WO2023121413A1 - Novel bicyclic heterocyclyl compound and use thereof - Google Patents

Novel bicyclic heterocyclyl compound and use thereof Download PDF

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WO2023121413A1
WO2023121413A1 PCT/KR2022/021249 KR2022021249W WO2023121413A1 WO 2023121413 A1 WO2023121413 A1 WO 2023121413A1 KR 2022021249 W KR2022021249 W KR 2022021249W WO 2023121413 A1 WO2023121413 A1 WO 2023121413A1
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ethyl
pyridazin
amine
methyl
difluoromethyl
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PCT/KR2022/021249
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French (fr)
Korean (ko)
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이창석
김명섭
이정미
김진웅
김진주
이예지
김지윤
이찬
구진모
김형국
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제일약품주식회사
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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to a bicyclic heterocyclyl compound exhibiting SOS1 inhibitory activity, and more particularly, to a novel bicyclic heterocyclyl compound exhibiting preventive, ameliorative or therapeutic activity against various carcinomas due to its excellent SOS1 inhibitory activity. It relates to a compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, uses thereof, and pharmaceutical compositions comprising the same.
  • RAS family proteins include KRAS, NRAS and HRAS, mutants of which are small GTPases present in cells in a GTP-bound or GDP-bound state.
  • RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. Binding of guanine nucleotide exchange factors (GEFs), such as Son of Sevenless 1 (SOS1), promotes GDP release from RAS proteins and enables GTP binding.
  • GEFs guanine nucleotide exchange factors
  • SOS1 Son of Sevenless 1
  • RAS family proteins are active when in a GTP-bound state, and are associated with effector proteins such as C-RAF and PI3K. These pathways affect various cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth.
  • KRAS mutations eg, amino acids G12, G13, Q61, A146 are found in a variety of human cancers, including lung, colorectal and pancreatic cancers.
  • SOS1 Son of Sevenless 1
  • SOS1 has two binding sites for RAS family proteins; It has a catalytic site binding to GDP-binding RAS family proteins and an allosteric site binding to GTP-binding RAS family proteins. Loss of SOS1 reduces the proliferation rate and survival of KRAS mutation-bearing tumor cells, and no effect was observed in KRAS wild-type cell lines. Additionally, SOS1 alterations have been implicated in cancer. SOS1 mutations are found in embryonic rhabdomyosarcomas, Sertolnic cell testicular tumors, granular cell tumors of the skin, and lung adenocarcinomas.
  • SOS1 is found in bladder cancer and prostate cancer.
  • hereditary SOS1 mutations are associated with the pathogenesis of RAS diseases such as Noonan syndrome (NS), cardio-facio-cutaneous (CFC) syndrome and hereditary gingival fibromatosis type 1.
  • An object of the present invention is a novel bicyclic heterocyclyl-based compound having excellent SOS1 inhibitory activity, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable form thereof. It is an object to provide a salt that is.
  • the present invention is a pharmaceutical agent comprising the bicyclic heterocyclyl-based compound, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object is to provide a scientific composition.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating various diseases caused by SOS1 activity, comprising the bicyclic heterocyclyl compound as an active ingredient.
  • Another object of the present invention is to provide a use of the bicyclic heterocyclyl compound for the preparation of a drug for preventing, ameliorating or treating various diseases caused by SOS1 activity.
  • Another object of the present invention is to provide a method for preventing, improving or treating various diseases caused by SOS1 activity by administering the bicyclic heterocyclyl compound.
  • a bicyclic heterocyclyl compound represented by Formula (I) below an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable form thereof. Possible salts may be provided.
  • R 1 to R 5 , A, L 3 , and p have the meanings given in the claims and specification.
  • a compound derivative containing the bicyclic heterocyclyl of Formula (I), a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof is provided.
  • pharmaceutical compositions and medicinal/pharmaceutical uses particularly uses as agents for preventing, ameliorating or treating diseases associated with SOS1 activity, such as cancer or RAS conditions.
  • a compound derivative containing the bicyclic heterocyclyl of Formula (I), a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof It provides a combination drug or use for the prevention, improvement or treatment of cancer or RAS, characterized in that it includes a pharmaceutical composition comprising a pharmaceutical composition and another additional therapy.
  • a bicyclic heterocyclyl-based compound exhibiting an excellent SOS1 inhibitory effect, or an optical isomer thereof, a stereoisomer thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof is provided.
  • these compounds, or stereoisomers thereof, solvates thereof, isotopic variants thereof, tautomers thereof, or pharmaceutically acceptable salts thereof can be effectively used for the prevention or treatment of diseases associated with SOS1 inhibition.
  • the term “independently” means that when more than one substituent is selected from a number of possible substituents, these substituents may be the same or different from each other.
  • halo As used herein, the term “halo,” “halogen,” “halide(s)” includes fluoro, chloro, bromo, and iodo.
  • alkyl refers to an aliphatic hydrocarbon radical and includes both linear and branched hydrocarbon radicals.
  • C 1 -C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
  • alkyl means C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably C 1 -C 3 alkyl.
  • alkenyl refers to an aliphatic hydrocarbon radical containing one or more carbon-carbon double bonds, and includes both linear and branched hydrocarbon radicals.
  • alkenyl is vinyl, allyl, but-1-enyl or but-2-enyl.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is defined as above.
  • Halo refers to F, Cl, Br or I and the term is used interchangeably with the term “halogen”.
  • haloalkyl means fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.
  • alkoxy refers to the group -O-alkyl or alkyl-O-, wherein the alkyl group is defined as above. For example, it may be methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.
  • hydroxy or "hydroxyl” alone or in combination with other terms means -OH.
  • amino means -NH 2 .
  • cycloalkyl refers to a cyclic alkyl which may be substituted or unsubstituted, for example, C 3 -C 20 cycloalkyl is a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • cycloalkyl can be C 3 -C 8 cycloalkyl or C 4 -C 6 cycloalkyl.
  • cycloalkenyl is an unsubstituted or substituted cyclic alkyl, the system being unsaturated, ie at least one C-C double bond present, but not an aromatic system.
  • a cycloalkyl as defined above when two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl results.
  • substitutions may occur independently of each other in mono- or polysubstitution in each case on all carbon atoms having hydrogen.
  • the cycloalkenyl itself may be attached to the molecule as a substituent at any suitable position of the ring system.
  • aryl refers to a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (C 6 -C 20 ), derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring. refers to system.
  • Aryl can include bicyclic radicals containing an aromatic ring fused to a saturated or partially unsaturated ring.
  • Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like.
  • aryl means C 6 -C 12 aryl, preferably C 6 -C 10 aryl.
  • heterocycle refers to an aromatic, saturated or partially unsaturated mono-, bi- or poly-ring system containing the specified number of ring atoms and containing one or more heteroatoms selected from N, O and S. .
  • Bicyclic systems can be 1,1-fused (spiro), 1,2-fused (fused) or 1,>2-fused (bridgeheaded).
  • heteroaryl is a compound derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon containing at least one selected from N, O and S, preferably 1 to 3 or 1 to 2 heteroatoms. Refers to a monovalent or divalent substituent.
  • heteroaryl are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl , 1,2,4-oxazoles, but are not limited thereto.
  • heteroaryl is a 4-12 membered heteroaryl, preferably a 4-10 membered heteroaryl, more preferably a 4-7 membered heteroaryl.
  • heterocycloalkyl is a ring member of 3 to 10 carbon atoms containing one or more selected from N, O and S, for example 1 to 4, 1 to 3, or 1 to 2 heteroatoms.
  • monocyclic, bicyclic, tricyclic or higher cyclic alkyl having Heterocycles according to the present invention may also be fused or bridged heterocycloalkyls.
  • non-aromatic rings examples include azetidinyl, oxetanyl, tetrahydro, tetrahydrofuran, pyrrole, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperidinyl.
  • Razinyl tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl , tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl, morpholinyl, indolinyl, azethiomorpholinyl and the like.
  • heterocycloalkyl can occur via a carbon atom or a heteroatom.
  • Heterocycloalkyl groups may be optionally substituted with one or more suitable groups through one or more of the foregoing groups.
  • heterocycloalkyl refers to 4 to 12 membered heterocycloalkyl, preferably 4 to 10 membered heterocycloalkyl, and more preferably 4 to 7 membered heterocycloalkyl.
  • heterocycloalkenyl (or “heterocyclenyl”) means a non-aromatic monocyclic or multicyclic ring system containing one or more carbon-carbon double bonds or carbon-nitrogen double bonds. and at least one of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen or sulfur alone or in combination. Heterocycloalkenyl groups may be optionally substituted with one or more suitable groups through one or more of the foregoing groups. Unless otherwise defined, heterocycloalkenyl refers to 4 to 12 membered heterocycloalkenyl, preferably 4 to 10 membered heterocycloalkenyl, more preferably 4 to 7 membered heterocycloalkenyl.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that each of at least one nitrogen, oxygen or sulfur atom is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • cyclic substituents eg, cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl, heterocycloalkyl, heterocycloalkenyl, etc.
  • cyclic substituents may be unsubstituted or substituted.
  • solvate refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for purposes of this disclosure may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates in which water is the solvent molecule are called hydrates. Hydrates include compositions containing variable amounts of water as well as compositions containing stoichiometric amounts of water.
  • isomers refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Structural differences may occur in composition (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds herein may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.
  • stereoisomers refers to a group of compounds that have the same atomic number and type and share the same bonding connectivity between their atoms, but differ in three-dimensional structure.
  • stereoisomer refers to any member of this class of compounds.
  • stereoisomers can be enantiomers or diastereomers.
  • enantiomers refers to a pair of stereoisomers that are non-superimposable mirror images of each other.
  • enantiomer refers to a single member of this pair of stereoisomers.
  • racemic refers to a 1:1 mixture of a pair of enantiomers.
  • diastereomer refers to a set of stereoisomers that cannot be made superimposable by rotation around a single bond.
  • compounds containing cis- and trans-double bonds on bicyclic ring systems, endo- and exo-substitutions, and multiple stereogenic centers with different relative configurations are considered to be diastereomers.
  • diastereomer refers to any member of this set of compounds. In some of the examples presented, the synthetic route may give rise to a single diastereomer or a mixture of diastereomers.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that are interconvertable through low energy barriers.
  • proton tautomers also known as protic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • isotopic variant is intended to mean a compound in which at least one atom has been exchanged for another atom having the same atomic number but a different atomic weight than the atomic weight commonly or predominantly occurring in nature.
  • an "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease in a subject as described herein.
  • the present invention provides a compound of Formula (I), or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 when R 1 is two or more, R 1 may combine with each other to form a 4- to 12-membered heterocycle;
  • the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 haloalkyl, hydroxy-C 1 -C 6 alkyl, Hydroxy-C 1 -C 6 -haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, hydroxy-C 3 -C 6 cycloalkyl, -NH 2 or 3-6 membered heterocyclyl is unsubstituted or hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, 3-6 membered heterocyclyl, -C 1 -C 4 alkyl-NH-C 1 -C 4 alkyl and -C 1 -C 4 alkyl-N(C
  • A is C 6 -C 10 aryl, 5-12 membered heteroaryl or 9-20 membered bicyclic heterocyclyl;
  • R 4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, substituted amino, cyano, hydroxy-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, -C 1 -C 4 alkyl-NH 2 , -C 1 -C 4 alkyl-NH-C 1 -C 4 alkyl or -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 ;
  • R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, -C(O)NH 2 or amino, wherein said amino or The amino group of -C(O)NH 2 may be unsubstituted or substituted with C 1 -C 4 alkyl;
  • L 3 is a bond, -C(O)-, -C(O)O-, -C(O)NH(CH 2 ) o -, -S(O) 2 -, , , , , -C(O)(CH 2 ) o -, -(CH 2 ) o -, -NH- or -O-, where o can be an integer of 0, 1 or 2;
  • R 3 can be 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl;
  • said 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl is unsubstituted or optionally substituted with R a1 and/or R bi ;
  • Each R b1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 It is selected from the group consisting of cycloalkyl, C 4 -C 10 cycloalkenyl, 3-12 membered heterocyclyl, C 6 -C 10 aryl and 5-12 membered heteroaryl, wherein, 3-12 membered hetero Cyclyl or 5-12 membered heteroaryl may be unsubstituted or substituted with C 1 -C 6 alkyl;
  • R 5 may be C 1 -C 6 alkyl, specifically C 1 -C 3 alkyl, more specifically methyl;
  • each R 1 may be the same or different.
  • R 1 is each independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro, fluoro, hydroxy, -NH 2 , cyano, -SO 2 , -SO 2 -C 1 -C 4 alkyl or phenyl, wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -SO 2 -C 1 -C 4 alkyl or phenyl is unsubstituted or hydroxy, halogen, C 1 - C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 3-6 membered heterocyclyl, and C 1 -C 6 alkyl substituted with methylamine or dimethylamine It may be substituted with 1 to 3 substituents selected from the group consisting of.
  • R 1 is methyl, methoxy, -CF 3 , -CHF 2 , fluoro, chloro, -NH 2 , cyano, hydroxy, -SO 2 , -SO 2 -CH 3 , and unsubstituted or substituted with one to three of methyl, methoxy, hydroxy, fluoro, cyclopropoxy, tetrahydrofuran, -CH 2 -NH-CH 3 and -CH 2 -N(CH 3 ) 2 C 1 -C 4 alkyl or phenyl.
  • R 1 is methyl, -CF 3 , -CHF 2 , fluoro, -NH 2 , cyano and C 1 -C 4 substituted with one to three of methoxy, hydroxy, and fluoro. It can be alkyl or phenyl substituted with -CH 2 -N(CH 3 ) 2 . More specifically, R 1 may be -CHF 2 , or fluoro.
  • the two or more substituents may together form cycloalkyl, specifically C 3 -C 6 cycloalkyl, more specifically cyclopropyl. there is.
  • the two or more types of R 1 cannot be halo at the same time.
  • A may be C 6 -C 9 aryl, 5- to 8-membered heteroaryl, or 9- to 12-membered bicyclic heterocyclyl. More specifically, A may be phenyl, thiophenyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl or dihydroindenyl. More specifically, A may be phenyl, thiophenyl, or dihydrobenzofuranyl. More specifically, the A may be phenyl.
  • R 4 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, amino substituted with C 1 -C 4 alkyl, -C 1 - C 4 alkyl-NH 2 , -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 . More specifically, R 4 may be hydrogen, methyl, methoxy, -CF 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 . More specifically R 4 may be methyl.
  • R 2 may each independently be hydrogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy, and more specifically, hydrogen, hydroxy, methyl, methoxy, -CF 3 , more specifically hydrogen, methoxy, more specifically hydrogen.
  • R 2 may each independently be hydrogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and more specifically, hydrogen, hydroxy, methyl, -CF 3 , Specifically, it may be hydrogen.
  • R 3 is 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 1,1-fused (spiro), 1,2-fused (fused), 1,>2-fused (bridged) It may be a 6-10 membered bicyclic heterocyclyl connected by a head). More specifically, R 3 may include an N atom in a ring, and the N atom part is connected to L 3 .
  • R 3 is azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, azaspiroheptanyl, diazaspiroheptanyl, oxaazaspiroheptanyl , oxaazaspirooctanyl, diazaspiroctanyl, oxaazaspirononanyl, oxaazaspirononanyl, diazaspirodecanyl, dioxaazaspirodecanyl, oxaazaspirodecanyl, hexahydrofuropyrrole , octahydropyrazinooxazinyl, octahydropyrrolopyrazinyl, tetrahydroimidazopyrazinyl, tetrahydropyrazolopyrazinyl, oxaazabicyclohept
  • R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiroheptanyl, diazaspiroheptanyl, oxazaspiroheptanyl, oxaazaspirooctanyl, oxa azaspirononanyl, hexahydrofuropyrroyl, octahydropyrazinooxazinyl, octahydropyrrolopyrazinyl, oxazabicycloheptanyl, or oxaazabicyclooctanyl.
  • R 3 may be azetidinyl, oxaazabicycloheptanyl, or oxaazabicyclooctanyl.
  • the N portion of the R 3 ring may be connected to L 3 .
  • the R 3 may be any one selected from the following groups.
  • R a1 is each independently C 1 -C 6 alkyl, -OR b1 , -NR b1 R b1 , halogen, -C(O)R b1 , oxo, -C 1 -C 3 alkylNR b1 R b1 , -C(O)NR b1 R b1 , -R b1 -OR b1 , and more specifically, R a1 is C 1 -C 6 alkyl, -OR b1 , -NR b1 R b1 , halogen, -C( O)R b1 , oxo, -C 1 -C 3 alkylNR b1 R b1 , more specifically C 1 -C 2 alkyl, -OR b1 , -NR b1 R b1 , fluoro, -C(O)R b1 , oxo, -CH 2 NR
  • R b1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, and 5-12 membered heteroaryl. , wherein the 5-12 membered heteroaryl may be unsubstituted or substituted with C 1 -C 6 alkyl;
  • R b1 may be hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, cyclopropyl, 4-6 membered heterocycloalkyl, 5-membered heteroaryl substituted with methyl, and more specifically hydrogen , C 1 -C 2 alkyl, -CH 2 CF 3 , cyclopropyl, or 4-membered heterocycloalkyl, and more specifically, hydrogen or methyl.
  • R 5 may be C 1 -C 3 alkyl, more specifically methyl.
  • p may be an integer from 1 to 3, more specifically 1 or 2, more specifically 2.
  • L 3 may be a bond.
  • heteroaryl, heterocycloalkyl, heterocycloalkenyl, and heterocyclyl among the residues are one to three selected from the group consisting of N, O, S, SO and SO 2 , and one to two may contain heteroatoms of the species.
  • cyclic substituents eg, cycloalkyl, aryl, heterocycle, heterocycloalkyl, heterocycloalkenyl, etc.
  • cyclic substituents eg, cycloalkyl, aryl, heterocycle, heterocycloalkyl, heterocycloalkenyl, etc.
  • the compounds of formula (I) according to the present invention may be one or more selected from the group consisting of compounds 1) to 89) in Table 1 below, but are not limited thereto.
  • the compound of Formula (I) according to the present invention may be one or more selected from the group consisting of the following compounds, but is not limited thereto.
  • formulas or names given in the specification and claims herein refer only to tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof. mixtures of separate enantiomers, mixtures of diastereomers, or mixtures of any of the above forms in which isomers and enantiomers are present, as well as pharmaceutically acceptable salts thereof and such as solvates and hydrates of free compounds, or corresponding It encompasses salts, including solvates thereof, such as hydrates, including solvates and hydrates of salts of the compounds.
  • the compounds of the present invention may exist in the form of pharmaceutically acceptable salts.
  • the salt an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt refers to any concentration of a compound having a relatively non-toxic and harmless effective effect on patients, and side effects caused by the salt do not reduce the beneficial effects of the compound according to the present invention. means any organic or inorganic addition salt.
  • Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
  • organic acids and inorganic acids can be used as the free acid
  • hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as the inorganic acid
  • methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid can be used as the organic acid.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • maleic acid succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.
  • citric acid lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto.
  • the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups which may be present in the compounds described in Formula (I) above.
  • pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of a hydroxy group
  • other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate.
  • dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, etc. preparation of salts known in the art It can be produced through the method.
  • the pharmaceutically acceptable salt of the compound of the present invention may be a hydrochloride salt.
  • the salt of the compound described in Formula (I) of the present invention is a pharmaceutically acceptable salt, and any salt of the compound described in Formula (I) exhibiting pharmacological activity equivalent to that of the compounds listed in Table 1 can be used without limitation. do.
  • the compound described in Formula (I) according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as hydrates and the like that can be prepared therefrom and all possible stereoisomers without limitation.
  • All stereoisomers of the present invention including enantiomeric and diastereomeric forms (eg, those that may exist due to asymmetric carbons in various substituents) are included within the scope of the present invention.
  • Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (eg, as pure or substantially pure optical isomers having a specific activity), or, for example, as racemates or It can be mixed with all other or other selected stereoisomers.
  • the chiral center of the compounds of the present invention may have the S or R structure defined by the IUPAC 1974 Recommendation. Racemic forms can be resolved by physical methods such as separation by chiral column chromatography or separation or crystallization of diastereomeric derivatives, fractional shape crystallization. Individual optical isomers may be obtained from the racemates by any suitable method including, but not limited to, salt formation with an optically active acid followed by crystallization.
  • Solvates and stereoisomers of the compounds of formula (I) can be prepared from these compounds using methods known in the art.
  • the compound of formula (I) according to the present invention may be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, it may be optionally hydrated or solvated.
  • compounds containing various amounts of water may be included as well as stoichiometric hydrates of the compounds described in formula (I) above.
  • Solvates of the compound of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
  • the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof is a cross-linked interaction between SOS1 and a RAS-family protein. It is characterized by inhibiting the action or inhibiting the interaction between SOS1 and RAC in cells.
  • the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof is a variety of drugs induced by the activity of SOS1. It is characterized by having preventive, ameliorative or therapeutic activity for diseases.
  • the compounds of the present invention can be used in various ways induced by the activity of SOS1. It may be suitable for preventing, ameliorating or treating a disease.
  • the present invention provides a compound of formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. It relates to a pharmaceutical composition for preventing, improving or treating various diseases caused by the activity of SOS1, including an acceptable carrier.
  • various diseases caused by the activity of SOS1 may be, for example, the following cancers, tumors, other proliferative diseases, or RASopathy.
  • the cancer is pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, stomach cancer, cervical cancer, head and neck squamous It may be a cancer selected from the group consisting of cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma, but is not limited thereto.
  • the RAS pathology is neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), capillaries Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome ) and a disease selected from the group consisting of hereditary gingival fibromatosis, but is not limited thereto.
  • NF1 neurofibromatosis type 1
  • NS Noonan Syndrome
  • NSML Noonan Syndrome with Multiple Lentigines
  • CCM-AVM Capillary Malformation-Arteriovenous Malformation Syndrome
  • CS Costello Syndrome
  • CFC Cardio-Facio-Cutaneous Syndrome
  • Legius Syndrome a disease selected from the group consisting of hereditary gingival fibromatosis, but is not limited thereto.
  • the pharmaceutical composition according to the present invention comprises the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and Together with a pharmaceutically acceptable carrier, an additional cancer therapeutic agent may be further included as an active ingredient.
  • the cancer therapeutic agent may be at least one selected from the group consisting of steroids, checkpoint inhibitors, anticancer agents, anti-angiogenic agents and autophagy inhibitors, but may be used without limitation as long as it is related to the treatment of cancer. Specific examples of these are the same as the agents described in combination therapy below.
  • the compound according to the present invention its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt and its pharmaceutical composition containing them are known in the art. It can be used in conjunction with non-drug therapies for cancer or RAS conditions known in . For example, in combination with radiotherapy and/or surgery and/or other compounds, it can be used for prevention, short-term or long-term treatment of the diseases mentioned above.
  • the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes.
  • the route of administration of the pharmaceutical composition is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, These include topical, sublingual or rectal.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursal, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition according to the present invention may further comprise one or more pharmaceutically acceptable carriers, one or more excipients and/or diluents.
  • Non-limiting examples of pharmaceutically suitable carriers include solids and/or liquids such as ethanol, glycerol, water and the like.
  • the amount of carrier in the therapeutic composition may range from about 5% to about 99% by weight based on the total weight of the therapeutic composition or therapeutic combination.
  • suitable pharmaceutically acceptable excipients and diluents include non-toxic, compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, bulking agents, antioxidants, lubricants, flavoring agents, thickeners, colorants, surfactants. , emulsifiers, turbidity agents, etc. are included.
  • excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto, and all other pharmaceutically acceptable carriers, excipients and diluents It is obvious to those skilled in the art that it can be used.
  • a composition containing the compound of the present invention or a salt thereof may be prepared according to conventional methods, such as oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions for internal use, emulsions, syrups, external preparations, suppositories or It may be formulated and used in the form of a sterile injectable solution.
  • the pharmaceutical composition according to the present invention may be in the form of a sterile injectable preparation as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (eg, as a solution in 1,3-butanediol). Acceptable vehicles and solvents include mannitol, water, Ringer's solution or isotonic sodium chloride solution.
  • sterile fixed oils are usually employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives, are useful in injectable preparations as are pharmaceutically acceptable natural oils (eg olive oil or castor oil), especially polyoxyethylated ones thereof.
  • composition according to the present invention may be administered orally in any orally acceptable dosage including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • compositions of the present invention may also be administered in the form of a suppository for rectal administration.
  • These compositions can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • Oral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves areas or organs that are easily accessible by topical application.
  • the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical composition of the present invention may also be topically applied to the lower intestinal tract by rectal suppository and also as a suitable enema. Topically applied transdermal patches are also included in the present invention.
  • compositions of the present invention can be administered by intranasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmaceuticals and prepared in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other solubilizers or dispersants known in the art. It can be prepared as a solution.
  • novel compound described above in the pharmaceutical composition of the present invention is contained in a therapeutically effective amount or a prophylactically effective amount.
  • a preferred dosage of the compound according to the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art.
  • the compound of formula (I) of the present invention may be administered in an amount of 0.0001 to 1000 mg/kg, preferably 0.01 to 500 mg/kg, divided into once to several times a day.
  • the compound of formula (I) may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the composition.
  • the present invention provides a compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. It relates to a method for preventing, improving or treating various diseases caused by the activity of SOS1 including a carrier.
  • the compound of formula (I) of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level is the patient's health condition.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can
  • the dosage may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., so the dosage is not limited to the scope of the present invention in any way.
  • a preferred dose of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art.
  • the compound of the present invention may be used alone or in addition to one or more additional therapies. (eg, non-drug treatment or therapeutic agent).
  • Combination therapy may, for example, combine two therapies or may combine three therapies (eg, a triple therapy of three therapeutic agents) or more.
  • the dosage of one or more of the additional therapies may be reduced from the standard dosage when administered alone.
  • a compound of the present invention may be a compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them prior to one or more such additional therapies. It can be administered after, or concurrently.
  • An additional therapy such as a compound of the present invention and an anti-cancer agent, can be administered together, eg, in a single pharmaceutical composition, or can be administered separately, and when administered separately, this can occur simultaneously or sequentially. Such sequential administration may be close in time or distant.
  • the additional therapy may be administration of a side effect limiting agent.
  • side effect limiting agents are agents that can be used to treat nausea, and may include dronabinol, granisetron, metoclopramide, ondansetron and prochlorperazine, or pharmaceutically acceptable salts thereof. there is.
  • the additional therapy includes non-drug therapy (eg, surgery or radiation therapy).
  • non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical resection of tumor tissue), and adoptive T cell transfer (ACT) therapy. It doesn't work.
  • Combinable therapeutic agents may be compounds used in the treatment of cancer or conditions associated therewith, and suitable steroids include 21-acetoxypregnenolone, alcomethasone, algestone, amcinonide, beclomethasone, betamethasone, Desonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflu Cortolone, difuprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, flu Ferolone acetate, fluprednidene acetate, flupredn
  • the biologic may be a biological agent (eg, a cytokine (eg, an interferon or an interleukin such as IL-2)) used in the treatment of cancer or a condition associated therewith.
  • a biological agent eg, a cytokine (eg, an interferon or an interleukin such as IL-2)
  • the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (eg, a humanized antibody, fully human antibody, Fc fusion protein or functional fragment thereof).
  • Antibody-drug conjugates are also included.
  • the checkpoint inhibitor can be a monospecific antibody such as a monoclonal antibody, a fusion protein such as an Fc-receptor fusion protein, more specifically an inhibitor of CTLA-4 (eg an inhibitory antibody or small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein), an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or small molecule inhibitor), an inhibitor or antagonist of PDL-1 (e.g., an inhibitory antibody or small molecule inhibitor), a PDL-1 2 inhibitors or antagonists (eg, inhibitory antibodies or Fc fusions or small molecule inhibitors) (eg, PDL-2/Ig fusion proteins), and the like, but are not limited thereto.
  • CTLA-4 eg an inhibitory antibody or small molecule inhibitor
  • PD-1 e.g., an inhibitory antibody or small molecule inhibitor
  • PDL-1 2 inhibitors or antagonists e.g, inhibitory antibodies or Fc fusions or small molecule inhibitors
  • the anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapy.
  • anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors.
  • vinca alkaloids e.g., vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocorticosteroids, progestins, Includes estrogens, antiestrogens, androgens, antiandrogens and gonadotropin analogues.
  • Additional anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, docetaxel, ALK inhibitor receptor tyrosine kinase (RTK)/growth factor receptor (e.g.
  • LV leucovorin
  • irenotecan oxaliplatin
  • capecitabine paclitaxel
  • docetaxel docetaxel
  • ALK inhibitor receptor tyrosine kinase (RTK)/growth factor receptor e.g.
  • MPK MAP kinase
  • anti-angiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.
  • the autophagy inhibitor is chloroquine, 3-methyladenine, hydroxy chloroquine (PlaquenilTM), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, type autophagy-inhibiting algal toxins that inhibit protein phosphatases of type 2A or type 1, cAMP, and drugs that elevate cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine, but these not limited to
  • the compounds according to the present invention may be used in combination with the agents described herein or other suitable agents depending on the condition being treated.
  • one or more compounds of the present disclosure will be co-administered with other therapies as described herein.
  • the compounds described herein may be administered simultaneously or separately with the second agent.
  • Such combined administration can include simultaneous administration of both agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any agent described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any therapy described herein may be administered simultaneously, wherein the two agents are in separate preparations.
  • a compound of the present disclosure may be administered followed by any therapy described herein, or vice versa.
  • the compounds of the present invention and any of the therapies described herein may be administered minutes apart, or hours apart, or days apart.
  • the first therapy eg, a compound of the invention
  • one or more additional therapies may be administered in any order, simultaneously or sequentially.
  • intermediates I-A and I-B The general synthesis of intermediates I-A and I-B is as follows.
  • Intermediate I-A-2 is synthesized by Stille coupling reaction of I-A-1 with tributyl(1-ethoxyvinyl)tin, and intermediate I-A-3 is obtained by acetylation with 10% hydrochloric acid.
  • Intermediate I-A is synthesized using hydrazine hydrate under heating conditions, and chlorination is performed using phosphorus oxychloride to synthesize intermediate I-B.
  • Tributyl(1-ethoxyvinyl ) After adding tin (3.88 g, 11.14 mmol) and triethylamine (2.6 ml, 28.28 mmol), PdCl 2 (PPh 3 ) 2 (234 mg, 0.40 mmol) was added and heated and stirred at 100 ° C. for 16 hours. do. When the reaction is complete, the reaction mixture is filtered through a celite pad and then concentrated. After dissolving the reaction concentrate in tetrahydrofuran (9 ml), hydrochloric acid/water [1:1] (0.60 ml) was slowly added dropwise at 0°C, followed by stirring for 15 minutes.
  • tert-butyl nitrite (0.68 mL, 5.7 mmol) and iodine ( 972 mg, 3.8 mmol) was added and stirred at room temperature for 24 hours. Thereafter, tert-butyl nitrite (0.45 mL, 3.8 mmol) was additionally added dropwise, followed by additional stirring for 3 days. After completion of the reaction, distilled water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated. The residue was purified by column chromatography to give methyl 5-bromo-2-iodo-6-methoxynicotinate (520 mg, 37%) as a yellow solid.
  • Phosphorus oxychloride (24 ⁇ L, 0.26 mmol) was added to 3-bromo-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (7 mg, 0.026 mmol). It was added and heated and stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, and then cooled to 0°C. Thereafter, a saturated solution of sodium hydrogen carbonate is added to neutralize the mixture, and the mixed solution is extracted with dichloromethane.
  • compound A-3 The general synthesis of compound A-3 is exemplified in synthesis method A.
  • Compound A-1 in which intermediate I-A is substituted with an amine is synthesized by Buchwald-Hartwig amination, and compound A-2 is synthesized by chlorination using phosphorus oxychloride.
  • Compound A-2 is selected from intermediates I-C to I-H or commercially available reagents to synthesize final compound A-3 through a nucleophilic aromatic substitution reaction.
  • Phosphorus oxychloride (302 ⁇ l, 3.24 mmol) was added to 8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5(6H)-one (10 mg, 0.16 mmol) and heated to 110 °C. Heat and stir for 3 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and after cooling to 0 deg. C, sodium hydrogen carbonate was added to neutralize it. The mixture was extracted three times with ethyl acetate, and the organic layer was washed once with a saturated sodium chloride solution.
  • compound B-2 The general synthesis of compound B-2 is exemplified in synthesis method B.
  • Compound B-1 was synthesized by a nucleophilic aromatic substitution reaction by selecting intermediates IB from intermediates IC to IH or commercially available reagents, and a Buchwald-Hartwig amination reaction was performed with HR 4 amine to obtain final compound B-2 synthesize

Abstract

The present invention relates to: a novel bicyclic heterocyclyl compound which has an SOS1 inhibitory activity and thus may be utilized for preventing, relieving or treating various carcinomas or RASopathy; a stereoisomer thereof; a solvate thereof; an isotope variant thereof; a tautomer thereof; or a pharmaceutically acceptable salt thereof.

Description

신규한 바이사이클릭 헤테로사이클릴 화합물 및 이의 용도 Novel bicyclic heterocyclyl compounds and uses thereof
본 발명은 SOS1 억제 활성을 나타내는 바이사이클릭 헤테로사이클릴 화합물에 관한 것으로, 보다 상세하게는 우수한 SOS1 억제 활성으로 인해 다양한 암종에 대한 예방, 개선 또는 치료 활성을 나타내는 신규한 바이사이클릭 헤테로사이클릴 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이의 약학적으로 허용가능한 염, 이들의 용도 및 이들을 포함하는 약학적 조성물에 관한 것이다. The present invention relates to a bicyclic heterocyclyl compound exhibiting SOS1 inhibitory activity, and more particularly, to a novel bicyclic heterocyclyl compound exhibiting preventive, ameliorative or therapeutic activity against various carcinomas due to its excellent SOS1 inhibitory activity. It relates to a compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, uses thereof, and pharmaceutical compositions comprising the same.
RAS 패밀리 단백질은 KRAS, NRAS 및 HRAS를 포함하며, 이들의 돌연변이는 GTP-결합 또는 GDP-결합 상태로 세포에 존재하는 소형 GTPase이다. RAS 패밀리 단백질은 약한 본질적인 GTPase 활성 및 느린 뉴클레오티드 교환 속도를 가지고 있다. SOS1 (Son of Sevenless 1)과 같은 구아닌 뉴클레오티드 교환 인자 (GEF)의 결합은 RAS 단백질로부터 GDP 방출을 촉진하고, GTP 결합을 가능하게 한다. RAS 패밀리 단백질은 GTP-결합 상태일 때, 활성적이고, C-RAF, PI3K와 같은 이펙터 단백질들과 연관이 있다. 이들 경로는 증식, 생존, 대사, 운동성, 혈관 형성, 면역 및 성장과 같은 다양한 세포 과정에 영향을 미친다. RAS 패밀리 단백질에서 암 관련 돌연변이는 GTP 결합/활성 RAS 패밀리 단백질을 증가시키기 위해 GAP 유발 GTPase 활성을 억제시킨다. 이는 RAS 패밀리 단백질의 하위에 이펙터 경로 (예를 들어, MEK/ERK, PI3K/AKT/mTOR, RalGDS 경로)의 지속적인 활성화로 이어진다. KRAS 돌연변이 (예를 들어, 아미노산 G12, G13, Q61, A146)는 폐암, 결장직장암 및 췌장암을 포함한 비롯한 다양한 인간 암에서 발견된다. RAS family proteins include KRAS, NRAS and HRAS, mutants of which are small GTPases present in cells in a GTP-bound or GDP-bound state. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates. Binding of guanine nucleotide exchange factors (GEFs), such as Son of Sevenless 1 (SOS1), promotes GDP release from RAS proteins and enables GTP binding. RAS family proteins are active when in a GTP-bound state, and are associated with effector proteins such as C-RAF and PI3K. These pathways affect various cellular processes such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth. Cancer-associated mutations in RAS family proteins suppress GAP-induced GTPase activity to increase GTP-binding/active RAS family proteins. This leads to sustained activation of effector pathways downstream of the RAS family proteins (eg MEK/ERK, PI3K/AKT/mTOR, RalGDS pathways). KRAS mutations (eg, amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colorectal and pancreatic cancers.
SOS1 (Son of Sevenless 1)는 최초 발견된 초파리 단백질 SOS (Son of Sevenless)의 인간 상동체이다. SOS1은 RAS 패밀리 단백질과 결합하는 사이트 2 곳을 가지고 있다; GDP 결합 RAS 패밀리 단백질과 결합하는 촉매 사이트 및 GTP 결합 RAS 패밀리 단백질과 결합하는 알로스테릭 사이트를 가진다. SOS1 소실은 KRAS 돌연변이를 갖는 종양 세포의 증식 속도 및 생존을 감소시키고, KRAS 야생형 세포주에는 효과가 관찰되지 않았다. 추가적으로, SOS1 변형이 암과 연루되어 있다. SOS1 돌연변이는 배아 횡문근육종, 세르톨니 세포 고환 종양, 피부의 과립 세포 종양 및 폐 선암종에서 발견된다. 한편, SOS1의 과발현은 방광암 및 전립선암에서 발견된다. 암뿐만 아니라 유전성 SOS1 돌연변이는 누난 증후군 (NS), CFC (cardio-facio-cutaneous) 증후군 및 유전성 치은섬유종증 1 형과 같은 RAS 질환 (RASopathy)의 발병기전과 연관된다.Son of Sevenless 1 (SOS1) is a human homolog of the Drosophila protein Son of Sevenless (SOS), which was first discovered. SOS1 has two binding sites for RAS family proteins; It has a catalytic site binding to GDP-binding RAS family proteins and an allosteric site binding to GTP-binding RAS family proteins. Loss of SOS1 reduces the proliferation rate and survival of KRAS mutation-bearing tumor cells, and no effect was observed in KRAS wild-type cell lines. Additionally, SOS1 alterations have been implicated in cancer. SOS1 mutations are found in embryonic rhabdomyosarcomas, Sertolnic cell testicular tumors, granular cell tumors of the skin, and lung adenocarcinomas. On the other hand, overexpression of SOS1 is found in bladder cancer and prostate cancer. In addition to cancer, hereditary SOS1 mutations are associated with the pathogenesis of RAS diseases such as Noonan syndrome (NS), cardio-facio-cutaneous (CFC) syndrome and hereditary gingival fibromatosis type 1.
SOS1 억제 관련하여 오늘날까지 RAS의 이펙터 결합 부위 또는 SOS1의 촉매 결합 부위를 표적으로 하는 결합체를 발견하고 최적화 하기 위한 여러 노력이 있었으나 (Lu et al., ChemMedChem. 2016, 11(8):814-21), 기대에 미치지 못하였다.Regarding SOS1 inhibition, until now, several efforts have been made to discover and optimize complexes that target the effector binding site of RAS or the catalytic binding site of SOS1 (Lu et al., ChemMedChem. 2016, 11(8):814-21 ), which did not meet expectations.
한편, 최근에, RAS 결합 부위에 근접하여 SOS1의 친유성 포켓에 결합하는 작은 활성화 분자를 발견하였다(Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). 그러나, 이들 분자의 결합은 뉴클레오티드 교환을 증가시켜 RAS를 불활성화 시키는 대신 활성화시키는 것으로 보인다.Meanwhile, recently, a small activating molecule that binds to the lipophilic pocket of SOS1 in close proximity to the RAS binding site was discovered (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). . However, binding of these molecules appears to activate RAS instead of inactivating it by increasing nucleotide exchange.
RAS 패밀리 단백질과 SOS1의 단백질-단백질 상호작용을 안정화시키고, GTP 결합 RAS 패밀리 단백질의 재로딩을 방지하기 위한 노력으로 다수의 조각 분자들을 발견했다 (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). 그러나 SOS1에 조각 분자들의 가역적 결합은 뉴클레오티드 교환에서 측정 가능한 효과로 해석되지 않았고, RAS에 공유 결합된 작은 분자들에 의한 약한 효과만 확인되었다.In an effort to stabilize protein-protein interactions of SOS1 with RAS family proteins and prevent reloading of GTP-bound RAS family proteins, a number of fragment molecules were discovered (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). However, reversible binding of fragment molecules to SOS1 did not translate into measurable effects on nucleotide exchange, and only weak effects by small molecules covalently bound to RAS were identified.
또한 최근에는 SOS1 소분자 억제제를 개발하기 위하여 합리적인 디자인과 스크리닝 플랫폼을 결합하여 연구가 진행되었다 (Evelyn et al., Chem. Biol. 2014, 21(12):1618-28; Evelyn et al., J. Biol. Chem. 2015, 290(20):12879-98; Zheng et al., WO 2016/077793). 비록 SOS1에 대해 약간의 억제 효과만을 갖는 화합물이 확인되었지만, 구아닌 뉴클레오티드 교환 및 세포 신호전달 조절 (예들 들어, ERK 인산화)에 대한 효과는 약하다.Recently, studies have been conducted by combining rational design and screening platforms to develop SOS1 small molecule inhibitors (Evelyn et al., Chem. Biol. 2014, 21(12):1618-28; Evelyn et al., J. Biol.Chem.2015, 290(20):12879-98;Zheng et al., WO 2016/077793). Although compounds with only a slight inhibitory effect on SOS1 have been identified, the effect on guanine nucleotide exchange and cell signaling regulation (eg, ERK phosphorylation) is weak.
본 발명의 목적은 우수한 SOS1 저해 활성을 갖는 바이사이클릭 헤테로사이클릴 기반의 신규 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이들의 약제학적으로 허용되는 염을 제공하는 것을 목적으로 한다. An object of the present invention is a novel bicyclic heterocyclyl-based compound having excellent SOS1 inhibitory activity, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable form thereof. It is an object to provide a salt that is.
또한, 본 발명은 상기 바이사이클릭 헤테로사이클릴 기반의 화합물, 또는 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이들의 약제학적으로 허용되는 염을 유효성분으로 포함하는 약제학적 조성물을 제공하는 것을 다른 목적으로 한다.In addition, the present invention is a pharmaceutical agent comprising the bicyclic heterocyclyl-based compound, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Another object is to provide a scientific composition.
본 발명의 다른 목적은 상기 바이사이클릭 헤테로사이클릴 화합물을 유효성분으로 포함하는 SOS1 활성에 의하여 유발되는 각종 질환의 예방, 개선 또는 치료를 위한 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating various diseases caused by SOS1 activity, comprising the bicyclic heterocyclyl compound as an active ingredient.
본 발명의 또 다른 목적은 SOS1 활성에 의하여 유발되는 각종 질환의 예방, 개선 또는 치료용 약제의 제조를 위한 상기 바이사이클릭 헤테로사이클릴 화합물의 용도를 제공하는 것이다. Another object of the present invention is to provide a use of the bicyclic heterocyclyl compound for the preparation of a drug for preventing, ameliorating or treating various diseases caused by SOS1 activity.
본 발명의 또 다른 목적은 상기 바이사이클릭 헤테로사이클릴 화합물을 투여하여 SOS1 활성에 의하여 유발되는 각종 질환의 예방, 개선 또는 치료하는 방법을 제공하는 것이다. Another object of the present invention is to provide a method for preventing, improving or treating various diseases caused by SOS1 activity by administering the bicyclic heterocyclyl compound.
본 발명의 일 측면으로, 하기 화학식 (I)로 표시되는 바이사이클릭 헤테로사이클릴 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이의 약학적으로 허용가능한 염이 제공될 수 있다.In one aspect of the present invention, a bicyclic heterocyclyl compound represented by Formula (I) below, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable form thereof. Possible salts may be provided.
Figure PCTKR2022021249-appb-img-000001
Figure PCTKR2022021249-appb-img-000001
상기 식에서, R1 내지 R5 , A, L3, 및 p는 청구 범위 및 명세서에 주어진 의미를 가진다.In the above formula, R 1 to R 5 , A, L 3 , and p have the meanings given in the claims and specification.
본 발명의 일 측면으로, 상기 화학식 (I)의 바이사이클릭 헤테로사이클릴을 포함하는 화합물 유도체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물 및 의약/약학적 용도, 특히 SOS1 활성과 관련된 질환, 예를 들어 암 또는 RAS병증의 예방, 개선 또는 치료용 약제로서의 용도를 제공한다.In one aspect of the present invention, a compound derivative containing the bicyclic heterocyclyl of Formula (I), a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. Provided are pharmaceutical compositions and medicinal/pharmaceutical uses, particularly uses as agents for preventing, ameliorating or treating diseases associated with SOS1 activity, such as cancer or RAS conditions.
본 발명의 일 측면으로, 상기 화학식 (I)의 바이사이클릭 헤테로사이클릴을 포함하는 화합물 유도체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이의 약학적으로 허용가능한 염을 포함하는 약학적 조성물과 다른 추가의 요법을 포함하는 것을 특징으로 하는 암 또는 RAS병증의 예방, 개선 또는 치료용 병용 약제 또는 용도를 제공한다.In one aspect of the present invention, a compound derivative containing the bicyclic heterocyclyl of Formula (I), a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. It provides a combination drug or use for the prevention, improvement or treatment of cancer or RAS, characterized in that it includes a pharmaceutical composition comprising a pharmaceutical composition and another additional therapy.
본 발명에 따르면, 우수한 SOS1 억제 효과를 나타내는 바이사이클릭 헤테로사이클릴 기반의 화합물, 또는 이의 광학 이성질체, 이의 입체 이성질체, 이의 동위원소 변형체, 이의 호변이성질체 또는 이들의 약제학적으로 허용되는 염이 제공될 수 있다. 따라서, 이러한 화합물, 또는 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이들의 약제학적으로 허용되는 염은 SOS1 저해와 관련된 질병의 예방 또는 치료를 위해 효과적으로 사용될 수 있다.According to the present invention, a bicyclic heterocyclyl-based compound exhibiting an excellent SOS1 inhibitory effect, or an optical isomer thereof, a stereoisomer thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof is provided. can Therefore, these compounds, or stereoisomers thereof, solvates thereof, isotopic variants thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, can be effectively used for the prevention or treatment of diseases associated with SOS1 inhibition.
이하, 본 발명을 좀 더 상세하게 설명한다. Hereinafter, the present invention will be described in more detail.
달리 정의되지 않는 한, 여기에서 사용되는 모든 기술 용어는 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 갖는다. 또한, 본 명세서에 기재된 수치는 명시적으로 언급되지 않는 한 "약"의 의미를 포함하는 것으로 간주된다. 여기에 언급된 모든 간행물 및 기타 참고 문헌은 그 전체가 참고로 여기에 포함된다. Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, numerical values recited herein are intended to include the meaning of "about" unless explicitly stated otherwise. All publications and other references mentioned herein are incorporated herein by reference in their entirety.
본 명세서에서 사용된 잔기의 정의가 이하에서 기술된다. 또한 잔기의 별도 정의가 없는 경우에는 당업자에 의해 일반적으로 이해되는 의미로 사용된다. The definitions of moieties used herein are set forth below. In addition, when there is no separate definition of a residue, it is used as a meaning commonly understood by those skilled in the art.
본원에서 사용된 용어 “독립적으로”는 1개 초과의 치환기가 다수의 가능한 치환기로부터 선택되는 경우, 이들 치환기가 서로 동일하거나 또는 상이할 수 있음을 의미한다.As used herein, the term “independently” means that when more than one substituent is selected from a number of possible substituents, these substituents may be the same or different from each other.
본원에 사용된 용어 "할로" "할로겐", "할라이드(들)"은 플루오로, 클로로, 브로모 및 요오도를 포함한다.As used herein, the term “halo,” “halogen,” “halide(s)” includes fluoro, chloro, bromo, and iodo.
본 명세서에 사용된 바와 같이, "알킬"은 지방족 탄화수소 라디칼을 말하며, 선형 및 분지형 탄화수소 라디칼을 모두 포함한다. 예를 들어, C1-C6알킬은 1 내지 6개의 탄소 원자를 갖는 지방족 탄화수소이며 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, sec-부틸, tert-부틸, 펜틸, 이소펜틸, 네오펜틸, 1-에틸프로필, 헥실, 이소헥실, 1,1-디메틸부틸, 2,2-디메틸부틸, 3,3-디메틸부틸 및 2-에틸부틸일 수 있다. 예를 들어, 알킬은 C1-C6 알킬, 바람직하게는 C1-C4 알킬, 보다 바람직하게는 C1-C3 알킬을 의미한다.As used herein, “alkyl” refers to an aliphatic hydrocarbon radical and includes both linear and branched hydrocarbon radicals. For example, C 1 -C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. For example, alkyl means C 1 -C 6 alkyl, preferably C 1 -C 4 alkyl, more preferably C 1 -C 3 alkyl.
본원에 사용된 용어 "알케닐"은 하나 이상의 탄소-탄소 이중 결합을 포함하는 지방족 탄화수소 라디칼을 지칭하고, 선형 및 분지형 탄화수소 라디칼을 모두 포함한다. 예를 들어, "알케닐"은 비닐, 알릴, 부트-1-에닐 또는 부트-2-에닐이다.As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon radical containing one or more carbon-carbon double bonds, and includes both linear and branched hydrocarbon radicals. For example, “alkenyl” is vinyl, allyl, but-1-enyl or but-2-enyl.
본원에 사용된 용어 "할로알킬"은 하나 이상의 할로겐 원자로 치환된 알킬기를 의미하며, 상기 알킬기는 상기와 같이 정의된다. "할로"는 F, Cl, Br 또는 I를 나타내며 용어는 "할로겐"이라는 용어와 호환하여 사용된다. 예를 들어, 할로알킬은 플루오로메틸, 디플루오로메틸, 클로로메틸, 트리플루오로메틸 또는 2,2,2-트리플루오로에틸을 의미한다.As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is defined as above. "Halo" refers to F, Cl, Br or I and the term is used interchangeably with the term "halogen". For example, haloalkyl means fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.
본원에 사용된 용어 "알콕시"는 -O-알킬 또는 알킬-O-기를 말하며, 상기 알킬기는 상기와 같이 정의된다. 예를 들어, 메톡시, 에톡시, n-프로폭시, n-부톡시 및 t-부톡시일 수 있다. As used herein, the term "alkoxy" refers to the group -O-alkyl or alkyl-O-, wherein the alkyl group is defined as above. For example, it may be methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.
본원에 사용된 용어 "히드록시" 또는 "히드록실"은 단독으로 또는 다른 용어와 조합하여 -OH를 의미한다.As used herein, the term "hydroxy" or "hydroxyl" alone or in combination with other terms means -OH.
본원에 사용된 용어 "아미노"는 -NH2를 의미한다.As used herein, the term "amino" means -NH 2 .
본원에 사용된 용어 "사이클로알킬"은 치환 또는 비치환될 수 있는 고리형 알킬을 말하며, 예를 들어, C3-C20사이클로알킬은 3 내지 20개의 탄소 원자를 갖는 1가 포화 탄화수소 고리계를 나타낸다. 사이클로알킬의 예는 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 사이클로옥틸 등을 포함하지만 이에 제한되지 않는다. 바람직하게는, 사이클로알킬은 C3-C8사이클로알킬 또는 C4-C6사이클로알킬일 수 있다.As used herein, the term “cycloalkyl” refers to a cyclic alkyl which may be substituted or unsubstituted, for example, C 3 -C 20 cycloalkyl is a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. indicate Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, cycloalkyl can be C 3 -C 8 cycloalkyl or C 4 -C 6 cycloalkyl.
본원에 사용된 용어 “사이클로알케닐”은 비치환 또는 치환된 고리형 알킬로서, 시스템은 불포화이며, 즉 적어도 하나의 C-C 이중결합이 존재하나 방향족 시스템은 아니다. 상기 정의된 바와 같은 사이클로알킬에서, 인접 탄소 원자상의 두 수소 원자가 공식적으로 제거되고 자유 원자가가 포화되어 제2 결합을 형성하는 경우, 상응하는 사이클로알케닐이 생긴다. 사이클로알케닐이 치환되는 경우, 치환은 수소를 가지는 모든 탄소 원자상에서 각 경우 일- 또는 다치환 형태로 서로 독립적으로 일어날 수 있다. 사이클로알케닐 자체가 환 시스템의 모든 적당한 위치에서 치환체로서 분자에 연결될 수 있다. As used herein, the term “cycloalkenyl” is an unsubstituted or substituted cyclic alkyl, the system being unsaturated, ie at least one C-C double bond present, but not an aromatic system. In a cycloalkyl as defined above, when two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding cycloalkenyl results. When cycloalkenyl is substituted, the substitutions may occur independently of each other in mono- or polysubstitution in each case on all carbon atoms having hydrogen. The cycloalkenyl itself may be attached to the molecule as a substituent at any suitable position of the ring system.
본원에 사용된 용어 "아릴"은 모 방향족 고리의 단일 탄소 원자로부터 1개의 수소 원자를 제거함으로써 유도되는, 예를 들어 6 내지 20개의 탄소 원자(C6-C20)를 갖는 1가 방향족 탄화수소를 지칭한다 체계. 아릴은 포화 또는 부분 불포화 고리에 융합된 방향족 고리를 함유하는 이환식 라디칼을 포함할 수 있다. 예시적인 아릴 기는 벤젠(페닐), 치환된 페닐, 비페닐, 나프틸, 톨루일, 나프탈레닐, 안트라세닐, 인데닐, 인다닐 등으로부터 유도된 라디칼을 포함할 수 있다. 구체적인 일 예로, 아릴은 C6-C12 아릴, 바람직하게는 C6-C10 아릴을 의미한다.As used herein, the term “aryl” refers to a monovalent aromatic hydrocarbon having, for example, 6 to 20 carbon atoms (C 6 -C 20 ), derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring. refers to system. Aryl can include bicyclic radicals containing an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. As a specific example, aryl means C 6 -C 12 aryl, preferably C 6 -C 10 aryl.
본원에 사용된 "헤테로사이클"은 지정된 수의 고리 원자를 함유하는 방향족, 포화 또는 부분 불포화 모노-, 바이- 또는 폴리-고리 시스템을 나타내며, N, O 및 S로부터 선택된 하나 이상의 헤테로원자를 포함한다. 고리 구성원, 여기서 헤테로사이클릭 고리는 고리 원자(C 또는 N일 수 있음)를 통해 기본 분자에 연결된다. 바이사이클릭 시스템은 1,1-융합(스피로), 1,2-융합(퓨즈드) 또는 1,>2-융합(브리지헤드)로 연결될 수 있다. As used herein, "heterocycle" refers to an aromatic, saturated or partially unsaturated mono-, bi- or poly-ring system containing the specified number of ring atoms and containing one or more heteroatoms selected from N, O and S. . A ring member, wherein a heterocyclic ring is linked to the base molecule through a ring atom (which can be C or N). Bicyclic systems can be 1,1-fused (spiro), 1,2-fused (fused) or 1,>2-fused (bridgeheaded).
본원에 사용된 "헤테로아릴"은 N, O 및 S 중에서 선택된 하나 이상, 바람직하게는 1 내지 3개 또는 1 내지 2개의 헤테로원자를 함유하는 모노헤테로사이클릭 또는 폴리헤테로사이클릭 방향족 탄화수소로부터 유도된 1가 또는 2가 치환기를 지칭한다. 헤테로아릴의 예는 싸이에닐, 푸릴, 피롤릴, 이미다졸릴, 피라졸릴, 싸이아졸릴, 이소싸이아졸릴, 옥사졸릴, 이속사졸릴, 피리딜, 피라진일, 피리미딘일, 피리다진일, 1,2,4-옥사졸을 포함하지만 이에 제한되지 않는다. 3,4-옥사디아졸릴, 1,2,4-티아디아졸릴, 1,3,4-티아디아졸릴, 트리아졸릴, 테트라졸릴, 트리아진일, 인돌릴 등. 바이사이클릭 헤테로아릴의 예는 인돌릴, 벤조티오페닐, 벤조푸란일, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤즈이속사졸릴, 벤즈티아졸릴, 벤즈티아디아졸릴, 퀴놀린일, 이소퀴놀린일, 푸로피리딘일 및 이들의 유사 그룹을 포함하나, 이에 제한되지 않는다. 달리 정의되지 않는 한, 헤테로아릴은 4-12원 헤테로아릴, 바람직하게는 4-10원 헤테로아릴, 보다 바람직하게는 4-7원 헤테로아릴이다.As used herein, "heteroaryl" is a compound derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon containing at least one selected from N, O and S, preferably 1 to 3 or 1 to 2 heteroatoms. Refers to a monovalent or divalent substituent. Examples of heteroaryl are thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl , 1,2,4-oxazoles, but are not limited thereto. 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl and the like. Examples of bicyclic heteroaryls are indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridine One and similar groups thereof, but are not limited thereto. Unless otherwise defined, heteroaryl is a 4-12 membered heteroaryl, preferably a 4-10 membered heteroaryl, more preferably a 4-7 membered heteroaryl.
본원에 사용된 "헤테로사이클로알킬"은 N, O 및 S 중에서 선택된 하나 이상, 예를 들어 1 내지 4개, 1 내지 3개, 또는 1 내지 2개의 헤테로원자를 함유하는 3 내지 10개의 탄소 고리 구성원을 갖는 모노사이클릭, 비사이클릭, 트리사이클릭 또는 고급 사이클릭 알킬을 지칭한다. 또한, 본 발명에 따른 헤테로사이클은 또한 융합되거나 가교된 헤테로사이클로알킬일 수 있다. 비 방향족 고리의 예로는 아제티딘일, 옥세타닐, 테트라 하이드로, 테트라 하이드로퓨란, 피롤, 피롤리딘일, 이미다졸린일, 이미다졸리딘일, 옥사졸린일, 옥사졸리딘일, 피페리딘일, 피페라진일, 테트라하이드로피란일, 디히드로피란일, 테트라히드로피리딘일, 디히드로피리딘일, 디히드로티오피란일, 테트라히드로피리미딘일, 테트라히드로피리다진일, 디히드로피란일, 테트라히드로피란일, 테트라히드로티오피란일, 테트라히드로피라졸로피리딘일, 모르폴린일, 인돌린일, 아제티오모르폴린일 등일 수 있다. As used herein, "heterocycloalkyl" is a ring member of 3 to 10 carbon atoms containing one or more selected from N, O and S, for example 1 to 4, 1 to 3, or 1 to 2 heteroatoms. Refers to monocyclic, bicyclic, tricyclic or higher cyclic alkyl having Heterocycles according to the present invention may also be fused or bridged heterocycloalkyls. Examples of non-aromatic rings include azetidinyl, oxetanyl, tetrahydro, tetrahydrofuran, pyrrole, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperidinyl. Razinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl , tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl, morpholinyl, indolinyl, azethiomorpholinyl and the like.
헤테로사이클로알킬 치환기의 부착은 탄소 원자 또는 헤테로원자를 통해 일어날 수 있다. 헤테로사이클로알킬 기는 하나 이상의 전술한 기를 통해 하나 이상의 적합한 기로 임의로 치환될 수 있다. 달리 정의되지 않는 한, 헤테로사이클로알킬은 4 내지 12원 헤테로사이클로알킬, 바람직하게는 4 내지 10원 헤테로사이클로알킬, 보다 바람직하게는 4 내지 7원 헤테로사이클로알킬을 지칭한다.Attachment of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. Heterocycloalkyl groups may be optionally substituted with one or more suitable groups through one or more of the foregoing groups. Unless otherwise defined, heterocycloalkyl refers to 4 to 12 membered heterocycloalkyl, preferably 4 to 10 membered heterocycloalkyl, and more preferably 4 to 7 membered heterocycloalkyl.
본원에서 사용된 "헤테로사이클로알케닐" (또는 "헤테로사이클레닐")은 하나 이상의 탄소-탄소 이중결합 또는 탄소-질소 이중결합을 함유하는 비-방향족 모노사이클릭 또는 멀티사이클릭 환 시스템을 의미하며, 환 시스템내의 원자들 중의 하나 이상은 탄소 이외의 원소, 예를 들면, 질소, 산소 또는 황의 단독 또는 조합이다. 헤테로사이클로알케닐 기는 하나 이상의 전술한 기를 통해 하나 이상의 적합한 기로 임의로 치환될 수 있다. 달리 정의되지 않는 한, 헤테로사이클로알케닐은 4 내지 12원 헤테로사이클로알케닐, 바람직하게는 4 내지 10원 헤테로사이클로알케닐, 보다 바람직하게는 4 내지 7원 헤테로사이클로알케닐을 지칭한다. 헤테로사이클레닐 근명 앞의 접두사 아자, 옥사 또는 티아는, 적어도 하나의 질소, 산소 또는 황 원자 각각이 환 원자로서 존재함을 의미한다. 헤테로사이클레닐의 질소 또는 황 원자는 상응하는 N-옥사이드, S-옥사이드 또는 S,S-디옥사이드로 임의 산화될 수 있다. As used herein, "heterocycloalkenyl" (or "heterocyclenyl") means a non-aromatic monocyclic or multicyclic ring system containing one or more carbon-carbon double bonds or carbon-nitrogen double bonds. and at least one of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen or sulfur alone or in combination. Heterocycloalkenyl groups may be optionally substituted with one or more suitable groups through one or more of the foregoing groups. Unless otherwise defined, heterocycloalkenyl refers to 4 to 12 membered heterocycloalkenyl, preferably 4 to 10 membered heterocycloalkenyl, more preferably 4 to 7 membered heterocycloalkenyl. The prefix aza, oxa or thia before the heterocyclenyl root name means that each of at least one nitrogen, oxygen or sulfur atom is present as a ring atom. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
상기 고리형 치환기들(예를 들어 사이클로알킬, 사이클로알케닐, 아릴, 헤테로사이클, 헤테로아릴, 헤테로사이클로알킬, 헤테로사이클로알케닐 등)은 비치환되거나 또는 치환된 것일 수 있다.The cyclic substituents (eg, cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl, heterocycloalkyl, heterocycloalkenyl, etc.) may be unsubstituted or substituted.
용어 "용매화물"은 용질과 용매에 의해 형성된 가변적 화학량론의 복합체를 지칭한다. 본 개시내용의 목적을 위한 이러한 용매는 용질의 생물학적 활성을 간섭하지 않을 수 있다. 적합한 용매의 예는 물, MeOH, EtOH 및 AcOH를 포함하지만, 이들로 제한되지 않는다. 물이 용매 분자인 용매화물은 수화물이라 지칭된다. 수화물은 화학량론적 양의 물을 함유하는 조성물뿐만 아니라 가변량의 물을 함유하는 조성물을 포함한다.The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for purposes of this disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates in which water is the solvent molecule are called hydrates. Hydrates include compositions containing variable amounts of water as well as compositions containing stoichiometric amounts of water.
용어 "이성질체"는 동일한 조성 및 분자량을 갖지만 물성 및/또는 화학적 특성이 상이한 화합물을 지칭한다. 구조적 차이는 구성(기하 이성질체) 또는 편광광의 평면을 회전하는 능력(입체이성질체)에 있어서 일어날 수 있다. 입체이성질체에 관하여, 본 명세서에서의 화합물은 1개 이상의 비대칭 탄소 원자를 가질 수 있고 라세미체, 라세미 혼합물로서 그리고 개별적인 거울상이성질체 또는 부분입체이성질체로서 존재할 수 있다.The term “isomers” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Structural differences may occur in composition (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds herein may have one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual enantiomers or diastereomers.
용어 "입체이성질체"는 동일한 원자 번호 및 유형을 갖고 이들 원자 간에 동일한 결합 연결성을 공유하지만 3차 원적 구조가 상이한 화합물의 집합을 지칭한다. 용어 "입체이성질체"는 이러한 집합의 화합물의 임의의 구성원을 지칭한다. 예를 들어, 입체이성질체는 거울상이성질체 또는 부분입체이성질체일 수 있다.The term “stereoisomers” refers to a group of compounds that have the same atomic number and type and share the same bonding connectivity between their atoms, but differ in three-dimensional structure. The term "stereoisomer" refers to any member of this class of compounds. For example, stereoisomers can be enantiomers or diastereomers.
용어 "거울상이성질체"는 서로 겹쳐질 수 없는 거울상인 한쌍의 입체이성질체를 지칭한다. 용어 "거울상이성질체"는 이러한 쌍의 입체이성질체의 단일의 구성원을 지칭한다. 용어 "라세미"는 한쌍의 거울상이성질체의 1:1혼합물을 지칭한다.The term “enantiomers” refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.
용어 "부분입체이성질체"는 단일 결합 둘레에 회전에 의해 중첩 가능하게 만들어질 수 없는 입체이성질체의 세트를 지칭한다. 예를 들어, 이환식 고리계 상의 시스- 및 트랜스- 이중 결합, 엔도- 및 엑소- 치환, 및 상이한 상대 입체배치를 가진 다수의 입체형성 중심을 함유하는 화합물은 부분입체이성질체인 것으로 간주된다. 용어 부분입체이성질체"는 이러한 세트의 화합물의 임의의 구성원을 지칭한다. 제시된 몇몇 예에서, 합성 경로는 단일의 부분입체이성질체 또는 부분입체이성질체의 혼합물을 생성할 수 있다.The term "diastereomer" refers to a set of stereoisomers that cannot be made superimposable by rotation around a single bond. For example, compounds containing cis- and trans-double bonds on bicyclic ring systems, endo- and exo-substitutions, and multiple stereogenic centers with different relative configurations are considered to be diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some of the examples presented, the synthetic route may give rise to a single diastereomer or a mixture of diastereomers.
용어 "호변 이성질체" 또는 "호변 이성질체 형태"는 낮은 에너지 장벽을 통하여 상호전환가능한 상이한 에너지의 구조 이성질체를 의미한다. 양성자 호변 이성질체 (양성자성 호변 이성질체로도 알려짐)의 일부 비제한적 예는 케토-에놀 및 이민-엔아민 이성질체화와 같은, 양성자 이동을 통한 상호전환을 포함한다. 원자가 호변 이성 질체는 결합 전자들 중 일부의 재구성에 의한 상호전환을 포함한다.The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertable through low energy barriers. Some non-limiting examples of proton tautomers (also known as protic tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
용어 “동위원소 변형체”는 임의의 화합물에 대해 적어도 1종의 원자가 동일한 원자수를 갖지만 자연에서 일반적으로 또는 주로 발생하는 원자량과는 상이한 원자량을 갖는 또 다른 원자로 교환된 화합물을 의미하는 것을 의미한다.The term “isotopic variant” is intended to mean a compound in which at least one atom has been exchanged for another atom having the same atomic number but a different atomic weight than the atomic weight commonly or predominantly occurring in nature.
화합물과 관련하여 사용되는 경우 "유효량"은 본 명세서에 기재된 바와 같이 대상체에서 질환을 치료 또는 예방하는데 효과적인 양이다An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease in a subject as described herein.
화합물compound
상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 (I)의 화합물, 또는 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체, 또는 이들의 약제학적으로 허용되는 염을 제공한다:In order to achieve the above object, the present invention provides a compound of Formula (I), or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTKR2022021249-appb-img-000002
Figure PCTKR2022021249-appb-img-000002
상기 식에서, In the above formula,
R1은 독립적으로 C1-C6알킬, C1-C6알콕시, C2-C4알케닐, C2-C4알키닐, C1-C6할로알킬, 하이드록시-C1-C6알킬, 하이드록시-C1-C6-할로알킬, C3-C6사이클로알킬, C6-C10아릴, 하이드록시-C3-C6사이클로알킬, 3-6원 헤테로사이클릴, 할로겐, 하이드록시, -NH2, -시아노, -SO2, -SO2-C1-C4알킬 및 이가 치환체 =O 로 구성된 그룹 중에서 선택되고, 이때, 상기 이가 치환체 =O 는 A가 비방향족 환인 경우에만 치환될 수 있으며, R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 haloalkyl, hydroxy-C 1 -C 6 alkyl, hydroxy-C 1 -C 6 -haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, hydroxy-C 3 -C 6 cycloalkyl, 3-6 membered heterocyclyl, halogen , hydroxy, -NH 2 , -cyano, -SO 2 , -SO 2 -C 1 -C 4 alkyl and a divalent substituent =O, wherein the divalent substituent =O is selected from the group consisting of A is non-aromatic It can be substituted only in the case of a ring,
또는 R1이 2종 이상인 경우 R1들이 서로 결합하여 4원 내지 12원의 헤테로사이클을 형성할 수 있고, Or, when R 1 is two or more, R 1 may combine with each other to form a 4- to 12-membered heterocycle;
이때 상기 C1-C6알킬, C1-C6알콕시, C2-C4알케닐, C2-C4알키닐, C1-C6할로알킬, 하이드록시-C1-C6알킬, 하이드록시-C1-C6-할로알킬, C3-C6사이클로알킬, C6-C10아릴, 하이드록시-C3-C6사이클로알킬, -NH2 또는 3-6원 헤테로사이클릴은 비치환되거나 또는 하이드록시, 할로겐, C1-C6알킬, C1-C6알콕시, C3-C6사이클로알킬, C3-C6사이클로알킬옥시, 3-6원 헤테로사이클릴, -C1-C4알킬-NH-C1-C4알킬 및 -C1-C4알킬-N(C1-C4알킬)2로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고, 이때 상기 치환기가 2종 이상인 경우, 이 2종 이상의 치환기가 함께 결합하여 C3-C6사이클로알킬을 형성할 수 있고;In this case, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 haloalkyl, hydroxy-C 1 -C 6 alkyl, Hydroxy-C 1 -C 6 -haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, hydroxy-C 3 -C 6 cycloalkyl, -NH 2 or 3-6 membered heterocyclyl is unsubstituted or hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, 3-6 membered heterocyclyl, -C 1 -C 4 alkyl-NH-C 1 -C 4 alkyl and -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 may be substituted with one or more substituents selected from the group consisting of When the substituents are two or more, these two or more substituents may be bonded together to form a C 3 -C 6 cycloalkyl;
A는 C6-C10아릴, 5-12 원 헤테로아릴 또는 9-20 원 바이사이클릭 헤테로사이클릴이고;A is C 6 -C 10 aryl, 5-12 membered heteroaryl or 9-20 membered bicyclic heterocyclyl;
R4는 수소, 할로겐, C1-C4알킬, C1-C4할로알킬, 하이드록시, 치환된 아미노, 시아노, 하이드록시-C1-C4알킬, -O-C1-C4할로알킬, C3-C6사이클로알킬, C1-C6알콕시, -C1-C4알킬-NH2, -C1-C4알킬-NH-C1-C4알킬 또는 -C1-C4알킬-N(C1-C4알킬)2이고;R 4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, substituted amino, cyano, hydroxy-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, -C 1 -C 4 alkyl-NH 2 , -C 1 -C 4 alkyl-NH-C 1 -C 4 alkyl or -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 ;
R2은 수소, 할로겐, 하이드록시, C1-C4알킬, C1-C4할로알킬, C1-C4알콕시, 시아노, -C(O)NH2 또는 아미노이고, 이때 상기 아미노 또는 -C(O)NH2의 아미노기는 비치환되거나 C1-C4알킬로 치환될 수 있고; R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, -C(O)NH 2 or amino, wherein said amino or The amino group of -C(O)NH 2 may be unsubstituted or substituted with C 1 -C 4 alkyl;
L3은 결합, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, -S(O)2-,
Figure PCTKR2022021249-appb-img-000003
,
Figure PCTKR2022021249-appb-img-000004
,
Figure PCTKR2022021249-appb-img-000005
,
Figure PCTKR2022021249-appb-img-000006
, -C(O)(CH2)o-, -(CH2)o-, -NH- 또는 -O- 이고, 이때 o는 0, 1 또는 2의 정수일 수 있고;L 3 is a bond, -C(O)-, -C(O)O-, -C(O)NH(CH 2 ) o -, -S(O) 2 -,
Figure PCTKR2022021249-appb-img-000003
,
Figure PCTKR2022021249-appb-img-000004
,
Figure PCTKR2022021249-appb-img-000005
,
Figure PCTKR2022021249-appb-img-000006
, -C(O)(CH 2 ) o -, -(CH 2 ) o -, -NH- or -O-, where o can be an integer of 0, 1 or 2;
R3은 4-12원 헤테로사이클릴, 4-12원 헤테로사이클로알킬, 4-12원 헤테로사이클로알케닐 또는 5-12원 헤테로아릴일 수 있고,R 3 can be 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl;
상기 4-12원 헤테로사이클릴, 4-12원 헤테로사이클로알킬, 4-12원 헤테로사이클로알케닐 또는 5-12원 헤테로아릴은 비치환되거나, Ra1 및/ 또는 Rb1으로 임의로 치환되고;said 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl is unsubstituted or optionally substituted with R a1 and/or R bi ;
각 Ra1 은 독립적으로 -ORb1, C1-C6알킬, -NRb1Rb1, -C1-C6알킬NRb1Rb1, 할로겐, -CN, 옥소, -C(O)Rb1, -C(O)ORb1, -C(O)NRb1Rb1, -Rb1-O-Rb1, -Rb1-CO-NRb1Rb1, -S(O)2Rb1, -S(O)2NRb1Rb1, -NHC(O)Rb1, -N(C1-C4알킬)C(O)Rb1, -NHC(O)ORb1 및 -N(C1-C4알킬)C(O)ORb1 로 이루어지는 그룹 중에서 선택되고;Each R a1 is independently -OR b1 , C 1 -C 6 alkyl, -NR b1 R b1 , -C 1 -C 6 alkylNR b1 R b1 , halogen, -CN, oxo, -C(O)R b1 , -C(O)OR b1 , -C(O)NR b1 R b1 , -R b1 -OR b1 , -R b1 -CO-NR b1 R b1 , -S(O) 2 R b1 , -S(O) 2 NR b1 R b1 , -NHC(O)R b1 , -N(C 1 -C 4 alkyl)C(O)R b1 , -NHC(O)OR b1 and -N(C 1 -C 4 alkyl)C (O)OR is selected from the group consisting of b1 ;
각 Rb1 은 독립적으로 수소, C1-C6알킬, C1-C6할로알킬, C1-C6하이드록시알킬, C2-C6알케닐, C2-C6알키닐, C3-C10사이클로알킬, C4-C10사이클로알케닐, 3-12원 헤테로사이클릴, C6-C10아릴 및 5-12원 헤테로아릴로 이루어지는 그룹 중에서 선택되고, 이때, 3-12원 헤테로사이클릴 또는 5-12원 헤테로아릴은 비치환되거나 또는 C1-C6알킬로 치환될 수 있고;Each R b1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 It is selected from the group consisting of cycloalkyl, C 4 -C 10 cycloalkenyl, 3-12 membered heterocyclyl, C 6 -C 10 aryl and 5-12 membered heteroaryl, wherein, 3-12 membered hetero Cyclyl or 5-12 membered heteroaryl may be unsubstituted or substituted with C 1 -C 6 alkyl;
R5는 C1-C6의 알킬일 수 있고, 구체적으로 C1-C3알킬, 더욱 구체적으로 메틸일 수 있고;R 5 may be C 1 -C 6 alkyl, specifically C 1 -C 3 alkyl, more specifically methyl;
p는 0 내지 3의 정수일 수 있고, 이때, p가 2 또는 3인 경우 각각의 R1은 각각 동일하거나 또는 상이할 수 있다.p may be an integer from 0 to 3, and in this case, when p is 2 or 3, each R 1 may be the same or different.
구체적인 일 양태로서, 상기 R1은 각각 독립적으로 C1-C4알킬, C1-C4알콕시, 클로로, 플루오로, 하이드록시, -NH2, 시아노, -SO2, -SO2-C1-C4알킬 또는 페닐이고, 이때, 상기 C1-C4알킬, C1-C4알콕시, -SO2-C1-C4알킬 또는 페닐은 비치환되거나 하이드록시, 할로겐, C1-C4알킬, C1-C4알콕시, C3-C6사이클로알킬, C3-C6사이클로알콕시, 3-6원 헤테로사이클릴, 및 메틸아민 또는 디메틸아민으로 치환된 C1-C6알킬로 이루어지는 군으로부터 선택되는 1 내지 3의 치환기로 치환될 수 있다. 보다 구체적으로, 상기 R1은 메틸, 메톡시, -CF3, -CHF2, 플루오로, 클로로, -NH2, 시아노, 하이드록시, -SO2, -SO2-CH3, 및 비치환되거나 메틸, 메톡시, 하이드록시, 플루오로, 사이클로프로폭시, 테트라하이드로퓨란, -CH2-NH-CH3 및 -CH2-N(CH3)2 중 1종 내지 3종으로 치환된 C1-C4알킬 또는 페닐일 수 있다. 보다 구체적으로, 상기 R1은 메틸, -CF3, -CHF2, 플루오로, -NH2, 시아노 및 메톡시, 하이드록시, 플루오로 중 1종 내지 3종으로 치환된 C1-C4알킬 또는 -CH2-N(CH3)2 로 치환된 페닐일 수 있다. 보다 구체적으로 상기 R1은 -CHF2, 플루오로일 수 있다.In a specific aspect, R 1 is each independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro, fluoro, hydroxy, -NH 2 , cyano, -SO 2 , -SO 2 -C 1 -C 4 alkyl or phenyl, wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -SO 2 -C 1 -C 4 alkyl or phenyl is unsubstituted or hydroxy, halogen, C 1 - C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 3-6 membered heterocyclyl, and C 1 -C 6 alkyl substituted with methylamine or dimethylamine It may be substituted with 1 to 3 substituents selected from the group consisting of. More specifically, R 1 is methyl, methoxy, -CF 3 , -CHF 2 , fluoro, chloro, -NH 2 , cyano, hydroxy, -SO 2 , -SO 2 -CH 3 , and unsubstituted or substituted with one to three of methyl, methoxy, hydroxy, fluoro, cyclopropoxy, tetrahydrofuran, -CH 2 -NH-CH 3 and -CH 2 -N(CH 3 ) 2 C 1 -C 4 alkyl or phenyl. More specifically, R 1 is methyl, -CF 3 , -CHF 2 , fluoro, -NH 2 , cyano and C 1 -C 4 substituted with one to three of methoxy, hydroxy, and fluoro. It can be alkyl or phenyl substituted with -CH 2 -N(CH 3 ) 2 . More specifically, R 1 may be -CHF 2 , or fluoro.
구체적인 일 양태로서, 상기 R1의 치환기가 2종 이상인 경우, 상기 2종 이상의 치환기들이 함께 사이클로알킬을 형성할 수 있으며, 구체적으로 C3-C6 사이클로알킬, 보다 구체적으로 사이클로프로필을 형성할 수 있다.In a specific aspect, when there are two or more substituents of R 1 , the two or more substituents may together form cycloalkyl, specifically C 3 -C 6 cycloalkyl, more specifically cyclopropyl. there is.
구체적인 일 양태로서, 상기 R1이 2종 이상인 경우, 상기 2종 이상의 R1이 동시에 할로가 될 수 없다.As a specific aspect, when the number of R 1 is two or more, the two or more types of R 1 cannot be halo at the same time.
구체적인 일 양태로서, 상기 A는 C6-C9아릴, 5원 내지 8원의 헤테로아릴 또는 9원 내지 12원의 바이사이클릭 헤테로사이클릴일 수 있다. 보다 구체적으로 상기 A는 페닐, 티오펜일, 피리딘일, 벤조푸란일, 디히드로벤조푸란일 또는 디하이드로인덴일일 수 있다. 보다 구체적으로 상기 A는 페닐, 티오펜일, 또는 디히드로벤조푸란일일 수 있다. 보다 구체적으로 상기 A는 페닐일 수 있다.In a specific aspect, A may be C 6 -C 9 aryl, 5- to 8-membered heteroaryl, or 9- to 12-membered bicyclic heterocyclyl. More specifically, A may be phenyl, thiophenyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl or dihydroindenyl. More specifically, A may be phenyl, thiophenyl, or dihydrobenzofuranyl. More specifically, the A may be phenyl.
구체적인 일 양태로서, R4는 각각 독립적으로 수소, C1-C4알킬, C1-C4알콕시, C1-C4할로알킬, C1-C4알킬로 치환된 아미노, -C1-C4알킬-NH2, -C1-C4알킬-N(C1-C4알킬)2일 수 있다. 보다 구체적으로 R4는 수소, 메틸, 메톡시, -CF3, -N(CH3)2, -CH2NH2, -CH2N(CH3)2일 수 있다. 보다 구체적으로 R4는 메틸일 수 있다.In a specific aspect, R 4 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, amino substituted with C 1 -C 4 alkyl, -C 1 - C 4 alkyl-NH 2 , -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 . More specifically, R 4 may be hydrogen, methyl, methoxy, -CF 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 . More specifically R 4 may be methyl.
구체적인 일 양태로서, R2은 각각 독립적으로 수소, 하이드록시, C1-C4알킬, C1-C4할로알킬, 또는 C1-C4알콕시일 수 있고, 보다 구체적으로 수소, 하이드록시, 메틸, 메톡시, -CF3, 보다 구체적으로 수소, 메톡시, 보다 구체적으로 수소일 수 있다.In a specific aspect, R 2 may each independently be hydrogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy, and more specifically, hydrogen, hydroxy, methyl, methoxy, -CF 3 , more specifically hydrogen, methoxy, more specifically hydrogen.
구체적인 일 양태로서, R2은 각각 독립적으로 수소, 하이드록시, C1-C4알킬, 또는 C1-C4할로알킬일 수 있고, 보다 구체적으로 수소, 하이드록시, 메틸, -CF3, 보다 구체적으로 수소일 수 있다.In a specific aspect, R 2 may each independently be hydrogen, hydroxy, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl, and more specifically, hydrogen, hydroxy, methyl, -CF 3 , Specifically, it may be hydrogen.
구체적인 일 양태로서, R3는 4-6원 헤테로사이클로알킬, 5-6원 헤테로아릴, 1,1-융합(스피로), 1,2-융합(퓨즈드), 1,>2-융합(브리지헤드)로 연결된 6-10원 바이사이클릭 헤테로사이클릴일 수 있다. 보다 구체적으로, 상기 R3는 고리 내에 N 원자를 포함하는 것일 수 있으며, N원자 부분이 L3과 연결되는 것을 특징으로 한다.In a specific aspect, R 3 is 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 1,1-fused (spiro), 1,2-fused (fused), 1,>2-fused (bridged) It may be a 6-10 membered bicyclic heterocyclyl connected by a head). More specifically, R 3 may include an N atom in a ring, and the N atom part is connected to L 3 .
보다 구체적으로 R3는 아제티딘일, 피롤리딘일, 피라졸일, 피페리딘일, 모르폴린일, 피페라진일, 티오모르폴린일, 아자스피로헵탄일, 디아자스피로헵탄일, 옥사아자스피로헵탄일, 옥사아자스피로옥탄일, 디아자스피로옥탄일, 옥사아자스피로노난일, 옥사디아자스피로노난일, 디아자스피로데칸일, 디옥사아자스피로데칸일, 옥사아자스피로데칸일, 헥사히드로푸로피롤일, 옥타히드로피라지노옥사진일, 옥타히드로피롤로피라진일, 테트라히드로이미다조피라진일, 테트라히드로피라졸로피라진일, 옥사아자비사이클로헵탄일, 또는 옥사아자비사이클로옥탄일일 수 있다. 보다 구체적으로 R3는 아제티딘일, 피롤리딘일, 피페리딘일, 모르폴린일, 피페라진일, 아자스피로헵탄일, 디아자스피로헵탄일, 옥사아자스피로헵탄일, 옥사아자스피로옥탄일, 옥사아자스피로노난일, 헥사히드로푸로피롤일, 옥타히드로피라지노옥사진일, 옥타히드로피롤로피라진일, 옥사아자비사이클로헵탄일, 또는 옥사아자비사이클로옥탄일일 수 있다. 보다 구체적으로 R3는 아제티딘일, 옥사아자비사이클로헵탄일, 또는 옥사아자비사이클로옥탄일일 수 있다. 또한 상기 R3 고리의 N 부분이 L3과 연결될 수 있다. More specifically, R 3 is azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, azaspiroheptanyl, diazaspiroheptanyl, oxaazaspiroheptanyl , oxaazaspirooctanyl, diazaspiroctanyl, oxaazaspirononanyl, oxaazaspirononanyl, diazaspirodecanyl, dioxaazaspirodecanyl, oxaazaspirodecanyl, hexahydrofuropyrrole , octahydropyrazinooxazinyl, octahydropyrrolopyrazinyl, tetrahydroimidazopyrazinyl, tetrahydropyrazolopyrazinyl, oxaazabicycloheptanyl, or oxaazabicyclooctanyl. More specifically, R 3 is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiroheptanyl, diazaspiroheptanyl, oxazaspiroheptanyl, oxaazaspirooctanyl, oxa azaspirononanyl, hexahydrofuropyrroyl, octahydropyrazinooxazinyl, octahydropyrrolopyrazinyl, oxazabicycloheptanyl, or oxaazabicyclooctanyl. More specifically, R 3 may be azetidinyl, oxaazabicycloheptanyl, or oxaazabicyclooctanyl. In addition, the N portion of the R 3 ring may be connected to L 3 .
더 보다 구체적으로, 상기 R3은 아래의 기들 중에서 선택되는 어느 하나일 수 있다. More specifically, the R 3 may be any one selected from the following groups.
Figure PCTKR2022021249-appb-img-000007
Figure PCTKR2022021249-appb-img-000007
Figure PCTKR2022021249-appb-img-000008
Figure PCTKR2022021249-appb-img-000008
구체적인 일 양태로서, Ra1은 각각 독립적으로 C1-C6알킬, -ORb1, -NRb1Rb1, 할로겐, -C(O)Rb1, 옥소, -C1-C3알킬NRb1Rb1, -C(O)NRb1Rb1, -Rb1-O-Rb1일 수 있고, 보다 구체적으로 Ra1은 C1-C6알킬, -ORb1, -NRb1Rb1, 할로겐, -C(O)Rb1, 옥소, -C1-C3알킬NRb1Rb1, 보다 구체적으로 C1-C2알킬, -ORb1, -NRb1Rb1, 플루오로, -C(O)Rb1, 옥소, -CH2NRb1Rb1, 보다 구체적으로 메틸, -ORb1일 수 있다.In a specific aspect, R a1 is each independently C 1 -C 6 alkyl, -OR b1 , -NR b1 R b1 , halogen, -C(O)R b1 , oxo, -C 1 -C 3 alkylNR b1 R b1 , -C(O)NR b1 R b1 , -R b1 -OR b1 , and more specifically, R a1 is C 1 -C 6 alkyl, -OR b1 , -NR b1 R b1 , halogen, -C( O)R b1 , oxo, -C 1 -C 3 alkylNR b1 R b1 , more specifically C 1 -C 2 alkyl, -OR b1 , -NR b1 R b1 , fluoro, -C(O)R b1 , oxo, -CH 2 NR b1 R b1 , more specifically methyl, -OR b1 .
구체적인 일 양태로서, Rb1은 각각 독립적으로 수소, C1-C6알킬, C1-C6할로알킬, C3-C10사이클로알킬, 3-10원 헤테로사이클로알킬, 5-12원 헤테로아릴일 수 있고, 이때, 5-12원 헤테로아릴은 비치환되거나 또는 C1-C6알킬로 치환될 수 있고;In a specific aspect, R b1 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, and 5-12 membered heteroaryl. , wherein the 5-12 membered heteroaryl may be unsubstituted or substituted with C 1 -C 6 alkyl;
보다 구체적으로 Rb1은 수소, C1-C2알킬, C1-C2할로알킬, 사이클로프로필, 4-6원 헤테로사이클로알킬, 메틸로 치환된 5원 헤테로아릴일 수 있고, 보다 구체적으로 수소, C1-C2알킬, -CH2CF3, 사이클로프로필, 4원 헤테로사이클로알킬일 수 있고, 보다 구체적으로 수소, 메틸일 수 있다.More specifically, R b1 may be hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, cyclopropyl, 4-6 membered heterocycloalkyl, 5-membered heteroaryl substituted with methyl, and more specifically hydrogen , C 1 -C 2 alkyl, -CH 2 CF 3 , cyclopropyl, or 4-membered heterocycloalkyl, and more specifically, hydrogen or methyl.
구체적인 일 양태로서, R5는 C1-C3알킬, 더욱 구체적으로 메틸일 수 있다. As a specific aspect, R 5 may be C 1 -C 3 alkyl, more specifically methyl.
구체적인 일 양태로서, p는 1 내지 3의 정수, 보다 구체적으로 1 또는 2, 보다 구체적으로 2일 수 있다. As a specific aspect, p may be an integer from 1 to 3, more specifically 1 or 2, more specifically 2.
구체적인 일 양태로서, L3은 결합일 수 있다. As a specific aspect, L 3 may be a bond.
구체적인 일 양태로서, 각 잔기 중 헤테로아릴, 헤테로사이클로알킬, 헤테로사이클로알켄일, 헤테로사이클릴은 N, O, S, SO 및 SO2로 이루어지는 군으로부터 선택되는 1종 내지 3종, 1종 내지 2종의 헤테로원자를 포함할 수 있다. In a specific aspect, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and heterocyclyl among the residues are one to three selected from the group consisting of N, O, S, SO and SO 2 , and one to two may contain heteroatoms of the species.
구체적인 일 양태로서, 각 잔기 중 고리형 치환기들(예를 들어 사이클로알킬, 아릴, 헤테로사이클, 헤테로사이클로알킬, 헤테로사이클로알케닐 등)은 비치환되거나 또는 치환된 것일 수 있다.As a specific aspect, cyclic substituents (eg, cycloalkyl, aryl, heterocycle, heterocycloalkyl, heterocycloalkenyl, etc.) of each moiety may be unsubstituted or substituted.
구체적인 일 양태로서, 본 발명에 따른 화학식 (I)의 화합물들은 아래 표 1의 화합물 1) 내지 89)로 이루어진 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되는 것은 아니다. As a specific aspect, the compounds of formula (I) according to the present invention may be one or more selected from the group consisting of compounds 1) to 89) in Table 1 below, but are not limited thereto.
Figure PCTKR2022021249-appb-img-000009
Figure PCTKR2022021249-appb-img-000009
Figure PCTKR2022021249-appb-img-000010
Figure PCTKR2022021249-appb-img-000010
Figure PCTKR2022021249-appb-img-000011
Figure PCTKR2022021249-appb-img-000011
Figure PCTKR2022021249-appb-img-000012
Figure PCTKR2022021249-appb-img-000012
Figure PCTKR2022021249-appb-img-000013
Figure PCTKR2022021249-appb-img-000013
Figure PCTKR2022021249-appb-img-000014
Figure PCTKR2022021249-appb-img-000014
Figure PCTKR2022021249-appb-img-000015
Figure PCTKR2022021249-appb-img-000015
Figure PCTKR2022021249-appb-img-000016
Figure PCTKR2022021249-appb-img-000016
Figure PCTKR2022021249-appb-img-000017
Figure PCTKR2022021249-appb-img-000017
Figure PCTKR2022021249-appb-img-000018
Figure PCTKR2022021249-appb-img-000018
Figure PCTKR2022021249-appb-img-000019
Figure PCTKR2022021249-appb-img-000019
Figure PCTKR2022021249-appb-img-000020
Figure PCTKR2022021249-appb-img-000020
Figure PCTKR2022021249-appb-img-000021
Figure PCTKR2022021249-appb-img-000021
구체적인 일 양태로서, 본 발명에 따른 화학식(I)의 화합물들은 아래 화합물들 이루어진 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되는 것은 아니다. As a specific aspect, the compound of Formula (I) according to the present invention may be one or more selected from the group consisting of the following compounds, but is not limited thereto.
Figure PCTKR2022021249-appb-img-000022
Figure PCTKR2022021249-appb-img-000022
Figure PCTKR2022021249-appb-img-000023
Figure PCTKR2022021249-appb-img-000023
Figure PCTKR2022021249-appb-img-000024
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Figure PCTKR2022021249-appb-img-000092
달리 특정되지 않으면, 본원 명세서 및 청구범위에서 주어진 화학식 또는 명칭은 호변이성질체 및 모든 입체, 광학 및 기하 이성질체(예를 들면, 거울상이성질체, 부분입체이성질체, E/Z 이성질체 등) 및 이들의 라세메이트 뿐 아니라 상이한 비율의 별개 거울상이성질체의 혼합물, 부분입체이성질체의 혼합물, 또는 이성질체 및 거울상 이성질체가 존재하는 상기 임의 형태의 혼합물, 및 이들의 약학적으로 허용되는 염 및 예컨대 자유 화합물의 용매화물 및 수화물 또는 해당 화합물의 염의 용매화물 및 수화물을 포함하는 수화물과 같은 이들의 용매화물을 비롯한 염을 망라한다. Unless otherwise specified, formulas or names given in the specification and claims herein refer only to tautomers and all stereoisomers, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof. mixtures of separate enantiomers, mixtures of diastereomers, or mixtures of any of the above forms in which isomers and enantiomers are present, as well as pharmaceutically acceptable salts thereof and such as solvates and hydrates of free compounds, or corresponding It encompasses salts, including solvates thereof, such as hydrates, including solvates and hydrates of salts of the compounds.
일 실시 양태에서, 본 발명의 화합물은 약학적으로 허용 가능한 염의 형태로 존재할 수 있다. 상기 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 본 발명에 따른 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미한다.In one embodiment, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to any concentration of a compound having a relatively non-toxic and harmless effective effect on patients, and side effects caused by the salt do not reduce the beneficial effects of the compound according to the present invention. means any organic or inorganic addition salt.
산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (eg, glycol monomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be suction filtered.
이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산(hydroiodic acid) 등을 사용할 수 있으며, 이들에 제한되지 않는다. At this time, organic acids and inorganic acids can be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, and maleic acid can be used as the organic acid. (maleic acid), succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid (gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used. , but not limited to these.
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for preparing a sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
본 발명의 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 (I)에 기재된 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트(메실레이트) 및 p-톨루엔술포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다. 구체적인 일 양태로, 상기 본 발명의 화합물의 약학적으로 허용가능한 염은 염산염일 수 있다. Pharmaceutically acceptable salts of the compounds of the present invention, unless otherwise indicated, include salts of acidic or basic groups which may be present in the compounds described in Formula (I) above. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of a hydroxy group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, and hydrogen phosphate. , dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, etc., preparation of salts known in the art It can be produced through the method. In a specific aspect, the pharmaceutically acceptable salt of the compound of the present invention may be a hydrochloride salt.
본 발명의 상기 화학식 (I)에 기재된 화합물의 염으로는 약학적으로 허용가능한 염으로서, 표 1에 기재된 화합물과 동등한 약리활성을 나타내는 상기 화학식 (I)에 기재된 화합물의 염이면 제한없이 모두 사용 가능하다.The salt of the compound described in Formula (I) of the present invention is a pharmaceutically acceptable salt, and any salt of the compound described in Formula (I) exhibiting pharmacological activity equivalent to that of the compounds listed in Table 1 can be used without limitation. do.
또한, 본 발명에 따른 상기 화학식 (I)에 기재된 화합물은, 이의 약학적으로 허용 가능한 염뿐만 아니라 이로부터 제조될 수 있는 가능한 수화물 등의 용매화물 및 가능한 모든 입체 이성질체를 제한없이 포함한다. 거울상이성질체 형태 및 부분입체이성질체 형태를 포함하는, 본 발명의 모든 입체 이성질체(예를 들어, 다양한 치환체에서 비대칭 탄소에 기인하여 존재할 수 있는 것들)가 본 발명의 범위에 포함된다. 본 발명의 화합물의 개별적인 입체이성질체는, 예를 들어, 실질적으로 다른 이성질체가 없거나(예를 들어, 특정의 활성을 갖는 순수한 또는 실질적으로 순수한 광학 이성질체로서), 또는 예를 들어, 라세미체로서 또는 모든 다른, 또는 다른 선택된 입체이성질체와 혼합될 수 있다. 본 발명의 화합물의 키랄 중심은 IUPAC 1974 권고에 의해 정의된 S 또는 R 구조를 가질 수 있다. 라세미 형태는 키랄 컬럼 크로마토그래피에 의한 분리 또는 부분입체이성질체 유도체의 분리 또는 결정화, 분별 형상 결정화와 같은 물리적 방법에 의해 분석될 수 있다. 개별적인 광학 이성질체는, 이에 한정되는 것은 아니지만, 광학적으로 활성인 산과의 염 형성에 이어, 결정화를 포함하는 임의의 적합한 방법에 의해 라세미체로부터 얻을 수 있다. In addition, the compound described in Formula (I) according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as hydrates and the like that can be prepared therefrom and all possible stereoisomers without limitation. All stereoisomers of the present invention, including enantiomeric and diastereomeric forms (eg, those that may exist due to asymmetric carbons in various substituents) are included within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (eg, as pure or substantially pure optical isomers having a specific activity), or, for example, as racemates or It can be mixed with all other or other selected stereoisomers. The chiral center of the compounds of the present invention may have the S or R structure defined by the IUPAC 1974 Recommendation. Racemic forms can be resolved by physical methods such as separation by chiral column chromatography or separation or crystallization of diastereomeric derivatives, fractional shape crystallization. Individual optical isomers may be obtained from the racemates by any suitable method including, but not limited to, salt formation with an optically active acid followed by crystallization.
상기 화학식 (I) 화합물의 용매화물 및 입체이성질체는 당업계에 공지된 방법을 사용하여 상기 화합물로부터 제조할 수 있다.Solvates and stereoisomers of the compounds of formula (I) can be prepared from these compounds using methods known in the art.
나아가, 본 발명에 따른 상기 화학식 (I)의 화합물은 결정 형태 또는 비결정 형태로 제조될 수 있으며, 결정 형태로 제조될 경우 임의로 수화되거나 용매화될 수 있다. 본 발명에서는 상기 화학식 (I)의 기재된 화합물의 화학양론적 수화물뿐만 아니라 다양한 양의 물을 함유하는 화합물이 포함될 수 있다. 본 발명에 따른 상기 화학식 (I) 화합물의 용매화물은 화학양론적 용매화물 및 비화학양론적 용매화물 모두를 포함한다.Furthermore, the compound of formula (I) according to the present invention may be prepared in a crystalline or amorphous form, and when prepared in a crystalline form, it may be optionally hydrated or solvated. In the present invention, compounds containing various amounts of water may be included as well as stoichiometric hydrates of the compounds described in formula (I) above. Solvates of the compound of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.
본 발명의 제조방법은, 상기 반응식들에 사용되는 반응물들로서, 시판되는 화합물을 구입하여 그대로 사용하거나, 당업계에 공지된 하나 이상의 반응을 그대로 또는 적절히 변경하여 수행함으로써 합성하여 사용할 수 있다. 예컨대, 골격 구조에 포함된 반응성 작용기 및/또는 헤테로원소의 존재, 종류 및/또는 위치를 고려하여 하나 이상의 반응을 일련의 순서로 수행하여 합성할 수 있으나, 이에 제한되지 않는다.In the preparation method of the present invention, as reactants used in the above schemes, commercially available compounds may be purchased and used as they are, or synthesized and used by carrying out one or more reactions known in the art as they are or with appropriate changes. For example, it may be synthesized by performing one or more reactions in a serial order in consideration of the presence, type and/or location of reactive functional groups and/or heteroelements included in the skeleton structure, but is not limited thereto.
일 실시양태에서, 상기 화학식 (I)의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염은 SOS1과 RAS-패밀리 단백질의 상호작용을 저해하거나 또는 세포에서 SOS1과 RAC의 상호작용을 저해하는 것을 특징으로 한다. In one embodiment, the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof is a cross-linked interaction between SOS1 and a RAS-family protein. It is characterized by inhibiting the action or inhibiting the interaction between SOS1 and RAC in cells.
일 실시양태에서, 상기 화학식 (I)의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염은 SOS1의 활성에 의해 유발되는 다양한 질환에 대한 예방, 개선 또는 치료 활성을 갖는 것을 특징으로 한다. In one embodiment, the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof is a variety of drugs induced by the activity of SOS1. It is characterized by having preventive, ameliorative or therapeutic activity for diseases.
약학적 조성물 및 의약용도Pharmaceutical compositions and medicinal uses
본 발명의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염은, 이들의 생물학적 특성으로 인해, SOS1의 활성에 의해 유발되는 다양한 질환을 예방, 개선 또는 치료하는데 적합할 수 있다.The compounds of the present invention, their optical isomers, their stereoisomers, their solvates, their isotopic variants, their tautomers, or their pharmaceutically acceptable salts, due to their biological properties, can be used in various ways induced by the activity of SOS1. It may be suitable for preventing, ameliorating or treating a disease.
따라서, 또 다른 양태로서, 본 발명은 상기 화학식 (I)의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염 및 약제학적으로 허용가능한 담체를 포함하는 SOS1의 활성에 의해 유발되는 다양한 질환을 예방, 개선 또는 치료용 약학적 조성물에 관한 것이다. Therefore, in another aspect, the present invention provides a compound of formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. It relates to a pharmaceutical composition for preventing, improving or treating various diseases caused by the activity of SOS1, including an acceptable carrier.
일 양태로서, 이러한 SOS1의 활성에 의해 유발되는 다양한 질환은 예를 들어, 하기 암, 종양, 기타 증식성 질환 또는 RAS병증(RASopathy)일 수 있다. As one aspect, various diseases caused by the activity of SOS1 may be, for example, the following cancers, tumors, other proliferative diseases, or RASopathy.
구체적인 일 양태로서, 상기 암은 췌장암, 폐암, 결장직장암, 혈액암, 담관암, 다발성 골수종, 흑색종, 자궁암, 자궁내막암, 갑상선암, 급성 골수성 백혈병, 방광암, 요로상피암, 위암, 자궁경부암, 두경부 편평세포암종, 미만성 거대 B 세포 림프종, 식도암, 만성 림프구성 백혈병, 간세포암, 유방암, 난소암, 전립선암, 교모세포종, 신장암 및 육종으로 이루어진 군으로부터 선택되는 암일 수 있으나, 이에 제한되는 것은 아니다. In a specific embodiment, the cancer is pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, stomach cancer, cervical cancer, head and neck squamous It may be a cancer selected from the group consisting of cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma, but is not limited thereto.
신체내 특정 개소/장기를 특징으로 하는 위에서 언급된 모든 암은 원발성 종양과 이로부터 유래된 전이성 종양 둘 다를 포함하는 것을 의미한다. 위에서 언급된 모든 암은 그들의 병리조직학적 분류에 의해 더욱 구별될 수 있다:All cancers mentioned above that characterize a specific site/organ in the body are meant to include both primary tumors and metastatic tumors derived therefrom. All cancers mentioned above can be further differentiated by their histopathological classification:
구체적인 일 양태로서, 상기 RAS병증은 제1형 신경섬유종증(Neurofibromatosis type 1: NF1), 누난 증후군(Noonan Syndrome: NS), 다발성 흑자증을 가진 누난 증후군(Noonan Syndrome with Multiple Lentigines: NSML), 모세혈관 기형-동정맥 기형 증후군(Capillary Malformation-Arteriovenous Malformation Syndrome: CM-AVM), 코스텔로 증후군(Costello Syndrome: CS), 심장-안면-피부 증후군(Cardio-Facio-Cutaneous Syndrome: CFC), 레지우스 증후군(Legius Syndrome) 및 유전성 치은 섬유종증으로 이루어진 군으로부터 선택되는 질환일 수 있으나 이에 제한되는 것은 아니다. In a specific aspect, the RAS pathology is neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), capillaries Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome ) and a disease selected from the group consisting of hereditary gingival fibromatosis, but is not limited thereto.
구체적인 일 양태로서, 본 발명에 따른 약학적 조성물은 상기 화학식 (I)의화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염 및 약제학적으로 허용가능한 담체와 함께, 유효성분으로서 추가의 암 치료제를 더 포함할 수 있다. In a specific aspect, the pharmaceutical composition according to the present invention comprises the compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and Together with a pharmaceutically acceptable carrier, an additional cancer therapeutic agent may be further included as an active ingredient.
상기 암 치료제는 스테로이드, 관문 저해제, 항암제, 항-혈관신생제 및 자가포식 저해제로 이루어지는 군으로부터 선택되는 1종 이상일 수 있으나, 암의 치료에 관련된 것이라면 제한없이 사용될 수 있다. 이들의 구체적인 예시는 아래 병용 요법에 기재된 제제들과 동일하다. The cancer therapeutic agent may be at least one selected from the group consisting of steroids, checkpoint inhibitors, anticancer agents, anti-angiogenic agents and autophagy inhibitors, but may be used without limitation as long as it is related to the treatment of cancer. Specific examples of these are the same as the agents described in combination therapy below.
구체적인 일 양태로서, 상기 본 발명에 따른 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염 및 이들을 포함하는 약학적 조성물은 당업계에서 공지된 암 또는 RAS병증에 관한 비약물 요법과 함께 사용될 수 있다. 예를 들어, 방사선요법 및/또는 수술 및/또는 기타 화합물과 조합하여, 위에서 언급된 질환의 예방, 단기 또는 장기 치료에 사용될 수 있다.As a specific aspect, the compound according to the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt and its pharmaceutical composition containing them are known in the art. It can be used in conjunction with non-drug therapies for cancer or RAS conditions known in . For example, in combination with radiotherapy and/or surgery and/or other compounds, it can be used for prevention, short-term or long-term treatment of the diseases mentioned above.
본 발명의 약학적 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 본 발명에 있어서, 약학적 조성물의 투여 경로는 이들로 한정되는 것은 아니지만 구강, 정맥내, 근육내, 동맥내, 골수내, 경막내, 심장내, 경피, 피하, 복강내, 비강내, 장관, 국소, 설하 또는 직장이 포함된다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes. In the present invention, the route of administration of the pharmaceutical composition is not limited to oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, These include topical, sublingual or rectal.
또한, 약학적 조성물의 투여 방법으로는 경구 및 비경구 투여가 바람직하다. 본원에 사용된 용어 "비경구"는 피하, 피내, 정맥내, 근육내, 관절내, 활액낭내, 흉골내, 경막내, 병소내 및 두개골내 주사 또는 주입 기술을 포함한다.In addition, as a method of administering the pharmaceutical composition, oral and parenteral administration are preferred. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursal, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
본 발명에 따른 약학적 조성물에는 하나 이상의 약제학적으로 허용되는 담체, 하나 이상의 부형제 및/또는 희석제를 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may further comprise one or more pharmaceutically acceptable carriers, one or more excipients and/or diluents.
약제학적으로 적합한 담체의 비-제한적 예에는 고형물 및/또는 액상물, 예를 들면, 에탄올, 글리세롤, 물 등이 포함된다. 당해 치료 조성물 중의 담체의 양은 치료 조성물 또는 치료학적 조합물의 총 중량을 기준으로 하여 약 5 내지 약 99중량%의 범위일 수 있다. 적합한 약제학적으로 허용되는 부형제 및 희석제의 비-제한적 예에는 비독성의 상용성 충진제, 결합제, 붕해제, 완충제, 방부제, 습윤제, 증량제, 산화방지제, 윤활제, 향미제, 점증제, 착색제, 계면활성제, 유화제, 헌탁제 등이 포함된다. 이러한 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있지만, 이에 한정되는 것은 아니며, 다른 약학적으로 허용가능한 모든 담체, 부형제 및 희석제가 사용될 수 있음은 통상의 기술자에게는 자명한 것이다.Non-limiting examples of pharmaceutically suitable carriers include solids and/or liquids such as ethanol, glycerol, water and the like. The amount of carrier in the therapeutic composition may range from about 5% to about 99% by weight based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic, compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, bulking agents, antioxidants, lubricants, flavoring agents, thickeners, colorants, surfactants. , emulsifiers, turbidity agents, etc. are included. Such excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto, and all other pharmaceutically acceptable carriers, excipients and diluents It is obvious to those skilled in the art that it can be used.
본 발명의 화합물 또는 이의 염을 포함하는 조성물은, 각각 통상의 방법에 따라 정제, 산제, 과립제, 환제, 캡슐제, 현탁액, 에멀젼, 내용액제, 유제, 시럽 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.A composition containing the compound of the present invention or a salt thereof may be prepared according to conventional methods, such as oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions for internal use, emulsions, syrups, external preparations, suppositories or It may be formulated and used in the form of a sterile injectable solution.
본 발명에 따른 약학적 조성물은 멸균 주사용 수성 또는 유성 현탁액으로서 멸균 주사용 제제의 형태일 수 있다. 이 현탁액은 적합한 분산제 또는 습윤제(예, 트윈 80) 및 현탁화제를 사용하여 본 분야에 공지된 기술에 따라 제형될 수 있다. 멸균 주사용 제제는 또한 무독성의 비경구적으로 허용되는 희석제 또는 용매중의 멸균 주사용액 또는 현탁액(예, 1,3-부탄디올 중의 용액)일 수 있다. 허용 가능한 비히클 및 용매로는 만니톨, 물, 링겔 용액 또는 등장성 염화나트륨 용액 등이 있다. 또한, 멸균 불휘발성 오일이 통상적으로 용매 또는 현탁화 매질로서 사용된다. 이러한 목적을 위해, 합성 모노 또는 디글리세라이드를 포함하여 자극성이 적은 어떠한 불휘발성 오일도 사용할 수 있다. 올레산 및 이의 글리세라이드 유도체와 같은 지방산이 약학적으로 허용되는 천연 오일(예, 올리브유 또는 피마자유), 특히 이들의 폴리옥시에틸화된 것과 마찬가지로 주사 제제에 유용하다.The pharmaceutical composition according to the present invention may be in the form of a sterile injectable preparation as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (eg, as a solution in 1,3-butanediol). Acceptable vehicles and solvents include mannitol, water, Ringer's solution or isotonic sodium chloride solution. In addition, sterile fixed oils are usually employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in injectable preparations as are pharmaceutically acceptable natural oils (eg olive oil or castor oil), especially polyoxyethylated ones thereof.
본 발명에 따른 약학적 조성물은 이들로 한정되는 것은 아니지만 캡슐, 정제 및 수성 현탁액 및 용액을 포함하여 경구적으로 허용되는 어떠한 용량으로도 경구 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered orally in any orally acceptable dosage including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
본 발명의 약학적 조성물은 또한 직장 투여를 위한 좌제의 형태로 투여될 수 있다. 이들 조성물은 본 발명의 화합물을 실온에서 고형이지만 직장 온도에서는 액상인 적합한 비자극성 부형제와 혼합하여 제조할 수 있다. 이러한 물질로는 이들로 한정되는 것은 아니지만 코코아 버터, 밀랍 및 폴리에틸렌글리콜이 포함된다.The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
본 발명에 따른 약학적 조성물의 경구 투여는 목적하는 치료가 국소 적용으로 접근이 용이한 부위 또는 기관과 관련이 있을 때 특히 유용하다. 피부에 국소적으로 적용하는 경우, 약학적 조성물은 담체에 현탁 또는 용해된 활성 성분을 함유한 적합한 연고로 제형화되어야 한다. 본 발명의 화합물을 국소 투여하기 위한 담체로는 이들로 한정되는 것은 아니지만 광유, 유동 파라핀, 백색 와셀린, 프로필렌 글리콜, 폴리옥시에틸렌, 폴리옥시프로필렌 화합물, 유화 왁스 및 물이 포함된다. 다른 방도로서, 약학적 조성물은 담체에 현탁 또는 용해된 활성 화합물을 함유한 적합한 로션 또는 크림으로 제형될 수 있다. 적합한 담체로는 이들로 한정되는 것은 아니지만 광유, 솔비탄 모노스테아레이트, 폴리솔베이트 60, 세틸 에스테르 왁스, 세테아릴 알코올, 2-옥틸도데카놀, 벤질알코올 및 물이 포함된다. 본 발명의 약학적 조성물은 또한 직장 좌제에 의해 또한 적합한 관장제로 하부 장관으로 국소 적용할 수 있다. 국소 적용된 경피 패치가 또한 본 발명에 포함된다.Oral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves areas or organs that are easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated in a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention may also be topically applied to the lower intestinal tract by rectal suppository and also as a suitable enema. Topically applied transdermal patches are also included in the present invention.
본 발명의 약학적 조성물은 비내 에어로졸 또는 흡입에 의해 투여할 수 있다. 이러한 조성물은 약제의 분야에 잘 알려진 기술에 따라 제조하며 벤질 알코올 또는 다른 적합한 보존제, 생체이용율을 증강시키기 위한 흡수 촉진제, 플루오로카본 및/또는 기타 본 분야에 알려진 가용화제 또는 분산제를 사용하여 염수중의 용액으로서 제조할 수 있다.The pharmaceutical composition of the present invention can be administered by intranasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceuticals and prepared in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other solubilizers or dispersants known in the art. It can be prepared as a solution.
본 발명의 약학적 조성물에 상기한 신규 화합물은 치료학적 유효량 또는 예방학적 유효량으로 함유된다. 본 발명에 따른 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위하여, 본 발명의 화학식 (I)의 화합물은 0.0001~1000㎎/㎏, 바람직하게는 0.01~500㎎/㎏의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다.The novel compound described above in the pharmaceutical composition of the present invention is contained in a therapeutically effective amount or a prophylactically effective amount. A preferred dosage of the compound according to the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of formula (I) of the present invention may be administered in an amount of 0.0001 to 1000 mg/kg, preferably 0.01 to 500 mg/kg, divided into once to several times a day.
본 발명의 조성물 중 상기 화학식 (I)의 화합물은 전체 조성물 총 중량에 대하여 0.0001~50중량%의 함량으로 배합될 수 있다.In the composition of the present invention, the compound of formula (I) may be formulated in an amount of 0.0001 to 50% by weight based on the total weight of the composition.
또 다른 양태로서, 본 발명은 상기 화학식 (I)의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염 및 약제학적으로 허용가능한 담체를 포함하는 SOS1의 활성에 의해 유발되는 다양한 질환을 예방, 개선 또는 치료하는 방법에 관한 것이다. In another aspect, the present invention provides a compound of Formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. It relates to a method for preventing, improving or treating various diseases caused by the activity of SOS1 including a carrier.
이때, 본 발명의 화학식 (I)의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염은 약학적으로 유효한 양으로 투여한다. 본 발명의 용어 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.At this time, the compound of formula (I) of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level is the patient's health condition, Depending on the type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field can The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
예컨대, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.For example, the dosage may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., so the dosage is not limited to the scope of the present invention in any way.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. A preferred dose of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the type of drug, the route and duration of administration, but can be appropriately selected by those skilled in the art.
병용 요법combination therapy
본 발명의 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용가능한 염, 이들을 포함하는 약학적 조성물은 단독으로 또는 1종 이상의 추가의 요법(예컨대, 비-약물 치료 또는 치료제)와 병용될 수 있다. The compound of the present invention, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them may be used alone or in addition to one or more additional therapies. (eg, non-drug treatment or therapeutic agent).
병용 요법은, 예를 들어, 2가지 요법을 조합할 수 있거나 또는 3가지 요법(예컨대, 3가지 치료제의 3중 요법) 또는 그 이상을 조합할 수 있다. 추가의 요법(예컨대, 비-약물 치료 또는 치료제) 중 하나 이상의 투여량은 단독으로 투여된 경우에 표준 투여량으로부터 저감될 수 있다. Combination therapy may, for example, combine two therapies or may combine three therapies (eg, a triple therapy of three therapeutic agents) or more. The dosage of one or more of the additional therapies (eg, non-drug treatments or therapeutics) may be reduced from the standard dosage when administered alone.
본 발명의 화합물은 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용가능한 염, 이들을 포함하는 약학적 조성물은 하나 이상의 이러한 추가의 요법 전에, 후에 또는 동시에 투여될 수 있다. A compound of the present invention may be a compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them prior to one or more such additional therapies. It can be administered after, or concurrently.
본 발명의 화합물 및 항암제와 같은 추가의 요법은, 예컨대, 단일 약제학적 조성물로 함께 투여할 수 있거나, 개별적으로 투여할 수 있고, 개별적으로 투여할 경우, 이는 동시에 또는 순차적으로 발생할 수 있다. 이러한 순차적 투여는 시간 상 가까울 수 있거나 또는 멀리 떨어져 있을 수 있다.An additional therapy, such as a compound of the present invention and an anti-cancer agent, can be administered together, eg, in a single pharmaceutical composition, or can be administered separately, and when administered separately, this can occur simultaneously or sequentially. Such sequential administration may be close in time or distant.
구체적인 일 실시 양태로서, 상기 추가의 요법은 부작용 제한제의 투여일 수 있다. 이러한 부작용 제한제의 예로는 메스꺼움을 치료하는 데 사용될 수 있는 제제로, 드로나비놀, 그라니세트론, 메토클로프라마이드, 온단세트론 및 프로클로르페라진, 또는 이들의 약제학적으로 허용 가능한 염 등일 수 있다. As a specific embodiment, the additional therapy may be administration of a side effect limiting agent. Examples of such side effect limiting agents are agents that can be used to treat nausea, and may include dronabinol, granisetron, metoclopramide, ondansetron and prochlorperazine, or pharmaceutically acceptable salts thereof. there is.
구체적인 일 실시 양태로서, 상기 추가의 요법은 비-약물 요법(예컨대, 수술 또는 방사선 요법)를 포함한다. 비-약물 치료의 예는 방사선 요법, 냉동요법(cryotherapy), 온열치료(hyperthermia), 수술(예컨대, 종양 조직의 외과적 절제), 및 T 세포 입양 전달(ACT) 요법을 포함하지만, 이들로 제한되지 않는다.In a specific embodiment, the additional therapy includes non-drug therapy (eg, surgery or radiation therapy). Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical resection of tumor tissue), and adoptive T cell transfer (ACT) therapy. It doesn't work.
병용가능한 치료제는 암 또는 이와 연관된 증상의 치료에 사용되는 화합물일 수 있으며, 적합한 스테로이드는 21-아세톡시프레그네놀론, 알클로메타손, 알게스톤, 암시노나이드, 베클로메타손, 베타메타손, 부데소나이드, 클로로프레드니손, 클로베타솔, 클로코르톨론, 클로프레드놀, 코르티코스테론, 코르티손, 코르티바졸, 데플라자코트(deflazacort), 데소나이드, 데속시메타손, 덱사메타손, 디플로라손, 디플루코르톨론, 디푸프레드네이트, 에녹솔론, 플루아자코트, 플루클로로나이드, 플루메타손, 플루니솔리드, 플루오시놀론 아세토나이드, 플루오시노나이드, 플루오코르틴 부틸, 플루오코르톨론, 플루오로메톨론, 플루페롤론 아세테이트, 플루프레드니덴 아세테이트, 플루프레드니솔론, 플루란드레놀라이드, 플루티카손 프로피오네이트, 포르모코르탈, 할로시노나이드, 할로베타솔 프로피오네이트, 할로메타손, 하이드로코르티손, 로테프레드놀 에타보네이트, 마지프레돈, 메드리손, 메프레드니손, 메틸프레드니솔론, 모메타손 퓨로에이트, 파라메타손, 프레드니카베이트, 프레드니솔론, 프레드니솔론 25-다이에틸아미노아세테이트, 프레드니솔론 나트륨 포스페이트, 프레드니손, 프레드니발, 프레드닐리덴, 리멕솔론, 틱소코르톨, 트라이암시놀론, 트라이암시놀론 아세토나이드, 트라이암시놀론 베네토나이드, 트라이암시놀론 헥사세토나이드 및 이의 염 또는 유도체를 포함할 수 있지만, 이들로 제한되지 않는다.Combinable therapeutic agents may be compounds used in the treatment of cancer or conditions associated therewith, and suitable steroids include 21-acetoxypregnenolone, alcomethasone, algestone, amcinonide, beclomethasone, betamethasone, Desonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflu Cortolone, difuprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, flu Ferolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halocinonide, halobetasol propionate, halometasone, hydrocortisone, lotepred Nol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, predcarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival , prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone venetonide, triamcinolone hexacetonide and salts or derivatives thereof. .
암 또는 이와 연관된 증상의 치료에 사용되는 생물학적 제제(예컨대, 사이토카인(예컨대, 인터페론 또는 IL-2와 같은 인터류킨))일 수 있다. 몇몇 실시형태에서, 생물학적 제제는 면역 글로불린 기반 생물학적 제제, 예컨대, 항암 반응을 자극하기 위해 표적에 작용하거나 암에 중요한 항원에 길항하는 단일 클론 항체(예컨대, 인간화 항체, 완전 인간 항체, Fc 융합 단백질 또는 이의 기능적 단편)이다. 항체-약물 접합체도 포함된다.It may be a biological agent (eg, a cytokine (eg, an interferon or an interleukin such as IL-2)) used in the treatment of cancer or a condition associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (eg, a humanized antibody, fully human antibody, Fc fusion protein or functional fragment thereof). Antibody-drug conjugates are also included.
일 실시양태에서, 관문 저해제는 단클론성 항체와 같은 단일 특이적 항체, 융합 단백질, 예컨대, Fc-수용체 융합 단백질일 수 있으며, 더욱 구체적으로는 CTLA-4의 저해제(예컨대, 저해 항체 또는 소분자 저해제)(예컨대, 항-CTLA-4 항체 또는 융합 단백질), PD-1의 저해제 또는 길항제(예컨대, 저해 항체 또는 소분자 저해제), PDL-1의 저해제 또는 길항제(예컨대, 저해 항체 또는 소분자 저해제), PDL-2의 저해제 또는 길항제(예컨대, 저해 항체 또는 Fc 융합 또는 소분자 저해제)(예컨대, PDL-2/Ig 융합 단백질) 등일 수 있으나, 이에 제한되는 것은 아니다.In one embodiment, the checkpoint inhibitor can be a monospecific antibody such as a monoclonal antibody, a fusion protein such as an Fc-receptor fusion protein, more specifically an inhibitor of CTLA-4 (eg an inhibitory antibody or small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or fusion protein), an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or small molecule inhibitor), an inhibitor or antagonist of PDL-1 (e.g., an inhibitory antibody or small molecule inhibitor), a PDL-1 2 inhibitors or antagonists (eg, inhibitory antibodies or Fc fusions or small molecule inhibitors) (eg, PDL-2/Ig fusion proteins), and the like, but are not limited thereto.
일 실시양태에서, 항암제는 예컨대, 화학 요법제 또는 표적 치료제일 수 있다. 구체적으로, 항암제는 유사 분열 저해제, 삽입 항생제, 성장 인자 저해제, 세포주기 저해제, 효소, 토포아이소머라제 저해제, 생물학적 반응 조절제, 알킬화제, 항대사물질, 엽산 유사체, 피리미딘 유사체, 퓨린 유사체 및 관련 저해제, 빈카 알칼로이드, 에피포도필로톡신, 항생제, L-아스파라기나제, 토포아이소머라제 저해제, 인터페론, 백금 배위 복합체, 안트라센다이온 치환 우레아, 메틸 히드라진 유도체, 부신피질 저해제, 아드레노코르티코스테로이드, 프로게스틴, 에스트로겐, 항에스트로겐, 안드로겐, 항안드로겐 및 성선 자극 호르몬 유사체를 포함한다. 추가의 항암제는 류코보린(LV), 이레노테칸, 옥살리플라틴, 카페시타빈, 파클리탁셀, 독세탁셀, ALK 저해제 수용체 타이로신 키나제(RTK)/성장 인자 수용체(예컨대, SHP2 저해제의 하류 구성원의 저해제, SOS1 저해제, Raf 저해제, MEK 저해제, ERK 저해제, PI3K 저해제, PTEN 저해제, AKT 저해제, 또는 mTOR 저해제, Ras 저해제, Ras 백신, MAP 키나제(MAPK) 경로의 저해제(또는 "MAPK 저해제"), RAS-RAF-ERK 또는 PI3K-AKT-TOR 또는 PI3K-AKT 신호 전달 경로의 파괴자(disrupter) 또는 저해제, PD-1 또는 PD-L1 길항제, 면역 조절 이미드(IMiD), GITR 작용제, 유전자 조작된 T-세포(예컨대, CAR-T 세포), 이중 특이적 항체(예컨대, BiTE) 및 항-PD-1, 항-PDL-1, 항-CTLA4, 항-LAGl 및 항-OX40 제제), EGFR 저해제, IGF-1R 저해제 등을 포함하나, 이에 제한되는 것은 아니다. In one embodiment, the anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapy. Specifically, anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogues, pyrimidine analogues, purine analogues and related inhibitors. , vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocorticosteroids, progestins, Includes estrogens, antiestrogens, androgens, antiandrogens and gonadotropin analogues. Additional anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, docetaxel, ALK inhibitor receptor tyrosine kinase (RTK)/growth factor receptor (e.g. inhibitors of downstream members of SHP2 inhibitors, SOS1) inhibitors, Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibitors, Ras inhibitors, Ras vaccines, inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"), RAS-RAF- Disrupters or inhibitors of the ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway, PD-1 or PD-L1 antagonists, immune modulating imides (IMiDs), GITR agonists, genetically engineered T-cells (such as , CAR-T cells), bispecific antibodies (e.g., BiTE) and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl and anti-OX40 agents), EGFR inhibitors, IGF-1R inhibitors and the like, but is not limited thereto.
일 실시양태에서, 항-혈관신생제는 시험관 내 합성으로 제조된 화학 조성물, 항체, 항원 결합 영역, 방사성 핵종, 및 이들의 조합 및 접합체를 포함하지만 이에 제한되지 않는다. In one embodiment, anti-angiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.
일 실시양태에서, 자가포식 저해제는 클로로퀸, 3-메틸아데닌, 하이드록시 클로로퀸(Plaquenil™), 바필로마이신 A1, 5-아미노-4-이미다졸 카복스아마이드 리보사이드(AICAR), 오카다산, 유형 2A 또는 유형 1, cAMP의 유사체의 단백질 포스파타제를 억제하는 자가포식 억제 조류 독소, 및 아데노신, LY204002, N6-머캅토퓨린 리보사이드, 및 빈블라스틴과 같이 cAMP 수준을 상승시키는 약물을 포함하지만, 이들로 제한되지 않는다. In one embodiment, the autophagy inhibitor is chloroquine, 3-methyladenine, hydroxy chloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, type autophagy-inhibiting algal toxins that inhibit protein phosphatases of type 2A or type 1, cAMP, and drugs that elevate cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine, but these not limited to
본 발명에 따른 화합물은 치료되는 병태에 따라 본 명세서에 기재된 제제 또는 다른 적합한 제제와 조합하여 사용될 수 있다. 따라서, 몇몇 실시형태에서 본 개시내용의 하나 이상의 화합물은 본 명세서에 기재된 바와 같은 다른 요법과 공동-투여될 것이다. 병용 요법으로 사용되는 경우, 본 명세서에 기재된 화합물은 제2 작용제와 동시에 또는 개별적으로 투여될 수 있다. 이러한 조합 투여는 동일한 투여 형태로 두 작용제의 동시 투여, 개별 투여 형태로 동시 투여, 및 개별 투여를 포함할 수 있다. 즉, 본 명세서에 기재된 화합물 및 본 명세서에 기재된 임의의 제제는 동일한 투여 형태로 함께 제형화되고 동시에 투여될 수 있다. 대안적으로, 본 발명의 화합물 및 본 명세서에 기재된 임의의 요법은 동시에 투여될 수 있으며, 여기서 두 제제는 별개의 제제로 존재한다. 또 다른 대안에서, 본 개시내용의 화합물이 투여되고 이어서 본 명세서에 기재된 임의의 요법이 후속될 수 있거나, 그 반대일 수 있다. 별도의 투여 프로토콜의 몇몇 실시형태에서, 본 발명의 화합물 및 본 명세서에 기재된 임의의 요법은 몇 분 간격으로, 또는 몇 시간 간격으로, 또는 며칠 간격으로 투여될 수 있다.The compounds according to the present invention may be used in combination with the agents described herein or other suitable agents depending on the condition being treated. Thus, in some embodiments one or more compounds of the present disclosure will be co-administered with other therapies as described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with the second agent. Such combined administration can include simultaneous administration of both agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any agent described herein may be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any therapy described herein may be administered simultaneously, wherein the two agents are in separate preparations. In another alternative, a compound of the present disclosure may be administered followed by any therapy described herein, or vice versa. In some embodiments of separate administration protocols, the compounds of the present invention and any of the therapies described herein may be administered minutes apart, or hours apart, or days apart.
본 명세서에 기재된 임의의 방법의 몇몇 실시형태에서, 제1 요법(예컨대, 본 발명의 화합물) 및 하나 이상의 추가의 요법은 임의의 순서로, 동시에 또는 순차적으로 투여될 수 있다.In some embodiments of any of the methods described herein, the first therapy (eg, a compound of the invention) and one or more additional therapies may be administered in any order, simultaneously or sequentially.
[실시예][Example]
본 발명은 하기 실시예를 참조하여 더욱 상세하게 설명된다. 그러나, 이들 실시예는 임의의 방식으로 본 발명의 범위를 제한하는 것으로 해석되어서는 안 된다.The invention is explained in more detail with reference to the following examples. However, these examples should not be construed as limiting the scope of the present invention in any way.
1. 화학합성1. Chemical Synthesis
중간체 I-A, I-BIntermediates I-A, I-B
Figure PCTKR2022021249-appb-img-000093
Figure PCTKR2022021249-appb-img-000093
중간체 I-A 와 I-B 의 일반적인 합성은 다음과 같다. I-A-1을 트리부틸(1-에톡시비닐)주석을 사용한 스틸 커플링 반응으로 중간체 I-A-2 을 합성하고, 10 % 염산 을 이용한 아세틸화를 통해 중간체 I-A-3 을 수득한다. 가열조건에서 히드라진 수화물을 이용하여 중간체 I-A 를 합성하고, 옥시염화인 을 사용한 염소화를 진행하여 중간체 I-B 를 합성한다. The general synthesis of intermediates I-A and I-B is as follows. Intermediate I-A-2 is synthesized by Stille coupling reaction of I-A-1 with tributyl(1-ethoxyvinyl)tin, and intermediate I-A-3 is obtained by acetylation with 10% hydrochloric acid. Intermediate I-A is synthesized using hydrazine hydrate under heating conditions, and chlorination is performed using phosphorus oxychloride to synthesize intermediate I-B.
단계 1Step 1
Figure PCTKR2022021249-appb-img-000094
Figure PCTKR2022021249-appb-img-000094
메틸 5-클로로-2-(1-에톡시비닐)니코티네이트Methyl 5-chloro-2-(1-ethoxyvinyl)nicotinate
무수 1,4-디옥산 (3 ml) 중 메틸 2,5-디클로로니코티네이트 (2.17 g, 8.66 mmol) 의 용액에 트리부틸(1-에톡시비닐)틴 (3.07 ml, 9.10 mmol), PdCl2(PPh3)2 (243 mg, 0.35 mmol) 을 첨가하고, 혼합물을 질소 환경에서 85 ℃ 로 가열하여 16 시간 동안 교반하였다. 실온으로 냉각시킨 후, 증류수를 첨가하여 반응을 종결하고 에틸 아세테이트로 3 회 추출하였다. 유기층을 염화나트륨 포화 용액으로 1 회 씻어 주고, 유기 혼합물을 황산마그네슘 상에서 건조 후 여과하였다. 여과액을 농축 후 진공 건조하여 수득한 메틸 5-클로로-2-(1-에톡시비닐)니코티네이트 를 별도의 정제없이 다음 반응에 사용하였다.To a solution of methyl 2,5-dichloronicotinate (2.17 g, 8.66 mmol) in anhydrous 1,4-dioxane (3 ml) tributyl(1-ethoxyvinyl) tin (3.07 ml, 9.10 mmol), PdCl 2 (PPh 3 ) 2 (243 mg, 0.35 mmol) was added and the mixture was heated to 85 °C in a nitrogen environment and stirred for 16 h. After cooling to room temperature, distilled water was added to terminate the reaction, followed by extraction with ethyl acetate three times. The organic layer was washed once with a saturated sodium chloride solution, and the organic mixture was dried over magnesium sulfate and filtered. Methyl 5-chloro-2-(1-ethoxyvinyl)nicotinate obtained by concentrating the filtrate and drying under vacuum was used in the next reaction without separate purification.
MS (ESI+) m/z 242 (M+H)+ MS (ESI+) m/z 242 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000095
Figure PCTKR2022021249-appb-img-000095
메틸 2-아세틸-5-클로로니코티네이트Methyl 2-acetyl-5-chloronicotinate
0 ℃ 로 냉각한 무수 테트라히드로푸란 (19 ml) 중 메틸 5-클로로-2-(1-에톡시비닐)니코티네이트 에 10 % 염산 (19 ml, 55.27 mmol) 을 천천히 첨가 하고, 실온에서 5시간 동안 교반하였다. 반응 용액에 탄산 수소 나트륨 포화용액을 첨가하여 반응을 종결하고 에틸 아세테이트로 3 회 추출하였다. 유기층을 염화나트륨 포화 용액으로 1 회 씻어 주고, 유기 혼합물을 황산마그네슘 상에서 건조시킨 후, 여과 및 농축 하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 메틸 2-아세틸-5-클로로니코티네이트 (1.08 g, 58 %) 를 노란색 오일로서 수득하였다.To methyl 5-chloro-2-(1-ethoxyvinyl)nicotinate in anhydrous tetrahydrofuran (19 ml) cooled to 0 °C was added slowly 10% hydrochloric acid (19 ml, 55.27 mmol) and stirred at room temperature for 5 Stir for an hour. The reaction was terminated by adding a saturated sodium hydrogen carbonate solution to the reaction solution, and then extracted with ethyl acetate three times. The organic layer was washed once with a saturated sodium chloride solution, and the organic mixture was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography to give methyl 2-acetyl-5-chloronicotinate (1.08 g, 58%) as a yellow oil.
MS (ESI+) m/z 214 (M+H)+ MS (ESI+) m/z 214 (M+H) +
단계 3Step 3
Figure PCTKR2022021249-appb-img-000096
Figure PCTKR2022021249-appb-img-000096
3-클로로-8-메틸피리도[2,3-d]피리다진-5(6H)-온3-chloro-8-methylpyrido[2,3-d]pyridazin-5(6H)-one
에탄올 (16 ml) 중 메틸 2-아세틸-5-클로로니코티네이트 (1.08 g, 5.06 mmol)의 용액에 히드라진 수화물 (735 μl, 15.17 mmol)을 첨가하였다. 반응 혼합물을 90 ℃ 에서 30 분 동안 교반하고, 실온으로 냉각 후 여과하여 3-클로로-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (890 mg, 90 %) 를 흰색 가루로서 수득하였다.To a solution of methyl 2-acetyl-5-chloronicotinate (1.08 g, 5.06 mmol) in ethanol (16 ml) was added hydrazine hydrate (735 μl, 15.17 mmol). The reaction mixture was stirred at 90 °C for 30 minutes, cooled to room temperature and filtered to obtain 3-chloro-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (890 mg, 90%) was obtained as a white powder.
MS (ESI+) m/z 196 (M+H)+ MS (ESI+) m/z 196 (M+H) +
단계 4.Step 4.
Figure PCTKR2022021249-appb-img-000097
Figure PCTKR2022021249-appb-img-000097
3,5-디클로로-8-메틸피리도[2,3-d]피리다진3,5-dichloro-8-methylpyrido[2,3-d]pyridazine
3-클로로-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (500 mg, 2.56 mmol) 에 옥시염화인 (4 ml, 20.48 mmol) 을 첨가하고 100 ℃ 에서 0.5 시간 동안 가열 교반한다. 반응 용액을 감압 농축하고, 잔류물에 증류수를 첨가하여 0 ℃ 로 냉각 후, 탄산 수소 나트륨을 첨가하여 중화 시킨다. 혼합액을 에틸 아세테이트로 3 회 추출 하고, 유기층을 염화나트륨 포화용액으로 1 회 씻어 주었다. 유기 추출액을 황산마그네슘상에서 건조시킨 후, 여과 및 농축 하여 3,5-디클로로-8-메틸피리도[2,3-d]피리다진 (45 mg, 2.10 mmol) 를 황색 고체로 수득하였다.Phosphorus oxychloride (4 ml, 20.48 mmol) was added to 3-chloro-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (500 mg, 2.56 mmol) and stirred at 100 °C for 0.5 Heat and stir for an hour. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and after cooling to 0°C, sodium hydrogen carbonate was added to neutralize it. The mixture was extracted three times with ethyl acetate, and the organic layer was washed once with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered and concentrated to give 3,5-dichloro-8-methylpyrido[2,3-d]pyridazine (45 mg, 2.10 mmol) as a yellow solid.
MS (ESI+) m/z 215 (M+H)+ MS (ESI+) m/z 215 (M+H) +
중간체 I-CIntermediates I-C
Figure PCTKR2022021249-appb-img-000098
Figure PCTKR2022021249-appb-img-000098
단계 1Step 1
Figure PCTKR2022021249-appb-img-000099
Figure PCTKR2022021249-appb-img-000099
1-(3-니트로-5-(트리플루오로메틸)페닐)에타논1-(3-nitro-5-(trifluoromethyl)phenyl)ethanone
1,4-디옥산 (200 ml) 중에 1-브로모-3-니트로-5-(트리플루오로메틸)벤젠 (20 g, 74.4 mmol) 의 용액이 있는 압력 플라스크에 실온에서 트리부틸(1-에톡시비닐)틴 (34.9 g, 96.7 mmol), PdCl2(PPh3)2 (5.22 g, 7.44 mmol), 트리에틸아민 (20.8 ml, 148.8 mmol), CuI (2.83 g), KF (8.65 g, 148.3 mmol) 을 첨가하고 80 ℃ 로 가열하면서 16 시간 동안 교반하였다. 실온으로 냉각시킨 후, 1 N 염산 수용액을 첨가하고 1 시간 동안 교반 후, 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 1-(3-니트로-5-(트리플루오로메틸)페닐)에타논 (14.3 g, 82 %)을 황색 고체로 수득하였다.Tributyl (1- Ethoxyvinyl) tin (34.9 g, 96.7 mmol), PdCl 2 (PPh 3 ) 2 (5.22 g, 7.44 mmol), triethylamine (20.8 ml, 148.8 mmol), CuI (2.83 g), KF (8.65 g, 148.3 mmol) was added and stirred for 16 hours while heating to 80 °C. After cooling to room temperature, 1 N hydrochloric acid aqueous solution was added and stirred for 1 hour, followed by extraction with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanone (14.3 g, 82%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6)δ 8.85 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 2.77 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 )δ 8.85 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 2.77 (s, 3H)
단계 2Step 2
Figure PCTKR2022021249-appb-img-000100
Figure PCTKR2022021249-appb-img-000100
(R,E)-2-메틸-N-(1-(3-니트로-5-(트리플루오로메틸)페닐)에틸리덴)프로판-2-설핀아미드(R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide
테트라히드로푸란 (154 ml) 중에 1-(3-니트로-5-(트리플루오로메틸)페닐)에타논 (14.3 g, 61.4 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (11.2 g, 92.0 mmol), Ti(OEt)4 (32 ml, 154 mmol) 을 첨가하고 80 ℃ 로 가열하면서 16 시간 동안 교반하였다. 실온으로 냉각시킨 후, 냉수를 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트에 녹인 후 셀라이트 패드를 통해 여과하였다. 여액을 진공 농축한 후 잔류물을 컬럼 크로마토그래피로 정제하여 (R,E)-2-메틸-N-(1-(3-니트로-5-(트리플루오로메틸)페닐)에틸리덴)프로판-2-설핀아미드 (10.4 g 49 %)를 황색 액체로서 수득하였다.To a solution of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethanone (14.3 g, 61.4 mmol) in tetrahydrofuran (154 ml) at room temperature (R)-2-methylpropane- 2-sulfinamide (11.2 g, 92.0 mmol) and Ti(OEt) 4 (32 ml, 154 mmol) were added and stirred while heating to 80 °C for 16 hours. After cooling to room temperature, the solid precipitated when cold water was added was filtered out, dissolved in ethyl acetate, and filtered through a celite pad. After the filtrate was concentrated in vacuo, the residue was purified by column chromatography to obtain (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane- 2-Sulfinamide (10.4 g 49 %) was obtained as a yellow liquid.
1H NMR (400 MHz, DMSO-d 6) δ 8.85 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 2.86 (s, 3H), 1.20 (s, 9H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.85 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 2.86 (s, 3H), 1.20 (s, 9H)
단계 3Step 3
Figure PCTKR2022021249-appb-img-000101
Figure PCTKR2022021249-appb-img-000101
(R)-2-메틸-N-((R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에틸)프로판-2-설핀아미드(R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide
테트라히드로푸란 (101 ml) 중에 (R,E)-2-메틸-N-(1-(3-니트로-5-(트리플루오로메틸)페닐)에틸리덴)프로판-2-설핀아미드 (10.4 g 30.9 mmol) 이 용해된 용액에 -78 ℃ 에서 NaBH4 (2.11 g, 55.7 mmol) 을 첨가한 후 교반하면서 물 (2 ml) 을 점적 주입한다. 이후, 반응 혼합물을 0 ℃ 에서 1 시간 동안 교반한다. 반응 종결을 확인하고 냉수를 첨가하여 식힌 후, 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-2-메틸-N-((R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에틸)프로판-2-설핀아미드(3.04 g, 30 %)을 흰색 고체로서 수득하였다.(R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (10.4 g in tetrahydrofuran (101 ml) 30.9 mmol) was dissolved in NaBH 4 (2.11 g, 55.7 mmol) at -78 °C, and then water (2 ml) was added dropwise while stirring. Thereafter, the reaction mixture is stirred at 0° C. for 1 hour. After confirming the completion of the reaction, cold water was added to cool, and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide ( 3.04 g, 30%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.64 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 6.08, (d, J = 8.80 Hz, 1H), 4.69 (m, 1H), 1.46 (d, J = 6.80 Hz, 3H), 1.14 (s, 9H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.64 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 6.08, (d, J = 8.80 Hz, 1H), 4.69 (m , 1H), 1.46 (d, J = 6.80 Hz, 3H), 1.14 (s, 9H)
단계 4step 4
Figure PCTKR2022021249-appb-img-000102
Figure PCTKR2022021249-appb-img-000102
(R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에탄아민(R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine
1,4-디옥산 (22.5 ml) 중에 (R)-2-메틸-N-((R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에틸)프로판-2-설핀아미드 (3.04 g, 8.98 mmol)이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (11 ml, 45 mmol) 을 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응 종결 후, 0 ℃ 에서 탄산 수소 나트륨 포화용액을 첨가하여 용액을 염기화 시키고, 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에탄아민(1.98 g, 94 %)을 흰색 고체로서 수득하였다.(R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfin in 1,4-dioxane (22.5 ml) After adding 4 N hydrochloric acid solution (11 ml, 45 mmol) in 1,4-dioxane to a solution in which amide (3.04 g, 8.98 mmol) was dissolved, the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solution was basified by adding a saturated sodium hydrogen carbonate solution at 0 °C and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine (1.98 g, 94%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.44 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 6.84 (d, J = 7.60 Hz, 1H), 4.89 (m, 1H), 1.37 (d, J = 6.80 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.44 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 6.84 (d, J = 7.60 Hz, 1H), 4.89 (m, 1H), 1.37 (d, J = 6.80 Hz, 3H)
단계 5step 5
Figure PCTKR2022021249-appb-img-000103
Figure PCTKR2022021249-appb-img-000103
(R)-3-(1-아미노에틸)-5-(트리플루오로메틸)아닐린(R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline
메탄올 (7.4 ml) 중에 (R)-1-(3-니트로-5-(트리플루오로메틸)페닐)에탄아민 (742 mg, 3.17 mmol) 이 용해된 용액에 10 % Pd/C (152 mg, 0.14 mmol) 을 첨가한 후 반응용기에 수소 가스를 충전하여 1 기압에서 교반한다. 반응혼합물은 셀라이트 패드를 통해 여과한 후 농축시켜 (R)-3-(1-아미노에틸)-5-(트리플루오로메틸)아닐린 (540 mg, 83 %)을 흰색 고체로서 수득하였다.10% Pd/C (152 mg, 152 mg, After adding 0.14 mmol), the reaction vessel was filled with hydrogen gas and stirred at 1 atm. The reaction mixture was filtered through a pad of celite and then concentrated to give (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (540 mg, 83%) as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 6.78 (m, 2H), 6.65 (s, 1H), 5.43 (s, 1H), 3.87 (m, 1H), 1.18 (d, J = 6.40 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 6.78 (m, 2H), 6.65 (s, 1H), 5.43 (s, 1H), 3.87 (m, 1H), 1.18 (d, J = 6.40 Hz, 3H)
중간체 I-DIntermediate I-D
Figure PCTKR2022021249-appb-img-000104
Figure PCTKR2022021249-appb-img-000104
단계1step 1
Figure PCTKR2022021249-appb-img-000105
Figure PCTKR2022021249-appb-img-000105
에틸 2-(3-브로모-2-플루오로페틸)-2,2-디플루오로아세테이트Ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate
디메틸설폭사이드 (15 ml) 중에 Cu (1.5 g, 24.93 mmol), 에틸 2-브로모-2,2-디플루오로아세테이트 (5.1 g, 24.93 mmol) 이 용해된 용액에 1-브로모-2-플루오로-3-요오도벤젠 (3 g, 9.97 mmol) 을 첨가한 후, 70 ℃ 에서 2 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가한 뒤, 반응 혼합물을 셀라이트 패드를 통해 여과한 후 농축시켜 디에틸 에테르로 3 회 이상 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축 시킨 뒤, 잔류물을 컬럼 크로마토그래피로 정제하여 에틸 2-(3-브로모-2-플루오로페틸)-2,2-디플루오로아세테이트 (2.45 g, 83 %)을 무색 액체로서 수득하였다.To a solution of Cu (1.5 g, 24.93 mmol) and ethyl 2-bromo-2,2-difluoroacetate (5.1 g, 24.93 mmol) in dimethyl sulfoxide (15 ml) was added 1-bromo-2- After adding fluoro-3-iodobenzene (3 g, 9.97 mmol), the mixture is stirred at 70 DEG C for 2 hours. After confirming the completion of the reaction and adding water, the reaction mixture was filtered through a celite pad, concentrated, and extracted three or more times with diethyl ether. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate (2.45 g, 83 %) was obtained as a colorless liquid.
1H NMR (400 MHz, DMSO-d 6) δ 8.00 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.00 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 8.0 Hz , 1H), 4.36 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 6.8 Hz, 3H)
단계 2Step 2
Figure PCTKR2022021249-appb-img-000106
Figure PCTKR2022021249-appb-img-000106
에틸 2-(3-아세틸-2-플루오로페닐)-2,2-디플루오로아세테이트Ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate
톨루엔 (15 ml) 중에 에틸 2-(3-브로모-2-플루오로페틸)-2,2-디플루오로아세테이트 (2.45 g, 8.08 mmol)이 용해된 용액에 트리부틸(1-에톡시비닐)틴 (3.88 g, 11.14 mmol), 트리에틸아민 (2.6 ml, 28.28 mmol)을 첨가한 뒤, PdCl2(PPh3)2 (234 mg, 0.40 mmol)을 첨가하여 100 ℃ 에서 16 시간 동안 가열 교반한다. 반응이 종결되면 반응혼합물을 셀라이트 패드를 통해 여과한 후 농축한다. 반응 농축액을 테트라히드로푸란 (9 ml) 에 용해시킨 후, 0 ℃ 에서 염산/물 [1:1] (0.60 ml) 을 천천히 적가한 후 15 분 동안 교반한다. 반응이 종결되면 탄산 수소 나트륨 포화용액을 첨가하여 용액을 염기화 시키고 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 에틸 2-(3-아세틸-2-플루오로페닐)-2,2-디플루오로아세테이트 (2.4 g, 99 %)을 무색 액체로 수득하였다. Tributyl(1-ethoxyvinyl ) After adding tin (3.88 g, 11.14 mmol) and triethylamine (2.6 ml, 28.28 mmol), PdCl 2 (PPh 3 ) 2 (234 mg, 0.40 mmol) was added and heated and stirred at 100 ° C. for 16 hours. do. When the reaction is complete, the reaction mixture is filtered through a celite pad and then concentrated. After dissolving the reaction concentrate in tetrahydrofuran (9 ml), hydrochloric acid/water [1:1] (0.60 ml) was slowly added dropwise at 0°C, followed by stirring for 15 minutes. When the reaction was complete, the solution was basified by adding saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate (2.4 g, 99%) as a colorless liquid.
1H NMR (400 MHz, DMSO-d 6) δ 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 1.23 (t, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 ( d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 1.23 (t, J = 6.8 Hz, 3H)
단계 3step 3
Figure PCTKR2022021249-appb-img-000107
Figure PCTKR2022021249-appb-img-000107
(R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)-2-플루오로페닐)-2,2-디플루오로아세테이트(R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate
테트라히드로푸란 (90 ml) 중에 에틸 2-(3-아세틸-2-플루오로페닐)-2,2-디플루오로아세테이트 (6.4 g, 24.59 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (4.48 g, 36.88 mmol), Ti(OEt)4 (16.83 ml, 73.77 mmol) 을 첨가하고 상온에서 16 시간 동안 교반하였다. 물을 첨가하여 반응을 종결시키고, 물을 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 진공 농축한 후 잔류물을 컬럼 크로마토그래피로 정제하여 (R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)-2-플루오로페닐)-2,2-디플루오로아세테이트 (3.25 g 39 %) 를 황색 액체로서 수득하였다.To a solution of ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate (6.4 g, 24.59 mmol) in tetrahydrofuran (90 ml) at room temperature (R)-2 -Methylpropane-2-sulfinamide (4.48 g, 36.88 mmol) and Ti(OEt) 4 (16.83 ml, 73.77 mmol) were added and stirred at room temperature for 16 hours. The reaction was terminated by adding water, and the solid precipitated when water was added was filtered out and then extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo and the residue was purified by column chromatography to give (R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluoro Phenyl)-2,2-difluoroacetate (3.25 g 39 %) was obtained as a yellow liquid.
MS (ESI+) m/z 364 (M+H)+ MS (ESI+) m/z 364 (M+H) +
단계 4step 4
Figure PCTKR2022021249-appb-img-000108
Figure PCTKR2022021249-appb-img-000108
(R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)-2-플루오로페닐)에틸)-2-메틸프로판-2-술핀아미드 (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (5 ml) 중에 (R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)-2-플루오로페닐)-2,2-디플루오로아세테이트 (1 g 2.75 mmol) 이 용해된 용액에 메탄올 (50 ul) 을 첨가한 뒤, 0 ℃ 에서 LiBH4 (120 mg, 5.50 mmol) 을 첨가한 후 상온에서 5 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)-2-플루오로페닐)에틸)-2-메틸프로판-2-술핀아미드 (650 mg, 70 %)을 흰색 고체로서 수득하였다.(R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoro in tetrahydrofuran (5 ml) After adding methanol (50 ul) to a solution in which rhoacetate (1 g, 2.75 mmol) was dissolved, LiBH 4 (120 mg, 5.50 mmol) was added at 0 °C, followed by stirring at room temperature for 5 hours. After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)- Obtained 2-methylpropane-2-sulfinamide (650 mg, 70%) as a white solid.
MS (ESI+) m/z 324 (M+H)+ MS (ESI+) m/z 324 (M+H) +
단계 5step 5
Figure PCTKR2022021249-appb-img-000109
Figure PCTKR2022021249-appb-img-000109
(R)-2-(3-(1-아미노에틸)-2-플루오로페닐)-2,2-디플루오로에탄올 염산염(R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride
디클로로메탄 (2 ml) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)-2-플루오로페닐)에틸)-2-메틸프로판-2-술핀아미드 (220 mg, 0.68 mmol)이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (0.65 ml, 20.4 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-2-(3-(1-아미노에틸)-2-플루오로페닐)-2,2-디플루오로에탄올 염산염 (153 g, 95 %)을 흰색 고체로서 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2- in dichloromethane (2 ml) To the solution in which methylpropane-2-sulfinamide (220 mg, 0.68 mmol) was dissolved, a 4 N hydrochloric acid solution (0.65 ml, 20.4 mmol) in 1,4-dioxane was added at 0 °C, followed by stirring at room temperature for 1 hour. did After completion of the reaction, it was concentrated to give (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride (153 g, 95%) as a white solid. did
MS (ESI+) m/z 220 (M+H)+ MS (ESI+) m/z 220 (M+H) +
중간체 I-EIntermediates I-E
Figure PCTKR2022021249-appb-img-000110
Figure PCTKR2022021249-appb-img-000110
단계 1Step 1
Figure PCTKR2022021249-appb-img-000111
Figure PCTKR2022021249-appb-img-000111
(R)-N-((R)-1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에틸)-2-메틸프로판-2-술핀아미드(R)-N-((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (5 ml) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)-2-플루오로페닐)에틸)-2-메틸프로판-2-술핀아미드 (500 mg, 1.54 mmol) 이 용해된 용액에 탄산세슘 (1.5 g, 4.62 mmol), 18-크라운-6 (200 mg, 0.77 mmol) 를 첨가한 후, 50 ℃ 에서 5 시간 동안 교반한 뒤, 상온에서 16 시간 추가로 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에틸)-2-메틸프로판-2-술핀아미드 (450 mg, 96 %)을 흰색 고체로서 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2 in tetrahydrofuran (5 ml) After adding cesium carbonate (1.5 g, 4.62 mmol) and 18-crown-6 (200 mg, 0.77 mmol) to a solution in which -methylpropane-2-sulfinamide (500 mg, 1.54 mmol) was dissolved, it was heated at 50 °C. After stirring for 5 hours, the mixture is further stirred for 16 hours at room temperature. After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-N-((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-2-methyl Propane-2-sulfinamide (450 mg, 96%) was obtained as a white solid.
MS (ESI+) m/z 304 (M+H)+ MS (ESI+) m/z 304 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000112
Figure PCTKR2022021249-appb-img-000112
(R)-1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에탄아민 염산염(R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethanamine hydrochloride
디클로로메탄 (4 ml) 중에 (R)-N-((R)-1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에틸)-2-메틸프로판-2-술핀아미드 (450 mg, 1.48 mmol) 이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (177 ul, 22.20 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에탄아민 염산염 (300 mg, 99 %)을 흰색 수득하였다.(R)-N-((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylpropane- in dichloromethane (4 ml) 4 N hydrochloric acid solution (177 ul, 22.20 mmol) in 1,4-dioxane was added to the solution in which 2-sulfinamide (450 mg, 1.48 mmol) was dissolved at 0 °C, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was concentrated to obtain (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethanamine hydrochloride (300 mg, 99%) as white.
MS (ESI+) m/z 200 (M+H)+ MS (ESI+) m/z 200 (M+H) +
중간체 I-FIntermediates I-F
Figure PCTKR2022021249-appb-img-000113
Figure PCTKR2022021249-appb-img-000113
단계 1Step 1
Figure PCTKR2022021249-appb-img-000114
Figure PCTKR2022021249-appb-img-000114
1-(3-브로보-2-플루오로페닐)-1,1-디플루오로-2-메틸프로판-2-올1-(3-brovo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol
테트라히드로푸란 (106 mL) 중 에틸 2-(3-브로모-2-플루오로페닐)-2.2-디플루오로아세테이트 (9.46 g, 31.8 mmol) 이 용해된 용액을 0°C로 냉각시킨 후 디에틸 에테르 중 MeMgBr 3 M (31.8 mL, 95.5 mmol) 을 천천히 적가한다. 0°C 에서 1 시간 30 분 동안 교반한 뒤, 염화 암모늄 포화수용액을 적가하여 반응을 종결한다. 그 후 디에틸 에테르로 추출하여 합쳐진 유기 추출물을 황산나트륨 상에서 건조하고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 1-(3-브로모-2-플루오로페닐)-1,1-디플루오로-2-메틸프로판-2-올 (7.7 g, 86 %)을 수득하였다.A solution of ethyl 2-(3-bromo-2-fluorophenyl)-2.2-difluoroacetate (9.46 g, 31.8 mmol) in tetrahydrofuran (106 mL) was cooled to 0°C and MeMgBr 3 M (31.8 mL, 95.5 mmol) in ethyl ether is slowly added dropwise. After stirring at 0°C for 1 hour and 30 minutes, the reaction was terminated by dropwise addition of a saturated aqueous solution of ammonium chloride. After extraction with diethyl ether, the combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give 1-(3-bromo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (7.7 g, 86%). .
1H NMR (400 MHz, DMSO-d 6) δ 7.87 (t, J = 7.0 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.44 (s, 1H), 1.19 (s, 6H) 1H NMR (400 MHz, DMSO- d6 ) δ 7.87 (t, J = 7.0 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz , 1H), 5.44 (s, 1H), 1.19 (s, 6H)
단계 2Step 2
Figure PCTKR2022021249-appb-img-000115
Figure PCTKR2022021249-appb-img-000115
1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에타논1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone
톨루엔 (22 mL) 중에 1-(3-브로보-2-플루오로페닐)-1,1-디플루오로-2-메틸프로판-2-올 (1.85 g, 6.54 mmol)이 용해된 용액에 트리부틸(1-에톡시비닐)틴 (2.7 mL, 7.84 mmol), 트리에틸아민 (2.3 mL, 16.4 mmol)을 첨가한 뒤, PdCl2(PPh3)2 (184 mg, 0.26 mmol)을 첨가하여 100 ℃ 에서 16 시간 동안 가열 교반한다. 반응이 종결되면 반응혼합물을 셀라이트 패드를 통해 여과한 후 농축한다. 반응 농축액을 테트라히드로푸란 (7 mL) 에 용해시킨 후, 0 ℃ 에서 염산/물 [1:1] (0.50 mL) 을 천천히 적가한 후 15 분 동안 교반한다. 반응이 종결되면 탄산 수소 나트륨 포화용액을 첨가하여 용액을 염기화 시키고 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에타논 (1.27 g, 79 %)을 황색 액체로 수득하였다. To a solution of 1-(3-brovo-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (1.85 g, 6.54 mmol) in toluene (22 mL), tri Butyl(1-ethoxyvinyl)tine (2.7 mL, 7.84 mmol) and triethylamine (2.3 mL, 16.4 mmol) were added, followed by PdCl 2 (PPh 3 ) 2 (184 mg, 0.26 mmol) to 100 Heat and stir at °C for 16 hours. When the reaction is complete, the reaction mixture is filtered through a celite pad and then concentrated. After dissolving the reaction concentrate in tetrahydrofuran (7 mL), hydrochloric acid/water [1:1] (0.50 mL) was slowly added dropwise at 0°C, followed by stirring for 15 minutes. When the reaction was complete, the solution was basified by adding saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain 1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone (1.27 g, 79%). Obtained as a yellow liquid.
1H NMR (400 MHz, DMSO-d 6) δ 7.91 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 5.44 (s, 1H), 2.58 (s, 3H), 1.22 (s, 6H) 1H NMR (400 MHz, DMSO- d6 ) δ 7.91 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz , 1H), 5.44 (s, 1H), 2.58 (s, 3H), 1.22 (s, 6H)
단계 3Step 3
Figure PCTKR2022021249-appb-img-000116
Figure PCTKR2022021249-appb-img-000116
(R,E)-N-(1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸리덴)-2-메틸프로한-2-술핀아미드(R,E)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylprohan- 2-sulfinamide
테트라히드로푸란 (17 mL) 중에 1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에타논 (1.27 g, 5.16 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (0.94 g, 7.74 mmol), Ti(OEt)4 (3.9 mL, 12.9 mmol) 을 첨가하고 상온에서 16 시간 동안 교반하였다. 물을 첨가하여 반응을 종결시키고, 물을 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 진공 농축한 후 잔류물을 컬럼 크로마토그래피로 정제하여 (R,E)-N-(1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸리덴)-2-메틸프로한-2-술핀아미드 (1.14 g, 63 %) 를 황색 액체로 수득하였다.1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone (1.27 g, 5.16 mmol) dissolved in tetrahydrofuran (17 mL) (R)-2-methylpropane-2-sulfinamide (0.94 g, 7.74 mmol) and Ti(OEt) 4 (3.9 mL, 12.9 mmol) were added to the solution at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction was terminated by adding water, and the solid precipitated when water was added was filtered out and then extracted with ethyl acetate. After concentration of the combined organic extracts in vacuo, the residue was purified by column chromatography to obtain (R,E)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl) Obtained -2-fluorophenyl)ethylidene)-2-methylprohan-2-sulfinamide (1.14 g, 63%) as a yellow liquid.
MS (ESI+) m/z 350 (M+H)+ MS (ESI+) m/z 350 (M+H) +
단계 4step 4
Figure PCTKR2022021249-appb-img-000117
Figure PCTKR2022021249-appb-img-000117
(R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸)-2-메틸프로한-2-술핀아미드(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylprohan -2-sulfinamide
테트라히드로푸란 (21 mL) 중에 (R,E)-N-(1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸리덴)-2-메틸프로한-2-술핀아미드 (1.13 g, 3.23 mmol) 이 용해된 용액에 -78 ℃ 에서 NaBH4 (147 mg, 3.88 mmol) 을 첨가한 후 -0 ℃ 에서 2 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸)-2-메틸프로한-2-술핀아미드 (327 mg, 29 %)을 흰색 고체로 수득하였다.(R,E)-N-(1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethylidene in tetrahydrofuran (21 mL) After adding NaBH 4 (147 mg, 3.88 mmol) to a solution of )-2-methylprohan-2-sulfinamide (1.13 g, 3.23 mmol) at -78 °C, the mixture was stirred at -0 °C for 2 hours. . After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl Obtained )ethyl)-2-methylprohan-2-sulfinamide (327 mg, 29%) as a white solid.
MS (ESI+) m/z 352 (M+H)+ MS (ESI+) m/z 352 (M+H) +
단계 5step 5
Figure PCTKR2022021249-appb-img-000118
Figure PCTKR2022021249-appb-img-000118
(R)-1-(3-(1-아미노에틸)-2-플루오로페닐)-1,1-디풀루오로-2-메틸프로판-2-올 염산염(R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride
디클로로메탄 (1.5 mL) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시-2-메틸프로필)-2-플루오로페닐)에틸)-2-메틸프로한-2-술핀아미드 (157 mg, 0.45 mmol)이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (0.56 ml, 2.25 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 30 분 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-1-(3-(1-아미노에틸)-2-플루오로페닐)-1,1-디풀루오로-2-메틸프로판-2-올 염산염 (97 mg, 76 %)을 흰색 고체로 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl in dichloromethane (1.5 mL) ) -2-methylprohan-2-sulfinamide (157 mg, 0.45 mmol) was added to a solution of 4 N hydrochloric acid in 1,4-dioxane (0.56 ml, 2.25 mmol) at 0 ° C. was stirred for 30 minutes. After completion of the reaction, concentrated (R) -1- (3- (1-aminoethyl) -2-fluorophenyl) -1,1-difluoro-2-methylpropan-2-ol hydrochloride (97 mg, 76%) as a white solid.
MS (ESI+) m/z 248 (M+H)+ MS (ESI+) m/z 248 (M+H) +
중간체 I-GIntermediates I-G
Figure PCTKR2022021249-appb-img-000119
Figure PCTKR2022021249-appb-img-000119
단계 1Step 1
Figure PCTKR2022021249-appb-img-000120
Figure PCTKR2022021249-appb-img-000120
(R,E)-N-(1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸리덴)-2-메틸프로판-2-설핀아미드(R,E)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (10 ml) 중에 1-(2-플루오로-3-(트리플루오로메틸)페닐)에타논 (1 g, 4.85 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (0.88 g, 7.28 mmol), Ti(OEt)4 (3.32 ml, 14.6 mmol) 을 첨가하고 80 ℃ 로 가열하면서 16 시간 동안 교반하였다. 실온으로 냉각시킨 후, 냉수를 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켜 (R,E)-N-(1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸리덴)-2-메틸프로판-2-설핀아미드 (1.35 g, 4.36 mmol) 를 황색 액체로서 수득하였다.To a solution of 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanone (1 g, 4.85 mmol) in tetrahydrofuran (10 ml) at room temperature (R)-2-methylpropane -2-sulfinamide (0.88 g, 7.28 mmol) and Ti(OEt) 4 (3.32 ml, 14.6 mmol) were added and stirred while heating to 80 °C for 16 hours. After cooling to room temperature, the solid precipitated when cold water was added was filtered out and then extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to (R,E)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide. (1.35 g, 4.36 mmol) was obtained as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 6.4 Hz, 1H), 7.70 (t, J = 6.6 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 2.79 (d, J = 2.4 Hz, 3H), 1.32 (s, 9H) 1H NMR (400 MHz, CDCl 3 ) δ 7.84 (t, J = 6.4 Hz, 1H), 7.70 (t, J = 6.6 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 2.79 (d , J = 2.4 Hz, 3H), 1.32 (s, 9H)
단계 2Step 2
Figure PCTKR2022021249-appb-img-000121
Figure PCTKR2022021249-appb-img-000121
(R)-N-((R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-2-메틸프로판-2-설핀아미드(R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (13 ml) 중 (R,E)-N-(1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸리덴)-2-메틸프로판-2-설핀아미드 (1.35 g, 4.36 mmol) 이 용해된 용액에 0 ℃ 에서 NaBH4 (198 mg, 5.24 mmol) 을 첨가한 후 실온에서 교반한다. 3 시간 후 반응 종결을 확인하고 냉수를 첨가하여 식힌 후, 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-2-메틸프로판-2-설핀아미드 (440 mg, 1.41 mmol) 을 흰색 고체로서 수득하였다.(R,E)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.35 g, 4.36 mmol) was added at 0 °C to a solution in which NaBH 4 (198 mg, 5.24 mmol) was dissolved, followed by stirring at room temperature. After confirming the completion of the reaction after 3 hours, cold water was added to cool, and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide. (440 mg, 1.41 mmol) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.62 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.26-7.23 (m, 1H), 4.90-4.83 (m, 1H), 3.55 (d, J = 5.2 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H) 1H NMR (400 MHz, CDCl 3 ) δ 7.62 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.26-7.23 (m, 1H), 4.90-4.83 (m, 1H), 3.55 (d, J = 5.2 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H)
단계 3Step 3
Figure PCTKR2022021249-appb-img-000122
Figure PCTKR2022021249-appb-img-000122
(R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에탄아민 염산염(R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride
1,4-디옥산 (3 ml) 중에 (R)-N-((R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-2-메틸프로판-2-설핀아미드 (440 mg, 1.41 mmol) 이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (1.5 ml, 6.2 mmol) 을 첨가한 후 상온에서 3 시간 동안 교반하였다. 반응 종결 후, 반응혼합물을 농축 한 후 디에틸 에테르를 첨가하고 고체를 필터하여 (R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에탄아민 염산염 (300 mg, 1.23 mmol)을 흰색 고체로서 수득하였다.(R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2- in 1,4-dioxane (3 ml) After adding 4 N hydrochloric acid solution (1.5 ml, 6.2 mmol) in 1,4-dioxane to a solution in which sulfinamide (440 mg, 1.41 mmol) was dissolved, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated, diethyl ether was added, and the solid was filtered to obtain (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride (300 mg, 1.23 mmol) was obtained as a white solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.67 (br s, 2H), 8.03 (t, J = 7.4 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 4.71 (q, J = 6.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.67 (br s, 2H), 8.03 (t, J = 7.4 Hz , 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 4.71 (q, J = 6.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H)
중간체 I-Hintermediate I-H
Figure PCTKR2022021249-appb-img-000123
Figure PCTKR2022021249-appb-img-000123
단계 1Step 1
Figure PCTKR2022021249-appb-img-000124
Figure PCTKR2022021249-appb-img-000124
(R,E)-N-(1-(5-브로모티오펜-2-일)에틸리덴)-2-메틸프로판-2-설핀아미드(R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (24 ml) 중 1-(5-브로모티오펜-2-일)에타논 (3.0 g, 9.75 mmol) 의 용액에 (R)-2-메틸프로판-2-설핀아미드 (1.53 g, 12.67 mmol) 와 Ti(OEt)4 (4.09 ml, 19.50 mmol) 를 첨가하였다. 혼합물을 70 ℃ 에서 16 시간 동안 교반 하고, 실온에서 증류수를 첨가하여 반응을 종결하였다. 혼합물을 에틸 아세테이트 (15 ml) 로 묽힌 후 침전물을 여과하여 제거하고, 여액을 에틸 아세테이트로 3 회 추출 하였다. 분리 된 유기층을 황산마그네슘 상에서 건조시키고, 여과하고 농축하였다. 잔류물을 진공 건조하여 (R,E)-N-(1-(5-브로모티오펜-2-일)에틸리덴)-2-메틸프로판-2-설핀아미드 (2.95 g, crude) 를 노란색 고체로서 수득하였다. To a solution of 1-(5-bromothiophen-2-yl)ethanone (3.0 g, 9.75 mmol) in tetrahydrofuran (24 ml) was added (R)-2-methylpropane-2-sulfinamide (1.53 g, 12.67 mmol) and Ti(OEt) 4 (4.09 ml, 19.50 mmol) were added. The mixture was stirred at 70 °C for 16 hours, and the reaction was terminated by adding distilled water at room temperature. After the mixture was diluted with ethyl acetate (15 ml), the precipitate was filtered off, and the filtrate was extracted with ethyl acetate three times. The separated organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was vacuum dried to give (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.95 g, crude) as a yellow solid was obtained as
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 4.1 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H)1H NMR (400 MHz, CDCl 3 ) δ 7.22 (d, J = 4.1 Hz, 1H), 7.04 (d, J = 4.0 Hz, 1H), 2.67 (s, 3H), 1.28 (s, 9H)
단계 2Step 2
Figure PCTKR2022021249-appb-img-000125
Figure PCTKR2022021249-appb-img-000125
(R)-N-((R)-1-(5-브로모티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드(R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (35 ml) 중 화합물 (R,E)-N-(1-(5-브로모티오펜-2-일)에틸리덴)-2-메틸프로판-2-설핀아미드 (2.95 g, crude) 의 용액을 0 ℃ 로 냉각하고, NaBH4 (1.10 g, 29.25 mmol) 을 첨가한다. 혼합물을 20 ℃ 에서 2 시간 동안 교반 하고, 0 ℃ 에서 탄산 수소 나트륨 포화용액 (6 ml) 와 증류수 (55 ml) 를 첨가하여 반응을 종결하였다. 혼합물을 에틸 아세테이트로 3 회 추출하고, 유기층을 황산마그네슘 상에서 건조 후 여과하였다. 여과액을 농축 하고 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(5-브로모티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드 (1.69 g, 56 %) 를 노란색 오일로 수득하였다Compound (R,E)-N-(1-(5-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (2.95 g, crude) in tetrahydrofuran (35 ml) The solution of is cooled to 0 °C and NaBH 4 (1.10 g, 29.25 mmol) is added. The mixture was stirred at 20 °C for 2 hours, and the reaction was terminated by adding saturated sodium hydrogen carbonate solution (6 ml) and distilled water (55 ml) at 0 °C. The mixture was extracted three times with ethyl acetate, and the organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated and purified by column chromatography to obtain (R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (1.69 g , 56%) as a yellow oil
1H NMR (400 MHz, CDCl3) δ 6.90 (t, J = 4.0 Hz, 1H), 6.79 (dd, J = 3.8, 0.6 Hz, 1H), 4.80-4.72 (m, 1H), 4.90-4.83 (m, 1H), 3.49 (d, J = 2.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H) 1H NMR (400 MHz, CDCl 3 ) δ 6.90 (t, J = 4.0 Hz, 1H), 6.79 (dd, J = 3.8, 0.6 Hz, 1H), 4.80-4.72 (m, 1H), 4.90-4.83 ( m, 1H), 3.49 (d, J = 2.8 Hz, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H)
단계 3step 3
Figure PCTKR2022021249-appb-img-000126
Figure PCTKR2022021249-appb-img-000126
(R)-N-((R)-1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드(R)-N-((R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide
(R)-N-((R)-1-(5-브로모티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드 (700 mg, 2.26 mmol) 및 N,N-디메틸-1-(2-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페닐)메탄아민 (589 mg, 2.26 mmol), Pd(PPh3)4 (261 mg, 0.226 mmol) 및 탄산세슘 (2.2 g, 6.78 mmol) 을 1,4-디옥산 과 물 (5:1, 6 mL) 에 질소 하에서 녹인 후 110 ℃ 에서 4 시간 동안 교반하였다. 반응 혼합물을 실온으로 냉각 시킨 후 진공에서 농축하였다. 농축물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드 (480 mg, 58 %) 를 노란색 액체로 수득하였다.(R)-N-((R)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (700 mg, 2.26 mmol) and N,N-dimethyl- 1-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (589 mg, 2.26 mmol), Pd(PPh 3 ) 4 (261 mg, 0.226 mmol) and cesium carbonate (2.2 g, 6.78 mmol) were dissolved in 1,4-dioxane and water (5:1, 6 mL) under nitrogen and stirred at 110 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was purified by column chromatography to obtain (R)-N-((R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methyl Propane-2-sulfinamide (480 mg, 58%) was obtained as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.47-7.40 (m, 2H), 7.33-7.25 (m, 3H), 7.01 (d, J = 0.8 Hz, 1H), 7.00 (d, J = 0.8 Hz, 1H), 4.87-4.81 (m, 1H), 3.55 (d, J = 2.8 Hz, 1H), 3.44 (s, 2H), 2.22 (s, 6H), 1.64 (d, J = 6.4 Hz, 3H), 1.25 (s, 9H) 1 H NMR (400 MHz, CDCl 3 ) δ 7.47-7.40 (m, 2H), 7.33-7.25 (m, 3H), 7.01 (d, J = 0.8 Hz, 1H), 7.00 (d, J = 0.8 Hz, 1H), 4.87-4.81 (m, 1H), 3.55 (d, J = 2.8 Hz, 1H), 3.44 (s, 2H), 2.22 (s, 6H), 1.64 (d, J = 6.4 Hz, 3H), 1.25 (s, 9H)
단계 4step 4
Figure PCTKR2022021249-appb-img-000127
Figure PCTKR2022021249-appb-img-000127
(R)-1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에탄아민(R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethanamine
(R)-N-((R)-1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-2-메틸프로판-2-설핀아미드 (480 mg, 1.31 mmol)을 테트라히드로푸란 (4 mL) 에 녹인 후 3 N 염산 수용액 (1 mL) 을 첨가하였다. 실온에서 밤새 교반 한 후 반응용액에 1 N 염산을 첨가 후 디클로로메탄 으로 씻어주었다. 얻어진 물 층을 탄산 칼륨을 첨가하여 pH 14까지 염기화하고, 디클로로메탄 으로 3 번 추출하였다. 합친 유기층은 무수 황산나트륨으로 건조, 여과하여 감압 하에 농축 한 뒤 별도의 정제 없이 (R)-1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에탄아민 (290 mg, 85 %) 를 노란색 액체로 수득하였다.(R)-N-((R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (480 mg , 1.31 mmol) was dissolved in tetrahydrofuran (4 mL), and then 3 N aqueous hydrochloric acid solution (1 mL) was added. After stirring at room temperature overnight, 1 N hydrochloric acid was added to the reaction solution and then washed with dichloromethane. The obtained water layer was basified to pH 14 by adding potassium carbonate, and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then (R)-1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethanamine ( 290 mg, 85%) as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H) 7.33-7.05 (m, 3H), 7.05 (d, J = 3.6 Hz, 1H), 6.88 (dd, J = 3.6, 0.8 Hz, 1H), 4.38 (q, J = 7.5 Hz, 1H), 3.48 (s, 2H), 2.23 (s, 6H), 1.53 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H) 7.33-7.05 (m, 3H), 7.05 (d, J = 3.6 Hz, 1H), 6.88 (dd, J = 3.6, 0.8 Hz, 1H), 4.38 (q, J = 7.5 Hz, 1H), 3.48 (s, 2H), 2.23 (s, 6H), 1.53 (d, J = 6.8 Hz, 3H)
중간체 I-IIntermediates I-I
Figure PCTKR2022021249-appb-img-000128
Figure PCTKR2022021249-appb-img-000128
단계1step 1
Figure PCTKR2022021249-appb-img-000129
Figure PCTKR2022021249-appb-img-000129
에틸-2-(3-아세틸페닐)-2,2-디플루오로아세테이트Ethyl-2-(3-acetylphenyl)-2,2-difluoroacetate
디메틸설폭사이드 (20 ml) 중에 Cu (6.6 g, 101 mmol), 에틸 2-브로모-2,2-디플루오로아세테이트 (23 g, 101 mmol) 이 용해된 용액에 1-(3-요오도페닐)에타논 (10 g, 40 mmol) 을 첨가한 후, 70 ℃ 에서 2 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가한 뒤, 반응 혼합물을 셀라이트 패드를 통해 여과한 후 농축시켜 디에틸 에테르로 3 회 이상 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축 시킨 뒤, 잔류물을 컬럼 크로마토그래피로 정제하여 에틸-2-(3-아세틸페닐)-2,2-디플루오로아세테이트 (8.2 g, 76 %)을 무색 액체로서 수득하였다.To a solution of Cu (6.6 g, 101 mmol), ethyl 2-bromo-2,2-difluoroacetate (23 g, 101 mmol) in dimethyl sulfoxide (20 ml) was added 1-(3-iodo After adding phenyl)ethanone (10 g, 40 mmol), the mixture is stirred at 70°C for 2 hours. After confirming the completion of the reaction and adding water, the reaction mixture was filtered through a celite pad, concentrated, and extracted three or more times with diethyl ether. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give ethyl-2-(3-acetylphenyl)-2,2-difluoroacetate (8.2 g, 76 %) as a colorless liquid. was obtained as
1H NMR (400 MHz, DMSO-d 6) δ 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 2.64 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.20 (d, J = 7.6 Hz, 1H), 8.08 (s, 1H), 7.87 ( d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 2.64 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H)
단계2step 2
Figure PCTKR2022021249-appb-img-000130
Figure PCTKR2022021249-appb-img-000130
(R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)페닐)-2,2-디플루오로아세테이트(R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)phenyl)-2,2-difluoroacetate
테트라히드로푸란 (100 mL) 중에 에틸-2-(3-아세틸페닐)-2,2-디플루오로아세테이트 (7 g, 28.9 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (5.2 g, 43.3 mmol), Ti(OEt)4 (20 mL, 25.9 mmol) 을 첨가하고 상온에서 16 시간 동안 교반하였다. 물을 첨가하여 반응을 종결시키고, 물을 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 진공 농축한 후 잔류물을 컬럼 크로마토그래피로 정제하여 (R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)페닐)-2,2-디플루오로아세테이트 (5.2 g, 45 %) 를 황색 액체로 수득하였다.To a solution of ethyl-2-(3-acetylphenyl)-2,2-difluoroacetate (7 g, 28.9 mmol) in tetrahydrofuran (100 mL) at room temperature (R)-2-methylpropane- After adding 2-sulfinamide (5.2 g, 43.3 mmol) and Ti(OEt) 4 (20 mL, 25.9 mmol), the mixture was stirred at room temperature for 16 hours. The reaction was terminated by adding water, and the solid precipitated when water was added was filtered out and then extracted with ethyl acetate. After the combined organic extracts were concentrated in vacuo, the residue was purified by column chromatography to obtain (R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)phenyl)-2, 2-difluoroacetate (5.2 g, 45%) was obtained as a yellow liquid.
MS (ESI+) m/z 346 (M+H)+ MS (ESI+) m/z 346 (M+H) +
단계3step 3
Figure PCTKR2022021249-appb-img-000131
Figure PCTKR2022021249-appb-img-000131
(R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (50 ml) 중에 (R,E)-에틸 2-(3-(1-((tert-부틸술피닐)이미노)에틸)페닐)-2,2-디플루오로아세테이트 (5.1 g 14.78 mmol) 이 용해된 용액에 메탄올 (500 ml) 을 첨가한 뒤, 0 ℃ 에서 LiBH4 (1 g, 51.73 mmol) 을 첨가한 후 상온에서 0.5 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드 (2.7 g, 60 %)을 흰색 액체로서 수득하였다.(R,E)-ethyl 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)phenyl)-2,2-difluoroacetate (5.1 g in tetrahydrofuran (50 ml) After adding methanol (500 ml) to the solution in which 14.78 mmol) was dissolved, LiBH 4 (1 g, 51.73 mmol) was added at 0 °C, followed by stirring at room temperature for 0.5 hour. After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane- 2-sulfinamide (2.7 g, 60%) was obtained as a white liquid.
MS (ESI+) m/z 306 (M+H)+ MS (ESI+) m/z 306 (M+H) +
단계4step 4
Figure PCTKR2022021249-appb-img-000132
Figure PCTKR2022021249-appb-img-000132
(R)-2-(3-(1-아미노에틸)페닐)-2,2-디플루오로에탄올 염산염(R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethanol hydrochloride
디클로로메탄 (10 ml) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드 (1 g, 3.27 mmol) 이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (2 ml, 65.4 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 3 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-2-(3-(1-아미노에틸)페닐)-2,2-디플루오로에탄올 염산염 (700 g, 98 %)을 흰색 고체로서 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2- in dichloromethane (10 ml) A 4N hydrochloric acid solution (2 ml, 65.4 mmol) in 1,4-dioxane was added to the solution in which sulfinamide (1 g, 3.27 mmol) was dissolved at 0°C, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, it was concentrated to give (R)-2-(3-(1-aminoethyl)phenyl)-2,2-difluoroethanol hydrochloride (700 g, 98%) as a white solid.
MS (ESI+) m/z 202 (M+H)+ MS (ESI+) m/z 202 (M+H) +
중간체 I-JIntermediates I-J
Figure PCTKR2022021249-appb-img-000133
Figure PCTKR2022021249-appb-img-000133
단계1step 1
Figure PCTKR2022021249-appb-img-000134
Figure PCTKR2022021249-appb-img-000134
(R)-N-((R)-1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드(R)-N-((R)-1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (20 ml) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-히드록시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드 (500 mg, 1.63 mmol) 이 용해된 용액에 수소화나트륨 (37 mg, 1.63 mmol) 을 0 ℃ 에서 넣은 뒤 아이오도메탄 (0.3 ml, 2.45 mmol) 을 천천히 첨가한 후 상온에서 6 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드 (250 mg, 63 %)을 노란색 액체로 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)-2-methylpropane-2 in tetrahydrofuran (20 ml) -Sodium hydride (37 mg, 1.63 mmol) was added to the solution in which sulfinamide (500 mg, 1.63 mmol) was dissolved at 0 °C, iodomethane (0.3 ml, 2.45 mmol) was slowly added, and the mixture was stirred at room temperature for 6 hours. Stir. After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-N-((R)-1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethyl)-2-methylpropane- Obtained 2-sulfinamide (250 mg, 63%) as a yellow liquid.
MS (ESI+) m/z 320 (M+H)+ MS (ESI+) m/z 320 (M+H) +
단계2step 2
Figure PCTKR2022021249-appb-img-000135
Figure PCTKR2022021249-appb-img-000135
(R)-1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에탄아민 염산염(R)-1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethanamine hydrochloride
디클로로메탄 (2 ml) 중에 (R)-N-((R)-1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에틸)-2-메틸프로판-2-술핀아미드 (230 mg, 0.72 mmol) 이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (0.8 ml, 14.4 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에탄아민 염산염 (160 mg, 98 %)을 흰색 고체로서 수득하였다.(R)-N-((R)-1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethyl)-2-methylpropane-2- in dichloromethane (2 ml) A 4 N hydrochloric acid solution (0.8 ml, 14.4 mmol) in 1,4-dioxane was added to the solution in which sulfinamide (230 mg, 0.72 mmol) was dissolved at 0 °C, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was concentrated to give (R)-1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethanamine hydrochloride (160 mg, 98%) as a white solid.
MS (ESI+) m/z 216 (M+H)+ MS (ESI+) m/z 216 (M+H) +
중간체 I-KIntermediates I-K
Figure PCTKR2022021249-appb-img-000136
Figure PCTKR2022021249-appb-img-000136
단계1step 1
Figure PCTKR2022021249-appb-img-000137
Figure PCTKR2022021249-appb-img-000137
(R,E)-N-(1-(3-브로모-2-메틸페닐)에틸리덴)-2-메틸프로판-2-설핀아미드(R,E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (10 mL) 중에 1-(3-브로모-2-메틸페닐)에타논 (10 g, 46.9 mmol) 이 용해된 용액에 실온에서 (R)-2-메틸프로판-2-설핀아미드 (6 g, 56.2 mmol), Ti(OEt)4 (46 mL, 234 mmol), 2-메톡시에틸 에테르 (6 ml, 46.9 mol) 을 첨가하고 80 ℃에서 2시간 동안 교반하였다. 물을 첨가하여 반응을 종결시키고, 물을 첨가했을 때 석출된 고체를 필터하여 걸러낸 후 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 진공 농축한 후 잔류물을 컬럼 크로마토그래피로 정제하여 (R,E)-N-(1-(3-브로모-2-메틸페닐)에틸리덴)-2-메틸프로판-2-설핀아미드 (12.6 g, 85 %) 를 황색 액체로 수득하였다.(R)-2-methylpropane-2-sulfinamide (R)-2-methylpropane-2-sulfinamide ( 6 g, 56.2 mmol), Ti(OEt) 4 (46 mL, 234 mmol), 2-methoxyethyl ether (6 ml, 46.9 mol) were added and stirred at 80 °C for 2 h. The reaction was terminated by adding water, and the solid precipitated when water was added was filtered out and then extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo, and the residue was purified by column chromatography to obtain (R,E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfin. The amide (12.6 g, 85%) was obtained as a yellow liquid.
MS (ESI+) m/z 316, 318 (M+H)+ MS (ESI+) m/z 316, 318 (M+H) +
단계2step 2
Figure PCTKR2022021249-appb-img-000138
Figure PCTKR2022021249-appb-img-000138
(R)-N-((R)-1-(3-브로모-2-메틸페닐)에틸)-2-메틸프로판-2-설핀아미드(R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide
테트라히드로푸란 (50 ml) 중에 (R,E)-N-(1-(3-브로모-2-메틸페닐)에틸리덴)-2-메틸프로판-2-설핀아미드 (5 g, 15.8 mmol) 이 용해된 용액에 메탄올 (0.5 ml) 을 첨가한 뒤, 0 ℃ 에서 LiBH4 (1 g, 47.4 mmol) 을 첨가한 후 상온에서 0.5 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-N-((R)-1-(3-브로모-2-메틸페닐)에틸)-2-메틸프로판-2-설핀아미드 (3 g, 60 %) 를 흰색 액체로서 수득하였다.(R,E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (5 g, 15.8 mmol) in tetrahydrofuran (50 ml) After adding methanol (0.5 ml) to the dissolved solution, LiBH 4 (1 g, 47.4 mmol) was added at 0 °C and stirred at room temperature for 0.5 hour. After confirming the completion of the reaction, water was added and extraction was performed with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to obtain (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (3 g, 60% ) was obtained as a white liquid.
MS (ESI+) m/z 318, 320 (M+H)+ MS (ESI+) m/z 318, 320 (M+H) +
단계3step 3
Figure PCTKR2022021249-appb-img-000139
Figure PCTKR2022021249-appb-img-000139
(R)-1-(3-브로모-2-메틸페닐)에탄아민 염산염(R)-1-(3-bromo-2-methylphenyl)ethanamine hydrochloride
메탄올 (7 ml) 중에 [S(R)]-N-[(1R)-1-(3-브로모-2-메틸페닐)에틸]-2-메틸-2-프로판설핀아미드 (2.5 g, 7.8 mmol) 이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (7 ml, 196.5 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 0.5 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-1-(3-브로모-2-메틸페닐)에탄아민 염산염 (2.0 g, 98 %)을 흰색 고체로서 수득하였다.[S(R)]-N-[(1R)-1-(3-bromo-2-methylphenyl)ethyl]-2-methyl-2-propanesulfinamide (2.5 g, 7.8 mmol in methanol (7 ml) ) was added with 4 N hydrochloric acid solution (7 ml, 196.5 mmol) in 1,4-dioxane to the dissolved solution at 0° C. and stirred at room temperature for 0.5 hour. After completion of the reaction, it was concentrated to give (R)-1-(3-bromo-2-methylphenyl)ethanamine hydrochloride (2.0 g, 98%) as a white solid.
MS (ESI+) m/z 214, 216 (M+H)+ MS (ESI+) m/z 214, 216 (M+H) +
중간체 I-LIntermediates I-L
Figure PCTKR2022021249-appb-img-000140
Figure PCTKR2022021249-appb-img-000140
단계 1Step 1
Figure PCTKR2022021249-appb-img-000141
Figure PCTKR2022021249-appb-img-000141
2-클로로-6-메톡시니코틴산2-chloro-6-methoxynicotinic acid
메탄올 (208 mL) 중에 2,6-디클로로니코틴산 (10 g, 52.0 mmol) 이 용해된 용액에 칼륨 터트-부톡사이드 (29 g, 260.0 mmol) 을 첨가한 후 환류 하에 18 시간 동안 교반하였다. 반응 종결을 확인하고 증류수로 묽힌 후 산성화를 진행한 후 여과한다. 여과 후 얻은 고체에 증류수를 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조 후 농축하여 2-클로로-6-메톡시니코틴산 (8.8 g, 91 %)을 수득하였다.After adding potassium tert-butoxide (29 g, 260.0 mmol) to a solution of 2,6-dichloronicotinic acid (10 g, 52.0 mmol) in methanol (208 mL), the mixture was stirred under reflux for 18 hours. After confirming the completion of the reaction, diluted with distilled water, acidified, and then filtered. Distilled water was added to the solid obtained after filtration, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give 2-chloro-6-methoxynicotinic acid (8.8 g, 91%).
단계 2Step 2
Figure PCTKR2022021249-appb-img-000142
Figure PCTKR2022021249-appb-img-000142
메틸 2-클로로-6-메톡시니코티네이트Methyl 2-chloro-6-methoxynicotinate
메탄올 (236 mL) 중에 2-클로로-6-메톡시니코틴산 (8.8 g, 47.1 mmol) 이 용해된 용액에 황산 (10.6 mL, 198.0 mmol) 을 첨가한 후 60 ℃ 에서 17 시간 동안 교반하였다. 반응 용액을 감압 농축한 뒤 증류수로 묽힌 후 탄산수소나트륨 포화 용액을 첨가하여 중화시킨다. 혼합액을 에틸 아세테이트로 추출하고, 합쳐진 유기 추출물을 황산나트륨 상에서 건조 후 농축하여 메틸 2-클로로-6-메톡시니코티네이트 (9.2 g, 97 %)를 수득하였다.After adding sulfuric acid (10.6 mL, 198.0 mmol) to a solution of 2-chloro-6-methoxynicotinic acid (8.8 g, 47.1 mmol) in methanol (236 mL), the mixture was stirred at 60 °C for 17 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water, and then neutralized by adding a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over sodium sulfate and concentrated to give methyl 2-chloro-6-methoxynicotinate (9.2 g, 97%).
단계 3Step 3
Figure PCTKR2022021249-appb-img-000143
Figure PCTKR2022021249-appb-img-000143
메틸 6-메톡시-2-((4-메톡시벤질)아미노)니코티네이트Methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate
디메틸포름아미드 (62 mL) 중에 메틸 2-클로로-6-메톡시니코티네이트 (9.2 g, 45.6 mmol) 이 용해된 용액을 0 ℃ 로 냉각한 후 4-메톡시벤질아민 (7.1 mL, 54.8 mmol) 과 탄산칼륨 (9.4 g, 68.4 mmol) 을 첨가한다. 이 후 120 ℃ 에서 16 시간 동안 교반하였다. 반응 종결 후 증류수를 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조 후 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 메틸 6-메톡시-2-((4-메톡시벤질)아미노)니코티네이트 (9 g, 66 %)를 수득하였다. After cooling a solution of methyl 2-chloro-6-methoxynicotinate (9.2 g, 45.6 mmol) in dimethylformamide (62 mL) to 0 ° C, 4-methoxybenzylamine (7.1 mL, 54.8 mmol) ) and potassium carbonate (9.4 g, 68.4 mmol) are added. Thereafter, the mixture was stirred at 120° C. for 16 hours. After completion of the reaction, distilled water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated. The residue was purified by column chromatography to give methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate (9 g, 66%).
단계 4step 4
Figure PCTKR2022021249-appb-img-000144
Figure PCTKR2022021249-appb-img-000144
메틸 2-아미노-6-메톡시니코티네이트Methyl 2-amino-6-methoxynicotinate
에탄올 (100 mL) 중에 메틸 6-메톡시-2-((4-메톡시벤질)아미노)니코티네이트 (9 g, 29.9 mmol) 이 용해된 용액에 10 % Pd/c (955 mg, 8.9 mmol) 을 첨가한 후 반응 용기에 수소 가스를 충전하여 1 기압에서 22 시간 동안 교반하였다. 반응 종결 후 혼합물을 셀라이트 패드를 통해 여과하고 농축시켜 메틸 2-아미노-6-메톡시니코티네이트 (9 g, 55 %)를 수득하였다. 10% Pd/c (955 mg, 8.9 mmol) in a solution of methyl 6-methoxy-2-((4-methoxybenzyl)amino)nicotinate (9 g, 29.9 mmol) in ethanol (100 mL) ) was added, and the reaction vessel was filled with hydrogen gas and stirred at 1 atm for 22 hours. After completion of the reaction, the mixture was filtered through a celite pad and concentrated to obtain methyl 2-amino-6-methoxynicotinate (9 g, 55%).
단계 5step 5
Figure PCTKR2022021249-appb-img-000145
Figure PCTKR2022021249-appb-img-000145
메틸 2-아미노-5-브로모-6-메톡시니코티네이트Methyl 2-amino-5-bromo-6-methoxynicotinate
아세트산 (165 mL) 중에 메틸 2-아미노-6-메톡시니코티네이트 (9 g, 49.4 mmol) 이 용해된 용액에 N-브로모숙신이미드 (10.6 g, 59.3 mmol) 을 첨가한 후 상온에서 24 시간 동안 교반하였다. 반응 종결 후 증류수를 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조 후 농축시켜 메틸 2-아미노-5-브로모-6-메톡시니코티네이트 (10.9 g, 85 %)을 수득하였다.After adding N-bromosuccinimide (10.6 g, 59.3 mmol) to a solution of methyl 2-amino-6-methoxynicotinate (9 g, 49.4 mmol) in acetic acid (165 mL), the mixture was stirred at room temperature. Stir for 24 hours. After completion of the reaction, distilled water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give methyl 2-amino-5-bromo-6-methoxynicotinate (10.9 g, 85%).
단계 6Step 6
Figure PCTKR2022021249-appb-img-000146
Figure PCTKR2022021249-appb-img-000146
메틸 5-브로모-2-요오도-6-메톡시니코티네이트Methyl 5-bromo-2-iodo-6-methoxynicotinate
요오드화메틸렌 (9.6 mL) 중에 메틸 2-아미노-5-브로모-6-메톡시니코티네이트 (1 g, 3.8 mmol) 이 용해된 용액에 tert-부틸 아질산염 (0.68 mL, 5.7 mmol) 과 요오드 (972 mg, 3.8 mmol) 을 첨가한 후 상온에서 24 시간 동안 교반하였다. 이 후 tert-부틸 아질산염 (0.45 mL, 3.8 mmol) 을 추가로 적가한 뒤 3일 동안 추가 교반하였다. 반응 종결 후 증류수를 첨가하여 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조 후 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 메틸 5-브로모-2-요오도-6-메톡시니코티네이트 (520 mg, 37 %) 을 황색 고체로 수득하였다. tert-butyl nitrite (0.68 mL, 5.7 mmol) and iodine ( 972 mg, 3.8 mmol) was added and stirred at room temperature for 24 hours. Thereafter, tert-butyl nitrite (0.45 mL, 3.8 mmol) was additionally added dropwise, followed by additional stirring for 3 days. After completion of the reaction, distilled water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated. The residue was purified by column chromatography to give methyl 5-bromo-2-iodo-6-methoxynicotinate (520 mg, 37%) as a yellow solid.
단계 7step 7
Figure PCTKR2022021249-appb-img-000147
Figure PCTKR2022021249-appb-img-000147
메틸 2-아세틸-5-브로모-6-메톡시니코티네이트Methyl 2-acetyl-5-bromo-6-methoxynicotinate
무수 1,4-디옥산 (3.5 mL) 중 메틸 5-브로모-2-요오도-6-메톡시니코티네이트 (518 mg, 1.4 mmol) 의 용액에 트리부틸(1-에톡시비닐)틴 (0.47 mL, 1.4 mmol), PdCl2(PPh3)2 (39 mg, 0.056 mmol) 을 첨가하고, 혼합물을 질소 환경에서 85 ℃ 로 가열하여 17 시간 동안 교반하였다. 실온으로 냉각시킨 후, 증류수를 첨가하여 반응을 종결하고 에틸 아세테이트로 추출하였다. 합쳐진 유기 혼합물을 황산나트륨 상에서 건조 후 여과하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 메틸 2-아세틸-5-브로모-6-메톡시니코티네이트 (296 mg, 67 %)을 갈색 고체로 수득하였다. To a solution of methyl 5-bromo-2-iodo-6-methoxynicotinate (518 mg, 1.4 mmol) in anhydrous 1,4-dioxane (3.5 mL) was added tributyl(1-ethoxyvinyl)tin (0.47 mL, 1.4 mmol), PdCl 2 (PPh 3 ) 2 (39 mg, 0.056 mmol) were added and the mixture was heated to 85 °C in a nitrogen environment and stirred for 17 hours. After cooling to room temperature, distilled water was added to terminate the reaction and extraction was performed with ethyl acetate. The combined organic mixture was dried over sodium sulfate and then filtered. The residue was purified by column chromatography to give methyl 2-acetyl-5-bromo-6-methoxynicotinate (296 mg, 67%) as a brown solid.
MS (ESI+) m/z 287, 289 (M+H)+ MS (ESI+) m/z 287, 289 (M+H) +
단계 8step 8
Figure PCTKR2022021249-appb-img-000148
Figure PCTKR2022021249-appb-img-000148
3-브로모-2-메톡시-8-메틸피리도[2,3-d]피리다진-5(6H)-온3-Bromo-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5(6H)-one
에탄올 (3.3 mL) 중 메틸 2-아세틸-5-브로모-6-메톡시니코티네이트 (284 mg, 0.99 mmol)의 용액에 히드라진 수화물 (0.14 mL, 2.9 mmol)을 첨가하였다. 반응 혼합물을 90 ℃ 에서 30 분 동안 교반하고, 실온으로 냉각 후 여과하여 3-브로모-2-메톡시-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (227 mg, 85 %) 를 흰색 고체로 수득하였다.To a solution of methyl 2-acetyl-5-bromo-6-methoxynicotinate (284 mg, 0.99 mmol) in ethanol (3.3 mL) was added hydrazine hydrate (0.14 mL, 2.9 mmol). The reaction mixture was stirred at 90 °C for 30 minutes, cooled to room temperature and filtered to obtain 3-bromo-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5(6H)-one ( 227 mg, 85%) as a white solid.
MS (ESI+) m/z 269, 271 (M+H)+ MS (ESI+) m/z 269, 271 (M+H) +
단계 9Step 9
Figure PCTKR2022021249-appb-img-000149
Figure PCTKR2022021249-appb-img-000149
3-브로모-5-클로로-2-메톡시-8-메틸피리도[2,3-d]피리다진3-Bromo-5-chloro-2-methoxy-8-methylpyrido[2,3-d]pyridazine
3-브로모-2-메톡시-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (7 mg, 0.026 mmol) 에 옥시염화인 (24 μL, 0.26 mmol) 을 첨가하고 80 ℃ 에서 1 시간 동안 가열 교반한다. 반응 용액을 감압 농축하고, 디클로로메탄을 첨가하여 묽힌 후 0 ℃ 로 냉각시킨다. 이 후 탄산수소나트륨 포화용액을 첨가하여 중화시킨 후 혼합액을 디클로로메탄으로 추출한다. 합쳐진 유기 혼합물을 황산나트륨 상에서 건조 후, 여과 및 농축 하여 3-브로모-5-클로로-2-메톡시-8-메틸피리도[2,3-d]피리다진 (6 mg, 75 %)을 황색 고체로 수득하였다.Phosphorus oxychloride (24 μL, 0.26 mmol) was added to 3-bromo-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (7 mg, 0.026 mmol). It was added and heated and stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, and then cooled to 0°C. Thereafter, a saturated solution of sodium hydrogen carbonate is added to neutralize the mixture, and the mixed solution is extracted with dichloromethane. The combined organic mixture was dried over sodium sulfate, filtered and concentrated to obtain 3-bromo-5-chloro-2-methoxy-8-methylpyrido[2,3-d]pyridazine (6 mg, 75%) as yellow Obtained as a solid.
MS (ESI+) m/z 287 (M+H)+ MS (ESI+) m/z 287 (M+H) +
합성법 및 실시예Synthesis and Examples
합성법 Asynthesis method A
Figure PCTKR2022021249-appb-img-000150
Figure PCTKR2022021249-appb-img-000150
화합물 A-3 의 일반적인 합성은 합성법 A 에 예시되어 있다. 중간체 I-A 을 부흐발트-하트위그 아민화 반응을 사용해 아민으로 치환된 화합물 A-1 을 합성하고, 옥시염화인 을 사용한 염소화 반응을 진행하여 화합물 A-2 을 합성한다. 화합물 A-2 을 중간체 I-C ~ I-H 또는 상업적으로 구매 가능한 시약 중 선택하여 친핵성 방향족 치환 반응으로 최종 화합물 A-3 을 합성한다.The general synthesis of compound A-3 is exemplified in synthesis method A. Compound A-1 in which intermediate I-A is substituted with an amine is synthesized by Buchwald-Hartwig amination, and compound A-2 is synthesized by chlorination using phosphorus oxychloride. Compound A-2 is selected from intermediates I-C to I-H or commercially available reagents to synthesize final compound A-3 through a nucleophilic aromatic substitution reaction.
실시예 1 Example 1
Figure PCTKR2022021249-appb-img-000151
Figure PCTKR2022021249-appb-img-000151
(R)-8-메틸-3-모르폴리노-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-8-methyl-3-morpholino-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyridazin-5-amine
단계 1Step 1
Figure PCTKR2022021249-appb-img-000152
Figure PCTKR2022021249-appb-img-000152
8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5(6H)-온8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5(6H)-one
무수 1,4-디옥산 (3 ml) 중 3-클로로-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (80 mg, 0.41 mmol) 의 용액에 모르폴린 (70 μl, 0.82 mmol), Pd2(dba)3 (37 mg, 0.041 mmol), Ruphos (38 mg, 0.082 mmol), 테트라히드로푸란 중 1 N KOtBu 용액 (1.23 ml, 1.23 mmol) 을 추가하고 100 ℃에서 2 시간 동안 가열 교반한다. 반응 혼합물을 실온으로 냉각 후 증류수로 반응을 종결하고 디클로로메탄 : 이소프로필알콜 (3:1) 혼합액으로 3 회 추출하였다. 유기 추출액을 황산마그네슘 상에서 건조시킨 후, 여과 및 농축 하였다. 농축 혼합물에 에틸 아세테이트 (5 ml) 를 첨가하여 10 분 교반 뒤 여과 하여, 8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5(6H)-온 (58 mg, 58 %) 를 황색 고체로서 수득하였다.To a solution of 3-chloro-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (80 mg, 0.41 mmol) in anhydrous 1,4-dioxane (3 ml) 70 μl, 0.82 mmol), Pd 2 (dba) 3 (37 mg, 0.041 mmol), Ruphos (38 mg, 0.082 mmol), 1 N KOtBu solution in tetrahydrofuran (1.23 ml, 1.23 mmol) were added and heated to 100 °C. Heat and stir for 2 hours. After cooling the reaction mixture to room temperature, the reaction was terminated with distilled water and extracted three times with a mixture of dichloromethane and isopropyl alcohol (3:1). The organic extract was dried over magnesium sulfate, then filtered and concentrated. Ethyl acetate (5 ml) was added to the concentrated mixture, stirred for 10 minutes, filtered, and 8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5(6H)-one (58 mg, 58%) was obtained as a yellow solid.
MS (ESI+) m/z 247 (M+H)+ MS (ESI+) m/z 247 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000153
Figure PCTKR2022021249-appb-img-000153
4-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)모르폴린4-(5-chloro-8-methylpyrido[2,3-d]pyridazin-3-yl)morpholine
8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5(6H)-온 (10 mg, 0.16 mmol) 에 옥시염화인 (302 μl, 3.24 mmol) 을 첨가하고 110 ℃에서 3 시간 동안 가열 교반한다. 반응 용액을 감압 농축하고, 잔류물에 증류수를 첨가하여 0 ℃ 로 냉각 후, 탄산 수소 나트륨을 첨가하여 중화시킨다. 혼합액을 에틸 아세테이트로 3 회 추출 하고, 유기층을 염화나트륨 포화용액으로 1 회 씻어 주었다. 유기 추출액을 황산마그네슘 상에서 건조시킨 후, 여과 및 농축 하여 4-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)모르폴린 (43 mg, 정량) 를 고체로 수득하였다.Phosphorus oxychloride (302 μl, 3.24 mmol) was added to 8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5(6H)-one (10 mg, 0.16 mmol) and heated to 110 °C. Heat and stir for 3 hours. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and after cooling to 0 deg. C, sodium hydrogen carbonate was added to neutralize it. The mixture was extracted three times with ethyl acetate, and the organic layer was washed once with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered and concentrated to obtain 4-(5-chloro-8-methylpyrido[2,3-d]pyridazin-3-yl)morpholine (43 mg, quant.) as a solid was obtained with
MS (ESI+) m/z 265 (M+H)+ MS (ESI+) m/z 265 (M+H) +
단계 3Step 3
Figure PCTKR2022021249-appb-img-000154
Figure PCTKR2022021249-appb-img-000154
(R)-8-메틸-3-모르폴리노-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-8-methyl-3-morpholino-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyridazin-5-amine
디메틸설폭사이드 (2.5 ml) 중 4-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)모르폴린 (43 mg, 0.16 mmol) 의 용액에 (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 (31 μl, 0.19 mmol), 세슘 플루오라이드 (73 mg, 0.48 mmol), 디이소프로필에틸아민 (140 μl, 0.80 mmol) 을 첨가하고 120 ℃ 에서 16 시간 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 탄산 수소 나트륨 포화용액을 첨가하고 디클로로메탄 : 이소프로필알콜 (3:1) 혼합액으로 3 회 추출하였다. 추출 용액을 황산마그네슘 상에서 건조시킨 후 여과 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-8-메틸-3-모르폴리노-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민 (25 mg, 34 %) 노란색 고체로서 수득하였다.To a solution of 4-(5-chloro-8-methylpyrido[2,3-d]pyridazin-3-yl)morpholine (43 mg, 0.16 mmol) in dimethylsulfoxide (2.5 ml) (R)- 1-(3-(trifluoromethyl)phenyl)ethanamine (31 μl, 0.19 mmol), cesium fluoride (73 mg, 0.48 mmol), diisopropylethylamine (140 μl, 0.80 mmol) were added and 120 μl Heat and stir at °C for 16 hours. After cooling the reactant to room temperature, a saturated sodium hydrogen carbonate solution was added and extracted three times with a mixture of dichloromethane and isopropyl alcohol (3:1). The extract solution was dried over magnesium sulfate, then filtered and concentrated. The residue was purified by column chromatography to give (R)-8-methyl-3-morpholino-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]. Pyridazin-5-amine (25 mg, 34%) Obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.04 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.58-7.51 (m, 3H), 5.52 (q, J = 6.8 Hz, 1H), 3.88-3.80 (m, 4H), 3.51-3.43 (m, 4H), 2.59 (s, 3H), 1.60 (d, J = 6.8Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.04 (s, 1H) , 7.95 (s, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.58-7.51 ( m, 3H), 5.52 (q, J = 6.8 Hz, 1H), 3.88–3.80 (m, 4H), 3.51–3.43 (m, 4H), 2.59 (s, 3H), 1.60 (d, J = 6.8 Hz) , 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 2 Example 2
Figure PCTKR2022021249-appb-img-000155
Figure PCTKR2022021249-appb-img-000155
(R)-8-메틸-3-(4-메틸피페라진-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-8-methyl-3-(4-methylpiperazin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyridox minced-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 1-메틸피페라진 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물 (30 mg, 33 %)을 수득하였다.After synthesis of compound A-2 using intermediate I-A and 1-methylpiperazine as described in Example 1, (R)-1-(3-(trifluoromethyl)phenyl)ethanamine was used to obtain the title compound ( 30 mg, 33%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 2H), 7.60-7.45 (m, 3H), 5.57-5.45 (m, 1H), 3.49 (br s, 4H), 2.58 (s, 3H), 2.53 (br s, 4H), 2.27 (s, 3H), 1.60 (d, J = 4.0 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 2H), 7.60-7.45 (m, 3H), 5.57-5.45 (m , 1H), 3.49 (br s, 4H), 2.58 (s, 3H), 2.53 (br s, 4H), 2.27 (s, 3H), 1.60 (d, J = 4.0 Hz, 3H)
MS (ESI+) m/z 431 (M+H)+ MS (ESI+) m/z 431 (M+H) +
실시예 3 Example 3
Figure PCTKR2022021249-appb-img-000156
Figure PCTKR2022021249-appb-img-000156
(R)-3-(4-에틸피페라진-1-일)-8-메틸-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-3-(4-ethylpiperazin-1-yl)-8-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyridox minced-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 1-에틸피페라진 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물(16 mg, 17 %)을 수득하였다.After synthesis of compound A-2 using intermediate I-A and 1-ethylpiperazine as described in Example 1, (R)-1-(3-(trifluoromethyl)phenyl)ethanamine was used to obtain the title compound ( 16 mg, 17%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.76-7.71 (m, 2H), 7.58-7.48 (m, 3H), 5.56-5.49 (m, 1H), 3.51-3.38 (m, 4H), 2.60-2.56 (m, 6H), 2.42 (q, J = 7.2 Hz, 2H), 1.61 (d, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.76-7.71 (m, 2H), 7.58-7.48 ( m, 3H), 5.56-5.49 (m, 1H), 3.51-3.38 (m, 4H), 2.60-2.56 (m, 6H), 2.42 (q, J = 7.2 Hz, 2H), 1.61 (d, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H)
MS (ESI+) m/z 445 (M+H)+ MS (ESI+) m/z 445 (M+H) +
실시예 4 Example 4
Figure PCTKR2022021249-appb-img-000157
Figure PCTKR2022021249-appb-img-000157
(R)-8-메틸-3-(4-(메틸아미노)피페리딘-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-8-methyl-3-(4-(methylamino)piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3 -d] pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 tert-부틸 N-메틸-N-(피페리딘-4-일)카바메이트 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물 (7 mg, 14 %)을 수득하였다.Synthesis of compound A-2 using intermediate I-A and tert-butyl N-methyl-N-(piperidin-4-yl)carbamate as described in Example 1 followed by (R)-1-(3-( Trifluoromethyl)phenyl)ethanamine gave the title compound (7 mg, 14%).
1H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.78-7.70 (m, 2H), 7.52-7.45 (m, 2H), 5.53 (q, J = 7.2 Hz, 1H), 4.02-4.08 (m, 1H), 3.90-3.82 (m, 1H), 3.39-3.21 (m, 1H), 3.16-3.09 (m, 1H), 3.97-3.88 (m, 1H), 2.70 (s, 3H), 2.59 (s, 3H), 2.19-2.10 (m, 1H), 2.02-2.93 (m, 1H), 1.87-1.72 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H), 1.63-1.52 (m, 1H) 1H NMR (400 MHz, CD 3 OD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.78-7.70 (m, 2H), 7.52-7.45 (m , 2H), 5.53 (q, J = 7.2 Hz, 1H), 4.02–4.08 (m, 1H), 3.90–3.82 (m, 1H), 3.39–3.21 (m, 1H), 3.16–3.09 (m, 1H) ), 3.97-3.88 (m, 1H), 2.70 (s, 3H), 2.59 (s, 3H), 2.19-2.10 (m, 1H), 2.02-2.93 (m, 1H), 1.87-1.72 (m, 1H) ), 1.71 (d, J = 6.8 Hz, 3H), 1.63–1.52 (m, 1H)
MS (ESI+) m/z 445 (M+H)+ MS (ESI+) m/z 445 (M+H) +
실시예 5 Example 5
Figure PCTKR2022021249-appb-img-000158
Figure PCTKR2022021249-appb-img-000158
(R)-8-메틸-3-(4-(2,2,2-트리플루오로에틸)피페라진-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-8-methyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl )pyrido[2,3-d]pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 1-(2,2,2-트리플루오로에틸)피페라진 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물 (18 mg, 17 %)을 수득하였다.After synthesis of compound A-2 using intermediate I-A and 1-(2,2,2-trifluoroethyl)piperazine as described in Example 1, (R)-1-(3-(trifluoromethyl) )phenyl)ethanamine gave the title compound (18 mg, 17%).
1H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.67-7,60 (m, 2H), 7.47-7.39 (m, 2H), 5.22 (q, J = 7.2 Hz, 1H), 3.72-3.65 (m, 4H), 3.11 (q, J = 10 Hz, 2H), 2.86-2.80 (m, 4H), 1.62 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, CD 3 OD) δ 9.02 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.67-7,60 (m, 2H), 7.47-7.39 (m, 2H), 5.22 (q, J = 7.2 Hz, 1H), 3.72–3.65 (m, 4H), 3.11 (q, J = 10 Hz, 2H), 2.86–2.80 (m, 4H), 1.62 ( d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 499 (M+H)+ MS (ESI+) m/z 499 (M+H) +
실시예 6 Example 6
Figure PCTKR2022021249-appb-img-000159
Figure PCTKR2022021249-appb-img-000159
(R)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-3-(4-(dimethylamino)piperidin-1-yl)-8-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3 -d] pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 4-(디메틸아미노)피페리딘 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물 (20 mg, 23 %)을 수득하였다.Synthesis of compound A-2 using intermediate I-A and 4-(dimethylamino)piperidine as described in Example 1 followed by (R)-1-(3-(trifluoromethyl)phenyl)ethanamine to give the title compound (20 mg, 23%).
1H NMR (400 MHz, CD3OD) δ 8.98 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.75-6.67 (m, 2H), 7.51-7.42 (m, 2H), 5.48 (q, J = 7.2 Hz, 1H), 4.32 (d, J = 12.8, 2H), 3.17-2.95 (m, 3H), 2.69 (s, 1H), 2.64 (s, 6H), 2.22-2.12 (m, 2H), 1.84-1.70 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, CD 3 OD) δ 8.98 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.75-6.67 (m, 2H), 7.51-7.42 (m , 2H), 5.48 (q, J = 7.2 Hz, 1H), 4.32 (d, J = 12.8, 2H), 3.17–2.95 (m, 3H), 2.69 (s, 1H), 2.64 (s, 6H), 2.22-2.12 (m, 2H), 1.84-1.70 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 459 (M+H)+ MS (ESI+) m/z 459 (M+H) +
실시예 7 Example 7
Figure PCTKR2022021249-appb-img-000160
Figure PCTKR2022021249-appb-img-000160
3-((S)-3-메톡시피롤리딘-1-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민3-((S)-3-methoxypyrrolidin-1-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2, 3-d] pyridazin-5-amine
단계 1Step 1
Figure PCTKR2022021249-appb-img-000161
Figure PCTKR2022021249-appb-img-000161
(S)-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5(6H)-온(S)-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5(6H)-one
테트라히드로푸란 (9 ml) 중 중간체 I-A (300 mg, 1.53 mmol) 의 용액에 Pd2(dba)3 (140 mg, 0.15 mmol), XPhos (146 mg, 0.31 mmol), 테트라히드로푸란 중 1 M LiHMDS (8 ml) 와 (S)-3-메톡시피롤리딘 염산염 (422 mg, 3.07 mmol) 의 용해액, 테트라히드로푸란 중 1 M LiHMDS (4.2 ml) 을 첨가하고 마이크로파 반응기를 사용하여 80 ℃ 에서 30 분 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 물을 첨가하고 디클로로메탄으로 3 회 추출하였다. 추출 용액을 황산마그네슘 상에서 건조시킨 후 여과 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 (S)-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (278 mg, 69 %)을 수득하였다.To a solution of intermediate IA (300 mg, 1.53 mmol) in tetrahydrofuran (9 ml) was added Pd 2 (dba) 3 (140 mg, 0.15 mmol), XPhos (146 mg, 0.31 mmol), 1 M LiHMDS in tetrahydrofuran. (8 ml) with (S)-3-methoxypyrrolidine hydrochloride (422 mg, 3.07 mmol), 1 M LiHMDS in tetrahydrofuran (4.2 ml) was added and heated at 80 °C for 30 °C using a microwave reactor. Heat and stir for a minute. After cooling the reaction to room temperature, water was added and extracted three times with dichloromethane. The extract solution was dried over magnesium sulfate, then filtered and concentrated. The residue was purified by column chromatography to (S)-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5(6H)-one ( 278 mg, 69%).
1H NMR (400 MHz, DMSO-d 6) δ 12.29 (s, 1H), 8.57 (d, J = 3.2 Hz, 1H), 7.29 (d, J = 3.2 Hz, 1H), 4.16 (m, 1H), 3.61-3.44 (m, 4H), 3.29 (s, 3H), 2.47 (s, 3H), 2.15-2.09 (m, 2H) 1H NMR (400 MHz, DMSO- d6 ) δ 12.29 (s, 1H), 8.57 (d, J = 3.2 Hz, 1H), 7.29 (d, J = 3.2 Hz, 1H), 4.16 (m, 1H) , 3.61-3.44 (m, 4H), 3.29 (s, 3H), 2.47 (s, 3H), 2.15-2.09 (m, 2H)
MS (ESI+) m/z 261 (M+H)+ MS (ESI+) m/z 261 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000162
Figure PCTKR2022021249-appb-img-000162
(S)-5-클로로-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진(S)-5-chloro-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyridazine
(S)-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5(6H)-온 (270 mg, 1.04 mmol) 에 옥시염화인 (1.0 ml, 10.37 mmol) 을 첨가하고 100 ℃에서 0.5 시간 동안 가열 교반한다. 반응 용액을 감압 농축하고, 잔류물에 증류수를 첨가하여 0 ℃ 로 냉각 후, 탄산 수소 나트륨을 첨가하여 중화시킨다. 혼합액을 디클로로메탄 으로 3 회 추출 하고, 유기층을 염화나트륨 포화용액으로 1 회 씻어 주었다. 유기 추출액을 황산마그네슘 상에서 건조시킨 후, 여과 및 농축 하여 (S)-5-클로로-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진 (307 mg, 정량)을 수득하였다.Oxychloride to (S)-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5(6H)-one (270 mg, 1.04 mmol) Phosphorus (1.0 ml, 10.37 mmol) is added and heated and stirred at 100° C. for 0.5 hour. The reaction solution was concentrated under reduced pressure, distilled water was added to the residue, and after cooling to 0 deg. C, sodium hydrogen carbonate was added to neutralize it. The mixture was extracted three times with dichloromethane, and the organic layer was washed once with a saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered and concentrated to give (S)-5-chloro-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyrido Mince (307 mg, quant.) was obtained.
MS (ESI+) m/z 279 (M+H)+ MS (ESI+) m/z 279 (M+H) +
단계 3Step 3
Figure PCTKR2022021249-appb-img-000163
Figure PCTKR2022021249-appb-img-000163
3-((S)-3-메톡시피롤리딘-1-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민3-((S)-3-methoxypyrrolidin-1-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2, 3-d] pyridazin-5-amine
디이소프로필에틸아민 (0.7 ml) 중 (S)-5-클로로-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진 (70 mg, 0.25 mmol) 의 용액에 (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 (48 μl, 0.30 mmol) 을 첨가하고 150 ℃ 에서 16 시간 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 1 N 염산 수용액을 첨가하고 디클로로메탄으로 3 회 추출하였다. 추출 용액을 황산마그네슘 상에서 건조시킨 후 여과 및 농축하였다. 잔류물을 컬럼 크로마토그래피로 정제하여 3-((S)-3-메톡시피롤리딘-1-일)-8-메틸-N-((R)-1-(3-트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민 (2.6 mg, 2 %)을 수득하였다.(S)-5-chloro-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2,3-d]pyridazine (70 mg) in diisopropylethylamine (0.7 ml) , 0.25 mmol) was added with (R)-1-(3-(trifluoromethyl)phenyl)ethanamine (48 μl, 0.30 mmol) and heated and stirred at 150° C. for 16 hours. After cooling the reaction product to room temperature, 1 N hydrochloric acid aqueous solution was added and extracted with dichloromethane 3 times. The extract solution was dried over magnesium sulfate, then filtered and concentrated. The residue was purified by column chromatography to obtain 3-((S)-3-methoxypyrrolidin-1-yl)-8-methyl-N-((R)-1-(3-trifluoromethyl)phenyl )ethyl)pyrido[2,3-d]pyridazin-5-amine (2.6 mg, 2%).
1H NMR (400 MHz, DMSO-d 6) δ 8.65 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.53 (m, 3H), 7.38 (d, J = 6.8 Hz, 1H), 5.52 (t, J = 7.2 Hz, 1H), 4.20 (m, 1H), 3.61-3.41 (m, 4H), 2.57 (s, 3H), 2.17 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.65 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.53 (m, 3H) , 7.38 (d, J = 6.8 Hz, 1H), 5.52 (t, J = 7.2 Hz, 1H), 4.20 (m, 1H), 3.61–3.41 (m, 4H), 2.57 (s, 3H), 2.17 ( m, 2H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 8 Example 8
Figure PCTKR2022021249-appb-img-000164
Figure PCTKR2022021249-appb-img-000164
N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-3-((S)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-3-((S)-3-methoxypyrrolidin-1-yl)-8-methylpyrido[2, 3-d] pyridazin-5-amine
실시예 7 에 기재된 바와 같이 중간체 I-A 와 (R)-1-(3-(디플루오로메틸)페닐)에탄아민 을 사용하여 표제 화합물 (13 mg, 11 %)을 수득하였다.Intermediate I-A and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 7 gave the title compound (13 mg, 11%).
1H NMR (400 MHz, DMSO-d 6) δ 8.65 (d, J = 5.6 Hz, 1H), 7.61-7.54 (m, 3H), 7.44 (t, J = 7.2 Hz, 1H), 7.53 (m, 3H), 7.38 (m, 1H), 7.00 (t, J = 56.0 Hz, 1H), 5.51 (m, 1H), 4.20 (m, 1H), 3.64-3.48 (m, 4H), 2.56 (s, 3H), 2.19-2.14 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.65 (d, J = 5.6 Hz, 1H), 7.61-7.54 (m, 3H), 7.44 (t, J = 7.2 Hz, 1H), 7.53 (m, 3H), 7.38 (m, 1H), 7.00 (t, J = 56.0 Hz, 1H), 5.51 (m, 1H), 4.20 (m, 1H), 3.64-3.48 (m, 4H), 2.56 (s, 3H) ), 2.19–2.14 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 413 (M+H)+ MS (ESI+) m/z 413 (M+H) +
실시예 9 Example 9
Figure PCTKR2022021249-appb-img-000165
Figure PCTKR2022021249-appb-img-000165
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyridine do[2,3-d]pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 4-(디메틸아미노)피페리딘 을 사용하여 화합물 A-2 합성 후, (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 (331 mg, 1.75 mmol)과 트리에틸아민 (1.9 mL, 1.4 mmol) 을 사용하여 표제 화합물 (25 mg, 15 %)을 황색 고체로 수득하였다.After synthesis of compound A-2 using intermediate I-A and 4-(dimethylamino)piperidine as described in Example 1, (R)-1-(3-(difluoromethyl)-2-fluorophenyl ) Ethanamine (331 mg, 1.75 mmol) and triethylamine (1.9 mL, 1.4 mmol) gave the title compound (25 mg, 15%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.01 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (m, 2H), 7.24 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 5.69 (t, J = 7.0 Hz, 1H), 4.12 (d, J = 12.0 Hz, 2H), 2.99 (t, J = 12.4 Hz, 2H), 2.58 (s, 3H), 2.33 (m, 1H), 2.22 (s, 6H), 1.92 (d, J = 12.4 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.54 (d, J = 11.6 Hz, 2H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.01 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.4 Hz , 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (m, 2H), 7.24 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 5.69 (t, J = 7.0 Hz, 1H), 4.12 (d, J = 12.0 Hz) , 2H), 2.99 (t, J = 12.4 Hz, 2H), 2.58 (s, 3H), 2.33 (m, 1H), 2.22 (s, 6H), 1.92 (d, J = 12.4 Hz, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.54 (d, J = 11.6 Hz, 2H)
MS (ESI+) m/z 459 (M+H)+ MS (ESI+) m/z 459 (M+H) +
실시예 10 Example 10
Figure PCTKR2022021249-appb-img-000166
Figure PCTKR2022021249-appb-img-000166
(R)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸-N-(1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민(R)-3-(4-(dimethylamino)piperidin-1-yl)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)pyrido [2,3-d]pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 4-(디메틸아미노)피페리딘 을 사용하여 화합물 A-2 합성 후, (R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에탄아민 (58 μL, 0.34 mmol)과 트리에틸아민 (0.32 mL, 2.3 mmol) 을 사용하여 표제 화합물 (27 mg, 25 %)을 미색 고체로 수득하였다.Synthesis of compound A-2 using intermediate I-A and 4-(dimethylamino)piperidine as described in Example 1 followed by (R)-1-(2-methyl-3-(trifluoromethyl)phenyl) Ethanamine (58 μL, 0.34 mmol) and triethylamine (0.32 mL, 2.3 mmol) gave the title compound (27 mg, 25%) as an off-white solid.
1H NMR (400 MHz, MeOD) δ 8.95 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.25 (d, J = 13.2 Hz, 2H), 3.05 (t, J = 11.6 Hz, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 2.53 (m, 1H), 2.38 (s, 6H), 2.09 (d, J = 12.8 Hz, 2H), 1.66 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.95 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.25 (d, J = 13.2 Hz, 2H), 3.05 (t, J = 6.8 Hz, 1H ) . 11.6 Hz, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 2.53 (m, 1H), 2.38 (s, 6H), 2.09 (d, J = 12.8 Hz, 2H), 1.66 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 473 (M+H)+ MS (ESI+) m/z 473 (M+H) +
실시예 11 Example 11
Figure PCTKR2022021249-appb-img-000167
Figure PCTKR2022021249-appb-img-000167
(R)-8-메틸-N-(1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)-3-모르폴리노피리도[2,3-d]피리다진-5-아민(R)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-morpholinopyrido[2,3-d]pyridazine-5- amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 모르폴린을 사용하여 화합물 A-2 합성 후, (R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에탄아민 (67 μL, 0.40 mmol)과 트리에틸아민 (0.36 mL, 2.6 mmol)을 사용하여 표제 화합물 (19 mg, 17 %) 을 노란색 고체로 수득하였다.After synthesis of compound A-2 using intermediate I-A and morpholine as described in Example 1, (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine (67 μL, 0.40 mmol) and triethylamine (0.36 mL, 2.6 mmol) to give the title compound (19 mg, 17%) as a yellow solid.
1H NMR (400 MHz, MeOD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 3.94 (t, J = 4.8 Hz, 4H), 3.53 (t, J = 5.0 Hz, 4H), 2.69 (s, 3H), 2.64 (s, 3H), 1.65 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 3.94 (t, J = 4.8 Hz, 4H), 3.53 (t, J = 6.8 Hz, 1H) 5.0 Hz, 4H), 2.69 (s, 3H), 2.64 (s, 3H), 1.65 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 12 Example 12
Figure PCTKR2022021249-appb-img-000168
Figure PCTKR2022021249-appb-img-000168
(R)-N-(1-(3-아미노-5-(트리플루오로메틸)페닐-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl-3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[2, 3-d] pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 4-(디메틸아미노)피페리딘 을 사용하여 화합물 A-2 유도체 1-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)-N,N-디메틸피페리딘-4-아민을 합성하였다.Compound A-2 derivative 1-(5-chloro-8-methylpyrido[2,3-d]pyridazine-3 using intermediate I-A and 4-(dimethylamino)piperidine as described in Example 1 -yl)-N,N-dimethylpiperidin-4-amine was synthesized.
1-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)-N,N-디메틸피페리딘-4-아민 (50 mg, 0.16 mmol) 에 중간체 I-D (133 mg, 0.65 mmol), 디이소프로필에틸아민 (111 ul, 0.80 mmol) 을 첨가하고, 130 ℃ 에서 4 시간 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 컬럼 크로마토그래피로 정제하여 표제 화합물 (9 mg, 12 %)을 노란색 고체로서 수득하였다.To 1-(5-chloro-8-methylpyrido[2,3-d]pyridazin-3-yl)-N,N-dimethylpiperidin-4-amine (50 mg, 0.16 mmol) intermediate I-D ( 133 mg, 0.65 mmol) and diisopropylethylamine (111 ul, 0.80 mmol) were added, and heated and stirred at 130° C. for 4 hours. After cooling the reaction to room temperature, it was purified by column chromatography to give the title compound (9 mg, 12%) as a yellow solid.
1H NMR (400 MHz, CD3OD) δ 8.94 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.0 (s, 2H), 6.79 (s, 1H), 5.45-5.40 (m, 2H), 4.23 (d, J = 13.2 Hz, 2H), 3.03 (t, J = 10.8 Hz, 2H), 2.70 (s, 3H), 2.55-2.48 (m, 1H), 2.37 (s, 6H), 2.09 (d, J = 12.8Hz, 2H), 1.66 (d, J = 6.8 Hz, 5H) 1H NMR (400 MHz, CD 3 OD) δ 8.94 (d, J = 2.8 Hz, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.0 (s, 2H), 6.79 (s, 1H), 5.45-5.40 (m, 2H), 4.23 (d, J = 13.2 Hz, 2H), 3.03 (t, J = 10.8 Hz, 2H), 2.70 (s, 3H), 2.55-2.48 (m, 1H), 2.37 (s, 6H), 2.09 (d, J = 12.8 Hz, 2H), 1.66 (d, J = 6.8 Hz, 5H)
MS (ESI+) m/z 474 (M+H)+ MS (ESI+) m/z 474 (M+H) +
실시예 13 Example 13
Figure PCTKR2022021249-appb-img-000169
Figure PCTKR2022021249-appb-img-000169
(R)-2,2-디플루오로-2-(2-플루오로-3-(1-((8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올(R)-2,2-difluoro-2-(2-fluoro-3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazine-5- yl)amino)ethyl)phenyl)ethanol
실시예 9 에 기재된 바와 같이 중간체 I-A, 모르폴린, 중간체 I-D 를 사용하여 표제 화합물 (20 mg, 20 %)을 노란색 고체로서 수득하였다.Intermediate I-A, morpholine, Intermediate I-D were used as described in Example 9 to give the title compound (20 mg, 20%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.04 (s, 1H), 8.00 (s, 1H), 7.52 (t, J = 8.4 Hz, 2H), 7.39 (t, J = 6.8 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 5.76-5.70 (m, 2H), 3.99-3.92 (m, 2H), 3.86-3.84 (m, 4H), 3.49-3.47 (m, 4H), 2.30(s, 3H), 1.60 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.04 (s, 1H) , 8.00 (s, 1H), 7.52 (t, J = 8.4 Hz, 2H), 7.39 (t, J = 6.8 Hz, 1H) , 7.20 (t, J = 7.6 Hz, 1H), 5.76–5.70 (m, 2H), 3.99–3.92 (m, 2H), 3.86–3.84 (m, 4H), 3.49–3.47 (m, 4H), 2.30 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 448 (M+H)+ MS (ESI+) m/z 448 (M+H) +
실시예 14 Example 14
Figure PCTKR2022021249-appb-img-000170
Figure PCTKR2022021249-appb-img-000170
(R)-2-(3-(1-((3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)-2-플루오로페닐)-2,2-디플루오로에탄올(R)-2-(3-(1-((3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5-yl )amino)ethyl)-2-fluorophenyl)-2,2-difluoroethanol
실시예 9 에 기재된 바와 같이 중간체 I-A, 4-(디메틸아미노)피페리딘, 중간체 I-D 를 사용하여 표제 화합물 (10 mg, 8 %)을 수득하였다.Intermediate I-A, 4-(dimethylamino)piperidine, Intermediate I-D were used as described in Example 9 to give the title compound (10 mg, 8%).
1H NMR (400 MHz, DMSO-d 6) δ 9.01 (s, 1H), 7.96 (s, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 5.74-5.69 (m, 2H), 4.13 (d, J = 12.4 Hz, 1H), 3.94 (t, J = 8.4, 2H), 2.99 (t, J = 12.4 Hz, 2H), 2.58 (s, 3H), 2.36-2.34 (m, 1H), 2.22 (s, 6H), 1.93-1.90 (m, 2H), 1.60 (d, J = 7.2 Hz, 3H), 1.56-1.53 (m, 2H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.01 (s, 1H), 7.96 (s , 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H) , 7.39 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 5.74–5.69 (m, 2H), 4.13 (d, J = 12.4 Hz, 1H), 3.94 (t, J = 8.4, 2H), 2.99 (t, J = 12.4 Hz, 2H), 2.58 (s, 3H), 2.36–2.34 (m, 1H), 2.22 (s, 6H), 1.93–1.90 (m, 2H) , 1.60 (d, J = 7.2 Hz, 3H), 1.56–1.53 (m, 2H)
MS (ESI+) m/z 489 (M+H)+ MS (ESI+) m/z 489 (M+H) +
실시예 15 Example 15
Figure PCTKR2022021249-appb-img-000171
Figure PCTKR2022021249-appb-img-000171
2,2-디플루오로-2-(2-플루오로-3-((R)-1-((3-((S)-3-메톡시피롤리딘-1일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올2,2-difluoro-2-(2-fluoro-3-((R)-1-((3-((S)-3-methoxypyrrolidin-1yl)-8-methylpyrido [2,3-d]pyridazin-5-yl)amino)ethyl)phenyl)ethanol
실시예 9 에 기재된 바와 같이 중간체 I-A, (S)-3-메톡시피롤리딘, 중간체 I-D 를 사용하여 표제 화합물 (9 mg, 9 %) 노란색 고체로 수득하였다.Intermediate I-A, (S)-3-methoxypyrrolidine, Intermediate I-D were used as described in Example 9 to give the title compound (9 mg, 9%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.79 (s, 1H), 7.82 (s, 1H), 7.59 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 5.76 (t, J = 6.4 Hz, 1H), 5.62-5.58 (m, 1H), 4.22 (s, 1H), 4.0-3.91 (m, 2H), 3.68 (s, 3H), 3.57-3.55 (m, 1H), 2.66 (s, 3H), 2.24-2.16 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.28-1.25 (m, 1H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.79 (s, 1H), 7.82 (s , 1H), 7.59 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H) , 7.23 (t, J = 7.6 Hz, 1H), 5.76 (t, J = 6.4 Hz, 1H), 5.62–5.58 (m, 1H), 4.22 (s, 1H), 4.0–3.91 (m, 2H), 3.68 (s, 3H), 3.57-3.55 (m, 1H), 2.66 (s, 3H), 2.24-2.16 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.28-1.25 (m, 1H)
MS (ESI+) m/z 462 (M+H)+ MS (ESI+) m/z 462 (M+H) +
실시예 16 Example 16
Figure PCTKR2022021249-appb-img-000172
Figure PCTKR2022021249-appb-img-000172
(R)-N-(1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-아민(R)—N-(1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-8-methyl-3-morpholinopyrido[2,3- d]pyridazin-5-amine
실시예 9 에 기재된 바와 같이 중간체 I-A, 모르폴린, 중간체 I-E 를 사용하여 표제 화합물 (30 mg, 27 %) 분홍색 고체로서 수득하였다.Using intermediate I-A, morpholine, intermediate I-E as described in Example 9, the title compound (30 mg, 27%) was obtained as a pink solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 8.00 (s, 1H), 7.46 (t, J = 7.2 Hz, 3H), 7.02 (t, J = 7.6 Hz, 1H), 5.64 (t, J = 7.2 Hz, 1H), 4.89 (t, J = 16.8 Hz, 2H), 3.86-3.84 (m, 4H), 3.49-3.43 (m, 4H), 2.67 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.03 (s, 1H) , 8.00 (s, 1H), 7.46 (t, J = 7.2 Hz, 3H), 7.02 (t, J = 7.6 Hz, 1H) , 5.64 (t, J = 7.2 Hz, 1H), 4.89 (t, J = 16.8 Hz, 2H), 3.86–3.84 (m, 4H), 3.49–3.43 (m, 4H), 2.67 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 428 (M+H)+ MS (ESI+) m/z 428 (M+H) +
실시예 17 Example 17
Figure PCTKR2022021249-appb-img-000173
Figure PCTKR2022021249-appb-img-000173
(R)-N-(1-(3,3-디플루오로-2,3-디히르도벤조푸란-7-일)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3,3-difluoro-2,3-dihydroxybenzofuran-7-yl)ethyl)-3-(4-(dimethylamino)piperidin-1- yl)-8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 9 에 기재된 바와 같이 중간체 I-A, 4-(디메틸아미노)피페리딘, 중간체 I-E 를 사용하여 표제 화합물 (8 mg, 8 %) 노란색 고체로서 수득하였다.Using intermediate I-A, 4-(dimethylamino)piperidine, intermediate I-E as described in Example 9 gave the title compound (8 mg, 8%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.01 (s, 1H), 7.96 (s, 1H), 7.47-7.45 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 5.63 (t, J = 7.2 Hz, 1H), 4.88 (t, J= 16.8 Hz, 2H), 4.12 (d, J = 12.4 Hz, 2H), 2.98 (t, J = 12.4 Hz, 2H), 2.57 (s, 3H), 2.36-2.33 (m, 2H), 2.22 (s, 6H), 1.59 (d, J = 7.2Hz, 3H), 1.55-1.53 (m, 2H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.01 (s, 1H), 7.96 (s, 1H), 7.47-7.45 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.02 ( t, J = 7.6 Hz, 1H), 5.63 (t, J = 7.2 Hz, 1H), 4.88 (t, J = 16.8 Hz, 2H), 4.12 (d, J = 12.4 Hz, 2H), 2.98 (t, J = 12.4 Hz, 2H), 2.57 (s, 3H), 2.36–2.33 (m, 2H), 2.22 (s, 6H), 1.59 (d, J = 7.2 Hz, 3H), 1.55–1.53 (m, 2H) )
MS (ESI+) m/z 469 (M+H)+ MS (ESI+) m/z 469 (M+H) +
실시예 18 Example 18
Figure PCTKR2022021249-appb-img-000174
Figure PCTKR2022021249-appb-img-000174
(R)-1-(3-(1-((3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)-2-플루오로페닐)-1,1-디플루오로-2-메틸프로판-2-올(R)-1-(3-(1-((3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5-yl )amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol
실시예 1 에 기재된 바와 같이 중간체 I-A 와 4-(디메틸아미노)피페리딘 을 사용하여 화합물 A-2 유도체 1-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)-N,N-디메틸피페리딘-4-아민 을 합성하였다.Compound A-2 derivative 1-(5-chloro-8-methylpyrido[2,3-d]pyridazine-3 using intermediate I-A and 4-(dimethylamino)piperidine as described in Example 1 -yl)-N,N-dimethylpiperidin-4-amine was synthesized.
1-(5-클로로-8-메틸피리도[2,3-d]피리다진-3-일)-N,N-디메틸피페리딘-4-아민 (70 mg, 0.23 mmol) 에 중간체 I-F (195 mg, 0.69 mmol), 트리에틸아민 (0.32 ml, 2.3 mmol) 을 첨가하고, 120 ℃ 에서 4 시간 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 컬럼 크로마토그래피로 정제하여 표제 화합물 (30 mg, 25 %) 보라색 고체로서 수득하였다.To 1-(5-chloro-8-methylpyrido[2,3-d]pyridazin-3-yl)-N,N-dimethylpiperidin-4-amine (70 mg, 0.23 mmol) intermediate I-F ( 195 mg, 0.69 mmol) and triethylamine (0.32 ml, 2.3 mmol) were added, and heated and stirred at 120° C. for 4 hours. After cooling the reaction to room temperature, it was purified by column chromatography to give the title compound (30 mg, 25%) as a purple solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.01 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.51 (t, J = 6.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 6.6 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 5.71 (t, J = 7.2 Hz, 1H), 5.33 (s, 1H), 4.12 (d, J = 12.0 Hz, 2H), 2.99 (t, J = 12.2 Hz, 2H), 2.58 (s, 3H), 2.33 (m, 1H), 2.22 (s, 6H), 1.92 (d, 10.4 Hz, 2H), 1.59 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 11.6 Hz, 2H), 1.04 (d, J = 6.0 Hz, 6H), 1H NMR (400 MHz, DMSO- d6 ) δ 9.01 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz , 1H), 7.51 (t, J = 6.6 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 6.6 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 5.71 (t, J = 7.2 Hz, 1H), 5.33 (s , 1H), 4.12 (d, J = 12.0 Hz, 2H), 2.99 (t, J = 12.2 Hz, 2H), 2.58 (s, 3H), 2.33 (m, 1H), 2.22 (s, 6H), 1.92 (d, 10.4 Hz, 2H), 1.59 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 11.6 Hz, 2H), 1.04 (d, J = 6.0 Hz, 6H),
MS (ESI+) m/z 517 (M+H)+ MS (ESI+) m/z 517 (M+H) +
실시예 19 Example 19
Figure PCTKR2022021249-appb-img-000175
Figure PCTKR2022021249-appb-img-000175
(R)-N-(1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도 [2,3-d]피리다진-5-아민(R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-3-(4-(dimethylamino)piperidin-1-yl )-8-methylpyrido [2,3-d] pyridazin-5-amine
실시예 18 에 기재된 바와 같이 중간체 I-A, 4-(디메틸아미노)피페리딘, 중간체 I-H 를 사용하여 표제 화합물 (15 mg, 10 %) 노란색 고체로서 수득하였다.Using intermediate I-A, 4-(dimethylamino)piperidine, intermediate I-H as described in Example 18 gave the title compound (15 mg, 10%) as a yellow solid.
1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.33-7.10 (m, 3H), 6.96 (dd, J = 3.6, 0.8 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.78 (q, J = 7.5 Hz, 1H), 4.09 (d, J = 13.2 Hz, 2H), 3.39 (s, 2H), 2.90 (t, J = 11.8 Hz, 2H), 2.63 (s, 3H), 2.45-2.31 (m, 1H), 2.23 (s, 6H), 2.05 (s, 6H), 1.94 (d, J = 12.4 Hz, 2H), 1.56 (d, J = 4 Hz, 3H), 1.54-1.45 (m, 2H) 1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.33-7.10 ( m, 3H), 6.96 (dd, J = 3.6, 0.8 Hz, 1H), 6.86 (d, J = 3.6 Hz, 1H), 5.78 (q, J = 7.5 Hz, 1H), 4.09 (d, J = 13.2 Hz, 2H), 3.39 (s, 2H), 2.90 (t, J = 11.8 Hz, 2H), 2.63 (s, 3H), 2.45-2.31 (m, 1H), 2.23 (s, 6H), 2.05 (s , 6H), 1.94 (d, J = 12.4 Hz, 2H), 1.56 (d, J = 4 Hz, 3H), 1.54–1.45 (m, 2H)
MS (ESI+) m/z 530 (M+H)+ MS (ESI+) m/z 530 (M+H) +
실시예 20 Example 20
Figure PCTKR2022021249-appb-img-000176
Figure PCTKR2022021249-appb-img-000176
(R)-N-(1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5- 아민(R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-8-methyl-3-morpholinopyrido[2,3- d]pyridazin-5-amine
실시예 18 에 기재된 바와 같이 중간체 I-A, 모르폴린, 중간체 I-H 를 사용하여 표제 화합물 (15 mg, 16 %) 노란색 고체로서 수득하였다.Using intermediate I-A, morpholine, intermediate I-H as described in Example 18, the title compound (15 mg, 16%) was obtained as a yellow solid.
1H NMR (400 MHz, MeOD) δ 8.81 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.33-7.10 (m, 3H), 6.96 (dd, J = 3.6, 0.8 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 5.77 (q, J = 7.5 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.38 (s, 2H), 3.34 (t, J = 4.8 Hz), 2.63 (s, 3H), 2.01 (s, 6H), 1.69 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.81 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.33-7.10 ( m, 3H), 6.96 (dd, J = 3.6, 0.8 Hz, 1H), 6.85 (d, J = 3.6 Hz, 1H), 5.77 (q, J = 7.5 Hz, 1H), 3.76 (t, J = 4.8 Hz, 4H), 3.38 (s, 2H), 3.34 (t, J = 4.8 Hz), 2.63 (s, 3H), 2.01 (s, 6H), 1.69 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 489 (M+H)+ MS (ESI+) m/z 489 (M+H) +
실시예 21 Example 21
Figure PCTKR2022021249-appb-img-000177
Figure PCTKR2022021249-appb-img-000177
(R)-2,2-디플루오로-2-(3-(1-((8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올(R)-2,2-difluoro-2-(3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-yl)amino)ethyl )phenyl)ethanol
실시예 18 에 기재된 바와 같이 중간체 I-A, 모르폴린, 중간체 I-I 를 사용하여 표제 화합물 (11 mg, 12 %) 노란색 고체로서 수득하였다.Intermediate I-A, morpholine, Intermediate I-I was used as described in Example 18 to give the title compound (11 mg, 12%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.04 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.58-7.53 (m, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.36-7.34 (m, 1H), 5.63 (t, J = 6.4 Hz, 1H), 5.52-5.50 (m, 1H), 3.85-3.79 (m, 4H), 3.49-3.46 (m, 4H), 2.67 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.04 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.58-7.53 (m, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.36-7.34 (m, 1H), 5.63 (t, J = 6.4 Hz, 1H), 5.52-5.50 (m, 1H), 3.85-3.79 (m, 4H), 3.49-3.46 (m, 4H), 2.67 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
합성법 Bsynthesis method B
Figure PCTKR2022021249-appb-img-000178
Figure PCTKR2022021249-appb-img-000178
화합물 B-2 의 일반적인 합성은 합성법 B 에 예시되어 있다. 중간체 I-B 를 중간체 I-C ~ I-H 또는 상업적으로 구매 가능한 시약 중 선택하여 친핵성 방향족 치환 반응으로 화합물 B-1을 합성하고, H-R4 아민과 부흐발트-하트위그 아민화 반응을 진행하여 최종 화합물 B-2를 합성한다.The general synthesis of compound B-2 is exemplified in synthesis method B. Compound B-1 was synthesized by a nucleophilic aromatic substitution reaction by selecting intermediates IB from intermediates IC to IH or commercially available reagents, and a Buchwald-Hartwig amination reaction was performed with HR 4 amine to obtain final compound B-2 synthesize
실시예 22 Example 22
Figure PCTKR2022021249-appb-img-000179
Figure PCTKR2022021249-appb-img-000179
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxyazetidin-1-yl)-8-methylpyrido[2 ,3-d] pyridazin-5-amine
단계 1Step 1
Figure PCTKR2022021249-appb-img-000180
Figure PCTKR2022021249-appb-img-000180
(R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-3-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine
3,5-디클로로-8-메틸피리도[2,3-d]피리다진 (300 mg, 1.40 mmol) 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 (386 ul, 2.10 mmol), 디이소프로필에틸아민 (0.59 ml, 4.2 mmol) 을 첨가하고 130 ℃ 에서 4 시간 동안 가열 교반한다. 반응물을 실온으로 냉각 후, 컬럼 크로마토그래피로 정제하여 (R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 (230 mg, 45 %)을 노란색 고체로서 수득하였다.3,5-dichloro-8-methylpyrido[2,3-d]pyridazine (300 mg, 1.40 mmol) with (R)-1-(3-(difluoromethyl)-2-fluorophenyl) Ethanamine (386 ul, 2.10 mmol) and diisopropylethylamine (0.59 ml, 4.2 mmol) are added and heated and stirred at 130° C. for 4 hours. After cooling the reaction to room temperature, it was purified by column chromatography to obtain (R)-3-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido [2,3-d]pyridazin-5-amine (230 mg, 45%) was obtained as a yellow solid.
MS (ESI+) m/z 367 (M+H)+ MS (ESI+) m/z 367 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000181
Figure PCTKR2022021249-appb-img-000181
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxyazetidin-1-yl)-8-methylpyrido[2 ,3-d] pyridazin-5-amine
무수 테트라히드로푸란 (2 ml) 중 (R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 (80 mg, 0.21 mmol) 의 용액에 3-메톡시아제티딘 (30 μl, 0.32 mmol), Pd2(dba)3 (30 mg, 0.02 mmol), Xphos (30 mg, 0.04 mmol), 테트라히드로푸란 중 1 M LiHMDS 용액 (1.23 ml, 1.00 mmol) 을 추가하고 80 ℃ 에서 4 시간 동안 가열 교반한다. 반응 혼합물을 실온으로 냉각 후 증류수로 반응을 종결하고 디클로로메탄 으로 3 회 추출하였다. 유기 추출액을 황산마그네슘 상에서 건조시킨 후, 여과 및 농축 하였다. 잔류물은 컬럼 크로마토그래피로 정제하여 (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민 (32 mg, 37 %) 노란색 고체로서 수득하였다.(R)-3-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3 in anhydrous tetrahydrofuran (2 ml) To a solution of -d]pyridazin-5-amine (80 mg, 0.21 mmol) was added 3-methoxyazetidine (30 μl, 0.32 mmol), Pd 2 (dba) 3 (30 mg, 0.02 mmol), Xphos (30 mg, 0.04 mmol), 1 M LiHMDS solution in tetrahydrofuran (1.23 ml, 1.00 mmol) and heated and stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the reaction was terminated with distilled water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate, then filtered and concentrated. The residue was purified by column chromatography (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxyazetidin-1-yl )-8-methylpyrido[2,3-d]pyridazin-5-amine (32 mg, 37%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 2.8 Hz, 1H), 7.61-7.58 (m, 2H), 7.46-7.38 (m, 2H), 7.25 (s, 1H), 7.23 (t, J = 7.6 Hz, 1.5H), 7.11 (s, 0.5H), 5.67 (t, J = 6.8Hz, 1H), 4.46-4.45 (m, 1H), 4.37-4.33 (m, 2H), 3.97-3.92 (m, 2H), 3.20 (s, 3H), 2.57 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.48 (d, J = 2.8 Hz, 1H), 7.61-7.58 (m , 2H), 7.46-7.38 (m, 2H), 7.25 (s, 1H), 7.23 (t, J = 7.6 Hz, 1.5H), 7.11 (s, 0.5H), 5.67 (t, J = 6.8 Hz, 1H), 4.46–4.45 (m, 1H), 4.37–4.33 (m, 2H) , 3.97–3.92 (m, 2H), 3.20 (s, 3H), 2.57 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 23 Example 23
Figure PCTKR2022021249-appb-img-000182
Figure PCTKR2022021249-appb-img-000182
3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1을 합성 후, 6-옥사-3-아자비시클로[3.1.1]헵탄 염산염 을 사용하여 표제 화합물 (50 mg, 56 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 6-oxa-3 -Azabicyclo[3.1.1]heptane hydrochloride was used to give the title compound (50 mg, 56%).
1H NMR (400 MHz, DMSO-d 6) δ 8.86 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (s, 0.25H), 7.25-7.21 (m, 1.5H), 7.12 (s, 0.5H), 5.71 (t, J = 7.2 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 3.85-3.80 (m, 2H), 3.69 (t, J = 11.6 Hz, 2H), 3.23-3.21 (m, 2H), 2.60 (s, 3H), 2.00-1.98 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.86 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 8.0 Hz , 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (s, 0.25H), 7.25–7.21 (m, 1.5H), 7.12 (s, 0.5H), 5.71 (t, J = 7.2 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 3.85–3.80 (m, 2H), 3.69 (t, J = 11.6 Hz, 2H), 3.23–3.21 (m, 2H), 2.60 (s, 3H), 2.00-1.98 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 24 Example 24
Figure PCTKR2022021249-appb-img-000183
Figure PCTKR2022021249-appb-img-000183
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptane-6- 1) pyrido [2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.3]헵탄 을 사용하여 표제 화합물 (43 mg, 73 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 2-oxa-6 -Azaspiro[3.3]heptane gave the title compound (43 mg, 73%).
1H NMR (400 MHz, CD3OD) δ 8.42 (d, J = 2.8 Hz, 1H), 7.59-7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.14 (s, 0.25H), 7.01 (s, 0.50H), 6.87 (s, 0.25H), 5.74-5.69 (m, 1H), 4.93 (s, 4H), 4.37 (s, 4H), 2.66 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, CD 3 OD) δ 8.42 (d, J = 2.8 Hz, 1H), 7.59-7.54 (m, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.14 (s, 0.25H), 7.01 (s, 0.50H), 6.87 (s, 0.25H), 5.74-5.69 (m, 1H), 4.93 (s, 4H), 4.37 (s , 4H), 2.66 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 25 Example 25
Figure PCTKR2022021249-appb-img-000184
Figure PCTKR2022021249-appb-img-000184
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-메틸모르폴리노)피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-methylmorpholino)pyrido[2,3-d ]Pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-메틸모르폴린 을 사용하여 표제 화합물 (40 mg, 34 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 2-methylmorpholine was used to give the title compound (40 mg, 34%).
1H NMR (400 MHz, DMSO-d 6) δ 9.00-8.98 (m, 1H), 7.91-7.90 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51-7.4 5(m, 2H), 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.69 (t, J = 7.2 Hz, 1H), 4.36-4.35 (m, 1H), 4.08-4.04 (m, 1H), 3.82 (s, 2H), 3.68-3.61 (m, 2H), 3.28-3.23 (m, 1H), 2.58 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00-8.98 (m, 1H), 7.91-7.90 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51-7.4 5 (m, 2H), 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.69 (t, J = 7.2 Hz, 1H), 4.36-4.35 (m, 1H), 4.08-4.04 (m, 1H), 3.82 (s, 2H), 3.68-3.61 (m, 2H), 3.28-3.23 (m, 1H), 2.58 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 26 Example 26
Figure PCTKR2022021249-appb-img-000185
Figure PCTKR2022021249-appb-img-000185
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(3-메틸모르폴리노)피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(3-methylmorpholino)pyrido[2,3-d ]Pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메틸모르폴린 을 사용하여 표제 화합물 (23 mg, 30 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-methylmorpholine was used to give the title compound (23 mg, 30%).
1H NMR (400 MHz, DMSO-d 6) δ 9.00-8.98 (m, 1H), 7.91-7.90 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51-7.45 (m, 2H), 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.69 (t, J = 6.8Hz, 1H), 4.36-4.35 (m, 1H), 4.08-4.04 (m, 1H), 3.82 (s, 2H), 3.65-3.62 (m, 2H), 3.28-3.24 (m, 1H), 2.59 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.00-8.98 (m, 1H), 7.91-7.90 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.51-7.45 (m, 2H) ), 7.38 (s, 0.25H), 7.25–7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.69 (t, J = 6.8 Hz, 1H), 4.36–4.35 (m, 1H), 4.08 -4.04 (m, 1H), 3.82 (s, 2H), 3.65-3.62 (m, 2H), 3.28-3.24 (m, 1H), 2.59 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H ), 1.16 (d, J = 6.4 Hz, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 27 Example 27
Figure PCTKR2022021249-appb-img-000186
Figure PCTKR2022021249-appb-img-000186
3-((1S,4S)-2-옥사-5-아자비시클로[2.2.1]헵탄-5-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸) -8-메틸피리도[2,3-d]피리다진-5-아민3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2- Fluorophenyl)ethyl) -8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-5-아자비시클로[2.2.1]헵탄 염산염 을 사용하여 표제 화합물 (20 mg, 26 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-oxa-5 -Azabicyclo[2.2.1]heptane hydrochloride was used to give the title compound (20 mg, 26%).
1H NMR (400 MHz, DMSO-d 6) δ 8.74 (d, J = 1.2 Hz, 1H), 7.68 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.34-7.36 (m, 1.25H), 7.25-7.21 (m, 1.5H), 7.11 (s, 0.25H), 5.69-5.67 (m, 1H), 4.98 (s, 1H), 4.79 (s, 1H), 3.87 (d, J = 7.6 Hz, 1H), 3.74 (t, J = 8.0 Hz, 1H), 3.6 7(d, J = 10.0 Hz, 2H), 2.52 (s, 3H), 2.02-1.99 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d 6 ) δ 8.74 (d, J = 1.2 Hz, 1H), 7.68 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.34-7.36 (m, 1.25H), 7.25-7.21 (m, 1.5H), 7.11 (s, 0.25H), 5.69-5.67 (m, 1H), 4.98 (s, 1H), 4.79 (s, 1H), 3.87 (d, J = 7.6 Hz, 1H), 3.74 (t, J = 8.0 Hz, 1H), 3.6 7 (d, J = 10.0 Hz, 2H), 2.52 (s, 3H) , 2.02–1.99 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 28 Example 28
Figure PCTKR2022021249-appb-img-000187
Figure PCTKR2022021249-appb-img-000187
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (8 mg, 8 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-oxa-8 -Azabicyclo[3.2.1]octane hydrochloride was used to give the title compound (8 mg, 8%).
1H NMR (400 MHz, DMSO-d 6) δ 8.92 (s, 1H), 7.91 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.4 Hz, 1H), 7.38-7.36 (m, 1.25H), 7.25-7.22 (m, 1.5H), 7.1 1(s, 0.5H), 5.69-5.65 (m, 1H), 4.58 (s, 2H), 3.76 (t, J = 8.4 Hz, 2H), 3.59 (d, J = 11.2 Hz, 3H), 2.58 (s, 3H), 2.09-1.99 (m, 4H), 1.61 (d, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.92 (s, 1H), 7.91 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.4 Hz, 1H) , 7.38-7.36 (m, 1.25H), 7.25-7.22 (m, 1.5H), 7.1 1(s, 0.5H), 5.69-5.65 (m, 1H), 4.58 (s, 2H), 3.76 (t, J = 8.4 Hz, 2H), 3.59 (d, J = 11.2 Hz, 3H), 2.58 (s, 3H), 2.09–1.99 (m, 4H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 29 Example 29
Figure PCTKR2022021249-appb-img-000188
Figure PCTKR2022021249-appb-img-000188
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-티오모르폴리노피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-thiomorpholinopyrido[2,3-d]pyridazine- 5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 티오모르폴린 을 사용하여 표제 화합물 (25 mg, 36 %) 을 수득하였다.As described in Example 22, compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, then thiomorpholine was used to give the title compound (25 mg, 36%).
1H NMR (400 MHz, DMSO-d 6) δ 8.99 (s, 1H), 7.94 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 6.8 Hz, 2H), 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.70-5.67 (m, 1H), 3.93-3.90 (m, 4H), 2.78-2.76 (m, 4H), 2.58 (s, 3H), 2.09-1.99 (m, 4H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.99 (s, 1H), 7.94 (s , 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 6.8 Hz, 2H) , 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.70-5.67 (m, 1H), 3.93-3.90 (m, 4H), 2.78-2.76 (m , 4H), 2.58 (s, 3H), 2.09–1.99 (m, 4H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 434 (M+H)+ MS (ESI+) m/z 434 (M+H) +
실시예 30 Example 30
Figure PCTKR2022021249-appb-img-000189
Figure PCTKR2022021249-appb-img-000189
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-헥사히드로피라지노[2,1-c][1,4]옥사진-8(1H)-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-hexahydropyrazino[2,1-c][1,4 ]oxazin-8(1H)-yl)-8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (S)-옥타하이드로피라지노[2,1-c][1,4]옥사진 을 사용하여 표제 화합물 (35 mg, 46 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (S)-octa Hydropyrazino[2,1-c][1,4]oxazine was used to give the title compound (35 mg, 46%).
1H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 7.94 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.38 (s, 0.25H), 7.24-7.21 (m, 1.5H), 7.11 (s, 0.5H), 5.71-5.67 (m, 1H), 4.08 (d, J = 8.4 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.84-3.80 (m, 2H), 3.61-3.58 (m, 1H), 3.25 (t, J = 10.4 Hz, 2H), 3.08-3.03 (m, 1H), 2.93 (d, J = 11.2 Hz, 1H), 2.74 (d, J = 11.2 Hz, 1H), 2.58 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.03 (s, 1H) , 7.94 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.38 ( s, 0.25 H), 7.24–7.21 (m, 1.5 H), 7.11 (s, 0.5 H), 5.71–5.67 (m, 1 H), 4.08 (d, J = 8.4 Hz, 1 H), 3.92 (d, J = 11.6 Hz, 1H), 3.84–3.80 (m, 2H), 3.61–3.58 (m, 1H), 3.25 (t, J = 10.4 Hz, 2H), 3.08–3.03 (m, 1H), 2.93 (d, J = 11.2 Hz, 1H), 2.74 (d, J = 11.2 Hz, 1H), 2.58 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 473 (M+H)+ MS (ESI+) m/z 473 (M+H) +
실시예 31 Example 31
Figure PCTKR2022021249-appb-img-000190
Figure PCTKR2022021249-appb-img-000190
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-methoxypiperidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (R)-3-메톡시피페리딘 을 사용하여 표제 화합물 (10 mg, 14 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (R)-3 -Methoxypiperidine was used to give the title compound (10 mg, 14%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.26-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.71-5.67 (m, 1H), 3.91-3.87 (m, 1H), 3.72-3.68 (m, 1H), 3.26-3.22 (m, 2H), 2.58 (s, 3H), 2.04-2.00 (m, 1H), 1.88-1.85 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.57-1.52 (m, 1H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.59 (t, J = 7.2 Hz , 1H), 7.52 (d, J = 7.2 Hz, 1H) , 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.26–7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.71–5.67 (m, 1H), 3.91– 3.87 (m, 1H), 3.72-3.68 (m, 1H), 3.26-3.22 (m, 2H), 2.58 (s, 3H), 2.04-2.00 (m, 1H), 1.88-1.85 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.57-1.52 (m, 1H)
MS (ESI+) m/z 446 (M+H)+ MS (ESI+) m/z 446 (M+H) +
실시예 32 Example 32
Figure PCTKR2022021249-appb-img-000191
Figure PCTKR2022021249-appb-img-000191
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-methoxypiperidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (S)-3-메톡시피페리딘 을 사용하여 표제 화합물 (10 mg, 14 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (S)-3 -Methoxypiperidine was used to give the title compound (10 mg, 14%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.70-5.67 (m, 1H), 3.92-3.88 (m, 1H), 3.74-3.70 (m, 1H), 3.33 (s, 3H), 3.26-3.21 (m, 2H), 2.58 (s, 3H), 2.05-2.03 (m, 1H), 1.88-1.85 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.56-1.54 (m, 1H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (s, 1H), 7.93 (s, 1H), 7.58 (t, J = 7.2 Hz , 1H), 7.52 (d, J = 7.2 Hz, 1H) , 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.25–7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.70–5.67 (m, 1H), 3.92– 3.88 (m, 1H), 3.74-3.70 (m, 1H), 3.33 (s, 3H), 3.26-3.21 (m, 2H), 2.58 (s, 3H), 2.05-2.03 (m, 1H), 1.88- 1.85 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.56-1.54 (m, 1H)
MS (ESI+) m/z 446 (M+H)+ MS (ESI+) m/z 446 (M+H) +
실시예 33 Example 33
Figure PCTKR2022021249-appb-img-000192
Figure PCTKR2022021249-appb-img-000192
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-7-아자스피로[3.5]노난-7-일)피리도[2,3-d]피리다진-5-아민(R)—N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-7-azaspiro[3.5]nonane-7- 1) pyrido [2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-7-아자스피로[3.5]노난 을 사용하여 표제 화합물 (20 mg, 28 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 2-oxa-7 -Azaspiro[3.5]nonane gave the title compound (20 mg, 28%).
1H NMR (400 MHz, DMSO-d 6) δ 9.03 (s, 1H), 7.97 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.25-7.21 (m, 1.5H), 7.11 (s, 0.5H), 5.71-5.67 (m, 1H), 4.41 (s, 4H), 3.46 (t, J = 5.6 Hz, 4H), 2.58 (s, 3H), 1.97 (t, J = 5.6 Hz, 4H), 1.61 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.03 (s, 1H), 7.97 ( s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H) , 7.47 (t, J = 6.8 Hz, 1H), 7.38 (s, 0.25H), 7.25–7.21 (m, 1.5H), 7.11 (s, 0.5H), 5.71–5.67 (m, 1H), 4.41 ( s, 4H), 3.46 (t, J = 5.6 Hz, 4H), 2.58 (s, 3H), 1.97 (t, J = 5.6 Hz, 4H), 1.61 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 458 (M+H)+ MS (ESI+) m/z 458 (M+H) +
실시예 34 Example 34
Figure PCTKR2022021249-appb-img-000193
Figure PCTKR2022021249-appb-img-000193
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-methoxypiperidin-1-yl)-8-methylpyrido[2 ,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 4-메톡시피페리딘 을 사용하여 표제 화합물 (28 mg, 33 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 4-methoxypiperidine Dean was used to give the title compound (28 mg, 33%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.0 Hz, 2H), 7.24 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 5.69 (t, J = 7.0 Hz, 1H), 3.83 (m, 2H), 3.49 (m, 2H), 3.26 (s, 3H), 3.25 (m, 1H), 2.67 (s, 3H), 2.02 (m, 2H), 1.62 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz , 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.0 Hz, 2H), 7.24 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 5.69 (t, J = 7.0 Hz, 1H), 3.83 (m , 2H), 3.49 (m, 2H), 3.26 (s, 3H), 3.25 (m, 1H), 2.67 (s, 3H), 2.02 (m, 2H), 1.62 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 446 (M+H)+ MS (ESI+) m/z 446 (M+H) +
실시예 35 Example 35
Figure PCTKR2022021249-appb-img-000194
Figure PCTKR2022021249-appb-img-000194
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-((디메틸아미노)메틸)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-((dimethylamino)methyl)piperidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, N,N-디메틸-1-(피페리딘-4-일)메탄아민 을 사용하여 표제 화합물 (3.1 mg, 4 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by N,N-dimethyl -1-(piperidin-4-yl)methanamine gave the title compound (3.1 mg, 4%).
1H NMR (400 MHz, MeOD) δ 8.95 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 6.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.20 (d, J = 12.0 Hz, 2H), 3.07 (t, J = 12.4 Hz, 2H), 2.68 (s, 3H), 2.31 (s, 6H), 2.31 (m, 2H), 1.98 (d, J = 13.2 Hz, 2H), 1.89 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 7.6 Hz, 2H) 1H NMR (400 MHz, MeOD) δ 8.95 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 6.6 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.74 (q, J = 6.8 Hz, 1H), 4.20 (d, J = 55.0 Hz, 1H) . 12.0 Hz, 2H), 3.07 (t, J = 12.4 Hz, 2H), 2.68 (s, 3H), 2.31 (s, 6H), 2.31 (m, 2H), 1.98 (d, J = 13.2 Hz, 2H) , 1.89 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H), 1.41 (d, J = 7.6 Hz, 2H)
MS (ESI+) m/z 473 (M+H)+ MS (ESI+) m/z 473 (M+H) +
실시예 36 Example 36
Figure PCTKR2022021249-appb-img-000195
Figure PCTKR2022021249-appb-img-000195
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(메틸아미노)피페리딘-1-일)피리도[2,3-d]피리다진-5-아민 2,2,2-트리플루오로아세테이트(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(methylamino)piperidin-1-yl)pyridine Do[2,3-d]pyridazin-5-amine 2,2,2-trifluoroacetate
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, tert-부틸 N-메틸-N-(피페리딘-4-일)카바메이트를 사용하여 tert-부틸 N-[1-(5-{[(1R)-1-[3-(디플루오로메틸)-2-플루오로페닐]에틸]아미노}-8-메틸피리도[2,3-d]피리다진-3-일)피페리딘-4-일]-N-메틸카바메이트 (122 mg, 82 %) 을 합성하였다. Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by tert-butyl N- tert-butyl N-[1-(5-{[(1R)-1-[3-(difluoromethyl)-2-fluoro using methyl-N-(piperidin-4-yl)carbamate Synthesis of lophenyl]ethyl]amino}-8-methylpyrido[2,3-d]pyridazin-3-yl)piperidin-4-yl]-N-methylcarbamate (122 mg, 82%) did
디클로로메탄 (0.1 ml) 중 tert-부틸 N-[1-(5-{[(1R)-1-[3-(디플루오로메틸)-2-플루오로페닐]에틸]아미노}-8-메틸피리도[2,3-d]피리다진-3-일)피페리딘-4-일]-N-메틸카바메이트 (30 mg, 0.055 mmol) 와 트리플루오로아세트산 (21 μl) 을 상온에서 1 시간 반응하여 농축한 후 표제 화합물 (29 mg, 97 %) 을 수득하였다.tert-butyl N-[1-(5-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl in dichloromethane (0.1 ml) Pyrido[2,3-d]pyridazin-3-yl)piperidin-4-yl]-N-methylcarbamate (30 mg, 0.055 mmol) and trifluoroacetic acid (21 μl) were dissolved in 1 After concentrating over time, the title compound (29 mg, 97%) was obtained.
1H NMR (400 MHz, MeOD) δ 9.19 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.54 (d, J = 13.6 Hz, 2H), 3.49 (m, 1H), 3.32 (m, 2H), 2.84 (s, 3H), 2.81 (s, 3H), 2.35 (d, J = 10.0 Hz, 2H), 1.83 (m, 2H), 1.76 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 9.19 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.57 (q, J = 6.8 Hz, 1H), 4.54 (d, J = 54.8 Hz, 1H) . 13.6 Hz, 2H), 3.49 (m, 1H), 3.32 (m, 2H), 2.84 (s, 3H), 2.81 (s, 3H), 2.35 (d, J = 10.0 Hz, 2H), 1.83 (m, 2H), 1.76 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 445 (M+H)+ MS (ESI+) m/z 445 (M+H) +
실시예 37 Example 37
Figure PCTKR2022021249-appb-img-000196
Figure PCTKR2022021249-appb-img-000196
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4,4-디플루오로피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4,4-difluoropiperidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 4,4-디플루오로피페리딘 을 사용하여 표제 화합물 (44 mg, 52 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 4,4-di Fluoropiperidine gave the title compound (44 mg, 52%).
1H NMR (400 MHz, MeOD) δ 9.02 (d, J = 3.2 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H), 3.77 (t, J = 5.8 Hz, 4H), 2.69 (s, 3H), 2.21 (m, 4H), 1.71 (t, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 9.02 (d, J = 3.2 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.73 (q, J = 6.8 Hz, 1H), 3.77 (t, J = 54.8 Hz, 1H ) 5.8 Hz, 4H), 2.69 (s, 3H), 2.21 (m, 4H), 1.71 (t, J = 6.8 Hz, 3H)
MS (ESI+) m/z 452 (M+H)+ MS (ESI+) m/z 452 (M+H) +
실시예 38 Example 38
Figure PCTKR2022021249-appb-img-000197
Figure PCTKR2022021249-appb-img-000197
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(2,2,2-트리플루오로에틸)피페라진-1-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(2,2,2-trifluoroethyl)pipette Razin-1-yl)pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 1-(2,2,2-트리플루오로에틸)피페라진 을 사용하여 표제 화합물 (42 mg, 45 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 1-(2, 2,2-Trifluoroethyl)piperazine was used to give the title compound (42 mg, 45%).
1H NMR (400 MHz, MeOD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.73 (q, J = 6.9 Hz, 1H), 3.60 (t, J = 5.2 Hz, 4H), 3.21 (q, J = 9.6 Hz, 2H), 2.94 (t, J = 5.0 Hz, 4H), 2.69 (s, 3H), 1.70 (t, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.97 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.73 (q, J = 6.9 Hz, 1H), 3.60 (t, J = 55.0 Hz, 1H) . 5.2 Hz, 4H), 3.21 (q, J = 9.6 Hz, 2H), 2.94 (t, J = 5.0 Hz, 4H), 2.69 (s, 3H), 1.70 (t, J = 7.2 Hz, 3H)
MS (ESI+) m/z 499 (M+H)+ MS (ESI+) m/z 499 (M+H) +
실시예 39 Example 39
Figure PCTKR2022021249-appb-img-000198
Figure PCTKR2022021249-appb-img-000198
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(옥세탄-3-일)피페라진-1-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(oxetan-3-yl)piperazin-1- 1) pyrido [2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 1-(옥세탄-3-일)피페라진 을 사용하여 표제 화합물 (42 mg, 63 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 1-(oxetane -3-yl)piperazine was used to give the title compound (42 mg, 63%).
1H NMR (400 MHz, MeOD) δ 8.99 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.73 (q, J = 7.1 Hz, 1H), 4.78 (t, J = 6.8 Hz, 2H), 4.70 (t, J = 3.2 Hz, 2H), 3.63 (t, J = 5.0 Hz, 5H), 2.69 (s, 3H), 2.63 (t, J = 5.0 Hz, 4H), 1.70 (t, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.99 (d, J = 2.8 Hz, 1H), 7.98 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.73 (q, J = 7.1 Hz, 1H), 4.78 (t, J = 55.0 Hz, 1H ) 6.8 Hz, 2H), 4.70 (t, J = 3.2 Hz, 2H), 3.63 (t, J = 5.0 Hz, 5H), 2.69 (s, 3H), 2.63 (t, J = 5.0 Hz, 4H), 1.70 (t, J = 7.2 Hz, 3H)
MS (ESI+) m/z 473 (M+H)+ MS (ESI+) m/z 473 (M+H) +
실시예 40 Example 40
Figure PCTKR2022021249-appb-img-000199
Figure PCTKR2022021249-appb-img-000199
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido[2 ,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메톡시피롤리딘 을 사용하여 표제 화합물 (11 mg, 13 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-methoxypyrroly Dean was used to give the title compound (11 mg, 13%).
1H NMR (400 MHz, MeOD) δ 8.66 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 54.8 Hz, 1H), 5.71 (t, J = 7.2 Hz, 1H), 4.23 (m, 1H), 3.68 (m, 4H), 3.43 (s, 3H), 2.69 (s, 3H), 2.33 (m, 1H), 2.25 (m, 1H), 1.7 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.66 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.45 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.02 (t, J = 54.8 Hz, 1H), 5.71 (t, J = 7.2 Hz, 1H), 4.23 (m, 1H), 3.68 (m, 4H), 3.43 (s, 3H), 2.69 ( s, 3H), 2.33 (m, 1H), 2.25 (m, 1H), 1.7 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 41 Example 41
Figure PCTKR2022021249-appb-img-000200
Figure PCTKR2022021249-appb-img-000200
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(6-메톡시-2-아자스피로[3.3]헵탄-2-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)- 8-Methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 6-메톡시-2-아자스피로[3.3]헵탄 염산염 을 사용하여 표제 화합물 (88 mg, 47 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 6-methoxy- 2-Azaspiro[3.3]heptane hydrochloride was used to give the title compound (88 mg, 47%).
1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 2.8 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.71 (q, J = 7.2 Hz, 1H), 4.20 (s, 2H), 4.15 (s, 2H), 3.93 (t, J = 6.8 Hz, 1H), 3.29 (s, 3H), 2.61 (s, 3H), 2.61 (m, 2H), 2.23 (m, 2H), 1.69 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 2.8 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.71 (q, J = 7.2 Hz, 1H), 4.20 (s, 2H) , 4.15 (s, 2H), 3.93 (t, J = 6.8 Hz, 1H), 3.29 (s, 3H), 2.61 (s, 3H), 2.61 (m, 2H), 2.23 (m, 2H), 1.69 ( d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 458 (M+H)+ MS (ESI+) m/z 458 (M+H) +
실시예 42 Example 42
Figure PCTKR2022021249-appb-img-000201
Figure PCTKR2022021249-appb-img-000201
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(6-메틸-2,6-디아자스피로[3.3]헵탄-2-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(6-methyl-2,6-diazaspiro[3.3]heptane -2-yl)pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-메틸-2,6-디아자스피로[3.3]헵탄 염산염 을 사용하여 표제 화합물 (37 mg, 53 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 2-methyl-2 ,6-diazaspiro[3.3]heptane hydrochloride was used to give the title compound (37 mg, 53%).
1H NMR (400 MHz, DMSO-d 6) δ 8.68 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 7.0 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 54.2 Hz, 1H), 5.49 (t, J = 6.8 Hz, 1H), 4.46 (m, 6H), 4.28 (m, 2H), 2.86 (s, 3H), 2.71 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.68 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 7.0 Hz , 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 54.2 Hz, 1H), 5.49 (t , J = 6.8 Hz, 1H), 4.46 (m, 6H), 4.28 (m, 2H), 2.86 (s, 3H), 2.71 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 443 (M+H)+ MS (ESI+) m/z 443 (M+H) +
실시예 43 Example 43
Figure PCTKR2022021249-appb-img-000202
Figure PCTKR2022021249-appb-img-000202
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시-3-메틸아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxy-3-methylazetidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메톡시-3-메틸아제티딘 염산염 을 사용하여 표제 화합물 (49 mg, 55 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-methoxy- The title compound (49 mg, 55%) was obtained using 3-methylazetidine hydrochloride.
1H NMR (400 MHz, DMSO-d 6) δ 8.50 (d, J = 2.8 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J = 6.8 Hz, 1H), 7.40 (t, J = 6.2 Hz, 1H), 7.25 (m, 2H), 5.67 (t, J = 7.2 Hz, 1H), 4.08 (d, J = 4.4 Hz, 1H), 4.06 (d, J = 4.8 Hz, 1H), 3.99 (d, J = 2.8 Hz, 1H), 3.97 (d, J = 3.2 Hz, 1H), 3.27 (s, 3H), 2.58 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.55 (s, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.50 (d, J = 2.8 Hz, 1H) , 7.59 (m, 2H), 7.47 (t, J = 6.8 Hz, 1H), 7.40 (t, J = 6.2 Hz, 1H), 7.25 (m, 2H), 5.67 (t, J = 7.2 Hz, 1H), 4.08 (d, J = 4.4 Hz, 1H), 4.06 (d, J = 4.8 Hz, 1H), 3.99 (d, J = 2.8 Hz, 1H), 3.97 (d, J = 3.2 Hz, 1H), 3.27 (s, 3H), 2.58 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.55 (s, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 44 Example 44
Figure PCTKR2022021249-appb-img-000203
Figure PCTKR2022021249-appb-img-000203
(R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-3-메틸아제티딘-3-올(R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine-3 -yl)-3-methylazetidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메틸아제티딘-3-올 을 사용하여 표제 화합물 (19 mg, 23 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3-methylazetidine -3-ol was used to give the title compound (19 mg, 23%).
1H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.47 (t, J = 6.6 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 5.76 (s, 1H), 5.67 (t, J = 7.2 Hz, 1H), 4.06 (d, J = 3.2 Hz, 1H), 4.04 (d, J = 3.2 Hz, 1H), 3.95 (t, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.52 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.47 (t, J = 6.6 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 5.76 (s, 1H), 5.67 (t, J = 7.2 Hz, 1H), 4.06 (d, J = 3.2 Hz, 1H), 4.04 (d, J = 3.2 Hz, 1H), 3.95 (t, J = 7.2 Hz, 2H), 2.58 (s, 3H), 1.60 (d, J = 6.8 Hz) , 3H), 1.52 (s, 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 45 Example 45
Figure PCTKR2022021249-appb-img-000204
Figure PCTKR2022021249-appb-img-000204
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(7-옥사-2-아자스피로[3.5]노난-2-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(7-oxa-2-azaspiro[3.5]nonane-2- 1) pyrido [2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 7-옥사-2-아자스피로[3.5]노난 을 사용하여 표제 화합물 (19 mg, 28 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 7-oxa-2 -Azaspiro[3.5]nonane gave the title compound (19 mg, 28%).
1H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.47 (t, J = 7.0 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 6.4 Hz, 1H), 5.68 (t, J = 7.0 Hz, 1H), 3.92 (s, 3H), 3.59 (t, J = 4.8 Hz, 4H), 2.57 (s, 3H), 1.83 (t, J = 4.8 Hz, 4H), 1.60 (d, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.47 (t, J = 7.0 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.23 (t, J = 6.4 Hz, 1H), 5.68 (t, J = 7.0 Hz, 1H), 3.92 (s, 3H), 3.59 (t, J = 4.8 Hz, 4H), 2.57 (s, 3H), 1.83 (t, J = 4.8 Hz, 4H), 1.60 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 458 (M+H)+ MS (ESI+) m/z 458 (M+H) +
실시예 46 Example 46
Figure PCTKR2022021249-appb-img-000205
Figure PCTKR2022021249-appb-img-000205
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-(디메틸아미노)아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-(dimethylamino)azetidin-1-yl)-8-methylpyrido [2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, N,N-디메틸아제티딘-3-아민 염산염 을 사용하여 표제 화합물 (5 mg, 6 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by N,N-dimethyl The title compound (5 mg, 6%) was obtained using azetidin-3-amine hydrochloride.
1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.45 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 4.02 (t, J = 6.8 Hz, 2H), 3.49 (m, 1H), 2.67 (s, 3H), 2.32 (s, 6H), 1.70 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 2.8 Hz, 1H), 7.58 (m, 2H), 7.45 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 5.71 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 4.02 (t, J = 6.8 Hz, 2H) , 3.49 (m, 1H), 2.67 (s, 3H), 2.32 (s, 6H), 1.70 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 431 (M+H)+ MS (ESI+) m/z 431 (M+H) +
실시예 47 Example 47
Figure PCTKR2022021249-appb-img-000206
Figure PCTKR2022021249-appb-img-000206
(R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)아제티딘-3-올(R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine-3 -yl)azetidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 아제티딘-3-올 염산염 을 사용하여 표제 화합물 (21 mg, 19 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 22, azetidine-3- All hydrochloride was used to give the title compound (21 mg, 19%).
1H NMR (400 MHz, DMSO-d 6) δ 8.47 (d, J = 2.8 Hz, 1H), 7.59 (m, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 54.2 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 5.67 (t, J = 7.0 Hz, 1H), 4.71 (m, 1H), 4.37 (q, J = 6.5 Hz, 2H), 3.86 (q, J = 6.5 Hz, 2H), 2.57 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (d, J = 2.8 Hz, 1H), 7.59 (m, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.25 (t, J = 54.2 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 5.67 (t, J = 7.0 Hz, 1H), 4.71 (m, 1H), 4.37 (q, J = 6.5 Hz, 2H), 3.86 (q, J = 6.5 Hz, 2H), 2.57 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 404 (M+H)+ MS (ESI+) m/z 404 (M+H) +
실시예 48 Example 48
Figure PCTKR2022021249-appb-img-000207
Figure PCTKR2022021249-appb-img-000207
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3-d]pyridazine-5 -amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 모르폴린 을 사용하여 표제 화합물 (3.4 mg, 6 %) 을 수득하였다.As described in Example 22, compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by morpholine This gave the title compound (3.4 mg, 6%).
1H NMR (400 MHz, MeOD) δ 8.98 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H). 7.01 (t, J = 54.8 Hz, 1H), 5.73 (q, J = 7.5 Hz, 1H), 3.94 (t, J = 4.8 Hz, 4H), 3.54 (t, J = 4.8 Hz, 4H), 2.69 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.98 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H). 7.01 (t, J = 54.8 Hz, 1H), 5.73 (q, J = 7.5 Hz, 1H), 3.94 (t, J = 4.8 Hz, 4H), 3.54 (t, J = 4.8 Hz, 4H), 2.69 ( s, 3H), 1.71 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 49 Example 49
Figure PCTKR2022021249-appb-img-000208
Figure PCTKR2022021249-appb-img-000208
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-플루오로피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-fluoropiperidin-1-yl)-8-methylpyrido[ 2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 4-플루오로피페리딘 염산염 을 사용하여 표제 화합물 (20 mg, 56 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 4-fluoro Peridine hydrochloride was used to give the title compound (20 mg, 56%).
1H NMR (400 MHz, MeOD) δ 8.92 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H). 7.00 (t, J = 55.0 Hz, 1H), 5.72 (q, J = 7.1 Hz, 1H), 5.00-4.84 (m, 1H), 3.75-3.55 (m, 4H), 2.69 (s, 3H), 2.7-1.98 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, MeOD) δ 8.92 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H). 7.00 (t, J = 55.0 Hz, 1H), 5.72 (q, J = 7.1 Hz, 1H), 5.00–4.84 (m, 1H), 3.75–3.55 (m, 4H), 2.69 (s, 3H), 2.7 -1.98 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 434 (M+H)+ MS (ESI+) m/z 434 (M+H) +
실시예 50 Example 50
Figure PCTKR2022021249-appb-img-000209
Figure PCTKR2022021249-appb-img-000209
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(6-옥사-2-아자스피로[3.4]옥탄-2-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(6-oxa-2-azaspiro[3.4]octane-2- 1) pyrido [2,3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 6-옥사-2-아자스피로[3.4]옥탄 염산염 을 사용하여 표제 화합물 (45 mg, 37 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 6-oxa-2 -Azaspiro[3.4]octane hydrochloride was used to give the title compound (45 mg, 37%).
1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H). 6.87 (t, J = 52.2 Hz, 1H), 6.74 (s, 1H), 5.77-5.70 (m, 1H), 4.10-4.05 (m, 4H), 3.96 (s, 2H), 3.90 (t, J = 7.0 Hz, 1H), 2.79 (s, 3H), 2.26 (t, J = 7.0 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.12 (t , J = 7.8 Hz, 1H). 6.87 (t, J = 52.2 Hz, 1H), 6.74 (s, 1H), 5.77–5.70 (m, 1H), 4.10–4.05 (m, 4H), 3.96 (s, 2H), 3.90 (t, J = 7.0 Hz, 1H), 2.79 (s, 3H), 2.26 (t, J = 7.0 Hz, 1H), 1.68 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 51 Example 51
Figure PCTKR2022021249-appb-img-000210
Figure PCTKR2022021249-appb-img-000210
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.4]옥탄-6-일)피리도[2, 3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.4]octane-6- 1) pyrido [2, 3-d] pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.4]옥탄 헤미옥살레이트 를 사용하여 표제 화합물 (14 mg, 23 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 2-oxa-6 -Azaspiro[3.4]octane hemioxalate was used to give the title compound (14 mg, 23%).
1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H). 6.87 (t, J = 52.2 Hz, 1H), 6.74 (s, 1H), 5.80-5.75 (m, 1H), 5.20 (br s, 1H), 4.72 (dd, J = 6.4, 17.2 Hz, 4H), 3.74 (s, 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.80 (s, 3H), 2.43 (t, J = 7.8 Hz, 2H),1.71 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, CDCl 3 ) δ 8.58 (d, J = 2.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 6.8 Hz, 1H), 7.14 (t , J = 7.8 Hz, 1H). 6.87 (t, J = 52.2 Hz, 1H), 6.74 (s, 1H), 5.80–5.75 (m, 1H), 5.20 (br s, 1H), 4.72 (dd, J = 6.4, 17.2 Hz, 4H), 3.74 (s, 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.80 (s, 3H), 2.43 (t, J = 7.8 Hz, 2H),1.71 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 52 Example 52
Figure PCTKR2022021249-appb-img-000211
Figure PCTKR2022021249-appb-img-000211
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-methoxypyrrolidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 유도체 (R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 을 합성하였다.Compound B-1 derivative (R)-3-chloro- N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine was synthesized.
(R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 (100 mg, 0.27 mmol) 을 (R)-3-메톡시피롤리딘 염산염 (75 mg, 0.55 mmol) 과 마이크로파 반응기에서 30 분간 가열 교반하여 표제 화합물 (56 mg, 48 %) 을 수득하였다.(R)-3-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine (100 mg, 0.27 mmol) was heated and stirred with (R)-3-methoxypyrrolidine hydrochloride (75 mg, 0.55 mmol) in a microwave reactor for 30 minutes to obtain the title compound (56 mg, 48%).
1H NMR (400 MHz, DMSO-d 6) δ 8.67 (d, J = 2.80 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J = 7.20 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 4.21 (s, 1H), 3.59 (m, 4H), 2.58 (s, 3H), 2.18 (m, 2H), 1.61 (d, J = 7.20 Hz, 3H) 1H NMR (400 MHz, DMSO- d 6 ) δ 8.67 (d, J = 2.80 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J = 7.20 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 4.21 (s, 1H), 3.59 (m, 4H), 2.58 (s, 3H), 2.18 (m, 2H), 1.61 (d, J = 7.20 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 53 Example 53
Figure PCTKR2022021249-appb-img-000212
Figure PCTKR2022021249-appb-img-000212
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-methoxypyrrolidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (S)-3-메톡시피롤리딘 염산염 을 사용하여 표제 화합물 (25 mg, 21 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (S)-3 -Methoxypyrrolidine hydrochloride was used to give the title compound (25 mg, 21%).
1H NMR (400 MHz, DMSO-d 6) δ 8.67 (d, J = 2.80 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J = 7.20 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 4.21 (s, 1H), 3.59 (m, 4H), 2.58 (s, 3H), 2.18 (m, 2H), 1.61 (d, J = 7.20 Hz, 3H) 1H NMR (400 MHz, DMSO- d 6 ) δ 8.67 (d, J = 2.80 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J = 7.20 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 4.21 (s, 1H), 3.59 (m, 4H), 2.58 (s, 3H), 2.18 (m, 2H), 1.61 (d, J = 7.20 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 54 Example 54
Figure PCTKR2022021249-appb-img-000213
Figure PCTKR2022021249-appb-img-000213
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피롤리딘-1-일)피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(pyrrolidin-1-yl)pyrido[2,3- d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 피롤리딘 을 사용하여 표제 화합물 (18 mg, 23 %) 을 수득하였다.As described in Example 52, compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then pyrrolidine was used to give the title compound (18 mg, 23%).
1H NMR (400 MHz, DMSO-d 6) δ 8.66 (d, J = 2.80 Hz, 1H), 7.58 (m, 2H), 7.45 (m, 2H), 7.38-7.11 (m, 2H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 3.50 (m, 4H), 2.57 (s, 3H), 2.06 (s, 2H), 1.61 (d, J = 7.20 Hz, 3H) 1H NMR (400 MHz, DMSO- d 6 ) δ 8.66 (d, J = 2.80 Hz, 1H), 7.58 (m, 2H), 7.45 (m, 2H), 7.38-7.11 (m, 2H), 7.39-7.11 (m, 2H), 5.70 (m, 1H), 3.50 (m, 4H), 2.57 (s, 3H), 2.06 (s, 2H), 1.61 (d, J = 7.20 Hz, 3H)
MS (ESI+) m/z 402 (M+H)+ MS (ESI+) m/z 402 (M+H) +
실시예 55 Example 55
Figure PCTKR2022021249-appb-img-000214
Figure PCTKR2022021249-appb-img-000214
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-((3aR,6aS)-테트라히드로-1H-푸로[3,4-c]피롤-5(3H)-일)피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3, 4-c] pyrrol-5 (3H) -yl) pyrido [2,3-d] pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (3aR,6aS)-헥사하이드로-1H-푸로[3,4-c]피롤 염산염 을 사용하여 표제 화합물 (20 mg, 24 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (3aR,6aS) -Hexahydro-1H-furo[3,4-c]pyrrole hydrochloride was used to give the title compound (20 mg, 24%).
1H NMR (400 MHz, DMSO-d 6) δ 8.70 (d, J = 2.40 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H), 7.59 (t, J = 7.20 Hz, 1H), 7.47 (m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 3.90 (m, 2H), 3.66 (m, 4H), 3.47 (m, 2H) 1.61 (s, 2H), 2.57 (s, 3H), 1.61 (d, J = 7.20 Hz, 3H)1H NMR (400 MHz, DMSO- d6 ) δ 8.70 (d, J = 2.40 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H) , 7.59 (t, J = 7.20 Hz, 1H), 7.47 ( m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 3.90 (m, 2H), 3.66 (m, 4H), 3.47 (m, 2H) 1.61 (s, 2H), 2.57 ( s, 3H), 1.61 (d, J = 7.20 Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 56 Example 56
Figure PCTKR2022021249-appb-img-000215
Figure PCTKR2022021249-appb-img-000215
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-fluoropyrrolidin-1-yl)-8- Methylpyrido[2,3-d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (R)-3-플루오로피롤리딘 염산염 을 사용하여 표제 화합물 (30 mg, 37 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (R)-3 -Fluoropyrrolidine hydrochloride was used to give the title compound (30 mg, 37%).
1H NMR (400 MHz, DMSO-d 6) δ 8.70 (d, J = 2.80 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.47 (m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 5.59 (d, J = 54.80 Hz, 1H), 3.83 (s, 1H), 3.73 (q, J = 7.20 Hz, 1H), 2.58 (s, 3H), 2.33 (m, 2H) 1.62 (d, J = 6.80 Hz, 3H)1H NMR (400 MHz, DMSO- d6 ) δ 8.70 (d, J = 2.80 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H) , 7.59 (t, J = 7.60 Hz, 1H), 7.47 ( m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 5.59 (d, J = 54.80 Hz, 1H), 3.83 (s, 1H), 3.73 (q, J = 7.20 Hz, 1H) ), 2.58 (s, 3H), 2.33 (m, 2H) 1.62 (d, J = 6.80 Hz, 3H)
MS (ESI+) m/z 420 (M+H)+ MS (ESI+) m/z 420 (M+H) +
실시예 57 Example 57
Figure PCTKR2022021249-appb-img-000216
Figure PCTKR2022021249-appb-img-000216
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-fluoropyrrolidin-1-yl)-8- Methylpyrido[2,3-d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (S)-3-플루오로피롤리딘 염산염 을 사용하여 표제 화합물 (6 mg, 7 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (S)-3 -Fluoropyrrolidine hydrochloride was used to give the title compound (6 mg, 7%).
1H NMR (400 MHz, DMSO-d 6) δ 8.70 (d, J = 2.80 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.47 (m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 5.59 (d, J = 54.80 Hz, 1H), 3.83 (s, 1H), 3.73 (q, J = 7.20 Hz, 1H), 2.58 (s, 3H), 2.33 (m, 2H) 1.62 (d, J = 6.80 Hz, 3H)1H NMR (400 MHz, DMSO- d6 ) δ 8.70 (d, J = 2.80 Hz, 1H), 7.64 (d, J = 2.80 Hz, 1H) , 7.59 (t, J = 7.60 Hz, 1H), 7.47 ( m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 5.59 (d, J = 54.80 Hz, 1H), 3.83 (s, 1H), 3.73 (q, J = 7.20 Hz, 1H) ), 2.58 (s, 3H), 2.33 (m, 2H) 1.62 (d, J = 6.80 Hz, 3H)
MS (ESI+) m/z 420 (M+H)+ MS (ESI+) m/z 420 (M+H) +
실시예 58 Example 58
Figure PCTKR2022021249-appb-img-000217
Figure PCTKR2022021249-appb-img-000217
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3,3-디플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3,3-difluoropyrrolidin-1-yl)-8-methyl Pyrido[2,3-d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3,3-디플루오로피롤리딘 염산염 을 사용하여 표제 화합물 (2.5 mg, 3 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3,3-di The title compound (2.5 mg, 3%) was obtained using fluoropyrrolidine hydrochloride.
1H NMR (400 MHz, DMSO-d 6) δ 8.72 (d, J = 2.80 Hz, 1H), 7.68 (d, J = 2.40 Hz, 1H), 7.59 (t, J = 7.20 Hz, 1H), 7.47 (m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 4.00 (t, J = 14.4 Hz, 2H), 3.78 (m, 2H), 2.67 (m, 2H), 2.59 (s, 3H), 1.62 (d, J = 6.80 Hz, 3H)1H NMR (400 MHz, DMSO- d6 ) δ 8.72 (d, J = 2.80 Hz, 1H), 7.68 (d, J = 2.40 Hz, 1H) , 7.59 (t, J = 7.20 Hz, 1H), 7.47 ( m, 2H), 7.38-7.11 (m, 2H), 5.70 (m, 1H), 4.00 (t, J = 14.4 Hz, 2H), 3.78 (m, 2H), 2.67 (m, 2H), 2.59 (s , 3H), 1.62 (d, J = 6.80 Hz, 3H)
MS (ESI+) m/z 438 (M+H)+ MS (ESI+) m/z 438 (M+H) +
실시예 59 Example 59
Figure PCTKR2022021249-appb-img-000218
Figure PCTKR2022021249-appb-img-000218
N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((3R,4S)-3,4-디메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((3R,4S)-3,4-dimethoxypyrrolidin-1-yl )-8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 52 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (3R,4S)-3,4-디메톡시피롤리딘 염산염 을 사용하여 표제 화합물 (21 mg, 24 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 52 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (3R,4S) -3,4-dimethoxypyrrolidine hydrochloride was used to give the title compound (21 mg, 24%).
1H NMR (400 MHz, DMSO-d 6) δ 8.65 (d, J = 2.80 Hz, 1H), 7.58 (m, 2H), 7.46 (t, J = 6.80 Hz, 1H), 7.48-7.11 (m, 3H), 5.69 (m, 1H), 4.16 (t, J = 14.4 Hz, 2H), 3.69 (m, 2H), 3.53 (m, 2H), 3.41 (s, 6H), 2.57 (s, 3H), 1.62 (d, J = 6.80 Hz, 3H)1H NMR (400 MHz, DMSO- d6 ) δ 8.65 (d, J = 2.80 Hz, 1H), 7.58 (m, 2H ), 7.46 (t, J = 6.80 Hz, 1H), 7.48-7.11 (m, 3H) ), 5.69 (m, 1H), 4.16 (t, J = 14.4 Hz, 2H), 3.69 (m, 2H), 3.53 (m, 2H), 3.41 (s, 6H), 2.57 (s, 3H), 1.62 (d, J = 6.80 Hz, 3H)
MS (ESI+) m/z 462 (M+H)+ MS (ESI+) m/z 462 (M+H) +
실시예 60 Example 60
Figure PCTKR2022021249-appb-img-000219
Figure PCTKR2022021249-appb-img-000219
(R)-4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)티오모르폴린 1,1-이산화물(R)-4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine-3 -yl)thiomorpholine 1,1-dioxide
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 유도체 (R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 을 합성하였다.Compound B-1 derivative (R)-3-chloro- N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine was synthesized.
(R)-3-클로로-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민 (60 mg, 0.16 mmol) 과 티오모르폴린 1,1-디옥사이드 (100 mg, 0.80 mmol) 을 넣고 160 ℃ 에서 4 시간 동안 가열 교반한다. 반응 혼합물을 실온으로 냉각 후, 컬럼 크로마토그래피로 정제하여 표제 화합물 (10 mg, 19 %) 을 노란색 고체로서 수득하였다.(R)-3-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine (60 mg, 0.16 mmol) and thiomorpholine 1,1-dioxide (100 mg, 0.80 mmol) were added and heated and stirred at 160°C for 4 hours. After cooling the reaction mixture to room temperature, it was purified by column chromatography to give the title compound (10 mg, 19%) as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 9.07 (s, 1H), 8.08 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 6.8 Hz, 2H), 7.39 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.12 (s, 0.5H), 5.70-5.67 (m, 1H), 4.11 (s, 4H), 3.08-3.04 (m, 1H), 2.96-2.98 (m, 1H), 2.68-2.67 (m, 1H), 2.58 (s, 3H), 2.34-2.33 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.07 (s, 1H), 8.08 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 6.8 Hz, 2H) , 7.39 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.12 (s, 0.5H), 5.70-5.67 (m, 1H), 4.11 (s, 4H), 3.08-3.04 (m, 1H) ), 2.96-2.98 (m, 1H), 2.68-2.67 (m, 1H), 2.58 (s, 3H), 2.34-2.33 (m, 1H), 1.62 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 466 (M+H)+ MS (ESI+) m/z 466 (M+H) +
실시예 61 Example 61
Figure PCTKR2022021249-appb-img-000220
Figure PCTKR2022021249-appb-img-000220
(R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페리딘-4-올(R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine-3 -yl)piperidin-4-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 4-하이드록시피페리딘 을 사용하여 표제 화합물 (10 mg, 10 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 4-hydroxyp Peridine was used to give the title compound (10 mg, 10%).
1H NMR (400 MHz, DMSO-d 6) δ 9.01 (s, 1H), 7.96 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.39 (s, 0.25H), 7.25-7.22 (m, 1.5H), 7.11 (s, 0.5H), 5.69 (t, J = 7.2 Hz, 1H), 4.80 (d, J = 4.4 Hz, 1H), 3.91-3.88 (m, 2H), 3.79-3.76 (m, 1H), 3.24-3.19 (m, 2H), 2.58 (s, 3H), 1.93-1.90 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.59-1.54 (m, 2H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.01 (s, 1H), 7.96 (s, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H) , 7.39 (s, 0.25 H), 7.25–7.22 (m, 1.5 H), 7.11 (s, 0.5 H), 5.69 (t, J = 7.2 Hz, 1 H), 4.80 (d, J = 4.4 Hz, 1 H) , 3.91–3.88 (m, 2H), 3.79–3.76 (m, 1H), 3.24–3.19 (m, 2H), 2.58 (s, 3H), 1.93–1.90 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H), 1.59-1.54 (m, 2H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 62 Example 62
Figure PCTKR2022021249-appb-img-000221
Figure PCTKR2022021249-appb-img-000221
(R)-2-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)헥사히드로피롤로 [1,2-a]피라진-6(2H)-온(R)-2-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d] Pyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (R)-헥사히드로피롤로[1,2-a]피라진-6(2H)-온 을 사용하여 표제 화합물 (14 mg, 16 %) 을 수득하였다.Compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 22, followed by (R)-hexane Hydropyrrolo[1,2-a]pyrazin-6(2H)-one was used to give the title compound (14 mg, 16%).
1H NMR (400 MHz, DMSO-d 6) δ 9.08 (s, 1H), 8.03 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.39 (s, 0.25H), 7.26-7.22 (m, 1.5H), 7.12 (s, 0.5H), 5.70 (t, J = 6.8 Hz, 1H), 4.38 (d, J = 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.78-3.74 (m, 1H), 3.03-2.99 (m, 1H), 2.94-2.90 (m, 1H), 2.77-2.72 (m, 1H), 2.59 (s, 3H), 2.35-2.30 (m, 2H), 2.34-2.21 (m, 1H), 1.72-1.69 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.08 (s, 1H), 8.03 (s, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H) , 7.47 (t, J = 6.8 Hz, 1H), 7.39 (s, 0.25H), 7.26–7.22 (m, 1.5H), 7.12 (s, 0.5H), 5.70 (t, J = 6.8 Hz, 1H) , 4.38 (d, J = 12.8 Hz, 1H), 4.18 (d, J = 12.8 Hz, 1H), 3.78–3.74 (m, 1H), 3.03–2.99 (m, 1H), 2.94–2.90 (m, 1H) ), 2.77-2.72 (m, 1H), 2.59 (s, 3H), 2.35-2.30 (m, 2H), 2.34-2.21 (m, 1H), 1.72-1.69 (m, 1H), 1.62 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 471 (M+H)+ MS (ESI+) m/z 471 (M+H) +
실시예 63 Example 63
Figure PCTKR2022021249-appb-img-000222
Figure PCTKR2022021249-appb-img-000222
(R)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d ]피리다진-5-아민(R)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[ 2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.3]헵탄 2-옥사-6-아자스피로[3.3]헵탄 을 사용하여 표제 화합물 (45 mg, 44 %) 을 수득하였다.Compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(trifluoromethyl)phenyl)ethanamine as described in Example 22, followed by 2-oxa-6-azaspiro[3.3 ]Heptane Using 2-oxa-6-azaspiro[3.3]heptane gave the title compound (45 mg, 44%).
1H NMR (400 MHz, DMSO-d 6) δ 8.46 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.55 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.79 (s, 4H), 4.29 (s, 4H), 2.57 (s, 3H), 1.6 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.46 (d, J = 2.4 Hz, 1H), 7.75 (s , 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.55 (m, 3H) , 7.45 (d, J = 7.6 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.79 (s, 4H), 4.29 (s, 4H), 2.57 (s, 3H), 1.6 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 64 Example 64
Figure PCTKR2022021249-appb-img-000223
Figure PCTKR2022021249-appb-img-000223
3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3 -d]피리다진-5-아민3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrid do[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 6-옥사-3-아자비시클로[3.1.1]헵탄 염산염 을 사용하여 표제 화합물 (38 mg, 56 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(trifluoromethyl)phenyl)ethanamine as described in Example 22, 6-oxa-3-azabicyclo[3.1 .1]heptane hydrochloride was used to give the title compound (38 mg, 56%).
1H NMR (400 MHz, DMSO-d 6) δ 8.86 (d, J = 2.8 Hz, 1H), 7.76 (m, 3H), 7.53 (m, 3H), 5.55 (t, J = 7.2 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 3.83 (d, J = 5.6 Hz, 1H), 3.81 (d, J = 5.2 Hz, 1H), 3.71 (t, J = 10.4 Hz, 2H), 3.22 (q, J = 7.2 Hz, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.8 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.86 (d, J = 2.8 Hz, 1H), 7.76 (m, 3H), 7.53 (m, 3H), 5.55 (t, J = 7.2 Hz, 1H) , 4.84 (d, J = 6.4 Hz, 2H), 3.83 (d, J = 5.6 Hz, 1H), 3.81 (d, J = 5.2 Hz, 1H), 3.71 (t, J = 10.4 Hz, 2H), 3.22 (q, J = 7.2 Hz, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.8 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 65 Example 65
Figure PCTKR2022021249-appb-img-000224
Figure PCTKR2022021249-appb-img-000224
(R)-N-(1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2 ,3-d]피리다진-5-아민(R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptane-6- yl)pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.3]헵탄 2-옥사-6-아자스피로[3.3]헵탄 을 사용하여 표제 화합물 (4.5 mg, 19 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine, followed by 2-oxa-6 -Azaspiro[3.3]heptane 2-Oxa-6-azaspiro[3.3]heptane was used to give the title compound (4.5 mg, 19%).
1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.8 Hz, 1H), 7.72 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H). 6.68 (d, J = 2.0 Hz, 1H), 5.75-5.70 (m, 1H), 5.29 (br s, 1H), 4.88 (s, 4H), 4.24-4.21 (m, 4H), 3.78 (s, 3H), 1.73 (d, J = 8.0 Hz, 3H) 1H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 2.8 Hz, 1H), 7.72 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.15 (t , J = 7.6 Hz, 1H). 6.68 (d, J = 2.0 Hz, 1H), 5.75–5.70 (m, 1H), 5.29 (br s, 1H), 4.88 (s, 4H), 4.24–4.21 (m, 4H), 3.78 (s, 3H) ), 1.73 (d, J = 8.0 Hz, 3H)
MS (ESI+) m/z 448 (M+H)+ MS (ESI+) m/z 448 (M+H) +
실시예 66 Example 66
Figure PCTKR2022021249-appb-img-000225
Figure PCTKR2022021249-appb-img-000225
(R)-N-(1-(3-(디플루오로메틸)페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d ]피리다진-5-아민(R)—N-(1-(3-(difluoromethyl)phenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[ 2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.3]헵탄 2-옥사-6-아자스피로[3.3]헵탄 을 사용하여 표제 화합물 (68 mg, 69 %) 을 수득하였다.Compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 22, followed by 2-oxa-6-azaspiro[3.3 ]Heptane Using 2-oxa-6-azaspiro[3.3]heptane gave the title compound (68 mg, 69%).
1H NMR (400 MHz, DMSO-d 6) δ 8.46 (d, J = 2.8 Hz, 1H), 7.59 (m, 3H), 7.42 (m, 3H), 7.00 (t, J = 55.8 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.79 (s, 4H), 4.30 (s, 4H), 2.57 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46 (d, J = 2.8 Hz, 1H), 7.59 (m, 3H), 7.42 (m, 3H), 7.00 (t, J = 55.8 Hz, 1H) , 5.50 (t, J = 7.2 Hz, 1H), 4.79 (s, 4H), 4.30 (s, 4H), 2.57 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 412 (M+H)+ MS (ESI+) m/z 412 (M+H) +
실시예 67 Example 67
Figure PCTKR2022021249-appb-img-000226
Figure PCTKR2022021249-appb-img-000226
3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-8-메틸피리도[2,3- d]피리다진-5-아민3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-8-methylpyryl do[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 6-옥사-3-아자비시클로[3.1.1]헵탄 염산염 을 사용하여 표제 화합물 (30 mg, 44 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 22, 6-oxa-3-azabicyclo[3.1 .1]heptane hydrochloride was used to give the title compound (30 mg, 44%).
1H NMR (400 MHz, DMSO-d 6) δ 8.86 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.61 (m, 2H), 7.44 (m, 3H), 7.01 (t, J = 55.8 Hz, 1H), 5.54 (t, J = 7.2 Hz, 1H), 4.83 (d, J = 6.4 Hz, 2H), 3.84 (d, J = 6.8 Hz, 1H) 3.81 (d, J = 6.4 Hz, 1H) 3.68 (t, J = 11.4 Hz, 2H), 3.22 (q, J = 7.3 Hz, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.86 (d, J = 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.61 (m, 2H), 7.44 (m, 3H) , 7.01 (t, J = 55.8 Hz, 1H), 5.54 (t, J = 7.2 Hz, 1H), 4.83 (d, J = 6.4 Hz, 2H), 3.84 (d, J = 6.8 Hz, 1H) 3.81 ( d, J = 6.4 Hz, 1H) 3.68 (t, J = 11.4 Hz, 2H), 3.22 (q, J = 7.3 Hz, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.8 Hz, 1H) ), 1.61 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 412 (M+H)+ MS (ESI+) m/z 412 (M+H) +
실시예 68 Example 68
Figure PCTKR2022021249-appb-img-000227
Figure PCTKR2022021249-appb-img-000227
(R)-1-(5-((1-(3-(디플루오로메틸)페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-3-메틸아제티딘-3-올(R)-1-(5-((1-(3-(difluoromethyl)phenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazin-3-yl)-3 -Methylazetidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메틸아제티딘-3-올 을 사용하여 표제 화합물 (16 mg, 29 %) 을 수득하였다.As described in Example 22, compound B-1 was synthesized using intermediate I-B and (R)-1-(3-(difluoromethyl)phenyl)ethanamine, followed by 3-methylazetidin-3-ol was used to give the title compound (16 mg, 29%).
1H NMR (400 MHz, DMSO-d 6) δ 8.47 (d, J = 2.4 Hz, 1H), 7.58 (m, 3H), 7.44 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 8.2 Hz, 2H), 7.00 (t, J = 56.0 Hz, 1H), 5.57 (s, 1H), 5.50 (t, J = 7.0 Hz, 1H), 4.03 (d, J = 3.6 Hz, 2H), 4.03 (d, J = 3.6 Hz, 2H), 2.58 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H), 1.51 (s, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.47 (d, J = 2.4 Hz, 1H), 7.58 (m, 3H), 7.44 ( t, J = 7.4 Hz, 1H), 7.38 (t, J = 8.2 Hz, 2H), 7.00 (t, J = 56.0 Hz, 1H), 5.57 (s, 1H), 5.50 (t, J = 7.0 Hz, 1H), 4.03 (d, J = 3.6 Hz, 2H), 4.03 (d, J = 3.6 Hz, 2H), 2.58 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H), 1.51 (s, 3H)
MS (ESI+) m/z 400 (M+H)+ MS (ESI+) m/z 400 (M+H) +
실시예 69 Example 69
Figure PCTKR2022021249-appb-img-000228
Figure PCTKR2022021249-appb-img-000228
(R)-3-(1-((8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-일)아미노) 에틸)벤조니트릴(R)-3-(1-((8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[2,3-d]pyridazin-5-yl )amino)ethyl)benzonitrile
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-3-(1-아미노에틸)벤조니트릴 을 사용하여 화합물 B-1 을 합성 후, 2-옥사-6-아자스피로[3.3]헵탄 2-옥사-6-아자스피로[3.3]헵탄 을 사용하여 표제 화합물 (30 mg, 45 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-3-(1-aminoethyl)benzonitrile as described in Example 22, 2-oxa-6-azaspiro[3.3]heptane 2-oxa -6-Azaspiro[3.3]heptane gave the title compound (30 mg, 45%).
1H NMR (400 MHz, DMSO-d 6) δ 8.47 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 5.46 (t, J = 6.8 Hz, 1H), 4.79 (s, 4H), 4.08 (s, 4H), 2.58 (s, 3H), 1.59 (t, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.47 (d, J = 2.8 Hz, 1H), 7.85 (s , 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 5.46 (t, J = 6.8 Hz) , 1H), 4.79 (s, 4H), 4.08 (s, 4H), 2.58 (s, 3H), 1.59 (t, J = 6.8 Hz, 3H)
MS (ESI+) m/z 387 (M+H)+ MS (ESI+) m/z 387 (M+H) +
실시예 70 Example 70
Figure PCTKR2022021249-appb-img-000229
Figure PCTKR2022021249-appb-img-000229
3-((1R)-1-((3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노 )에틸)벤조니트릴3-((1R)-1-((3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-methylpyrido[2,3-d]pyridazine-5 -yl) amino ) ethyl) benzonitrile
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-3-(1-아미노에틸)벤조니트릴 을 사용하여 화합물 B-1 을 합성 후, 6-옥사-3-아자비시클로[3.1.1]헵탄 염산염 을 사용하여 표제 화합물 (15 mg, 20 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-3-(1-aminoethyl)benzonitrile, followed by 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used to give the title compound (15 mg, 20%).
1H NMR (400 MHz, DMSO-d 6) δ 8.86 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.50 (m, 2H), 5.50 (t, J = 7.0 Hz, 1H), 4.83 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 7.2 Hz, 1H), 3.81 (d, J = 6.4 Hz, 1H), 3.69 (d, J = 12.2 Hz, 2H), 3.26 (m, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.4 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.86 (d, J = 2.4 Hz, 1H), 7.86 ( s , 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.50 (m, 2H), 5.50 (t, J = 7.0 Hz, 1H), 4.83 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 7.2 Hz, 1H), 3.81 (d, J = 6.4 Hz, 1H), 3.69 (d, J = 12.2 Hz, 2H), 3.26 (m, 1H), 2.61 (s, 3H), 1.99 (d, J = 8.4 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 387 (M+H)+ MS (ESI+) m/z 387 (M+H) +
실시예 71 Example 71
Figure PCTKR2022021249-appb-img-000230
Figure PCTKR2022021249-appb-img-000230
(R)-3-(1-((3-(3-히드록시-3-메틸아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴(R)-3-(1-((3-(3-hydroxy-3-methylazetidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5-yl)amino )ethyl)benzonitrile
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-3-(1-아미노에틸)벤조니트릴 을 사용하여 화합물 B-1 을 합성 후, 3-메틸아제티딘-3-올 을 사용하여 표제 화합물 (9 mg, 13 %) 을 수득하였다.As described in Example 22, after synthesizing compound B-1 using intermediate I-B and (R)-3-(1-aminoethyl)benzonitrile, using 3-methylazetidin-3-ol to obtain the title compound ( 9 mg, 13%).
1H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.52 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 5.76 (s, 1H), 5.45 (t, J = 7.2 Hz, 1H), 4.05 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 4.4 Hz, 1H), 3.94 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.51 (s, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.48 (d, J = 2.4 Hz, 1H), 7.86 (s , 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 6.4 Hz, 1H), 7.52 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 5.76 (s, 1H), 5.45 (t, J = 7.2 Hz, 1H), 4.05 (d, J = 7.2 Hz, 1H) 4.8 Hz, 1H), 4.03 (d, J = 4.4 Hz, 1H), 3.94 (d, J = 8.0 Hz, 2H), 2.58 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.51 (s, 3H)
MS (ESI+) m/z 375 (M+H)+ MS (ESI+) m/z 375 (M+H) +
실시예 72 Example 72
Figure PCTKR2022021249-appb-img-000231
Figure PCTKR2022021249-appb-img-000231
(S)-1-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피롤리딘-3-올(S)-1-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d] Pyridazin-3-yl)pyrrolidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (S)-피롤리딘-3-올 을 사용하여 표제 화합물 (57 mg, 51 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 22, (S)-P Rolidin-3-ol gave the title compound (57 mg, 51%).
1H NMR (400 MHz, DMSO-d 6) δ 8.73 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.0 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.62 (t, J = 7.0 Hz, 1H), 5.20 (d, J = 3.6 Hz, 1H), 3.63 (m, 3H), 3.45 (m, 1H), 2.62 (s, 3H), 2.14 (m, 1H), 2.02 (m, 1H), 1.63 (d, J = 6.8 Hz, 1H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.73 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 7.60 (t, J = 7.4 Hz, 1H) , 7.49 (t, J = 7.0 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 5.62 (t, J = 7.0 Hz, 1H), 5.20 (d, J = 3.6 Hz, 1H), 3.63 (m, 3H), 3.45 (m, 1H), 2.62 (s, 3H), 2.14 (m, 1H), 2.02 (m, 1H), 1.63 (d, J = 6.8 Hz, 1H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 73 Example 73
Figure PCTKR2022021249-appb-img-000232
Figure PCTKR2022021249-appb-img-000232
(R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-4-메틸피페리딘-4-올(R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine-3 -yl) -4-methylpiperidin-4-ol
실시예 60 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 4-메틸-4-피페리디놀을 사용하여 표제 화합물 (10 mg, 14 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 60 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 4-methyl-4 -Piperidinol was used to give the title compound (10 mg, 14%).
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.39 (s, 0.25H), 7.26-7.21 (m, 1.5H), 7.12 (s, 0.25H), 5.69-5.66 (m, 1H), 4.49 (s, 1H), 3.78-3.75 (m, 2H), 2.67 (s, 3H), 1.65-1.59 (m, 7H), 1.20 (s, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.8 Hz , 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.39 (s, 0.25H), 7.26–7.21 (m, 1.5H), 7.12 (s, 0.25H), 5.69 -5.66 (m, 1H), 4.49 (s, 1H), 3.78-3.75 (m, 2H), 2.67 (s, 3H), 1.65-1.59 (m, 7H), 1.20 (s, 3H)
MS (ESI+) m/z 446 (M+H)+ MS (ESI+) m/z 446 (M+H) +
실시예 74 Example 74
Figure PCTKR2022021249-appb-img-000233
Figure PCTKR2022021249-appb-img-000233
(R)-(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)(옥세탄-3-일)메탄온(R)-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine- 3-yl)piperazin-1-yl)(oxetan-3-yl)methanone
단계 1Step 1
Figure PCTKR2022021249-appb-img-000234
Figure PCTKR2022021249-appb-img-000234
(R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피페라진-1-일)피리도[2,3-d]피리다진-5-아민 염산염(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(piperazin-1-yl)pyrido[2,3-d ]Pyridazin-5-amine hydrochloride
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 1-(tert-부톡시카르보닐)피페라진을 사용하여 (R)-tert-부틸 4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-카복실레이트 (50 mg, 60 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 1-(tert- (R)-tert-butyl 4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl using butoxycarbonyl)piperazine Pyrido[2,3-d]pyridazin-3-yl)piperazine-1-carboxylate (50 mg, 60%) was obtained.
디클로로메탄 (0.5 ml) 중 (R)-tert-부틸 4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-카복실레이트 (50 mg, 0.10 mmol)이 용해된 용액에 1,4-디옥산 중 4 N 염산 용액 (0.12 ml, 2.0 mmol) 을 0 ℃ 에서 첨가한 후 상온에서 1 시간 동안 교반하였다. 반응 종결 후, 농축시켜 (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피페라진-1-일)피리도[2,3-d]피리다진-5-아민 염산염 (70 mg, 98 %) 을 갈색 고체로서 수득하였다. (R)-tert-butyl 4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[ 2,3-d]pyridazin-3-yl)piperazine-1-carboxylate (50 mg, 0.10 mmol) was dissolved in a solution of 4 N hydrochloric acid in 1,4-dioxane (0.12 ml, 2.0 mmol) was added at 0 °C and stirred at room temperature for 1 hour. After completion of the reaction, it is concentrated to (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(piperazin-1-yl)pyrido [2,3-d]pyridazin-5-amine hydrochloride (70 mg, 98%) was obtained as a brown solid.
MS (ESI+) m/z 417 (M+H)+ MS (ESI+) m/z 417 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000235
Figure PCTKR2022021249-appb-img-000235
(R)-(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)(옥세탄-3-일)메탄온(R)-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine- 3-yl)piperazin-1-yl)(oxetan-3-yl)methanone
디메틸설폭사이드 (0.25 ml) 중에 (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피페라진-1-일)피리도[2,3-d]피리다진-5-아민 염산염 (10 mg, 0.020 mmol), 옥세탄-3-카복실산 (3 mg, 0.024 mmol), HATU (10 mg, 0.024 mmol), N,N-디이소프로필에틸아민 (0.10 ml, 0.06 mmol) 을 첨가한 후, 상온에서 1 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가한 뒤, 에틸 아세테이트로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축 시킨 뒤, 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)(옥세탄-3-일)메탄온 (10 mg, 42 %) 을 노란색 고체로 수득하였다.(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(piperazin-1-yl) in dimethyl sulfoxide (0.25 ml) Pyrido[2,3-d]pyridazin-5-amine hydrochloride (10 mg, 0.020 mmol), oxetane-3-carboxylic acid (3 mg, 0.024 mmol), HATU (10 mg, 0.024 mmol), N,N After adding -diisopropylethylamine (0.10 ml, 0.06 mmol), the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and extracted with ethyl acetate. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to obtain (R)-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-8-methylpyrido[2,3-d]pyridazin-3-yl)piperazin-1-yl)(oxetan-3-yl)methanone (10 mg, 42%) Obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ 8.88 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.03 (s, 0.25H), 6.89 (s, 0.50H), 6.76 (s, 0.25H), 5.62-5.60 (m, 1H), 3.94 (s, 2H), 3.76 (s, 2H), 3.58 (s, 2H), 3.48 (s, 2H), 2.57 (s, 3H), 1.97-1.93 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 0.86-0.77 (m, 4H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.88 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 7.2 Hz , 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.03 (s, 0.25H), 6.89 (s, 0.50H), 6.76 (s, 0.25H), 5.62–5.60 (m, 1H), 3.94 (s, 2H), 3.76 (s, 2H), 3.58 (s, 2H), 3.48 (s, 2H), 2.57 (s, 3H), 1.97-1.93 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 0.86-0.77 (m, 4H)
MS (ESI+) m/z 485 (M+H)+ MS (ESI+) m/z 485 (M+H) +
실시예 75 Example 75
Figure PCTKR2022021249-appb-img-000236
Figure PCTKR2022021249-appb-img-000236
(R)-1-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피롤리딘-3-올(R)-1-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d] Pyridazin-3-yl)pyrrolidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (R)-피롤리딘-3-올 을 사용하여 표제 화합물 (8 mg, 11 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 22, (R)-P Rolidin-3-ol was used to give the title compound (8 mg, 11%).
1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (s, 0.25H), 7.25-7.21 (m, 1.50H), 7.12 (s, 0.25H), 5.70-5.67 (m, 1H), 5.14 (d, J = 3.6 Hz, 1H), 4.51 (s, 1H), 3.66-3.57 (m, 3H), 2.57 (s, 3H), 2.33-2.14 (m, 1H), 2.03-1.99 (m, 1H), 1.58 (d, J = 12.4 Hz, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (d, J = 2.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (s, 0.25H) , 7.25–7.21 (m, 1.50H), 7.12 (s, 0.25H), 5.70–5.67 (m, 1H), 5.14 (d, J = 3.6 Hz, 1H), 4.51 (s, 1H), 3.66–3.57 (m, 3H), 2.57 (s, 3H), 2.33-2.14 (m, 1H), 2.03-1.99 (m, 1H), 1.58 (d, J = 12.4 Hz, 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 76 Example 76
Figure PCTKR2022021249-appb-img-000237
Figure PCTKR2022021249-appb-img-000237
(R)-3-메틸-1-(8-메틸-5-((1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)아미노)피리도[2,3-d]피리다진-3-일)아제티딘-3-올(R)-3-methyl-1-(8-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyridonium minced-3-yl)azetidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-메틸아제티딘-3-올 을 사용하여 표제 화합물 (10 mg, 13 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine, followed by 3-methylazetidine- Use of 3-ol gave the title compound (10 mg, 13%).
1H NMR (400 MHz, DMSO-d 6) δ 8.47 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 5.67 (t, J = 6.8 Hz, 1H), 4.05 (d, J = 4.4 Hz, 1H), 4.03 (d, J = 4.4 Hz, 1H), 3.94 (t, J = 8.0 Hz, 2H), 2.56 (s, 6H), 1.55 (d, J = 6.8 Hz, 3H), 1.51 (s, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.47 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 2.8 Hz , 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 5.67 (t, J = 6.8 Hz) , 1H), 4.05 (d, J = 4.4 Hz, 1H), 4.03 (d, J = 4.4 Hz, 1H), 3.94 (t, J = 8.0 Hz, 2H), 2.56 (s, 6H), 1.55 (d , J = 6.8 Hz, 3H), 1.51 (s, 3H)
MS (ESI+) m/z 432 (M+H)+ MS (ESI+) m/z 432 (M+H) +
실시예 77 Example 77
Figure PCTKR2022021249-appb-img-000238
Figure PCTKR2022021249-appb-img-000238
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-8-메틸-N-((R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl )ethyl)pyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (5 mg, 6 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine, followed by 3-oxa-8- The title compound (5 mg, 6%) was obtained using azabicyclo[3.2.1]octane hydrochloride.
1H NMR (400 MHz, DMSO-d 6) δ 8.79 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 5.53 (t, J = 6.8 Hz, 1H), 4.45 (s, 2H), 3.65 (d, J = 5.2 Hz, 1H), 3.62 (d, J = 5.2 Hz, 1H), 3.46 (d, J = 10.8 Hz, 2H), 2.45 (s, 6H), 1.92 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.79 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 7.6 Hz , 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 5.53 (t, J = 6.8 Hz, 1H), 4.45 (s , 2H), 3.65 (d, J = 5.2 Hz, 1H), 3.62 (d, J = 5.2 Hz, 1H), 3.46 (d, J = 10.8 Hz, 2H), 2.45 (s, 6H), 1.92 (m , 4H), 1.42 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 458 (M+H)+ MS (ESI+) m/z 458 (M+H) +
실시예 78 Example 78
Figure PCTKR2022021249-appb-img-000239
Figure PCTKR2022021249-appb-img-000239
(R)-N-(1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에틸)-8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-아민(R)-N-(1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3-d] Pyridazin-5-amine
실시예 18 에 기재된 바와 같이 중간체 I-A, 모르폴린, 중간체 I-J 를 사용하여 표제 화합물 (55 mg, 41 %) 을 노란색 고체로서 수득하였다.Intermediate I-A, morpholine, intermediate I-J were used as described in Example 18 to give the title compound (55 mg, 41%) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 5.54-5.50 (m, 1H), 3.91-3.83 (m, 6H), 3.48-3.46 (m, 4H), 3.29 (s, 3H), 2.60 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.03 (d, J = 2.8 Hz, 1H), 7.96 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 5.54-5.50 (m, 1H) , 3.91–3.83 (m, 6H), 3.48–3.46 (m, 4H), 3.29 (s, 3H), 2.60 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 79 Example 79
Figure PCTKR2022021249-appb-img-000240
Figure PCTKR2022021249-appb-img-000240
3-(8-옥사-3-아자비시클로[3.2.1]옥탄-3-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 8-옥사-3-아자비시클로[3.2.1]옥탄 을 사용하여 표제 화합물 (12 mg, 14 %)을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 8-oxa-3 -Azabicyclo[3.2.1]octane was used to give the title compound (12 mg, 14%).
1H NMR (400 MHz, DMSO-d 6) δ 8.95 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.50-7.47 (m, 2H), 7.39 (s, 0.25H), 7.25 (m, 1.50H), 7.11 (s, 0.28H), 5.69-5.62 (m, 1H), 4.56 (s, 2H), 3.80-3.76 (m, 2H), 3.12-3.08 (m, 2H), 2.58 (s, 3H), 1.90 (, s, 4H), 1.61 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.95 (d, J = 2.8 Hz, 1H), 7.86 (d, J = 2.4 Hz , 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.50 -7.47 (m, 2H), 7.39 (s, 0.25H), 7.25 (m, 1.50H), 7.11 (s, 0.28H), 5.69-5.62 (m, 1H), 4.56 (s, 2H), 3.80- 3.76 (m, 2H), 3.12-3.08 (m, 2H), 2.58 (s, 3H), 1.90 (, s, 4H), 1.61 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 80 Example 80
Figure PCTKR2022021249-appb-img-000241
Figure PCTKR2022021249-appb-img-000241
(R)-시클로프로필(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)메타논(R)-cyclopropyl(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridonium Chopped-3-yl)piperazin-1-yl)methanone
실시예 74 에 기재된 바와 같이 (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피페라진-1-일)피리도[2,3-d]피리다진-5-아민 염산염 을 얻는다. As described in Example 74 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(piperazin-1-yl)pyridine Do[2,3-d]pyridazin-5-amine hydrochloride is obtained.
디클로로메탄 (0.2 ml) 중에 (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피페라진-1-일)피리도[2,3-d]피리다진-5-아민 염산염 (5 mg, 0.01 mmol), 사이클로펜탄카보닐 클로라이드 (5 mg, 0.03 mmol), 트리에틸아민 (0.02 ml, 0.06 mmol) 을 첨가한 후 상온에서 2시간 동안 교반한다. 반응 종결을 확인하고 농축 시킨 뒤, 잔류물을 컬럼 크로마토그래피로 정제하여 (R)-시클로프로필(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)메타논 (2 mg, 43 %) 을 노란색 고체로 수득하였다. (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(piperazin-1-yl)pyridine in dichloromethane (0.2 ml) After adding do[2,3-d]pyridazin-5-amine hydrochloride (5 mg, 0.01 mmol), cyclopentanecarbonyl chloride (5 mg, 0.03 mmol) and triethylamine (0.02 ml, 0.06 mmol) Stir for 2 hours at room temperature. After confirming the completion of the reaction and concentrating, the residue was purified by column chromatography to obtain (R)-cyclopropyl(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl) Obtained ethyl)amino)-8-methylpyrido[2,3-d]pyridazin-3-yl)piperazin-1-yl)methanone (2 mg, 43%) as a yellow solid.
1H NMR (400 MHz, MeOD) δ 8.88 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.03 (s, 0.25H), 6.89 (s, 0.50H), 6.76 (s, 0.25H), 5.62-5.60 (m, 1H), 3.94 (s, 2H), 3.76 (s, 2H), 3.58 (s, 2H), 3.48 (s, 2H), 2.57 (s, 3H), 1.97-1.93 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 0.86-0.77 (m, 4H) 1H NMR (400 MHz, MeOD) δ 8.88 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.03 (s, 0.25H), 6.89 (s, 0.50H), 6.76 (s, 0.25H), 5.62–5.60 (m, 1H), 3.94 (s, 2H), 3.76 (s, 2H), 3.58 (s, 2H), 3.48 (s, 2H), 2.57 (s, 3H), 1.97-1.93 (m, 1H), 1.59 (d , J = 6.8 Hz, 3H), 0.86–0.77 (m, 4H)
MS (ESI+) m/z 485 (M+H)+ MS (ESI+) m/z 485 (M+H) +
실시예 81 Example 81
Figure PCTKR2022021249-appb-img-000242
Figure PCTKR2022021249-appb-img-000242
(R)-2-메틸-3-(1-((8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴(R)-2-methyl-3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-yl)amino)ethyl)benzonitrile
단계 1.Step 1.
Figure PCTKR2022021249-appb-img-000243
Figure PCTKR2022021249-appb-img-000243
(R)-N-(1-(3-브로모-2-메틸페닐)에틸)-8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-아민(R)—N-(1-(3-bromo-2-methylphenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-amine
실시예 1 에 기재된 바와 같이 중간체 I-A 와 모르폴린을 사용하여 화합물 A-2 합성 후, I-K (90 mg, 0.36 mmol)과 N,N-디이소프로필에틸아민 (0.16 mL, 0.9 mmol) 을 사용하여 (R)-N-(1-(3-브로모-2-메틸페닐)에틸)-8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-아민 (124 mg, 94 %) 을 수득하였다. Compound A-2 was synthesized using intermediate I-A and morpholine as described in Example 1, followed by I-K (90 mg, 0.36 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) (R) -N- (1- (3-bromo-2-methylphenyl) ethyl) -8-methyl-3-morpholinopyrido [2,3-d] pyridazin-5-amine (124 mg, 94%) was obtained.
MS (ESI+) m/z 442 (M+H)+ MS (ESI+) m/z 442 (M+H) +
단계 2. Step 2.
Figure PCTKR2022021249-appb-img-000244
Figure PCTKR2022021249-appb-img-000244
(R)-2-메틸-3-(1-((8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴(R)-2-methyl-3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-yl)amino)ethyl)benzonitrile
N,N-디메틸아세트아미드 (1.8mL) 중에 (R)-N-(1-(3-브로모-2-메틸페닐)에틸)-8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-아민 (80 mg, 0.18 mmol), 시안화아연 (42 mg, 0.36 mmol), 트리스(디벤질리덴아세톤)디팔라듐 (16 mg, 0.018 mmol), 1,1'-비스(디페닐포스피노)페로센 (20 mg, 0.036 mmol), 아연 (1.2 mg, 0.018 mmol) 을 첨가한 후 질소 충전하여 140°C에서 15 시간 동안 교반한다. 반응 종결을 확인하고 물을 첨가한 뒤, 디클로로메탄 으로 추출하였다. 합쳐진 유기 추출물을 황산나트륨 상에서 건조시키고 농축 시킨 뒤, 잔류물을 컬럼 크로마토그래피, 분취 크로마토그래피로 정제하여 (R)-2-메틸-3-(1-((8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴 (15 mg, 21 %) 을 수득하였다. (R)-N-(1-(3-bromo-2-methylphenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3- in N,N-dimethylacetamide (1.8 mL) d] pyridazin-5-amine (80 mg, 0.18 mmol), zinc cyanide (42 mg, 0.36 mmol), tris (dibenzylideneacetone) dipalladium (16 mg, 0.018 mmol), 1,1'-bis( After adding diphenylphosphino)ferrocene (20 mg, 0.036 mmol) and zinc (1.2 mg, 0.018 mmol), the mixture was filled with nitrogen and stirred at 140°C for 15 hours. After confirming the completion of the reaction, water was added and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was purified by column chromatography, preparative chromatography, (R)-2-methyl-3-(1-((8-methyl-3-morpholinopyr Do[2,3-d]pyridazin-5-yl)amino)ethyl)benzonitrile (15 mg, 21%) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 9.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 5.57 (t, J = 7.0 Hz, 1H), 4.45 (s, 2H), 3.84 (t, J = 4.6 Hz, 4H), 3.47 (t, J = 4.8 Hz, 4H, 2.67 (s, 3H), 2.59 (s, 3H), 1.55 (d, J = 6.8 Hz, 1H) 1H NMR (400 MHz, DMSO- d6 ) δ 9.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.0 Hz , 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 5.57 (t, J = 7.0 Hz, 1H), 4.45 (s , 2H), 3.84 (t, J = 4.6 Hz, 4H), 3.47 (t, J = 4.8 Hz, 4H, 2.67 (s, 3H), 2.59 (s, 3H), 1.55 (d, J = 6.8 Hz, 1H)
MS (ESI+) m/z 389 (M+H)+ MS (ESI+) m/z 389 (M+H) +
실시예 82 Example 82
Figure PCTKR2022021249-appb-img-000245
Figure PCTKR2022021249-appb-img-000245
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-8-메틸피리도[2,3- d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-8-methylpyridine do[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (38 mg, 45 %) 을 수득하였다.After synthesizing compound B-1 using intermediate I-B and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 22, 3-oxa-8-azabicyclo[3.2 .1]octane hydrochloride was used to give the title compound (38 mg, 45%).
1H NMR (400 MHz, DMSO-d 6) δ 8.92 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 56.0 Hz, 1H), 5.52 (t, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.77 (d, J = 4.0 Hz, 2H), 3.74 (d, J = 5.2 Hz, 2H), 2.51 (s, 3H), 2.05 (m, 4H), 1.60 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.92 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H) , 7.45 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 56.0 Hz, 1H), 5.52 (t, J = 7.4 Hz, 1H), 4.57 (s, 2H), 3.77 (d, J = 4.0 Hz, 2H), 3.74 (d, J = 5.2 Hz, 2H), 2.51 (s, 3H), 2.05 (m, 4H), 1.60 (d, J = 7.2 Hz, 3H)
MS (ESI+) m/z 426 (M+H)+ MS (ESI+) m/z 426 (M+H) +
실시예 83 Example 83
Figure PCTKR2022021249-appb-img-000246
Figure PCTKR2022021249-appb-img-000246
3-((1R,4R)-2-옥사-5-아자비시클로[2.2.1]헵탄-5-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2- Fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 을 사용하여 화합물 B-1 을 합성 후, (1R,4R)-2-옥사-5-아자비시클로[2.2.1]헵탄 염산염을 사용하여 표제 화합물 (9 mg, 13 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by (1R,4R) -2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used to give the title compound (9 mg, 13%).
1H NMR (400 MHz, DMSO-d 6) δ 8.74 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.38-7.04 (m, 3H), 5.69 (t, J = 7.2 Hz, 1H), 4.97 (s, 1H), 4.78(s, 1H), 3.88 (d, J = 7.6 Hz, 1H), 3.75 (d, J = 7.6 Hz, 1H), 3.67 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H), 2.07-1.97 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.74 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.58 (t, J = 7.2 Hz , 1H), 7.47 (t, J = 6.8 Hz, 1H), 7.38-7.04 (m, 3H), 5.69 (t, J = 7.2 Hz, 1H), 4.97 (s, 1H), 4.78(s, 1H), 3.88 (d, J = 7.6 Hz, 1H), 3.75 (d, J = 7.6 Hz, 1H), 3.67 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H), 2.07–1.97 (m, 2H), 1.61 ( d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 430 (M+H)+ MS (ESI+) m/z 430 (M+H) +
실시예 84 Example 84
Figure PCTKR2022021249-appb-img-000247
Figure PCTKR2022021249-appb-img-000247
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3 -d]피리다진-5-아민 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrid do[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (1R)-1-[3-(트리플루오로메틸)페닐]에탄-1-아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (7.5 mg, 9 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine, followed by 3-oxa-8-azabi Cyclo[3.2.1]octane hydrochloride was used to give the title compound (7.5 mg, 9%).
1H NMR (400 MHz, DMSO-d 6) δ 8.93 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.55 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.57 (s, 2H), 3.77 (d, J = 4.8 Hz, 1H), 3.74 (d, J = 4.8 Hz, 1H), 3.58 (d, J = 10.8 Hz, 2H), 2.58 (s, 3H), 2.04 (m, 4H), 1.60 (d, J = 7.2 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.93 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H ), 7.75 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.55 (m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.57 (s, 2H), 3.77 (d, J = 4.8 Hz, 1H), 3.74 (d, J = 4.8 Hz, 1H), 3.58 (d, J = 10.8 Hz, 2H), 2.58 (s, 3H), 2.04 (m, 4H), 1.60 (d, J = 10.8 Hz, 2H ) . 7.2Hz, 3H)
MS (ESI+) m/z 444 (M+H)+ MS (ESI+) m/z 444 (M+H) +
실시예 85 Example 85
Figure PCTKR2022021249-appb-img-000248
Figure PCTKR2022021249-appb-img-000248
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2,3-디플루오로페닐)에틸)-8-메틸피리도[2,3-d ]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2,3-difluorophenyl)ethyl)-8-methylpyrido [2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (1R)-1-(2,3-디플루오로페닐)에탄-1-아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (40 mg, 46 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (1R)-1-(2,3-difluorophenyl)ethan-1-amine, followed by 3-oxa-8-azabicyclo [3.2.1]octane hydrochloride was used to give the title compound (40 mg, 46%).
1H NMR (400 MHz, DMSO-d 6) δ 8.92 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.28-7.18 (m, 2H), 7.12-7.07 (m, 1H), 5.64 (quin, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.77 (d, J = 7.2 Hz, 1H), 3.74 (d, J = 7.2 Hz, 1H), 3.60 (s, 1H), 3.57 (s, 1H), 2.58 (s, 3H), 2.08-1.97 (m, 4H), 1.60 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.92 (d, J = 2.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 7.2 Hz , 1H), 7.28 -7.18 (m, 2H), 7.12-7.07 (m, 1H), 5.64 (quin, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.77 (d, J = 7.2 Hz, 1H), 3.74 ( d, J = 7.2 Hz, 1H), 3.60 (s, 1H), 3.57 (s, 1H), 2.58 (s, 3H), 2.08–1.97 (m, 4H), 1.60 (d, J = 6.8 Hz, 3H) )
MS (ESI+) m/z 412 (M+H)+ MS (ESI+) m/z 412 (M+H) +
실시예 86 Example 86
Figure PCTKR2022021249-appb-img-000249
Figure PCTKR2022021249-appb-img-000249
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2,4-디플루오로페닐)에틸)-8-메틸피리도[2,3-d ]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-methylpyrido [2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (1R)-1-(2,4-디플루오로페닐)에탄-1-아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (4 mg, 3 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (1R)-1-(2,4-difluorophenyl)ethan-1-amine, followed by 3-oxa-8-azabicyclo [3.2.1]octane hydrochloride was used to give the title compound (4 mg, 3%).
1H NMR (400 MHz, MeOD-d 4) δ 8.86 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.46-7.40 (m, 1H), 6.94-6.83 (m, 2H), 5.64 (q, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.91 (d, J = 11.2 Hz, 2H), 3.65 (d, J = 10.8 Hz, 2H), 2.69 (s, 3H), 2.23-2.11 (m, 4H), 1.67 (d, J = 6.8 Hz, 3H) 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.86 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.46-7.40 (m, 1H), 6.94-6.83 ( m, 2H), 5.64 (q, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.91 (d, J = 11.2 Hz, 2H), 3.65 (d, J = 10.8 Hz, 2H), 2.69 ( s, 3H), 2.23–2.11 (m, 4H), 1.67 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 412 (M+H)+ MS (ESI+) m/z 412 (M+H) +
실시예 87 Example 87
Figure PCTKR2022021249-appb-img-000250
Figure PCTKR2022021249-appb-img-000250
(R)-3-메틸-1-(8-메틸-5-((1-(3-(트리플루오로메틸)페닐)에틸)아미노)피리도[2,3-d]피리다진-3-일)아제티딘-3-올(R)-3-methyl-1-(8-methyl-5-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyridazine-3- 1) azetidin-3-ol
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (1R)-1-[3-(트리플루오로메틸)페닐]에탄-1-아민 을 사용하여 화합물 B-1 을 합성 후, 3-메틸아제티딘-3-올 을 사용하여 표제 화합물 (67 mg, 74 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine, followed by 3-methylazetidine-3 -Ol gave the title compound (67 mg, 74%).
1H NMR (400 MHz, DMSO-d 6) δ 8.48 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.54 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.05 (d, J = 3.2 Hz, 1H), 4.03 (d, J = 3.6 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 2.58 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.51 (s, 3H) 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.48 (d, J = 2.8 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.54 (m, 3H) , 7.40 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.05 (d, J = 3.2 Hz, 1H), 4.03 (d, J = 3.6 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 2.58 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.51 (s, 3H)
MS (ESI+) m/z 418 (M+H)+ MS (ESI+) m/z 418 (M+H) +
실시예 88 Example 88
Figure PCTKR2022021249-appb-img-000251
Figure PCTKR2022021249-appb-img-000251
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl) -8-methylpyrido[2,3-d]pyridazin-5-amine
실시예 22 에 기재된 바와 같이 중간체 I-B 와 (1R)-1-[2-플루오로-3-(트리플루오로메틸)페닐]에탄-1-아민 을 사용하여 화합물 B-1 을 합성 후, 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 을 사용하여 표제 화합물 (33 mg, 28 %) 을 수득하였다.Compound B-1 was synthesized as described in Example 22 using intermediate I-B and (1R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]ethan-1-amine, followed by 3- Oxa-8-azabicyclo[3.2.1]octane hydrochloride was used to give the title compound (33 mg, 28%).
1H NMR (400 MHz, DMSO-d 6) δ 8.92 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.61 (t, J = 6.8 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 5.66 (q, J = 6.8 Hz, 1H), 4.58 (s, 2H), 3.79-3.74 (m, 2H), 3.60 (s, 1H), 3.57 (s, 1H), 2.57 (s, 3H), 2.11-1.97 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H) 1H NMR (400 MHz, DMSO- d6 ) δ 8.92 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 2.4 Hz , 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.61 (t, J = 6.8 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 5.66 (q, J = 6.8 Hz, 1H), 4.58 (s , 2H), 3.79-3.74 (m, 2H), 3.60 (s, 1H), 3.57 (s, 1H), 2.57 (s, 3H), 2.11-1.97 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H)
MS (ESI+) m/z 462 (M+H)+ MS (ESI+) m/z 462 (M+H) +
합성법 Csynthesis method C
Figure PCTKR2022021249-appb-img-000252
Figure PCTKR2022021249-appb-img-000252
화합물 C-2 의 일반적인 합성은 합성법 C 에 예시되어 있다. 중간체 I-L 를 중간체 I-C ~ I-H 또는 상업적으로 구매 가능한 시약 중 선택하여 친핵성 방향족 치환 반응으로 화합물 C-1 을 합성하고, H-R4 아민과 부흐발트-하트위그 아민화 반응을 진행하여 최종 화합물 C-2 를 합성한다.The general synthesis of compound C-2 is illustrated in Synthesis Method C. Intermediate IL was selected from intermediates IC to IH or commercially available reagents to synthesize compound C-1 through a nucleophilic aromatic substitution reaction, followed by Buchwald-Hartwig amination reaction with HR 4 amine to obtain final compound C-2 synthesize
실시예 89 Example 89
Figure PCTKR2022021249-appb-img-000253
Figure PCTKR2022021249-appb-img-000253
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-methoxy-8-methylpyrido[2,3-d]pyridazin-5-amine
단계 1Step 1
Figure PCTKR2022021249-appb-img-000254
Figure PCTKR2022021249-appb-img-000254
(R)-3-브로모-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민(R)-3-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methoxy-8-methylpyrido[2,3-d] Pyridazin-5-amine
중간체 I-L (1 eq) 과 (R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에탄아민 (1.2 eq) 에 디이소프로필에틸아민 (3 eq) 을 첨가한 후 140°C 에서 12 시간 교반하였다. 반응물을 실온으로 냉각 후, 컬럼 크로마토그래피로 정제하여 3-브로모-N-[(1R)-1-[3-(디플루오로메틸)-2-플루오로페닐]에틸]-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민 을 수득하였다. After adding diisopropylethylamine (3 eq) to intermediate I-L (1 eq) and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine (1.2 eq) 140 Stirred at °C for 12 hours. After cooling the reaction to room temperature, it was purified by column chromatography to obtain 3-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-2-methoxy Obtained -8-methylpyrido[2,3-d]pyridazin-5-amine.
MS (ESI+) m/z 441 (M+H)+ MS (ESI+) m/z 441 (M+H) +
단계 2Step 2
Figure PCTKR2022021249-appb-img-000255
Figure PCTKR2022021249-appb-img-000255
3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-methoxy-8-methylpyrido[2,3-d]pyridazin-5-amine
무수 테트라히드로푸란 (0.25 mol) 중 (R)-3-브로모-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민 의 용액에 3-옥사-8-아자비시클로[3.2.1]옥탄 염산염 (2 eq), Pd2(dba)3 (0.1 eq), Xphos (0.2 eq), 테트라히드로푸란 중 1 M LiHMDS 용액 (8 eq) 을 추가하고 80 ℃ 에서 4 시간 동안 가열 교반한다. 반응 혼합물을 실온으로 냉각 후 증류수로 반응을 종결하고 디클로로메탄 으로 추출하였다. 유기 추출액을 황산나트륨 상에서 건조시킨 후, 여과 및 농축 하였다. 잔류물은 컬럼 크로마토그래피로 정제하여 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8 -메틸피리도[2,3-d]피리다진-5-아민 을 수득하였다.(R)-3-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methoxy-8-methyl in anhydrous tetrahydrofuran (0.25 mol) 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (2 eq), Pd 2 (dba) 3 (0.1 eq), Xphos in a solution of pyrido[2,3-d]pyridazin-5-amine (0.2 eq), 1 M LiHMDS solution (8 eq) in tetrahydrofuran is added and heated and stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the reaction was terminated with distilled water and extracted with dichloromethane. The organic extract was dried over sodium sulfate, then filtered and concentrated. The residue was purified by column chromatography to give 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl) This gives -2-fluorophenyl)ethyl)-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5-amine.
MS (ESI+) m/z 474 (M+H)+ MS (ESI+) m/z 474 (M+H) +
실험예 1. 생화학적 시험Experimental Example 1. Biochemical test
1-1. KRAS::SOS1 HTRF 결합 분석1-1. KRAS::SOS1 HTRF binding assay
본 발명의 실시예 1 내지 89에 따른 화합물들의 SOS1 과 KRAS G12C 사이의 단백질-단백질 상호작용을 억제하는 효능을 확인하여, 본 발명의 실시예 화합물들의 SOS1 억제능을 확인하였다. The ability of the compounds according to Examples 1 to 89 of the present invention to inhibit the protein-protein interaction between SOS1 and KRAS G12C was confirmed, and the SOS1 inhibitory ability of the compounds of Examples 1 to 89 of the present invention was confirmed.
구체적으로, KRAS G12C / SOS1 결합 키트 (64KRASG12PEG, Cisbio, France) 를 구입하여 사용하였다. Tag1-KRAS G12C 2 ㎕ 및 GTP 2 ㎕ 를 미리 혼합시켜 384 웰 플레이트 (6007290, PerkinElmer, USA) 에 각 웰 당 4 ㎕ 씩 분주하였다. 화합물을 2 ㎕, Tag2-SOS1 4 ㎕ 를 넣어 준 후 10 ㎕ 의 미리 혼합된 Anti-Tag1 XL665 항체 및 Anti-Tag2 Tb 크립테이트 항체를 각 웰에 분주하였다. 플레이트를 밀봉하고 1 시간 40 분 동안 실온에서 반응시킨 후 HTRF® 호환 판독기 (Synergy H4, BioTeK, USA) 를 이용하여 665 nm 파장과 620 nm 파장을 측정하였고 각 웰에 대한 수용체 및 공여자 방출 신호의 비율을 665 nm / 620 nm ×104 으로 계산하였다. Specifically, a KRAS G12C/SOS1 binding kit (64KRASG12PEG, Cisbio, France) was purchased and used. 2 μl of Tag1-KRAS G12C and 2 μl of GTP were mixed in advance and dispensed in 4 μl per well in a 384-well plate (6007290, PerkinElmer, USA). After adding 2 μl of the compound and 4 μl of Tag2-SOS1, 10 μl of anti-Tag1 XL665 antibody and anti-Tag2 Tb cryptate antibody pre-mixed were dispensed into each well. After sealing the plate and reacting at room temperature for 1 hour and 40 minutes, the 665 nm wavelength and 620 nm wavelength were measured using a HTRF ® compatible reader (Synergy H4, BioTeK, USA), and the ratio of the acceptor and donor emission signals for each well was calculated as 665 nm / 620 nm × 10 4 .
상기 방법은 화합물들의 분자 작용 방식을 입증하며, 상기 분석 환경에서의 높은 저해율은 SOS1 억제제 화합물의 높은 효능을 나타낸다The method demonstrates the molecular mode of action of the compounds, and the high rate of inhibition in the assay environment indicates the high potency of the SOS1 inhibitor compound.
계산 결과를 아래 표 2에 나타내었다.The calculation results are shown in Table 2 below.
(+++: 70 초과 내지 100 % 저해, ++: 40 초과 내지 70 % 저해, +: 0 내지 40 % 저해)(+++: >70 to 100% inhibition, ++: >40 to 70% inhibition, +: 0 to 40% inhibition)
화합물compound % inhibition at 0.1 uM% inhibition at 0.1 uM 화합물compound % inhibition at 0.1 uM% inhibition at 0.1 uM
실시예 1Example 1 ++++ 실시예 46Example 46 ++++
실시예 2Example 2 ++++ 실시예 47Example 47 ++++++
실시예 3Example 3 ++++++ 실시예 48Example 48 ++
실시예 4Example 4 ++++++ 실시예 49Example 49 ++
실시예 5Example 5 ++ 실시예 50Example 50 ++++++
실시예 6Example 6 ++++++ 실시예 51Example 51 ++++++
실시예 7Example 7 ++++ 실시예 52Example 52 ++++++
실시예 8Example 8 ++++ 실시예 53Example 53 ++++++
실시예 9Example 9 ++++++ 실시예 54Example 54 ++++
실시예 10Example 10 ++++++ 실시예 55Example 55 ++++++
실시예 11Example 11 ++ 실시예 56Example 56 ++++
실시예 12Example 12 ++++++ 실시예 57Example 57 ++
실시예 13Example 13 ++++++ 실시예 58Example 58 ++++
실시예 14Example 14 ++++++ 실시예 59Example 59 ++++++
실시예 15Example 15 ++++++ 실시예 60Example 60 ++++
실시예 16Example 16 ++++++ 실시예 61Example 61 ++++++
실시예 17Example 17 ++++++ 실시예 62Example 62 ++++++
실시예 18Example 18 ++++++ 실시예 63Example 63 ++++++
실시예 19Example 19 ++++++ 실시예 64Example 64 ++++++
실시예 20Example 20 ++++++ 실시예 65Example 65 ++++
실시예 21Example 21 ++++++ 실시예 66Example 66 ++++++
실시예 22Example 22 ++++ 실시예 67Example 67 ++++++
실시예 23Example 23 ++++++ 실시예 68Example 68 ++++++
실시예 24Example 24 ++++++ 실시예 69Example 69 ++++
실시예 25Example 25 ++ 실시예 70Example 70 ++++
실시예 26Example 26 ++ 실시예 71Example 71 ++++
실시예 27Example 27 ++++++ 실시예 72Example 72 ++++++
실시예 28Example 28 ++++++ 실시예 73Example 73 ++++++
실시예 29Example 29 ++++ 실시예 74Example 74 ++++++
실시예 30Example 30 ++++++ 실시예 75Example 75 ++++
실시예 31Example 31 ++++ 실시예 76Example 76 ++++
실시예 32Example 32 ++++ 실시예 77Example 77 ++
실시예 33Example 33 ++++ 실시예 78Example 78 ++++
실시예 34Example 34 ++++ 실시예 79Example 79 ++++
실시예 35Example 35 ++++++ 실시예 80Example 80 ++
실시예 36Example 36 ++++++ 실시예 81Example 81 ++++
실시예 37Example 37 ++ 실시예 82Example 82 ++++++
실시예 38Example 38 ++ 실시예 83Example 83 ++++++
실시예 39Example 39 ++++++ 실시예 84Example 84 ++
실시예 40Example 40 ++++++ 실시예 85Example 85 ++
실시예 41Example 41 ++++ 실시예 86Example 86 ++
실시예 42Example 42 ++++++ 실시예 87Example 87 ++++
실시예 43Example 43 ++++ 실시예 88Example 88 ++
실시예 44Example 44 ++++++ 실시예 89Example 89 NDND
실시예 45Example 45 ++++
상기 표 2에서 확인되는 것과 같이, 본 발명의 실시예들에 따른 화합물들은 0.1 uM 농도에서 SOS1를 저해할 수 있음을 확인할 수 있고, 특히, 본 발명의 화합물들 대다수가 매우 높은 SOS1 저해율 (++: 70 초과 내지 100 %)을 나타내는 것을 확인할 수 있다. As confirmed in Table 2, it can be seen that the compounds according to the embodiments of the present invention can inhibit SOS1 at a concentration of 0.1 uM, and in particular, most of the compounds of the present invention have a very high SOS1 inhibition rate (++ : greater than 70 to 100%).
즉, 본 발명에 따른 화합물들은 높은 SOS1 억제 효능을 나타낼 수 있음을 확인할 수 있다.That is, it can be confirmed that the compounds according to the present invention can exhibit high SOS1 inhibitory efficacy.
1-2. EGFR kinase 저해 분석1-2. EGFR kinase inhibition assay
본 발명의 실시예 화합물들의 EGFR kinase 저해 효능을 확인하였다. EGFR kinase inhibitory efficacy of the compounds of the examples of the present invention was confirmed.
구체적으로, ADP-Glo™ 효소 분석 시스템 (V3831, Promega Corporation, USA)을 구입하여 사용하였다. 5x Kinase reaction buffer (인산화효소 반응 버퍼) 를 1.5x 로 희석시켜 준비한 후 EGFR (Epidermal growth factor receptor, 표피성장인자수용체) kinase (인산화효소) 와 ATP 에 1.5x Kinase reaction buffer 를 이용하여 EGFR 은 6 ng, ATP 는 25 M 로 준비한 후, 384 웰 플레이트 (REF4513, Corning, USA) 에 화합물 1 ㎕ 에 EGFR kinase 2 ㎕ Substrate / ATP mix 2 ㎕ 를 섞어 실온에서 60 분간 반응시켰다. ADP-Glo™ 시약을 각 웰 당 5 ㎕ 씩 추가하여 실온에서 40 분간 반응시켜 EGFR Kinase 반응 중지 및 사용되지 않은 ATP 를 소거하였다. Kinase Detection Reagent (인산화효소 검출 시약) 를 10 ㎕ 첨가하고 실온에서 30 분 동안 반응시켜 ADP 를 ATP 로 전환시키고 luciferase (루시퍼라아제) 와 luciferin (루시퍼린) 을 이용하여 ATP 를 나타나게 하였다. ELISA 리더기 (Synergy H4, BioTek, USA) 의 발광 (Luminescence) 을 이용하여 검출하였다.Specifically, an ADP-Glo™ enzyme assay system (V3831, Promega Corporation, USA) was purchased and used. After preparing by diluting 5x Kinase reaction buffer to 1.5x, EGFR (Epidermal growth factor receptor) kinase and ATP using 1.5x Kinase reaction buffer, EGFR is 6 ng After preparing ATP at 25 M, 2 μl of EGFR kinase 2 μl Substrate / ATP mix was mixed with 1 μl of the compound in a 384-well plate (REF4513, Corning, USA) and reacted at room temperature for 60 minutes. 5 μl of ADP-Glo™ reagent was added to each well and reacted at room temperature for 40 minutes to stop the EGFR kinase reaction and remove unused ATP. 10 μl of Kinase Detection Reagent was added and reacted at room temperature for 30 minutes to convert ADP into ATP, and ATP was expressed using luciferase and luciferin. It was detected using Luminescence of an ELISA reader (Synergy H4, BioTek, USA).
상기 방법은 화합물들의 EGFR kinase 선택적인 분자 작용 방식을 입증하며, 상기 분석 환경에서 높은 IC50 값은 EGFR kinase 저해 효능이 없음을 나타낸다.The method demonstrates the selective molecular action mode of EGFR kinase of the compounds, and a high IC 50 value in the assay environment indicates no EGFR kinase inhibitory effect.
분석 결과를 아래 표 3에 나타내었다. The analysis results are shown in Table 3 below.
화합물compound IC50 (nM)IC 50 (nM)
GefitinibGefitinib 13.9013.90
실시예 9Example 9 >10,000>10,000
실시예 34Example 34 >10,000>10,000
상기 표 3에서 확인되는 것과 같이, 대조물질 EGFR kinase 억제제 (Gefitinib) 대비하여 본 발명의 화합물들의 EGFR kinase 저해 효능이 없음이 확인되므로 SOS1 에 대한 높은 선택성을 가짐을 확인할 수 있다.As confirmed in Table 3, it can be confirmed that the compounds of the present invention have no EGFR kinase inhibitory efficacy compared to the control EGFR kinase inhibitor (Gefitinib), so they have high selectivity for SOS1.
즉, 본 발명의 화합물들은 SOS1에 대한 높은 선택성을 나타낼 수 있고, 높은 SOS1 억제 효능을 나타낼 수 있으며, 따라서, 본 발명의 화합물들은 SOS1 활성 관련 질환의 치료에 유용하게 사용될 수 있다.That is, the compounds of the present invention can exhibit high selectivity for SOS1 and high SOS1 inhibitory efficacy, and therefore, the compounds of the present invention can be usefully used for the treatment of diseases related to SOS1 activity.
이상, 본 발명을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예 일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As above, the present invention has been described in detail, to those skilled in the art, it will be clear that these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereby. Accordingly, the substantial scope of the invention will be defined by the appended claims and their equivalents.

Claims (24)

  1. 하기 화학식 (I) 로 표시되는 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염: A compound represented by the following formula (I), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof:
    [화학식 I][Formula I]
    Figure PCTKR2022021249-appb-img-000256
    Figure PCTKR2022021249-appb-img-000256
    R1은 독립적으로 C1-C6알킬, C1-C6알콕시, C2-C4알케닐, C2-C4알키닐, C1-C6할로알킬, 하이드록시-C1-C4알킬, 하이드록시-C1-C4-할로알킬, C3-C6사이클로알킬, C6-C10아릴, 3-6원 헤테로사이클릴, 하이드록시-C3-C6사이클로알킬, 할로겐, 하이드록시, -NH2, -시아노, -SO2, -SO2-C1-C4알킬 및 이가 치환체 =O 로 구성된 그룹 중에서 선택되고, 이때, 상기 이가 치환체 =O 는 A가 비방향족 환인 경우에만 치환될 수 있으며, R 1 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 6 haloalkyl, hydroxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 -haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 3-6 membered heterocyclyl, hydroxy-C 3 -C 6 cycloalkyl, halogen , hydroxy, -NH 2 , -cyano, -SO 2 , -SO 2 -C 1 -C 4 alkyl and a divalent substituent =O, wherein the divalent substituent =O is selected from the group consisting of A is non-aromatic It can be substituted only in the case of a ring,
    또는 R1이 2종 이상인 경우 R1들이 서로 결합하여 4원 내지 12원의 헤테로사이클을 형성할 수 있고, 이때 상기 C1-C6알킬, C1-C6알콕시, C2-C4알케닐, C2-C4알키닐, C1-C6할로알킬, 하이드록시-C1-C4알킬, 하이드록시-C1-C4-할로알킬, C3-C6사이클로알킬, C6-C10아릴, 3-6원 헤테로사이클릴, 하이드록시-C3-C6사이클로알킬, C1-C4할로알킬 또는 3-6원 헤테로사이클릴은 비치환되거나 또는 하이드록시, 할로겐, C1-C6알킬, C1-C6알콕시, C3-C6사이클로알킬, C3-C6사이클로알콕시, 3-6원 헤테로사이클릴, -C1-C4알킬-NH-C1-C4알킬 및 -C1-C4알킬-N(C1-C4알킬)2로 이루어진 군으로부터 선택되는 1종 이상의 치환기로 치환될 수 있고, 이때 상기 치환기가 2종 이상인 경우, 이 2종 이상의 치환기가 함께 결합하여 C3-C6사이클로알킬을 형성할 수 있고;Alternatively, when R 1 is two or more, R 1 may combine with each other to form a 4- to 12-membered heterocycle, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 4 alkoxy kenyl, C 2 -C 4 alkynyl, C 1 -C 6 haloalkyl, hydroxy-C 1 -C 4 alkyl, hydroxy-C 1 -C 4 -haloalkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 3-6 membered heterocyclyl, hydroxy-C 3 -C 6 cycloalkyl, C 1 -C 4 haloalkyl or 3-6 membered heterocyclyl is unsubstituted or hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 3-6 membered heterocyclyl, -C 1 -C 4 alkyl-NH-C 1 - It may be substituted with one or more substituents selected from the group consisting of C 4 alkyl and -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 , wherein when the substituents are two or more, the two substituents More than one substituent may be joined together to form a C 3 -C 6 cycloalkyl;
    A는 C6-C10아릴, 5-12원 헤테로아릴 또는 9-20원 바이사이클릭 헤테로사이클릴이고;A is C 6 -C 10 aryl, 5-12 membered heteroaryl or 9-20 membered bicyclic heterocyclyl;
    R4는 수소, 할로겐, C1-C4알킬, C1-C4할로알킬, 하이드록시, 치환된 아미노, 시아노, 하이드록시-C1-C4알킬, -O-C1-C4할로알킬, C3-C6사이클로알킬, C1-C6알콕시, -C1-C4알킬-NH2, -C1-C4알킬-NH-C1-C4알킬 또는 -C1-C4알킬-N(C1-C4알킬)2이고;R 4 is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxy, substituted amino, cyano, hydroxy-C 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl , C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, -C 1 -C 4 alkyl-NH 2 , -C 1 -C 4 alkyl-NH-C 1 -C 4 alkyl or -C 1 -C 4 alkyl-N(C 1 -C 4 alkyl) 2 ;
    R2는 수소, 할로겐, 하이드록시, C1-C4알킬, C1-C4할로알킬, C1-C4알콕시, 시아노, -C(O)NH2 또는 아미노이고, 이때 상기 아미노 또는 -C(O)NH2의 아미노기는 비치환되거나 C1-C4알킬로 치환될 수 있고; R 2 is hydrogen, halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, -C(O)NH 2 or amino, wherein said amino or The amino group of -C(O)NH 2 may be unsubstituted or substituted with C 1 -C 4 alkyl;
    L3은 결합, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, -S(O)2-,
    Figure PCTKR2022021249-appb-img-000257
    ,
    Figure PCTKR2022021249-appb-img-000258
    ,
    Figure PCTKR2022021249-appb-img-000259
    ,
    Figure PCTKR2022021249-appb-img-000260
    , -C(O)(CH2)o-, -(CH2)o-, -NH- 또는 -O- 이고, 이때 o는 0, 1 또는 2의 정수일 수 있고;    L 3 is a bond, -C(O)-, -C(O)O-, -C(O)NH(CH 2 ) o -, -S(O) 2 -,
    Figure PCTKR2022021249-appb-img-000257
    ,
    Figure PCTKR2022021249-appb-img-000258
    ,
    Figure PCTKR2022021249-appb-img-000259
    ,
    Figure PCTKR2022021249-appb-img-000260
    , -C(O)(CH 2 ) o -, -(CH 2 ) o -, -NH- or -O-, where o can be an integer of 0, 1 or 2;
    R3은 4-12원 헤테로사이클릴, 4-12원 헤테로사이클로알킬, 4-12원 헤테로사이클로알케닐 또는 5-12원 헤테로아릴일 수 있고,R 3 can be 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl;
    상기 4-12원 헤테로사이클릴, 4-12원 헤테로사이클로알킬, 4-12원 헤테로사이클로알케닐 또는 5-12원 헤테로아릴은 비치환되거나, Ra1 및/또는 Rb1으로 임의로 치환되고;said 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl is unsubstituted or optionally substituted with R a1 and/or R bi ;
    각 Ra1 은 독립적으로 -ORb1, C1-C6알킬, -NRb1Rb1, -C1-C3알킬NRb1Rb1, 할로겐, -CN, 옥소, -C(O)Rb1, -C(O)ORb1, -C(O)NRb1Rb1, -Rb1-O-Rb1, -Rb1-CO-NRb1Rb1, -S(O)2Rb1, -S(O)2NRb1Rb1, -NHC(O)Rb1, -N(C1-C4알킬)C(O)Rb1, -NHC(O)ORb1 및 -N(C1-C4알킬)C(O)ORb1 로 이루어지는 그룹 중에서 선택되고;Each R a1 is independently -OR b1 , C 1 -C 6 alkyl, -NR b1 R b1 , -C 1 -C 3 alkylNR b1 R b1 , halogen, -CN, oxo, -C(O)R b1 , -C(O)OR b1 , -C(O)NR b1 R b1 , -R b1 -OR b1 , -R b1 -CO-NR b1 R b1 , -S(O) 2 R b1 , -S(O) 2 NR b1 R b1 , -NHC(O)R b1 , -N(C 1 -C 4 alkyl)C(O)R b1 , -NHC(O)OR b1 and -N(C 1 -C 4 alkyl)C (O)OR is selected from the group consisting of b1 ;
    각 Rb1 은 독립적으로 수소, C1-C6알킬, C1-C6할로알킬, C1-C6하이드록시알킬, C2-C6알케닐, C2-C6알키닐, C3-C10사이클로알킬, C4-C10사이클로알케닐, 3-12원 헤테로사이클릴, C6-C10아릴 및 5-12원 헤테로아릴로 이루어지는 그룹 중에서 선택되고, 이 때 3-12원 헤테로사이클릴 또는 5-12원 헤테로아릴은 비치환되거나 또는 C1-C6알킬로 치환될 수 있고;Each R b1 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 It is selected from the group consisting of -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, 3-12 membered heterocyclyl, C 6 -C 10 aryl and 5-12 membered heteroaryl, wherein 3-12 membered hetero Cyclyl or 5-12 membered heteroaryl may be unsubstituted or substituted with C 1 -C 6 alkyl;
    R5는 C1-C6의 알킬일 수 있고;R 5 can be C 1 -C 6 alkyl;
    p는 0 내지 3의 정수일 수 있고, 이때, p가 2 또는 3인 경우 각각의 R1은 각각 동일하거나 또는 상이할 수 있다.p may be an integer from 0 to 3, and in this case, when p is 2 or 3, each R 1 may be the same or different.
  2. 제1항에 있어서, According to claim 1,
    상기 R1은 독립적으로 C1-C4알킬, C1-C4알콕시, 클로로, 플루오로, 하이드록시, -NH2, 시아노, -SO2, -SO2-C1-C4알킬 또는 페닐이고, 이때, 상기 C1-C4알킬, C1-C4알콕시, -SO2-C1-C4알킬 또는 페닐은 비치환되거나 하이드록시, 할로겐, C1-C4알킬, C1-C4알콕시, C3-C6사이클로알킬, C3-C6사이클로알콕시, 3-6원 헤테로사이클릴, 및 메틸아민 또는 디메틸아민으로 치환된 C1-C6알킬로 이루어지는 군으로부터 선택되는 1 내지 3의 치환기로 치환되고, 이때 상기 치환기가 2 이상인 경우 함께 사이클로프로필을 형성할 수 있는 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.R 1 is independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, chloro, fluoro, hydroxy, -NH 2 , cyano, -SO 2 , -SO 2 -C 1 -C 4 alkyl or phenyl, wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, -SO 2 -C 1 -C 4 alkyl or phenyl is unsubstituted or hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, 3-6 membered heterocyclyl, and C 1 -C 6 alkyl substituted with methylamine or dimethylamine selected from the group consisting of Substituted with 1 to 3 substituents, wherein, when the substituents are two or more, together they can form cyclopropyl, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or A pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서, According to claim 1,
    상기 R1은 독립적으로 메틸, 메톡시, 플루오로, 클로로, -CF3, -CHF2, -NH2, 시아노, 하이드록시, -SO2, 및 비치환되거나 메틸, 메톡시, 하이드록시, 플루오로, 사이클로프로폭시, 테트라하이드로퓨란, -CH2-NH-CH3 및 -CH2-N(CH3)2로 이루어지는 군으로부터 선택되는 1종 내지 3종의 치환기로 치환된 C1-C4알킬 또는 페닐이며, 이 때 상기 R1의 치환기가 2종 이상인 경우 함께 사이클로프로필을 형성할 수 있는 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.R 1 is independently selected from methyl, methoxy, fluoro, chloro, -CF 3 , -CHF 2 , -NH 2 , cyano, hydroxy, -SO 2 , and unsubstituted or methyl, methoxy, hydroxy, C 1 -C substituted with one to three substituents selected from the group consisting of fluoro, cyclopropoxy, tetrahydrofuran, -CH 2 -NH-CH 3 and -CH 2 -N(CH 3 ) 2 4 Alkyl or phenyl, wherein when two or more substituents of R 1 are present, a compound capable of forming cyclopropyl together, optical isomers thereof, stereoisomers thereof, solvates thereof, isotopic variants thereof, and tautomers thereof Isomers or pharmaceutically acceptable salts thereof.
  4. 제1항에 있어서,According to claim 1,
    상기 R1이 2종 이상인 경우, 상기 2종 이상의 R1이 동시에 할로가 될 수 없는 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.A compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutical thereof, wherein when the R 1 is two or more, the two or more R 1 cannot be halo at the same time. an acceptable salt.
  5. 제1항에 있어서, 상기 A는 C6-C9아릴, 5원 내지 8원의 헤테로아릴 또는 9원 내지 12원의 바이사이클릭 헤테로사이클릴인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, wherein A is C 6 -C 9 aryl, 5- to 8-membered heteroaryl or 9- to 12-membered bicyclic heterocyclyl, an optical isomer thereof, or a stereoisomer thereof , A solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  6. 제1항에 있어서, 상기 A는 페닐, 티오펜일, 피리딘일, 벤조푸란일, 디히드로벤조푸란일, 디하이드로인덴일인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, wherein A is phenyl, thiophenyl, pyridinyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, Isotopic variants thereof, tautomers thereof, or pharmaceutically acceptable salts thereof.
  7. 제1항에 있어서, 상기 R4는 수소, 메틸, 메톡시, -CF3, -N(CH3)2, -CH2NH2, -CH2N(CH3)2 인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The compound of claim 1, wherein R 4 is hydrogen, methyl, methoxy, -CF 3 , -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , An optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  8. 제1항에 있어서, 상기 R2는 수소, 하이드록시, 메틸, 메톡시, -CF3, 인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, wherein R 2 is hydrogen, hydroxy, methyl, methoxy, -CF 3 , an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, or a tautomer thereof. or a pharmaceutically acceptable salt thereof.
  9. 제1항에 있어서, 상기 R3로서 4-12원 헤테로사이클릴, 4-12원 헤테로사이클로알킬, 4-12원 헤테로사이클로알케닐 또는 5-12원 헤테로아릴은 N원자를 포함하며, 상기 N원자 부분이 L3과 연결되는 것을 특징으로 하는 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The method according to claim 1, wherein R 3 as 4-12 membered heterocyclyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl or 5-12 membered heteroaryl contains N atoms, wherein N A compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that an atomic moiety is linked to L 3 .
  10. 제1항에 있어서, According to claim 1,
    R3은 아제티딘일, 피롤리딘일, 피라졸일, 피페리딘일, 모르폴린일, 피페라진일, 티오모르폴린일, 아자스피로헵탄일, 디아자스피로헵탄일, 옥사아자스피로헵탄일, 옥사아자스피로옥탄일, 디아자스피로옥탄일, 옥사아자스피로노난일, 옥사디아자스피로노난일, 디아자스피로데칸일, 디옥사아자스피로데칸일, 옥사아자스피로데칸일, 헥사히드로푸로피롤일, 옥타히드로피라지노옥사진일, 옥타히드로피롤로피라진일, 테트라히드로이미다조피라진일, 테트라히드로피라졸로피라진일, 옥사아자비사이클로헵탄일, 또는 옥사아자비사이클로옥탄일인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.R 3 is azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, azaspiroheptanyl, diazaspiroheptanyl, oxazaspiroheptanyl, oxaaza Spirooctanyl, diazaspiroctanyl, oxaazaspirononanyl, oxadiazaspironanyl, diazaspirodecanyl, dioxazaspirodecanyl, oxaazaspirodecanyl, hexahydrofuropyrroyl, octahydro A compound that is pyrazinoxazinyl, octahydropyrrolopyrazinyl, tetrahydroimidazopyrazinyl, tetrahydropyrazolopyrazinyl, oxazabicycloheptanyl, or oxaazabicyclooctanyl, an optical isomer thereof, a stereoisomer thereof, A solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  11. 제1항에 있어서, According to claim 1,
    R3는 하기 기들 중에서 선택되는 어느 하나인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염:A compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is any one selected from the following groups:
    Figure PCTKR2022021249-appb-img-000261
    Figure PCTKR2022021249-appb-img-000261
    Figure PCTKR2022021249-appb-img-000262
    .
    Figure PCTKR2022021249-appb-img-000262
    .
  12. 제1항에 있어서,According to claim 1,
    상기 R5는 C1-C3알킬인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.Wherein R 5 is C 1 -C 3 Alkyl, the compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  13. 제1항에 있어서,According to claim 1,
    상기 L3은 결합인 것인, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.Wherein L 3 is a bond, a compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.
  14. 하기 화합물 1) 내지 89)로 이루어지는 군으로부터 선택되는 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염:A compound selected from the group consisting of the following compounds 1) to 89), an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof:
    1) (R)-8-메틸-3-모르폴리노-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;1) (R)-8-methyl-3-morpholino-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyridazin-5-amine;
    2) (R)-8-메틸-3-(4-메틸피페라진-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;2) (R)-8-methyl-3-(4-methylpiperazin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d ]pyridazin-5-amine;
    3) (R)-3-(4-에틸피페라진-1-일)-8-메틸-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;3) (R)-3-(4-ethylpiperazin-1-yl)-8-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d ]pyridazin-5-amine;
    4) (R)-8-메틸-3-(4-(메틸아미노)피페리딘-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;4) (R)-8-methyl-3-(4-(methylamino)piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2 ,3-d] pyridazin-5-amine;
    5) (R)-8-메틸-3-(4-(2,2,2-트리플루오로에틸)피페라진-1-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;5) (R)-8-methyl-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl )ethyl)pyrido[2,3-d]pyridazin-5-amine;
    6) (R)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;6) (R)-3-(4-(dimethylamino)piperidin-1-yl)-8-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[2 ,3-d] pyridazin-5-amine;
    7) 3-((S)-3-메톡시피롤리딘-1-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;7) 3-((S)-3-methoxypyrrolidin-1-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)pyrido[ 2,3-d] pyridazin-5-amine;
    8) N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-3-((S)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;8) N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-3-((S)-3-methoxypyrrolidin-1-yl)-8-methylpyrido[ 2,3-d] pyridazin-5-amine;
    9) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;9) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-(dimethylamino)piperidin-1-yl)-8- methylpyrido[2,3-d]pyridazin-5-amine;
    10) (R)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸-N-(1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;10) (R)-3-(4-(dimethylamino)piperidin-1-yl)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) pyrido[2,3-d]pyridazin-5-amine;
    11) (R)-8-메틸-N-(1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)-3-모르폴리노피리도[2,3-d]피리다진-5-아민;11) (R)-8-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-3-morpholinopyrido[2,3-d]pyridazine- 5-amine;
    12) (R)-N-(1-(3-아미노-5-(트리플루오로메틸)페닐-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;12) (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl-3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[ 2,3-d] pyridazin-5-amine;
    13) (R)-2,2-디플루오로-2-(2-플루오로-3-(1-((8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올;13) (R)-2,2-difluoro-2-(2-fluoro-3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazine- 5-yl)amino)ethyl)phenyl)ethanol;
    14) (R)-2-(3-(1-((3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)-2-플루오로페닐)-2,2-디플루오로에탄올;14) (R)-2-(3-(1-((3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[2,3-d]pyridazine-5 -yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethanol;
    15) 2,2-디플루오로-2-(2-플루오로-3-((R)-1-((3-((S)-3-메톡시피롤리딘-1일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올;15) 2,2-difluoro-2-(2-fluoro-3-((R)-1-((3-((S)-3-methoxypyrrolidin-1yl)-8-methyl pyrido[2,3-d]pyridazin-5-yl)amino)ethyl)phenyl)ethanol;
    16) (R)-N-(1-(3,3-디플루오로-2,3-디히드로벤조푸란-7-일)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-아민;16) (R)-N-(1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-8-methyl-3-morpholinopyrido[2, 3-d] pyridazin-5-amine;
    17) (R)-N-(1-(3,3-디플루오로-2,3-디히르도벤조푸란-7-일)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;17) (R)-N-(1-(3,3-difluoro-2,3-dihydroxybenzofuran-7-yl)ethyl)-3-(4-(dimethylamino)piperidine- 1-yl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    18) (R)-1-(3-(1-((3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)-2-플루오로페닐)-1,1-디플루오로-2-메틸프로판-2-올;18) (R)-1-(3-(1-((3-(4-(dimethylamino)piperidin-1-yl)-8-methylpyrido[2,3-d]pyridazine-5 -yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol;
    19) (R)-N-(1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-3-(4-(디메틸아미노)피페리딘-1-일)-8-메틸피리도 [2,3-d]피리다진-5-아민;19) (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-3-(4-(dimethylamino)piperidin-1 -yl)-8-methylpyrido [2,3-d]pyridazin-5-amine;
    20) (R)-N-(1-(5-(2-((디메틸아미노)메틸)페닐)티오펜-2-일)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-아민;20) (R)-N-(1-(5-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)-8-methyl-3-morpholinopyrido[2, 3-d] pyridazin-5-amine;
    21) (R)-2,2-디플루오로-2-(3-(1-((8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)페닐)에탄올;21) (R)-2,2-difluoro-2-(3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-yl)amino )ethyl)phenyl)ethanol;
    22) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민; 22) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxyazetidin-1-yl)-8-methylpyrido [2,3-d]pyridazin-5-amine;
    23) 3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;23) 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    24) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-아민;24) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptane- 6-yl)pyrido[2,3-d]pyridazin-5-amine;
    25) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-메틸모르폴리노)피리도[2,3-d]피리다진-5-아민;25) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-methylmorpholino)pyrido[2,3 -d] pyridazin-5-amine;
    26) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(3-메틸모르폴리노)피리도[2,3-d]피리다진-5-아민;26) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(3-methylmorpholino)pyrido[2,3 -d] pyridazin-5-amine;
    27) 3-((1S,4S)-2-옥사-5-아자비시클로[2.2.1]헵탄-5-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;27) 3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)- 2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    28) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;28) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    29) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-티오모르폴리노피리도[2,3-d]피리다진-5-아민;29) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-thiomorpholinopyrido[2,3-d]pyrido[2,3-d]pyr minced-5-amine;
    30) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-헥사히드로피라지노[2,1-c][1,4]옥사진-8(1H)-일)-8-메틸피리도[2,3-d]피리다진-5-아민;30) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    31) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;31) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-methoxypiperidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    32) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;32) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-methoxypiperidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    33) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-7-아자스피로[3.5]노난-7-일)피리도[2,3-d]피리다진-5-아민;33) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-7-azaspiro[3.5]nonane- 7-yl)pyrido[2,3-d]pyridazin-5-amine;
    34) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-메톡시피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;34) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-methoxypiperidin-1-yl)-8-methylpyrido [2,3-d]pyridazin-5-amine;
    35) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-((디메틸아미노)메틸)피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;35) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-((dimethylamino)methyl)piperidin-1-yl) -8-methylpyrido[2,3-d]pyridazin-5-amine;
    36) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(메틸아미노)피페리딘-1-일)피리도[2,3-d]피리다진-5-아민 2,2,2-트리플루오로아세테이트;36) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(methylamino)piperidin-1-yl )pyrido[2,3-d]pyridazin-5-amine 2,2,2-trifluoroacetate;
    37) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4,4-디플루오로피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;37) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4,4-difluoropiperidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    38) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(2,2,2-트리플루오로에틸)피페라진-1-일)피리도[2,3-d]피리다진-5-아민;38) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(2,2,2-trifluoroethyl) )piperazin-1-yl)pyrido[2,3-d]pyridazin-5-amine;
    39) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(4-(옥세탄-3-일)피페라진-1-일)피리도[2,3-d]피리다진-5-아민;39) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(4-(oxetan-3-yl)piperazine- 1-yl)pyrido[2,3-d]pyridazin-5-amine;
    40) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;40) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxypyrrolidin-1-yl)-8-methylpyrido [2,3-d]pyridazin-5-amine;
    41) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(6-메톡시-2-아자스피로[3.3]헵탄-2-일)-8-메틸피리도[2,3-d]피리다진-5-아민;41) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(6-methoxy-2-azaspiro[3.3]heptan-2-yl )-8-methylpyrido[2,3-d]pyridazin-5-amine;
    42) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(6-메틸-2,6-디아자스피로[3.3]헵탄-2-일)피리도[2,3-d]피리다진-5-아민;42) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(6-methyl-2,6-diazaspiro[3.3 ]heptan-2-yl)pyrido[2,3-d]pyridazin-5-amine;
    43) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-메톡시-3-메틸아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;43) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-methoxy-3-methylazetidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    44) (R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-3-메틸아제티딘-3-올;44) (R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine -3-yl)-3-methylazetidin-3-ol;
    45) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(7-옥사-2-아자스피로[3.5]노난-2-일)피리도[2,3-d]피리다진-5-아민;45) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(7-oxa-2-azaspiro[3.5]nonane- 2-yl)pyrido[2,3-d]pyridazin-5-amine;
    46) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3-(디메틸아미노)아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;46) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3-(dimethylamino)azetidin-1-yl)-8-methyl pyrido[2,3-d]pyridazin-5-amine;
    47) (R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)아제티딘-3-올;47) (R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine -3-yl)azetidin-3-ol;
    48) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-모르폴리노피리도[2,3-d]피리다진-5-아민;48) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3-d]pyridazine -5-amine;
    49) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(4-플루오로피페리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;49) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(4-fluoropiperidin-1-yl)-8-methylpyridine do[2,3-d]pyridazin-5-amine;
    50) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(6-옥사-2-아자스피로[3.4]옥탄-2-일)피리도[2,3-d]피리다진-5-아민;50) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(6-oxa-2-azaspiro[3.4]octane- 2-yl)pyrido[2,3-d]pyridazin-5-amine;
    51) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.4]옥탄-6-일)피리도[2,3-d]피리다진-5-아민;51) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.4]octane- 6-yl)pyrido[2,3-d]pyridazin-5-amine;
    52) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;52) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-methoxypyrrolidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    53) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;53) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-methoxypyrrolidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    54) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-(피롤리딘-1-일)피리도[2,3-d]피리다진-5-아민;54) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-(pyrrolidin-1-yl)pyrido[2, 3-d] pyridazin-5-amine;
    55) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸-3-((3aR,6aS)-테트라히드로-1H-푸로[3,4-c]피롤-5(3H)-일)피리도[2,3-d]피리다진-5-아민;55) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-8-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[ 3,4-c]pyrrol-5(3H)-yl)pyrido[2,3-d]pyridazin-5-amine;
    56) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((R)-3-플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;56) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((R)-3-fluoropyrrolidin-1-yl)- 8-methylpyrido[2,3-d]pyridazin-5-amine;
    57) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((S)-3-플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;57) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((S)-3-fluoropyrrolidin-1-yl)- 8-methylpyrido[2,3-d]pyridazin-5-amine;
    58) (R)-N-(1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-(3,3-디플루오로피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;58) (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-(3,3-difluoropyrrolidin-1-yl)-8 -Methylpyrido[2,3-d]pyridazin-5-amine;
    59) N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-3-((3R,4S)-3,4-디메톡시피롤리딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-아민;59) N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-3-((3R,4S)-3,4-dimethoxypyrrolidine-1 -yl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    60) (R)-4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)티오모르폴린 1,1-이산화물;60) (R)-4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine -3-yl)thiomorpholine 1,1-dioxide;
    61) (R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페리딘-4-올;61) (R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine -3-yl)piperidin-4-ol;
    62) (R)-2-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)헥사히드로피롤로 [1,2-a]피라진-6(2H)-온;62) (R)-2-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3- d]pyridazin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one;
    63) (R)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)-N-(1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;63) (R)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyryl do[2,3-d]pyridazin-5-amine;
    64) 3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;64) 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl )pyrido[2,3-d]pyridazin-5-amine;
    65) (R)-N-(1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-아민;65) (R)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptane- 6-yl)pyrido[2,3-d]pyridazin-5-amine;
    66) (R)-N-(1-(3-(디플루오로메틸)페닐)에틸)-8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-아민;66) (R)-N-(1-(3-(difluoromethyl)phenyl)ethyl)-8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine do[2,3-d]pyridazin-5-amine;
    67) 3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;67) 3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-8- methylpyrido[2,3-d]pyridazin-5-amine;
    68) (R)-1-(5-((1-(3-(디플루오로메틸)페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-3-메틸아제티딘-3-올;68) (R)-1-(5-((1-(3-(difluoromethyl)phenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazin-3-yl) -3-methylazetidin-3-ol;
    69) (R)-3-(1-((8-메틸-3-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피리도[2,3-d]피리다진-5-일)아미노) 에틸)벤조니트릴;69) (R)-3-(1-((8-methyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[2,3-d]pyridazine-5 -yl)amino)ethyl)benzonitrile;
    70) 3-((1R)-1-((3-(6-옥사-3-아자비시클로[3.1.1]헵탄-3-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴;70) 3-((1R)-1-((3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-8-methylpyrido[2,3-d]pyridazine -5-yl)amino)ethyl)benzonitrile;
    71) (R)-3-(1-((3-(3-히드록시-3-메틸아제티딘-1-일)-8-메틸피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴;71) (R)-3-(1-((3-(3-hydroxy-3-methylazetidin-1-yl)-8-methylpyrido[2,3-d]pyridazin-5-yl )amino)ethyl)benzonitrile;
    72) (S)-1-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피롤리딘-3-올;72) (S)-1-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3- d]pyridazin-3-yl)pyrrolidin-3-ol;
    73) (R)-1-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)-4-메틸피페리딘-4-올;73) (R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridazine -3-yl)-4-methylpiperidin-4-ol;
    74) (R)-(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1-일)(옥세탄-3-일)메탄온;74) (R)-(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d]pyridonium Dazin-3-yl) piperazin-1-yl) (oxetan-3-yl) methanone;
    75) (R)-1-(5-(((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피롤리딘-3-올;75) (R)-1-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3- d]pyridazin-3-yl)pyrrolidin-3-ol;
    76) (R)-3-메틸-1-(8-메틸-5-((1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)아미노)피리도[2,3-d]피리다진-3-일 )아제티딘-3-올;76) (R)-3-methyl-1-(8-methyl-5-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d ]pyridazin-3-yl)azetidin-3-ol;
    77) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-8-메틸-N-((R)-1-(2-메틸-3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;77) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-methyl-N-((R)-1-(2-methyl-3-(trifluoromethyl) )phenyl)ethyl)pyrido[2,3-d]pyridazin-5-amine;
    78) (R)-N-(1-(3-(1,1-디플루오로-2-메톡시에틸)페닐)에틸)-8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-아민;78) (R)-N-(1-(3-(1,1-difluoro-2-methoxyethyl)phenyl)ethyl)-8-methyl-3-morpholinopyrido[2,3- d] pyridazin-5-amine;
    79) 3-(8-옥사-3-아자비시클로[3.2.1]옥탄-3-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;79) 3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    80) (R)-시클로프로필(4-(5-((1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)아미노)-8-메틸피리도[2,3-d]피리다진-3-일)피페라진-1 -일)메타논;80) (R)-cyclopropyl(4-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methylpyrido[2,3-d ]pyridazin-3-yl)piperazin-1-yl)methanone;
    81) (R)-2-메틸-3-(1-((8-메틸-3-모폴리노피리도[2,3-d]피리다진-5-일)아미노)에틸)벤조니트릴;81) (R)-2-methyl-3-(1-((8-methyl-3-morpholinopyrido[2,3-d]pyridazin-5-yl)amino)ethyl)benzonitrile;
    82) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;82) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-8- methylpyrido[2,3-d]pyridazin-5-amine;
    83) 3-((1R,4R)-2-옥사-5-아자비시클로[2.2.1]헵탄-5-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;83) 3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)- 2-fluorophenyl)ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine;
    84) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-8-메틸-N-((R)-1-(3-(트리플루오로메틸)페닐)에틸)피리도[2,3-d]피리다진-5-아민;84) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl )pyrido[2,3-d]pyridazin-5-amine;
    85) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2,3-디플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;85) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2,3-difluorophenyl)ethyl)-8-methyl pyrido[2,3-d]pyridazin-5-amine;
    86) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2,4-디플루오로페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민;86) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-methyl pyrido[2,3-d]pyridazin-5-amine;
    87) (R)-3-메틸-1-(8-메틸-5-((1-(3-(트리플루오로메틸)페닐)에틸)아미노)피리도[2,3-d]피리다진-3-일)아제티딘-3-올;87) (R)-3-methyl-1-(8-methyl-5-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyridazine- 3-yl)azetidin-3-ol;
    88) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(2-플루오로-3-(트리플루오로메틸)페닐)에틸)-8-메틸피리도[2,3-d]피리다진-5-아민; 및88) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl) ethyl)-8-methylpyrido[2,3-d]pyridazin-5-amine; and
    89) 3-(3-옥사-8-아자비시클로[3.2.1]옥탄-8-일)-N-((R)-1-(3-(디플루오로메틸)-2-플루오로페닐)에틸)-2-메톡시-8-메틸피리도[2,3-d]피리다진-5-아민.89) 3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl) Ethyl)-2-methoxy-8-methylpyrido[2,3-d]pyridazin-5-amine.
  15. 제1항에 있어서, SOS1과 RAS-패밀리 단백질의 상호작용을 저해하거나 또는 세포에서 SOS1과 RAC의 상호작용을 저해하는 것을 특징으로 하는, 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, which inhibits the interaction between SOS1 and RAS-family proteins or inhibits the interaction between SOS1 and RAC in cells, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, and a compound thereof. Isotopic variants, tautomers thereof, or pharmaceutically acceptable salts thereof.
  16. 제1항 내지 제14항에 따른 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염 및 약제학적으로 허용가능한 담체를 포함하는, SOS1의 활성에 의해 유발되는 질환의 예방, 개선 또는 치료용 약학적 조성물.A compound according to claims 1 to 14, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, A pharmaceutical composition for preventing, improving or treating diseases caused by the activity of SOS1.
  17. 제16항에 있어서, 상기 SOS1의 활성에 의해 유발되는 질환은 암 또는 RAS병증(RASopathy)인 것인, 약학적 조성물.The pharmaceutical composition according to claim 16, wherein the disease caused by the activity of SOS1 is cancer or RASopathy.
  18. 제17항에 있어서, 상기 암은 췌장암, 폐암, 결장직장암, 혈액암, 담관암, 다발성 골수종, 흑색종, 자궁암, 자궁내막암, 갑상선암, 급성 골수성 백혈병, 방광암, 요로상피암, 위암, 자궁경부암, 두경부 편평세포암종, 미만성 거대 B 세포 림프종, 식도암, 만성 림프구성 백혈병, 간세포암, 유방암, 난소암, 전립선암, 교모세포종, 신장암 및 육종으로 이루어진 군으로부터 선택되는 것인, 약학적 조성물. The method of claim 17, wherein the cancer is pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, stomach cancer, cervical cancer, head and neck cancer A pharmaceutical composition selected from the group consisting of squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.
  19. 제17항에 있어서, 상기 RAS병증은 제1형 신경섬유종증(Neurofibromatosis type 1: NF1), 누난 증후군(Noonan Syndrome: NS), 다발성 흑자증을 가진 누난 증후군(Noonan Syndrome with Multiple Lentigines: NSML), 모세혈관 기형-동정맥 기형 증후군(Capillary Malformation-Arteriovenous Malformation Syndrome: CM-AVM), 코스텔로 증후군(Costello Syndrome: CS), 심장-안면-피부 증후군(Cardio-Facio-Cutaneous Syndrome: CFC), 레지우스 증후군(Legius Syndrome) 및 유전성 치은 섬유종증으로 이루어진 군으로부터 선택되는 것인, 약학적 조성물.The method of claim 17, wherein the RAS pathology is Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), capillary Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome Syndrome) and hereditary gingival fibromatosis, which is selected from the group consisting of, a pharmaceutical composition.
  20. 제16항에 있어서, 추가의 암 치료제를 더 포함하는 것인, 약학적 조성물.17. The pharmaceutical composition according to claim 16, further comprising an additional cancer treatment agent.
  21. SOS1의 활성에 의해 유발되는 질환의 예방, 개선 또는 치료용 약학적 조성물의 제조를 위한 제1항 내지 제14항에 따른 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염의 용도.The compound according to claims 1 to 14, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, Use of a tautomer thereof or a pharmaceutically acceptable salt thereof.
  22. 제21항에 있어서, 상기 SOS1의 활성에 의해 유발되는 질환은 암 또는 RAS병증(RASopathy)인 것인, 용도.The use according to claim 21, wherein the disease caused by the activity of SOS1 is cancer or RASopathy.
  23. 제1항 내지 제14항에 따른 화합물, 이의 광학 이성질체, 이의 입체 이성질체, 이의 용매화물, 이의 동위원소변형체, 이의 호변이성질체 또는 이의 약학적으로 허용 가능한 염을 대상체에 투여하는 단계를 포함하는, SOS1의 활성에 의해 유발되는 질환의 예방, 개선 또는 치료 방법.SOS1 comprising administering the compound according to claims 1 to 14, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof to a subject. A method for preventing, improving or treating a disease caused by the activity of
  24. 제23항에 있어서, 상기 SOS1의 활성에 의해 유발되는 질환은 암 또는 RAS병증(RASopathy)인 것인, 방법.The method according to claim 23, wherein the disease caused by the activity of SOS1 is cancer or RASopathy.
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