WO2023218241A1 - Heteroaryl derivative compounds, and pharmaceutical composition comprising thereof - Google Patents

Heteroaryl derivative compounds, and pharmaceutical composition comprising thereof Download PDF

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Publication number
WO2023218241A1
WO2023218241A1 PCT/IB2023/000256 IB2023000256W WO2023218241A1 WO 2023218241 A1 WO2023218241 A1 WO 2023218241A1 IB 2023000256 W IB2023000256 W IB 2023000256W WO 2023218241 A1 WO2023218241 A1 WO 2023218241A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
optical isomer
cancer
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PCT/IB2023/000256
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French (fr)
Inventor
Seohyun JO
Dahoon MA
Yeseul Park
Jungbeom SON
Namdoo Kim
Hwangeun CHOI
Sunghwan Kim
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Voronoi Inc.
Voronoibio Inc.
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Publication of WO2023218241A1 publication Critical patent/WO2023218241A1/en

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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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

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 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: (Chemical Formula 1) in the Chemical Formula 1, X is CH 2 , or O;
  • Y is CH or N
  • Ri is -Ci-ealkyl, -Ci-ehaloalkyl, aryl or heteroaryl in which at least one H of the aryl or heteroaryl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
  • R 2 and R3 are each independently -H, -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
  • R4 is -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
  • R5 is -Ci-ealkyl, -Ci-ehaloalkyl, cycloalkyl, or -Ci-ealkyl-cycloalkyl.
  • 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 15 described in Table 1.
  • alkyl may refer to a straight or branched chain acyclic, cyclic, or saturated hydrocarbon to which they are bonded.
  • “Ci-ealkyl” 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.
  • hydroxyalkyl 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-ealkyl, 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 heterocycloalkyl 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-di oxane, 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
  • 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-aryl carb azole, N- heteroaryl carb azole, 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.
  • heteroaryl 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, and 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 solidline 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 compound 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 compound represented by Chemical Formula 1 of which side effects caused by the salt do not reduce the beneficial efficacy of the compound 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 compound 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 compound 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 compound 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 compound 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.
  • Ri is phenyl that may be substituted with -Ci-ealkyl, -Ci- ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • Ri is 5- or 6-membered monocyclic heteroaryl that may be substituted with -Ci-ealkyl, -Ci-ehydroxyalkyl, - Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • Ri is pyridinyl that may be substituted with -Ci-ealkyl, -Ci-ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • Ri is -Ci-ealkyl that may be substituted with -Ci-ealkyl, -Ci- ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
  • Ri is -Ci- ehaloalkyl.
  • Ri is aryl in which at least one H of the aryl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, or -halo. In certain embodiments, Ri is phenyl in which at least one H of the phenyl may be substituted with -Ci-ealkyl, -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 -Ci-ealkyl (e.g., Me or Et). In certain embodiments, Ri is - Ci-ehaloalkyl. In certain embodiments, Ri is -Ci-6 fluoroalkyl. In certain embodiments, Ri is fluoroethyl (e.g., -CH2CF3).
  • R2 is H. In certain embodiments, R2 is -Ci-ealkyl (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-ealkyl (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 -Ci-ealkyl (e.g., Me or Et). In certain embodiments, R4 is Me. In certain embodiments, R4 is halo (e.g., F or Cl). In certain embodiments, R4 is F.
  • R5 is -Ci-ealkyl (e.g., Me or Et). In certain embodiments, R5 is Me. In certain embodiments, R5 is -Ci-ehaloalkyl. In certain embodiments, R5 is -Ci-6 fluoroalkyl. In certain embodiments, R5 is fluoroethyl (e.g., -CH2CF3). In certain embodiments, R5 is cycloalkyl (e.g., cyclopropyl or cyclobutyl). In certain embodiments, R5 is cyclopropyl.
  • R5 is -Ci-ealkyl-cycloalkyl (e.g., -Ci-ealkyl-cyclopropyl or -Ci-ealkyl-cyclobutyl). In certain embodiments, R5 is -CEE-cycloalkyl. In certain embodiments, R5 is Ci-ealkyl- cyclopropyl. In certain embodiments, R5 is -CFE-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 15), 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.
  • Chemical Formula 1 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 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 compounds 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 compounds 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.
  • the 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. Best Mode
  • 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 (corning #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.

Abstract

The present invention relates to a heteroaryl derivative compound and a pharmaceutical composition comprising thereof. Specifically, the present invention relates to a heteroaryl derivative compounds having RAF inhibitory activity.

Description

HETEROARYL DERIVATIVE COMPOUNDS, AND PHARMACEUTICAL COMPOSITION COMPRISING THEREOF
RELATED APPLICATIONS
This application claims priority to KR10-2022-0058714, filed May 13, 2022, incorporated herein by reference in its entirety.
FIELD
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.
BACKGROUND
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). In the signaling pathway, when guanosine triphosphate (GTP) is bound to the RAS protein, phosphorylation and activation of the RAF protein in the protoplasmic membrane proceeds. Subsequently, the activated RAF protein phosphorylates and activates the MEK protein, and 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. Among them, when controlled by a receptor, 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. In this signaling pathway, a series of kinases are arranged into species to transmit signals, which play an essential role in cell growth and differentiation (Nature Rev. Mol. Cell. Biol., 2004, 5, 875-885), and the activity of RAF/MEK/ERK has been reported to be upregulated in a number of factor-dependent tumors.
As such, 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. Although 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).
Studies have shown that 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.
Accordingly, as a result of careful efforts to develop a new drug capable of inhibiting the activity of RAF, 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.
DISCLOSURE
Technical Problem
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. Technical Solution
In order to achieve the above-described objects, the present inventors made efforts to study, and as a result, found that the following heteroaryl derivative compounds represented by Chemical Formula 1 inhibited the proliferation of RAF-activated cells, and completed the present invention. TECHNICAL SOLUTION
Preparation methods
Reaction Scheme 1
Figure imgf000004_0001
Heteroaryl derivative compounds
The present invention provides a compound represented by following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0002
(Chemical Formula 1) in the Chemical Formula 1, X is CH2, or O;
Y is CH or N;
Ri is -Ci-ealkyl, -Ci-ehaloalkyl, aryl or heteroaryl in which at least one H of the aryl or heteroaryl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
R2 and R3 are each independently -H, -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
R4 is -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
R5 is -Ci-ealkyl, -Ci-ehaloalkyl, cycloalkyl, or -Ci-ealkyl-cycloalkyl.
According to an embodiment of the present invention, 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 15 described in Table 1.
In the present invention, unless otherwise specified, the term "alkyl" may refer to a straight or branched chain acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "Ci-ealkyl" may indicate an alkyl containing 1 to 6 carbon atoms. As an example, 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. In certain embodiments, the cycloalkyl is monocyclic. In certain embodiments, the cycloalkyl is 3- 7-membered.
In the present invention, “halo” or “halogen” may be F, Cl, Br, or I.
As used herein, "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.
As used herein, "hydroxyalkyl" may indicate a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with -hydroxy (-OH). 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 -OH.
As used herein, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (-NR'R"). Here, R' and R" may be each independently selected from the group consisting of hydrogen and Ci-ealkyl, and the selected R' and R" may be each independently substituted or unsubstituted.
In the present invention, "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. In certain embodiments, heterocycloalkyl is not aromatic. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or a multiple ring such as a spiro ring, a bridged ring or a fused ring. In addition, "3- to 12-membered heterocycloalkyl" may indicate a heterocycloalkyl containing 3 to 12 atoms forming a ring. As an example, 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-di oxane, 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)-2-azabicyclo[2.2.2]octane, or (lR,4R)-2-oxa-5- azabicyclo[2.2.2]octane, and the like.
In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming 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. In the present specification, the residue obtained by removing one hydrogen atom from "arene" is referred to as "aryl".
In the present invention, "heteroarene" 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. Examples of the 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-aryl carb azole, N- heteroaryl carb azole, N-alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, dibenzofuran, and the like, but are not limited thereto. In an embodiment of the present invention, heteroarene may also include bicyclic heterocyclo-arene containing heteroarene fused to an arene ring or a cycloalkyl ring fused to heterocycloalkyl rings. In the present specification, 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.
In addition, the connection radicals listed above do not specify the coupling direction, and the coupling direction is arbitrary. For example, the radical L connected in
Figure imgf000006_0001
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
Figure imgf000006_0002
and ring A and ring B can be connected in the opposite direction to the reading order from left to right to form
Figure imgf000007_0001
In the present invention, the term "stereoisomers (e.g., 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. Unless otherwise specified, the straight solidline bond (-) connecting an asymmetric carbon atom may include a wedge-shaped solid-line bond
Figure imgf000007_0002
or a wedge-shaped dashed-line bond indicating the absolute configuration of the stereocenter. The term “stereoisomer” and “optical isomer” are used interchangeably.
The compound of Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. The term "pharmaceutically acceptable salt" as used herein means any and all organic or inorganic acid addition salts of the compound represented by Chemical Formula 1 of which side effects caused by the salt do not reduce the beneficial efficacy of the compound 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 compound in an excess of aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. An acid or alcohol in an equimolar amount of the compound and water may be heated, and the mixture may then be evaporated to dryness, or the precipitated salt may be filtered off with suction.
Here, 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. However, the present invention is not limited thereto.
In addition, it is possible to prepare a pharmaceutically acceptable metal salt using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving a compound 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. Here, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but the present invention is not limited thereto. Further, 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).
Unless otherwise indicated, the pharmaceutically acceptable salt of the present invention includes salts of acidic or basic groups that may be present in the compound of Chemical Formula 1. For example, 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.
In certain embodiments, X is O. In certain embodiments, X is CH2.
In certain embodiments, Ri is phenyl that may be substituted with -Ci-ealkyl, -Ci- ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo. In certain embodiments, Ri is 5- or 6-membered monocyclic heteroaryl that may be substituted with -Ci-ealkyl, -Ci-ehydroxyalkyl, - Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo. In certain embodiments, Ri is pyridinyl that may be substituted with -Ci-ealkyl, -Ci-ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo. In certain embodiments, Ri is -Ci-ealkyl that may be substituted with -Ci-ealkyl, -Ci- ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo. In certain embodiments, Ri is -Ci- ehaloalkyl.
In certain embodiments,
Figure imgf000008_0001
certain embodiments,
Figure imgf000008_0002
, certain embodiments,
Figure imgf000008_0003
certain embodiments,
Figure imgf000008_0004
Figure imgf000008_0005
,
In certain embodiments, Ri is aryl in which at least one H of the aryl may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, or -halo. In certain embodiments, Ri is phenyl in which at least one H of the phenyl may be substituted with -Ci-ealkyl, -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. In certain embodiments, 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 -Ci-ealkyl (e.g., Me or Et). In certain embodiments, Ri is - Ci-ehaloalkyl. In certain embodiments, Ri is -Ci-6 fluoroalkyl. In certain embodiments, Ri is fluoroethyl (e.g., -CH2CF3).
In certain embodiments, R2 is H. In certain embodiments, R2 is -Ci-ealkyl (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.
In certain embodiments, R3 is -H. In certain embodiments, R3 is -Ci-ealkyl (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.
In certain embodiments, R4 is -Ci-ealkyl (e.g., Me or Et). In certain embodiments, R4 is Me. In certain embodiments, R4 is halo (e.g., F or Cl). In certain embodiments, R4 is F.
In certain embodiments, R5 is -Ci-ealkyl (e.g., Me or Et). In certain embodiments, R5 is Me. In certain embodiments, R5 is -Ci-ehaloalkyl. In certain embodiments, R5 is -Ci-6 fluoroalkyl. In certain embodiments, R5 is fluoroethyl (e.g., -CH2CF3). In certain embodiments, R5 is cycloalkyl (e.g., cyclopropyl or cyclobutyl). In certain embodiments, R5 is cyclopropyl. In certain embodiments, R5 is -Ci-ealkyl-cycloalkyl (e.g., -Ci-ealkyl-cyclopropyl or -Ci-ealkyl-cyclobutyl). In certain embodiments, R5 is -CEE-cycloalkyl. In certain embodiments, R5 is Ci-ealkyl- cyclopropyl. In certain embodiments, R5 is -CFE-cyclopropyl.
In certain embodiments, a compound of the present invention is a compound of Chemical Formula 1 (e.g., a compound of any one of Examples 1 to 15), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound of the present invention is a compound of Chemical Formula 1, or a pharmaceutically acceptable salt thereof.
Use of Heteroaryl Derivative Compounds
The present invention provides use of a compound represented by the following Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
(Chemical Formula 1)
Figure imgf000009_0001
The Chemical Formula 1 is as defined above.
According to an embodiment of the present invention, 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. Specifically, 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.
In the present invention, 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. For example, 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 melanoma, ampulla of vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic tumor, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymus cancer, but is not limited thereto. The cancer includes not only primary cancer but also metastatic cancer.
In another aspect, the present invention provides a pharmaceutical composition comprising: a compound of the present invention; and optionally a pharmaceutically acceptable excipient. In another aspect, 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.
In certain embodiments, the instructions are information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA). In certain embodiments, a kit further comprises one or more containers.
According to an embodiment of the present invention, 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. Specifically, the RAF-related disease may be cancer. In certain embodiments, 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. In addition, diluents, dispersants, surfactants, binders, and lubricants can be added to formulations for injection, such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets. Accordingly, 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.
In another aspect, 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. In another aspect, 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.
In certain embodiments, the disease is a RAF-related disease. In certain embodiments, the disease is a disease induced by RAF mutations.
In certain embodiments, 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.
In certain embodiments, the disease is cancer.
In certain embodiments, 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.
In another aspect, 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.
In certain embodiments, the subject is a human.
In another aspect, 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.
Further, according to an embodiment of the present invention, there is provided 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. In certain embodiments, the effective amount is a therapeutically effective amount (e.g., when a desired biological response is treatment of a disease). In certain embodiments, the effective amount is a prophylactically effective amount (e.g., when a desired biological response is prevention of a disease).
The term "therapeutically effective amount" as used herein 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. In addition, 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.
Further, according to an embodiment of the present invention, the present invention provides use of the compounds 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 compounds 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.
Matters mentioned in the uses, compositions and treatment methods of the present invention are applied equally except to the extent that they are inconsistent with each other.
An embodiment of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more fully explain the present invention to those with average knowledge in the art. Furthermore, "includes" a component throughout the specification means that it may include other components, not excluding other components unless otherwise opposed.
Advantageous Effects
The 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. Best Mode
Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely presented to illustrate the present invention, and the scope of the present invention is not limited thereto.
EXAMPLES The compounds of Examples 1 to 15 were prepared in a manner similar to Reaction
Scheme 1. The compound name, chemical structural formula, NMR and LCMS analysis results of each Example compound are summarized in Table 1 below. Table 1
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Experimental Example 1: Evaluation of cell proliferation inhibition activity in A375P cells of certain compounds according to the present invention
The following experiments were performed to evaluate the cell proliferation inhibitory activity of the compounds according to the present invention. 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 (corning #3903) at a concentration of 3,000 cells/well, respectively, and then cultured at 37°C for 24 hours under 5% CO2 conditions. Compounds in each well were treated with 11 concentrations by giving a 3 -fold concentration gradient to the highest concentration of 10 pM, and dimethylsulfoxide (DMSO) was treated at the same concentration of 0.5% (v/v) as in the compound treatment as each control group. The compound treated cells were incubated for 72 hours. To check the degree of cell viability, 100 pl of Cell Titer-Gio (Promega #G7573) was added to the culture medium of each cultured cell, and then incubated for another 10 minutes at room temperature, and then luminescence was measured using a microplate reader. 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. Experimental Example 2: Evaluation of cell proliferation inhibition activity in HCT116 cell of certain compounds according to the present invention
The following experiments were performed to evaluate the cell proliferation inhibitory activity of the compounds according to the present invention. Cell viability analysis was performed by culturing HCT116 cell line (Korea Cell Line Bank #10247) with a medium of McCoy's 5A (Modified) Medium (Gibco #16600082) 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 2,000 cells/well, respectively, and then cultured at 37°C for 24 hours under 5% CO2 conditions. Compounds in each well were treated with 11 concentrations by giving a 3-fold concentration gradient to the highest concentration of 10 pM, and dimethylsulfoxide (DMSO) was treated at the same concentration of 0.5% (v/v) as in the compound treatment as each control group. The compound treated cells were incubated for 72 hours. To check the degree of cell viability, 100 pl of Cell Titer-Gio (Promega #G7573) was added to the culture medium of each cultured cell, and then incubated for another 10 minutes at room temperature, and then luminescence was measured using a microplate reader. 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.
Table 2
Figure imgf000021_0001
Figure imgf000022_0001

Claims

1. A compound represented by the following Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000023_0001
(Chemical Formula 1) in the Chemical Formula 1,
X is CH2, or O;
Y is CH or N;
Ri is -Ci-ealkyl, -Ci-ehaloalkyl, aryl or heteroaryl in which at least one H of the aryl or heteroaryl ring may be substituted with -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
R2 and R3 are each independently -H, -Ci-ealkyl, -Ci-ehaloalkyl, or -halo;
R4 is -Ci-ealkyl, -Ci-ehaloalkyl, or -halo; and
R5 is -Ci-ealkyl, -Ci-ehaloalkyl, cycloalkyl, or -Ci-ealkyl-cycloalkyl.
2. The compound of claim 1, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein X is O.
3. The compound of claim 1, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein X is CH2.
4. The compound of any one of claims 1-3, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is phenyl that may be substituted with -Ci- ealkyl, -Ci-ehydroxyalkyl, -Ci-eaminoalkyl, -Ci-ehaloalkyl, -CN, or -halo.
5. The compound of claim 4, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is unsubstituted phenyl or phenyl in which at least one H of the phenyl is substituted with -halo.
6. The compound of claim 5, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is phenyl in which at least one -H of the phenyl is substituted with -F.
7. The compound of any one of claims 1-3, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is -Ci-ealkyl or -Ci-ehaloalkyl.
8. The compound of claim 7, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is -Ci-6 fluoroalkyl.
9. The compound of claim 8, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Ri is -CH2CF3.
10. The compound of any one of claims 1-9, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein
Figure imgf000024_0001
11. The compound of any one of claims 1-9, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein
Figure imgf000024_0002
12. The compound of any one of claims 1-9, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein
Figure imgf000024_0003
13. The compound of any one of claims 1-12, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Y is CH.
14. The compound of any one of claims 1-12, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein Y is N.
15. The compound of any one of claims 1-14, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R2 is -H.
16. The compound of any one of claims 1-14, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R2 is -halo.
17. The compound of claim 16, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R2 is -F.
18. The compound of any one of claims 1-17, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R3 is -Ci-ealkyl.
19. The compound of claim 18, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R3 is Me.
20. The compound of any one of claims 1-19, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R4 is -halo or -Ci-ealkyl.
21. The compound of claim 20, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R4 is -F or Me.
22. The compound of any one of claims 1-21, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R5 is -Ci-ealkyl or -Ci-ehaloalkyl.
23. The compound of claim 22, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R5 is Me or -CH2CF3.
24. The compound of any one of claims 1-21, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R5 is cycloalkyl or -Ci-ealkyl-cycloalkyl.
25. The compound of claim 24, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, wherein R5 is cyclopropyl or -CFF-cyclopropyl.
26. The compound of claim 1, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is of the formula:
Figure imgf000026_0001
2 27. The compound of any one of claims 1-26, or the pharmaceutically acceptable salt thereof.
4 28. A pharmaceutical composition comprising: a compound of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient.
29. The pharmaceutical composition of claim 28 further comprising one or more active ingredients.
30. A kit compri sing : a compound of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28-29; and instructions for using the compound, optical isomer, pharmaceutically acceptable salt, or pharmaceutical composition.
31. 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 of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28-29.
32. 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 of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28-29.
33. The method of any one of claims 31-32, wherein the disease is a RAF-related disease.
34. The method of any one of claims 31-33, wherein the disease is a disease induced by RAF mutations.
35. The method of any one of claims 33-34, wherein the RAF is BRAF.
36. The method of any one of claims 31-35, wherein the disease is cancer.
37. The method of any one of claims 31-35, wherein the disease is melanoma.
38. The method of any one of claims 31-35, wherein the disease is colorectal cancer.
39. The method of any one of claims 31-35, wherein the disease is thyroid cancer.
40. The method of any one of claims 31-35, wherein the disease is ovarian cancer.
41. 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 of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28-29.
42. The method of any one of claims 31-41, wherein the subject is a human.
43. 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 of any one of claims 1-26, or the optical isomer thereof, or the pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 28-29.
44. The method of any one of claims 41-43, wherein the RAF is BRAF.
45. A pharmaceutical composition for the treatment or prevention of cancer, comprising the compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1-26 as an active ingredient.
PCT/IB2023/000256 2022-05-13 2023-05-12 Heteroaryl derivative compounds, and pharmaceutical composition comprising thereof WO2023218241A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113548A1 (en) * 2004-05-20 2005-12-01 Sugen, Inc. Thiophene heteroaryl amines
WO2007117607A2 (en) * 2006-04-06 2007-10-18 Novartis Ag Quinazolines for pdk1 inhibition
WO2008079988A2 (en) * 2006-12-22 2008-07-03 Novartis Ag Quinazolines for pdk1 inhibition
WO2009153313A1 (en) * 2008-06-20 2009-12-23 Novartis Ag 2 -arylaminoquinazolines for treating proliferative diseases
WO2010019637A1 (en) * 2008-08-12 2010-02-18 Smithkline Beecham Corporation Chemical compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005113548A1 (en) * 2004-05-20 2005-12-01 Sugen, Inc. Thiophene heteroaryl amines
WO2007117607A2 (en) * 2006-04-06 2007-10-18 Novartis Ag Quinazolines for pdk1 inhibition
WO2008079988A2 (en) * 2006-12-22 2008-07-03 Novartis Ag Quinazolines for pdk1 inhibition
WO2009153313A1 (en) * 2008-06-20 2009-12-23 Novartis Ag 2 -arylaminoquinazolines for treating proliferative diseases
WO2010019637A1 (en) * 2008-08-12 2010-02-18 Smithkline Beecham Corporation Chemical compounds

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