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WO2024134514A1 - Nouveau composé en tant qu'inhibiteur de ron - Google Patents

Nouveau composé en tant qu'inhibiteur de ron Download PDF

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Publication number
WO2024134514A1
WO2024134514A1 PCT/IB2023/062979 IB2023062979W WO2024134514A1 WO 2024134514 A1 WO2024134514 A1 WO 2024134514A1 IB 2023062979 W IB2023062979 W IB 2023062979W WO 2024134514 A1 WO2024134514 A1 WO 2024134514A1
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amino
oxy
carboxamide
pyrazole
trifluoromethyl
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Korean (ko)
Inventor
함영진
조중희
윤홍빈
김정준
곽영신
장성웅
김우숙
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LG Chem Ltd
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LG Chem Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further 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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/5375—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
    • A61K31/535—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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 novel compound as a protein kinase inhibitor. Specifically, the present invention relates to novel compounds as RON inhibitors.
  • At least 400 protein kinases are known that catalyze the phosphate transfer reaction from adenosine triphosphate (ATP) to protein substrates. Since the specific amino acid in the target protein to which the phosphate group is transferred is tyrosine, serine, or threonine, protein kinase enzymes are commonly referred to as protein terosine kinases (PTKs) or serine/threonine kinases (STKs).
  • PTKs protein terosine kinases
  • STKs serine/threonine kinases
  • Protein kinases consist of a large family of structurally related proteins that are required to regulate a wide variety of signaling pathways within cells.
  • the signaling pathway includes many different signaling pathways through the transfer of phosphate groups to target proteins. These phosphorylation processes act as molecular on/off switches that can regulate the biological function of target proteins or protein complexes.
  • the proper function of protein kinases in signaling pathways is to activate or deactivate metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels and pumps, transcription factors, etc. Improperly regulated signaling due to defective regulation of protein phosphorylation is associated with numerous diseases, including inflammation, cancer, allergies/asthma, diseases of the immune system, diseases of the central nervous system, angiogenesis, etc.
  • kinases [7] Most kinases contain a similar 250-300 amino acid catalytic site. Kinases can be classified by the substrates they phosphorylate, and sequence motifs that broadly correspond to each of these kinase families have been identified.
  • RON receptor originated from nantes, Recepteur d'origine nantais
  • MSTlR tyrosine protein kinase receptor
  • tyrosine protein kinases such as RON
  • tyrosine protein kinases such as RON
  • selective small molecule kinase modulators targeting tyrosine protein kinases such as RON are expected to have therapeutic potential for the treatment of cancers in which activation of RON receptors and the like plays an important role in the development and progression of primary tumors and secondary metastases. Accordingly, continuous research is being conducted on various inhibitors to selectively inhibit the activity of RON, one of the tyrosine proteins.
  • One object of the present invention is to provide a novel compound having protein kinase inhibitory activity.
  • Another object of the present invention is to provide a compound useful as an RON inhibitor.
  • Another object of the present invention is to provide a compound useful for preventing or treating RON-mediated diseases.
  • Another object of the present invention is to provide a compound useful for preventing or treating cancer or immune diseases.
  • one aspect of the present invention provides a compound having the chemical structure of the following formula (1) or a pharmaceutically acceptable salt thereof.
  • another aspect of the present invention is a compound of Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the compounds according to the present invention have the effect of inhibiting protein kinase activity, especially the protein kinase activity of the RON receptor.
  • the above symbol may be omitted and may be displayed when necessary, such as when specifying a bonding atom or bonding position.
  • Halogen as used in the present invention means fluorine (F), chlorine (C1), bromine (Br), and iodine (I).
  • [25] 'Alkyl' as used in the present invention is an aliphatic hydrocarbon group that does not contain a double or triple bond and, unless otherwise indicated, has 1 to 20 carbon atoms, 1 to 19, 1 to 18, 1 to 17, 1 to 16, It may have 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, such as 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, and may be straight chain or branched.
  • alkyl group examples include methyl group, ethyl group, propyl group, n-propyl group, isopropyl group, butyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, 1-methylbutyl group, 1-ethylbutyl group, pentyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 4-methyl - 2-pentyl group, 3, 3-dimethyl butyl group, 2-ethylbutyl group, heptyl group, n-heptyl group, 1-methylhexyl group, octyl group, n-octyl group, tert-octyl group, 1-methyl Heptyl group
  • Alkenyl as used in the present invention is an aliphatic hydrocarbon group containing at least one double bond and, unless otherwise indicated, has 2 to 20 carbon atoms, 2 to 19 carbon atoms, or 2 to 2 carbon atoms. 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, such as 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, It may be straight chain or branched.
  • alkenyl group examples include vinyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 3-pentenyl group.
  • Alkynyl as used in the present invention is an aliphatic hydrocarbon group containing at least one triple bond and, unless otherwise indicated, has 2 to 20 carbon atoms, 2 to 19 carbon atoms, 2 to 18 carbon atoms, 2 to 17 carbon atoms, and 2 to 16 carbon atoms. It may have 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, such as 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, and may be straight chain or branched. Specific examples of the alkynyl group include, but are not limited to, ethynyl group, propynyl group, butynyl group, pentynyl group, and hexynyl group.
  • ‘Cycloalkyl’ as referred to in the present invention is a cyclic aliphatic hydrocarbon group that does not contain a double or triple bond, and has 3 to 30, 3 to 28, 3 to 26, or 3 to 24 carbon atoms, unless otherwise specified. 3 to 22, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 3 to 10, such as 3 to 8 carbon atoms, especially 3 to 6 carbon atoms, and may be monocyclic or polycyclic. .
  • the polycyclic refers to a group in which a cycloalkyl group is directly connected or condensed with another ring group.
  • the other ring group may be a cycloalkyl group, but may also be another type of ring group, such as a heterocycloalkyl group, an aryl group, or a heteroaryl group.
  • the cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, 3-methylcyclopentyl group, 2, 3-dimethylcyclopentyl group, cyclohexyl group, 3-methylcyclohexyl group, and 4-methylcyclo Hexyl group, 2, 3-dimethylcyclohexyl group, 3, 4, 5-trimethylcyclohexyl group, 4-tert-butylcyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, cycloundecyl group Syl group, cyclododecyl group, bicyclo [2.2.1]heptyl
  • cycloalkenyl used in the present invention refers to a cyclic aliphatic hydrocarbon group containing at least one double bond and has 3 carbon atoms unless otherwise indicated. to 30, 3 to 28, 3 to 26, 3 to 24, 3 to 22, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 3 to 10, such as 3 to 8 carbon atoms, especially It may have 3 to 6 carbon atoms and may be monocyclic or polycyclic.
  • the polycyclic refers to a group in which a cycloalkenyl group is directly connected or condensed with another ring group.
  • the other ring group may be a cycloalkyl group, but may also be another type of ring group, such as a heterocycloalkyl group, an aryl group, or a heteroaryl group.
  • cycloalkenyl group include, but are limited to, cyclopentenyl group, cyclohexenyl group, cyclopenta-1,3-dienyl group, cycloheptenyl group, cyclooctenyl group, and cycloocta-1,4-dienyl group. It doesn't work.
  • 'Aryl' referred to in the present invention is an aromatic hydrocarbon group, unless otherwise indicated, having 6 to 30 carbon atoms, 6 to 28, 6 to 26, 6 to 24, 6 to 22, 6 to 20, 6 to 18, 6 It may have 16 to 16 carbon atoms, 6 to 14 carbon atoms, for example, 6 to 12 carbon atoms, and may be monocyclic or polycyclic.
  • the polycyclic term refers to a group in which an aryl group is directly connected to or condensed with another ring group.
  • the other ring group may be an aryl group, but may also be another type of ring group, such as a cycloalkyl group, heterocycloalkyl group, heteroaryl group, etc.
  • the aryl group includes a spiro group.
  • Specific examples of the aryl group include phenyl group, biphenyl group, triphenyl group, naphthyl group, anthryl group, chrysenyl group, phenanthrenyl group, perylenyl group, fluoranthenyl group, triphenylenyl group, phenalenyl group, and pyrenyl group.
  • tetracenyl group pentacenyl group, fluorenyl group, indenyl group, acenaphthylenyl group, benzofluorenyl group, spirobifluorenyl group, 2, 3-dihydro-1H-indenyl group, condensed ring groups thereof, etc.
  • examples include, but are not limited to.
  • Heteroaryl means that at least one atom constituting the above-described cycloalkyl, cycloalkenyl, and aryl rings is substituted with a hetero atom such as 0, S, Se, N, Si, etc.
  • 'Pharmaceutically acceptable' as used in the present invention means that it can be used in animals, and more specifically in humans, by avoiding significant toxic effects when used in normal medicinal dosages, by the federal or state government. means capable of being approved by, or preferably approved by, the regulatory body of the United States Pharmacopoeia, or listed in the United States Pharmacopoeia, or other commonly recognized pharmacopoeia.
  • ‘pharmaceutically acceptable salt’ refers to a salt that is pharmaceutically acceptable and has the desired biological or pharmacological properties of the parent compound. It means a salt of an active compound of the present invention.
  • examples of such salts include, but are not limited to, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid). acid addition salts formed from [acid, etc.], and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, and fumaric acid.
  • the compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylic acid.
  • Boxylates e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate
  • diphenylacetate e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate
  • the compound of the formula of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.
  • ‘Hydrate’ as referred to in the present invention includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. refers to the compound of the present invention or its salt.
  • solvent refers to the compound of the present invention or its salt containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therefor include solvents that are volatile, non-toxic, and/or suitable for administration to humans.
  • Prodrug refers to a substance that is transformed into a parent drug in vivo. This means a compound of the invention that is capable of being hydrolyzed, oxidized and subjected to other reactions under biological conditions (in vitro or in vivo) to give an active compound, in particular a compound of the invention.
  • prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable esters.
  • biohydrolyzable phosphate analogs which contain biohydrolyzable moieties, and which biohydrolyze to produce the compounds of the invention, but are limited to this specific embodiment. It doesn't work.
  • These prodrugs include compounds that are readily prepared based on various known literature.
  • ‘Isomers’ as used in the present invention refer to compounds of the present invention or salts thereof that have the same chemical or molecular formula but are structurally or sterically different. These isomers include structural isomers such as tautomers, stereoisomers such as R or S isomers with asymmetric carbon centers, geometric isomers (trans, cis), and optical isomers (enantiomers). Additionally, all these isomers and mixtures thereof are also included within the scope of the present invention.
  • ‘Pharmaceutically acceptable carrier’ as used in the present invention refers to a diluent, adjuvant, additive or carrier administered with the compound of the present invention.
  • 'Prevention' refers to a reduction in the risk of acquiring a disease or disorder (i.e., one or more clinical symptoms of a disease, being exposed to or susceptible to developing the disease, but not yet developing the disease, or having symptoms of the disease This refers to preventing the process from proceeding from an invisible entity.
  • ‘Treatment’ as used in the present invention refers to improving a disease or disorder (i.e., arresting or reducing the progression of a disease or one or more clinical symptoms of the disease), or one or more physical symptoms that cannot be recognized by the individual. It refers to improving physical parameters, or controlling a disease or disorder physically (e.g. stabilization of unrecognized symptoms), psychologically (e.g. stabilization of physical parameters), or both.
  • One aspect of the present invention provides a compound having the chemical structure of Formula 1 below, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug thereof.
  • A is substituted or unsubstituted heterocycloalkylene; Substituted or unsubstituted heterocycloalkenylene; And substituted or unsubstituted heteroarylene; may be any one selected from the group consisting of.
  • A is substituted or unsubstituted heterocycloalkenylene; And substituted or unsubstituted heteroarylene; may be any one selected from the group consisting of.
  • the A is substituted or unsubstituted pyrazolylene; substituted or unsubstituted dihydropyr idinylene; and substituted or unsubstituted dihydropyrazolylene; It may be any one selected from the group.
  • the A is 1,3-pyrazolylene (1,3-pyrazolylene), 2-oxo-1,2-dihydropyridinyl-1,3-ene (2-oxo-1,2-dihydropyr idinyl-1 ,3-ene) and 3-oxo-2,3-dihydro-1H-pyrazolylene (3-oxo-2,3-dihydro-1H-pyrazolylene), and Accordingly, the compound having the chemical structure of Formula 1 may have the chemical structures of Formulas 2 to 4 below.
  • Ri and R2 are each independently hydrogen; halogen; hydroxy; alkoxy; Substituted or unsubstituted alkyl; and substituted or unsubstituted cycloalkyl.
  • R2 are each independently hydrogen; halogen; hydroxy; alkoxy; Substituted or unsubstituted alkyl; and substituted or unsubstituted cycloalkyl.
  • Ri and R2 are each independently hydrogen; halogen; hydroxy; alkoxy; And substituted or unsubstituted alkyl; It may be any one selected from the group consisting of. Specifically, Ri and R2 are each independently hydrogen; halogen; hydroxy; alkoxy; and alkyl substituted or unsubstituted with at least one selected from the group consisting of hydrogen, halogen, hydroxy, and alkoxy.
  • B is hydrogen; Substituted or unsubstituted alkyl; Substituted or unsubstituted cycloalkyl; Substituted or unsubstituted heterocycloalkyl; Substituted or unsubstituted aryl; And substituted or unsubstituted heteroaryl; may be any one selected from the group consisting of.
  • B is substituted or unsubstituted cycloalkyl; Substituted or unsubstituted heterocycloalkyl; Substituted or unsubstituted aryl; And substituted or unsubstituted heteroaryl; may be any one selected from the group consisting of.
  • B is aryl substituted or unsubstituted with halogen; And heteroaryl substituted or unsubstituted with halogen; It may be any one selected from the group consisting of. [55] In Formulas 1 to 4, 1 may be carbon or nitrogen.
  • Y is hydrogen; halogen; Substituted or unsubstituted alkyl; and substituted or unsubstituted cycloalkyl.
  • halogen and substituted or unsubstituted alkyl.
  • the hydrogen hydrogen; And halogen may be any one selected from the group consisting of.
  • [57] in Formulas 1 to 4 may be any one selected from the group consisting of -N(R')(R"); and substituted or unsubstituted heterocycloalkyl.
  • the 1 may be -N(R')(R'').
  • R' and R'' are each independently hydrogen; and substituted or unsubstituted alkyl.
  • R' and R'' are each independently hydrogen; or alkyl substituted or unsubstituted with at least one selected from the group consisting of halogen, alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, and alkylamino.
  • R' and R'' are each independently hydrogen; or alkyl substituted or unsubstituted with at least one selected from the group consisting of hydroxy and alkoxy.
  • the above may be substituted or unsubstituted heterocycloalkyl.
  • the substituted or unsubstituted heterocycloalkyl includes substituted or unsubstituted piperazinyl; substituted or unsubstituted morpholinyl; substituted or unsubstituted pyrrolidinyl (pyrrol idinyl); Substituted or unsubstituted piperidinyl; Substituted or unsubstituted azetidinyl; Substituted or unsubstituted heterospiroalkyl; and substituted or unsubstituted heterobicycloalkyl.
  • the substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted piperazinyl with at least one selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, and oxo; halogen, alkyl, hydroxy, Morpholinyl (morphol inyl) substituted or unsubstituted with at least one selected from the group consisting of alkoxy and oxo; Pyrrolidinyl substituted or unsubstituted with at least one selected from the group consisting of halogen, alkyl, hydroxy, alkoxy and oxo (pyrrolidinyl); piperidinyl substituted or unsubstituted with at least one selected from the group consisting of halogen, alkyl, hydroxy, alkoxy and oxo; selected from the group consisting of halogen, alkyl, hydroxy, alkoxy and oxo At least one substituted or unsubstituted
  • n may be an integer of 0 to 3, for example, an integer of 0 to 2, specifically an integer of 1 to 2.
  • each substituted functional group is independently halogen; alkyl; hydroxyalkyl; alkoxyalkyl; hydroxy; alkoxy; alkylamino; and oxo; and may be substituted with at least one selected from the group consisting of.
  • the compounds of the present invention having the chemical structure of Formula 1 above inhibit the enzymatic activity of RON.
  • the compounds of the present invention having the chemical structure of Formula 1 can also inhibit the enzymatic activity of MET.
  • the compounds having the chemical structure of Formula 1 of the present invention are effective as so-called 'dual inhibitors', inhibiting both the enzymatic activity of RON and the enzymatic activity of MET. . Therefore, the compound having the chemical structure of Formula 1 of the present invention, or its pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug, is used for the prevention or treatment of diseases related to the enzymatic activity of RON and/or MET. It can be used as an active ingredient in pharmaceutical compositions.
  • Another aspect of the present invention provides a pharmaceutical composition containing a compound having the chemical structure of Formula 1 above, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug thereof as an active ingredient.
  • compounds having the chemical structure of Formula 1 include RON and/or MET, which increase the proliferation, invasion, and metastasis of tumor cells, and increase resistance to apoptosis and cytotoxic therapy of tumor cells.
  • RON and/or MET which increase the proliferation, invasion, and metastasis of tumor cells, and increase resistance to apoptosis and cytotoxic therapy of tumor cells.
  • same tyrosine protein Since it has activity as a RON inhibitor and/or MET inhibitor, which inhibits the expression or activity of kinases, the pharmaceutical composition of the present invention is used to treat diseases mediated by RON and/or MET, so-called RON and/or MET. It can be used to prevent or treat vector diseases.
  • the RON and/or MET mediated disease may be a disease caused by overexpression or overactivation of RON and/or MET.
  • composition of the present invention may further include a pharmaceutically acceptable carrier or additive.
  • the active ingredient of the present invention can be administered alone or in mixture with any convenient carrier, etc., and the dosage form may be a single dose or repeated dosage form.
  • the pharmaceutical composition may be a solid formulation or a liquid formulation.
  • Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, etc.
  • Solid preparations may include, but are not limited to, carriers, flavoring agents, binders, preservatives, disintegrants, lubricants, fillers, etc.
  • Liquid preparations include, but are not limited to, solutions such as water and propylene glycol solutions, suspensions, and emulsions, and can be prepared by adding appropriate colorants, flavoring agents, stabilizers, and viscosifiers.
  • powders can be prepared by simply mixing the active ingredient of the present invention with a suitable pharmaceutically acceptable carrier such as lactose, starch, or microcrystalline cellulose.
  • Granules are prepared by mixing the active ingredient of the present invention, a suitable pharmaceutically acceptable carrier, and a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone and hydroxypropyl cellulose, and then mixing them with a solvent such as water, ethanol, or isopropanol. It can be manufactured using a wet granulation method or a dry granulation method using compression force.
  • tablets can be manufactured by mixing the granules with a suitable pharmaceutically acceptable lubricant such as magnesium stearate and then compressing them using a tablet press.
  • the pharmaceutical composition of the present invention may be administered as an oral agent, an injectable agent (e.g., intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection, implant), depending on the disease to be treated and the condition of the individual. It may be administered as an inhalation agent, nasal administration agent, vaginal agent, rectal administration agent, sublingual agent, transdermal agent, topical agent, etc., but is not limited thereto. Depending on the route of administration, it may be formulated in an appropriate dosage unit form containing commonly used, non-toxic, pharmaceutically acceptable carriers, excipients, and vehicles.
  • the pharmaceutical composition of the present invention is administered in an amount of about 0.0001 mg/kg to about 10 g/kg daily. It can be administered in a daily dosage of about 0.001 mg/kg to about 1 g/kg. However, the dosage may vary depending on the degree of purification of the mixture, the patient's condition (age, gender, weight, etc.), and the severity of the condition being treated. If necessary, for convenience, the total daily dose may be administered in divided doses several times throughout the day.
  • the present invention involves administering a therapeutically effective amount of a compound having the chemical structure of Formula 1, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug thereof, to a subject.
  • a method of treating RON-mediated diseases such as cancer or immune diseases.
  • the present invention involves administering a therapeutically effective amount of a compound having the chemical structure of Formula 1, or a pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug thereof, to a subject.
  • a pharmaceutically acceptable salt, isomer, solvate, hydrate or prodrug thereof Provides a method of inhibiting the activity of RON.
  • Step 2 ethyl l-(3-f luoropyr idin-2-yl)-5-( tr if luoromethyl )-lH-pyr azo le-4-carboxy late
  • 4-f luoro-2- hydr az i ney 1 pyr idi ne (0.24 g, 1.87 mmol) was dissolved in 6 ml of ethanol. After stirring at 60°C for 12 hours, the reaction mixture was extracted using Toyo and water. The residue was purified by column chromatography to obtain the title compound (0.35 g, yield: 55%).
  • Step 3 1- (3- f luoropyr idin- 2- yl)- 5- (tr if luoromethyl)- IH-pyrazole-
  • Step 2 tert-butyl (4- (4- amino- 2- f luorophenoxy)- 3-((4- methylpiperazin-l-yl )methyl )pyr idin-2-yl )carbamate ⁇ .
  • Step 3 4— (4— amino— 2— f luorophenoxy)— 3— ((4— methylpiperazin— 1— yl )methyl )pyr idin— 2— amine
  • Example 6 l-(3-chloropyr idin-2-yl)-5-(tr i f luoromethyl)-lH-pyrazole-4-carboxyl ic acid was used to prepare the title compound in a similar manner to Example 6. (50 mg, yield: 75%) was obtained.
  • Example 10 According to Example 10, l-(3-chloropyr idin-2-yl)-5-(tr i f luoromethyl)-lH-pyrazole-4-carboxyl ic acid was used to prepare the title compound in a similar manner to Example 10. (20 mg, yield: 56%) was obtained.
  • Example 15 11- (3- chloropyridin- 2- yl) - 5- (tri fluoromethyl) - lH-pyrazole-4-carboxyl ic acid
  • the title compound (9 mg, yield : 48%) was obtained.
  • Example 5 l-(3-chloropyr idin-2-yl)-5-(tr i f luoromethyl)-lH-pyrazole-4-carboxyl ic acid was used to prepare the title compound in a manner similar to Example 5. (40 mg, yield: 59%) was obtained.
  • Example 20 According to Example 20, 1- (3- chloropyr idin-2-yl ) -5- (tr i fluoromethyl) - lH-pyrazole-4-carboxyl ic acid was used to prepare the title compound in a similar manner to Example 20. (12 mg, yield: 28%) was obtained.
  • Example 22 N-(4-( (2-amino-3-( (3, 3-di f luoropyrrol idin-1-yl)methyl)pyridin-4-yl)oxy)-3-f luorophenyl )-l-(pyr imidin-2-yl)-5-(trif luoromethyl)-lH-pyr azo 1 e-4-carboxami de
  • Example 23 N-(4-( (2-amino-3-( (3, 3-di f luoropyrrol idin-1-yl)methyl)pyridin-4-yl)oxy)-3-f luorophenyl )-l-(pyr i daz in-3-y 1 )-5- (trif luoromethyl )-lH-pyr azo 1 e-4-carboxami de
  • the title compound (7 mg, yield: 15%) was prepared in a manner similar to Example 20 using n-3-y 1 ) -5 - ( trif 1 uor ome t hy 1 )-lH- pyrazole-4-carboxyl ic acid. got it
  • Example 24 N-(4-((2-amino-3-( (dimethyl amino )methyl)pyr idin-4- yl )oxy)-3-f luorophenyl )-l-(3-chloropyr idin -2-y 1 )-5-( tr if luoromethyl )-lH- pyr azo le-4-carboxami de
  • Example 4 According to Example 4, l-(3-chloropyr idin-2-yl)-5-(tr i f luoromethyl)-lH-pyrazole-4-carboxyl ic acid was used to prepare the title compound in a manner similar to Example 4. (10 mg, yield: 39%) was obtained.
  • Example 25 N-(4-((2-amino-3-( (dimethyl amino )methyl)pyr idin-4- yl )oxy)-3-f luorophenyl )-l-(pyrimidin-2- yl )-5-( tr if luoromethyl )-lH-pyrazo le-4-carboxami de
  • the title compound (10 mg, yield: 30%) was obtained in a similar manner to Example 4 using pyrazole-4-carboxyl ic acid.
  • Example 30 N-(4-( (2-amino-3-(pyrrol idin-l-ylmethyl )pyr idin-4- yl )oxy)-3-f luorophenyl )-l-(pyridazin-3-yl)-5-( tr if luoromethyl )-lH-pyrazo le-4-carboxami de
  • Example 10 According to Example 10, l-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxyl ic acid was used to obtain the title compound (25 mg, yield) in a similar manner to Example 10. : 99%) was obtained.
  • Example 2 the title compound (12 mg, yield: 40%) was obtained in a similar manner to Example 2 using (R)-2-methylmorphol ine.
  • Example 2 According to Example 2, the title compound (20 mg, yield: 19%) was obtained in a similar manner to Example 2 using 2,2-dimethylmorphol ine.
  • Example 36 N-(4-( (2-amino-3-(azet idin-l-ylmethyl)pyr idin-4-yl)oxy)-3-f luorophenyl)-l-(3-f luoropyr idin-2-yl)-5-(trif luoromethyl)-lH-pyrazole-
  • Step 5 N- (4- ((2- amino- 3- (azetidin- 1- ylmethyl) pyridin- 4- yl) oxy)- 3 - f luorophenyl )—1— (3— f 1 uoropyr i d i n-2-y 1 )— 5— (tr i f luoromethyl )— 1H— pyr azole— 4-carboxamide
  • Example 37 N-(4-( (2-amino-3-(morphol inomethyl)pyr idin-4-yl)oxy)-3-f luorophenyl)-l-(4-f luorophenyl)-6 -methyl-2-oxo-l , 2-dihydropyr i dine-3- carboxamide
  • the title compound (30 mg, yield: 15%) was obtained in a similar manner to Example 5 using rophenyl)—6—methyl—2—oxo—l,2—dihydropyr idine-3-carboxyl ic acid.
  • DMS0-d 6 6 12.03 (s, 1H), 8349 (d, 1H), 7.95 (d,
  • Example 38 N-(4-((2-amino-3-(morphol inomethyl)pyridin-4-yl)oxy)-3-f luorophenyl)-4-ethoxy ⁇ l-(4-f luorophenyl )-2-oxo-l, 2-dihydropyr idine-3-carboxamide
  • Example 39 N-(4-( (2-amino-3-(morphol inomethyl)pyr idin-4-yl)oxy)-3-f luorophenyl)-l-(2-hydroxy-2-methy lpropy 1 ) -5-methy 1 -3-oxo-2-pheny 1 -2 , 3- dihydro-lH-pyrazole-4-carboxamide
  • Example 5 According to Example 5, using 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-IH-pyrazole-4-carboxyl ic acid The title compound (40 mg, yield: 36%) was obtained in a similar manner to Example 5.
  • Example 36 According to Example 36, the title compound (2 mg, yield: 80%) was obtained in a similar manner to Example 36 using 3-methoxyazet idine.
  • Example 36 the title compound (8 mg, yield: 3%) was obtained in a similar manner to Example 1 using 3-methylazet idin-3-ol.
  • Example 2 According to Example 2, the title compound (2 mg, yield: 24%) was obtained in a similar manner to Example 2 using (S)-3-ethylmorphol ine.
  • Example 36 N,N-dimethylpyrrol idin-3-amine was used to obtain the title compound (4 mg, yield: 31%) in a similar manner to Example 36.
  • Step 3 N- (4- ((6- amino- 5- ((4- methylpiperazin- 1- yl )methyl )pyr imidin-4-yl )oxy)— 3— f luorophenyl )—1— ( 3— f 1 uor opyr idi n-2-y 1 )- 5-(trif 1 uoromethy 1 ) — 1H— pyr azo 1 e— 4— car boxam i de
  • Example 57 1— phenyl— 5— (trif luoromethyl)— IH—pyrazole— 4— carboxylic acid was used to obtain the title compound (40 mg, yield: 58%) in a similar manner to Example 57. .
  • Example 60 N-[4 - [6-amino-5-(morpholinomethyl)pyrimidin-4-yl]oxy ⁇ 3 - f luoro-phenyl ] -l-pheny 1 -5-( tr if luoromethyl ) pyr azo 1 e-4-carboxami de
  • the title compound (42 mg, yield: 60%) was obtained in a similar manner to Example 59 using tr i fluoromethyl )—lH—pyrazole—4— carboxylic acid.
  • Example 1 According to Example 1, thiomorpholine 1,1- dioxide was used to obtain the title compound (25 mg, yield: 38%) in a similar manner to Example 1.
  • Example 2 thiomorpholine 1,1- dioxide was used to obtain the title compound (25 mg, yield: 38%) in a similar manner to Example 2O.
  • the compound was prepared at ImM concentration with 100% DMSO and stepwise diluted 10 times through 3-fold dilution. 2ul of the stepwise diluted compound was added to a 96-well containing 48ul lx kinase reaction buffer (50mM HEPES (pH 7.4), 0.01% Tween-20, 5mM DTT, 0.5mM Na3V04, 2mM EGTA, 10mM MgCh). - Added to plate.
  • 48ul lx kinase reaction buffer 50mM HEPES (pH 7.4), 0.01% Tween-20, 5mM DTT, 0.5mM Na3V04, 2mM EGTA, 10mM MgCh).
  • RON protein was diluted in RON storage buffer (50mM Tris-HC1 (pH 7.5), 150mM NaCl, 0.5mM EDTA, 0.02% Triton It was diluted to 0.4nM.
  • RON-specific substrate mixture 40uM ULight-labeled Poly GT, 100 nM ATP
  • concentration twice the final reaction concentration was prepared.
  • 5uL 4x phosphotyrosine antibody (Perkin Elmer) containing europium was added to all wells and incubated at room temperature for 60 minutes. After incubation, the 384-well-plate was read with a Vi son plate reader. At this time, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm.
  • the IC50 value of each example compound was derived using the GraphPd Prism7 program.
  • the compound was prepared at an ImM concentration with 100% DMSO and serially diluted 10 times through 3-fold dilution. 2ul of stepwise diluted compounds were added to 96-wells containing 48ul lx kinase reaction buffer (50mM HEPES (pH 7.4), 0.05% BSA, 0.005% Tween-20, 1mM DTT, 0.5mM MnC12, 20mM MgC12). - Added to plate.
  • 48ul lx kinase reaction buffer 50mM HEPES (pH 7.4), 0.05% BSA, 0.005% Tween-20, 1mM DTT, 0.5mM MnC12, 20mM MgC12).
  • the cMET protein was diluted in cMET storage buffer (50mM Tr is-HC1 (pH 7.5), 150mM NaCl, 0.05% Brij35, 1mM DTT, 10% Glycerol) to a concentration of 263nM, and then again in lx kinase reaction buffer. It was diluted to 2 nM.
  • a MET-specific substrate mixture (5 uM TK peptide, 10 mM ATP) with a concentration twice the final reaction concentration was prepared.
  • UL was dispensed, and 2.5 uL of lx kinase reaction buffer was added to the low control well, centrifuged at 1000 RPM for 40 seconds at room temperature, and incubated at room temperature for 20-30 minutes. Afterwards, 5uL of substrate cocktai 1 (2x) was dispensed into all wells, centrifuged at 1000 RPM for 40 seconds at room temperature, and incubated at room temperature for 60 minutes. Afterwards, 5uL of 90mM EDTA was added to all wells to terminate the reaction, and the cells were incubated again at room temperature for 5 minutes.
  • 5uL 4x phosphotyrosine antibody (Perkin Elmer) containing europium was added to all wells and incubated at room temperature for 60 minutes. Cultured. After incubation, the 384-well-plate was read with a Vi son plate reader. At this time, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. The IC50 value of each example compound was derived using the GraphPd Prism7 program.

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Abstract

La présente invention concerne un nouveau composé fonctionnant en tant qu'inhibiteur de protéine kinase, en particulier un inhibiteur de RON.
PCT/IB2023/062979 2022-12-23 2023-12-20 Nouveau composé en tant qu'inhibiteur de ron Ceased WO2024134514A1 (fr)

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Citations (4)

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KR20070006923A (ko) * 2004-04-23 2007-01-11 브리스톨-마이어스 스큅 컴퍼니 키나제 억제제로서의 모노시클릭 헤테로사이클
WO2008057280A1 (fr) * 2006-10-27 2008-05-15 Amgen Inc. Composés à cycles multiples et procédés d'utilisation
US20120172382A1 (en) * 2010-04-29 2012-07-05 Deciphera Pharmaceuticals, Llc. Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activities
WO2021224186A1 (fr) * 2020-05-04 2021-11-11 Institut Curie Nouveaux dérivés de pyridine en tant que radiosensibilisateurs

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Publication number Priority date Publication date Assignee Title
KR20070006923A (ko) * 2004-04-23 2007-01-11 브리스톨-마이어스 스큅 컴퍼니 키나제 억제제로서의 모노시클릭 헤테로사이클
WO2008057280A1 (fr) * 2006-10-27 2008-05-15 Amgen Inc. Composés à cycles multiples et procédés d'utilisation
US20120172382A1 (en) * 2010-04-29 2012-07-05 Deciphera Pharmaceuticals, Llc. Pyridone amides and analogs exhibiting anti-cancer and anti-proliferative activities
WO2021224186A1 (fr) * 2020-05-04 2021-11-11 Institut Curie Nouveaux dérivés de pyridine en tant que radiosensibilisateurs

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Title
GRETCHEN SCHROEDER: "Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 52, no. 5, 12 March 2009 (2009-03-12), pages 1251 - 1254, XP055002050, ISSN: 00222623, DOI: 10.1021/jm801586s *

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