ppm (parts per million(δ))으로 나타내었다.NMR analysis was performed using a Bruker NMR AVANCE NEO 400 MHz, and data were expressed in ppm (parts per million(δ)).
사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온 또는 상온이란 5~40 ℃, 일 예로서, 10~30 ℃, 다른 예로서 20~27 ℃ 정도의 온도를 말하는 것으로, 상기 범위 내로 엄밀하게 한정되는 것은 아니다. 감압 하 농축 또는 용매 증류 제거는, 회전식 증발기 (rotary evaporator)를 사용하였다.The commercially available reagents used were used without further purification. In the present invention, room temperature or ambient temperature refers to a temperature of about 5 to 40°C, for example, 10 to 30°C, and for another example, 20 to 27°C, and is not strictly limited to the above range. Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.
제조예 1 내지 제조예 7: 본 발명의 중간체 화합물의 제조Manufacturing Examples 1 to 7: Manufacturing of intermediate compounds of the present invention
<제조예 1> 3-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조<Manufacturing Example 1> Manufacturing of 3-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
[반응식 1][Reaction Formula 1]
Figure PCTKR2024004758-appb-img-000122
Figure PCTKR2024004758-appb-img-000122
[단계 1] [Step 1] terttert -부틸 9-(1-메톡시-2-메틸-1-옥소프로판-2-일)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트의 제조- Preparation of butyl 9-(1-methoxy-2-methyl-1-oxopropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
tert-부틸 3,9-다이아자스피로[5.5]운데칸-3-카복실레이트(1.0 당량)를 다이메틸폼아마이드(0.39 M)에 녹인 후 탄산칼륨(2.0 당량)과 메틸 2-브로모-2-메틸프로파노에이트(1.4 당량)를 첨가하고, 100 ℃에서 12 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 반응 혼합물을 여과하고 농축한 다음, 농축한 혼합물은 MPLC(에테르:에틸아세테이트)로 정제하여 노란색 액체의 목적 화합물을 수득하였다(수율: 58 %). tert -Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 equiv) was dissolved in dimethylformamide (0.39 M), potassium carbonate (2.0 equiv) and methyl 2-bromo-2-methylpropanoate (1.4 equiv) were added, and the mixture was stirred at 100 ℃ for 12 hours. After confirming the completion of the reaction by TLC, the reaction mixture was filtered and concentrated, and the concentrated mixture was purified by MPLC (ether:ethyl acetate) to obtain the target compound as a yellow liquid (yield: 58%).
1H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 3.40-3.32 (m, 4H), 2.59-2.45 (m, 4H), 1.56-1.50 (m, 4H), 1.45 (s, 9H), 1.43-1.37 (m, 4H), 1.31 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.71 (s, 3H), 3.40-3.32 (m, 4H), 2.59-2.45 (m, 4H), 1.56-1.50 (m, 4H), 1.45 (s, 9H) ), 1.43-1.37 (m, 4H), 1.31 (s, 6H).
[단계 2] [Step 2] terttert -부틸 9-(1-하이드록시-2-메틸프로판-2-일)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트의 제조- Preparation of butyl 9-(1-hydroxy-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
단계 1에서 얻어진 tert-부틸 9-(1-메톡시-2-메틸-1-옥소프로판-2-일)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트(1.0 당량)를 테트라하이드로퓨란(0.25 M)에 녹이고, 질소 하에서 테트라하이드로퓨란에 녹여진 리튬알루미늄하이드라이드(2,5 M, 2.0 당량)를 -40 ℃에서 첨가한 후 2 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 반응 혼합물에 물을 첨가하여 -40 ℃에서 30 분 동안 교반하고, 15 % 소듐하이드록사이드 수용액을 첨가하여 -40 ℃에서 30 분 동안 교반한 다음, 반응 혼합물에 물을 첨가하여 -40 ℃에서 30 분 동안 교반하였다. 에틸아세테이트로 유기물을 추출하고, 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 얻어진 흰색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 97 %).In Step 1, tert -butyl 9-(1-methoxy-2-methyl-1-oxopropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq) obtained was dissolved in tetrahydrofuran (0.25 M), and lithium aluminum hydride (2.5 M, 2.0 eq) dissolved in tetrahydrofuran under nitrogen was added at -40 °C, and the mixture was stirred for 2 h. After confirming the completion of the reaction by TLC, water was added to the reaction mixture, and the mixture was stirred at -40 °C for 30 min, 15% sodium hydroxide aqueous solution was added, and the mixture was stirred at -40 °C for 30 min, and then water was added to the reaction mixture, and the mixture was stirred at -40 °C for 30 min. The organic matter was extracted with ethyl acetate, sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a white solid was used in the next reaction without further purification (yield: 97%).
1H NMR (400 MHz, CDCl3) δ 3.41-3.34 (m, 4H), 3.31 (s, 2H), 2.50 (br t, J = 5.2 Hz, 4H), 1.57-1.48 (m, 4H), 1.46 (s, 9H), 1.41 (br d, J = 5.2 Hz, 4H), 1.03 (s, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.41-3.34 (m, 4H), 3.31 (s, 2H), 2.50 (br t, J = 5.2 Hz, 4H), 1.57-1.48 (m, 4H), 1.46 (s, 9H), 1.41 (br d, J = 5.2 Hz, 4H), 1.03 (s, 6H).
[단계 3] [Step 3] terttert -부틸 9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트의 제조- Preparation of butyl 9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate
단계 2에서 얻어진 tert-부틸 9-(1-하이드록시-2-메틸프로판-2-일)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트(1.0 당량)를 다이클로로메탄(0.3 M)에 녹이고, 0 ℃에서 DAST(2.2 당량)를 천천히 첨가한 후, 상온에서 1 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 포화 탄산수소나트륨 수용액과 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 얻어진 노란색 액체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 99 %).In step 2, tert -butyl 9-(1-hydroxy-2-methylpropan-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.3 M), DAST (2.2 eq.) was slowly added at 0 °C, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC, the organic matter was extracted with a saturated sodium bicarbonate aqueous solution and dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow liquid was used in the next reaction without further purification (yield: 99%).
1H NMR (400 MHz, CDCl3) δ 3.39-3.34 (m, 4H), 2.53-2.38 (m, 6H), 1.52-1.49 (m, 4H), 1.46 (s, 9H), 1.44-1.40 (m, 4H), 1.38-1.33 (m, 6H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.39-3.34 (m, 4H), 2.53-2.38 (m, 6H), 1.52-1.49 (m, 4H), 1.46 (s, 9H), 1.44-1.40 (m , 4H), 1.38-1.33 (m, 6H).
[단계 4] 3-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조[Step 4] Preparation of 3-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
단계 3에서 얻어진 tert-부틸 9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸-3-카복실레이트(1.0 당량)를 다이클로로메탄(0.4 M)에 녹이고, 1,4-다이옥세인에 녹여진 염산 용액(4M, 6.6 당량)을 0 ℃에서 첨가한 후, 상온에서 1 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 반응 혼합물을 농축하고, 에틸아세테이트를 첨가하여 상온에서 30 분 동안 교반하였다. 반응 혼합물에 염기 레진을 첨가하여 pH 8이 되도록 한 후, 반응 혼합물을 여과하여 얻어진 여과액을 농축하였다. 얻어진 노란색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 65 %, MS (ESI): m/z 229 [M+H]+). In step 3, tert -Butyl 9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.0 eq) obtained was dissolved in dichloromethane (0.4 M), and a solution of hydrochloric acid (4 M, 6.6 eq) dissolved in 1,4-dioxane was added at 0 °C, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated, ethyl acetate was added, and the mixture was stirred at room temperature for 30 min. A base resin was added to the reaction mixture to adjust the pH to 8, and the reaction mixture was filtered, and the obtained filtrate was concentrated. The target compound as a yellow solid was used in the next reaction without further purification (yield: 65%, MS (ESI): m/z 229 [M+H] + ).
1H NMR (400 MHz, CDCl3) δ 3.18-3.12 (m, 4H), 2.59-2.39 (m, 6H), 1.82-1.76 (m, 4H), 1.58 (br s, 4H), 1.38 (s, 3H), 1.32 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 3.18-3.12 (m, 4H), 2.59-2.39 (m, 6H), 1.82-1.76 (m, 4H), 1.58 (br s, 4H), 1.38 (s, 3H), 1.32 (s, 3H).
<제조예 2> 2-((4-메틸피페라진-1-일)옥시)에탄-1-올의 제조<Manufacturing Example 2> Manufacturing of 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol
[반응식 2][Reaction Formula 2]
Figure PCTKR2024004758-appb-img-000123
Figure PCTKR2024004758-appb-img-000123
[단계 1] 벤질 4-알릴피페라진-1-카복실레이트의 제조[Step 1] Preparation of benzyl 4-allylpiperazine-1-carboxylate
벤질 피페라진-1-카복실레이트(1.0 당량)를 테트라하이드로퓨란(0.4 M)에 녹인 후 탄산칼륨(2.0 당량)과 3-브로모프로프-1-엔(2.0 당량)을 첨가하고 65 ℃에서 16 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 반응 혼합물에 얼음물을 첨가하고 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(석유에테르/에틸아세테이트)로 정제하여 갈색 액체의 목적 화합물을 수득하였다(수율: 59 %).Benzyl piperazine-1-carboxylate (1.0 equiv.) was dissolved in tetrahydrofuran (0.4 M), potassium carbonate (2.0 equiv.) and 3-bromoprop-1-ene (2.0 equiv.) were added, and the mixture was stirred at 65 ℃ for 16 hours. After confirming the completion of the reaction by TLC, ice water was added to the reaction mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (petroleum ether/ethyl acetate) to obtain the target compound as a brown liquid (yield: 59%).
1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 5.95-5.60 (m, 1H), 5.25-5.15 (m, 2H), 5.14 (s, 2H), 3.60-3.45 (m, 4H), 3.01 (d, J = 6.8 Hz, 2H), 2.42 (br s, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45-7.30 (m, 5H), 5.95-5.60 (m, 1H), 5.25-5.15 (m, 2H), 5.14 (s, 2H), 3.60-3.45 (m) , 4H), 3.01 (d, J = 6.8 Hz, 2H), 2.42 (br s, 4H).
[단계 2] 벤질 4-(알릴옥시)피페라진-1-카복실레이트의 제조[Step 2] Preparation of benzyl 4-(allyloxy)piperazine-1-carboxylate
단계 1에서 얻어진 벤질 4-알릴피페라진-1-카복실레이트(1.0 당량)를 다이클로로메탄(0.3 M)에 녹인 후 -30 ℃에서 m-CPBA(순도: 85 %, 1.0 당량)를 첨가하고 -30 ℃에서 1 시간 동안 교반하였다. LC-MS를 이용하여 반응물이 소모된 것을 확인한 후, 반응 혼합물에 포화 탄산수소나트륨 수용액을 첨가하고 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물을 톨루엔(0.4 M)에 녹인 후 80 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축한 혼합물은 MPLC(석유에테르/에틸아세테이트)로 정제하여 무색 액체의 목적 화합물을 수득하였다(수율: 34 %).In step 1, benzyl 4-allylpiperazine-1-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.3 M), m-CPBA (purity: 85%, 1.0 eq.) was added at -30 °C, and the mixture was stirred at -30 °C for 1 hour. After confirming that the reactant was consumed using LC-MS, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was dissolved in toluene (0.4 M) and stirred at 80 °C for 16 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (petroleum ether/ethyl acetate) to obtain the target compound as a colorless liquid (yield: 34%).
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 6.03-5.90 (m, 1H), 5.29 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.4 Hz, 1H), 5.13 (s, 2H), 4.22 (d, J = 6.0 Hz, 2H), 4.04 (br s, 2H), 3.35-3.10 (m, 4H), 2.58 (br s, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.42-7.30 (m, 5H), 6.03-5.90 (m, 1H), 5.29 (d, J = 17.2 Hz, 1H), 5.19 (d, J = 10.4 Hz, 1H), 5.13 (s, 2H), 4.22 (d, J = 6.0 Hz, 2H), 4.04 (br s, 2H), 3.35-3.10 (m, 4H), 2.58 (br s, 2H).
[단계 3] 벤질 4-(2-하이드록시에톡시)피페라진-1-카복실레이트의 제조[Step 3] Preparation of benzyl 4-(2-hydroxyethoxy)piperazine-1-carboxylate
단계 2에서 얻어진 벤질 4-(알릴옥시)피페라진-1-카복실레이트(1.0 당량)를 다이클로로메탄(0.1 M)과 메탄올(0.36 M)에 녹인 후, -78 ℃에서 30분 동안 오존을 첨가하면서 교반하였다. 질소를 첨가하여 남아있는 오존을 제거한 후, -78 ℃에서 반응 혼합물에 NaBH4(1.5 당량)를 첨가하고 온도를 서서히 올리면서 상온에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 포화 탄산수소나트륨을 첨가하고, 다이클로로메탄을 이용하여 유기화합물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 얻어진 노랑색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 71 %).Benzyl 4-(allyloxy)piperazine-1-carboxylate (1.0 eq.) obtained in step 2 was dissolved in dichloromethane (0.1 M) and methanol (0.36 M), and the mixture was stirred at -78 °C for 30 minutes while adding ozone. After removing the remaining ozone by adding nitrogen, NaBH 4 (1.5 eq.) was added to the reaction mixture at -78 °C, and the temperature was gradually raised while stirring at room temperature for 2 hours. After confirming that the target compound was produced using LC-MS, saturated sodium bicarbonate was added to the reaction mixture, and the organic compound was extracted using dichloromethane. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 71%).
1H NMR (400 MHz, CDCl3) δ 7.42-7.30 (m, 5H), 5.14 (s, 2H), 4.08 (s, 2H), 3.88-3.77 (m, 4H), 3.25-3.00 (m, 5H), 2.70-2.50 (m, 2H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.30 (m, 5H), 5.14 (s, 2H), 4.08 (s, 2H), 3.88-3.77 (m, 4H), 3.25-3.00 (m, 5H) ), 2.70-2.50 (m, 2H).
[단계 4] 2-((4-메틸피페라진-1-일)옥시)에탄-1-올의 제조[Step 4] Preparation of 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol
단계 3에서 얻어진 벤질 4-(2-하이드록시에톡시)피페라진-1-카복실레이트 (1.0 당량)를 테트라하이드로퓨란(0.23 M)에 녹인 후, 0 ℃에서 리튬알루미늄하이드라이드(3.0 당량)를 첨가하고 상온에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 0 ℃에서 반응 혼합물에 물을 첨가한 다음, 15 % 수산화나트륨 수용액을 첨가하였다. 반응 혼합물에 황산나트륨을 첨가한 후 상온에서 15 분 동안 교반한 다음, 반응 혼합물을 여과한 후 감압 농축 하였다. 농축한 혼합물에 물을 첨가한 후, 반응 혼합물의 pH가 2~3이 되도록 염산을 첨가하고 에틸아세테이트로 유기물을 추출하였다. 얻어진 유기물을 농축하고 메탄올에 녹인 후, 염기 레진을 첨가하여 여과한 다음, 반응 혼합물을 농축하였다. 얻어진 노란색 액체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 100 %). Benzyl 4-(2-hydroxyethoxy)piperazine-1-carboxylate (1.0 eq.) obtained in step 3 was dissolved in tetrahydrofuran (0.23 M), lithium aluminum hydride (3.0 eq.) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture at 0 °C, and then 15% sodium hydroxide aqueous solution was added. Sodium sulfate was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes, filtered, and concentrated under reduced pressure. Water was added to the concentrated mixture, and hydrochloric acid was added such that the pH of the reaction mixture became 2-3, and the organic matter was extracted with ethyl acetate. The obtained organic matter was concentrated and dissolved in methanol, and then a base resin was added, filtered, and the reaction mixture was concentrated. The target compound of the obtained yellow liquid was used in the next reaction without further purification (yield: 100%).
1H NMR (400 MHz, CDCl3): δ 3.83 (s, 4H), 3.50-3.31 (m, 2H), 3.15-2.78 (m, 4H), 2.59-2.32 (m, 5H). 1 H NMR (400 MHz, CDCl 3 ): δ 3.83 (s, 4H), 3.50-3.31 (m, 2H), 3.15-2.78 (m, 4H), 2.59-2.32 (m, 5H).
<제조예 3> <Manufacturing Example 3> terttert -부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1-Butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
[반응식 3][Reaction Formula 3]
Figure PCTKR2024004758-appb-img-000124
Figure PCTKR2024004758-appb-img-000124
[단계 1] 5-브로모-7-메틸-1[Step 1] 5-bromo-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
6-브로모-2,4-다이메틸-피리딘-3-아민(1.0 당량)을 아세트산(0.15 M)에 녹인 후 반응 혼합물에 아질산나트륨 수용액(2.0 M, 1.2 당량)을 0 ℃에서 천천히 첨가하고, 반응 혼합물을 20 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 감압 농축하여 아세트산를 제거한 다음, 에틸아세테이트로 희석하였다. 희석한 혼합물에 포화 탄산수소나트륨 수용액을 첨가한 후 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))를 이용하여 정제하였고, 갈색 액체의 목적 화합물을 수득하였다(수율: 47 %).6-Bromo-2,4-dimethyl-pyridin-3-amine (1.0 eq) was dissolved in acetic acid (0.15 M), and sodium nitrite aqueous solution (2.0 M, 1.2 eq) was slowly added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 20 °C for 16 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure to remove acetic acid, and then diluted with ethyl acetate. A saturated aqueous sodium bicarbonate solution was added to the diluted mixture, and the organic matter was extracted. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified using prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to obtain the target compound as a brown liquid (yield: 47%).
1H NMR (400 MHz, CDCl3) δ 11.63 (br s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 2.84 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 11.63 (br s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 2.84 (s, 3H).
[단계 2] 5-브로모-7-메틸-1-(테트라하이드로-2[Step 2] 5-Bromo-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 1에서 얻어진 5-브로모-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 테트라하이드로퓨란(0.25 M)에 녹인 후 다이하이드로피란(5.0 당량)과 p-톨루엔설폰산(0.2 당량)을 첨가하였다. 반응 혼합물을 70 ℃에서 6 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 물과 에틸아세테이트로 희석하고, 포화 탄산수소나트륨 수용액과 포화 염화나트륨 수용액을 첨가하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(석유에테르:에틸아세테이트)를 이용하여 정제하였고, 갈색 액체의 목적 화합물을 수득하였다(수율: 85 %, MS (ESI): m/z 298 [M+2H]+).In step 1, 5-bromo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.25 M), and then dihydropyran (5.0 equiv.) and p -toluenesulfonic acid (0.2 equiv.) were added. The reaction mixture was stirred at 70 °C for 6 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was diluted with water and ethyl acetate, and saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution were added to extract the organic matter. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified using MPLC (petroleum ether: ethyl acetate) to obtain the target compound as a brown liquid (yield: 85%, MS (ESI): m / z 298 [M + 2H] + ).
[단계 3] 5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2[Step 3] 5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 2에서 얻어진 5-브로모-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 1,4-다이옥세인/물 (5/1 v/v, 0.1 M)에 녹인 후, 4-메톡시-3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로란-2-일)피리딘(1.2 당량), 탄산나트륨(3.0 당량), Pd(dppf)Cl2·DCM(0.1 당량)을 첨가하였다. 반응 혼합물을 질소 하에서 90 ℃에서 3 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 포화 탄산수소나트륨 수용액을 첨가한 다음 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(석유에테르:에틸아세테이트)를 이용하여 정제하였고, 갈색 고체의 목적 화합물을 수득하였다(수율: 99 %, MS (ESI): m/z 325 [M+H]+). 5-Bromo-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained in Step 2 was dissolved in 1,4-dioxane/water (5/1 v/v, 0.1 M), and 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 equiv.), sodium carbonate (3.0 equiv.), and Pd(dppf)Cl 2 ·DCM (0.1 equiv.) were added. The reaction mixture was stirred at 90 °C under nitrogen for 3 h. After confirming the production of the target compound using LC-MS, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and then the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified using MPLC (petroleum ether: ethyl acetate), and the target compound as a brown solid was obtained (yield: 99%, MS (ESI): m/z 325 [M+H] + ).
[단계 4] 5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 4] 5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 3에서 얻어진 5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘(1.0 당량)에 1,4-다이옥세인에 녹여진 4M 염산 용액(18.8 당량)을 0 ℃에서 첨가한 후 상온에서 12 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 여과한 다음 여과된 고체를 메탄올/다이클로로메탄 (1/3 v/v)에 녹인 후, 염기 레진을 이용하여 pH가 7이 되도록 교반하였다. 반응 혼합물을 여과한 후에 감압 농축하였고, 얻어진 갈색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 89 %). In step 3, 4 M hydrochloric acid solution (18.8 equivalents) dissolved in 1,4-dioxane was added to 5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equivalent) obtained at 0 °C, and the mixture was stirred at room temperature for 12 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was filtered, and the filtered solid was dissolved in methanol/dichloromethane (1/3 v/v), and then stirred using a base resin until the pH became 7. After filtering the reaction mixture, it was concentrated under reduced pressure, and the target compound obtained as a brown solid was used in the next reaction without further purification (yield: 89%).
1H NMR (400 MHz, DMSO-d 6) δ 13.83 (s, 1H), 8.92 (s, 1H), 8.52 (br s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H), 2.81 (s, 3H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.83 (s, 1H), 8.92 (s, 1H), 8.52 (br s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.29 (s, 1H), 3.97 (s, 3H), 2.81 (s, 3H).
[단계 5] 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 5] 3-Iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 4에서 얻어진 5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이메틸폼아마이드(0.4 M)에 녹인 후 N-아이오도숙신이미드(1.1 당량)를 첨가하고 상온에서 3 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가한 다음 다이클로로메탄과 메탄올을 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물에 에틸아세테이트를 첨가하여 고체를 생성한 후 여과하였고, 얻어진 회색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 75 %).In step 4, 5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in dimethylformamide (0.4 M), N -iodosuccinimide (1.1 eq.) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted using dichloromethane and methanol. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. Ethyl acetate was added to the concentrated mixture to produce a solid, which was then filtered, and the target compound obtained as a gray solid was used in the next reaction without further purification (yield: 75%).
1H NMR (400 MHz, DMSO-d 6) δ 14.22 (s, 1H), 8.87 (s, 1H), 8.45 (bd, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.20 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H), 2.81 (s, 3H). 1H NMR (400 MHz, DMSO -d6 ) δ 14.22 (s, 1H), 8.87 (s, 1H), 8.45 (bd, J = 5.6 Hz, 1H), 7.70 (s, 1H), 7.20 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H), 2.81 (s, 3H).
[단계 6] [Step 6] terttert -부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트의 제조- Preparation of butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
단계 5에서 얻어진 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이클로로메탄 (0.1 M)에 녹인 후, Boc2O(2.0 당량), 트라이에틸아민(2.0 당량), N,N-다이메틸피리딘-4-아민(0.5 당량)을 첨가하여 상온에서 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 혼합물을 농축하여 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 91 %, MS (ESI): m/z 467 [M+H]+). In step 5, 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and Boc 2 O (2.0 equiv.), triethylamine (2.0 equiv.), and N,N -dimethylpyridin-4-amine (0.5 equiv.) were added, and the mixture was stirred at room temperature for 30 min. After confirming the production of the target compound using LC-MS, the mixture was concentrated and purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 91%, MS (ESI): m/z 467 [M+H] + ).
<제조예 4><Manufacturing Example 4>
상기 제조예 3과 유사한 방법으로 제조예 4 화합물을 제조하였다.Compound Manufacturing Example 4 was manufactured using a method similar to Manufacturing Example 3.
제조예 4의 화학구조식, 화합물명, 및 LC-MS 분석 결과를 하기 표 1에 정리하여 나타내었다.The chemical structure, compound name, and LC-MS analysis results of Manufacturing Example 4 are summarized in Table 1 below.
[표 1][Table 1]
Figure PCTKR2024004758-appb-img-000125
Figure PCTKR2024004758-appb-img-000125
<제조예 5> 5-브로모-3-아이오도-7-메틸-1-(테트라하이드로-2<Manufacturing Example 5> 5-Bromo-3-iodo-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
[반응식 4][Reaction Formula 4]
Figure PCTKR2024004758-appb-img-000126
Figure PCTKR2024004758-appb-img-000126
[단계 1] 5-브로모-3-아이오도-7-메틸-1[Step 1] 5-Bromo-3-iodo-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
제조예 3의 단계 1에서 얻어진 5-브로모-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 테트라하이드로퓨란(0.27 M)에 녹인 후, 0 ℃에서 t-BuOK(3.0 당량)와 아이오딘(2.0 당량)을 첨가하고, 상온에서 6 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 0 ℃에서 반응 혼합물에 포화 아황산나트륨 수용액을 첨가하고 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(석유에테르:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 68 %, MS (ESI): m/z 338 [M+H]+).In step 1 of Manufacturing Example 3, 5-bromo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in tetrahydrofuran (0.27 M), t-BuOK (3.0 eq.) and iodine (2.0 eq.) were added at 0 °C, and the mixture was stirred at room temperature for 6 hours. After confirming that the target compound was produced using LC-MS, a saturated sodium bisulfite aqueous solution was added to the reaction mixture at 0 °C, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (petroleum ether: ethyl acetate) to obtain the target compound as a yellow solid (yield: 68%, MS (ESI): m/z 338 [M+H] + ).
[단계 2] 5-브로모-3-아이오도-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘의 제조[Step 2] Preparation of 5-bromo-3-iodo-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
단계 1에서 얻어진 5-브로모-3-아이오도-7-메틸-1H-피라졸로[3,4-c]피리딘 (1.0 당량)을 톹루엔(0.15 M)에 녹인 후, 다이하이드로피란(4.0 당량)과 TsOH(0.15 당량)을 첨가하고, 90 ℃에서 16 시간 동안 교반하였다. TLC로 반응이 종결된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축한 혼합물은 MPLC(석유에테르:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 63 %, MS (ESI): m/z 422 [M+H]+).5-Bromo-3-iodo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained in Step 1 was dissolved in thiosulfonate (0.15 M), dihydropyran (4.0 equiv.) and TsOH (0.15 equiv.) were added, and the mixture was stirred at 90 ℃ for 16 h. After confirming the completion of the reaction by TLC, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (petroleum ether:ethyl acetate) to obtain the target compound as a yellow solid (yield: 63%, MS (ESI): m/z 422 [M+H] + ).
<제조예 6> <Manufacturing Example 6> terttert -부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1-Butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
[반응식 5][Reaction Formula 5]
Figure PCTKR2024004758-appb-img-000127
Figure PCTKR2024004758-appb-img-000127
[단계 1] 6-클로로-2-아이오도-4-메틸피리딘-3-아민의 제조[Step 1] Preparation of 6-chloro-2-iodo-4-methylpyridin-3-amine
6-클로로-4-메틸피리딘-3-아민(1.0 당량)을 다이메틸폼아마이드(0.2 M)에 녹인 후, N-아이오도숙신이미드(1.1 당량)를 첨가하여 상온에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 싸이오황산 나트륨 수용액을 첨가하고, 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(헥세인:에틸아세테이트)를 이용하여 정제하였고, 주황색 액체의 목적 화합물을 수득하였다(수율: 46 %, MS (ESI): m/z 269 [M+H]+).6-Chloro-4-methylpyridin-3-amine (1.0 eq) was dissolved in dimethylformamide (0.2 M), N -iodosuccinimide (1.1 eq) was added, and the mixture was stirred at room temperature for 16 hours. After confirming that the target compound was produced using LC-MS, an aqueous sodium thiosulfate solution was added, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. The concentrated mixture was purified using MPLC (hexane:ethyl acetate) to obtain the target compound as an orange liquid (yield: 46%, MS (ESI): m/z 269 [M+H] + ).
[단계 2] 6-클로로-4-메틸-2-(트라이플루오로메틸)피리딘-3-아민의 제조[Step 2] Preparation of 6-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine
단계 1에서 얻어진 6-클로로-2-아이오도-4-메틸피리딘-3-아민(1.0 당량)을 다이메틸폼아마이드(0.2 M)에 녹인 후, 플루오르화 칼륨(2.0 당량)과 아이오딘화 구리(I)(1.1 당량), 메틸 2,2-다이플루오로-2-(플루오로설폰일)아세테이트(1.0 당량)를 첨가하여 100 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가하고, 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(다이클로로메탄:메탄올)를 이용하여 정제하였고, 주황색 고체의 목적 화합물을 수득하였다(수율: 40 %, MS (ESI): m/z 211 [M+H]+).In step 1, 6-chloro-2-iodo-4-methylpyridin-3-amine (1.0 eq.) obtained was dissolved in dimethylformamide (0.2 M), potassium fluoride (2.0 eq.), copper(I) iodide (1.1 eq.), and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.0 eq.) were added, and the mixture was stirred at 100 °C for 16 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified using MPLC (dichloromethane:methanol), and the target compound was obtained as an orange solid (yield: 40%, MS (ESI): m/z 211 [M+H] + ).
[단계 3] 4'-메톡시-4-메틸-6-(트라이플루오로메틸)-[2,3'-바이피리딘]-5-아민의 제조[Step 3] Preparation of 4'-methoxy-4-methyl-6-(trifluoromethyl)-[2,3'-bipyridin]-5-amine
단계 2에서 얻어진 6-클로로-4-메틸-2-(트라이플루오로메틸)피리딘-3-아민(1.0 당량)을 1,4-다이옥세인(0.2 M)에 녹인 후, 4-메톡시-3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리딘(2.0 당량)과 탄산세슘(3.0 당량)을 첨가하였다. 질소 하에서 반응 혼합물에 Pd(dppf)Cl2(0.1 당량)을 첨가한 후 마이크로웨이브 기기를 사용하여 130 ℃에서 10 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 셀라이트로 여과하고, 에틸아세테이트로 씻어주었다. 얻어진 여과액을 감압 농축한 후 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 액체의 목적 화합물을 수득하였다(수율: 90 %, MS (ESI): m/z 284 [M+H]+).In step 2, 6-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (1.0 eq.) obtained was dissolved in 1,4-dioxane (0.2 M), and 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 eq.) and cesium carbonate (3.0 eq.) were added. Pd(dppf)Cl 2 (0.1 eq.) was added to the reaction mixture under nitrogen, and the mixture was stirred at 130 °C for 10 min using a microwave apparatus. After confirming the production of the target compound using LC-MS, the reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure and purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown liquid (yield: 90%, MS (ESI): m/z 284 [M+H] + ).
[단계 4] 5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1[Step 4] 5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 3에서 얻어진 4'-메톡시-4-메틸-6-(트라이플루오로메틸)-[2,3'-바이피리딘]-5-아민(1.0 당량)을 아세트산(0.037 M)에 녹인 후, 아질산나트륨 수용액(1.1 당량)을 첨가하여 상온에서 3 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 감압 농축하였다. 농축한 반응 혼합물을 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 액체의 목적 화합물을 수득하였다(수율: 96 %, MS (ESI): m/z 295 [M+H]+).In step 3, 4'-methoxy-4-methyl-6-(trifluoromethyl)-[2,3'-bipyridin]-5-amine (1.0 eq.) obtained was dissolved in acetic acid (0.037 M), and then sodium nitrite aqueous solution (1.1 eq.) was added, and the mixture was stirred at room temperature for 3 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. The concentrated reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown liquid (yield: 96%, MS (ESI): m/z 295 [M+H] + ).
[단계 5] 3-아이오도-5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1[Step 5] 3-Iodo-5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 4에서 얻어진 5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이메틸폼아마이드(0.2 M)에 녹인 후, N-아이오도숙신이미드(1.3 당량)를 첨가하여 상온에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 싸이오황산 나트륨 수용액을 첨가하고, 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(헥세인:에틸아세테이트)로 정제하여 노란색 액체의 목적 화합물을 수득하였다(수율: 44 %, MS (ESI): m/z 421 [M+H]+).In step 4, 5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained was dissolved in dimethylformamide (0.2 M), N -iodosuccinimide (1.3 eq.) was added, and the mixture was stirred at room temperature for 16 hours. After confirming that the target compound was produced using LC-MS, an aqueous sodium thiosulfate solution was added, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow liquid (yield: 44%, MS (ESI): m/z 421 [M+H] + ).
[단계 6] [Step 6] terttert -부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1-Butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 5에서 얻어진 3-아이오도-5-(4-메톡시피리딘-3-일)-7-(트라이플루오로메틸)-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이클로로메탄 (0.1 M)에 녹인 후 DMAP(0.5 당량), Boc2O(2.0 당량), 트라이에틸아민(2.0 당량)을 첨가하여 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 감압 농축하였다. 농축한 혼합물은 MPLC(헥세인:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 20 %, MS (ESI): m/z 521 [M+H]+).In step 5, 3-iodo-5-(4-methoxypyridin-3-yl)-7-(trifluoromethyl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and DMAP (0.5 equiv.), Boc 2 O (2.0 equiv.), and triethylamine (2.0 equiv.) were added, and the mixture was stirred at room temperature for 1 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 20%, MS (ESI): m/z 521 [M+H] + ).
<제조예 7> <Manufacturing Example 7> terttert -부틸 3-아이오도-5-(5-메톡시-1-메틸-1H-피라졸-4-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트의 제조- Preparation of butyl 3-iodo-5-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-7-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
[반응식 6][Reaction Formula 6]
Figure PCTKR2024004758-appb-img-000128
Figure PCTKR2024004758-appb-img-000128
[단계 1] 6-(5-메톡시-1-메틸-1[Step 1] 6-(5-methoxy-1-methyl-1 HH -피라졸-4-일)-2,4-다이메틸피리딘-3-아민의 제조- Preparation of pyrazol-4-yl)-2,4-dimethylpyridin-3-amine
6-브로모-2,4-다이메틸피리딘-3-아민(1.5 당량)을 1,4-다이옥세인/물(4/1 v/v, 0.1 M)에 녹인 후, 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란)(4.0 당량), 탄산 나트륨(3.0 당량)을 첨가하고 질소로 탈기한 다음, Pd(amphos)Cl2(0.15 당량)을 넣고 70 ℃에서 1 시간 동안 교반하였다. 반응 혼합물에 4-브로모-5-메톡시-1-메틸-1H-피라졸(1.0 당량)을 넣고, 90 ℃에서 4 시간 동안 교반하고, LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 감압 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 18 %, MS (ESI): m/z 233 [M+H]+). 6-Bromo-2,4-dimethylpyridin-3-amine (1.5 equiv) was dissolved in 1,4-dioxane/water (4/1 v/v, 0.1 M), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.0 equiv) and sodium carbonate (3.0 equiv) were added, and the mixture was degassed with nitrogen. Pd(amphos)Cl 2 (0.15 equiv) was added, and the mixture was stirred at 70 ℃ for 1 h. 4-Bromo-5-methoxy-1-methyl-1H-pyrazole (1.0 equiv) was added to the reaction mixture, stirred at 90 ℃ for 4 h, and the production of the target compound was confirmed using LC-MS, followed by filtration using Celite and concentration under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to give the target compound as a brown solid (yield: 18%, MS (ESI): m/z 233 [M+H] + ).
[단계 2] [Step 2] NN -(6-(5-메톡시-1-메틸-1-(6-(5-methoxy-1-methyl-1 HH -피라졸-4-일)-2,4-다이메틸피리딘-3-일)아세트아마이드의 제조- Preparation of pyrazol-4-yl)-2,4-dimethylpyridin-3-yl)acetamide
단계 1에서 얻어진 6-(5-메톡시-1-메틸-1H-피라졸-4-일)-2,4-다이메틸피리딘-3-아민(1.0 당량)을 톨루엔(0.07 M)에 녹인 후, 아세트산 무수물(2.0 당량)을 첨가하고 100 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후 감압 농축하였다. 얻어진 노란색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 100 %, MS (ESI): m/z 275 [M+H]+).6-(5-Methoxy-1-methyl-1 H -pyrazol-4-yl)-2,4-dimethylpyridin-3-amine (1.0 eq.) obtained in Step 1 was dissolved in toluene (0.07 M), acetic anhydride (2.0 eq.) was added, and the mixture was stirred at 100 ℃ for 16 h. After confirming the production of the target compound using LC-MS, the mixture was concentrated under reduced pressure. The target compound as a yellow solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m/z 275 [M+H] + ).
[단계 3] 5-(5-메톡시-1-메틸-1[Step 3] 5-(5-methoxy-1-methyl-1 HH -피라졸-4-일)-7-메틸-1-pyrazol-4-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 2에서 얻어진 N-(6-(5-메톡시-1-메틸-1H-피라졸-4-일)-2,4-다이메틸피리딘-3-일)아세트아마이드(1.0 당량)를 벤젠(0.07 M)에 녹인 후, 아세트산 무수물(3.0 당량), 아세트산 칼륨(1.5 당량), 아이소펜틸 아질산염(2.0 당량)을 첨가하고 80 ℃에서 16 시간 동안 교반하고, 반응 혼합물을 감압 농축하였다. 반응 혼합물을 물/에탄올(1/3 v/v, 0.07 M)에 녹인 후 수산화리튬(7.0 당량)을 첨가하고 상온에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후 감압 농축하였다. 반응 혼합물에 물을 첨가한 후, 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 29 %, MS (ESI): m/z 244 [M+H]+). N- (6-(5-methoxy-1-methyl-1 H -pyrazol-4-yl)-2,4-dimethylpyridin-3-yl)acetamide (1.0 equiv.) obtained in step 2 was dissolved in benzene (0.07 M), acetic anhydride (3.0 equiv.), potassium acetate (1.5 equiv.), and isopentyl nitrite (2.0 equiv.) were added, and the mixture was stirred at 80 ℃ for 16 hours, and the reaction mixture was concentrated under reduced pressure. The reaction mixture was dissolved in water/ethanol (1/3 v/v, 0.07 M), lithium hydroxide (7.0 equiv.) was added, and the mixture was stirred at room temperature for 2 hours. After confirming the production of the target compound using LC-MS, the mixture was concentrated under reduced pressure. Water was added to the reaction mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 29%, MS (ESI): m/z 244 [M+H] + ).
[단계 4] 3-아이오도-5-(5-메톡시-1-메틸-1[Step 4] 3-Iodo-5-(5-methoxy-1-methyl-1 HH -피라졸-4-일)-7-메틸-1-pyrazol-4-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 3에서 얻어진 5-(5-메톡시-1-메틸-1H-피라졸-4-일)-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이메틸폼아마이드(0.3 M)에 녹인 후 N-아이오도숙신이미드(1.5 당량)를 첨가하고 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가하고, 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 MPLC(헥세인:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 25 %, MS (ESI): m/z 370 [M+H]+).5-(5-methoxy-1-methyl-1 H -pyrazol-4-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 eq.) obtained in step 3 was dissolved in dimethylformamide (0.3 M), N -iodosuccinimide (1.5 eq.) was added, and the mixture was stirred at room temperature for 1 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane: ethyl acetate) to obtain the target compound as a yellow solid (yield: 25%, MS (ESI): m/z 370 [M+H] + ).
[단계 5] [Step 5] terttert -부틸 3-아이오도-5-(5-메톡시-1-메틸-1H-피라졸-4-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트의 제조- Preparation of butyl 3-iodo-5-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-7-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate
단계 4에서 얻어진 3-아이오도-5-(5-메톡시-1-메틸-1H-피라졸-4-일)-7-메틸-1H-피라졸로[3,4-c]피리딘(1.0 당량)을 다이클로로메탄(0.1 M)에 녹인 후, DMAP(0.5 당량), Boc2O(2.0 당량), 트라이에틸아민(2.0 당량)을 첨가하고 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후 감압 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 79 %, MS (ESI): m/z 470 [M+H]+).3-Iodo-5-(5-methoxy-1-methyl-1 H -pyrazol-4-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.) obtained in Step 4 was dissolved in dichloromethane (0.1 M), and DMAP (0.5 equiv.), Boc 2 O (2.0 equiv.), and triethylamine (2.0 equiv.) were added, and the mixture was stirred at room temperature for 1 h. After confirming the production of the target compound using LC-MS, the mixture was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 79%, MS (ESI): m/z 470 [M+H] + ).
실시예: 본 발명의 화합물의 제조Example: Preparation of the compound of the present invention
<실시예 1> 3-(4-(4,4-다이플루오로피페리딘-1-일)-6-(5-(4-메톡시피리딘-3-일)-7-메틸-1<Example 1> 3-(4-(4,4-difluoropiperidin-1-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-1]pyridin-3-yl)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조Preparation of ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
[반응식 7][Reaction Formula 7]
Figure PCTKR2024004758-appb-img-000129
Figure PCTKR2024004758-appb-img-000129
[단계 1] 2,6-다이클로로-[Step 1] 2,6-Dichloro- NN -메틸-3-나이트로피리딘-4-아민의 제조- Preparation of methyl-3-nitropyridin-4-amine
2,6-다이클로로-3-나이트로피리딘-4-아민(1.0 당량)과 탄산 칼륨(2.5 당량)을 아세토나이트릴(0.5 M)에 녹인 후, 상온에서 30 분 동안 교반하고, 아이오도메테인(5.0 당량)을 첨가하였다. 반응 용액을 80 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 감압 농축한 다음, 농축한 혼합물에 물을 첨가한 후 에틸아세테이트를 이용하여 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(헥세인:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 70 %, MS (ESI): m/z 222 [M+H]+). 2,6-Dichloro-3-nitropyridin-4-amine (1.0 eq.) and potassium carbonate (2.5 eq.) were dissolved in acetonitrile (0.5 M), stirred at room temperature for 30 minutes, and then iodomethane (5.0 eq.) was added. The reaction solution was stirred at 80 °C for 16 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure, and water was added to the concentrated mixture, followed by extraction using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 70%, MS (ESI): m/z 222 [M+H] + ).
[단계 2] 2,6-다이클로로-[Step 2] 2,6-Dichloro- NN 44 -메틸피리딘-3,4-다이아민의 제조- Manufacture of methylpyridine-3,4-diamine
단계 1에서 얻어진 2,6-다이클로로-N-메틸-3-나이트로피리딘-4-아민(1.0 당량), 염화 암모늄(5.0 당량), 철(5.0 당량)을 물/에탄올(1/4 v/v, 0.35 M)에 녹인 후 90 ℃에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 철을 제거한 뒤, 걸러진 여액을 감압 농축하여 에탄올을 제거하였다. 농축한 혼합물에 물을 첨가한 후 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 75 %, MS (ESI): m/z 192 [M+H]+).In step 1, 2,6-dichloro- N -methyl-3-nitropyridin-4-amine (1.0 eq), ammonium chloride (5.0 eq), and iron (5.0 eq) obtained were dissolved in water/ethanol (1/4 v/v, 0.35 M) and stirred at 90 °C for 2 hours. After confirming that the target compound was produced using LC-MS, iron was removed using celite, and the filtered filtrate was concentrated under reduced pressure to remove ethanol. Water was added to the concentrated mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtering was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 75%, MS (ESI): m/z 192 [M+H] + ).
[단계 3] 4,6-다이클로로-1-메틸-1[Step 3] 4,6-Dichloro-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-싸이올의 제조 ]Preparation of pyridine-2-thiol
단계 2에서 얻어진 2,6-다이클로로-N 4-메틸피리딘-3,4-다이아민(1.0 당량)을 테트라하이드로퓨란(0.5 M)에 녹인 후 다이(1H-이미다졸-1-일)메테인싸이온(2.0 당량)을 첨가하여 80 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가하고, 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 얻어진 노란색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 78 %, MS (ESI): m/z 234 [M+H]+).In step 2, 2,6-Dichloro- N 4 -methylpyridine-3,4-diamine (1.0 eq.) obtained was dissolved in tetrahydrofuran (0.5 M), di(1 H -imidazol-1-yl)methanethione (2.0 eq.) was added, and the mixture was stirred at 80 ℃ for 16 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 78%, MS (ESI): m / z 234 [M + H] + ).
[단계 4] 2,4,6-트라이클로로-1-메틸-1[Step 4] 2,4,6-Trichloro-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘의 제조]Production of pyridine
단계 3에서 얻어진 4,6-다이클로로-1-메틸-1H-이미다조[4,5-c]피리딘-2-싸이올(1.0 당량)을 염화싸이오닐(20.0 당량)에 녹인 후 다이메틸폼아마이드(4.0 당량)를 0 ℃에서 천천히 첨가하고, 반응 혼합물을 60 ℃에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 감압 농축하였다. 농축한 혼합물에 포화 탄산수소나트륨 수용액을 천천히 첨가한 후, 에틸아세테이트를 이용하여 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축한 화합물은 MPLC(다이클로로메탄:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 66 %, MS (ESI): m/z 236 [M+H]+). In step 3, 4,6-dichloro-1-methyl-1 H -imidazo[4,5- c ]pyridine-2-thiol (1.0 eq.) obtained was dissolved in thionyl chloride (20.0 eq.), dimethylformamide (4.0 eq.) was slowly added at 0 °C, and the reaction mixture was stirred at 60 °C for 1 hour. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution was slowly added to the concentrated mixture, and the organic matter was extracted using ethyl acetate. Sodium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated compound was purified by MPLC (dichloromethane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 66%, MS (ESI): m/z 236 [M+H] + ).
[단계 5] 3-(4,6-다이클로로-1-메틸-1[Step 5] 3-(4,6-Dichloro-1-methyl-1 HH -이미다조[4,5-c]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조- Preparation of imidazo[4,5-c]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
단계 4에서 얻어진 2,4,6-트라이클로로-1-메틸-1H-이미다조[4,5-c]피리딘(1.0 당량)과 제조예 1에서 얻어진 3-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸(1.3 당량), 다이아이소프로필에틸아민(5.0 당량)을 아세토나이트릴(0.5 M)에 녹인 후, 80 ℃에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 95 %, MS (ESI): m/z 428 [M+H]+). 2,4,6-Trichloro-1-methyl-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained in Step 4, 3-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane (1.3 eq.) obtained in Preparation Example 1, and diisopropylethylamine (5.0 eq.) were dissolved in acetonitrile (0.5 M), and the mixture was stirred at 80 ° C. for 2 hours. After confirming that the target compound was produced using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (dichloromethane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 95%, MS (ESI): m/z 428 [M+H] + ).
[단계 6] 3-(6-클로로-4-(4,4-다이플루오로피페리딘-1-일)-1-메틸-1[Step 6] 3-(6-chloro-4-(4,4-difluoropiperidin-1-yl)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조Preparation of ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
단계 5에서 얻어진 3-(4,6-다이클로로-1-메틸-1H-이미다조[4,5-c]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸(1.0 당량)을 1,3-다이메틸-2-이미다졸리디논(0.23 M)에 녹인 후, 4,4-다이플루오로피페리딘 염산염(1.0 당량), 탄산수소나트륨(10.0 당량)을 첨가하고 180 ℃에서 5 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가한 다음 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 92 %, MS (ESI): m/z 513 [M+H]+).In step 5, 3-(4,6-dichloro-1-methyl-1 H -imidazo[4,5- c ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane (1.0 eq) obtained was dissolved in 1,3-dimethyl-2-imidazolidinone (0.23 M), 4,4-difluoropiperidine hydrochloride (1.0 eq) and sodium bicarbonate (10.0 eq) were added, and the mixture was stirred at 180 ℃ for 5 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to give the target compound as a yellow solid (yield: 92%, MS (ESI): m/z 513 [M+H] + ).
[단계 7] [Step 7] terttert -부틸 3-(4-(4,4-다이플루오로피페리딘-1-일)-2-(9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸-3-일)-1-메틸-1-Butyl 3-(4-(4,4-difluoropiperidin-1-yl)-2-(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 6에서 얻어진 3-(6-클로로-4-(4,4-다이플루오로피페리딘-1-일)-1-메틸-1H-이미다조[4,5-c]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸(1.0 당량), 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란)(5.0 당량)과 탄산 나트륨(3.0 당량)을 물/1,4-다이옥세인(1/2 v/v, 0.1 M)에 녹인 후, 질소 하에서 Pd(amphos)Cl2(0.15 당량)을 80 ℃에서 첨가한 후, 80 ℃에서 15 분 동안 교반하였다. 이후, 제조예 3에서 얻어진 tert-부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 첨가하고 15 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 액체의 목적 화합물을 수득하였다(수율: 69 %, MS (ESI): m/z 817 [M+H]+).3-(6-Chloro-4-(4,4-difluoropiperidin-1-yl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane (1.0 equiv.) obtained in step 6, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.0 equiv.) and sodium carbonate (3.0 equiv.) were dissolved in water/1,4-dioxane (1/2 v/v, 0.1 M), and Pd(amphos)Cl 2 (0.15 equiv.) was added at 80 °C under nitrogen, and the mixture was stirred at 80 °C for 15 min. Thereafter, tert -butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 eq) obtained in Manufacturing Example 3 was added and stirred for 15 minutes. After confirming that the target compound was produced using LC-MS, it was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown liquid (yield: 69%, MS (ESI): m/z 817 [M+H] + ).
[단계 8] 3-(4-(4,4-다이플루오로피페리딘-1-일)-6-(5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 8] 3-(4-(4,4-difluoropiperidin-1-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-1]pyridin-3-yl)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-일)-9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸의 제조Preparation of ]pyridin-2-yl)-9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecane
단계 7에서 얻어진 tert-부틸 3-(4-(4,4-다이플루오로피페리딘-1-일)-2-(9-(2-플루오로-2-메틸프로필)-3,9-다이아자스피로[5.5]운데칸-3-일)-1-메틸-1H-이미다조[4,5-c]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)에 다이클로로메탄(0.2 M)에 녹인 후, 트라이플루오로아세트산(44.0 당량)을 첨가하여 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후 감압 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 25 %, MS (ESI): m/z 717 [M+H]+).In step 7, tert -butyl 3-(4-(4,4-difluoropiperidin-1-yl)-2-(9-(2-fluoro-2-methylpropyl)-3,9-diazaspiro[5.5]undecan-3-yl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 eq.) obtained was dissolved in dichloromethane (0.2 M), trifluoroacetic acid (44.0 eq.) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the production of the target compound using LC-MS, the mixture was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 25%, MS (ESI): m/z 717 [M+H] + ).
<실시예 1> 내지 <실시예 86><Example 1> to <Example 86>
상기 실시예 1과 유사한 방법으로 실시예 2 내지 86 화합물을 제조하였다.Compounds of Examples 2 to 86 were prepared in a similar manner to Example 1.
실시예 1 내지 86 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 2에 정리하여 나타내었다.The chemical structures, compound names, NMR, and LC-MS analysis results of compounds of Examples 1 to 86 are summarized in Table 2 below.
[표 2][Table 2]
Figure PCTKR2024004758-appb-img-000130
Figure PCTKR2024004758-appb-img-000130
Figure PCTKR2024004758-appb-img-000131
Figure PCTKR2024004758-appb-img-000131
Figure PCTKR2024004758-appb-img-000132
Figure PCTKR2024004758-appb-img-000132
Figure PCTKR2024004758-appb-img-000133
Figure PCTKR2024004758-appb-img-000133
Figure PCTKR2024004758-appb-img-000134
Figure PCTKR2024004758-appb-img-000134
Figure PCTKR2024004758-appb-img-000135
Figure PCTKR2024004758-appb-img-000135
Figure PCTKR2024004758-appb-img-000136
Figure PCTKR2024004758-appb-img-000136
Figure PCTKR2024004758-appb-img-000137
Figure PCTKR2024004758-appb-img-000137
Figure PCTKR2024004758-appb-img-000138
Figure PCTKR2024004758-appb-img-000138
Figure PCTKR2024004758-appb-img-000139
Figure PCTKR2024004758-appb-img-000139
Figure PCTKR2024004758-appb-img-000140
Figure PCTKR2024004758-appb-img-000140
Figure PCTKR2024004758-appb-img-000141
Figure PCTKR2024004758-appb-img-000141
Figure PCTKR2024004758-appb-img-000142
Figure PCTKR2024004758-appb-img-000142
Figure PCTKR2024004758-appb-img-000143
Figure PCTKR2024004758-appb-img-000143
Figure PCTKR2024004758-appb-img-000144
Figure PCTKR2024004758-appb-img-000144
Figure PCTKR2024004758-appb-img-000145
Figure PCTKR2024004758-appb-img-000145
Figure PCTKR2024004758-appb-img-000146
Figure PCTKR2024004758-appb-img-000146
Figure PCTKR2024004758-appb-img-000147
Figure PCTKR2024004758-appb-img-000147
Figure PCTKR2024004758-appb-img-000148
Figure PCTKR2024004758-appb-img-000148
Figure PCTKR2024004758-appb-img-000149
Figure PCTKR2024004758-appb-img-000149
Figure PCTKR2024004758-appb-img-000150
Figure PCTKR2024004758-appb-img-000150
Figure PCTKR2024004758-appb-img-000151
Figure PCTKR2024004758-appb-img-000151
<실시예 87> (<Example 87> ( RR )-3-(3-(4-(다이메틸아미노)-2-(헥사하이드로피롤로[1,2-)-3-(3-(4-(dimethylamino)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-1-메틸-1)-1)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-7-메틸-1]pyridin-6-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-5-일)피리딘-4-올의 제조]Pyridin-5-yl) Preparation of pyridin-4-ol
[반응식 8] [Reaction Formula 8]
Figure PCTKR2024004758-appb-img-000152
Figure PCTKR2024004758-appb-img-000152
(R)-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-6-(5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량)을 N-메틸-2-피롤리돈(0.1 M)에 녹인 후, p-톨루엔설폰산 (10.0 ,당량), 염화 리튬(10.0 당량)을 첨가하고, 마이크로웨이브를 이용하여 120 ℃에서 10 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 포화 탄산수소나트륨 수용액을 첨가하고 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 51 %, MS (ESI): m/z 525 [M+H]+).( R )-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridin-3-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) was dissolved in N -methyl-2-pyrrolidone (0.1 M), p -toluenesulfonic acid (10.0 equiv.) and lithium chloride (10.0 equiv.) were added, and the mixture was stirred using a microwave at 120 °C for 10 min. After confirming the production of the target compound using LC-MS, a saturated aqueous sodium bicarbonate solution was added, and the organic matter was extracted with dichloromethane. Sodium sulfate was added to the collected organic layer, the remaining water was removed, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to obtain the target compound as a yellow solid (yield: 51%, MS (ESI): m/z 525 [M+H] + ).
<실시예 87> 내지 <실시예 88><Example 87> to <Example 88>
상기 실시예 87과 유사한 방법으로 실시예 88 화합물을 제조하였다.Compound Example 88 was prepared in a similar manner to Example 87 above.
실시예 87 내지 88 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 3에 정리하여 나타내었다.The chemical structures, compound names, NMR, and LC-MS analysis results of compounds of Examples 87 to 88 are summarized in Table 3 below.
[표 3][Table 3]
Figure PCTKR2024004758-appb-img-000153
Figure PCTKR2024004758-appb-img-000153
<실시예 89> 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1<Example 89> 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-]pyridin-3-yl)- NN ,, NN ,1-트라이메틸-2-(1-메틸피페리딘-4-일)-1,1-Trimethyl-2-(1-methylpiperidin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
[반응식 9] [Reaction Formula 9]
Figure PCTKR2024004758-appb-img-000154
Figure PCTKR2024004758-appb-img-000154
[단계 1] 4,6-다이클로로-1-메틸-2-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)-1[Step 1] 4,6-Dichloro-1-methyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘의 제조]Production of pyridine
2,4,6-트라이클로로-1-메틸-1H-이미다조[4,5-c]피리딘(1.0 당량)을 1,4-다이옥세인/물 (1/1 v/v, 0.05 M)에 녹인 후, 탄산 칼륨(5.0 당량), Pd(PPh3)4(0.15 당량), tert-부틸 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-3,6-다이하이드로피리딘-1(2H)-카복실레이트(1.1 당량)를 첨가하고 100 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하였다. 반응 혼합물에 물을 첨가한 후, 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 36 %, MS (ESI): m/z 297 [M+H]+).2,4,6-Trichloro-1-methyl-1 H -imidazo[4,5- c ]pyridine (1.0 equiv) was dissolved in 1,4-dioxane/water (1/1 v/v, 0.05 M), potassium carbonate (5.0 equiv), Pd(PPh 3 ) 4 (0.15 equiv), and tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylate (1.1 equiv) were added, and the mixture was stirred at 100 ℃ for 16 h. After confirming the production of the target compound using LC-MS, the mixture was filtered using Celite. Water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 36%, MS (ESI): m/z 297 [M+H] + ).
[단계 2] 4,6-다이클로로-1-메틸-2-(1-메틸피페리딘-4-일)-1[Step 2] 4,6-Dichloro-1-methyl-2-(1-methylpiperidin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘의 제조]Production of pyridine
단계 1에서 얻어진 4,6-다이클로로-1-메틸-2-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)-1H-이미다조[4,5-c]피리딘(1.0 당량)을 에탄올(0.3 M)에 녹인 후, PtO2(0.3 당량)을 첨가하고 수소 하, 상온에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고, 반응 혼합물을 감압 농축하였다. 얻어진 갈색 액체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 100 %, MS (ESI): m/z 299 [M+H]+).The 4,6-dichloro-1-methyl-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained in Step 1 was dissolved in ethanol (0.3 M), PtO 2 (0.3 eq.) was added, and the mixture was stirred at room temperature under hydrogen for 2 h. After confirming the production of the target compound using LC-MS, the mixture was filtered using Celite, and the reaction mixture was concentrated under reduced pressure. The target compound obtained as a brown liquid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 299 [M + H] + ).
[단계 3] 6-클로로-[Step 3] 6-Chloro- NN ,, NN ,1-트라이메틸-2-(1-메틸피페리딘-4-일)-1,1-Trimethyl-2-(1-methylpiperidin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
단계 2에서 얻어진 4,6-다이클로로-1-메틸-2-(1-메틸피페리딘-4-일)-1H-이미다조[4,5-c]피리딘(1.0 당량)에 40 % 다이메틸아민 수용액(50.0 당량)을 첨가하고 80 ℃에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가한 다음 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 마그네슘을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 얻어진 노란색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 51 %, MS (ESI): m/z 308 [M+H]+).In step 2, 4,6-dichloro-1-methyl-2-(1-methylpiperidin-4-yl)-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained was added a 40% dimethylamine aqueous solution (50.0 eq.) and stirred at 80 ℃ for 1 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. Magnesium sulfate was added to the combined organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The target compound obtained as a yellow solid was used in the next reaction without further purification (yield: 51%, MS (ESI): m/z 308 [M+H] + ).
[단계 4] [Step 4] terttert -부틸 3-(4-(다이메틸아미노)-1-메틸-2-(1-메틸피페리딘-4-일)-1-Butyl 3-(4-(dimethylamino)-1-methyl-2-(1-methylpiperidin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 3에서 얻어진 6-클로로-N,N,1-트라이메틸-2-(1-메틸피페리딘-4-일)-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량), 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란)(5.0 당량)과 탄산 나트륨(3.0 당량)을 물/다이옥세인(1/2 v/v, 0.2 M)에 녹인 후, 질소 하에서 Pd(amphos)Cl2(0.15 당량)을 80 ℃에서 첨가한 후, 80 ℃에서 10 분 동안 교반하였다. 이후, 제조예 3에서 얻어진 tert-부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(0.9 당량)를 첨가하고 10 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 액체의 목적 화합물을 수득하였다(수율: 34 %, MS (ESI): m/z 612 [M+H]+). 6-Chloro- N , N , 1-trimethyl-2-(1-methylpiperidin-4-yl)-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) obtained in Step 3, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.0 equiv.) and sodium carbonate (3.0 equiv.) were dissolved in water/dioxane (1/2 v/v, 0.2 M), and Pd(amphos)Cl 2 (0.15 equiv.) was added at 80 ° C. under nitrogen, followed by stirring at 80 ° C. for 10 min. Thereafter, tert -butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (0.9 equivalents) obtained in Manufacturing Example 3 was added and stirred for 10 minutes. After confirming that the target compound was produced using LC-MS, it was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow liquid (yield: 34%, MS (ESI): m/z 612 [M+H] + ).
[단계 5] 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 5] 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-]pyridin-3-yl)- NN ,, NN ,1-트라이메틸-2-(1-메틸피페리딘-4-일)-1,1-Trimethyl-2-(1-methylpiperidin-4-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
단계 4에서 얻어진 tert-부틸 3-(4-(다이메틸아미노)-1-메틸-2-(1-메틸피페리딘-4-일)-1H-이미다조[4,5-c]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 다이클로로메탄(0.1 M)에 녹인 후, 트라이플루오로아세트산(10.0 당량)을 첨가하여 상온에서 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 8 %, MS (ESI): m/z 512 [M+H]+).In step 4, tert -butyl 3-(4-(dimethylamino)-1-methyl-2-(1-methylpiperidin-4-yl)-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 30 minutes. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 8%, MS (ESI): m/z 512 [M+H] + ).
<실시예 89> 내지 <실시예 92><Example 89> to <Example 92>
상기 실시예 89와 유사한 방법으로 실시예 90 내지 92 화합물을 제조하였다.Compounds of Examples 90 to 92 were prepared in a similar manner to Example 89.
실시예 89 내지 92 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 4에 정리하여 나타내었다.The chemical structures, compound names, NMR, and LC-MS analysis results of compounds of Examples 89 to 92 are summarized in Table 4 below.
[표 4][Table 4]
Figure PCTKR2024004758-appb-img-000155
Figure PCTKR2024004758-appb-img-000155
<실시예 93> (<Example 93> ( RR )-3-(2-(헥사하이드로피롤로[1,2-)-3-(2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-4-아이소프로필-1-메틸-1)-1)-4-isopropyl-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
[반응식 10] [Reaction Formula 10]
Figure PCTKR2024004758-appb-img-000156
Figure PCTKR2024004758-appb-img-000156
[단계 1] ([Step 1] ( RR )-6-클로로-2-(헥사하이드로피롤로[1,2-)-6-chloro-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-1-메틸-4-(프로프-1-엔-2-일)-1)-1-methyl-4-(prop-1-en-2-yl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘의 제조]Production of pyridine
(R)-4,6-다이클로로-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-1-메틸-1H-이미다조[4,5-c]피리딘(1.0 당량), 4,4,5,5-테트라메틸-2-(프로프-1-엔-2-일)-1,3,2-다이옥사보로레인(1.8 당량), 탄산 나트륨(3.0 당량)을 1,4-다이옥세인/물 (4/1 v/v, 0.1 M)에 녹인 후 질소로 탈기하였다. 반응 혼합물에 Pd(dppf)Cl2·DCM(0.1 당량)을 첨가하여 100 ℃에서 3 시간 동안 반응하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고, 얻어진 여액을 감압 농축하였다. 농축한 혼합물을 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 49 %, MS (ESI): m/z 332 [M+H]+). ( R )-4,6-dichloro-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-1-methyl-1 H -imidazo[4,5-c]pyridine (1.0 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.8 equiv.), and sodium carbonate (3.0 equiv.) were dissolved in 1,4-dioxane/water (4/1 v/v, 0.1 M), and degassed with nitrogen. Pd(dppf)Cl 2 ·DCM (0.1 equiv.) was added to the reaction mixture, and the mixture was reacted at 100 °C for 3 h. After confirming the production of the target compound using LC-MS, the mixture was filtered using Celite, and the resulting filtrate was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 49%, MS (ESI): m/z 332 [M+H] + ).
[단계 2] ([Step 2] ( RR )-6-클로로-2-(헥사하이드로피롤로[1,2-)-6-chloro-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-4-아이소프로필-1-메틸-1)-1)-4-isopropyl-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘의 제조]Production of pyridine
단계 1에서 얻어진 (R)-6-클로로-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-1-메틸-4-(프로프-1-엔-2-일)-1H-이미다조[4,5-c]피리딘(1.0 당량)을 에탄올(0.1 M)에 녹인 후, 트리스(트라이페닐포스핀)로듐(I) 클로라이드(0.2 당량)를 넣고 수소 하, 상온에서 12 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고, 얻어진 여액을 감압 농축하였다. 농축한 혼합물을 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 60 %, MS (ESI): m/z 334 [M+H]+).In Step 1, ( R )-6-chloro-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-1-methyl-4-(prop-1-en-2-yl)-1 H -imidazo[4,5- c ]pyridine (1.0 eq.) obtained was dissolved in ethanol (0.1 M), tris(triphenylphosphine)rhodium(I) chloride (0.2 eq.) was added, and the mixture was stirred at room temperature under hydrogen for 12 hours. After confirming the production of the target compound using LC-MS, the mixture was filtered using celite, and the obtained filtrate was concentrated under reduced pressure. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 60%, MS (ESI): m/z 334 [M+H] + ).
[단계 3] [Step 3] terttert -부틸 (-Butyl ( RR )-3-(2-(헥사하이드로피롤로[1,2-)-3-(2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-4-아이소프로필-1-메틸-1)-1)-4-isopropyl-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 2에서 얻어진 (R)-6-클로로-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-4-아이소프로필-1-메틸-1H-이미다조[4,5-c]피리딘(1.0 당량), 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-바이(1,3,2-다이옥사보롤란)(5.0 당량)과 탄산 나트륨(3.0 당량)을 물/다이옥세인(1/4, 0.1 M)에 녹인 후, 질소 하에서 Pd(amphos)Cl2(0.15 당량)을 80 ℃에서 첨가하고, 80 ℃에서 10 분 동안 교반하였다. 이후, tert-부틸 3-브로모-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 첨가하고 80 ℃에서 10분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 17 %, MS (ESI): m/z 638 [M+H]+).( R )-6-Chloro-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1 H )-yl)-4-isopropyl-1-methyl-1 H -imidazo[4,5-c]pyridine (1.0 equiv.) obtained in Step 2, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.0 equiv.) and sodium carbonate (3.0 equiv.) were dissolved in water/dioxane (1/4, 0.1 M). Then, Pd(amphos)Cl 2 (0.15 equiv.) was added at 80 °C under nitrogen, and the mixture was stirred at 80 °C for 10 min. Then, tert -butyl 3-bromo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 eq) was added and stirred at 80 °C for 10 min. After confirming the production of the target compound using LC-MS, the mixture was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 17%, MS (ESI): m/z 638 [M+H] + ).
[단계 4] ([Step 4] ( RR )-3-(2-(헥사하이드로피롤로[1,2-)-3-(2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-4-아이소프로필-1-메틸-1)-1)-4-isopropyl-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘의 제조]Production of pyridine
단계 3에서 얻어진 tert-부틸 (R)-3-(2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-4-아이소프로필-1-메틸-1H-이미다조[4,5-c]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 다이클로로메탄(0.1 M)에 녹인 후, 트라이플루오로아세트산(10.0 당량)을 첨가하여 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 감압 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 10 %, MS (ESI): m/z 538 [M+H]+).In step 3, tert -butyl ( R )-3-(2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-4-isopropyl-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 1 hour. After confirming the production of the target compound using LC-MS, the mixture was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 10%, MS (ESI): m/z 538 [M+H] + ).
<실시예 93> <Example 93>
실시예 93 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 5에 정리하여 나타내었다.The chemical structure, compound name, NMR, and LC-MS analysis results of the compound of Example 93 are summarized in Table 5 below.
[표 5][Table 5]
Figure PCTKR2024004758-appb-img-000157
Figure PCTKR2024004758-appb-img-000157
<실시예 94> (<Example 94> ( RR )-2-(헥사하이드로피롤로[1,2-)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-6-(5-(4-메톡시피리딘-3-일)-1,7-다이메틸-1)-yl)-6-(5-(4-methoxypyridin-3-yl)-1,7-dimethyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-]pyridin-3-yl)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
[반응식 11] [Reaction Formula 11]
Figure PCTKR2024004758-appb-img-000158
Figure PCTKR2024004758-appb-img-000158
[단계 1] ([Step 1] ( RR )-6-(5-브로모-7-메틸-1)-6-(5-bromo-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-2-(헥사하이드로피롤로[1,2-]pyridin-3-yl)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-)-Day)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
(R)-6-클로로-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량), 헥사부틸틴(6.0 당량)을 다이옥세인(0.2 M)에 녹인 후, 질소 하에서 Pd(dppf)Cl2(0.2 당량)을 100 ℃에서 첨가하고 16 시간 동안 교반하였다. 반응 혼합물에 5-브로모-3-아이오도-7-메틸-1H-피라졸로[3,4-c]피리딘(2.0 당량)을 첨가하고, 100 ℃에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 25 %, MS (ESI): m/z 510 [M+H]+).( R )-6-chloro-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) and hexabutyltin (6.0 equiv.) were dissolved in dioxane (0.2 M). Pd(dppf)Cl 2 (0.2 equiv.) was added at 100 °C under nitrogen, and the mixture was stirred for 16 h. 5-Bromo-3-iodo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (2.0 equiv.) was added to the reaction mixture, and the mixture was stirred at 100 °C for 1 h. After confirming the production of the target compound using LC-MS, the mixture was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to give the target compound as a yellow solid (yield: 25%, MS (ESI): m/z 510 [M+H] + ).
[단계 2] ([Step 2] ( RR )-2-(헥사하이드로피롤로[1,2-)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-6-(5-(4-메톡시피리딘-3-일)-7-메틸-1)-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-]pyridin-3-yl)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
단계 1에서 얻어진 (R)-6-(5-브로모-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량), 세슘카보네이트(3.0 당량)와 (4-메톡시피리딘-3-일)보론산(3.0 당량)을 물/다이옥세인(1/2 v/v, 0.2 M)에 녹인 후, 질소 하에서 Pd(amphos)Cl2(0.2 당량)을 100 ℃에서 첨가하고, 100 ℃에서 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 91 %, MS (ESI): m/z 539 [M+H]+). ( R )-6-(5-Bromo-7-methyl-1H-pyrazolo[3,4- c ]pyridin-3-yl)-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)- N , N , 1-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.0 equiv.) obtained in Step 1, cesium carbonate (3.0 equiv.) and (4-methoxypyridin-3-yl)boronic acid (3.0 equiv.) were dissolved in water/dioxane (1/2 v/v, 0.2 M), and Pd(amphos)Cl 2 (0.2 equiv.) was added at 100 °C under nitrogen, and the mixture was stirred at 100 °C for 30 min. After confirming that the target compound was produced using LC-MS, it was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 91%, MS (ESI): m/z 539 [M+H] + ).
[단계 3] ([Step 3] ( RR )-2-(헥사하이드로피롤로[1,2-)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-6-(5-(4-메톡시피리딘-3-일)-1,7-다이메틸-1)-yl)-6-(5-(4-methoxypyridin-3-yl)-1,7-dimethyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-]pyridin-3-yl)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
단계 2에서 얻어진 (R)-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-6-(5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량)을 테트라하이드로퓨란(0.2 M)에 녹인 후, 소듐하이드라이드(3.0 당량)를 0 ℃에서 첨가하고, 0 ℃에서 30 분 동안 교반한 다음, 아이오딘화 메틸(1.5 당량)을 첨가한 후 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 물을 첨가하고, 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층에 황산 나트륨을 첨가하여 남은 물을 제거하고, 여과하여 얻어진 유기층을 감압 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 4 %, MS (ESI): m/z 553 [M+H]+). In step 2, ( R )-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridin-3-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.2 M). Sodium hydride (3.0 equiv.) was added at 0 °C, and the mixture was stirred at 0 °C for 30 min. Methyl iodide (1.5 equiv.) was added, and the mixture was stirred for 30 min. After confirming the production of the target compound using LC-MS, water was added, and the organic matter was extracted with ethyl acetate. Sodium sulfate was added to the collected organic layer to remove the remaining water, and the organic layer obtained by filtration was concentrated under reduced pressure. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to obtain the target compound as a yellow solid (yield: 4%, MS (ESI): m/z 553 [M+H] + ).
<실시예 94> <Example 94>
실시예 94 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 6에 정리하여 나타내었다.The chemical structure, compound name, NMR, and LC-MS analysis results of the compound of Example 94 are summarized in Table 6 below.
[표 6][Table 6]
Figure PCTKR2024004758-appb-img-000159
Figure PCTKR2024004758-appb-img-000159
<실시예 95> 6-(5-((3<Example 95> 6-(5-((3 RR ,4,4 SS )-3-플루오로-4-메톡시피페리딘-1-일)-7-메틸-1)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-2-((]pyridin-3-yl)-2-(( RR )-헥사하이드로피롤로[1,2-)-hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-)-Day)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
[반응식 12] [Reaction Formula 12]
Figure PCTKR2024004758-appb-img-000160
Figure PCTKR2024004758-appb-img-000160
[단계 1] ([Step 1] ( RR )-6-(5-브로모-7-메틸-1)-6-(5-bromo-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-2-(헥사하이드로피롤로[1,2-]pyridin-3-yl)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-)-Day)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
(R)-6-클로로-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량)을 다이메틸폼아마이드 (0.2 M)에 녹인 후, 헥사부틸틴(3.0 당량)을 첨가하였다. 반응 혼합물을 질소로 탈기시킨 후, Pd(dppf)Cl2(0.1 당량)를 첨가하고, 100 ℃에서 16 시간 동안 교반하였다. 이후, 5-브로모-3-아이오도-7-메틸-1H-피라졸로[3,4-c]피리딘(1.5 당량)과 Pd(PPh3)4(0.1 당량)를 첨가하고, 반응 혼합물을 100 ℃에서 4 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 셀라이트로 여과하고, 다이클로로메탄과 메탄올로 씻어주었다. 얻어진 여과액을 감압 농축한 후 MPLC(다이클로로메탄:메탄올)로 정제하여 회색 고체의 목적 화합물을 수득하였다(수율: 64 %, MS (ESI): m/z 510 [M+H]+).( R )-6-Chloro-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv) was dissolved in dimethylformamide (0.2 M), and hexabutyltin (3.0 equiv) was added. The reaction mixture was degassed with nitrogen, Pd(dppf)Cl 2 (0.1 equiv) was added, and the mixture was stirred at 100 °C for 16 h. Thereafter, 5-bromo-3-iodo-7-methyl-1 H -pyrazolo[3,4- c ]pyridine (1.5 eq.) and Pd(PPh 3 ) 4 (0.1 eq.) were added, and the reaction mixture was stirred at 100 ℃ for 4 h. After confirming that the target compound was produced using LC-MS, the reaction mixture was filtered through Celite and washed with dichloromethane and methanol. The obtained filtrate was concentrated under reduced pressure and then purified by MPLC (dichloromethane:methanol) to obtain the target compound as a gray solid (yield: 64%, MS (ESI): m/z 510 [M+H] + ).
[단계 2] [Step 2] terttert -부틸(-Butyl( RR )-5-브로모-3-(4-(다이메틸아미노)-2-(헥사하이드로피롤로[1,2-)-5-bromo-3-(4-(dimethylamino)-2-(hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-1-메틸-1)-1)-1-methyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-7-메틸-1]pyridin-6-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 1에서 얻어진 (R)-6-(5-브로모-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-N,N,1-트라이메틸-1H-이미다조[4,5-c]피리딘-4-아민(1.0 당량)을 다이클로로메탄(0.2 M)에 녹인 후, Boc2O(2.0 당량)와 트라이에틸아민(3.0 당량), N,N-다이메틸피리딘-4-아민(0.5 당량)을 첨가하여 상온에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 감압 농축한 다음 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 96 %, MS (ESI): m/z 610 [M+H]+).( R )-6-(5-Bromo-7-methyl-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)- N , N , 1-trimethyl-1 H -imidazo[4,5- c ]pyridin-4-amine (1.0 equiv.) obtained in Step 1 was dissolved in dichloromethane (0.2 M), and Boc 2 O (2.0 equiv.), triethylamine (3.0 equiv.), and N , N -dimethylpyridin-4-amine (0.5 equiv.) were added, and the mixture was stirred at room temperature for 1 h. After confirming that the target compound was produced using LC-MS, the residue was concentrated under reduced pressure and purified using MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 96%, MS (ESI): m/z 610 [M+H] + ).
[단계 3] 6-(5-((3[Step 3] 6-(5-((3 RR ,4,4 SS )-3-플루오로-4-메톡시피페리딘-1-일)-7-메틸-1)-3-fluoro-4-methoxypiperidin-1-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-2-((]pyridin-3-yl)-2-(( RR )-헥사하이드로피롤로[1,2-)-hexahydropyrrolo[1,2- aa ]피라진-2(1]Pyrazine-2(1 HH )-일)-)-Day)- NN ,, NN ,1-트라이메틸-1,1-trimethyl-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-아민의 제조]Preparation of pyridin-4-amine
단계 2에서 얻어진 tert-부틸(R)-5-브로모-3-(4-(다이메틸아미노)-2-(헥사하이드로피롤로[1,2-a]피라진-2(1H)-일)-1-메틸-1H-이미다조[4,5-c]피리딘-6-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 테트라하이드로퓨란(0.2 M)에 녹인 후, (3R,4S)-3-플루오로-4-메톡시피페리딘 염산염(1.5 당량)과 소듐 트라이메틸실라놀레이트(3.0 당량)를 첨가하였다. 반응 혼합물을 질소로 탈기시키고, [(Cinnamyl)PdCl]2(0.2 당량)와 Gphos(0.2 당량)를 첨가한 후 마이크로웨이브 기기를 사용하여 110 ℃에서 10 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 셀라이트로 여과하고, 다이클로로메탄과 메탄올로 씻어주었다. 얻어진 여과액을 감압 농축한 후, prep-HPLC(물(0.1 % 트라이플루오로아세트산)/메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 17 %, MS (ESI): m/z 563 [M+H]+). In step 2, tert -butyl( R )-5-bromo-3-(4-(dimethylamino)-2-(hexahydropyrrolo[1,2- a ]pyrazin-2(1 H )-yl)-1-methyl-1 H -imidazo[4,5- c ]pyridin-6-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in tetrahydrofuran (0.2 M), and then (3 R ,4 S )-3-fluoro-4-methoxypiperidine hydrochloride (1.5 equiv.) and sodium trimethylsilanolate (3.0 equiv.) were added. The reaction mixture was degassed with nitrogen, and [(Cinnamyl)PdCl] 2 (0.2 equiv.) and Gphos (0.2 equiv.) were added, and the mixture was stirred at 110 °C for 10 min using a microwave apparatus. After confirming that the target compound was produced using LC-MS, the reaction mixture was filtered through Celite and washed with dichloromethane and methanol. The obtained filtrate was concentrated under reduced pressure, and then purified by prep-HPLC (water (0.1% trifluoroacetic acid)/methanol (0.1% trifluoroacetic acid)) to obtain the target compound as a yellow solid (yield: 17%, MS (ESI): m/z 563 [M+H] + ).
<실시예 95> 내지 <실시예 96><Example 95> to <Example 96>
상기 실시예 95와 유사한 방법으로 실시예 96 화합물을 제조하였다.Compound Example 96 was prepared in a similar manner to Example 95 above.
실시예 95 내지 96 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 7에 정리하여 나타내었다.The chemical structures, compound names, NMR, and LC-MS analysis results of compounds of Examples 95 to 96 are summarized in Table 7 below.
[표 7][Table 7]
Figure PCTKR2024004758-appb-img-000161
Figure PCTKR2024004758-appb-img-000161
<실시예 97> 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1<Example 97> 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1,3-다이메틸-4-모폴리노-1,3-다이하이드로-2]pyridin-3-yl)-1,3-dimethyl-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
[반응식 13] [Reaction Formula 13]
Figure PCTKR2024004758-appb-img-000162
Figure PCTKR2024004758-appb-img-000162
[단계 1] 2,6-다이클로로-[Step 1] 2,6-Dichloro- NN -메틸-3-나이트로피리딘-4-아민의 제조- Preparation of methyl-3-nitropyridin-4-amine
2,6-다이클로로-3-나이트로피리딘-4-아민(1.0 당량)과 탄산 칼륨(2.5 당량)을 아세토나이트릴(0.3 M)에 녹인 후 0 ℃에서 15 분 동안 교반하였다. 상온에서 반응 혼합물에 아이오딘화 메틸(6.0 당량)을 첨가하고 80 ℃에서 15 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가한 다음 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 농축된 혼합물은 MPLC(헥세인:에틸아세테이트)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 81 %, MS (ESI): m/z 222 [M+H]+). 2,6-Dichloro-3-nitropyridin-4-amine (1.0 equiv) and potassium carbonate (2.5 equiv) were dissolved in acetonitrile (0.3 M) and stirred at 0 °C for 15 min. Methyl iodide (6.0 equiv) was added to the reaction mixture at room temperature and stirred at 80 °C for 15 h. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture and the organic matter was extracted with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (hexane:ethyl acetate) to obtain the target compound as a yellow solid (yield: 81%, MS (ESI): m/z 222 [M+H] + ).
[단계 2] 2,6-다이클로로-[Step 2] 2,6-Dichloro- NN 44 -메틸피리딘-3,4-다이아민의 제조- Manufacture of methylpyridine-3,4-diamine
단계 1에서 얻어진 2,6-다이클로로-N-메틸-3-나이트로피리딘-4-아민(1.0 당량), 염화 암모늄(5.0 당량)과 철(5.0 당량)을 물/에탄올(1/4 v/v, 0.35 M)에 녹인 후, 90 ℃에서 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 76 %, MS (ESI): m/z 192 [M+H]+).2,6-Dichloro- N -methyl-3-nitropyridin-4-amine (1.0 equiv.), ammonium chloride (5.0 equiv.), and iron (5.0 equiv.) obtained in Step 1 were dissolved in water/ethanol (1/4 v/v, 0.35 M) and stirred at 90 °C for 30 min. After the production of the target compound was confirmed using LC-MS, it was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow solid (yield: 76%, MS (ESI): m/z 192 [M+H] + ).
[단계 3] 4,6-다이클로로-1-메틸-1,3-다이하이드로-2[Step 3] 4,6-Dichloro-1-methyl-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 2에서 얻어진 2,6-다이클로로-N 4-메틸피리딘-3,4-다이아민(1.0 당량)과 1,1'-카보닐다이이미다졸(1.3 당량)을 다이클로로에테인(0.3 M)에 녹인 후, 50 ℃에서 15 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 아세토나이트릴을 첨가하였다. 생성된 고체를 여과한 다음, 아세토나이트릴로 고체를 씻어주었고, 흰색 고체의 목적 화합물을 수득하였다(수율: 75 %, MS (ESI): m/z 218 [M+H]+).In step 2, 2,6-dichloro- N 4 -methylpyridine-3,4-diamine (1.0 eq.) and 1,1'-carbonyldiimidazole (1.3 eq.) obtained were dissolved in dichloroethane (0.3 M) and stirred at 50 ℃ for 15 h. After confirming that the target compound was produced using LC-MS, acetonitrile was added to the reaction mixture. The produced solid was filtered and washed with acetonitrile, and the target compound was obtained as a white solid (yield: 75%, MS (ESI): m / z 218 [M + H] + ).
[단계 4] 4,6-다이클로로-1,3-다이메틸-1,3-다이하이드로-2[Step 4] 4,6-Dichloro-1,3-dimethyl-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 3에서 얻어진 4,6-다이클로로-1-메틸-1,3-다이하이드로-2H-이미다조[4,5-c]피리딘-2-온(1.0 당량)을 다이메틸폼아마이드(0.4 M)에 녹인 후, -5 ℃에서 소듐하이드라이드(1.2 당량)를 첨가하고 10 분 동안 교반하고, 아이오딘화 메틸(1.2 당량)을 첨가한 다음, -5 ℃에서 1 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가한 다음 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄: 메탄올)로 정제하여 흰색 고체의 목적 화합물을 수득하였다(수율: 63 %, MS (ESI): m/z 232 [M+H]+).In step 3, 4,6-dichloro-1-methyl-1,3-dihydro-2 H -imidazo[4,5- c ]pyridin-2-one (1.0 eq.) obtained was dissolved in dimethylformamide (0.4 M), sodium hydride (1.2 eq.) was added at -5 °C, the mixture was stirred for 10 minutes, methyl iodide (1.2 eq.) was added, and the mixture was stirred for 1 hour at -5 °C. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The combined organic layers were concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (dichloromethane: methanol) to obtain the target compound as a white solid (yield: 63%, MS (ESI): m/z 232 [M+H] + ).
[단계 5] 6-클로로-1,3-다이메틸-4-모폴리노-1,3-다이하이드로-2[Step 5] 6-Chloro-1,3-dimethyl-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 4에서 얻어진 4,6-다이클로로-1,3-다이메틸-1,3-다이하이드로-2H-이미다조[4,5-c]피리딘-2-온(1.0 당량)에 모폴린(15.0 당량)을 첨가하고, 140 ℃에서 3 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 물을 첨가하고, 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 흰색 고체의 목적 화합물을 수득하였다(수율: 60 %, MS (ESI): m/z 283 [M+H]+).Morpholine (15.0 equivalents) was added to 4,6-dichloro-1,3-dimethyl-1,3-dihydro-2 H -imidazo[4,5- c ]pyridin-2-one (1.0 equivalents) obtained in Step 4, and the mixture was stirred at 140 °C for 3 hours. After confirming that the target compound was produced using LC-MS, water was added to the reaction mixture, and the organic matter was extracted with dichloromethane. The combined organic layers were concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a white solid (yield: 60%, MS (ESI): m/z 283 [M+H] + ).
[단계 6] [Step 6] terttert -부틸 3-(1,3-다이메틸-4-모폴리노-2-옥소-2,3-다이하이드로-1-Butyl 3-(1,3-dimethyl-4-morpholino-2-oxo-2,3-dihydro-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-1-카복실레이트의 제조]Preparation of pyridine-1-carboxylate
단계 5에서 얻어진 6-클로로-1,3-다이메틸-4-모폴리노-1,3-다이하이드로-2H-이미다조[4,5-c]피리딘-2-온(1.0 당량), 4,4,4',4',5,5,5',5'-옥타메틸-2,2'-비(1,3,2-다이옥사보로란)(5.0 당량)과 탄산 나트륨(6.0 당량)을 물/다이옥세인(1/4 v/v, 0.1 M)에 녹인 후, 질소 하에서 Pd(amphos)Cl2(0.15 당량)을 80 ℃에서 첨가하고, 80 ℃에서 10 분 동안 교반한 후, 제조예 3에서 얻어진 tert-부틸 3-아이오도-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(0.9 당량)를 첨가한 다음, 80 ℃에서 30 분 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 셀라이트를 이용하여 여과하고 농축하였다. 농축된 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 노란색 액체의 목적 화합물을 수득하였다(수율: 100 %, MS (ESI): m/z 587 [M+H]+).In step 5, 6-chloro-1,3-dimethyl-4-morpholino-1,3-dihydro-2 H -imidazo[4,5- c ]pyridin-2-one (1.0 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.0 equiv.) and sodium carbonate (6.0 equiv.) were dissolved in water/dioxane (1/4 v/v, 0.1 M), and then Pd(amphos)Cl 2 (0.15 equiv.) was added at 80 ° C. under nitrogen, and stirred at 80 ° C. for 10 minutes, followed by the addition of tert -butyl 3-iodo-5-(4-methoxypyridin-3-yl)-7-methyl-1 H obtained in Preparation Example 3. - Pyrazolo[3,4- c ]pyridine-1-carboxylate (0.9 equivalents) was added, and the mixture was stirred at 80 °C for 30 minutes. After confirming that the target compound was produced using LC-MS, it was filtered using Celite and concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a yellow liquid (yield: 100%, MS (ESI): m / z 587 [M + H] + ).
[단계 7] 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 7] 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1,3-다이메틸-4-모폴리노-1,3-다이하이드로-2]pyridin-3-yl)-1,3-dimethyl-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 6에서 얻어진 tert-부틸 3-(1,3-다이메틸-4-모폴리노-2-옥소-2,3-다이하이드로-1H-이미다조[4,5-c]피리딘-6-일)-5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-1-카복실레이트(1.0 당량)를 다이클로로메탄(0.1 M)에 녹인 후, 트라이플루오로아세트산(10.0 당량)을 첨가하여 상온에서 15 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축된 혼합물은 prep-HPLC(물(0.1 % 트라이플루오로아세트산):메탄올(0.1 % 트라이플루오로아세트산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(수율: 3 %, MS (ESI): m/z 487 [M+H]+).In step 6, tert -butyl 3-(1,3-dimethyl-4-morpholino-2-oxo-2,3-dihydro-1 H -imidazo[4,5- c ]pyridin-6-yl)-5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridine-1-carboxylate (1.0 equiv.) obtained was dissolved in dichloromethane (0.1 M), and trifluoroacetic acid (10.0 equiv.) was added. The mixture was stirred at room temperature for 15 h. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by prep-HPLC (water (0.1% trifluoroacetic acid): methanol (0.1% trifluoroacetic acid)) to give the target compound as a yellow solid (yield: 3%, MS (ESI): m/z 487 [M+H] + ).
<실시예 97> <Example 97>
실시예 97 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 8에 정리하여 나타내었다.The chemical structure, compound name, NMR, and LC-MS analysis results of Example 97 compound are summarized in Table 8 below.
[표 8][Table 8]
Figure PCTKR2024004758-appb-img-000163
Figure PCTKR2024004758-appb-img-000163
<실시예 98> 4-(6-(5-(4-메톡시피리딘-3-일)-7-메틸-1<Example 98> 4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-2-(2-(((4-메틸피페라진-1-일)옥시)에톡시)-1]pyridin-3-yl)-1-methyl-2-(2-(((4-methylpiperazin-1-yl)oxy)ethoxy)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-일)모폴린 및 <실시예 99> 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1]pyridin-4-yl)morpholine and <Example 99> 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-3-(2-((4-메틸피페라진)-1-일)옥시)에틸)-4-모폴리노-1,3-다이하이드로-2]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin)-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
[반응식 14] [Reaction Formula 14]
Figure PCTKR2024004758-appb-img-000164
Figure PCTKR2024004758-appb-img-000164
[단계 1] 6-클로로-1-메틸-4-모폴리노-1[Step 1] 6-chloro-1-methyl-4-morpholino-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-올의 제조]Production of pyridin-2-ol
4,6-다이클로로-1-메틸-1H-이미다조[4,5-c]피리딘-2-올(1.0 당량)에 모폴린(22.3 당량)을 첨가하고 마이크로웨이브를 이용하여 140 ℃에서 8 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 얼음물을 첨가하고, 에틸아세테이트로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 농축된 혼합물에 에틸아세테이트를 첨가하여 고체를 생성하고 생성된 고체는 여과하였다. 얻어진 갈색 고체는 추가 정제 없이 다음 반응에 사용하였다(수율: 100 %, MS (ESI): m/z 269 [M+H]+).4,6-Dichloro-1-methyl-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) was added to morpholine (22.3 equiv.) and stirred at 140 ℃ using a microwave for 8 h. After confirming that the target compound was produced using LC-MS, ice water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The combined organic layer was concentrated to remove the remaining water using sodium sulfate. Ethyl acetate was added to the concentrated mixture to produce a solid, which was filtered. The obtained brown solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 269 [M + H] + ).
[단계 2] 1-메틸-4-모폴리노-6-(트리부틸스탄닐)-1[Step 2] 1-Methyl-4-morpholino-6-(tributylstannyl)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-올의 제조]Production of pyridin-2-ol
단계 1에서 얻어진 6-클로로-1-메틸-4-모폴리노-1H-이미다조[4,5-c]피리딘-2-올(1.0 당량)을 1,4-다이옥세인(0.08 M)에 녹인 후, 비스(트라이부틸틴)(1.8 당량), 염화리튬(6.0 당량), PCy3(0.2 당량), Pd2(dba)3(0.1 당량)을 넣고, 질소로 탈기 후, 질소 하에서 110 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축한 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제한 후, 에틸아세테이트를 첨가하여 고체를 생성하고 여과하여 노란색 고체의 목적 화합물을 수득하였다(수율: 90 %, MS (ESI): m/z 525 [M+H]+).In Step 1, 6-chloro-1-methyl-4-morpholino-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained was dissolved in 1,4-dioxane (0.08 M), and bis(tributyltin) (1.8 equiv.), lithium chloride (6.0 equiv.), PCy 3 (0.2 equiv.), and Pd 2 (dba) 3 (0.1 equiv.) were added. After degassing with nitrogen, the mixture was stirred at 110 °C for 16 h under nitrogen. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by MPLC (dichloromethane:methanol), and ethyl acetate was added to generate a solid, which was then filtered to obtain the target compound as a yellow solid (yield: 90%, MS (ESI): m/z 525 [M+H] + ).
[단계 3] 6-(5-브로모-7-메틸-1-(테트라하이드로-2[Step 3] 6-(5-bromo-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-4-모폴리노-1]pyridin-3-yl)-1-methyl-4-morpholino-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-올의 제조]Production of pyridin-2-ol
단계 2에서 얻어진 1-메틸-4-모폴리노-6-(트리부틸스탄닐)-1H-이미다조[4,5-c]피리딘-2-올(1.0 당량)을 1,4-다이옥세인(0.04 M)에 녹인 후, 제조예 5 화합물 5-브로모-3-요오도-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘(1.0 당량), 아이오딘화 구리(0.1 당량), Pd(PPh3)4(0.15 당량)을 첨가하고 질소로 탈기 후, 질소하에서 16 시간 동안 110 ℃에서 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 생성된 고체를 여과하였다. 얻어진 노란색 고체의 목적 화합물은 추가 정제 없이 다음 반응에 사용하였다(수율: 58 %, MS (ESI): m/z 528 [M+H]+).In Step 2, 1-methyl-4-morpholino-6-(tributylstannyl)-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained was dissolved in 1,4-dioxane (0.04 M). Then, compound 5 of Preparation Example 5, 5-bromo-3-iodo-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridine (1.0 equiv.), copper iodide (0.1 equiv.), and Pd(PPh 3 ) 4 (0.15 equiv.) were added. After degassing with nitrogen, the mixture was stirred at 110 °C for 16 h under nitrogen. After confirming the production of the target compound using LC-MS, the produced solid was filtered. The target compound as a yellow solid obtained was used in the next reaction without further purification (yield: 58%, MS (ESI): m/z 528 [M+H] + ).
[단계 4] 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2[Step 4] 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-4-모르폴리노-1]pyridin-3-yl)-1-methyl-4-morpholino-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-올의 제조]Production of pyridin-2-ol
단계 3에서 얻어진 6-(5-브로모-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-4-모폴리노-1H-이미다조[4,5-c]피리딘-2-올(1.0 당량)을 물/DMSO(1/7 v/v, 0.017 M)에 녹인 후, (4-메톡시피리딘-3-일)보론산(1.5 당량), Pd(dppf)Cl2(0.1 당량), 탄산칼륨(2.5 당량)을 첨가하고, 질소로 탈기 후, 질소 하에서 90 ℃에서 16 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물에 얼음물을 첨가하고, 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 68 %, MS (ESI): m/z 557 [M+H]+).6-(5-Bromo-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-4-morpholino-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained in Step 3 was dissolved in water/DMSO (1/7 v/v, 0.017 M). Then, (4-methoxypyridin-3-yl)boronic acid (1.5 equiv.), Pd(dppf)Cl 2 (0.1 equiv.), and potassium carbonate (2.5 equiv.) were added, and after degassing with nitrogen, the mixture was stirred at 90 ℃ under nitrogen for 16 h. After confirming the production of the target compound using LC-MS, ice-cold water was added to the reaction mixture, and the organic matter was extracted with dichloromethane. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 68%, MS (ESI): m/z 557 [M+H] + ).
[단계 5] 4-(6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2[Step 5] 4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-2-(2-((4-메틸피페라진-1-일)옥시)에톡시)-1]pyridin-3-yl)-1-methyl-2-(2-((4-methylpiperazin-1-yl)oxy)ethoxy)-1 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-4-일)모폴린 및 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2]pyridin-4-yl)morpholine and 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 HH -피란-2-일)-1-Evacuation-2-days)-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-3-(2-((4-메틸피페라진-1-일)옥시)에틸)-4-모폴리노-1,3-다이하이드로-2]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 4에서 얻어진 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-4-모르폴리노-1H-이미다조[4,5-c]피리딘-2-올(1.0 당량)을 테트라하이드로퓨란(0.017 M)에 녹인 후, 제조예 2 화합물 2-((4-메틸피페라진-1-일)옥시)에탄-1-올(1.0 당량), DIAD(6.0 당량), PPh3(6.0 당량)을 0 ℃에서 첨가하고, 상온에서 4 시간 동안 질소 하에서 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 0 ℃에서 반응 혼합물에 포화 탄산수소나트륨 수용액을 첨가하고, 다이클로로메탄으로 유기물을 추출하였다. 모아진 유기층은 황산나트륨을 이용해 남은 물을 제거하고 농축하였다. 반응 혼합물은 MPLC(다이클로로메탄:메탄올)로 정제하여 갈색 고체의 목적 화합물을 수득하였다(수율: 64 %, MS (ESI): m/z 699 [M+H]+).6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-4-morpholino-1 H -imidazo[4,5- c ]pyridin-2-ol (1.0 equiv.) obtained in Step 4 was dissolved in tetrahydrofuran (0.017 M), and then Compound 2 of Preparation Example 2, 2-((4-methylpiperazin-1-yl)oxy)ethan-1-ol (1.0 equiv.), DIAD (6.0 equiv.), and PPh 3 (6.0 equiv.) were added at 0 °C, and the mixture was stirred at room temperature for 4 h under nitrogen. After confirming that the target compound was produced using LC-MS, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0 °C, and the organic matter was extracted with dichloromethane. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the target compound as a brown solid (yield: 64%, MS (ESI): m/z 699 [M+H] + ).
[단계 6] 4-(6-(5-(4-메톡시피리딘-3-일)-7-메틸-1[Step 6] 4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4--Pyrazolo[3,4- cc ]피리딘-3-일)-1-메틸-2-(2-(((4-메틸피페라진-1-일)옥시)에톡시)-1]pyridin-3-yl)-1-methyl-2-(2-(((4-methylpiperazin-1-yl)oxy)ethoxy)-1 HH -이미다조[4,5-c]피리딘-4-일)모폴린 및 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-Imidazo[4,5-c]pyridin-4-yl)morpholine and 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 HH -피라졸로[3,4-c]피리딘-3-일)-1-메틸-3-(2-((4-메틸피페라진)-1-일)옥시)에틸)-4-모폴리노-1,3-다이하이드로-2-Pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin)-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 HH -이미다조[4,5--Imidazo[4,5- cc ]피리딘-2-온의 제조]Preparation of pyridin-2-one
단계 5에서 얻어진 4-(6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-2-(2-((4-메틸피페라진-1-일)옥시)에톡시)-1H-이미다조[4,5-c]피리딘-4-일)모폴린 및 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-3-(2-((4-메틸피페라진-1-일)옥시)에틸)-4-모폴리노-1,3-다이하이드로-2H-이미다조[4,5-c]피리딘-2-온 혼합물(1.0 당량) 혼합물을 메탄올에 녹여진 2 M 염산(86.0 당량)에 녹인 후, 50 ℃에서 2 시간 동안 교반하였다. LC-MS를 이용하여 목적 화합물이 생성된 것을 확인한 후, 반응 혼합물을 농축하였다. 농축된 혼합물은 prep-HPLC(물(1 % 포름산):메탄올(1 % 포름산))로 정제하여 노란색 고체의 목적 화합물을 수득하였다(4-(6-(5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-2-(2-(((4-메틸피페라진-1-일)옥시)에톡시)-1H-이미다조[4,5-c]피리딘-4-일)모폴린: 수율: 7 %, MS (ESI): m/z 615 [M+H]+, 6-(5-(4-메톡시피리딘-3-일)-7-메틸-1H-피라졸로[3,4-c]피리딘-3-일)-1-메틸-3-(2-((4-메틸피페라진)-1-일)옥시)에틸)-4-모폴리노-1,3-다이하이드로-2H-이미다조[4,5-c]피리딘-2-온: 수율: 40 %, MS (ESI): m/z 615 [M+H]+).4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-2-(2-((4-methylpiperazin-1-yl)oxy)ethoxy)-1 H -imidazo[4,5- c ]pyridin-4-yl)morpholine obtained in step 5 and 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1-(tetrahydro-2 H -pyran-2-yl)-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro-2 H -Imidazo[4,5- c ]pyridin-2-one mixture (1.0 equiv) was dissolved in 2 M hydrochloric acid (86.0 equiv) dissolved in methanol and stirred at 50 °C for 2 h. After confirming the production of the target compound using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified by prep-HPLC (water (1% formic acid): methanol (1% formic acid)) to give the target compound as a yellow solid (4-(6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -pyrazolo[3,4- c ]pyridin-3-yl)-1-methyl-2-(2-(((4-methylpiperazin-1-yl)oxy)ethoxy)-1 H -imidazo[4,5-c]pyridin-4-yl)morpholine: Yield: 7 %, MS (ESI): m/z 615 [M+H] + , 6-(5-(4-methoxypyridin-3-yl)-7-methyl-1 H -Pyrazolo[3,4-c]pyridin-3-yl)-1-methyl-3-(2-((4-methylpiperazin)-1-yl)oxy)ethyl)-4-morpholino-1,3-dihydro- 2H -imidazo[4,5- c ]pyridin-2-one: Yield: 40 %, MS (ESI): m/z 615 [M+H] + ).
<실시예 98> 내지 <실시예 100><Example 98> to <Example 100>
상기 실시예 98, 99와 유사한 방법으로 실시예 100 화합물을 제조하였다.Compound Example 100 was prepared in a similar manner to Examples 98 and 99 above.
실시예 98 내지 100 화합물의 화학구조식, 화합물명, NMR, 및 LC-MS 분석 결과를 하기 표 9에 정리하여 나타내었다.The chemical structures, compound names, NMR, and LC-MS analysis results of compounds of Examples 98 to 100 are summarized in Table 9 below.
[표 9][Table 9]
Figure PCTKR2024004758-appb-img-000165
Figure PCTKR2024004758-appb-img-000165
<실험예 1> Ba/F3 세포 및 PC9 암세포에서 EGFR에 대한 억제활성 평가<Experimental Example 1> Evaluation of inhibitory activity against EGFR in Ba/F3 cells and PC9 cancer cells
본 발명에 따른 화합물의 EGFR 돌연변이의 증식 억제 활성을 평가하기 위해, EGFR L858R/T790M/C797S(EGFR LTC), Del19/T790M/C797S(EGFR DTC) 돌연변이를 발현하는 Ba/F3 세포 및 EGFR Del19/T790M/C797S(EGFR DTC) 돌연변이를 발현하는 PC9 세포에서 하기와 같은 실험을 수행하였다.To evaluate the proliferation inhibitory activity of the compound according to the present invention on EGFR mutants, the following experiments were performed in Ba/F3 cells expressing EGFR L858R/T790M/C797S (EGFR LTC), Del19/T790M/C797S (EGFR DTC) mutants and PC9 cells expressing EGFR Del19/T790M/C797S (EGFR DTC) mutants.
각 세포는 10 % 소태아혈청(FBS)을 넣은 배지(RPMI-1640)를 사용하여 배양하였으며, 화합물을 처리하기 24 시간 전에 3000 개 세포를 웰 플레이트(white clear bottom 96 well plate, Corning)에 분주하였다. 화합물은 최종농도가 0.2 nM - 5 μM이 되도록 다이메틸설폭사이드에 희석(3 배씩 희석, 총 12 개 농도)시킨 후, 1 μl씩 주입하였다. 살아있는 세포에 화합물을 처리한 후 72 시간 동안 37 ℃, CO2 배양기에서 반응시키고, 시약(Cell Titer-Glo luminescent cell-viability reagent, Promega)을 사용하여 상온에서 10 분 보관한 후에, 판독기(SynergyNeo2, Biotek)를 이용하여 발광강도를 측정하였다. 결과값을 대조군과 비교하여 세포성장비율(%)을 산출하고, 소프트웨어(GraphPad Prism 8.4.3, GraphPad software Inc., San Diego)를 이용하여 GI50 값을 계산하였다. 그 결과는 하기 표 10에 정리하였다.Each cell was cultured using a medium (RPMI-1640) containing 10% fetal bovine serum (FBS), and 3,000 cells were seeded in a well plate (white clear bottom 96 well plate, Corning) 24 hours before treatment with compounds. The compounds were diluted in dimethyl sulfoxide to a final concentration of 0.2 nM to 5 μM (3-fold dilution, total of 12 concentrations) and injected 1 μl each. After treating the living cells with the compounds, the cells were reacted in a CO2 incubator at 37 °C for 72 hours, and the luminescence intensity was measured using a reagent (Cell Titer-Glo luminescent cell-viability reagent, Promega) after storing at room temperature for 10 minutes. Then, the luminescence intensity was measured using a reader (SynergyNeo2, Biotek). The cell growth rate (%) was calculated by comparing the result values with the control group, and the GI 50 value was calculated using software (GraphPad Prism 8.4.3, GraphPad software Inc., San Diego). The results are summarized in Table 10 below.
[표 10][Table 10]
Figure PCTKR2024004758-appb-img-000166
Figure PCTKR2024004758-appb-img-000166
Figure PCTKR2024004758-appb-img-000167
Figure PCTKR2024004758-appb-img-000167
Figure PCTKR2024004758-appb-img-000168
Figure PCTKR2024004758-appb-img-000168
(A: GI50 ≤ 100 nM; B: 100 nM < GI50 ≤ 500 nM; C: 500 nM < GI50)(A: GI 50 ≤ 100 nM; B: 100 nM < GI 50 ≤ 500 nM; C: 500 nM < GI 50 )
상기 표 10에서 나타난 바와 같이, 본 발명의 실시예 화합물들은 EGFR 돌연변이에 대하여 높은 억제 활성을 나타냄을 알 수 있다. As shown in Table 10 above, it can be seen that the exemplary compounds of the present invention exhibit high inhibitory activity against EGFR mutations.
이상, 본 발명을 바람직한 제조예, 실시예, 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특정 실시예 화합물에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.Above, the present invention has been described in detail through preferred manufacturing examples, examples, and experimental examples, but the scope of the present invention is not limited to specific example compounds, and should be interpreted by the appended claims. In addition, those who have acquired common knowledge in this technical field should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (16)

  1. 하기 화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염:A compound represented by the following chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2024004758-appb-img-000169
    Figure PCTKR2024004758-appb-img-000169
    상기 화학식 1에서,In the above chemical formula 1,
    Figure PCTKR2024004758-appb-img-000170
    는 단일 결합 또는 이중 결합이고;
    Figure PCTKR2024004758-appb-img-000170
    is a single bond or a double bond;
    X1은 NR1 또는 S이고;X 1 is NR 1 or S;
    X2는 N 또는 NR2이고;X 2 is N or NR 2 ;
    X3는 CR3 또는 C(=O)이고;X 3 is CR 3 or C(=O);
    R1 및 R2는 각각 독립적으로 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
    R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
    L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
    L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
    W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
    RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
    W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
    RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -C1-6할로알킬, 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo};
    RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
    V는 -NH-, -O-, 또는 아무것도 아니고(null);V is -NH-, -O-, or nothing (null);
    고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
    RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  2. 제 1 항에 있어서,In paragraph 1,
    상기
    Figure PCTKR2024004758-appb-img-000171
    는     Above
    Figure PCTKR2024004758-appb-img-000171
    Is
    Figure PCTKR2024004758-appb-img-000172
    ,
    Figure PCTKR2024004758-appb-img-000173
    , 또는
    Figure PCTKR2024004758-appb-img-000174
    인,
    Figure PCTKR2024004758-appb-img-000172
    ,
    Figure PCTKR2024004758-appb-img-000173
    , or
    Figure PCTKR2024004758-appb-img-000174
    person,
    화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염.A compound represented by chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서, In paragraph 1,
    상기 고리 Z는 The above ring Z is
    Figure PCTKR2024004758-appb-img-000175
    ,
    Figure PCTKR2024004758-appb-img-000176
    ,
    Figure PCTKR2024004758-appb-img-000177
    ,
    Figure PCTKR2024004758-appb-img-000178
    ,
    Figure PCTKR2024004758-appb-img-000179
    ,
    Figure PCTKR2024004758-appb-img-000180
    ,
    Figure PCTKR2024004758-appb-img-000181
    ,
    Figure PCTKR2024004758-appb-img-000182
    ,
    Figure PCTKR2024004758-appb-img-000183
    ,
    Figure PCTKR2024004758-appb-img-000184
    ,
    Figure PCTKR2024004758-appb-img-000185
    ,
    Figure PCTKR2024004758-appb-img-000186
    ,
    Figure PCTKR2024004758-appb-img-000187
    ,
    Figure PCTKR2024004758-appb-img-000188
    ,
    Figure PCTKR2024004758-appb-img-000189
    ,
    Figure PCTKR2024004758-appb-img-000190
    ,
    Figure PCTKR2024004758-appb-img-000191
    ,
    Figure PCTKR2024004758-appb-img-000192
    ,
    Figure PCTKR2024004758-appb-img-000193
    ,
    Figure PCTKR2024004758-appb-img-000194
    ,
    Figure PCTKR2024004758-appb-img-000195
    ,
    Figure PCTKR2024004758-appb-img-000196
    ,
    Figure PCTKR2024004758-appb-img-000197
    ,
    Figure PCTKR2024004758-appb-img-000198
    ,
    Figure PCTKR2024004758-appb-img-000199
    ,
    Figure PCTKR2024004758-appb-img-000200
    ,
    Figure PCTKR2024004758-appb-img-000201
    ,
    Figure PCTKR2024004758-appb-img-000202
    , 또는
    Figure PCTKR2024004758-appb-img-000203
    인 {여기서, 상기 고리 Z의 하나 이상의 H는 각각 독립적으로 RZ1 및 RZ2로 치환될 수 있음};
    Figure PCTKR2024004758-appb-img-000175
    ,
    Figure PCTKR2024004758-appb-img-000176
    ,
    Figure PCTKR2024004758-appb-img-000177
    ,
    Figure PCTKR2024004758-appb-img-000178
    ,
    Figure PCTKR2024004758-appb-img-000179
    ,
    Figure PCTKR2024004758-appb-img-000180
    ,
    Figure PCTKR2024004758-appb-img-000181
    ,
    Figure PCTKR2024004758-appb-img-000182
    ,
    Figure PCTKR2024004758-appb-img-000183
    ,
    Figure PCTKR2024004758-appb-img-000184
    ,
    Figure PCTKR2024004758-appb-img-000185
    ,
    Figure PCTKR2024004758-appb-img-000186
    ,
    Figure PCTKR2024004758-appb-img-000187
    ,
    Figure PCTKR2024004758-appb-img-000188
    ,
    Figure PCTKR2024004758-appb-img-000189
    ,
    Figure PCTKR2024004758-appb-img-000190
    ,
    Figure PCTKR2024004758-appb-img-000191
    ,
    Figure PCTKR2024004758-appb-img-000192
    ,
    Figure PCTKR2024004758-appb-img-000193
    ,
    Figure PCTKR2024004758-appb-img-000194
    ,
    Figure PCTKR2024004758-appb-img-000195
    ,
    Figure PCTKR2024004758-appb-img-000196
    ,
    Figure PCTKR2024004758-appb-img-000197
    ,
    Figure PCTKR2024004758-appb-img-000198
    ,
    Figure PCTKR2024004758-appb-img-000199
    ,
    Figure PCTKR2024004758-appb-img-000200
    ,
    Figure PCTKR2024004758-appb-img-000201
    ,
    Figure PCTKR2024004758-appb-img-000202
    , or
    Figure PCTKR2024004758-appb-img-000203
    {wherein, one or more H of the ring Z may be independently substituted with R Z1 and R Z2 };
    화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염.A compound represented by chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 1 항에 있어서, In paragraph 1,
    상기 고리 W1은 The above ring W 1 is
    Figure PCTKR2024004758-appb-img-000204
    ,
    Figure PCTKR2024004758-appb-img-000205
    ,
    Figure PCTKR2024004758-appb-img-000206
    ,
    Figure PCTKR2024004758-appb-img-000207
    ,
    Figure PCTKR2024004758-appb-img-000208
    ,
    Figure PCTKR2024004758-appb-img-000209
    ,
    Figure PCTKR2024004758-appb-img-000210
    ,
    Figure PCTKR2024004758-appb-img-000211
    ,
    Figure PCTKR2024004758-appb-img-000212
    ,
    Figure PCTKR2024004758-appb-img-000213
    ,
    Figure PCTKR2024004758-appb-img-000214
    ,
    Figure PCTKR2024004758-appb-img-000215
    ,
    Figure PCTKR2024004758-appb-img-000216
    ,
    Figure PCTKR2024004758-appb-img-000217
    ,
    Figure PCTKR2024004758-appb-img-000218
    ,
    Figure PCTKR2024004758-appb-img-000219
    ,
    Figure PCTKR2024004758-appb-img-000220
    ,
    Figure PCTKR2024004758-appb-img-000221
    ,
    Figure PCTKR2024004758-appb-img-000222
    ,
    Figure PCTKR2024004758-appb-img-000223
    ,
    Figure PCTKR2024004758-appb-img-000224
    ,
    Figure PCTKR2024004758-appb-img-000225
    ,
    Figure PCTKR2024004758-appb-img-000226
    ,
    Figure PCTKR2024004758-appb-img-000227
    ,
    Figure PCTKR2024004758-appb-img-000228
    ,
    Figure PCTKR2024004758-appb-img-000229
    ,
    Figure PCTKR2024004758-appb-img-000230
    ,
    Figure PCTKR2024004758-appb-img-000231
    ,
    Figure PCTKR2024004758-appb-img-000232
    ,
    Figure PCTKR2024004758-appb-img-000233
    ,
    Figure PCTKR2024004758-appb-img-000234
    ,
    Figure PCTKR2024004758-appb-img-000235
    ,
    Figure PCTKR2024004758-appb-img-000236
    ,
    Figure PCTKR2024004758-appb-img-000237
    ,
    Figure PCTKR2024004758-appb-img-000238
    ,
    Figure PCTKR2024004758-appb-img-000239
    ,
    Figure PCTKR2024004758-appb-img-000240
    ,
    Figure PCTKR2024004758-appb-img-000241
    ,
    Figure PCTKR2024004758-appb-img-000242
    ,
    Figure PCTKR2024004758-appb-img-000243
    ,
    Figure PCTKR2024004758-appb-img-000244
    ,
    Figure PCTKR2024004758-appb-img-000245
    ,
    Figure PCTKR2024004758-appb-img-000246
    ,
    Figure PCTKR2024004758-appb-img-000247
    ,
    Figure PCTKR2024004758-appb-img-000248
    ,
    Figure PCTKR2024004758-appb-img-000249
    ,
    Figure PCTKR2024004758-appb-img-000250
    ,
    Figure PCTKR2024004758-appb-img-000251
    ,
    Figure PCTKR2024004758-appb-img-000252
    ,
    Figure PCTKR2024004758-appb-img-000253
    ,
    Figure PCTKR2024004758-appb-img-000254
    ,
    Figure PCTKR2024004758-appb-img-000255
    ,
    Figure PCTKR2024004758-appb-img-000256
    ,
    Figure PCTKR2024004758-appb-img-000257
    ,
    Figure PCTKR2024004758-appb-img-000258
    ,
    Figure PCTKR2024004758-appb-img-000259
    ,
    Figure PCTKR2024004758-appb-img-000260
    ,
    Figure PCTKR2024004758-appb-img-000261
    ,
    Figure PCTKR2024004758-appb-img-000262
    ,
    Figure PCTKR2024004758-appb-img-000263
    ,
    Figure PCTKR2024004758-appb-img-000264
    ,
    Figure PCTKR2024004758-appb-img-000265
    ,
    Figure PCTKR2024004758-appb-img-000266
    ,
    Figure PCTKR2024004758-appb-img-000267
    ,
    Figure PCTKR2024004758-appb-img-000268
    ,
    Figure PCTKR2024004758-appb-img-000269
    , 또는
    Figure PCTKR2024004758-appb-img-000270
    인 {여기서, 상기 고리 W1의 하나 이상의 H는 각각 독립적으로 RW로 치환될 수 있고; 상기 고리 W1의 -CH2-는 -C(=O)-로 치환될 수 있음};
    Figure PCTKR2024004758-appb-img-000204
    ,
    Figure PCTKR2024004758-appb-img-000205
    ,
    Figure PCTKR2024004758-appb-img-000206
    ,
    Figure PCTKR2024004758-appb-img-000207
    ,
    Figure PCTKR2024004758-appb-img-000208
    ,
    Figure PCTKR2024004758-appb-img-000209
    ,
    Figure PCTKR2024004758-appb-img-000210
    ,
    Figure PCTKR2024004758-appb-img-000211
    ,
    Figure PCTKR2024004758-appb-img-000212
    ,
    Figure PCTKR2024004758-appb-img-000213
    ,
    Figure PCTKR2024004758-appb-img-000214
    ,
    Figure PCTKR2024004758-appb-img-000215
    ,
    Figure PCTKR2024004758-appb-img-000216
    ,
    Figure PCTKR2024004758-appb-img-000217
    ,
    Figure PCTKR2024004758-appb-img-000218
    ,
    Figure PCTKR2024004758-appb-img-000219
    ,
    Figure PCTKR2024004758-appb-img-000220
    ,
    Figure PCTKR2024004758-appb-img-000221
    ,
    Figure PCTKR2024004758-appb-img-000222
    ,
    Figure PCTKR2024004758-appb-img-000223
    ,
    Figure PCTKR2024004758-appb-img-000224
    ,
    Figure PCTKR2024004758-appb-img-000225
    ,
    Figure PCTKR2024004758-appb-img-000226
    ,
    Figure PCTKR2024004758-appb-img-000227
    ,
    Figure PCTKR2024004758-appb-img-000228
    ,
    Figure PCTKR2024004758-appb-img-000229
    ,
    Figure PCTKR2024004758-appb-img-000230
    ,
    Figure PCTKR2024004758-appb-img-000231
    ,
    Figure PCTKR2024004758-appb-img-000232
    ,
    Figure PCTKR2024004758-appb-img-000233
    ,
    Figure PCTKR2024004758-appb-img-000234
    ,
    Figure PCTKR2024004758-appb-img-000235
    ,
    Figure PCTKR2024004758-appb-img-000236
    ,
    Figure PCTKR2024004758-appb-img-000237
    ,
    Figure PCTKR2024004758-appb-img-000238
    ,
    Figure PCTKR2024004758-appb-img-000239
    ,
    Figure PCTKR2024004758-appb-img-000240
    ,
    Figure PCTKR2024004758-appb-img-000241
    ,
    Figure PCTKR2024004758-appb-img-000242
    ,
    Figure PCTKR2024004758-appb-img-000243
    ,
    Figure PCTKR2024004758-appb-img-000244
    ,
    Figure PCTKR2024004758-appb-img-000245
    ,
    Figure PCTKR2024004758-appb-img-000246
    ,
    Figure PCTKR2024004758-appb-img-000247
    ,
    Figure PCTKR2024004758-appb-img-000248
    ,
    Figure PCTKR2024004758-appb-img-000249
    ,
    Figure PCTKR2024004758-appb-img-000250
    ,
    Figure PCTKR2024004758-appb-img-000251
    ,
    Figure PCTKR2024004758-appb-img-000252
    ,
    Figure PCTKR2024004758-appb-img-000253
    ,
    Figure PCTKR2024004758-appb-img-000254
    ,
    Figure PCTKR2024004758-appb-img-000255
    ,
    Figure PCTKR2024004758-appb-img-000256
    ,
    Figure PCTKR2024004758-appb-img-000257
    ,
    Figure PCTKR2024004758-appb-img-000258
    ,
    Figure PCTKR2024004758-appb-img-000259
    ,
    Figure PCTKR2024004758-appb-img-000260
    ,
    Figure PCTKR2024004758-appb-img-000261
    ,
    Figure PCTKR2024004758-appb-img-000262
    ,
    Figure PCTKR2024004758-appb-img-000263
    ,
    Figure PCTKR2024004758-appb-img-000264
    ,
    Figure PCTKR2024004758-appb-img-000265
    ,
    Figure PCTKR2024004758-appb-img-000266
    ,
    Figure PCTKR2024004758-appb-img-000267
    ,
    Figure PCTKR2024004758-appb-img-000268
    ,
    Figure PCTKR2024004758-appb-img-000269
    , or
    Figure PCTKR2024004758-appb-img-000270
    {wherein, one or more H of the ring W 1 may be independently substituted with R W ; and -CH 2 - of the ring W 1 may be substituted with -C(=O)-};
    화학식 1로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염.A compound represented by chemical formula 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 하기 화학식 2로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염:A compound represented by the following chemical formula 2, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 2][Chemical formula 2]
    Figure PCTKR2024004758-appb-img-000271
    Figure PCTKR2024004758-appb-img-000271
    상기 화학식 2에서,In the above chemical formula 2,
    R1은 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 is -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
    R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
    L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
    L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
    W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
    RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
    W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
    RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
    RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
    V는 -NH- 또는 아무것도 아니고(null);V is -NH- or nothing (null);
    고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
    RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  6. 하기 화학식 3로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염:A compound represented by the following chemical formula 3, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 3][Chemical Formula 3]
    Figure PCTKR2024004758-appb-img-000272
    Figure PCTKR2024004758-appb-img-000272
    상기 화학식 3에서,In the above chemical formula 3,
    R3는 -O-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), 또는 -L1-L2-W1이고;R 3 is -OC 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), or -L 1 -L 2 -W 1 ;
    L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
    L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
    W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
    RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
    W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
    RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
    RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, 또는 -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo;
    고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
    RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  7. 하기 화학식 4로 표시되는 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염:A compound represented by the following chemical formula 4, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 4][Chemical Formula 4]
    Figure PCTKR2024004758-appb-img-000273
    Figure PCTKR2024004758-appb-img-000273
    상기 화학식 4에서,In the above chemical formula 4,
    R1 및 R2는 각각 독립적으로 -H, -C1-6알킬, 또는 -L1-L2-W1이고;R 1 and R 2 are each independently -H, -C 1-6 alkyl, or -L 1 -L 2 -W 1 ;
    L1은 -NH-, -O-, 또는 아무것도 아니고(null);L 1 is -NH-, -O-, or nothing (null);
    L2는 -(CH2)m-, -(CH2)m-O-, 또는 아무것도 아니고(null) {여기서, 상기 m은 1 내지 6의 정수임};L 2 is -(CH 2 )m-, -(CH 2 )mO-, or null {wherein m is an integer from 1 to 6};
    W1은 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐이고 {여기서, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로바이사이클로알킬), -(5-6원 헤테로아릴), -(5-12원 헤테로하이드로아릴), 또는 페닐 고리의 하나 이상의 H는 Rw로 치환될 수 있고, 상기 -(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 -CH2-는 -C(=O)-로 치환될 수 있음};W 1 is -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl {wherein, one or more H of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), -(5-12 membered heterobicycloalkyl), -(5-6 membered heteroaryl), -(5-12 membered heterohydroaryl), or phenyl ring may be replaced with Rw, and -CH 2 - of the -(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be replaced with -C(=O)-};
    RW는 -C1-6알킬, -C1-6할로알킬, -할로, -C1-6알킬-O-C1-6알킬, -C1-6알킬-N(C1-6알킬)(C1-6알킬), -(CH2)n-C(=O)-C1-6알킬, -(CH2)n-S(=O)2-C1-6알킬, 또는 -(CH2)n-W2이고 {여기서, 상기 n은 0 내지 6의 정수임};R W is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, -C 1-6 alkyl-OC 1-6 alkyl, -C 1-6 alkyl-N(C 1-6 alkyl)(C 1-6 alkyl), -(CH 2 )nC(=O)-C 1-6 alkyl, -(CH 2 )nS(=O) 2 -C 1-6 alkyl, or -(CH 2 )nW 2 {wherein, n is an integer from 0 to 6};
    W2는 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬)이고 {여기서, 상기 -(3-7원 사이클로알킬) 또는 -(3-7원 헤테로사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬, -할로, 또는 -(3-7원 사이클로알킬)로 치환될 수 있음};W 2 is -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) {wherein, one or more H of the -(3-7 membered cycloalkyl) or -(3-7 membered heterocycloalkyl) ring may be substituted with -C 1-6 alkyl, -halo, or -(3-7 membered cycloalkyl)};
    RX는 -C1-6알킬, -S-C1-6알킬, -NH-C1-6알킬, -N(C1-6알킬)(C1-6알킬), -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬)이고 {여기서, 상기 -NH-(3-7원 사이클로알킬), -(3-7원 헤테로사이클로알킬), 또는 -(5-12원 헤테로바이사이클로알킬) 고리의 하나 이상의 H는 -C1-6알킬 또는 -할로로 치환될 수 있음};R X is -C 1-6 alkyl, -S- C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) {wherein at least one H of the -NH-(3-7 membered cycloalkyl), -(3-7 membered heterocycloalkyl), or -(5-12 membered heterobicycloalkyl) ring may be substituted with -C 1-6 alkyl or -halo};
    RY1 및 RY2는 각각 독립적으로 -H, -C1-6알킬, -C1-6할로알킬, -할로이고;R Y1 and R Y2 are each independently -H, -C 1-6 alkyl, -C 1-6 haloalkyl, -halo;
    고리 Z는 -(3-7원 헤테로사이클로알킬), -(5-12원 헤테로아릴), 또는 페닐이고;Ring Z is -(3-7 membered heterocycloalkyl), -(5-12 membered heteroaryl), or phenyl;
    RZ1 및 RZ2는 각각 독립적으로 -H, -C1-6알킬, -CN, -OH, -O-C1-6알킬, 또는 -할로이다.R Z1 and R Z2 are each independently -H, -C 1-6 alkyl, -CN, -OH, -OC 1-6 alkyl, or -halo.
  8. 하기 화합물로 이루어진 군으로부터 선택된 것인 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염:A compound selected from the group consisting of the following compounds, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTKR2024004758-appb-img-000274
    Figure PCTKR2024004758-appb-img-000274
    Figure PCTKR2024004758-appb-img-000275
    Figure PCTKR2024004758-appb-img-000275
    Figure PCTKR2024004758-appb-img-000276
    Figure PCTKR2024004758-appb-img-000276
    Figure PCTKR2024004758-appb-img-000277
    Figure PCTKR2024004758-appb-img-000277
    Figure PCTKR2024004758-appb-img-000278
    Figure PCTKR2024004758-appb-img-000278
    Figure PCTKR2024004758-appb-img-000279
    .
    Figure PCTKR2024004758-appb-img-000279
    .
  9. 제 1 항 내지 제 8 항 중 어느 한 항에 따른 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염, 및 약학적으로 허용가능한 첨가제를 포함하는, 약학적 조성물.A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  10. 제 1 항 내지 제 8 항 중 어느 한 항에 따른 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, containing a compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  11. 제 10 항에 있어서,In Article 10,
    EGFR를 억제하는 것인, 약학적 조성물.A pharmaceutical composition which inhibits EGFR.
  12. 제 11 항에 있어서,In Article 11,
    EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, 및 EGFR L858R/T790M/C797S로 이루어진 군으로부터 선택된 어느 하나 이상을 억제하는 것인, 약학적 조성물.A pharmaceutical composition that inhibits at least one selected from the group consisting of EGFR Del19, EGFR Del19/T790M, EGFR Del19/C797S, EGFR Del19/T790M/C797S, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, and EGFR L858R/T790M/C797S.
  13. 제 10 항에 있어서,In Article 10,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 흑색종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 편평세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물.The above cancers are pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, A pharmaceutical composition comprising at least one selected from the group consisting of duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, melanoma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, pulmonary adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. Composition.
  14. EGFR 관련 질환의 치료 또는 예방에 사용하기 위한 약제의 제조에 사용하기 위한, 제 1 항 내지 제 8 항 중 어느 한 항에 따른 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도.Use of a compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of an EGFR-related disease.
  15. 제 1 항 내지 제 8 항 중 어느 한 항에 따른 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, EGFR 관련 질환을 치료 또는 예방하는 방법.A method for treating or preventing an EGFR-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 8, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  16. 제 1 항 내지 제 8 항 중 어느 한 항에 따른 화합물, 이의 호변 이성질체, 이들의 입체 이성질체, 또는 이들의 약학적으로 허용가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상에게 투여하는 것을 포함하는, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 흑색종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 편평세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상의 질환을 치료 또는 예방하는 방법.A method for treating pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, Non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small bowel cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, melanoma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, A method for treating or preventing at least one disease selected from the group consisting of lung cancer, squamous cell carcinoma of the lung, squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.
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