WO2023218245A1 - Composés dérivés d'hétéroaryle et composition pharmaceutique les comprenant - Google Patents

Composés dérivés d'hétéroaryle et composition pharmaceutique les comprenant Download PDF

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WO2023218245A1
WO2023218245A1 PCT/IB2023/000286 IB2023000286W WO2023218245A1 WO 2023218245 A1 WO2023218245 A1 WO 2023218245A1 IB 2023000286 W IB2023000286 W IB 2023000286W WO 2023218245 A1 WO2023218245 A1 WO 2023218245A1
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compound
pharmaceutically acceptable
acceptable salt
optical isomer
halo
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PCT/IB2023/000286
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English (en)
Inventor
Seohyun JO
Dahoon MA
Yeseul Park
Gyuseok SIM
Jungbeom SON
Namdoo Kim
Hwangeun CHOI
Sunghwan Kim
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Voronoi Inc.
Voronoibio Inc.
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Publication of WO2023218245A1 publication Critical patent/WO2023218245A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to heteroaryl derivative compounds and a pharmaceutical composition comprising thereof. Specifically, the present invention relates to heteroaryl derivative compounds having RAF inhibitory activity.
  • the RAS/RAF/MEK/ERK protein kinase signaling pathway plays a very important role in the regulation of cellular function, and is specifically involved in cell proliferation, differentiation, survival, and angiogenesis (Biology of the Cell, 2001, 93, 53-62).
  • GTP guanosine triphosphate
  • phosphorylation and activation of the RAF protein in the protoplasmic membrane proceeds.
  • the activated RAF protein phosphorylates and activates the MEK protein
  • the MEK protein phosphorylates and activates the ERK protein.
  • Translocation of activated ERK from the cytoplasm to the nucleus results in regulation and phosphorylation of transcription factors such as Elk-1 and Myc.
  • RAF protooncogenes are serine/thr protein kinases that transmit signals from growth factor receptors activated in the cell membrane to transcription factors in the nucleus.
  • the activation of the RAF protein is accompanied by phosphorylation of tyrosine, serine, and threonine residues of RAF protein, and direct phosphorylation by receptor tyrosine kinase or phosphorylation by protein phosphorylation enzymes controlled by these receptors is known as the mechanism of RAF activation.
  • RAS is involved in the activation of RAF. Signals reaching RAF are then transferred to the nucleus via a signaling pathway leading to the RAF/MEK/ERK protein kinase.
  • RAF acts as a major propagator of RAS function, providing a theoretical background for chemotherapy in the case of cancer with mutations or activations of RAS in inhibiting the action of this protein.
  • RAF proteins have three isoforms of ARAF, BRAF, and CRAF (also known as RAF-1) with three functions(Biochim. Biophys. Acta., 2003, 1653, 25- 40), all three RAF genes are expressed in most tissues, and high expression of BRAF occurs in neurocellular tissues and ARAF occurs in urinary reproductive tissues.
  • each RAF family has a very similar amino acid sequence, biochemical activity and biological functionality are distinguished from each other (Exp. Cell. Res. 1999, 253, 34-46).
  • BRAF is an important isoform protein related to cell proliferation and is an important target of oncogenic RAS.
  • Abnormal mutations in the body have only been identified in BRAF cases, and are known to occur at a frequency of 30-60% in malignant skin melanoma (Nature, 2002, 417, 949-954), 30-50% in thyroid cancer, 5-20% in colon cancer, and 30% or less in ovarian cancer (Nature Rev. Mol. Cell Biology, 20045, 875 and 885). So far, more than 45 BRAF mutations have been known, but the most frequent mutation is that valine number 600 mutates with glutamic acid (V600E), which is observed in more than 90% of human cancers. This mutation is believed to increase the kinase activity of BRAF and transmit RAF/MEK/ERK signals to sub-signaling pathways that include structural activity of ERK as a result of RAS and growth factor receptor activation.
  • the present inventors confirmed that the compounds of the present invention have an anticancer effect by inhibiting the activity of RAF, thereby completing the present invention.
  • An object of the present invention is to provide a heteroaryl derivative having a novel structure, an stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the heteroaryl derivative compounds.
  • Still another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compounds, and specifically, to a pharmaceutical composition for the treatment or prevention of RAF-related diseases comprising the heteroaryl derivative compounds as an active ingredient, use of the compounds for the treatment or prevention of RAF-related diseases, or a method for treating or preventing RAF-related diseases comprising administering the compounds.
  • the present invention provides a compound represented by following Chemical Formula
  • X is CH 2 , or O
  • Y is CH or N
  • Z is CH or N
  • Ri is -Ci-6alkyl, -Ci-ehaloalkyl, aryl or heteroaryl in which at least one H of the aryl or heteroaryl ring may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo;
  • R 2 and R3 are each independently -H, -Ci-6alkyl, -Ci-ehaloalkyl, or -halo;
  • R4 is -H, -Ci-6alkyl, -Ci-ehaloalkyl, -O-Ci-6alkyl, -O-Ci-ehaloalkyl, or -halo;
  • R5 and Re are linked together to form heteroaryl or heterocycloalkyl in which at least one H of the heteroaryl or heterocycloalkyl ring may be substituted with -Ci-ealkyl, -Ci- ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-6alkyl,
  • R7 and Rs are each independently -H, -Ci-6alkyl, or cycloalkyl
  • R9 and Rio are each independently -H, -Ci-6alkyl, or -Ci-ehaloalkyl.
  • the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be selected from the group consisting of the compounds of Examples 1 to 58 described in Table 1.
  • alkyl may refer to a straight or branched chain acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • “Ci-6alkyl” may indicate an alkyl containing 1 to 6 carbon atoms.
  • acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, secbutyl, isobutyl, tert-butyl, or the like.
  • Cyclic alkyl may be used interchangeably with “cycloalkyl” as used herein, and as an example, may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or the like.
  • the cycloalkyl is monocyclic.
  • the cycloalkyl is 3- 7-membered.
  • halo or “halogen” may be F, Cl, Br, or I.
  • haloalkyl may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo-substituted carbon atoms as defined herein.
  • examples of the haloalkyl may include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I.
  • hydroxy alkyl may indicate a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with -hydroxy (-OH).
  • haloalkyl may include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more -OH.
  • aminoalkyl may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (-NR'R”).
  • R' and R may be each independently selected from the group consisting of hydrogen and Ci-6alkyl, and the selected R' and R” may be each independently substituted or unsubstituted.
  • heterocycloalkyl may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated.
  • heterocycloalkyl is not aromatic.
  • when unsaturated it may be referred to as a heterocycloalkene.
  • heterocycloalkyl may be a single ring or a multiple ring such as a spiro ring, a bridged ring or a fused ring.
  • “3- to 12-membered heterocycloalkyl” may indicate a heterocyclo alkyl containing 3 to 12 atoms forming a ring.
  • the heterocycloalkyl may include, but is not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidin-2,4(lH,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3 -pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (lR,5S)-3- azabicyclo[3.2.1]octane, (ls,4s)
  • “Ci-6alkenyl” may indicate an alkenyl containing 1 to 6 carbon atoms.
  • the cyclic alkenyl is monocyclic. In certain embodiments, the cyclic alkenyl is 3- 7-membered.
  • arene may mean an aromatic hydrocarbon ring.
  • the arene may be a monocyclic arene or a polycyclic arene.
  • the number of ring-forming carbons in the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less.
  • Examples of the arene may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinquebenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like.
  • the residue obtained by removing one hydrogen atom from “arene” is referred to as “aryl”.
  • heteroene may be a ring containing at least one of O, N, P, Si, and S as a heterogeneous element.
  • the number of ring-forming carbons in the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less.
  • the heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene.
  • the polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure.
  • heteroarene may include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N- heteroarylcarbazole, N-alkylcarbazole, benzoxazole,
  • heteroarene may also include bicyclic heterocyclo-arene containing heteroarene fused to an arene ring or a cycloalkyl ring fused to heterocycloalkyl rings.
  • the residue obtained by removing one hydrogen atom from the “heteroarene” is referred to as “heteroaryl”.
  • the above-mentioned homogeneous or heterogeneous substituents may be substituted one or more at the same or different positions, and may be sequentially substituted.
  • the meaning of “sequentially” means that in the formula, one substituent is substituted and then another substituent is successively substituted in the substituent, for example, a cycloalkyl group is substituted in the alkyl group after the alkyl group is substituted, and the When a carbonyl group is sequentially substituted for a cycloalkyl group, it can be indicated that the cycloalkyl group is sequentially substituted by naming it carbonylcycloalkylalkyl.
  • connection radicals listed above do not specify the coupling direction
  • the coupling direction is arbitrary.
  • the radical L connected in « can be -M-W-, where ring A and ring B can be connected in the same direction as the reading order from left to right to form and ring A and ring B can be connected in the opposite direction to the reading order from left to right to form
  • stereoisomers e.g., enantiomers
  • enantiomers mean compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but are different in stereostructure. Each of these enantiomers and mixtures thereof are also included within the scope of the present invention.
  • the straight solid- line bond (-) connecting an asymmetric carbon atom may include a wedge-shaped solid-line bond ' ? or a wedge-shaped dashed-line bond ' indicating the absolute configuration of the stereocenter.
  • stereoisomer and “optical isomer” are used interchangeably.
  • the compounds of Chemical Formula 1 of the present invention may exist in the form of a “pharmaceutically acceptable salt”.
  • a pharmaceutically acceptable salt As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • pharmaceutically acceptable salt as used herein means any and all organic or inorganic acid addition salts of the compounds represented by Chemical Formula 1 of which side effects caused by the salt do not reduce the beneficial efficacy of the compounds at concentrations having an effective action that is relatively non-toxic and harmless to a patient.
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compounds in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • An acid or alcohol in an equimolar amount of the compounds and water may be heated, and the mixture may then be evaporated to dryness, or the precipitated salt may be filtered off with suction.
  • an organic acid and an inorganic acid may be used as the free acid, wherein the inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, or the like, and the organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, or the like.
  • the present invention is not limited thereto.
  • the alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving a compounds in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • a sodium, potassium, or calcium salt as the metal salt, but the present invention is not limited thereto.
  • the corresponding silver salt may be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • the pharmaceutically acceptable salt of the present invention includes salts of acidic or basic groups that may be present in the compounds of Chemical Formula 1.
  • the pharmaceutically acceptable salt may include sodium, calcium and potassium salts of hydroxyl groups, and the like, and as other pharmaceutically acceptable salts of amino groups, may include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate(mesylate), and p-toluenesulfonate (tosylate) salts, and the like, and may be prepared by a method for preparing a salt known in the art.
  • X is O. In certain embodiments, X is CH2.
  • R is phenyl that may be substituted with -Ci-6alkyl, -Ci- ehydroxyalkyl, -Ci-6aminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • R is 5- or 6-membered monocyclic heteroaryl that may be substituted with -Ci-6alkyl, -Ci-ehydroxyalkyl, - Ci-6aminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • R is pyridinyl that may be substituted with -Ci-6alkyl, -Ci-ehydroxyalkyl, -Ci-6aminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • R is -Ci-6alkyl that may be substituted with -Ci-6alkyl, -Ci-ehydroxyalkyl, - Ci-6aminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • R is -Ci-ehaloalkyl.
  • Y is CH. In certain embodiments, Y is N.
  • Z is CH. In certain embodiments, Z is N.
  • Ri is aryl in which at least one H of the aryl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl, or -halo. In certain embodiments, Ri is phenyl in which at least one H of the phenyl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl, or -halo. In certain embodiments, Ri is unsubstituted phenyl. In certain embodiments, Ri is phenyl in which at least one H of the phenyl is substituted with -halo (e.g., F). In certain embodiments, Ri is ortho monosubstituted phenyl.
  • -halo e.g., F
  • Ri is meta mono-substituted phenyl. In certain embodiments, Ri is para mono-substituted phenyl. In certain embodiments, Ri is di-substituted phenyl. In certain embodiments, Ri is heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo. In certain embodiments, Ri is 5-membered monocyclic heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci- ealkyl, -Ci-ehaloalkyl or -halo.
  • Ri is pyrazolyl (e.g., 4-pyrazolyl) or furanyl (e.g., 2-furanyl), in which at least one H of the pyrazolyl or furanyl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo.
  • Ri is 6-membered monocyclic heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci-ealkyl, -Ci- ehaloalkyl or -halo.
  • Ri is -Ci-6alkyl (e.g., Me or Et).
  • Ri is -Ci-ehaloalkyl.
  • Ri is -Ci-6 fluoroalkyl.
  • Ri is fluoroethyl (e.g., -CH2CF3).
  • R2 is H. In certain embodiments, R2 is -Ci-6alkyl (e.g., Me or Et). In certain embodiments, R2 is Me. In certain embodiments, R2 is halo (e.g., F or Cl). In certain embodiments, R2 is F. In certain embodiments, R2 is H or F.
  • R3 is -H. In certain embodiments, R3 is -Ci-6alkyl (e.g., Me or Et). In certain embodiments, R3 is Me. In certain embodiments, R3 is halo (e.g., F or Cl). In certain embodiments, R3 is F.
  • R4 is ortho to Z. In certain embodiments, R4 is meta to Z. In certain embodiments, R4 is para to Z.
  • R4 is -H. In certain embodiments, R4 is -Ci-ealkyl (e.g., Me or Et). In certain embodiments, R4 is Me. In certain embodiments, R4 is -Ci-ehaloalkyl. In certain embodiments, R4 is -C1-6 fluoroalkyl. In certain embodiments, R4 is fluoromethyl (e.g., -CF3). In certain embodiments, R4 is -O-Ci-6alkyl (e.g., -OMe, -OEt, -O(zz-Pr), or -O(z-Pr)). In certain embodiments, R4 is -OMe.
  • R4 is -O-Ci -ehaloalky 1.
  • R4 is -O-Ci-efluoroalkyl (e.g., -O-fluoromethyl, -O-fluoroethyl, -O(zz- fluoropropyl), or -O(z-fluoropropyl)).
  • R4 is -O-fluoromethyl (e.g., -O- CH2F, -O-CHF2, or -O-CF3).
  • R4 is -O-CHF2.
  • R4 is -O-CF3.
  • R4 is halo.
  • R4 is F. In certain embodiments, R4 is Cl. In certain embodiments, R4 is -H, Me, F, Cl, -CF3, -OMe, -O-CHF2, or - O-CF3. In certain embodiments, R4 is Me, F, Cl, -CF3, -OMe, -O-CHF2, or -O-CF3.
  • R5 and Re are each independently -Ci-ealkyl, -Ci-ealkenyl, -Ci- eaminoalkyl, -Ci-ehaloalkyl, -NR7R8, -OR9, -SR10, or -halo, or R5 and Re are linked together to form heteroaryl or heterocycloalkyl in which at least one H of the heteroaryl or heterocycloalkyl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl may be substituted with -Ci-ealkyl, -Ci- ehaloalkyl or -halo.
  • R5 and Re are linked together to form 5-membered monocyclic heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci- ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form pyrrolyl, imidazolyl, thienyl, furanyl, or thiazolyl in which at least one H of the pyrrolyl, imidazolyl, thienyl, furanyl, or thiazolyl may be substituted with -Ci-ealkyl, -Ci- ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form 6-membered monocyclic heteroaryl in which at least one H of the heteroaryl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form heterocycloalkyl in which at least one H of the heterocycloalkyl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci- ealkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form 5- membered monocyclic heterocycloalkyl in which at least one H of the heterocycloalkyl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form 6-membered monocyclic heterocycloalkyl in which at least one H of the heterocycloalkyl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, - halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-6alkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form morpholinyl in which at least one H of the morpholinyl may be substituted with -Ci-ealkyl, -Ci- ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl or -halo.
  • R5 and Re are linked together to form 7-membered monocyclic heterocycloalkyl in which at least one H of the heterocycloalkyl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci-6alkyl, -C 1 -ehaloalky 1 or -halo.
  • R5 and Re are linked together to form 1,4-oxazepanyl in which at least one H of the 1,4-oxazepanyl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, -halo, aryl, or heteroaryl, wherein at least one H of aryl or heteroaryl ring may be substituted with -Ci- ealkyl, -Ci-ehaloalkyl or -halo.
  • R5 is -H. In certain embodiments, R5 is -halo (e.g., F or Cl). In certain embodiments, R5 is F.
  • Re is -NR7R8. In certain embodiments, Re is -NH2. In certain embodiments, Re is -NHRs. In certain embodiments, Re is -NHCi-ealkyl (e.g., -NHMe or -NHEt). In certain embodiments, Re is -NHMe. In certain embodiments, Re is -NH-cycloalkyl (e.g., -NH- cyclopropyl or -NH-cyclobutyl). In certain embodiments, Re is -NH-cyclopropyl.
  • R7 is -H.
  • Rs is -H. In certain embodiments, Rs is -Ci-ealkyl (e.g., Me or Et). In certain embodiments, Rs is Me. In certain embodiments, Rs is cycloalkyl (e.g., cyclopropyl or cyclobutyl). In certain embodiments, Rs is cyclopropyl.
  • a compound of the present invention is a compound of Chemical Formula 1 (e.g., a compound of any one of Examples 1 to 58), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a compound of the present invention is a compound of Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides use of a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the Chemical Formula 1 is as defined above.
  • the heteroaryl derivative compound represented by Chemical Formula 1 exhibits excellent inhibitory activity against RAF among kinases, and thus may be usefully employed for the treatment or prevention of RAF- related diseases, in particular, cancer.
  • the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against RAF mutations and can be usefully employed for treatment or prevention of carcinoma induced by RAF or RAF mutations.
  • the cancer includes any cancer capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of RAF activity, and may be a solid cancer or a hematologic cancer.
  • the cancer may be one or more selected from the group consisting of pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanom
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound of the present invention; and optionally a pharmaceutically acceptable excipient.
  • the present invention provides a kit comprising: a compound or pharmaceutical composition of the present invention; and instructions for using the compound or pharmaceutical composition.
  • kits further comprises one or more containers.
  • the present invention provides a pharmaceutical composition for treatment or prevention of RAF-related diseases containing the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the RAF-related disease may be cancer.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of cancer, comprising the compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, as an active ingredient.
  • the types of cancer are the same as described above.
  • the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for administration.
  • the pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, ringer’s solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components, and other conventional additives such as antioxidants, buffers, and fungicides can be added as necessary.
  • compositions for injection such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
  • the composition of the present invention may be a patch agent, a liquid agent, a pill, a capsule, a granule, a tablet, a suppository, or the like.
  • These formulations may be prepared by the usual method used in formulation in the art or by the method disclosed in the literature [Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA], and may be formulated into various formulations depending on each disease or ingredient.
  • the pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar drug efficacy in addition to the compound represented by Chemical Formula 1 above, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of the present invention.
  • the present invention provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound or pharmaceutical composition of the present invention.
  • the disease is a RAF-related disease. In certain embodiments, the disease is a disease induced by RAF mutations.
  • the RAF is ARAF. In certain embodiments, the RAF is BRAF. In certain embodiments, the RAF is BRAF V600E. In certain embodiments, the RAF is RAFI.
  • the disease is cancer.
  • the disease is melanoma. In certain embodiments, the disease is colorectal cancer. In certain embodiments, the disease is thyroid cancer. In certain embodiments, the disease is ovarian cancer.
  • the present invention provides a method of inhibiting the activity and/or production of RAF in a subject, cell, tissue, or biological sample, the method comprising administering to the subject or contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition of the present invention.
  • the subject is a human.
  • the present invention provides an in vitro method of inhibiting the activity and/or production of RAF in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition of the present invention.
  • a method for treating or preventing RAF-related diseases comprising: administering to a subject in need thereof a therapeutically effective amount of the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the subject may be a mammal including a human.
  • an “effective amount” of a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to elicit a desired biological response.
  • An effective amount may vary depending on such factors as the desired biological endpoint, the pharmacokinetics, the condition being treated, the mode of administration, and/or the age and health of the subject.
  • the effective amount is a therapeutically effective amount (e.g., when a desired biological response is treatment of a disease).
  • the effective amount is a prophylactically effective amount (e.g., when a desired biological response is prevention of a disease).
  • therapeutically effective amount refers to an amount of the compound represented by Chemical Formula 1 that is effective for the treatment or prevention of RAF-related diseases. Specifically, “therapeutically effective amount” indicates an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level may be determined depending on factors including the subject type and severity, age, sex, type of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, treatment period, drugs used at the same time, and other factors well-known in medical fields.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents.
  • the pharmaceutical composition of the present invention may be administered in a single dose or multiple doses. It is important to administer the minimum amount capable of obtaining the maximum effect without side effects in consideration of all of the above factors, and the amount may be readily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention may be determined by a medical specialist according to various factors such as the patient's condition, age, sex, complications, and the like. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it may be used at a dose higher than the determined dosage.
  • the present invention provides use of the compound represented by Chemical Formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for use in preparation of a medicament to treat or prevent RAF-related diseases.
  • the compound represented by Chemical Formula 1 for preparing the medicament may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may have a synergistic effect of active ingredients by being prepared as a complex formulation with other active agents.
  • compositions and treatment methods of the present invention are applied equally except to the extent that they are inconsistent with each other.
  • heteroaryl derivative compounds of the present invention exhibits excellent inhibitory activity against RAF, and thus may be usefully employed for the treatment or prevention of RAF-related diseases.
  • Cell viability analysis was performed by culturing A375P cell line (Korea Cell Line Bank #80003) with a medium of Dulbecco' s Modified Eagles Medium (High Glucose)(Hyclone #SH30243.01) containing 10% fetal bovine serum(FBS) and 1% penicillin/streptomycin. More specifically, when performing the test, the cell line was aliquoted in a 96-well flat-bottom plate (coming #3903) at a concentration of 3,000 cells/well, respectively, and then cultured at 37°C for 24 hours under 5% CO2 conditions.
  • the degree of cell proliferation inhibitory activity according to the treatment concentration of each compound was calculated based on the luminescence of the control cells not treated with the compound, and the concentration with 50% cell proliferation inhibitory activity was determined as the GIso(nM) value.
  • GIso(nM) value was obtained using Prism (version 8.4.3 #GraphPad) software, and the results are shown in Table 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés dérivés d'hétéroaryle et une composition pharmaceutique les comprenant. Plus particulièrement, la présente invention concerne des composés dérivés d'hétéroaryle ayant une activité inhibitrice de RAF.
PCT/IB2023/000286 2022-05-13 2023-05-12 Composés dérivés d'hétéroaryle et composition pharmaceutique les comprenant WO2023218245A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008115369A2 (fr) * 2007-03-16 2008-09-25 The Scripps Research Institute Inhibiteurs de kinase d'adhérence focale
WO2009087238A2 (fr) * 2008-01-10 2009-07-16 Centre National De La Recherche Scientifique (Cnrs) Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage
WO2010129802A1 (fr) * 2009-05-06 2010-11-11 Portola Pharmaceuticals, Inc. Inhibiteurs de jak
WO2017135589A1 (fr) * 2016-02-03 2017-08-10 삼진제약주식회사 Raf kinase inhibant un dérivé pyridine et récepteur de facteur de croissance endothélial vasculaire, procédé pour le préparer, composition pharmaceutique le contenant, et son utilisation
CN113999206A (zh) * 2021-12-31 2022-02-01 北京鑫开元医药科技有限公司 异喹啉-1,3-二胺类似物、制备方法、药物组合物及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008115369A2 (fr) * 2007-03-16 2008-09-25 The Scripps Research Institute Inhibiteurs de kinase d'adhérence focale
WO2009087238A2 (fr) * 2008-01-10 2009-07-16 Centre National De La Recherche Scientifique (Cnrs) Molécules chimiques inhibant le mécanisme d'épissage pour traiter des maladies résultant d'anomalies d'épissage
WO2010129802A1 (fr) * 2009-05-06 2010-11-11 Portola Pharmaceuticals, Inc. Inhibiteurs de jak
WO2017135589A1 (fr) * 2016-02-03 2017-08-10 삼진제약주식회사 Raf kinase inhibant un dérivé pyridine et récepteur de facteur de croissance endothélial vasculaire, procédé pour le préparer, composition pharmaceutique le contenant, et son utilisation
CN113999206A (zh) * 2021-12-31 2022-02-01 北京鑫开元医药科技有限公司 异喹啉-1,3-二胺类似物、制备方法、药物组合物及其应用

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