WO2022107919A1 - N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient - Google Patents

N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient Download PDF

Info

Publication number
WO2022107919A1
WO2022107919A1 PCT/KR2020/016377 KR2020016377W WO2022107919A1 WO 2022107919 A1 WO2022107919 A1 WO 2022107919A1 KR 2020016377 W KR2020016377 W KR 2020016377W WO 2022107919 A1 WO2022107919 A1 WO 2022107919A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
pyridin
pyrazol
cyclopropyl
heptan
Prior art date
Application number
PCT/KR2020/016377
Other languages
French (fr)
Korean (ko)
Inventor
조서현
김현경
김승수
최현진
마다훈
류희선
손정범
김성환
김남두
Original Assignee
주식회사 보로노이
주식회사 보로노이바이오
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 보로노이, 주식회사 보로노이바이오 filed Critical 주식회사 보로노이
Priority to PCT/KR2020/016377 priority Critical patent/WO2022107919A1/en
Publication of WO2022107919A1 publication Critical patent/WO2022107919A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention provides a heteroaryl derivative containing N, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and prevention or treatment of a protein kinase-related disease comprising the same as an active ingredient It relates to a pharmaceutical composition for use.
  • Protein kinase is an enzyme that catalyzes the transfer of the terminal phosphate group of adenosine triphosphate (ATP) to specific residues of proteins (tyrosine, serine, and threonine). involved in regulating signals.
  • ATP adenosine triphosphate
  • Inappropriately high protein kinase activity is directly or indirectly associated with a number of diseases resulting from abnormal cellular functions.
  • Disease is caused by, for example, mutation, over-expression or failure of an appropriate regulatory mechanism of a kinase involved in inappropriate enzymatic activity, or production of an excess or deficiency of cytokines or factors that participate in signaling upstream or downstream of the kinase can be Therefore, selective inhibition of kinase activity can be a beneficial target for the development of new drugs for the treatment of diseases.
  • LRRK2 leucin-rich repeat kinase-2
  • LRRK2 leucin-rich repeat kinase-2
  • LRRK2 is a protein belonging to the leucine-rich repeat kinase family, and consists of 2527 amino acid sequences with high similarity between species, and is characteristically a GTP number in one protein. It has both GTPase and Serine-threonine kinase activity.
  • LRRK2 has been observed in various organs and tissues including the brain, and at the cellular level, it is known to exist in the cytoplasm or the cell membrane and the outer mitochondrial membrane.
  • Parkinson's disease causative genes causing Parkinson's disease by mutations are known, such as parkin, PINK1, DJ-1, ⁇ -synuclein, and leucine-rich repeat kinase 2 (LRRK2).
  • LRRK2 gene was first reported in 2004 as a dominant gene of a homologous chromosome like ⁇ -synuclein.
  • Parkinson's disease patients caused by LRRK2 mutation unlike other Parkinson's disease causative genes, symptoms are very similar to sporadic Parkinson's disease patients.
  • LRRK2 mutation is found in 1-2% of patients with sporadic Parkinson's disease as well as patients with a family history of Parkinson's disease. .
  • LRRK2 is involved in the transmission of mild cognitive impairment associated with Alzheimer's disease, L-Dopa induced dyskinesia, CNS disorders associated with neuronal progenitor differentiation, cancers such as brain cancer, kidney cancer, breast cancer, prostate cancer, blood cancer and lung cancer and Known to be associated with acute myeloid leukemia, papillary renal and thyroid carcinoma, multiple myeloma, amyotrophic lateral sclerosis, rheumatoid arthritis and ankylosing spondylitis, compounds and compositions effective in modulating LRRK2 activity include neurodegenerative diseases, CNS It can provide therapeutic effects for disorders, cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases.
  • hematopoietic progenitor kinase 1 is a hematopoietic cell-restricted Ste20 serine/threonine kinase.
  • HPK1 kinase activity can be induced upon ligand binding by activation signals generated by a variety of different cell surface receptors found in hematopoietic cells.
  • T cell receptor (TCR) B cell antigen receptor (BCR)
  • BCR B cell antigen receptor
  • TGF- ⁇ R transforming growth factor ⁇ receptor
  • HPK1 acts as a down-regulator of T and B cell function through the AP-1, NF ⁇ B, Erk2, and Fos pathways;
  • HPK1 has been shown as a negative regulator of signal transduction in T-cells through phosphorylation and activation of the T-cell receptor adapter protein SLP-76 (Di Bartolo et al., 2007, J. Exp. Med. 204). :681), which leads to subsequent downregulation of the AP-1 and Erk2 pathways.
  • HPK1 downregulates B-cell receptor (BCR) signaling through phosphorylation of the SLP-76 paralog BLINK (Wang et al., 2012, J. Biol. Chem. 287:11037).
  • BCR B-cell receptor
  • HPK1 is currently seen as a possible target for therapeutic intervention.
  • HPK1 may be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). Specifically, targeted cleavage of the HPK1 allele causes T cells to produce increased Th1 cytokines in response to TCR binding.
  • HPK1 (-/-) T cells proliferate more rapidly than their haplotype-matched wild-type counterparts and are resistant to prostaglandin E2 (PGE(2))-mediated inhibition. Most notably, mice that have undergone adoptive transfer of HPK1 (-/-) T cells become resistant to lung tumor growth. Loss of HPK1 from dendritic cells (DCs) also confers superior antigen presenting ability, which allows HPK1 (-/-) DCs to induce a stronger anti-tumor immune response when used as a cancer vaccine.
  • DCs dendritic cells
  • One object of the present invention is to provide a compound, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof that can be used for the prevention or treatment of protein kinase-related diseases.
  • Another object of the present invention is to provide a method for preparing the compound.
  • Another object of the present invention is one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease containing the compound, its isomer, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention or treatment of protein kinase-related diseases of more than one species.
  • Another object of the present invention is cancer, degenerative brain disease, and inflammation comprising administering the compound, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof
  • administering comprising administering the compound, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof
  • Another object of the present invention is to prevent or treat at least one protein kinase-related disease selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease.
  • a cargo or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
  • the 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
  • R 3 is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocycloalkyl
  • R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen
  • R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 12 membered heterocycloalkyl,
  • 3 to 12 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 12 membered heterocycloalkyl, —(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
  • R 8 is a 4 to 12 membered monocyclic ring or a bicyclic ring and is unsubstituted or substituted with one or more substituents R 9 ,
  • Another aspect of the present invention comprises the steps of preparing a compound of Formula 3 from a compound of Formula 2 (step 1); preparing a compound of Formula 4 from a compound of Formula 3 (step 2); preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5 (step 3); and preparing a compound of Formula 1 from a compound of Formula 6 (step 4);
  • LG is a leaving group
  • PG is a protecting group
  • R 1 to R 6 are each the same as defined above.
  • Another aspect of the present invention is from the group consisting of cancer, degenerative brain disease, and inflammatory disease containing a compound of the present invention, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of one or more selected protein kinase-related diseases.
  • an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof exhibits a high inhibitory ability against various protein kinases including HPK1 and LRRK2.
  • a pharmaceutical composition comprising a protein kinase-related disease, for example, cancer, degenerative brain disease, or inflammatory disease can be usefully used for prevention or treatment.
  • Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
  • the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
  • the symbol may be omitted, and may be indicated if necessary, such as when specifying a bonding atom or a bonding position.
  • connection between atoms may include not only a case of direct connection between atoms, but also a case of indirect connection between atoms through the mediation of other atoms and/or groups.
  • the other atom and/or group (group) may be oxygen, sulfur, C 1-8 alkylamino, or C 1-8 alkylene group, and the like, but is not limited thereto, and the atom/or group (group) ) may be substituted or unsubstituted.
  • substituted or unsubstituted may mean that one or a plurality of hydrogen atoms are substituted or not substituted with other atoms or substituents unless otherwise specified.
  • single ring is a single ring, and may mean a saturated, unsaturated or aromatic ring, and may include a heteroatom. Furthermore, it may include a ring in which hydrogen is removed from the ring.
  • bicyclic ring may mean two rings fused to each other while having one or more atoms in common. Specifically, it may be formed through a common single or double bond (polycyclic bicyclic ring), formed by sharing three or more arranged atoms (bridged bicyclic ring), or formed through a common single atom (spirobicyclic ring).
  • the bicyclic ring may be a saturated, partially unsaturated, unsaturated or aromatic ring and may contain heteroatoms. Furthermore, it may include a ring in which hydrogen is removed from the ring.
  • halogen may be F, Cl, Br, or I.
  • alkyl unless otherwise specified, a straight-chain or branched acyclic type; cyclic; Or it may mean a saturated hydrocarbon to which they are bound.
  • C 1-8 alkyl may refer to an alkyl containing 1 to 8 carbon atoms.
  • Acyclic alkyl is, for example, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl, isopropyl, sec-butyl, isobutyl , tert-butyl, isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like, but is not limited thereto.
  • Cyclic alkyl may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as an example.
  • Alkyl in which acyclic and cyclic alkyl are bonded is, for example, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylethyl, methylcyclobutyl, cyclobutylmethyl, ethylcyclopentyl, or cyclopentylmethyl.
  • cycloalkyl when “cycloalkyl” is described, it may mean a cyclic alkyl among alkyls, where alkyl is as defined above.
  • alkoxy may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above.
  • C 1-8 alkoxy may mean an alkoxy containing C 1-8 alkyl, that is, -(OC 1-8 alkyl), for example, C 1-8 alkoxy is methoxy (methoxy ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy ( sec-butoxy), tert-butoxy, n-pentoxy, etc., but is not limited thereto.
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Unless otherwise stated, heterocycloalkyl may be a single ring or a multicyclic ring such as a spiro ring, a bridged ring, or a fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring
  • heterocycloalkyl is pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 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, 2-azaspiro[3.3
  • alkylamino may mean -(NR′R′′), where R′ and R′′ may each independently be selected from the group consisting of hydrogen and C 1-8 alkyl, and the selected R 'and R' may each independently be substituted or unsubstituted.
  • C 1-8 alkylamino may mean an amino containing C 1-8 alkyl, that is, -NH(C 1-8 alkyl) or -N-(C 1-8 alkyl) 2 , dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.
  • hydroxyalkyl refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by a hydroxy group.
  • examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxy hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2- (hydroxymethyl)-3-hydroxypropyl, but is not limited thereto.
  • haloalkyl may mean -RX (X is one or more halogens (F, Cl, Br, or I, etc.)), i.e., "haloalkyl” is an alkyl form in which one or more halogens are substituted.
  • X is one or more halogens (F, Cl, Br, or I, etc.)
  • haloalkyl is an alkyl form in which one or more halogens are substituted.
  • C 1-8 haloalkyl may include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • the present invention is not limited thereto.
  • haloalkoxy may mean -(O-RX) (X is one or more halogens (F, Cl, Br, or I, etc.)), that is, "haloalkoxy” means one or more halogens It may be in the form of a substituted alkoxy.
  • haloalkoxy is trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropoxy, etc. may include, but is not limited thereto.
  • aryl may mean an aromatic ring in which one hydrogen is removed from an aromatic hydrocarbon ring, and may be a single ring or a multicyclic ring.
  • 3 to 12 membered aryl may mean an aryl containing 3 to 12 atoms forming a ring, for example, phenyl, benzyl, naphthyl, anthracenyl, phenanthryl, biphenyl, or ter It may include, but is not limited to, phenyl and the like.
  • heteroaryl may mean an aromatic ring containing one or more heteroatoms among N, O, and S as atoms forming the ring, and may be a single ring or a polycyclic ring.
  • heteroaryl may mean a heteroaryl containing 3 to 12 atoms forming a ring, for example, thienyl, thiophene, furyl, pyrrolyl, pyrazolyl , imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridyl, pyrimidyl, triazinyl, triazolyl, acridyl group, pyridazinyl group , pyrazinyl, quinolinyl, quinazoline, quinoxalinyl, phenoxazil, phthalaziny
  • hydroxy may mean -OH.
  • alkenyl may mean a straight-chain, branched-chain acyclic or cyclic hydrocarbon having one or more double bonds, unless otherwise specified.
  • cyano may mean -(CN).
  • alkynyl may mean a straight-chain, branched-chain acyclic or cyclic hydrocarbon having one or more triple bonds.
  • C 2-8 alkynyl may mean alkynyl containing 2 to 8 carbon atoms, for example, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyne -2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl, but is not limited thereto.
  • aralkyl may mean -(alkyl-aryl), where alkyl and aryl are as defined above. Also, “aralkyl of 3 to 8 atoms” may mean aralkyl containing 3 to 8 carbon atoms.
  • hydrate refers to the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. a compound of the invention or a salt thereof.
  • the hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces.
  • the hydrate may contain 1 equivalent or more, preferably, 1 to 5 equivalents of water.
  • Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
  • solvent may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.
  • isomers may mean a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or sterically different.
  • isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.
  • One aspect of the present invention is to provide a compound of Formula 1 below, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
  • the 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
  • R 3 is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocycloalkyl
  • R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen
  • R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 12 membered heterocycloalkyl,
  • 3 to 12 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 12 membered heterocycloalkyl, —(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
  • R 8 is a 4 to 12 membered monocyclic ring or a bicyclic ring and is unsubstituted or substituted with one or more substituents R 9 ,
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
  • the 8 to 12 membered bicyclic ring formed by R 1 and R 2 may be unsubstituted or substituted with hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or halogen,
  • R 4 may be hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or halogen.
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
  • the 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-6 alkyl
  • R 3 is 3 to 8 membered cycloalkyl
  • R 4 is hydrogen or halogen
  • R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl,
  • the 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-8 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
  • R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
  • the 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl
  • R 3 is 3 to 6 membered cycloalkyl
  • R 4 is hydrogen or halogen
  • R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or they are joined together with the N atom to which they are attached to form a 3-8 membered heterocycloalkyl,
  • the 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3-6 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
  • R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
  • the 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl
  • R 3 is 3 to 6 membered cycloalkyl
  • R 4 is hydrogen or halogen
  • R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or at least one selected from the group consisting of N, O and S linked together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl containing heteroatoms,
  • 3 to 8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3 to 6 atoms including at least one O atom substituted or unsubstituted with one or more substituents R 7 selected from the group consisting of heterocycloalkyl, -(CH 2 )nR 8 , and -C(O)-R 8 , wherein n is an integer from 1 to 3;
  • R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
  • the 3 to 8 membered heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S formed by R 5 and R 6 may be in the form of a single ring or a bridged ring.
  • the bridged ring form may be a form bridged by a divalent hydrocarbon bridge, and specifically, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl, or diazabicyclo[2.2.2 ] may be octane.
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members, the 8 to 10 membered bicyclic ring formed together with the pyrimidine ring is quinazoline, puropyrimidine, thienopyrimidine, cyclopentapyrimidine, or pyrrolopyrimidine;
  • R 8 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, pyrazolyl, imidazopyridinyl, thiazolyl, oxazolyl, quinolinyl, furanyl, naphtanyl, oxadiazolyl, dihydro benzodioxinyl, or dihydrobenzofuranyl.
  • R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a quinazoline, furopyrimidine, thienopyrimidine, cyclopentapyrimidine, or pyrrolopyrimidine;
  • R 3 is cyclopropyl or cyclobutyl
  • R 4 is hydrogen or fluoro
  • Piperazinyl, diazabicyclo[3.1.1]heptanyl, or morpholinyl formed by R 5 and R 6 is methyl, hydroxyethyl, oxetanyl, -(CH 2 )-R 8 , and -C (O)-R 8 substituted or unsubstituted with one or more substituents R 7 selected from the group consisting of,
  • R 8 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, pyrazolyl, imidazopyridinyl, thiazolyl, oxazolyl, quinolinyl, furanyl, naphtanyl, oxadiazolyl, dihydro benzodioxinyl, or dihydrobenzofuranyl, unsubstituted or substituted with one or more substituents R 9 ,
  • the substituent R 9 may be methyl, methoxy, difluoromethoxy, ethoxy, methoxy, cyano, methanesulfonamido, oxo, methylamino, trifluoromethyl, or benzyl.
  • Examples of the compound of Formula 1 according to the present invention include compounds 1 to 53 listed in [Table 1] in the following Examples, or a free base (when shown as a pharmaceutically acceptable salt in Table 1), isomers thereof, and hydrates thereof , a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be an acid addition salt formed with a free acid.
  • the acid addition salt includes inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, and hydroxy alkanoates.
  • non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. It can be obtained from the same organic acid.
  • Such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate , methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chloro
  • the acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid to filter the resulting precipitate , it can be prepared by drying, or by distilling the solvent and excess acid under reduced pressure and then drying and crystallizing in an organic solvent.
  • the pharmaceutically acceptable salt may be a salt or a metal salt obtained using a base.
  • the 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 the undissolved compound salt, and evaporating and drying the filtrate.
  • alkali metal salts sodium, potassium or calcium salts may be pharmaceutically suitable.
  • the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the present invention may be a compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, as well as an isomer, particularly a stereoisomer, particularly an enantiomer thereof, and a hydrate and/or solvent prepared therefrom. It can be cargo.
  • Another aspect of the present invention may be to provide a method for preparing the compound of Formula 1.
  • the method for preparing the compound of Formula 1 includes the steps of preparing a compound of Formula 3 from the compound of Formula 2 (step 1), as shown in Scheme 1 below; preparing a compound of Formula 4 from a compound of Formula 3 (step 2); preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5 (step 3); and preparing a compound of Formula 1 from a compound of Formula 6 (step 4).
  • LG is a leaving group
  • PG is a protecting group
  • R 1 to R 6 may be the same as defined herein, respectively.
  • the leaving group may be a functional group such as halogen, sulfonic acid ester, or alkoxy, and a compound of Formula 4 may be prepared from a compound of Formula 3, and a compound of Formula 4 may be reacted with a compound of Formula 5 to prepare a compound of Formula 6 It is not limited as long as it is a functional group that can do it.
  • the protecting group is tetrahydropyran (THP), (2-(trimethylsilyl)methoxy)methyl (SEM), p-methoxybenzyl (PMB), t-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz) , 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), aryloxycarbonyl (Alloc), or p-methoxybenzyl (PMB) ) may be a functional group, and is not limited as long as it is a functional group capable of protecting the secondary amine.
  • step 1 is a step of preparing a compound of Formula 3 from a compound of Formula 2, and may be a step of protecting a secondary amine of pyrazole of the compound of Formula 2 with a protecting group.
  • the protecting group may be used without limitation as long as it is a functional group capable of protecting the secondary amine, and may be, for example, tetrahydropyran (THP).
  • the mixture was stirred at 30° C. to 100° C. for 10 to 20 hours, specifically at 60° C. for 15 hours, and if the reaction proceeds smoothly, the conditions may not be limited. have.
  • the usable solvent includes toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, dichloromethane, water, ethyl acetate, acetonitrile; lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, and the like; and the like, and these may be used alone or in combination, and an example may be dichloromethane.
  • DMA dimethylacetamide
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • methylene chloride dichloroethane
  • dichloromethane water
  • ethyl acetate acetonitrile
  • lower alcohols including isopropanol,
  • Step 2 is a step of preparing a compound of Formula 4 from a compound of Formula 3, and the compound of Formula 3 and may be dissolved in water and a solvent, and then a palladium catalyst may be added. After that, the mixture was stirred at 50° C. to 120° C. for 0.5 to 3 hours, specifically at 90° C. for 1 hour, and if the reaction proceeds smoothly, it may not be limited to the above conditions.
  • the solvent may be the same as listed in the usable solvents of step 1 above, and an example may be dioxane.
  • Step 3 is a step of preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5.
  • a compound of Formula 4 After dissolving a compound of Formula 4 and a compound of Formula 5 in a solvent, at 60° C. to 120° C. for 10 to 15 hours , Specifically, it was stirred at 90 ° C. for 12 hours, and if the reaction proceeds smoothly, it may not be limited to the above conditions.
  • the solvent may be the same as those listed in the usable solvents of step 1 above, and specifically may be dimethyl sulfoxide (DMSO).
  • the compound of Formula 5 may be in a form in which a heteroatom is protected by a protecting group.
  • Step 4 is a step of preparing a compound of Formula 1 from the compound of Formula 6, and may be a step of removing a protecting group by adding an acid to the compound of Formula 6, and if necessary, a substituent on the compound of Formula 6 from which the protecting group is removed It may further comprise the step of attaching R 7 .
  • the mixture was stirred at room temperature for 10 to 15 hours, specifically for 13 hours, and as long as the reaction proceeds smoothly, the conditions may not be limited.
  • the solvent may be the same as listed in the usable solvents of step 1 above, and an example may be dioxane.
  • the resultant may be washed with brine, and the remaining water may be removed from the organic layer as Na 2 SO 4 .
  • Another aspect of the present invention is a pharmaceutical composition for preventing or treating protein kinase-related diseases, comprising the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for preventing or treating protein kinase-related diseases comprising the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect of the present invention may provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein Formula 1
  • the compound of Formula 1 may exhibit phosphorylation inhibitory activity of SLP76 (S376).
  • the protein kinase-related disease may be at least one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease.
  • the type of cancer is not limited, but for example, the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides.
  • Sarcoma acute myeloid leukemia, acute lymphocytic 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, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, Retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, Meningiomas, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesot
  • the type of degenerative brain disease is not limited, but for example, the degenerative brain disease may include Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, stroke, and mild cognitive impairment. It may be one or more diseases selected from the group.
  • inflammatory diseases include dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis , pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, cystitis, periodontitis, and may be at least one disease selected from the group consisting of gingivitis.
  • the pharmaceutical composition for preventing or treating protein kinase-related diseases of the present invention can be used in clinical administration, and can be prepared to be administered in various oral and parenteral formulations.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like, and the composition of the present invention may be formulated using these together.
  • Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations include one or more compounds and at least one excipient, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. can be mixed and prepared. In addition, it may be formulated using lubricants such as magnesium stearate, talc, etc. in addition to simple excipients.
  • liquid formulations for oral administration may correspond to suspensions, internal solutions, emulsions, syrups, etc., and these liquid formulations are commonly used simple diluents, in addition to water and liquid paraffin, various excipients, for example, wetting agents, sweetening agents, flavoring agents, preservatives, and the like.
  • Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, ethyl oleate, and the like. Injectable esters such as can be used.
  • parenteral administration may be by a method of injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.
  • the pharmaceutical composition is prepared as a solution or suspension by mixing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in water together with a stabilizer or buffer, and this is an ampoule.
  • it may be prepared in a vial unit dosage form.
  • the composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and may be mixed and granulated in a conventional manner. It can be formulated according to the method of formulation or coating.
  • a pharmaceutical composition for the prevention or treatment of protein kinase-related diseases containing the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered or used as an individual therapeutic agent It can be used in combination with other therapeutic agents currently being used.
  • cancer degenerative brain disease comprising administering the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof , and provides a method for preventing or treating one or more protein kinase-related diseases selected from the group consisting of inflammatory diseases.
  • Another aspect of the present invention is the compound of Formula 1 or an isomer thereof, a solvate thereof in the prevention or treatment of at least one protein kinase-related disease selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease, Or to provide the use of a pharmaceutically acceptable salt thereof.
  • the compound synthesized in the Examples of the present invention was purified by the following HPLC conditions or subjected to structural analysis: Medium pressure liquid chromatography (MPLC) for purification; Medium pressure liquid chromatography was performed using TELEEDYNE ISCO's CombiFlash Rf +UV.
  • Mobile phase A used water containing 0.1% formic acid
  • mobile phase B used acetonitrile containing 0.1% formic acid.
  • the Autopurification HPLC system manufactured by Waters (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a mass QDA Detector manufactured by Waters was used.
  • the column used was Waters' SunFire ® Prep C18 OBD TM (5 ⁇ m, 19X50 mm), and the column temperature was performed at room temperature.
  • the equipment manufactured by Waters was used for the Prep 150 LC system manufactured by Waters (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III).
  • the column used was Waters' XTERRA ® Prep RP18 OBD TM (10 ⁇ m, 30X300 mm), and the column temperature was performed at room temperature.
  • room temperature refers to a temperature of about 1-35 °C.
  • Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.
  • Step 2 Preparation of 2-chloro-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)quinazolin-4-amine
  • Step 3 N-(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(6-fluoropyridin-3-yl)quina Preparation of zolin-4-amine
  • Step 4 tert-Butyl 3-(5-(4-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)quinazoline- Preparation of 2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate
  • Step 5 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl ) Preparation of quinazolin-4-amine dihydrochloride
  • Step 6 N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi Preparation of cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine
  • Examples 2-53 were prepared in a manner similar to that of Example 1, and the chemical structures, compound names, and NMR and LC-MS analysis results of Examples 1-53 are summarized and shown in Table 1 below.
  • HPK1 Hematopoietic Progenitor Kinase 1
  • Example compounds were reacted with purified human HPK1 (1-346, SignalChem) enzyme to evaluate the enzyme inhibitory ability as follows.
  • the reaction buffer was 40 mM Tris-HCl pH7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 ⁇ M DTT composition, and all test articles were reacted in the reaction buffer.
  • the compound was diluted in 12 steps with 10 mM DMSO stock by a serial dilution method, and the enzyme activity was measured at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, and 0.00003 ⁇ M of the final compound.
  • Example compounds were reacted with purified human LRRK2(G2019S) (L10-12GG, SignalChem) enzyme to evaluate the enzyme inhibitory ability as follows.
  • the reaction buffer was 40 mM Tris-HCl pH7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 ⁇ M DTT composition, and all test materials were reacted on the reaction buffer.
  • the compound was diluted in 12 steps with 10 mM DMSO stock by a serial dilution method, and the enzyme activity was measured at the concentrations of 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512, 0.000001024, 0.0000002 ⁇ M of the final compound. .
  • Enzyme inhibitory activity IC 50 value of the compound measured in Experimental Example 1 and Experimental Example 2 is 0.05 ⁇ M or less, “A”, 0.05 or more and 0.25 ⁇ M or less, “B”, 0.25 or more and 0.5 ⁇ M or less, “C”, 0.5 ⁇ M or less If it is, it is classified as "D” and summarized in Table 2 below.
  • Example HPK1 Enzyme IC 50 LRRK2 (G2019S) Enzyme IC 50 Example HPK1 Enzyme IC 50 LRRK2 (G2019S) Enzyme IC 50
  • Example HPK1 Enzyme IC 50 LRRK2 (G2019S) Enzyme IC 50 One A B 28 C 2 A 29 B 3 A A 30 A 4 B B 31 A C 5 A B 32 B D 6 B 33 A 7 B B 34 A 8 A B 35 A 9 A B 36 A 10 A A 37 A B 11 B C 38 C 12 B D 39 A 13 B C 40 A 14 B B 41 A D 15 D 42 C 16 A A 43 A 17 B B 44 A 18 B A 45 D 19 A 46 B 20 A B 47 D 21 B B 48 A 22 B C 49 B 23 A A 50 A 24 A A 51 A 25 A 52 A 26 A 53 A 27 D C
  • Jurkat T cells ATCC
  • human T Lymphocyte cell line a human T Lymphocyte cell line
  • the cells were planted in a clear 96-well plate to 5 ⁇ 10 4 /25 ⁇ l wells, and the compound was diluted with 10 mM DMSO stock in 10 steps by serial dilution. , and the final compound concentrations were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, and 0.0001 ⁇ M.
  • Compounds were incubated for 4 hours in a 37° C. CO 2 incubator after treatment. After 4 hours, the plate treated with the compound was taken out and treated with CD3 (5 pg/mL, OKT3 clone) for 20 minutes.
  • the HTRF test was conducted based on the experimental method in the Phospho-SLP-76 (Ser376) cellular kit (Cisbio). Put 15 ⁇ l of 4 x Lysis Buffer (including blocking reagent) into each well, incubate in a shaking incubator for 1 hour, transfer 16 ⁇ l of cell lysate to a clear bottom white 96-well plate, and p-SLP76(s376) HTRF reagents (2 ul donor, 2ul acceptor) and allowed to react overnight at 4°C.
  • the homogeneous time resolved fluorescence was measured and the expression level of p-SLP76(S376) according to the treatment concentration of each compound was calculated based on the fluorescence value of the solvent control group not treated with the compound and expressed as a percentage, GraphPad Prism 8.3.0 ( IC 50 ( ⁇ M) values were calculated using GraphPad software Inc., San Diego).
  • Measured SLP76 (S376) phosphorylation inhibitory activity IC 50 value of 0.15 ⁇ M or less “A”, “B” when 0.15 ⁇ M or more and 0.5 ⁇ M or less, “C” when it exceeds 0.5 ⁇ M and 1 ⁇ M or less, “C”, and “D” when it exceeds 1 ⁇ M It is summarized and shown in Table 3 below.
  • Example p-SLP76 (S376) HTRF IC 50 Example p-SLP76 (S376) HTRF IC 50 One A 28 B 2 B 29 3 B 30 A 4 31 5 A 32 6 33 7 34 8 35 9 B 36 10 37 11 38 12 39 13 40 14 41 15 42 16 43 17 44 18 45 19 46 20 47 21 48 22 49 23 50 A 24 A 51 B 25 52 B 26 B 53 27
  • Example 1 the enzyme (kinase) selectivity was measured by requesting DiscoverX, and the experiment was conducted using a scanMAX TM Kinase analysis panel.
  • concentration of the drug treated with the enzyme was 1 ⁇ M in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Table 4 below.
  • the positive control refers to a compound showing a percentage control of 0%
  • the negative control indicates a percentage control of 100% with DMSO.
  • the enzyme selectivity of the present invention was judged to have activity for each enzyme if the control percentage was ⁇ 35% (ie, less than 35%) for each enzyme.
  • the compounds according to the present invention are AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3 (D835H), FLT3 (D835V) ), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, HPK1, JAK1(JH1domain) -catalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576
  • the compound of the present invention can be usefully used as a composition for treating or preventing diseases related to the enzymes listed above.

Abstract

The present invention relates to: an N-containing heteroaryl derivative; an isomer thereof; a hydrate thereof; a solvate thereof or a pharmaceutically acceptable salt thereof; a method for preparing same; and a pharmaceutical composition which is for preventing or treating protein kinase-related diseases and comprises same as an active ingredient. The N-containing heteroaryl derivative according to the present invention exhibits high inhibitory ability against various protein kinases, and thus a pharmaceutical composition containing same as an active ingredient can be effectively used for preventing or treating protein kinase-related diseases, for example, cancer, degenerative brain disease, or inflammatory disease.

Description

N을 포함하는 헤테로아릴 유도체 및 이를 유효성분으로 포함하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물 Heteroaryl derivative containing N and a pharmaceutical composition for preventing or treating protein kinase-related diseases comprising the same as an active ingredient
본 발명은 N을 포함하는 헤테로아릴 유도체, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염, 이를 제조하는 방법, 및 이를 유효성분으로 포함하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention provides a heteroaryl derivative containing N, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and prevention or treatment of a protein kinase-related disease comprising the same as an active ingredient It relates to a pharmaceutical composition for use.
단백질 키나아제는 아데노신삼인산(ATP)의 말단 인산기를 단백질의 특정 잔기(타이로신, 세린, 트레오닌)에 전이시키는 반응을 촉매하는 효소로서, 세포외 매개체 및 환경의 변화에 대한 세포의 활성, 성장 및 분화를 조절하는 신호에 관여한다.Protein kinase is an enzyme that catalyzes the transfer of the terminal phosphate group of adenosine triphosphate (ATP) to specific residues of proteins (tyrosine, serine, and threonine). involved in regulating signals.
부적절하게 높은 단백질 키나아제 활성은 비정상 세포 작용으로부터 기인하는 다수의 질병과 직접적 또는 간접적으로 연관이 있다. 예를 들면, 돌연변이, 과잉-발현 또는 부적절한 효소 활성에 관련된 키나아제의 적절한 조절메카니즘의 실패, 또는 사이토카인 또는 키나아제의 업스트림 또는 다운스트림의 신호 전달에 참여하는 인자들의 과잉 또는 결핍 생성에 의해 질병이 야기될 수 있다. 따라서, 키나아제 활성의 선택적인 억제는 질병 치료를 위한 신약 개발의 유익한 표적이 될 수 있다.Inappropriately high protein kinase activity is directly or indirectly associated with a number of diseases resulting from abnormal cellular functions. Disease is caused by, for example, mutation, over-expression or failure of an appropriate regulatory mechanism of a kinase involved in inappropriate enzymatic activity, or production of an excess or deficiency of cytokines or factors that participate in signaling upstream or downstream of the kinase can be Therefore, selective inhibition of kinase activity can be a beneficial target for the development of new drugs for the treatment of diseases.
LRRK2 (leucin-rich repeat kinase-2)는 류신 풍부 반복 키나아제 집단(leucin-rich repeat kinase family)에 속하는 단백질이며, 종간 유사성이 높은 2527개의 아미노산 배열로 구성되어 있고, 특징적으로 하나의 단백질 안에 GTP가수분해효소(GTPase)와 세린-트레오닌 키나아제(Serine-threonine kinase)활성을 모두 가지고 있다.LRRK2 (leucin-rich repeat kinase-2) is a protein belonging to the leucine-rich repeat kinase family, and consists of 2527 amino acid sequences with high similarity between species, and is characteristically a GTP number in one protein. It has both GTPase and Serine-threonine kinase activity.
발현된 LRRK2는 뇌를 포함한 다양한 기관과 조직에서 관찰되고 있으며, 세포수준에서는 세포질 또는 세포막 및 미토콘드리아 외막에서 존재하는 것으로 알려져 있다. 현재 LRRK2의 정확한 생체 내 기능에 대해서는 연구가 활발히 진행되고 있는데, 기능상 중요한 5개의 도메인(domain)을 가지고 있어, 자가인산화작용(Autophosphorylation)에 의한 자가활성조절작용과 단백질 상호작용 및 효소작용을 통한 세포기능 조절작용이 예상되고 있으며, 특히 샤페론기전(chaperone machinery), 세포골격 배열(cytoskelecton arrangement), 단백질 번역기전(protein translational machinery), 시냅스소포 세포내유입(synaptic vesicle endocytosis), 미토젠 활성화단백질키나아제신호전달과정(mitogen-activated protein kinases signaling cascades), 유비퀴틴/오토파지단백질 분해과정(ubiquitin/autophageprotein degradation pathways)이 LRRK2에 의해 조절되는 것으로 알려져 있다.The expressed LRRK2 has been observed in various organs and tissues including the brain, and at the cellular level, it is known to exist in the cytoplasm or the cell membrane and the outer mitochondrial membrane. Currently, research on the exact in vivo function of LRRK2 is being actively conducted. It has five functionally important domains, so it regulates self-activation by autophosphorylation and cell through protein interaction and enzymatic action. Functional regulation is expected, and in particular, chaperone machinery, cytoskeleton arrangement, protein translational machinery, synaptic vesicle endocytosis, mitogen-activated protein kinase signaling It is known that mitogen-activated protein kinases signaling cascades and ubiquitin/autophageprotein degradation pathways are regulated by LRRK2.
파킨슨병은 대부분이 산발적으로 일어나지만 5-10%의 환자는 가족력을 가지는데 이들 환자 시료의 연구로부터 PARK 1-16의 유전자자리가 현재까지 밝혀졌으며, 그 중 몇 개의 유전자자리에서 돌연변이에 의해 파킨슨병을 유발하는 유전자가 확인되었다. 돌연변이에 의해 파킨슨병을 일으키는 파킨슨병 원인 유전자는 파킨(parkin), PINK1, DJ-1, α-시누클레인(α-synuclein), LRRK2(leucine-rich repeat kinase 2) 등이 알려져 있다. 이 중 LRRK2 유전자는, α-시누클레인처럼 상동염색체의 우성 유전자로 2004년에 최초로 보고되었다. LRRK2 돌연변이에 의한 파킨슨병 환자는, 다른 파킨슨병 원인 유전자와는 달리, 그 증상이 산발적 파킨슨병 환자와 아주 유사하다. LRRK2 돌연변이는 가족력이 있는 파킨슨병 환자뿐 아니라 산발적 파킨슨병의 환자의 1-2%에서도 발견되므로 이 유전자의 돌연변이에 의한 파킨슨병 발병 기작을 밝히면 파킨슨병의 발병 기작 이해와 치료제 개발에 큰 도움이 된다.Most of Parkinson's disease occurs sporadically, but 5-10% of patients have a family history. Disease-causing genes have been identified. Parkinson's disease causative genes causing Parkinson's disease by mutations are known, such as parkin, PINK1, DJ-1, α-synuclein, and leucine-rich repeat kinase 2 (LRRK2). Among them, the LRRK2 gene was first reported in 2004 as a dominant gene of a homologous chromosome like α-synuclein. Parkinson's disease patients caused by LRRK2 mutation, unlike other Parkinson's disease causative genes, symptoms are very similar to sporadic Parkinson's disease patients. LRRK2 mutation is found in 1-2% of patients with sporadic Parkinson's disease as well as patients with a family history of Parkinson's disease. .
또한, LRRK2는 알츠하이머병과 관련된 경도 인지 손상의 전가, L-도파(Dopa) 유도된 운동이상증, 뉴런 전구 분화와 관련된 CNS 장애, 암, 예컨대 뇌암, 신장암, 유방암, 전립선암, 혈액암 및 폐암 및 급성 골수성 백혈병, 유두상(papillary) 신장 및 갑상선 암종, 다발성 골수종, 근위축성 측삭 경화증, 류마티스 관절염 및 강직 척추염과 관련된 것으로 알려져 있어, LRRK2 활성을 조절하는 데에 효과적인 화합물 및 조성물은 신경퇴행성 질환, CNS 장애, 암, 급성 골수성 백혈병 및 다발성 골수종, 및 염증성 질환 등의 치료효과를 제공할 수 있다.In addition, LRRK2 is involved in the transmission of mild cognitive impairment associated with Alzheimer's disease, L-Dopa induced dyskinesia, CNS disorders associated with neuronal progenitor differentiation, cancers such as brain cancer, kidney cancer, breast cancer, prostate cancer, blood cancer and lung cancer and Known to be associated with acute myeloid leukemia, papillary renal and thyroid carcinoma, multiple myeloma, amyotrophic lateral sclerosis, rheumatoid arthritis and ankylosing spondylitis, compounds and compositions effective in modulating LRRK2 activity include neurodegenerative diseases, CNS It can provide therapeutic effects for disorders, cancer, acute myeloid leukemia and multiple myeloma, and inflammatory diseases.
한편, 조혈 전구 키나아제 1 (HPK1)는 조혈 세포-제한 Ste20 세린/트레오닌 키나아제이다. HPK1 키나아제 활성은 리간드 결합시 조혈 세포에서 발견되는 다양한 상이한 세포 표면 수용체에 의해 생성된 활성화 신호에 의해 유도될 수 있다. T 세포 수용체 (TCR), B 세포 항원 수용체 (BCR) (Liou et al., 2000, Immunity 12:399), 전환 성장 인자 β 수용체 (TGF-βR) (Wang et al., 1997. J. Biol. Chem. 272:22771; Zhou et al., 1999, J. Biol.Chem. 274:13133), 에리트로포이에틴 수용체 (EPOR) (Nagata et al., 1999, Blood 93:3347), 및 Fas (Chen et al., 1999, Oncogene 18:7370)의 항체-매개 가교결합의 리간드 결합은 HPK1 키나아제 활성을 유도할 수 있다.On the other hand, hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine/threonine kinase. HPK1 kinase activity can be induced upon ligand binding by activation signals generated by a variety of different cell surface receptors found in hematopoietic cells. T cell receptor (TCR), B cell antigen receptor (BCR) (Liou et al., 2000, Immunity 12:399), transforming growth factor β receptor (TGF-βR) (Wang et al., 1997. J. Biol. Chem. 272:22771; Zhou et al., 1999, J. Biol. Chem. 274:13133), erythropoietin receptor (EPOR) (Nagata et al., 1999, Blood 93:3347), and Fas (Chen et al.) al., 1999, Oncogene 18:7370), ligand binding of antibody-mediated crosslinking can induce HPK1 kinase activity.
각각의 수용체는 HPK1을 활성화시키기 위해 독특하지만 때때로 중첩되는 신호 기작을 이용한다. HPK1은 AP-1, NFκB, Erk2, 및 Fos 경로를 통해 T 및 B 세포 작용의 하향 조절자로서 역할을 하고; 예를 들면 HPK1은 T-세포 수용체 어댑터 단백질 SLP-76의 인산화 및 활성화를 통한 T-세포에서의 신호 전달의 음성 조절자로서 나타내었고 (Di Bartolo et al., 2007, J. Exp. Med. 204:681), 이는 AP-1 및 Erk2 경로의 후속 하향조절을 야기한다. B-세포에서, HPK1은 SLP-76 파라로그 BLINK의 인산화를 통한 B-세포 수용체 (BCR) 신호전달을 하향조절한다(Wang et al., 2012, J. Biol. Chem. 287:11037). 따라서, HPK1은 현재 치료적 중재를 위한 가능한 표적으로서 보여진다. 예를 들면, HPK1은 암 면역치료를 위한 신규한 표적일 수 있는 것으로 보고된다 (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). 구체적으로는, HPK1 대립 유전자의 표적화된 분해는 T 세포가 TCR 결합에 반응하여 증가된 Th1 사이토카인 생성하게 한다. HPK1 (-/-) T 세포는 단상형-일치된 야생형 대응물보다 더 급속하게 증식되고, 프로스타글란딘 E2(PGE(2))-매개 억제에 대해 저항성이다. 가장 현저하게는, HPK1 (-/-) T 세포의 양자 전이를 받은 마우스는 폐종양 성장에 저항성이게 된다. 또한 수상 세포 (DC)로부터의 HPK1의 손실은 우수한 항원 제시 능력을 부여하고, 이는 HPK1 (-/-) DC가 암 백신으로서 사용되는 경우 보다 강력한 항-종양 면역 반응을 유도하게 한다.Each receptor utilizes a unique but sometimes overlapping signaling mechanism to activate HPK1. HPK1 acts as a down-regulator of T and B cell function through the AP-1, NFκB, Erk2, and Fos pathways; For example, HPK1 has been shown as a negative regulator of signal transduction in T-cells through phosphorylation and activation of the T-cell receptor adapter protein SLP-76 (Di Bartolo et al., 2007, J. Exp. Med. 204). :681), which leads to subsequent downregulation of the AP-1 and Erk2 pathways. In B-cells, HPK1 downregulates B-cell receptor (BCR) signaling through phosphorylation of the SLP-76 paralog BLINK (Wang et al., 2012, J. Biol. Chem. 287:11037). Thus, HPK1 is currently seen as a possible target for therapeutic intervention. For example, it is reported that HPK1 may be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 Dec;54(1-3):262-5). Specifically, targeted cleavage of the HPK1 allele causes T cells to produce increased Th1 cytokines in response to TCR binding. HPK1 (-/-) T cells proliferate more rapidly than their haplotype-matched wild-type counterparts and are resistant to prostaglandin E2 (PGE(2))-mediated inhibition. Most notably, mice that have undergone adoptive transfer of HPK1 (-/-) T cells become resistant to lung tumor growth. Loss of HPK1 from dendritic cells (DCs) also confers superior antigen presenting ability, which allows HPK1 (-/-) DCs to induce a stronger anti-tumor immune response when used as a cancer vaccine.
이에, 다양한 단백질 키나아제, 특히 LRRK2 및 HPK1의 활성을 억제시킬 수 있는 신규 화합물에 대한 필요성이 존재하였다.Accordingly, there was a need for novel compounds capable of inhibiting the activity of various protein kinases, particularly LRRK2 and HPK1.
본 발명의 일 목적은 단백질 키나아제 관련 질환의 예방 또는 치료에 사용 가능한 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.One object of the present invention is to provide a compound, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof that can be used for the prevention or treatment of protein kinase-related diseases.
본 발명의 다른 목적은 상기 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the compound.
본 발명의 또 다른 목적은 상기 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease containing the compound, its isomer, its hydrate, its solvate, or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention or treatment of protein kinase-related diseases of more than one species.
본 발명의 또 다른 목적은 상기 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is cancer, degenerative brain disease, and inflammation comprising administering the compound, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof To provide a method for preventing or treating one or more protein kinase-related diseases selected from the group consisting of diseases.
본 발명의 또 다른 목적은 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료에 있어서의 상기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염의 용도를 제공하는 것이다.Another object of the present invention is to prevent or treat at least one protein kinase-related disease selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease. To provide the use of a cargo, or a pharmaceutically acceptable salt thereof.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2020016377-appb-img-000001
Figure PCTKR2020016377-appb-img-000001
상기 화학식 1에 있어서,In Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리(bicyclic ring)를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
상기 R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐으로 치환되거나 비치환되며,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
R 3은 3 내지 8 원자의 사이클로알킬 또는 3 내지 8 원자의 헤테로사이클로알킬이며,R 3 is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocycloalkyl,
R 4는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐이고,R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
R 5 및 R 6은 각각 독립적으로 C 1-6 알킬아미노로 치환되거나 비치환된 C 1-6 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 12 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 12 membered heterocycloalkyl,
상기 R 5 및 R 6이 형성한 3 내지 12 원자의 헤테로사이클로알킬은 C 1-6 알킬, C 1-6 하이드록시알킬, C 1-6 알콕시, 3 내지 12 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,3 to 12 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 12 membered heterocycloalkyl, —(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
상기 R 8은 4 내지 12 원자의 단일 고리(monocyclic ring) 또는 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 12 membered monocyclic ring or a bicyclic ring and is unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 C 1-6 알킬, C 1-6 알콕시, 5 내지 8 원자의 아릴, 사이아노, C 1-6 알킬아미노, C 1-6 할로알킬, C 1-6 할로알콕시, C 1-6 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택된다.The substituent R 9 is C 1-6 alkyl, C 1-6 alkoxy, 5-8 membered aryl, cyano, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkylsulfonamido, and oxo (=O).
본 발명의 다른 일 측면은, 하기 반응식 1에 나타난 바와 같이, 화학식 2의 화합물로부터 화학식 3의 화합물을 제조하는 단계(단계 1); 화학식 3의 화합물로부터 화학식 4의 화합물을 제조하는 단계(단계 2); 화학식 4의 화합물과 화학식 5의 화합물을 반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3); 및 화학식 6의 화합물로부터 화학식 1의 화합물을 제조하는 단계(단계 4);를 포함하는 것인, 화학식 1의 화합물의 제조방법을 제공한다.Another aspect of the present invention, as shown in Scheme 1 below, comprises the steps of preparing a compound of Formula 3 from a compound of Formula 2 (step 1); preparing a compound of Formula 4 from a compound of Formula 3 (step 2); preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5 (step 3); and preparing a compound of Formula 1 from a compound of Formula 6 (step 4);
[반응식 1][Scheme 1]
Figure PCTKR2020016377-appb-img-000002
Figure PCTKR2020016377-appb-img-000002
상기 반응식 1에서, LG는 이탈기이고, PG는 보호기이며, R 1 내지 R 6는 각각 앞서 정의한 것과 동일하다.In Scheme 1, LG is a leaving group, PG is a protecting group, and R 1 to R 6 are each the same as defined above.
본 발명의 또 다른 일 측면은 본 발명의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is from the group consisting of cancer, degenerative brain disease, and inflammatory disease containing a compound of the present invention, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of one or more selected protein kinase-related diseases.
본 발명의 일 측면에서 제공하는 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염은 HPK1 및 LRRK2등을 포함하는 다양한 단백질 키나아제에 대하여 높은 억제능을 나타내므로, 이를 유효성분으로 포함하는 약학적 조성물은 단백질 키나아제 관련 질환, 예를 들어, 암, 퇴행성 뇌질환, 또는 염증질환 등의 예방 또는 치료에 유용하게 사용될 수 있다. The compound provided in one aspect of the present invention, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof exhibits a high inhibitory ability against various protein kinases including HPK1 and LRRK2. A pharmaceutical composition comprising a protein kinase-related disease, for example, cancer, degenerative brain disease, or inflammatory disease can be usefully used for prevention or treatment.
이하, 본 발명을 실시 태양으로 예를 들어 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of example.
본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 태양으로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art.
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.In the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
본 명세서의 구조식에서, 원자 및/또는 기(group)를 결합하는 기호 "-"는 단일 결합, 기호 "="는 이중 결합을 의미할 수 있다. 상기 기호는 생략될 수 있으며, 결합 원자 또는 결합 위치를 특정하는 경우 등 필요한 경우 표시될 수도 있다. In the structural formulas of the present specification, the symbol "-" bonding an atom and/or a group may mean a single bond, and the symbol "=" may mean a double bond. The symbol may be omitted, and may be indicated if necessary, such as when specifying a bonding atom or a bonding position.
본 명세서에서 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, C 1-8 알킬아미노, 또는 C 1-8의 알킬렌기 등일 수 있고, 이에 제한되는 것이 아니며, 상기 원자/및 또는 기(group)는 치환되거나 비치환될 수 있다.In the present specification, "connected" between atoms may include not only a case of direct connection between atoms, but also a case of indirect connection between atoms through the mediation of other atoms and/or groups. At this time, the other atom and/or group (group) may be oxygen, sulfur, C 1-8 alkylamino, or C 1-8 alkylene group, and the like, but is not limited thereto, and the atom/or group (group) ) may be substituted or unsubstituted.
본 명세서에서 "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)), C 1~10 알킬, C 2~10 알켄일, C 2~10 알킨일, 하이드록실, C 1~10 알콕시, 아미노, 나이트로, 싸이올(thiol), 싸이오에터, 이민, 사이아노, 포스포나토(phosphonato), 포스핀(phosphine), 카복시, 카바모일(carbamoyl), 카밤산, 아세탈, 요소, 싸이오카보닐, 설폰일, 설폰아마이드(sulfonamide), 케톤, 알데히드, 에스터, 아세틸, 이세톡시, 아마이드, 산소(=0), 할로알킬(예를 들어, 트라이플루오로메틸), 치환 아미노아실과 아미노알킬, 탄소고리 사이클로 알킬로서 단일 고리이거나 융합 혹은 비융합 다중 고리 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 또는 사이클로헥실), 혹은 헤테로 사이클로 알킬로서 단일 고리이거나 융합 또는 비융합된 다중 고리 (예를 들어, 피롤리딘일, 피페리딘일, 피페라진일, 모폴린일, 또는 싸이아진일), 탄소고리 또는 헤테로 고리, 단일고리 또는 융합 또는 비융합 다중 고리 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 specification, "substituted or unsubstituted" may mean that one or a plurality of hydrogen atoms are substituted or not substituted with other atoms or substituents unless otherwise specified. The substituent is halogen (chloro (Cl), iodo (I), bromo (Br), fluoro (F)), C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, hydr Roxy, C 1~10 Alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphonato, phosphine, carboxy, carbamoyl, car Bamic acid, acetal, urea, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, isetoxy, amide, oxygen (=0), haloalkyl (eg trifluoromethyl) , substituted aminoacyl and aminoalkyl, single ring as carbocyclic cycloalkyl or fused or unfused multiple rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or single ring or fused as heterocycloalkyl or unfused multiple rings (eg, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), carbocyclic or heterocyclic, monocyclic or fused or unfused multicyclic aryl ( For example, 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), aryl, aryloxy, and may be at least one selected from the group consisting of aryl-alkyl, but is not limited thereto. In addition, each of the substituents exemplified above may again be unsubstituted or substituted with a substituent selected from these substituent groups.
본 명세서에서, "단일 고리"는 1개의 고리로, 포화, 불포화 또는 방향족 고리를 의미할 수 있으며, 헤테로원자를 포함할 수 있다. 더욱이, 상기 고리에 수소가 제거된 형태의 고리도 포함할 수 있다.As used herein, "single ring" is a single ring, and may mean a saturated, unsaturated or aromatic ring, and may include a heteroatom. Furthermore, it may include a ring in which hydrogen is removed from the ring.
본 명세서에서, "이환 고리"는 하나 이상의 원자를 공통으로 가지면서 서로 융합된 2개의 고리를 의미할 수 있다. 구체적으로는 공통적인 단일 또는 이중 결합을 통해 형성되거나(다중고리화된 이환 고리), 3개 이상의 배열된 원자들을 공유하여 형성되거나(가교된 이환 고리) 또는 공통적인 단일 원자를 통해 형성될 수 있다(스피로 이환 고리). 이환 고리는 포화, 부분 불포화, 불포화 또는 방향족 고리일 수 있으며, 헤테로원자를 포함할 수 있다. 더욱이, 상기 고리에 수소가 제거된 형태의 고리도 포함할 수 있다.As used herein, "bicyclic ring" may mean two rings fused to each other while having one or more atoms in common. Specifically, it may be formed through a common single or double bond (polycyclic bicyclic ring), formed by sharing three or more arranged atoms (bridged bicyclic ring), or formed through a common single atom (spirobicyclic ring). The bicyclic ring may be a saturated, partially unsaturated, unsaturated or aromatic ring and may contain heteroatoms. Furthermore, it may include a ring in which hydrogen is removed from the ring.
본 명세서에서, "할로겐"은, F, Cl, Br, 또는 I일 수 있다.As used herein, "halogen" may be F, Cl, Br, or I.
본 명세서에서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형; 고리형; 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 또한, "C 1-8 알킬"은 탄소 원자를 1 내지 8개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, N-프로필, N-부틸, N-펜틸, N-헥실, N-헵틸, N-옥틸, 아이소프로필, 2급(sec)-부틸, 아이소부틸, 3급(tert)-부틸, 아이소펜틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2,3-다이메틸부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 비고리형과 고리형 알킬이 결합된 알킬은, 예를 들어, 메틸사이클로프로필, 사이클로프로필메틸, 에틸사이클로프로필, 사이클로프로필에틸, 메틸사이클로부틸, 사이클로부틸메틸, 에틸사이클로펜틸, 또는 사이클로펜틸메틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present specification, "alkyl", unless otherwise specified, a straight-chain or branched acyclic type; cyclic; Or it may mean a saturated hydrocarbon to which they are bound. Also, "C 1-8 alkyl" may refer to an alkyl containing 1 to 8 carbon atoms. Acyclic alkyl is, for example, methyl, ethyl, N-propyl, N-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl, isopropyl, sec-butyl, isobutyl , tert-butyl, isopentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like, but is not limited thereto. Cyclic alkyl may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as an example. Alkyl in which acyclic and cyclic alkyl are bonded is, for example, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, cyclopropylethyl, methylcyclobutyl, cyclobutylmethyl, ethylcyclopentyl, or cyclopentylmethyl. may include, but is not limited to.
본 명세서에서, "사이클로알킬"이라고 기재한 경우, 알킬 중에서도 특히 고리형 알킬을 의미할 수 있고, 여기서 알킬은 상기에서 정의된 바와 같다. In the present specification, when "cycloalkyl" is described, it may mean a cyclic alkyl among alkyls, where alkyl is as defined above.
본 명세서에서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서 알킬은 상기에서 정의된 바와 같다. 또한, "C 1-8 알콕시"는 C 1-8 알킬을 함유하는 알콕시, 즉, -(O-C 1-8알킬)을 의미할 수 있으며, 일 예로서, C 1-8 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소-부톡시(iso-butoxy), sec-부톡시(sec-butoxy), tert-부톡시(tert-butoxy), n-펜톡시(n-pentoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. As used herein, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, where alkyl is as defined above. In addition, "C 1-8 alkoxy" may mean an alkoxy containing C 1-8 alkyl, that is, -(OC 1-8 alkyl), for example, C 1-8 alkoxy is methoxy (methoxy ), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy ( sec-butoxy), tert-butoxy, n-pentoxy, etc., but is not limited thereto.
본 명세서에서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일고리이거나, 스피로(spiro)고리, 다리(bridged)고리 또는 융합(fused)고리와 같은 다중고리일 수 있다. 또한, "3 내지 12 원자의 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, N-메틸피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모폴린, 싸이오모폴린, 싸이오모폴린-S-옥사이드, 싸이오모폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스피로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Unless otherwise stated, heterocycloalkyl may be a single ring or a multicyclic ring such as a spiro ring, a bridged ring, or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, heterocycloalkyl is pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 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, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1] octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane; It is not limited.
본 명세서에서, "알킬아미노"는 -(NR′R″)을 의미할 수 있으며, 여기서 R′ 및 R″은 각각 독립적으로 수소 및 C 1-8 알킬 이루어진 군 중에서 선택될 수 있으며, 상기 선택된 R′및 R″은 각각 독립적으로 치환되거나 비치환될 수 있다. 또한, "C 1-8 알킬아미노"는 C 1-8 알킬을 함유하는 아미노, 즉, -N-H(C 1-8알킬) 또는 -N-(C 1-8알킬) 2을 의미할 수 있으며, 다이메틸아미노, 다이에틸아미노, 메틸에틸아미노, 메틸프로필아미노, 또는 에틸프로필아미노를 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present specification, "alkylamino" may mean -(NR′R″), where R′ and R″ may each independently be selected from the group consisting of hydrogen and C 1-8 alkyl, and the selected R 'and R' may each independently be substituted or unsubstituted. Also, "C 1-8 alkylamino" may mean an amino containing C 1-8 alkyl, that is, -NH(C 1-8 alkyl) or -N-(C 1-8 alkyl) 2 , dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.
본 명세서에서, "하이드록시알킬"은 알킬 기의 하나 이상의 수소 원자가 하이드록시기로 대체된 알킬기를 나타낸다. 하이드록시알킬의 예는 하이드록시메틸, 2-하이드록시에틸, 2-하이드록시프로필, 3-하이드록시프로필, 1-(하이드록시메틸)-2-메틸프로필, 2-하이드록시부틸, 3-하이드록시부틸, 4-하이드록시부틸, 2,3-다이하이드록시프로필, 2-하이드록시-1-하이드록시메틸에틸, 2,3-다이하이드록시부틸, 3,4-다이하이드록시부틸 또는 2-(하이드록시메틸)-3-하이드록시프로필을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by a hydroxy group. Examples of hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxy hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2- (hydroxymethyl)-3-hydroxypropyl, but is not limited thereto.
본 명세서에서, "할로알킬"은 -RX(X는 하나 이상의 할로겐(F, Cl, Br, 또는 I 등))을 의미할 수 있으며, 즉, "할로알킬"은 하나 이상의 할로겐이 치환된 알킬 형태일 수 있다. 예컨대, "C 1-8 할로알킬"은 트라이플루오로메틸, 다이플루오로메틸, 플루오로메틸, 2,2,2-트라이플루오로에틸, 4-클로로부틸, 3-브로모프로필 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "haloalkyl" may mean -RX (X is one or more halogens (F, Cl, Br, or I, etc.)), i.e., "haloalkyl" is an alkyl form in which one or more halogens are substituted. can be For example, “C 1-8 haloalkyl” may include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. However, the present invention is not limited thereto.
본 명세서에서, "할로알콕시"는 -(O-RX) (X는 하나 이상의 할로겐(F, Cl, Br, 또는 I 등))을 의미할 수 있으며, 즉, "할로알콕시"는 하나 이상의 할로겐이 치환된 알콕시 형태일 수 있다. 예컨대, "C 1-8 할로알콕시"는 트라이플루오로메톡시, 다이플루오로메톡시, 플루오로메톡시, 2,2,2-트라이플루오로에톡시, 4-클로로부톡시, 3-브로모프로폭시 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "haloalkoxy" may mean -(O-RX) (X is one or more halogens (F, Cl, Br, or I, etc.)), that is, "haloalkoxy" means one or more halogens It may be in the form of a substituted alkoxy. For example, "C 1-8 haloalkoxy" is trifluoromethoxy, difluoromethoxy, fluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropoxy, etc. may include, but is not limited thereto.
본 명세서에서, "아릴"은 방향족 탄화수소 고리로부터 하나의 수소가 제거된 방향족 고리를 의미할 수 있고, 단일고리 또는 다중고리일 수 있다. "3 내지 12 원자의 아릴"은 고리를 형성하는 원자를 3 내지 12개 포함하는 아릴을 의미할 수 있으며, 일 예로서, 페닐, 벤질, 나프틸, 안트라센일, 페난트릴, 바이페닐, 또는 터페닐 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "aryl" may mean an aromatic ring in which one hydrogen is removed from an aromatic hydrocarbon ring, and may be a single ring or a multicyclic ring. "3 to 12 membered aryl" may mean an aryl containing 3 to 12 atoms forming a ring, for example, phenyl, benzyl, naphthyl, anthracenyl, phenanthryl, biphenyl, or ter It may include, but is not limited to, phenyl and the like.
본 명세서에서, "헤테로아릴"은 고리를 형성하는 원자로 N, O, 및 S 중 1개 이상의 헤테로 원자를 함유하는 방향족 고리를 의미할 수 있고, 단일고리 또는 다중고리일 수 있다. 또한, "3 내지 12 원자의 헤테로아릴"은 고리를 형성하는 원자를 3 내지 12개 포함하는 헤테로아릴을 의미할 수 있으며, 일 예로서, 싸이에닐, 싸이오펜, 퓨릴, 피롤릴, 피라졸릴, 이미다졸릴, 싸이아졸릴, 옥사졸릴, 아이소싸이아졸릴, 옥사다이아졸릴, 트라이아졸릴, 피리딘일, 비피리딜, 피리미딜, 트라이아진일, 트라이아졸릴, 아크리딜기, 피리다진일기, 피라진일, 퀴놀린일, 퀴나졸린, 퀴녹살린일, 페녹사질, 프탈라진일, 피리미딘일, 피리도 피리미딘일, 피리도 피라진일, 피라지노 피라진일, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진일, 이미다조피리딘일, 이미다조피리미딘일, 피라졸로피리미딘일, 이미다조피라진일, 또는 피라졸로피리딘일, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸기, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오페닐, 싸이에노싸이오펜, 벤조퓨란일, 페난트롤린, 아이소옥사졸릴, 옥사다이아졸릴, 싸이아다이아졸릴, 벤조싸이아졸릴, 테트라졸릴, 페노싸이아진일, 다이벤조실롤 또는 다이벤조퓨란일 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. As used herein, "heteroaryl" may mean an aromatic ring containing one or more heteroatoms among N, O, and S as atoms forming the ring, and may be a single ring or a polycyclic ring. In addition, "3 to 12 membered heteroaryl" may mean a heteroaryl containing 3 to 12 atoms forming a ring, for example, thienyl, thiophene, furyl, pyrrolyl, pyrazolyl , imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridyl, pyrimidyl, triazinyl, triazolyl, acridyl group, pyridazinyl group , pyrazinyl, quinolinyl, quinazoline, quinoxalinyl, phenoxazil, phthalazinyl, pyrimidinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazinopyrazinyl, isoquinoline, indole, carbazole, Imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazopyrazinyl, or pyrazolopyridinyl, N-arylcarbazole, N-heteroarylcarbazole, N-alkyl Carbazole group, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophenyl, thienothiophene, benzofuranyl, phenanthroline, isoxazolyl, oxadiazolyl , thiadiazolyl, benzothiazolyl, tetrazolyl, phenothiazinyl, dibenzosilol or dibenzofuranyl, and the like, but is not limited thereto.
본 명세서에서, "하이드록시"는 -OH를 의미할 수 있다.As used herein, "hydroxy" may mean -OH.
본 명세서에서, "카보닐"은 -(C=(O))-을 의미할 수 있고, 고리형 알킬, 아릴, 헤테로사이클로알킬이 카보닐로 치환된 경우, 수소 원자가 (=O)로 치환되는 경우를 의미할 수 있다. In the present specification, "carbonyl" may mean -(C=(O))-, and when cyclic alkyl, aryl, or heterocycloalkyl is substituted with carbonyl, a hydrogen atom is substituted with (=O) case can mean
본 명세서에서, "알킬카보닐"은 -(C(=O)-알킬)을 의미할 수 있으며, 여기서 알킬은 상기에서 정의된 바와 같다. 또한, "C 1-8 알킬카보닐"은 C 1-8 알킬을 함유하는 카보닐, 즉, -(C(=O)-C 1-8알킬)을 의미할 수 있으며, 일 예로서, 메틸카보닐(아세틸, -(C=(O)-CH 3)), 에틸카보닐, n-프로필카보닐, 아이소-프로필카보닐, n-부틸카보닐, sec-부틸카보닐, 아이소부틸카보닐, tert-부틸카보닐, n-옥틸카보닐, 사이클로프로필카보닐, 사이클로부틸카보닐, 사이클로펜틸카보닐, 또는 사이클로헥실카보닐 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. As used herein, "alkylcarbonyl" may mean -(C(=O)-alkyl), where alkyl is as defined above. In addition, "C 1-8 alkylcarbonyl" may mean a carbonyl containing C 1-8 alkyl, that is, -(C(=O)-C 1-8 alkyl), for example, methyl Carbonyl (acetyl, -(C=(O)-CH 3 )), ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl , tert-butylcarbonyl, n-octylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, or cyclohexylcarbonyl, but is not limited thereto.
본 명세서에서, "알케닐"은 다른 기재가 없는 한 1개 이상의 이중 결합을 갖는 직쇄, 분지쇄의 비고리형 또는 고리형의 탄화수소를 의미할 수 있다. 또한, "C 2-8 알케닐"은 탄소 원자를 2 내지 8개 포함하는 알케닐을 의미할 수 있으며, 일 예로서, 에텐일, 1-프로펜일, 프로프-2-엔-1-일[-(CH 2-CH=CH 2)], 2-부텐일, 아이소프로펜일, 3-부텐일, 4-펜텐일, 5-헥센일, 1-사이클로헥센일, 사이클로펜타다이엔일, 1,3-사이클로헥사다이엔일, 1,4-사이클로헥사다이엔일, 1,3-사이클로헵타다이엔일, 또는 1,3,5-사이클로헵타트라이엔일 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, "alkenyl" may mean a straight-chain, branched-chain acyclic or cyclic hydrocarbon having one or more double bonds, unless otherwise specified. In addition, "C 2-8 alkenyl" may mean alkenyl containing 2 to 8 carbon atoms, for example, ethenyl, 1-propenyl, prop-2-en-1-yl [-(CH 2 -CH=CH 2 )], 2-butenyl, isopropenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 1-cyclohexenyl, cyclopentadienyl, 1 ,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, or 1,3,5-cycloheptatrienyl, etc., but are limited thereto it is not going to be
본 명세서에서, "알케닐카보닐"은 -(C(=O)-알케닐)을 의미할 수 있으며, 여기서 알케닐은 상기에서 정의된 바와 같다. 또한, "C 2-8 알케닐카보닐"은 C 2-8 알케닐을 함유하는 카보닐, 즉, -(C(=O)- C 2-8알케닐)을 의미할 수 있다. As used herein, "alkenylcarbonyl" may mean -(C(=O)-alkenyl), where alkenyl is as defined above. Also, "C 2-8 alkenylcarbonyl" may mean a carbonyl containing C 2-8 alkenyl, ie, -(C(=O)-C 2-8 alkenyl).
본 명세서에서, "사이아노"는 -(CN)을 의미할 수 있다.As used herein, "cyano" may mean -(CN).
본 명세서에서, "알키닐"은 다른 기재가 없는 한 1개 이상의 삼중 결합을 갖는 직쇄, 분지쇄의 비고리형 도는 고리형의 탄화수소를 의미할 수 있다. 또한, "C 2-8 알키닐"은 탄소 원자를 2 내지 8개 포함하는 알키닐을 의미할 수 있으며, 일 예로서, 에틴일, 프로핀일, 하이드록시프로핀일, 부틴-1-일, 부틴-2-일, 펜틴-1-일, 3-메틸부틴-1-일, 또는 헥신-2-일 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.As used herein, unless otherwise specified, "alkynyl" may mean a straight-chain, branched-chain acyclic or cyclic hydrocarbon having one or more triple bonds. In addition, "C 2-8 alkynyl" may mean alkynyl containing 2 to 8 carbon atoms, for example, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyne -2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl, but is not limited thereto.
본 명세서에서, "아르알킬"은 -(알킬-아릴)을 의미할 수 있으며, 여기서, 알킬 및 아릴은 상기에서 정의된 바와 같다. 또한, "3 내지 8 원자의 아르알킬"은 탄소 원자를 3 내지 8개 포함하는 아르알킬을 의미할 수 있다. As used herein, "aralkyl" may mean -(alkyl-aryl), where alkyl and aryl are as defined above. Also, "aralkyl of 3 to 8 atoms" may mean aralkyl containing 3 to 8 carbon atoms.
본 명세서에서, "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미할 수 있다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 량의 물을 포함할 수 있다. 상기 수화물은 1 당량 이상, 바람직하게는, 1 당량 내지 5 당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약제학적으로 허용가능한 염을 결정화시켜 제조될 수 있다.As used herein, "hydrate" refers to the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. a compound of the invention or a salt thereof. The hydrate of the compound represented by Formula 1 of the present invention may include a stoichiometric or non-stoichiometric amount of water that is bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more, preferably, 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 of the present invention, an isomer thereof, or a pharmaceutically acceptable salt thereof from water or a solvent containing water.
본 명세서에서, "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 량의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미할 수 있다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.As used herein, "solvate" may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.
본 명세서에서, "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미할 수 있다. 이러한 이성질체에는 호변이성질체(tautomer) 등의 구조이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체, 광학 이성질체(enantiomer)가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.As used herein, "isomer" may mean a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula but is structurally or sterically different. These isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.
본 발명의 일 측면은, 하기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.One aspect of the present invention is to provide a compound of Formula 1 below, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2020016377-appb-img-000003
Figure PCTKR2020016377-appb-img-000003
상기 화학식 1에 있어서,In Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리(bicyclic ring)를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
상기 R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐으로 치환되거나 비치환되며,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
R 3은 3 내지 8 원자의 사이클로알킬 또는 3 내지 8 원자의 헤테로사이클로알킬이며,R 3 is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocycloalkyl,
R 4는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐이고,R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
R 5 및 R 6은 각각 독립적으로 C 1-6 알킬아미노로 치환되거나 비치환된 C 1-6 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 12 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 12 membered heterocycloalkyl,
상기 R 5 및 R 6이 형성한 3 내지 12 원자의 헤테로사이클로알킬은 C 1-6 알킬, C 1-6 하이드록시알킬, C 1-6 알콕시, 3 내지 12 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,3 to 12 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 12 membered heterocycloalkyl, —(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
상기 R 8은 4 내지 12 원자의 단일 고리(monocyclic ring) 또는 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 12 membered monocyclic ring or a bicyclic ring and is unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 C 1-6 알킬, C 1-6 알콕시, 5 내지 8 원자의 아릴, 사이아노, C 1-6 알킬아미노, C 1-6 할로알킬, C 1-6 할로알콕시, C 1-6 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택된다.The substituent R 9 is C 1-6 alkyl, C 1-6 alkoxy, 5-8 membered aryl, cyano, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkylsulfonamido, and oxo (=O).
본 발명의 일 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In one embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 수소, C 1-3 알킬, C 1-3 알콕시, 또는 할로겐으로 치환되거나 비치환될 수 있고,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 may be unsubstituted or substituted with hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or halogen,
상기 R 4는 수소, C 1-3 알킬, C 1-3 알콕시, 또는 할로겐일 수 있다.R 4 may be hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or halogen.
본 발명의 일 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In one embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
상기 R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 C 1-6 알킬로 치환되거나 비치환되며,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-6 alkyl,
R 3은 3 내지 8 원자의 사이클로알킬이며,R 3 is 3 to 8 membered cycloalkyl,
R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
R 5 및 R 6은 각각 독립적으로 C 1-6 알킬아미노로 치환되거나 비치환된 C 1-6 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl,
상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-6 알킬, C 1-6 하이드록시알킬, C 1-6 알콕시, 3 내지 8 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,The 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-8 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 C 1-6 알킬, C 1-6 알콕시, 5 내지 8 원자의 아릴, 사이아노, C 1-6 알킬아미노, C 1-6 할로알킬, C 1-6 할로알콕시, C 1-6 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택될 수 있다. The substituent R 9 is C 1-6 alkyl, C 1-6 alkoxy, 5-8 membered aryl, cyano, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkylsulfonamido, and oxo (=O).
본 발명의 다른 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In another embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 10 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
상기 R 1 및 R 2가 형성한 8 내지 10 원자의 이환 고리는 C 1-3 알킬로 치환되거나 비치환되며,The 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl,
R 3은 3 내지 6 원자의 사이클로알킬이며,R 3 is 3 to 6 membered cycloalkyl,
R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
R 5 및 R 6은 각각 독립적으로 C 1-3 알킬아미노로 치환되거나 비치환된 C 1-3 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or they are joined together with the N atom to which they are attached to form a 3-8 membered heterocycloalkyl,
상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-3 알킬, C 1-3 하이드록시알킬, C 1-3 알콕시, 3 내지 6 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,The 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3-6 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 C 1-3 알킬, C 1-3 알콕시, 벤질, 사이아노, C 1-3 알킬아미노, C 1-3 할로알킬, C 1-3 할로알콕시, C 1-3 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택될 수 있다. The substituent R 9 is C 1-3 alkyl, C 1-3 alkoxy, benzyl, cyano, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylsulfonami It may be selected from the group consisting of degrees, and oxo (=O).
본 발명의 또 다른 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In another embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 10 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
상기 R 1 및 R 2가 형성한 8 내지 10 원자의 이환 고리는 C 1-3 알킬로 치환되거나 비치환되며,The 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl,
R 3은 3 내지 6 원자의 사이클로알킬이며,R 3 is 3 to 6 membered cycloalkyl,
R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
R 5 및 R 6은 각각 독립적으로 C 1-3 알킬아미노로 치환되거나 비치환된 C 1-3 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 N, O 및 S 로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or at least one selected from the group consisting of N, O and S linked together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl containing heteroatoms,
상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-3 알킬, C 1-3 하이드록시알킬, C 1-3 알콕시, O 원자를 하나 이상 포함하는 3 내지 6 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,3 to 8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3 to 6 atoms including at least one O atom substituted or unsubstituted with one or more substituents R 7 selected from the group consisting of heterocycloalkyl, -(CH 2 )nR 8 , and -C(O)-R 8 , wherein n is an integer from 1 to 3;
상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 C 1-3 알킬, C 1-3 알콕시, 벤질, 사이아노, C 1-3 알킬아미노, C 1-3 할로알킬, C 1-3 할로알콕시, C 1-3 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택될 수 있다. The substituent R 9 is C 1-3 alkyl, C 1-3 alkoxy, benzyl, cyano, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylsulfonami It may be selected from the group consisting of degrees, and oxo (=O).
본 발명의 다른 구체적인 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In another specific embodiment of the present invention, in the compound represented by Formula 1,
상기 R 5 및 R 6이 형성한 N, O 및 S 로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬은 단일 고리 또는 브릿지 고리 형태일 수도 있다. 여기서 브릿지 고리 형태는 2가 탄화수소 브릿지로 가교된 형태일 수 있으며, 구체적으로는 다이아자바이사이클로[2.2.1]헵탄일, 다이아자바이사이클로[3.1.1]헵탄일, 또는 다이아자바이사이클로[2.2.2]옥탄일일 수 있다.The 3 to 8 membered heterocycloalkyl including at least one hetero atom selected from the group consisting of N, O and S formed by R 5 and R 6 may be in the form of a single ring or a bridged ring. Here, the bridged ring form may be a form bridged by a divalent hydrocarbon bridge, and specifically, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl, or diazabicyclo[2.2.2 ] may be octane.
본 발명의 또 다른 구체적인 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In another specific embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 10 원자의 이환 고리를 형성하고, 상기 피리미딘 고리와 함께 형성된 8 내지 10 원자의 이환고리는 퀴나졸린, 퓨로피리미딘, 싸이에노피리미딘, 사이클로펜타피리미딘, 또는 피롤로피리미딘이고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members, the 8 to 10 membered bicyclic ring formed together with the pyrimidine ring is quinazoline, puropyrimidine, thienopyrimidine, cyclopentapyrimidine, or pyrrolopyrimidine;
R 8은 페닐, 피리딘일, 피리미딘일, 피라진일, 아이소옥사졸일, 피라졸일, 이미다조피리딘일, 싸이아졸일, 옥사졸일, 퀴놀린일, 퓨란일, 나프탄일, 옥사다이아졸일, 다이하이드로벤조다이옥신일, 또는 다이하이드로벤조퓨란일일 수 있다.R 8 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, pyrazolyl, imidazopyridinyl, thiazolyl, oxazolyl, quinolinyl, furanyl, naphtanyl, oxadiazolyl, dihydro benzodioxinyl, or dihydrobenzofuranyl.
본 발명의 구체적인 다른 실시 양태에서, 화학식 1로 표시되는 화합물에 있어서,In another specific embodiment of the present invention, in the compound represented by Formula 1,
R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 퀴나졸린, 퓨로피리미딘, 싸이에노피리미딘, 사이클로펜타피리미딘, 또는 피롤로피리미딘을 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a quinazoline, furopyrimidine, thienopyrimidine, cyclopentapyrimidine, or pyrrolopyrimidine;
R 3은 사이클로프로필 또는 사이클로부틸이고,R 3 is cyclopropyl or cyclobutyl,
R 4는 수소 또는 플루오로이고,R 4 is hydrogen or fluoro,
Figure PCTKR2020016377-appb-img-000004
는 (2-(다이메틸아미노)에틸)(메틸)아미노, 피페라진일, 다이아자바이사이클로[3.1.1]헵탄일, 또는 모폴린일이고,
Figure PCTKR2020016377-appb-img-000004
is (2-(dimethylamino)ethyl)(methyl)amino, piperazinyl, diazabicyclo[3.1.1]heptanyl, or morpholinyl,
상기 R 5 및 R 6이 형성한 피페라진일, 다이아자바이사이클로[3.1.1]헵탄일, 또는 모폴린일은 메틸, 하이드록시에틸, 옥세탄일, -(CH 2)-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며,Piperazinyl, diazabicyclo[3.1.1]heptanyl, or morpholinyl formed by R 5 and R 6 is methyl, hydroxyethyl, oxetanyl, -(CH 2 )-R 8 , and -C (O)-R 8 substituted or unsubstituted with one or more substituents R 7 selected from the group consisting of,
R 8은 페닐, 피리딘일, 피리미딘일, 피라진일, 아이소옥사졸일, 피라졸일, 이미다조피리딘일, 싸이아졸일, 옥사졸일, 퀴놀린일, 퓨란일, 나프탄일, 옥사다이아졸일, 다이하이드로벤조다이옥신일, 또는 다이하이드로벤조퓨란일이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,R 8 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, isoxazolyl, pyrazolyl, imidazopyridinyl, thiazolyl, oxazolyl, quinolinyl, furanyl, naphtanyl, oxadiazolyl, dihydro benzodioxinyl, or dihydrobenzofuranyl, unsubstituted or substituted with one or more substituents R 9 ,
상기 치환기 R 9는 메틸, 메톡시, 다이플루오로메톡시, 에톡시, 메톡시, 사이아노, 메탄설폰아미도, 옥소, 메틸아미노, 트라이플루오로메틸, 또는 벤질일 수 있다.The substituent R 9 may be methyl, methoxy, difluoromethoxy, ethoxy, methoxy, cyano, methanesulfonamido, oxo, methylamino, trifluoromethyl, or benzyl.
본 발명에 따른 상기 화학식 1의 화합물의 예로는 하기 실시예 중 [표 1]에 나열된 화합물 1 내지 53, 또는 유리 염기(표 1에 약학적으로 허용가능한 염으로 나타낸 경우), 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 들 수 있다. Examples of the compound of Formula 1 according to the present invention include compounds 1 to 53 listed in [Table 1] in the following Examples, or a free base (when shown as a pharmaceutically acceptable salt in Table 1), isomers thereof, and hydrates thereof , a solvate thereof, or a pharmaceutically acceptable salt thereof.
본 발명의 상기 화학식 1로 표시되는 화합물은 이의 약학적으로 허용가능한 염의 형태로 사용될 수 있다. 특히, 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. 이러한 약학적으로 허용가능한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 아이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-다이오에이트, 헥산-1,6-다이오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 다이나이트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함할 수 있다. 상기 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 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. 또한, 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 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다. The compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt thereof. In particular, the pharmaceutically acceptable salt may be an acid addition salt formed with a free acid. Here, the acid addition salt includes inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, and the like, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, and hydroxy alkanoates. and non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. It can be obtained from the same organic acid. Examples of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate , methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate , glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. The acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid to filter the resulting precipitate , it can be prepared by drying, or by distilling the solvent and excess acid under reduced pressure and then drying and crystallizing in an organic solvent. In addition, the pharmaceutically acceptable salt may be a salt or a metal salt obtained using a base. As an example of the metal salt, the 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 the undissolved compound salt, and evaporating and drying the filtrate. As alkali metal salts, sodium, potassium or calcium salts may be pharmaceutically suitable. Also, the corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이의 이성질체, 특히, 입체 이성질체, 특히, 거울상 이성질체일 수 있으며, 이로부터 제조될 수 있는 수화물 및/또는 용매화물일 수 있다. Furthermore, the present invention may be a compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, as well as an isomer, particularly a stereoisomer, particularly an enantiomer thereof, and a hydrate and/or solvent prepared therefrom. It can be cargo.
본 발명의 다른 측면은, 화학식 1의 화합물의 제조방법을 제공하는 것일 수 있다.Another aspect of the present invention may be to provide a method for preparing the compound of Formula 1.
화학식 1의 화합물의 제조방법은 하기 반응식 1에 나타난 바와 같이, 화학식 2의 화합물로부터 화학식 3의 화합물을 제조하는 단계(단계 1); 화학식 3의 화합물로부터 화학식 4의 화합물을 제조하는 단계(단계 2); 화학식 4의 화합물과 화학식 5의 화합물을 반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3); 및 화학식 6의 화합물로부터 화학식 1의 화합물을 제조하는 단계(단계 4);를 포함할 수 있다.The method for preparing the compound of Formula 1 includes the steps of preparing a compound of Formula 3 from the compound of Formula 2 (step 1), as shown in Scheme 1 below; preparing a compound of Formula 4 from a compound of Formula 3 (step 2); preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5 (step 3); and preparing a compound of Formula 1 from a compound of Formula 6 (step 4).
[반응식 1][Scheme 1]
Figure PCTKR2020016377-appb-img-000005
Figure PCTKR2020016377-appb-img-000005
상기 반응식 1에서, LG는 이탈기이고, PG는 보호기이며, R 1 내지 R 6는 각각 본 명세서에서 정의한 것과 동일할 수 있다. In Scheme 1, LG is a leaving group, PG is a protecting group, and R 1 to R 6 may be the same as defined herein, respectively.
이탈기는 할로겐, 설폰산 에스터, 또는 알콕시 등의 작용기일 수 있으며, 화학식 3의 화합물로부터 화학식 4의 화합물을 제조할 수 있고, 화학식 4의 화합물과 화학식 5의 화합물이 반응하여 화학식 6의 화합물을 제조할 수 있는 작용기이면 제한되지 않는다. The leaving group may be a functional group such as halogen, sulfonic acid ester, or alkoxy, and a compound of Formula 4 may be prepared from a compound of Formula 3, and a compound of Formula 4 may be reacted with a compound of Formula 5 to prepare a compound of Formula 6 It is not limited as long as it is a functional group that can do it.
보호기는 테트라하이드로피란(THP), (2-(트라이메틸실릴)메톡시)메틸(SEM), p-메톡시벤질(PMB), t-부틸옥시카보닐(BOC), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트라이클로로에톡시카보닐(Troc), 2-트라이메틸실릴에톡시카보닐(Teoc), 아릴옥시카보닐(Alloc), 또는 p-메톡시벤질(PMB) 등의 작용기일 수 있으며, 2차 아민을 보호할 수 있는 작용기라면 제한되지 않는다.The protecting group is tetrahydropyran (THP), (2-(trimethylsilyl)methoxy)methyl (SEM), p-methoxybenzyl (PMB), t-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz) , 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), aryloxycarbonyl (Alloc), or p-methoxybenzyl (PMB) ) may be a functional group, and is not limited as long as it is a functional group capable of protecting the secondary amine.
이하, 본 발명에 따른 상기 제조 방법을 상세히 설명한다.Hereinafter, the manufacturing method according to the present invention will be described in detail.
먼저, 상기 단계 1은 화학식 2의 화합물로부터 화학식 3의 화합물을 제조하는 단계로, 화학식 2의 화합물의 피라졸의 2차 아민을 보호기로 보호하는 단계일 수 있다. 상기 보호기는 2차 아민을 보호할 수 있는 작용기라면 제한없이 이용될 수 있으며, 일 예로 테트라하이드로피란(THP)일 수 있다.First, step 1 is a step of preparing a compound of Formula 3 from a compound of Formula 2, and may be a step of protecting a secondary amine of pyrazole of the compound of Formula 2 with a protecting group. The protecting group may be used without limitation as long as it is a functional group capable of protecting the secondary amine, and may be, for example, tetrahydropyran (THP).
화학식 2의 화합물과 보호기 화합물을 용매에 녹인 후, 30℃ 내지 100℃에서 10 내지 20시간, 구체적으로는 60℃에서 15시간 교반하였으며, 반응이 원활히 진행되는 조건이라면, 상기 조건에 제한되지 않을 수 있다. After dissolving the compound of Formula 2 and the protecting group compound in a solvent, the mixture was stirred at 30° C. to 100° C. for 10 to 20 hours, specifically at 60° C. for 15 hours, and if the reaction proceeds smoothly, the conditions may not be limited. have.
여기서, 사용 가능한 용매로는 톨루엔, 다이메틸아세트아마이드(DMA), 다이메틸포름아마이드(DMF), 다이메틸설폭사이드(DMSO), 메틸렌 클로라이드, 다이클로로에테인, 다이클로로메테인, 물, 에틸아세테이트, 아세토나이트릴; 아이소프로판올, 메탄올, 에탄올, 프로판올 및 부탄올을 포함하는 저급 알코올; 테트라하이드로퓨란(THF), 다이옥세인, 에틸에터, 1,2-다이메톡시에테인 등을 포함하는 에터 용매; 등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있고, 일 예로는 다이클로로메테인일 수 있다.Here, the usable solvent includes toluene, dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methylene chloride, dichloroethane, dichloromethane, water, ethyl acetate, acetonitrile; lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; ether solvents including tetrahydrofuran (THF), dioxane, ethyl ether, 1,2-dimethoxyethane, and the like; and the like, and these may be used alone or in combination, and an example may be dichloromethane.
단계 2는 화학식 3의 화합물로부터 화학식 4의 화합물을 제조하는 단계로, 화학식 3의 화합물과
Figure PCTKR2020016377-appb-img-000006
을 물 및 용매에 녹인 뒤 팔라듐 촉매를 첨가할 수 있다. 그 후 50℃ 내지 120℃에서 0.5 내지 3시간, 구체적으로는 90℃에서 1시간 교반하였으며, 반응이 원활히 진행되는 조건이라면, 상기 조건에 제한되지 않을 수 있다. 여기서 용매는 상기 단계 1의 사용 가능한 용매에 나열되어 있는 바와 동일할 수 있으며, 일 예로는 다이옥세인일 수 있다.Step 2 is a step of preparing a compound of Formula 4 from a compound of Formula 3, and the compound of Formula 3 and
Figure PCTKR2020016377-appb-img-000006
may be dissolved in water and a solvent, and then a palladium catalyst may be added. After that, the mixture was stirred at 50° C. to 120° C. for 0.5 to 3 hours, specifically at 90° C. for 1 hour, and if the reaction proceeds smoothly, it may not be limited to the above conditions. Here, the solvent may be the same as listed in the usable solvents of step 1 above, and an example may be dioxane.
단계 3은 화학식 4의 화합물과 화학식 5의 화합물을 반응시켜 화학식 6의 화합물을 제조하는 단계로, 화학식 4의 화합물과 화학식 5의 화합물을 용매에 녹인 후, 60℃ 내지 120℃에서 10 내지 15시간, 구체적으로 90℃에서 12시간 교반하였으며, 반응이 원활히 진행되는 조건이라면, 상기 조건에 제한되지 않을 수 있다. 여기서 용매는 상기 단계 1의 사용 가능한 용매에 나열되어 있는 바와 동일할 수 있으며, 구체적으로는 다이메틸설폭사이드(DMSO)일 수 있다. Step 3 is a step of preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5. After dissolving a compound of Formula 4 and a compound of Formula 5 in a solvent, at 60° C. to 120° C. for 10 to 15 hours , Specifically, it was stirred at 90 ° C. for 12 hours, and if the reaction proceeds smoothly, it may not be limited to the above conditions. Here, the solvent may be the same as those listed in the usable solvents of step 1 above, and specifically may be dimethyl sulfoxide (DMSO).
단계 3에서 화학식 5의 화합물은 헤테로원자가 보호기로 보호된 형태일 수 있다.In step 3, the compound of Formula 5 may be in a form in which a heteroatom is protected by a protecting group.
단계 4는 화학식 6의 화합물을 화학식 1의 화합물을 제조하는 단계로, 화학식 6의 화합물에 산을 첨가하여 보호기를 제거하는 단계일 수 있으며, 필요에 따라, 보호기가 제거된 화학식 6의 화합물에 치환기 R 7을 부착하는 단계를 추가로 포함할 수 있다.Step 4 is a step of preparing a compound of Formula 1 from the compound of Formula 6, and may be a step of removing a protecting group by adding an acid to the compound of Formula 6, and if necessary, a substituent on the compound of Formula 6 from which the protecting group is removed It may further comprise the step of attaching R 7 .
화학식 6의 화합물을 용매에 녹인 후, 상온에서 10 내지 15시간, 구체적으로는 13시간 교반하였으며, 반응이 원활히 진행되는 조건이라면, 상기 조건에 제한되지 않을 수 있다. 여기서 용매는 상기 단계 1의 사용 가능한 용매에 나열되어 있는 바와 동일할 수 있으며, 일 예로는 다이옥세인일 수 있다.After dissolving the compound of Formula 6 in a solvent, the mixture was stirred at room temperature for 10 to 15 hours, specifically for 13 hours, and as long as the reaction proceeds smoothly, the conditions may not be limited. Here, the solvent may be the same as listed in the usable solvents of step 1 above, and an example may be dioxane.
각 단계별로 반응 후 결과물은 브린(brine)으로 세척할 수 있고, 유기층은 Na 2SO 4 로 남아있는 물을 제거할 수 있다. After the reaction in each step, the resultant may be washed with brine, and the remaining water may be removed from the organic layer as Na 2 SO 4 .
본 발명의 다른 측면은, 상기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공할 수 있다.Another aspect of the present invention is a pharmaceutical composition for preventing or treating protein kinase-related diseases, comprising the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. can provide
본 발명의 또 다른 측면은, 상기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 약학적 조성물을 제공할 수 있고, 여기서 화학식 1의 화합물은 AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, HPK1, JAK1(JH1domain-catalytic), JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LRRK2, LRRK2(G2019S), TRKA, TRKB, TRKC, 및 TYK2(JH1domain-catalytic)로 이루어지는 군으로부터 선택되는 하나 이상의 단백질 키나아제에 대하여 저해활성을 나타낼 수 있다.Another aspect of the present invention may provide a pharmaceutical composition comprising the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein Formula 1 The compounds of AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD) , FLT3 (ITD,D835V), FLT3 (ITD,F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, HPK1, JAK1 (JH1domain-catalytic), JAK1 (JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT( V559D, V654A), LRRK2, LRRK2 (G2019S), TRKA, TRKB, TRKC, and TYK2 (JH1 domain-catalytic) may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of.
또한, 화학식 1의 화합물은 SLP76(S376)의 인산화 저해 활성을 나타낼 수 있다.In addition, the compound of Formula 1 may exhibit phosphorylation inhibitory activity of SLP76 (S376).
상기 단백질 키나아제 관련 질환은 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상일 수 있다.The protein kinase-related disease may be at least one selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease.
암의 종류는 제한되지 않으나, 예를 들어, 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 갑상선수질암, 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, 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, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상의 암인 것일 수 있다.The type of cancer is not limited, but for example, the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides. Sarcoma, acute myeloid leukemia, acute lymphocytic 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, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, Retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, Meningiomas, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, unknown primary site Cancer, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, Mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anus It may be one or more types of cancer selected from the group consisting of cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymus cancer.
퇴행성 뇌질환의 종류는 제한되지 않으나, 예를 들어, 퇴행성 뇌질환은 알츠하이머 질환, 파킨슨병, 루게릭병, 치매, 헌팅턴 질환, 다발성 경화증, 근위측성 측삭 경화증, 중풍, 뇌졸중, 및 경도 인지장애로 이루어진 군으로부터 선택되는 1종 이상의 질환일 수 있다. The type of degenerative brain disease is not limited, but for example, the degenerative brain disease may include Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, stroke, and mild cognitive impairment. It may be one or more diseases selected from the group.
염증질환의 종류는 제한되지 않으나, 예를 들어, 염증질환은 피부염, 알레르기, 위궤양, 십이지장궤양, 간염, 식도염, 위염, 장염, 췌장염, 대장염, 신장염, 전신부종, 국소부종, 관절염, 각막염, 기관지염, 흉막염, 복막염, 척추염, 염증성 통증, 요도염, 방광염, 치주염, 및 치은염으로 이루어진 군으로부터 선택되는 1종 이상의 질환일 수 있다.The type of inflammatory disease is not limited, but for example, inflammatory diseases include dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis , pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, cystitis, periodontitis, and may be at least one disease selected from the group consisting of gingivitis.
본 발명의 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물은, 임상 투여시에 이용될 수 있으며, 경구 및 비경구의 여러 가지 제형으로 투여될 수 있도록 제조될 수 있다. The pharmaceutical composition for preventing or treating protein kinase-related diseases of the present invention can be used in clinical administration, and can be prepared to be administered in various oral and parenteral formulations.
본 발명의 약학적 조성물은 약학적으로 허용가능한 담체를 포함할 수 있다. 상기 약학적으로 허용가능한 담체는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함하고, 본 발명의 조성물은 이들과 함께 사용하여 제제화될 수 있다.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like, and the composition of the present invention may be formulated using these together.
경구 투여를 위한 고형제제로는 정제, 환제, 산제, 과립제, 캡슐제 등이 해당될 수 있으며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들을 사용하여 조제될 수 있다. Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid preparations include one or more compounds and at least one excipient, for example, starch, calcium carbonate, sucrose ) or lactose, gelatin, etc. can be mixed and prepared. In addition, it may be formulated using lubricants such as magnesium stearate, talc, etc. in addition to simple excipients.
또한, 경구 투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당될 수 있으며, 이러한 액상제제는 흔히 사용되는 단순 희석제로서 물, 리퀴드 파라핀 이외에도 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다. In addition, liquid formulations for oral administration may correspond to suspensions, internal solutions, emulsions, syrups, etc., and these liquid formulations are commonly used simple diluents, in addition to water and liquid paraffin, various excipients, for example, wetting agents, sweetening agents, flavoring agents, preservatives, and the like.
비경구 투여를 위한 제제로는, 멸균된 수용액, 비수성용제, 현탁제, 유제 등이 해당될 수 있으며, 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스터 등을 이용할 수 있다.Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions, and non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, ethyl oleate, and the like. Injectable esters such as can be used.
또한, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의할 수 있다. 이 때, 비경구 투여용 제형으로 제제화하기 위하여, 약학적 조성물은 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법으로 혼합, 과립화 또는 코팅 방법에 따라 제제화될 수 있다. In addition, parenteral administration may be by a method of injecting subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. At this time, in order to formulate a formulation for parenteral administration, the pharmaceutical composition is prepared as a solution or suspension by mixing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in water together with a stabilizer or buffer, and this is an ampoule. Alternatively, it may be prepared in a vial unit dosage form. The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and may be mixed and granulated in a conventional manner. It can be formulated according to the method of formulation or coating.
상기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물은 개별 치료제로 투여되거나, 사용중인 다른 치료제와 병용 투여되어 사용할 수 있다.A pharmaceutical composition for the prevention or treatment of protein kinase-related diseases containing the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is administered or used as an individual therapeutic agent It can be used in combination with other therapeutic agents currently being used.
본 발명의 다른 측면은, 상기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention, cancer, degenerative brain disease comprising administering the compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof , and provides a method for preventing or treating one or more protein kinase-related diseases selected from the group consisting of inflammatory diseases.
본 발명의 또 다른 측면은, 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료에 있어서의 상기 화학식 1의 화합물 또는 이의 이성질체, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염의 용도를 제공하는 것이다.Another aspect of the present invention is the compound of Formula 1 or an isomer thereof, a solvate thereof in the prevention or treatment of at least one protein kinase-related disease selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease, Or to provide the use of a pharmaceutically acceptable salt thereof.
이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 이에 한정되는 것은 아니다.However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited thereto.
본 발명의 실시예에서 합성된 화합물은 다음의 HPLC 조건에 의해 정제하거나 또는 구조 분석을 실시하였다: 정제용 중압액체크로마토그래피(Medium pressure liquid chromatography; MPLC); 중압액체크로마토그래피는 TELEEDYNE ISCO사의 CombiFlash Rf +UV을 사용하였다.The compound synthesized in the Examples of the present invention was purified by the following HPLC conditions or subjected to structural analysis: Medium pressure liquid chromatography (MPLC) for purification; Medium pressure liquid chromatography was performed using TELEEDYNE ISCO's CombiFlash Rf +UV.
분석용 HPLC 조건 (ACQUITY UPLC H-Class Core System)Analytical HPLC conditions (ACQUITY UPLC H-Class Core System)
Waters사 제조 UPLC system (ACQUITY UPLC PDA Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 ACQUITY UPLC ®BEH C18 (1.7　㎛, 2.1X50 mm)였으며 컬럼온도는 30℃에서 진행하였다.An instrument equipped with a mass QDA Detector manufactured by Waters was used in the UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters. The column used was ACQUITY UPLC ® BEH C18 (1.7 μm, 2.1X50 mm) from Waters, and the column temperature was performed at 30°C.
이동상 A는 0.1% 개미산이 포함된 물, 이동상 B는 0.1%의 개미산이 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=0.6ml/min)Gradient condition (10-100% B for 3 minutes, movement speed = 0.6ml/min)
정제용 Prep-LCMS (Preparative-Liquid chromatography mass spectrometry)Prep-LCMS for purification (Preparative-Liquid chromatography mass spectrometry)
Waters사 제조 Autopurification HPLC system(2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 SunFire ®Prep C18 OBD TM(5　㎛, 19X50 mm)였으며 컬럼온도는 실온에서 진행하였다.The Autopurification HPLC system manufactured by Waters (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a mass QDA Detector manufactured by Waters was used. The column used was Waters' SunFire ® Prep C18 OBD TM (5 ㎛, 19X50 mm), and the column temperature was performed at room temperature.
이동상 A는 0.035% 트라이플루오로아세트산이 포함된 물, 이동상 B는 0.035%의 트라이플루오로아세트산이 포함된 메탄올을 사용하였다.Water containing 0.035% trifluoroacetic acid was used for mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used for mobile phase B.
Gradient condition(15-100% B로 10분, 이동속도=25ml/min)Gradient condition (15-100% B for 10 minutes, movement speed = 25ml/min)
정제용 Prep-150 LC System(Preparative-Liquid chromatography UV spectrometry)Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)
Waters사 제조 Prep 150 LC system(2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector Ⅲ)에 Waters사 제조 장비를 사용하였다. 사용 컬럼은 Waters사의 XTERRA ®Prep RP18 OBD TM(10　㎛, 30X300 mm)였으며 컬럼온도는 실온에서 진행하였다.The equipment manufactured by Waters was used for the Prep 150 LC system manufactured by Waters (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector Ⅲ). The column used was Waters' XTERRA ® Prep RP18 OBD TM (10 μm, 30X300 mm), and the column temperature was performed at room temperature.
Gradient condition(3-100% B로 120분, 이동속도=40ml/min)Gradient condition (120 minutes with 3-100% B, movement speed = 40ml/min)
사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온은 1~35℃ 정도의 온도를 말한다. 감압하 농축 또는 용매 증류 제거는 회전식 증발기(rotary evaporator)를 사용하였다.Commercial reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 1-35 °C. Concentration or solvent distillation under reduced pressure was performed using a rotary evaporator.
<실시예 1> N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민의 제조<Example 1> N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6- Preparation of diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine
Figure PCTKR2020016377-appb-img-000007
Figure PCTKR2020016377-appb-img-000007
단계 1: 2-클로로-N-(5-사이클로프로필-1H-피라졸-3-일)퀴나졸린-4-아민의 제조Step 1: Preparation of 2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl) quinazolin-4-amine
　2,4-다이클로로퀴나졸린 (10 g, 50.2 mmol, 1 eq), 5-사이클로프로필-1H-피라졸-3-아민 (6.81 g, 55.3 mmol, 5.92 mL, 1.1 eq), DIPEA (12.99 g, 100 mmol, 17.55 mL, 2 eq)를 DMSO (100 mL)에 녹인 뒤 80 ℃에서 30분간 교반하였다. 반응 혼합물에 물을 천천히 첨가하고 생성된 고체를 여과하였다. 고체를 물로 씻어준 뒤 회수하여 목적화합물 (9.14 g)을 수득하였다.2,4-dichloroquinazoline (10 g, 50.2 mmol, 1 eq), 5-cyclopropyl-1H-pyrazol-3-amine (6.81 g, 55.3 mmol, 5.92 mL, 1.1 eq), DIPEA (12.99 g) , 100 mmol, 17.55 mL, 2 eq) was dissolved in DMSO (100 mL) and stirred at 80 °C for 30 minutes. Water was slowly added to the reaction mixture and the resulting solid was filtered off. The solid was washed with water and recovered to obtain the target compound (9.14 g).
MS (m/z) : 286.1 [M+1] + MS (m/z): 286.1 [M+1] +
단계 2: 2-클로로-N-(5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)퀴나졸린-4-아민의 제조Step 2: Preparation of 2-chloro-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)quinazolin-4-amine
　2-클로로-N-(5-사이클로프로필-1H-피라졸-3-일)퀴나졸린-4-아민 (1 g, 3.50 mmol, 1 eq), TsOH·H 2O (0.133 g, 0.700 mmol, 0.2 eq)를 DCM (12 mL)에 녹인 후 3,4-다이하이드로-2H-피란 (0.883 g, 10.50 mmol, 0.960 mL, 3 eq)을 첨가하고 60 ℃에서 15시간 교반하였다. 반응혼합물에 NaHCO 3 수용액 (100 mL)와 DCM (100 mL) 그리고 물 (200 mL)을 첨가하고 유기층을 회수하여 유기층을 brine (100 mL)으로 씻어주고 Na 2SO 4을 이용하여 건조하였다. 유기층을 필터하고 감압농축기로 농축하여 목적화합물 (1.2 g)을 수득하였다. 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (1 g, 3.50 mmol, 1 eq), TsOH H 2 O (0.133 g, 0.700 mmol, 0.2 eq) was dissolved in DCM (12 mL), 3,4-dihydro-2H-pyran (0.883 g, 10.50 mmol, 0.960 mL, 3 eq) was added, and the mixture was stirred at 60 °C for 15 hours. NaHCO 3 aqueous solution (100 mL), DCM (100 mL) and water (200 mL) were added to the reaction mixture, the organic layer was recovered, the organic layer was washed with brine (100 mL), and dried using Na 2 SO 4 . The organic layer was filtered and concentrated with a vacuum concentrator to obtain the target compound (1.2 g).
MS (m/z) : 370.2 [M+1] + MS (m/z): 370.2 [M+1] +
단계 3: N-(5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)-2-(6-플루오로피리딘-3-일)퀴나졸린-4-아민의 제조Step 3: N-(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(6-fluoropyridin-3-yl)quina Preparation of zolin-4-amine
2-클로로-N-(5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)퀴나졸린-4-아민 (7.68 g, 20.77 mmol, 1 eq), 2-플루오로-5-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로란-2-일)피리딘 (5.56 g, 24.92 mmol, 1.20 eq), Na 2CO 3 (6.60 g, 62.3 mmol, 3 eq)를　1,4-다이옥세인(1,4-Dioxane; 100 mL) 그리고 물 (25 mL)에 녹인 뒤 Pd(PPh 3) 4 (2.40 g, 2.08 mmol, 0.1 eq)를 첨가하였다. 반응 혼합물을 질소가스하에 90 ℃에서 1시간 동안 교반하였다. 반응혼합물을 여과한 뒤 여액을 농축하고 물과 EtOAc를 첨가하였다. 유기층을 모아 brine (1.0 L)으로 씻어 준뒤 Na 2SO 4을 이용하여 건조하였다. 유기층을 필터하고 감압농축기로 농축한 뒤 중압크로마토그래피를 이용하여 정제하였다(Hexane/EtOAc=5/1 to 1/1). 정제 후 감압농축하여 목적화합물 (6.4 g, 14.87 mmol, 71.6% yield)을 수득하였다.2-Chloro-N-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)quinazolin-4-amine (7.68 g, 20.77 mmol, 1 eq ), 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.56 g, 24.92 mmol, 1.20 eq ), Na 2 CO 3 (6.60 g, 62.3 mmol, 3 eq ) was dissolved in 1,4-dioxane (1,4-Dioxane; 100 mL) and water (25 mL) and then Pd(PPh 3 ) 4 (2.40 g, 2.08) mmol, 0.1 eq ) was added. The reaction mixture was stirred at 90° C. under nitrogen gas for 1 hour. After filtration of the reaction mixture, the filtrate was concentrated, and water and EtOAc were added. The organic layers were collected, washed with brine (1.0 L), and dried using Na 2 SO 4 . The organic layer was filtered, concentrated with a vacuum concentrator, and purified using medium pressure chromatography (Hexane/EtOAc=5/1 to 1/1). After purification, the target compound (6.4 g, 14.87 mmol, 71.6% yield) was obtained by concentration under reduced pressure.
MS (m/z) : 431.3 [M+1] + MS (m/z): 431.3 [M+1] +
단계 4: 터트-부틸 3-(5-(4-((5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵테인-6-카복실레이트의 제조Step 4: tert-Butyl 3-(5-(4-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)quinazoline- Preparation of 2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate
N-(5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)-2-(6-플루오로피리딘-3-일)퀴나졸린-4-아민 (6.4 g, 14.87 mmol, 1 eq) , 터트-부틸 3,6-다이아자바이사이클로[3.1.1]헵테인-6-카복실레이트(3.24 g, 16.35 mmol, 1.1 eq), K 2CO 3 (10.27 g, 74.3 mmol, 5 eq)를 DMSO (15 mL)에 녹인 후 90 ℃에서 12시간 교반하였다. 반응 혼합물에 물 (500 mL), EtOAc (1 L)를 넣고 유기층을 brine (800 ml)으로 씻어준 뒤 Na 2SO 4을 이용하여 건조하였다. 유기층을 필터하고 감압농축기로 농축한 뒤 중압크로마토그래피를 이용하여 정제하였다(Hexane/EtOAc=5/2 to 5/4). 정제 후 감압농축하여 목적화합물 (7.05 g, 11.58 mmol, 78% yield)을 수득하였다.N-(5-Cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-(6-fluoropyridin-3-yl)quinazoline-4 -amine (6.4 g, 14.87 mmol, 1 eq ) , tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (3.24 g, 16.35 mmol, 1.1 eq ), K 2 CO 3 (10.27 g, 74.3 mmol, 5 eq ) was dissolved in DMSO (15 mL) and stirred at 90 °C for 12 hours. Water (500 mL) and EtOAc (1 L) were added to the reaction mixture, and the organic layer was washed with brine (800 ml) and dried over Na 2 SO 4 . The organic layer was filtered, concentrated with a vacuum concentrator, and purified using medium pressure chromatography (Hexane/EtOAc=5/2 to 5/4). After purification, it was concentrated under reduced pressure to obtain the target compound (7.05 g, 11.58 mmol, 78% yield).
MS (m/z) : 609.5 [M+1] + MS (m/z): 609.5 [M+1] +
단계 5: 2-(6-(3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)-N-(5-사이클로프로필-1H-피라졸-3-일)퀴나졸린-4-아민 다이하이드로클로라이드의 제조Step 5: 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl ) Preparation of quinazolin-4-amine dihydrochloride
터트-부틸 3-(5-(4-((5-사이클로프로필-1-(테트라하이드로-2H-피란-2-일)-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵테인-6-카복실레이트 (2.2 g, 3.61 mmol, 1 eq)를 4M HCl/1,4-다이옥세인 (50 mL)에 녹인 후 상온에서 13시간 교반하였다. 반응 혼합물을 감압농축한 후 아세톤 (100 mL)을 첨가하였다. 생성된 고체를 여과하여 회수한 뒤 건조하여 목적화합물 (1.76 g)을 수득하였다.tert-Butyl 3-(5-(4-((5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl )pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2.2 g, 3.61 mmol, 1 eq) was mixed with 4M HCl/1,4-dioxane (50 mL) ) and stirred at room temperature for 13 hours. After the reaction mixture was concentrated under reduced pressure, acetone (100 mL) was added. The resulting solid was collected by filtration and dried to the target compound (1.76 g) was obtained.
MS (m/z) : 425.3 [M+1] + MS (m/z): 425.3 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 12.25 (s,1H), 10.28 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.51 (dd, J = 2.3, 9.0 Hz, 1H), 7.82 - 7.70 (m, 2H), 7.46 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 6.65 (s, 1H), 3.73 (dd, J = 6.3, 14.4 Hz, 6H), 3.17 (s, 1H), 2.56 (q, J = 6.6 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.52 (d, J = 8.6 Hz, 1H), 1.01 (d, J = 7.4 Hz, 2H), 0.82 - 0.73 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 12.25 (s,1H), 10.28 (s, 1H), 9.19 (d, J = 2.3 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H) ), 8.51 (dd, J = 2.3, 9.0 Hz, 1H), 7.82 - 7.70 (m, 2H), 7.46 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 9.0 Hz, 1H), 6.65 (s, 1H), 3.73 (dd, J = 6.3, 14.4 Hz, 6H), 3.17 (s, 1H), 2.56 (q, J = 6.6 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.52 ( d, J = 8.6 Hz, 1H), 1.01 (d, J = 7.4 Hz, 2H), 0.82 - 0.73 (m, 2H)
단계 6: N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민의 제조Step 6: N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi Preparation of cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine
2-(6-(3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)-N-(5-사이클로프로필-1H-피라졸-3-일)퀴나졸린-4-아민 다이하이드로클로라이드 (2 g, 4.71 mmol), 6-메톡시니코틴알데하이드 (1.292 g, 9.42 mmol, 2 eq),　TEA (1.907 g, 18.85 mmol, 2.63 mL, 4 eq)를 DMF (15.7 ml)에 녹인 후 NaBH(OAc) 3 (3.00 g, 14.13 mmol, 3 eq)을 첨가하고 50 ℃에서 12시간 교반하였다. 반응 혼합물에 물 (1 L), EtOAc (1.6 L)를 넣고 유기층을 회수하였다. 유기층을 brine (800 ml)으로 씻어준 뒤 Na 2SO 4을 이용하여 건조하였다. 유기층을 필터하고 감압농축기로 농축한 뒤 중압크로마토그래피를 이용하여 정제하여 목적화합물 (1.3 g, 2.382 mmol, 50.6% yield)을 수득하였다.2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline -4-amine dihydrochloride (2 g, 4.71 mmol), 6-methoxynicotinaldehyde (1.292 g, 9.42 mmol, 2 eq ), TEA (1.907 g, 18.85 mmol, 2.63 mL, 4 eq ) with DMF (15.7) ml), NaBH(OAc) 3 (3.00 g, 14.13 mmol, 3 eq) was added, and the mixture was stirred at 50° C. for 12 hours. Water (1 L) and EtOAc (1.6 L) were added to the reaction mixture, and the organic layer was recovered. The organic layer was washed with brine (800 ml) and dried using Na 2 SO 4 . The organic layer was filtered, concentrated with a reduced pressure concentrator, and purified using medium pressure chromatography to obtain the target compound (1.3 g, 2.382 mmol, 50.6% yield).
MS (m/z) : 546.4 [M+1] + MS (m/z): 546.4 [M+1] +
1H NMR (400 MHz, DMSO-d 6) δ = 12.27 (s, 1H), 10.32 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.54 (dd, J = 2.3, 9.0 Hz, 1H), 8.11 - 8.04 (m, 1H), 7.83-7.73 (m, 2H), 7.68 (dd, J = 2.5, 8.5 Hz, 1H), 7.47 (ddd, J = 2.3, 6.1, 8.4 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.77 (dd, J = 0.7, 8.5 Hz, 1H), 6.68 (s, 1H), 3.82 (s, 3H), 3.77 (d, J = 12.1 Hz, 2H), 3.67 (d, J = 5.9 Hz, 2H), 3.65 - 3.51 (m, 2H), 3.50 (s, 2H), 2.55 - 2.51 (m, 1H), 2.01 (dp, J = 5.1, 8.8 Hz, 1H), 1.58 (d, J = 8.4 Hz, 1H), 1.06 - 0.95 (m, 2H), 0.83 - 0.73 (m, 2H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 12.27 (s, 1H), 10.32 (s, 1H), 9.23 (d, J = 2.3 Hz, 1H), 8.59 (d, J = 8.3 Hz, 1H) ), 8.54 (dd, J = 2.3, 9.0 Hz, 1H), 8.11 - 8.04 (m, 1H), 7.83-7.73 (m, 2H), 7.68 (dd, J = 2.5, 8.5 Hz, 1H), 7.47 ( ddd, J = 2.3, 6.1, 8.4 Hz, 1H), 6.81 (d, J = 9.0 Hz, 1H), 6.77 (dd, J = 0.7, 8.5 Hz, 1H), 6.68 (s, 1H), 3.82 (s) , 3H), 3.77 (d, J = 12.1 Hz, 2H), 3.67 (d, J = 5.9 Hz, 2H), 3.65 - 3.51 (m, 2H), 3.50 (s, 2H), 2.55 - 2.51 (m, 1H), 2.01 (dp, J = 5.1, 8.8 Hz, 1H), 1.58 (d, J = 8.4 Hz, 1H), 1.06 - 0.95 (m, 2H), 0.83 - 0.73 (m, 2H)
상기 실시예 1과 유사한 방법으로 실시예 2 내지 53를 제조하였으며, 실시예 1 내지 53의 화학구조, 화합물명과 NMR, LC-MS 분석 결과를 하기 표 1에 정리하여 나타내었다.Examples 2-53 were prepared in a manner similar to that of Example 1, and the chemical structures, compound names, and NMR and LC-MS analysis results of Examples 1-53 are summarized and shown in Table 1 below.
Figure PCTKR2020016377-appb-img-000008
Figure PCTKR2020016377-appb-img-000008
Figure PCTKR2020016377-appb-img-000009
Figure PCTKR2020016377-appb-img-000009
Figure PCTKR2020016377-appb-img-000010
Figure PCTKR2020016377-appb-img-000010
Figure PCTKR2020016377-appb-img-000011
Figure PCTKR2020016377-appb-img-000011
Figure PCTKR2020016377-appb-img-000012
Figure PCTKR2020016377-appb-img-000012
Figure PCTKR2020016377-appb-img-000013
Figure PCTKR2020016377-appb-img-000013
Figure PCTKR2020016377-appb-img-000014
Figure PCTKR2020016377-appb-img-000014
Figure PCTKR2020016377-appb-img-000015
Figure PCTKR2020016377-appb-img-000015
Figure PCTKR2020016377-appb-img-000016
Figure PCTKR2020016377-appb-img-000016
Figure PCTKR2020016377-appb-img-000017
Figure PCTKR2020016377-appb-img-000017
Figure PCTKR2020016377-appb-img-000018
Figure PCTKR2020016377-appb-img-000018
Figure PCTKR2020016377-appb-img-000019
Figure PCTKR2020016377-appb-img-000019
<실험예 1> 본 발명에 따른 화합물의 HPK1(Hematopoietic Progenitor Kinase 1) 효소 저해능 활성 평가<Experimental Example 1> HPK1 (Hematopoietic Progenitor Kinase 1) enzyme inhibitory activity evaluation of the compound according to the present invention
본 발명에 따른 화합물의 HPK1 키나아제에 대한 활성 억제를 평가하기 위하여 다음과 같은 방법으로 수행하였다.In order to evaluate the inhibition of HPK1 kinase activity of the compound according to the present invention, the following method was performed.
실시예 화합물을 정제된 human HPK1 (1-346, SignalChem)효소와 반응하여 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH7.4, 20 mM MgCl 2, 0.5 mg/ml BSA, 50 μM DTT 조성으로 사용하였으며, 모든 시험물의 반응은 반응 버퍼상에서 이루어졌다. 화합물은 10mM DMSO stock을 계열 희석법으로 12단계로 희석하였으며, 최종 화합물의 농도 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 μM에서 효소 활성을 측정하였다. 시험시 human HPK1(3ng) 효소와 정제된 ATP (3 μM), 효소 기질 (0.1 μg) 과 25℃에서 2시간 반응시킨 후 효소활성은 in vitro ADP-Glo TM kinase assay (promega)를 이용하여 확인하였다. 2:2:1 비율로 효소활성반응액과 ADP-Glo 반응액, 효소능 detection 용액을 반응시켜서 효소의 활성 저해도를 Luminescence로 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 발광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성 저해를 50% 억제하는 각 화합물의 농도를 IC 50(μM) 값으로 결정하였고, GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)을 이용하여 구하였다. 그 결과를 하기 표 2에 나타내었다. Example compounds were reacted with purified human HPK1 (1-346, SignalChem) enzyme to evaluate the enzyme inhibitory ability as follows. The reaction buffer was 40 mM Tris-HCl pH7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 μM DTT composition, and all test articles were reacted in the reaction buffer. The compound was diluted in 12 steps with 10 mM DMSO stock by a serial dilution method, and the enzyme activity was measured at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, and 0.00003 μM of the final compound. In the test, after reacting with human HPK1 (3ng) enzyme, purified ATP (3 μM), and enzyme substrate (0.1 μg) at 25°C for 2 hours, the enzyme activity was confirmed using in vitro ADP-Glo TM kinase assay (promega). did In a 2:2:1 ratio, the enzyme activity reaction solution, ADP-Glo reaction solution, and enzyme activity detection solution were reacted, and the degree of inhibition of enzyme activity was measured by luminescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the luminescence degree of the enzyme activity of the solvent control that was not treated with the compound. was determined, and was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are shown in Table 2 below.
<실험예 2> 본 발명에 따른 화합물의 LRRK2(G2019S) 효소 저해능 활성 평가<Experimental Example 2> LRRK2 (G2019S) enzyme inhibitory activity evaluation of the compound according to the present invention
본 발명에 따른 화합물의 LRRK2(G2019S) 키나아제에 대한 활성 억제를 평가하기 위하여 다음과 같은 방법으로 수행하였다.In order to evaluate the inhibition of the LRRK2 (G2019S) kinase activity of the compound according to the present invention, the following method was performed.
실시예 화합물을 정제된 human LRRK2(G2019S) (L10-12GG, SignalChem)효소와 반응하여 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH7.4, 20 mM MgCl 2, 0.5 mg/ml BSA, 50 μM DTT 조성으로 사용하였으며, 모든 시험물의 반응은 반응버퍼상에서 이루어졌다. 화합물은 10 mM DMSO stock을 계열 희석법으로 12단계로 희석하였으며, 최종 화합물의 농도 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512, 0.000001024, 0.0000002 μM에서 효소 활성을 측정하였다. 시험시 human LRRK2(G2019S) (16 ng) 효소와 정제된 ATP (25 μM), 효소 기질 (0.2 μg)과 25℃에서 2시간 반응시킨 후 효소활성은 in vitro ADP-Glo TM kinase assay (promega)를 이용하여 확인하였다. 2:2:1 비율로 효소활성반응액과 ADP-Glo 반응액, 효소능 detection 용액을 반응시켜서 효소의 활성 저해도를 Luminescence로 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 발광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성 저해를 50% 억제하는 각 화합물의 농도를 IC 50(μM) 값으로 결정하였고, GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)을 이용하여 구하였다.Example compounds were reacted with purified human LRRK2(G2019S) (L10-12GG, SignalChem) enzyme to evaluate the enzyme inhibitory ability as follows. The reaction buffer was 40 mM Tris-HCl pH7.4, 20 mM MgCl 2 , 0.5 mg/ml BSA, and 50 μM DTT composition, and all test materials were reacted on the reaction buffer. The compound was diluted in 12 steps with 10 mM DMSO stock by a serial dilution method, and the enzyme activity was measured at the concentrations of 10, 2, 0.4, 0.08, 0.016, 0.0032, 0.00064, 0.000128, 0.0000256, 0.00000512, 0.000001024, 0.0000002 μM of the final compound. . In the test, after reacting with human LRRK2(G2019S) (16 ng) enzyme, purified ATP (25 μM), and enzyme substrate (0.2 μg) at 25°C for 2 hours, the enzyme activity was evaluated by in vitro ADP-Glo TM kinase assay (promega). was confirmed using . In a 2:2:1 ratio, the enzyme activity reaction solution, ADP-Glo reaction solution, and enzyme activity detection solution were reacted, and the degree of inhibition of enzyme activity was measured by luminescence. The degree of inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the luminescence degree of the enzyme activity of the solvent control that was not treated with the compound. was determined, and was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego).
실험예 1, 실험예 2에서 측정된 화합물의 효소 저해 활성 IC 50값을 0.05 μM 이하인 경우"A", 0.05 초과 0.25 μM 이하인 경우"B", 0.25 초과 0.5 μM 이하인 경우 "C", 0.5 μM 초과하는 경우"D"로 분류하여 하기 표 2에 정리하여 나타내었다.Enzyme inhibitory activity IC 50 value of the compound measured in Experimental Example 1 and Experimental Example 2 is 0.05 μM or less, “A”, 0.05 or more and 0.25 μM or less, “B”, 0.25 or more and 0.5 μM or less, “C”, 0.5 μM or less If it is, it is classified as "D" and summarized in Table 2 below.
실시예Example HPK1
Enzyme IC 50 HPK1
Enzyme IC 50 		LRRK2
(G2019S)
Enzyme IC 50 LRRK2
(G2019S)
Enzyme IC 50 		실시예Example HPK1
Enzyme IC 50 HPK1
Enzyme IC 50 		LRRK2
(G2019S)
Enzyme IC 50 LRRK2
(G2019S)
Enzyme IC 50
1One AA BB 2828 CC
22 AA 2929 BB
33 AA AA 3030 AA
44 BB BB 3131 AA CC
55 AA BB 3232 BB DD
66 BB 3333 AA
77 BB BB 3434 AA
88 AA BB 3535 AA
99 AA BB 3636 AA
1010 AA AA 3737 AA BB
1111 BB CC 3838 CC
1212 BB DD 3939 AA
1313 BB CC 4040 AA
1414 BB BB 4141 AA DD
1515 DD 4242 CC
1616 AA AA 4343 AA
1717 BB BB 4444 AA
1818 BB AA 4545 DD
1919 AA 4646 BB
2020 AA BB 4747 DD
2121 BB BB 4848 AA
2222 BB CC 4949 BB
2323 AA AA 5050 AA
2424 AA AA 5151 AA
2525 AA 5252 AA
2626 AA AA 5353 AA
2727 DD CC
<실험예 3> 본 발명에 따른 화합물의 SLP76(S376) 인산화 억제 활성 평가<Experimental Example 3> Evaluation of SLP76 (S376) phosphorylation inhibitory activity of the compound according to the present invention
본 발명에 따른 화합물의 SLP76(S376) 인산화 억제 활성을 평가하기 위하여 다음과 같은 방법으로 수행하였다.In order to evaluate the SLP76 (S376) phosphorylation inhibitory activity of the compound according to the present invention, the following method was performed.
본 실험에는 사람 T Lymphocyte세포주인 Jurkat T 세포(ATCC)를 사용하였으며, 세포는 clear 96-웰 플레이트에 5 Х 10 4/25μl 웰이 되도록 심은 뒤, 화합물은 10 mM DMSO stock을 계열 희석법으로 10단계로 희석하였으며, 최종 화합물의 농도 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001μM에서 시험을 진행하였다. 화합물은 처리후 37℃ CO 2배양기에서 4시간 동안 배양하였다. 4시간 후, 화합물을 처리한 플레이트를 꺼내어, CD3(5 pg/mL, OKT3 clone)을 20분간 처리하여 주었다. HTRF 시험은 Phospho-SLP-76 (Ser376) cellular kit(Cisbio) 내의 실험방법을 기준으로 진행되었다. 4 x Lysis Buffer(blocking reagent가 포함된) 15μl씩 웰에 넣고 shaking incubator에서 1시간 반응시켜주고, 세포 lysate 16μl를 clear bottom white 96-웰 플레이트에 옮겨주고 p-SLP76(s376) HTRF reagents (2 ul donor, 2ul acceptor)를 넣고 4℃ 상에서 밤새도록 반응을 시켜준다. The homogeneous time resolved fluorescence를 측정하여 화합물을 처리하지 않은 용매 대조군의 형광값을 기준으로 각 화합물들의 처리 농도에 따른 p-SLP76(S376) 발현 정도를 산출하여 백분율로 나타내었고, GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)을 이용하여 IC 50(μM) 값을 산출하였다.In this experiment, Jurkat T cells (ATCC), a human T Lymphocyte cell line, were used, and the cells were planted in a clear 96-well plate to 5 Х 10 4 /25 μl wells, and the compound was diluted with 10 mM DMSO stock in 10 steps by serial dilution. , and the final compound concentrations were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, and 0.0001 μM. Compounds were incubated for 4 hours in a 37° C. CO 2 incubator after treatment. After 4 hours, the plate treated with the compound was taken out and treated with CD3 (5 pg/mL, OKT3 clone) for 20 minutes. The HTRF test was conducted based on the experimental method in the Phospho-SLP-76 (Ser376) cellular kit (Cisbio). Put 15 μl of 4 x Lysis Buffer (including blocking reagent) into each well, incubate in a shaking incubator for 1 hour, transfer 16 μl of cell lysate to a clear bottom white 96-well plate, and p-SLP76(s376) HTRF reagents (2 ul donor, 2ul acceptor) and allowed to react overnight at 4°C. The homogeneous time resolved fluorescence was measured and the expression level of p-SLP76(S376) according to the treatment concentration of each compound was calculated based on the fluorescence value of the solvent control group not treated with the compound and expressed as a percentage, GraphPad Prism 8.3.0 ( IC 50 (μM) values were calculated using GraphPad software Inc., San Diego).
측정된 SLP76(S376) 인산화 억제 활성 IC 50값을 0.15μM 이하인 경우 "A", 0.15μM 초과 0.5μM 이하인 경우 "B", 0.5μM 초과 1μM 이하인 경우 "C", 1 μM 초과하는 경우 "D"로 분류하여 하기 표 3에 정리하여 나타내었다.Measured SLP76 (S376) phosphorylation inhibitory activity IC 50 value of 0.15 μM or less “A”, “B” when 0.15 μM or more and 0.5 μM or less, “C” when it exceeds 0.5 μM and 1 μM or less, “C”, and “D” when it exceeds 1 μM It is summarized and shown in Table 3 below.
실시예Example p-SLP76(S376)
HTRF IC 50 p-SLP76 (S376)
HTRF IC 50 		실시예Example p-SLP76(S376)
HTRF IC 50 p-SLP76 (S376)
HTRF IC 50
1One AA 2828 BB
22 BB 2929
33 BB 3030 AA
44 3131
55 AA 3232
66 3333
77 3434
88 3535
99 BB 3636
1010 3737
1111 3838
1212 3939
1313 4040
1414 4141
1515 4242
1616 4343
1717 4444
1818 4545
1919 4646
2020 4747
2121 4848
2222 4949
2323 5050 AA
2424 AA 5151 BB
2525 5252 BB
2626 BB 5353
2727
<실험예 4> 본 발명에 따른 화합물의 다양한 키나아제 저해 활성 평가<Experimental Example 4> Evaluation of various kinase inhibitory activities of the compound according to the present invention
본 발명에 따른 화합물의 보다 많은 효소에 대한 저해활성을 평가하기 위해 하기와 같은 실험을 수행하였다. 구체적으로, 본 발명의 실시예 화합물 중 선별된 실시예 1에 대하여, DiscoverX 사에 의뢰하여 효소 (kinase) 선택성을 측정하기로 하고, scanMAX TM Kinase 분석용 패널을 사용하여 실험을 진행하였다. 이때, 효소에 처리되는 약물의 농도는 DMSO에 1μM로 하였고, 하기 식 1과 같은 방법으로 조절 백분율 (% control)을 정하였고, 그 결과를 하기 표 4에 나타내었다.In order to evaluate the inhibitory activity of the compound according to the present invention to more enzymes, the following experiment was performed. Specifically, with respect to Example 1 selected among the example compounds of the present invention, the enzyme (kinase) selectivity was measured by requesting DiscoverX, and the experiment was conducted using a scanMAX TM Kinase analysis panel. At this time, the concentration of the drug treated with the enzyme was 1 μM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Table 4 below.
[식 1][Equation 1]
(실시예 화합물 - 양성 대조군)/(음성 대조군 - 양성대조군) Х 100(Example compound - positive control) / (negative control - positive control) Х 100
여기서, 상기 양성 대조군은 0%의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100%의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 각각의 효소에 대하여 조절 백분율이 < 35% (즉 35% 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, the enzyme selectivity of the present invention was judged to have activity for each enzyme if the control percentage was <35% (ie, less than 35%) for each enzyme.
KinaseKinase 실시예1Example 1 KinaseKinase 실시예1Example 1 KinaseKinase 실시예1Example 1
AURKAAURKA 1.71.7 FLT3(D835V)FLT3 (D835V) 00 KIT(A829P)KIT(A829P) 2121
AURKBAURKB 77 FLT3(D835Y)FLT3 (D835Y) 00 KIT(D816H)KIT(D816H) 1.91.9
AURKCAURKC 00 FLT3(ITD)FLT3 (ITD) 00 KIT(D816V)KIT(D816V) 0.70.7
AXLAXL 0.550.55 FLT3(ITD,D835V)FLT3(ITD,D835V) 0.20.2 KIT(L576P)KIT(L576P) 00
BTKBTK 6.66.6 FLT3(ITD,F691L)FLT3 (ITD, F691L) 0.40.4 KIT(V559D)KIT(V559D) 0.650.65
CDK7CDK7 1.31.3 FLT3(K663Q)FLT3(K663Q) 3.83.8 KIT(V559D,T670I)KIT(V559D,T670I) 2121
CLK1CLK1 2.92.9 FLT3(N841I)FLT3 (N841I) 00 KIT(V559D,V654A)KIT(V559D,V654A) 3333
CLK2CLK2 1212 FLT3(R834Q)FLT3 (R834Q) 00 LRRK2LRRK2 2121
CLK3CLK3 1515 FLT3-autoinhibitedFLT3-autoinhibited 1.11.1 LRRK2(G2019S)LRRK2(G2019S) 1616
CLK4CLK4 3.73.7 HPK1HPK1 00 TRKATRKA 00
DDR1DDR1 0.90.9 JAK1(JH1domain-catalytic)JH1 domain-catalytic (JAK1) 1313 TRKBTRKB 0.10.1
DDR2DDR2 0.40.4 JAK1(JH2domain-pseudokinase)JH2domain-pseudokinase (JAK1) 5.15.1 TRKCTRKC 00
DLKDLK 3.53.5 JAK2(JH1domain-catalytic)JH1 domain-catalytic (JAK2) 0.50.5 TYK2(JH1domain-catalytic)TYK2 (JH1 domain-catalytic) 2.72.7
FLT3FLT3 0.150.15 JAK3(JH1domain-catalytic)JH1 domain-catalytic (JAK3) 0.050.05
FLT3(D835H)FLT3 (D835H) 00 KITKIT 2.32.3
상기 표 4에서 확인할 수 있듯이, 본 발명에 따른 화합물은 AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, HPK1, JAK1(JH1domain-catalytic), JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LRRK2, LRRK2(G2019S), TRKA, TRKB, TRKC, TYK2(JH1domain-catalytic) 키나아제에 대하여 조절 백분율 35% 미만의 값을 나타내었다. 이는 본 발명의 화합물이 상기 나열된 효소에 대하여 억제 활성을 갖고 있음을 나타내는 것이며, 이로부터 상기 나열된 효소와 관련된 질환에 적용하여 유용한 효과를 나타낼 수 있음을 암시하는 것이다. As can be seen in Table 4, the compounds according to the present invention are AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3 (D835H), FLT3 (D835V) ), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, HPK1, JAK1(JH1domain) -catalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D) ), KIT (V559D, T670I), KIT (V559D, V654A), LRRK2, LRRK2 (G2019S), TRKA, TRKB, TRKC, TYK2 (JH1 domain-catalytic) kinase showed a value of less than 35% in percent regulation. This indicates that the compound of the present invention has inhibitory activity against the enzymes listed above, suggesting that it may exhibit useful effects by application to diseases related to the enzymes listed above.
따라서, 본 발명의 화합물은 상기 나열된 효소와 관련된 질환의 치료 또는 예방용 조성물로 유용하게 사용될 수 있다. Accordingly, the compound of the present invention can be usefully used as a composition for treating or preventing diseases related to the enzymes listed above.

Claims (13)

  1. 하기 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염:A compound of Formula 1 below, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2020016377-appb-img-000020
    Figure PCTKR2020016377-appb-img-000020
    상기 화학식 1에 있어서,In Formula 1,
    R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리(bicyclic ring)를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
    상기 R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐으로 치환되거나 비치환되며,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
    R 3은 3 내지 8 원자의 사이클로알킬 또는 3 내지 8 원자의 헤테로사이클로알킬이며,R 3 is 3 to 8 membered cycloalkyl or 3 to 8 membered heterocycloalkyl,
    R 4는 수소, C 1-6 알킬, C 1-6 알콕시, 또는 할로겐이고,R 4 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, or halogen,
    R 5 및 R 6은 각각 독립적으로 C 1-6 알킬아미노로 치환되거나 비치환된 C 1-6 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 12 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 12 membered heterocycloalkyl,
    상기 R 5 및 R 6이 형성한 3 내지 12 원자의 헤테로사이클로알킬은 C 1-6 알킬, C 1-6 하이드록시알킬, C 1-6 알콕시, 3 내지 12 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,3 to 12 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 12 membered heterocycloalkyl, —(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
    상기 R 8은 4 내지 12 원자의 단일 고리(monocyclic ring) 또는 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 12 membered monocyclic ring or a bicyclic ring and is unsubstituted or substituted with one or more substituents R 9 ,
    상기 치환기 R 9는 C 1-6 알킬, C 1-6 알콕시, 5 내지 8 원자의 아릴, 사이아노, C 1-6 알킬아미노, C 1-6 할로알킬, C 1-6 할로알콕시, C 1-6 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택된다.The substituent R 9 is C 1-6 alkyl, C 1-6 alkoxy, 5-8 membered aryl, cyano, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 alkylsulfonamido, and oxo (=O).
  2. 제 1 항에 있어서,The method of claim 1,
    R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 12 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 12 members,
    상기 R 1 및 R 2가 형성한 8 내지 12 원자의 이환 고리는 C 1-6 알킬로 치환되거나 비치환되며,The 8 to 12 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-6 alkyl,
    R 3은 3 내지 8 원자의 사이클로알킬이며,R 3 is 3 to 8 membered cycloalkyl,
    R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
    R 5 및 R 6은 각각 독립적으로 C 1-6 알킬아미노로 치환되거나 비치환된 C 1-6 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-6 alkyl unsubstituted or substituted with C 1-6 alkylamino, or they are joined together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl,
    상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-6 알킬, C 1-6 하이드록시알킬, C 1-6 알콕시, 3 내지 8 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,The 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-8 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
    상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
    상기 치환기 R 9는 C 1-6 알킬, C 1-6 알콕시, 5 내지 8 원자의 아릴, 사이아노, C 1-6 알킬아미노, C 1-6 할로알킬, C 1-6 할로알콕시, C 1-6 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택되는,The substituent R 9 is C 1-6 alkyl, C 1-6 alkoxy, 5-8 membered aryl, cyano, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1 -6 selected from the group consisting of alkylsulfonamido, and oxo (=O),
    화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염. A compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  3. 제 1 항에 있어서,The method of claim 1,
    R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 10 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
    상기 R 1 및 R 2가 형성한 8 내지 10 원자의 이환 고리는 C 1-3 알킬로 치환되거나 비치환되며,The 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl,
    R 3은 3 내지 6 원자의 사이클로알킬이며,R 3 is 3 to 6 membered cycloalkyl,
    R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
    R 5 및 R 6은 각각 독립적으로 C 1-3 알킬아미노로 치환되거나 비치환된 C 1-3 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or they are joined together with the N atom to which they are attached to form a 3-8 membered heterocycloalkyl,
    상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-3 알킬, C 1-3 하이드록시알킬, C 1-3 알콕시, 3 내지 6 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,The 3-8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3-6 membered heterocycloalkyl, -(CH 2 ) nR 8 , and one or more substituents R 7 selected from the group consisting of -C(O)-R 8 , which is substituted or unsubstituted, wherein n is an integer from 1 to 3;
    상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
    상기 치환기 R 9는 C 1-3 알킬, C 1-3 알콕시, 벤질, 사이아노, C 1-3 알킬아미노, C 1-3 할로알킬, C 1-3 할로알콕시, C 1-3 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택되는,The substituent R 9 is C 1-3 alkyl, C 1-3 alkoxy, benzyl, cyano, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylsulfonami selected from the group consisting of degrees, and oxo (=O),
    화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염. A compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  4. 제 1 항에 있어서,The method of claim 1,
    R 1 및 R 2는 이들이 결합된 탄소 원자가 속한 피리미딘 고리와 함께 8 내지 10 원자의 이환 고리를 형성하고,R 1 and R 2 together with the pyrimidine ring to which the carbon atom to which they are attached form a bicyclic ring of 8 to 10 members,
    상기 R 1 및 R 2가 형성한 8 내지 10 원자의 이환 고리는 C 1-3 알킬로 치환되거나 비치환되며,The 8 to 10 membered bicyclic ring formed by R 1 and R 2 is unsubstituted or substituted with C 1-3 alkyl,
    R 3은 3 내지 6 원자의 사이클로알킬이며,R 3 is 3 to 6 membered cycloalkyl,
    R 4는 수소 또는 할로겐이고,R 4 is hydrogen or halogen,
    R 5 및 R 6은 각각 독립적으로 C 1-3 알킬아미노로 치환되거나 비치환된 C 1-3 알킬이거나, 이들이 결합된 N 원자와 함께 연결되어 N, O 및 S 로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로 원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬을 형성하며, R 5 and R 6 are each independently C 1-3 alkyl unsubstituted or substituted with C 1-3 alkylamino, or at least one selected from the group consisting of N, O and S linked together with the N atom to which they are attached to form a 3 to 8 membered heterocycloalkyl containing heteroatoms,
    상기 R 5 및 R 6이 형성한 3 내지 8 원자의 헤테로사이클로알킬은 C 1-3 알킬, C 1-3 하이드록시알킬, C 1-3 알콕시, O 원자를 하나 이상 포함하는 3 내지 6 원자의 헤테로사이클로알킬, -(CH 2)n-R 8, 및 -C(O)-R 8로 이루어지는 군으로부터 선택된 하나 이상의 치환기 R 7로 치환되거나 비치환되며, 여기서 n 은 1 내지 3의 정수이고,3 to 8 membered heterocycloalkyl formed by R 5 and R 6 is C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, 3 to 6 atoms including at least one O atom substituted or unsubstituted with one or more substituents R 7 selected from the group consisting of heterocycloalkyl, -(CH 2 )nR 8 , and -C(O)-R 8 , wherein n is an integer from 1 to 3;
    상기 R 8은 4 내지 8 원자의 방향족 단일 고리 또는 8 내지 12 원자의 이환 고리이고 하나 이상의 치환기 R 9로 치환되거나 비치환되며,wherein R 8 is a 4 to 8 membered aromatic single ring or an 8 to 12 membered bicyclic ring, which is unsubstituted or substituted with one or more substituents R 9 ,
    상기 치환기 R 9는 C 1-3 알킬, C 1-3 알콕시, 벤질, 사이아노, C 1-3 알킬아미노, C 1-3 할로알킬, C 1-3 할로알콕시, C 1-3 알킬설폰아미도, 및 옥소(=O)로 이루어지는 군으로부터 선택되는,The substituent R 9 is C 1-3 alkyl, C 1-3 alkoxy, benzyl, cyano, C 1-3 alkylamino, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 alkylsulfonami selected from the group consisting of degrees, and oxo (=O),
    화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염. A compound of Formula 1, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  5. 제 1 항에 있어서, The method of claim 1,
    화학식 1로 표시되는 화합물이 하기 화합물 1 내지 53 중 어느 하나인, 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염:A compound, an isomer, a hydrate, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by Formula 1 is any one of the following compounds 1 to 53:
    <1>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <2> N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((2-메틸피리미딘-5-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <3>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((2-메톡시피리미딘-5-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <4>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메톡시피라진-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <5>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메틸아이소옥사졸-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <6>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메틸피라진-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <7>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-(다이플루오로메톡시)피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <8>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-에톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <9>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메톡시피리딘-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <10>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(이미다조[1,2-a]피리딘-2-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <11>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(4-메톡시벤질)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <12>5-((3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)메틸)-2-메톡시벤조나이트릴; <13>5-((3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)메틸)피콜리노나이트릴; <14>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((4-메틸싸이아졸-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <15>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(4-((6-메톡시피리딘-3-일)메틸)피페라진-1-일)피리딘-3-일)퀴나졸린-4-아민; <16>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(옥사졸-2-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <17>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((1,3-다이메틸-1H-피라졸-5-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <18>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메틸싸이아졸-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <19>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((5-메틸피리딘-2-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <20>N-(4-((3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)메틸)페닐)메테인설폰아마이드; <21>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(퀴놀린-2-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <22>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(퀴놀린-3-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <23>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(피리미딘-5-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <24>4-((3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)메틸)-1-메틸피리딘-2(1H)-온; <25>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(퓨란-3-일메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <26>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-(메틸아미노)피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <27>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-(트라이플루오로메틸)피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <28>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((2,3-다이하이드로벤조[b][1,4]다이옥신-6-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <29>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((2,3-다이하이드로벤조퓨란-5-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <30>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퓨로[3,2-d]피리미딘-4-아민; <31>N-(5-사이클로부틸-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퓨로[3,2-d]피리미딘-4-아민; <32>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(5-플루오로-6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퓨로[3,2-d]피리미딘-4-아민; <33>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(4-메틸피페라진-1-일)피리딘-3-일)퀴나졸린-4-아민; <34>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(피페라진-1-일)피리딘-3-일)퀴나졸린-4-아민; <35>2-(6-(3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)-N-(5-사이클로프로필-1H-피라졸-3-일)퀴나졸린-4-아민; <36> N 1-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-N 1,N 2,N 2-트라이메틸에테인-1,2-다이아민; <37>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-메틸-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <38>2-(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)에탄-1-올; <39>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-(옥세탄-3-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)퀴나졸린-4-아민; <40>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-모폴리노피리딘-3-일)퀴나졸린-4-아민; <41>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(6-메톡시피리딘-3-일)메탄온; <42>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(피리딘-3-일)메탄온; <43>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(피리딘-2-일)메탄온; <44>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(피리딘-4-일)메탄온; <45>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(4-(트라이플루오로메틸)피리딘-2-일)메탄온; <46>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(나프탈렌-2-일)메탄온; <47>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(4-메틸-3-(트라이플루오로메틸)페닐)메탄온; <48>(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퀴나졸린-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)(싸이아졸-5-일)메탄온; <49>(5-벤질-1,3,4-옥사다이아졸-2-일)(3-(5-(4-((5-사이클로프로필-1H-피라졸-3-일)아미노)퓨로[3,2-d]피리미딘-2-일)피리딘-2-일)-3,6-다이아자바이사이클로[3.1.1]헵탄-6-일)메탄온; <50>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)싸이에노[2,3-d]피리미딘-4-아민; <51>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)싸이에노[3,2-d]피리미딘-4-아민; <52>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)-6,7-다이하이드로-5H-사이클로펜타[d]피리미딘-4-아민; 및 <53>N-(5-사이클로프로필-1H-피라졸-3-일)-2-(6-(6-((6-메톡시피리딘-3-일)메틸)-3,6-다이아자바이사이클로[3.1.1]헵탄-3-일)피리딘-3-일)-7-메틸-7H-피롤로[2,3-d]피리미딘-4-아민.<1>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <2> N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((2-methylpyrimidin-5-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <3>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((2-methoxypyrimidin-5-yl)methyl)-3,6-dia javaycyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <4>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methoxypyrazin-2-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <5>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methylisoxazol-3-yl)methyl)-3,6-dia javaycyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <6>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methylpyrazin-2-yl)methyl)-3,6-diazabicyclo [3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <7>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(difluoromethoxy)pyridin-3-yl)methyl)-3, 6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <8>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-ethoxypyridin-3-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <9>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methoxypyridin-2-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <10>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(imidazo[1,2-a]pyridin-2-ylmethyl)-3,6 -diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <11>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane -3-yl)pyridin-3-yl)quinazolin-4-amine; <12>5-((3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6 -diazabicyclo[3.1.1]heptan-6-yl)methyl)-2-methoxybenzonitrile; <13>5-((3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6 -diazabicyclo[3.1.1]heptan-6-yl)methyl)picolinonitrile; <14>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((4-methylthiazol-2-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <15>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl) pyridin-3-yl)quinazolin-4-amine; <16>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(oxazol-2-ylmethyl)-3,6-diazabicyclo[3.1.1 ]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <17>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((1,3-dimethyl-1H-pyrazol-5-yl)methyl)- 3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <18>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methylthiazol-2-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <19>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((5-methylpyridin-2-yl)methyl)-3,6-diazabicyclo [3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <20>N-(4-((3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)phenyl)methanesulfonamide; <21>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(quinolin-2-ylmethyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <22>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(quinolin-3-ylmethyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <23>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(pyrimidin-5-ylmethyl)-3,6-diazabicyclo[3.1.1 ]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <24>4-((3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6 -diazabicyclo[3.1.1]heptan-6-yl)methyl)-1-methylpyridin-2(1H)-one; <25>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(furan-3-ylmethyl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <26>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(methylamino)pyridin-3-yl)methyl)-3,6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <27>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-(trifluoromethyl)pyridin-3-yl)methyl)-3, 6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <28>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((2,3-dihydrobenzo[b][1,4]dioxin-6-) yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <29>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((2,3-dihydrobenzofuran-5-yl)methyl)-3,6 -diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <30>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)furo[3,2-d]pyrimidin-4-amine; <31>N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabi cyclo[3.1.1]heptan-3-yl)pyridin-3-yl)furo[3,2-d]pyrimidin-4-amine; <32>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-fluoro-6-(6-((6-methoxypyridin-3-yl)methyl)-3 ,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)furo[3,2-d]pyrimidin-4-amine; <33>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazolin-4-amine;<34>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-4-amine;<35>2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine;<36> N 1 -(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-N 1 ,N 2 , N 2 -trimethylethane-1,2-diamine; <37>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine -3-yl)quinazolin-4-amine; <38>2-(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptan-6-yl)ethan-1-ol; <39>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)pyridin-3-yl)quinazolin-4-amine; <40>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-morpholinopyridin-3-yl)quinazolin-4-amine;<41>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(6-methoxypyridin-3-yl)methanone;<42>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(pyridin-3-yl)methanone;<43>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(pyridin-2-yl)methanone;<44>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(pyridin-4-yl)methanone;<45>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone;<46>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(naphthalen-2-yl)methanone;<47>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(4-methyl-3-(trifluoromethyl)phenyl)methanone;<48>(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)(thiazol-5-yl)methanone;<49>(5-benzyl-1,3,4-oxadiazol-2-yl)(3-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)puro[3,2-d]pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methanone;<50>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)thieno[2,3-d]pyrimidin-4-amine;<51>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)thieno[3,2-d]pyrimidin-4-amine;<52>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; and <53>N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-dia Javacyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine.
  6. 하기 반응식 1에 나타난 바와 같이,As shown in Scheme 1 below,
    화학식 2의 화합물로부터 화학식 3의 화합물을 제조하는 단계(단계 1);preparing a compound of Formula 3 from a compound of Formula 2 (Step 1);
    화학식 3의 화합물로부터 화학식 4의 화합물을 제조하는 단계(단계 2); preparing a compound of Formula 4 from a compound of Formula 3 (step 2);
    화학식 4의 화합물과 화학식 5의 화합물을 반응시켜 화학식 6의 화합물을 제조하는 단계(단계 3); 및preparing a compound of Formula 6 by reacting a compound of Formula 4 with a compound of Formula 5 (step 3); and
    화학식 6의 화합물로부터 화학식 1의 화합물을 제조하는 단계(단계 4);를 포함하는 것인, 화학식 1의 화합물의 제조방법:Preparing a compound of Formula 1 from a compound of Formula 6 (Step 4); A method for preparing a compound of Formula 1, comprising:
    [반응식 1][Scheme 1]
    Figure PCTKR2020016377-appb-img-000021
    Figure PCTKR2020016377-appb-img-000021
    상기 반응식 1에서, LG는 이탈기이고, PG는 보호기이며, R 1 내지 R 6은 각각 제 1 항에서 정의한 것과 동일하다.In Scheme 1, LG is a leaving group, PG is a protecting group, and R 1 to R 6 are each the same as defined in claim 1.
  7. 유효성분으로 제 1 항 내지 제 5 항 중 어느 한 항에 따른 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 포함하는, 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물.A cancer, degenerative brain disease, and A pharmaceutical composition for the prevention or treatment of one or more protein kinase-related diseases selected from the group consisting of inflammatory diseases.
  8. 유효성분으로 제 1 항 내지 제 5 항 중 어느 한 항에 따른 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물로서,A pharmaceutical composition comprising the compound of Formula 1 according to any one of claims 1 to 5, an isomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, as an active ingredient,
    상기 화합물은 AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, HPK1, JAK1(JH1domain-catalytic), JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LRRK2, LRRK2(G2019S), TRKA, TRKB, TRKC, 및 TYK2(JH1domain-catalytic)로 이루어지는 군으로부터 선택되는 하나 이상의 단백질 키나아제에 대하여 저해활성을 나타내는 것을 특징으로 하는 것인, 약학적 조성물.The compound is AURKA, AURKB, AURKC, AXL, BTK, CDK7, CLK1, CLK2, CLK3, CLK4, DDR1, DDR2, DLK, FLT3, FLT3 (D835H), FLT3 (D835V), FLT3 (D835Y), FLT3 (ITD) , FLT3 (ITD,D835V), FLT3 (ITD,F691L), FLT3 (K663Q), FLT3 (N841I), FLT3 (R834Q), FLT3-autoinhibited, HPK1, JAK1 (JH1domain-catalytic), JAK1 (JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT( V559D, V654A), LRRK2, LRRK2 (G2019S), TRKA, TRKB, TRKC, and TYK2 (JH1 domain-catalytic) characterized in that it exhibits inhibitory activity against one or more protein kinases selected from the group consisting of composition.
  9. 제 7 항에 있어서, 8. The method of claim 7,
    상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 갑상선수질암, 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, 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, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상의 암인 것을 특징으로 하는, 약학적 조성물.The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, medullary thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, Basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell carcinoma, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, Bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer , heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid carcinoma, gastrointestinal tract Interstitial cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord Cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood A pharmaceutical composition, characterized in that at least one cancer selected from the group consisting of cancer and thymus cancer.
  10. 제 7 항에 있어서, 8. The method of claim 7,
    상기 퇴행성 뇌질환은 알츠하이머 질환, 파킨슨병, 루게릭병, 치매, 헌팅턴 질환, 다발성 경화증, 근위측성 측삭 경화증, 중풍, 뇌졸중, 및 경도 인지장애로 이루어진 군으로부터 선택되는 1종 이상의 질환인 것을 특징으로 하는, 약학적 조성물.The degenerative brain disease is Alzheimer's disease, Parkinson's disease, Lou Gehrig's disease, dementia, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, stroke, and mild cognitive impairment It is characterized in that at least one disease selected from the group consisting of , pharmaceutical composition.
  11. 제 7 항에 있어서,8. The method of claim 7,
    상기 염증질환은 피부염, 알레르기, 위궤양, 십이지장궤양, 간염, 식도염, 위염, 장염, 췌장염, 대장염, 신장염, 전신부종, 국소부종, 관절염, 각막염, 기관지염, 흉막염, 복막염, 척추염, 염증성 통증, 요도염, 방광염, 치주염, 및 치은염으로 이루어진 군으로부터 선택되는 1종 이상의 질환인 것을 특징으로 하는, 약학적 조성물.The inflammatory disease is dermatitis, allergy, gastric ulcer, duodenal ulcer, hepatitis, esophagitis, gastritis, enteritis, pancreatitis, colitis, nephritis, systemic edema, local edema, arthritis, keratitis, bronchitis, pleurisy, peritonitis, spondylitis, inflammatory pain, urethritis, A pharmaceutical composition, characterized in that at least one disease selected from the group consisting of cystitis, periodontitis, and gingivitis.
  12. 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료에 있어서의 제 1 항 내지 제 5 항 중 어느 한 항에 따른 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염의 용도.A compound of Formula 1 according to any one of claims 1 to 5, an isomer thereof, for the prevention or treatment of at least one protein kinase-related disease selected from the group consisting of cancer, degenerative brain disease, and inflammatory disease Use of a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  13. 제 1 항 내지 제 5 항 중 어느 한 항에 따른 화학식 1의 화합물, 이의 이성질체, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염을, 이를 필요로 하는 대상에게 투여하는 단계를 포함하는, 암, 퇴행성 뇌질환, 및 염증질환으로 이루어지는 군으로부터 선택되는 1종 이상인 단백질 키나아제 관련 질환의 예방 또는 치료방법.The method of any one of claims 1 to 5, comprising administering the compound of Formula 1, an isomer, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof , cancer, degenerative brain disease, and a method for preventing or treating one or more protein kinase-related diseases selected from the group consisting of inflammatory diseases.
PCT/KR2020/016377 2020-11-19 2020-11-19 N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient WO2022107919A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/KR2020/016377 WO2022107919A1 (en) 2020-11-19 2020-11-19 N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2020/016377 WO2022107919A1 (en) 2020-11-19 2020-11-19 N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient

Publications (1)

Publication Number Publication Date
WO2022107919A1 true WO2022107919A1 (en) 2022-05-27

Family

ID=81709124

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2020/016377 WO2022107919A1 (en) 2020-11-19 2020-11-19 N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient

Country Status (1)

Country Link
WO (1) WO2022107919A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022607A1 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
WO2007023382A2 (en) * 2005-08-25 2007-03-01 Pfizer Inc. Pyrimidine amino pyrazole compounds, potent kinase inhibitors
KR20120089648A (en) * 2009-08-14 2012-08-13 버텍스 파마슈티칼스 인코포레이티드 Pyrimidine compounds as tuberculosis inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022607A1 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
WO2007023382A2 (en) * 2005-08-25 2007-03-01 Pfizer Inc. Pyrimidine amino pyrazole compounds, potent kinase inhibitors
KR20120089648A (en) * 2009-08-14 2012-08-13 버텍스 파마슈티칼스 인코포레이티드 Pyrimidine compounds as tuberculosis inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHENZHOU HAO, ZHAO FAN, SONG HONGYAN, GUO JING, LI XIAODONG, JIANG XIAOLIN, HUAN RAN, SONG SHUAI, ZHANG QIAOLING, WANG RUIFENG, WA: "Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 61, no. 1, 11 January 2018 (2018-01-11), US , pages 265 - 285, XP055767957, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.7b01342 *
CRAWFORD JAMES J., LEE WENDY, ALIAGAS IGNACIO, MATHIEU SIMON, HOEFLICH KLAUS P., ZHOU WEI, WANG WEIRU, ROUGE LIONEL, MURRAY LESLEY: "Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 58, no. 12, 25 June 2015 (2015-06-25), US , pages 5121 - 5136, XP055931857, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.5b00572 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11897878B2 (en) 2018-10-31 2024-02-13 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds
US11925631B2 (en) 2018-10-31 2024-03-12 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds

Similar Documents

Publication Publication Date Title
EP2945623B1 (en) Hedgehog pathway signaling inhibitors and therapeutic applications thereof
RU2368602C2 (en) Compounds and compositions as protein kinase inhibitors
RU2411242C2 (en) Compounds and compositions as proteinkinase inhibitors
WO2016085221A2 (en) Heteroaryl amine derivative useful as protein kinase inhibitor
WO2020190119A1 (en) Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
WO2010024258A1 (en) Ring-fused azole derivative having pi3k-inhibiting activity
AU2005254982A1 (en) Compounds and compositions as protein kinase inhibitors
WO2020149723A1 (en) Pyrrolopyrimidine derivative, and pharmaceutical composition for preventing or treating protein kinase-related disease comprising same as active ingredient
AU2008228964A1 (en) Pyrazolopyrimidine analogs and their use as mTOR kinase and PI3 kinase inhibitors
WO2020235902A1 (en) Heterocycle-fused pyrimidine derivative and use thereof
AU2018285131B2 (en) Heteroaromatic compounds as Vanin inhibitors
WO2020149715A1 (en) Pyrrolopyridine derivative and use thereof in prevention and treatment of protein kinase-related disease
WO2021145521A1 (en) Pyrido[3,4-d]pyrimidine derivative and therapeutic pharmaceutic composition comprising same
WO2022107919A1 (en) N-containing heteroaryl derivative, and pharmaceutical composition for preventing or treating protein kinase-related diseases comprising same as active ingredient
WO2023067546A1 (en) Novel bicyclic heteroaryl derivatives as sos1:kras proteinprotein interaction inhibitors
WO2022131741A1 (en) Isoxazolidine derivative compound and use thereof
WO2020185044A1 (en) Heteroaryl derivatives and pharmaceutical composition comprising same as active ingredient
WO2018030800A1 (en) Urea compound having 3,4-dihydropyrimido[4,5-d]pyrimidine-2(1h)-one skeleton having protein kinase inhibiting activity
WO2020235945A1 (en) N-containing heteroaryl derivative and pharmaceutical composition comprising same as active ingredient for prevention or treatment of cancer
CN111377873B (en) Aminopyrimidine compounds, their preparation and use
WO2022146027A1 (en) Heteroaryl derivative compound and use thereof
KR102329720B1 (en) NOVEL PYRIMIDO[4,5-d]PYRIMIDIN-2-ONE DERIVATIVES AS PROTEIN KINASE INHIBITORS
WO2024048809A1 (en) Heteroaryl derivative containing n, pharmaceutical composition comprising same, and use thereof
WO2023214772A1 (en) Compound including 2,4-diaminopyridine, preparation method therefor, and pharmaceutical composition containing same as active ingredient for prevention or treatment of cancer
WO2022015051A1 (en) Aryl or heteroaryl derivative, and pharmaceutical composition comprising same as active ingredient for prevention or treatment of kinase-related disease

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20962525

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20962525

Country of ref document: EP

Kind code of ref document: A1