WO2023128350A1 - Dérivé hétéroaryle et composition pharmaceutique pour la prévention ou le traitement du cancer le comprenant en tant que principe actif - Google Patents

Dérivé hétéroaryle et composition pharmaceutique pour la prévention ou le traitement du cancer le comprenant en tant que principe actif Download PDF

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WO2023128350A1
WO2023128350A1 PCT/KR2022/019664 KR2022019664W WO2023128350A1 WO 2023128350 A1 WO2023128350 A1 WO 2023128350A1 KR 2022019664 W KR2022019664 W KR 2022019664W WO 2023128350 A1 WO2023128350 A1 WO 2023128350A1
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phenyl
amino
hydroxypropan
methoxyquinazolin
oxy
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English (en)
Korean (ko)
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이화
강세인
김승수
손정범
김남두
고은화
최환근
김성환
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주식회사 비투에스바이오
보로노이 주식회사
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Publication of WO2023128350A1 publication Critical patent/WO2023128350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a heteroaryl derivative, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient. .
  • Cancer is often the result of mutations that can occur in numerous genes that play a role in a wide range of cellular processes.
  • cancer cells harbor mutations in genes that control processes such as cell growth, division, differentiation, or interaction with the extracellular environment.
  • mutations that increase the activity of HER2 (Human epidermal growth factor receptor 2), a cell surface receptor that promotes cell growth and division are associated with many cancers.
  • tumors are resistant to certain cancer treatment drugs, or initially sensitive to certain drugs, but develop resistance (resistance) later.
  • the development of resistance is often the result of mutations that alter cell activity (e.g., mutations that constitutively activate signaling molecules) or result in alterations in gene expression (e.g., increased expression of cell signaling receptors such as HER2). mutations that cause).
  • the drug resistance of such tumors is consistent with or the result of mutations that transform the cancer into a more aggressive (eg, metastatic) form. Metastatic cancer is typically correlated with worse prognosis compared to non-metastatic cancer.
  • HER2-positive breast cancer HER2-positive gastric cancer
  • HER2-positive colon cancer HER2-positive colon cancer
  • HER2-positive esophageal cancer it was confirmed through animal experiments that the combination of tucatinib and trastuzumab (HERCEPTIN TM , Genentech) inhibits cancer growth.
  • HERCEPTIN TM trastuzumab
  • MOUNTAINEER clinical trial ClinicalTrials.gov Identifier #NCT03043313
  • HER2 is an important prognostic and predictive factor in invasive breast cancer, and gene amplification is observed in 20-25% of breast cancer, resulting in HER2 overexpression.
  • Breast cancer patients with amplification or overexpression of the HER2 gene have a poor prognosis, but are targeted for targeted therapy using trastuzumab, a monoclonal antibody against HER2.
  • trastuzumab a monoclonal antibody against HER2.
  • HER2 status is an important treatment predictor for gastric cancer as well as breast cancer. It is becoming.
  • HER2 positive cancers cancers that exhibit overexpression of HER2
  • HER2 positive cancers often have a poor prognosis or are resistant to many standard therapies. Therefore, new drugs effective for the treatment of HER2-positive cancer or metastatic HER2-positive cancer are needed.
  • One object of the present invention is to provide a compound usable for preventing or treating cancer, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preparing the above compound.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating cancer comprising administering the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. is to do
  • Another object of the present invention is to provide a use of the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.
  • the present invention provides a compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 is hydrogen or C 1-6 alkoxy, wherein C 1-6 alkoxy is a 3- to 12-membered heteroatom including at least one heteroatom of N, O, and S which is unsubstituted or substituted with C 1-6 alkyl. may be substituted with cycloalkyl;
  • Y is -NH- or -OR 8 -, wherein R 8 is a 3 to 12 membered heterocycloalkyl containing at least one heteroatom of N, O, and S, wherein the 3 to 12 membered heterocycloalkyl may be substituted with one or more substituents of C 1-6 alkyl and halogen;
  • R 2 to R 4 are each independently hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkyl of 3 to 12 atoms including at least one heteroatom of N, O, and S substituted or unsubstituted.
  • heterocycloalkyl wherein the C 1-6 alkyl may be optionally substituted with C 1-6 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl; and
  • R 9 is a direct bond or C 1-6 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is C 1-6 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and a heteroatom of 5 to 12 members including at least one heteroatom of N, O, and S.
  • the aryl may be unsubstituted or substituted with one or more substituents A, and the 5 to 12-membered heteroaryl or phenyl of the substituent A may be substituted with C 1-6 alkyl.
  • Another aspect of the present invention provides a method for preparing the compound of Formula 1.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound of the present invention, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for preventing or treating cancer comprising administering the compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the present invention also provides a use of the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.
  • a compound provided in one aspect of the present invention a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof exhibits high inhibitory activity against HER2. It can be usefully used for preventing or treating diseases related to, for example, cancer, particularly HER2-positive cancer.
  • Embodiments of the present invention can be modified in many different forms, and the scope of the present invention is not limited to the embodiments described below.
  • embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
  • the symbol may be omitted, and may be displayed if necessary, such as when specifying a bonding atom or bonding position.
  • connection between atoms may include not only a case in which atoms are directly connected, but also a case in which atoms are indirectly connected through another atom and/or group.
  • other atoms and/or groups may be oxygen, sulfur, C 1-8 alkylamino, or C 1-8 alkylene groups, etc., but are not limited thereto, and the atoms and/or groups may be substituted or unsubstituted.
  • halogen may be F, Cl, Br, or I.
  • alkyl unless otherwise specified, is a straight-chain or branched-chain acyclic; cyclic; or a saturated hydrocarbon to which they are bonded.
  • C 1-8 alkyl may mean an alkyl containing 1 to 8 carbon atoms.
  • Acyclic alkyl is, for example, methyl, ethyl, N-propyl, N-butyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, or 2-methyl pentyl, and the like, but are not limited thereto.
  • Cyclic alkyl may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, etc., but is not limited thereto.
  • Alkyl in which acyclic and cyclic alkyl are bonded may include, for example, methylcyclopropyl, cyclopropylmethyl, ethylcyclopropyl, or cyclopropylethyl, but is not limited thereto.
  • cycloalkyl when “cycloalkyl” is described, it may mean especially cyclic alkyl among alkyls, where alkyl is as defined above.
  • alkoxy is an alkyl ether group and may mean -(O-alkyl), wherein alkyl is as defined above.
  • C 1-8 alkoxy can mean an alkoxy containing C 1-8 alkyl, ie -(OC 1-8 alkyl).
  • heterocycloalkyl may refer to a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Unless otherwise stated, a heterocycloalkyl can be a single ring or a multi-ring such as a spiro ring, bridged ring or fused ring.
  • heterocycloalkyl may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, and as an example, heterocycloalkyl is pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4 (1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3- It may include pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and tropane, but
  • alkylamino may mean -(NR′R′′), where R′ and R′′ may each independently be selected from the group consisting of hydrogen and C 1-8 alkyl, and the selected R′ and R′′ may each independently be substituted or unsubstituted.
  • C 1-8 alkylamino may refer to amino containing C 1-8 alkyl, that is, -NH(C 1-8 alkyl) or -N-(C 1-8 alkyl) 2 ; dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.
  • haloalkyl may refer to —RX (X is one or more halogens (F, Cl, Br, or I, etc.)), i.e., “haloalkyl” is an alkyl form in which one or more halogens are substituted.
  • C 1-8 haloalkyl may include, but is not limited to, trifluoromethyl or difluoromethyl.
  • haloalkoxy may mean -(O-RX) (X is one or more halogens (F, Cl, Br, or I, etc.), that is, “haloalkoxy” means that one or more halogens are substituted
  • haloalkoxy means that one or more halogens are substituted
  • C 1-8 haloalkoxy may include trifluoromethoxy, difluoromethoxy, etc., but is not limited thereto.
  • aryl may mean an aromatic ring in which one hydrogen is removed from an aromatic hydrocarbon ring, and may be monocyclic or multicyclic.
  • Aryl of 3 to 12 atoms may mean an aryl containing 3 to 12 atoms forming a ring, and as an example, phenyl, benzyl, naphthyl, anthracenyl, phenanthryl, biphenyl, or ter phenyl; and the like, but are not limited thereto.
  • heteroaryl may mean an aromatic ring containing at least one heteroatom of N, O, and S as an atom forming the ring, and may be monocyclic or multicyclic.
  • 3 to 12 membered heteroaryl may mean a heteroaryl containing 3 to 12 atoms forming a ring, and as an example, thienyl, thiophenyl, furyl, pyrrolyl, pyra Zolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, bipyridinyl, pyrimidinyl, triazinyl, acridyl, pyridazinyl, pyrazine It may include, but is not limited to, yl, quinolinyl, or quinazoline.
  • hydroxy may mean -OH.
  • alkenyl may mean a straight-chain, branched-chain, acyclic or cyclic hydrocarbon having one or more double bonds unless otherwise specified.
  • cyano may mean -(CN).
  • hydrate refers to a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. It may mean a compound of the invention or a salt thereof.
  • the hydrate of the compound represented by Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the hydrate may contain at least 1 equivalent of water, preferably from 1 to 5 equivalents of water.
  • Such a hydrate may be prepared by crystallizing the compound represented by Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present invention from water or a water-containing solvent.
  • solvate may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
  • isomers may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but structurally or sterically different.
  • isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers (enantiomers). All these isomers and mixtures thereof are also included within the scope of the present invention.
  • One aspect of the present invention is to provide a compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 is hydrogen or C 1-6 alkoxy, wherein C 1-6 alkoxy is a 3- to 12-membered heteroatom including at least one heteroatom of N, O, and S which is unsubstituted or substituted with C 1-6 alkyl. may be substituted with cycloalkyl;
  • Y is -NH- or -OR 8 -, wherein R 8 is a 3 to 12 membered heterocycloalkyl containing at least one heteroatom of N, O, and S, wherein the 3 to 12 membered heterocycloalkyl may be substituted with one or more substituents of C 1-6 alkyl and halogen;
  • R 2 to R 4 are each independently hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkyl of 3 to 12 atoms including at least one heteroatom of N, O, and S substituted or unsubstituted.
  • heterocycloalkyl wherein the C 1-6 alkyl may be optionally substituted with C 1-6 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl; and
  • R 9 is a direct bond or C 1-6 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is C 1-6 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S It may be unsubstituted or substituted with at least one substituent A, and the 5 to 12 membered heteroaryl or phenyl of the substituent A may be substituted with C 1-6 alkyl.
  • R 1 is hydrogen or C 1-5 alkoxy, and C 1-5 alkoxy is a 3 to 6-membered heteroatom including at least one heteroatom of N, O, and S, which is unsubstituted or substituted with C 1-3 alkyl. may be substituted with cycloalkyl;
  • Y is -NH- or -OR 8 -, wherein R 8 is a 3 to 6 membered heterocycloalkyl containing at least one heteroatom of N, O, and S, wherein the 3 to 12 membered heterocycloalkyl may be substituted with one or more substituents of C 1-3 alkyl and halogen;
  • R 2 to R 4 are each independently hydrogen, C 1-3 alkyl, halogen, or 3 to 12 atoms including at least one heteroatom of N, O, and S unsubstituted or substituted with C 1-3 alkyl.
  • heterocycloalkyl wherein the C 1-3 alkyl may be optionally substituted with C 1-3 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-3 alkyl; and
  • R 9 is a direct bond or C 1-3 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is C 1-3 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S It may be unsubstituted or substituted with one or more substituents B, and the 5 to 12 membered heteroaryl or phenyl of the substituent B may be substituted with C 1-3 alkyl.
  • R 1 is hydrogen or C 1-5 alkoxy, and C 1-5 alkoxy is a 3 to 6-membered heteroatom including at least one heteroatom of N, O, and S, which is unsubstituted or substituted with C 1-3 alkyl. may be substituted with cycloalkyl;
  • Y is -NH- or -OR 8 -, wherein R 8 is a 3 to 6 membered heterocycloalkyl containing at least one heteroatom of N, O, and S, wherein the 3 to 12 membered heterocycloalkyl may be substituted with one or more substituents of C 1-3 alkyl and halogen;
  • R 2 to R 4 are each independently hydrogen, C 1-3 alkyl, halogen, or 3 to 12 atoms including at least one heteroatom of N, O, and S unsubstituted or substituted with C 1-3 alkyl.
  • heterocycloalkyl wherein the C 1-3 alkyl may be optionally substituted with C 1-3 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-3 alkyl; and
  • R 9 is a direct bond or C 1-3 alkylene
  • R 10 is phenyl or a 5- to 12-membered heteroaryl containing at least one heteroatom selected from N, O, and S;
  • R 10 is phenyl
  • the phenyl may be substituted with one or more substituents C selected from C 1-3 alkyl, halogen, cyano, phenyl and haloalkyl;
  • the R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom selected from N, O, and S
  • the 5 to 12 membered heteroaryl is C 1-3 alkyl, C 1-6 cycloalkyl , halogen, haloalkyl, and 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S unsubstituted or substituted with C 1-3 alkyl.
  • Examples of the compound represented by Formula 1 according to the present invention include the compounds or free bases listed in [Table 1] in the following Examples (when indicated as pharmaceutically acceptable salts in Table 1), stereoisomers thereof, hydrates thereof, and solvents thereof. cargo, or a pharmaceutically acceptable salt thereof.
  • the compound represented by Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid.
  • acid addition salts are inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.
  • Types of such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, i.
  • the acid addition salt can be prepared by a conventional method.
  • the derivative of Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., and an organic or inorganic acid is added to filter the precipitate.
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.
  • an organic or inorganic acid is added to filter the precipitate.
  • It can be prepared by drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.
  • the pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt.
  • an alkali metal or alkaline earth metal salt can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate.
  • alkali metal salts sodium, potassium or calcium salts may be pharmaceutically suitable.
  • Corresponding salts can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • the present invention may be a compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, as well as a stereoisomer, particularly an enantiomer thereof, and may be a hydrate and/or a solvate prepared therefrom. .
  • Another aspect of the present invention provides a method for preparing the compound of Formula 1.
  • Step 1 preparing a compound of Formula 4 by reacting a compound of Formula 3 with a compound of Formula 2 (Step 1); And reacting the compound of Formula 4 and the compound of Formula 5 to prepare a compound of Formula 1 (step 2); provides a method for preparing a compound of Formula 1 comprising:
  • LG (Leaving Group) is halogen
  • R 1 is hydrogen or C 1-6 alkoxy, wherein C 1-6 alkoxy is a 3- to 12-membered heteroatom including at least one heteroatom of N, O, and S which is unsubstituted or substituted with C 1-6 alkyl. may be substituted with cycloalkyl;
  • Y is -OR 8 -, wherein R 8 is a 3 to 12 membered heterocycloalkyl containing at least one heteroatom of N, O, and S, wherein the 3 to 12 membered heterocycloalkyl is C 1- 6 may be substituted with one or more substituents of alkyl and halogen;
  • R 2 to R 4 are each independently hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkyl of 3 to 12 atoms including at least one heteroatom of N, O, and S substituted or unsubstituted.
  • heterocycloalkyl wherein the C 1-6 alkyl may be unsubstituted or substituted with C 1-6 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl; and
  • R 9 is a direct bond or C 1-6 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is C 1-6 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S It may be unsubstituted or substituted with at least one substituent A, and the 5 to 12 membered heteroaryl or phenyl of the substituent A may be substituted with C 1-6 alkyl.
  • a method for preparing a compound of Formula 1 comprising the steps of preparing a compound of Formula 1 by reacting a compound of Formula 7 with a compound of Formula 3 (step 2) is provided:
  • LG (Leaving Group) is halogen
  • R 1 is hydrogen or C 1-6 alkoxy, wherein C 1-6 alkoxy is a 3- to 12-membered heteroatom including at least one heteroatom of N, O, and S which is unsubstituted or substituted with C 1-6 alkyl. may be substituted with cycloalkyl;
  • Y is -NH-
  • R 2 to R 4 are each independently hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkyl of 3 to 12 atoms including at least one heteroatom of N, O, and S substituted or unsubstituted.
  • heterocycloalkyl wherein the C 1-6 alkyl may be unsubstituted or substituted with C 1-6 alkylamino or a 3 to 12-membered heterocycloalkyl optionally substituted with C 1-6 alkyl; and
  • R 9 is a direct bond or C 1-6 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is C 1-6 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S It may be unsubstituted or substituted with at least one substituent A, and the 5 to 12 membered heteroaryl or phenyl of the substituent A may be substituted with C 1-6 alkyl.
  • a method for preparing a compound of Formula 1 comprising the steps of preparing a compound of Formula 1 by reacting a compound of Formula 12 with a compound of Formula 3 (step 5) is provided:
  • LG (Leaving Group) is halogen
  • R 1 is hydrogen or C 1-6 alkoxy, and the C 1-6 alkoxy is 3 to 12 substituted or unsubstituted C 1-6 alkyl containing at least one heteroatom of N, O, and S; may be substituted with atomic heterocycloalkyl;
  • Y is -NH-
  • R 2 to R 4 are each independently hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkyl substituted or unsubstituted N, O, and S 3 to 12 containing one or more heteroatoms of S atomic heterocycloalkyl, and the C 1-6 alkyl may be unsubstituted or substituted with a 3 to 12-membered heterocycloalkyl which is unsubstituted or substituted with C 1-6 alkylamino or C 1-6 alkyl. can; and
  • R 9 is a direct bond or C 1-6 alkylene
  • R 10 is a 5 to 12 membered heteroaryl containing at least one heteroatom of N, O, and S or phenyl, wherein the N, O, and S 5 to 12 membered heteroatom containing at least one heteroatom Heteroaryl or phenyl is a group of 5 to 12 atoms including C 1-6 alkyl, C 1-6 cycloalkyl, halogen, cyano, haloalkyl, phenyl, and heteroatoms of one or more of N, O, and S.
  • the heteroaryl may be unsubstituted or substituted with one or more substituents A, and the 5 to 12-membered heteroaryl or phenyl of the substituent A may be substituted with C 1-6 alkyl.
  • Another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound represented by Chemical Formula 1 of the present invention may exhibit inhibitory activity against HER2 overexpressed in cancer.
  • Another aspect of the present invention is to provide a pharmaceutical composition for preventing or treating HER2-related diseases, comprising the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical composition for preventing or treating HER2-related diseases comprising the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the type of cancer is not limited, but may include any number of cancers known to be associated with HER2, including solid tumors, specifically HER2-positive cancers.
  • the cancer is colorectal cancer, gastric cancer, lung cancer (eg, non-small cell lung cancer (NSCLC)), cholangiocarcinoma (eg, cholangiocarcinoma, gallbladder cancer), bladder cancer, esophageal cancer, melanoma, ovarian cancer, liver cancer, prostate cancer, pancreatic cancer , It can be selected from the group consisting of colorectal cancer, head and neck cancer, uterine cancer, breast cancer, and cervical cancer.
  • the cancer to be prevented or treated by the pharmaceutical composition of the present invention is colorectal cancer, esophageal cancer, gastric cancer, cholangiocarcinoma, and non-small cell carcinoma. It may be selected from the group consisting of lung cancer, bladder cancer, breast cancer, and biliary tract cancer, and more specifically, the cancer may be breast cancer,
  • the pharmaceutical composition for preventing or treating cancer of the present invention can be used during clinical administration, and can be prepared to be administered in various oral and parenteral dosage forms.
  • a pharmaceutical composition for preventing or treating cancer containing the compound of Formula 1, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as an individual therapeutic agent or used as another therapeutic agent. It can be used in combination with
  • Mobile phase A was water containing 0.1% formic acid
  • mobile phase B used acetonitrile containing 0.1% formic acid.
  • Mobile phase A was water containing 0.035% trifluoroacetic acid
  • mobile phase B was methanol containing 0.035% trifluoroacetic acid.
  • room temperature or room temperature refers to a temperature of about 5 ° C to 40 ° C, for example, 10 ° C to 30 ° C, and another example, 20 ° C to 27 ° C, and is not strictly limited within the above range.
  • Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.
  • Step 4 Preparation of 1-(4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one
  • Triethylamine (6.27 ml, 6.27 ml, 45 mmol) was added dropwise at 0 ° C and then stirred at the same temperature for 30 minutes.
  • acrylyl chloride (1.341 ml, 16.5 mmol) dissolved in dichloromethane (16.5 ml) was added dropwise at 0°C, followed by stirring for 1 hour.
  • the reaction was terminated by adding a saturated aqueous solution of sodium hydrogen carbonate to the reaction solution, the mixture was extracted with dichloromethane and the organic layer was dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure to obtain the target compound (4.5 g, 86% yield).
  • Step 5 1-(4-((4-((4-fluoro-5-(furan-2-yl)-2-(2-hydroxypropan-2-yl)phenyl)amino)-7-methyl Preparation of toxyquinazolin-6-yl) oxy) piperidin-1-yl) prop-2-en-1-one
  • Step 1 2-(4-chloro-5-(2-fluoro-3-(trifluoromethyl)phenoxy)-2-((7-methoxy-6-nitroquinazolin-4-yl) Preparation of amino) phenyl) propan-2-ol
  • Step 2 2-(2-((6-amino-7-methoxyquinazolin-4-yl)amino)-4-chloro-5-(2-fluoro-3-(trifluoromethyl)phenoxy ) Preparation of phenyl) propan-2-ol
  • Step 3 ( E )- N -(4-((5-chloro-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-2-(2-hydroxypropan-2-yl)phenyl)amino)-7- Preparation of methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide
  • Step 1 tert-butyl ( R , E Preparation of )-2-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate
  • Step 2 Ethyl ( R , E Preparation of )-3-(1-methylpyrrolidin-2-yl)acrylate
  • Step 3 ( R , E Preparation of )-3-(1-methylpyrrolidin-2-yl)acrylic acid hydrochloride
  • Step 4 ( R , E Preparation of )-3-(1-methylpyrrolidin-2-yl)acrylic chloride
  • Step 5 ( R , E )- N -(4-((4-(3-fluorophenoxy)-2-(2-hydroxypropan-2-yl)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-( Preparation of 1-methylpyrrolidin-2-yl)acrylamide
  • Step 1 7-(2-morpholinoethoxy)-6-nitroquinazoline-4(1 H ) - Preparation of one
  • Step 2 2-(4-chloro-2-((7-(2-morpholinoethoxy)-6-nitroquinazolin-4-yl)amino)-5-(3-(trifluoromethyl) Preparation of phenoxy) phenyl) propan-2-ol
  • Step 3 2-(2-((6-amino-7-(2-morpholinoethoxy)quinazolin-4-yl)amino)-4-chloro-5-(3-(trifluoromethyl)phenoxy Preparation of cy)phenyl)propan-2-ol
  • Step 4 N -(4-((5-chloro-2-(2-hydroxypropan-2-yl)-4-(3-(trifluoromethyl)phenoxy)phenyl)amino)-7-(2-morpholino Preparation of ethoxy) quinazolin-6-yl) acrylamide
  • HER2-overexpressing SK-BR-3 cells HER2-positive breast cancer cells, DSMZ
  • McCoy's 5A medium supplemented with 10% FBS was used.
  • 5000 cells were dispensed into each well of a white clear bottom 96 well plate (Corning).
  • the compound was diluted in dimethyl sulfoxide (three-fold dilution, total of 12 concentrations) and injected 0.5 ⁇ L at a time so that the final concentration was 0.3 nM - 50 ⁇ M.
  • Live cells were measured 72 hours after compound treatment, stored for 10 minutes at room temperature using CellTiter-Glo luminescent cell-viability reagent (Promega), and then the luminescence intensity was measured using a reader (SynergyNeo, Biotek). The result value was calculated as a cell growth rate (%) compared to the control group.
  • Example compound SK-BR-3 Example compound SK-BR-3 Example 1 C Example 65 B Example 2 C Example 66 B Example 3 A Example 67 A Example 4 B Example 68 B Example 5 B Example 69 A Example 6 A Example 70 - Example 7 A Example 71 B Example 8 - Example 72 B Example 9 C Example 73 A Example 10 A Example 74 A Example 11 A Example 75 A Example 12 A Example 76 A Example 13 A Example 77 A Example 14 B Example 78 - Example 15 A Example 79 A Example 16 A Example 80 - Example 17 A Example 81 - Example 18 B Example 82 - Example 19 A Example 83 - Example 20 A Example 84 - Example 21 A Example 85 B Example 22 A Example 86 B Example 23 A Example 87 B Example 24 A Example 88 B Example 25 A Example 89 A Example 26 A Example 90 A Example 27 C Example 91 A Example 28 B Example 92 B Example 29 A Example 93 B Example 30 B Example 94 B Example 31 B Example 95 A Example 32 A Example 96 A Example 33 A Example 97 A Example 34 A Example 98 B Example 35
  • the exemplary compounds of the present invention exhibit inhibitory activity against breast cancer cells (SK-BR-3) overexpressing HER2.

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Abstract

La présente invention concerne un dérivé hétéroaryle, un stéréoisomère de celui-ci, un hydrate de celui-ci, un solvate de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci, et une composition pharmaceutique pour la prévention ou le traitement du cancer le comprenant en tant que principe actif. Le dérivé hétéroaryle de la présente invention présente une activité inhibitrice élevée contre HER2 surexprimé, et ainsi une composition pharmaceutique contenant le dérivé hétéroaryle en tant que principe actif peut être particulièrement utile pour prévenir ou traiter le cancer HER2-positif.
PCT/KR2022/019664 2021-12-30 2022-12-06 Dérivé hétéroaryle et composition pharmaceutique pour la prévention ou le traitement du cancer le comprenant en tant que principe actif WO2023128350A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100511700B1 (ko) * 1997-08-01 2005-09-02 와이어쓰 홀딩스 코포레이션 치환된 퀴나졸린 유도체, 이를 포함하는 약제학적 조성물 및 이의 제조방법
WO2007055514A1 (fr) * 2005-11-08 2007-05-18 Hanmi Pharm. Co., Ltd. Dérivés de quinazoline en tant qu'inhibiteurs multiplex et méthode de synthèse desdits dérivés
WO2008150118A2 (fr) * 2007-06-05 2008-12-11 Hanmi Pharm. Co., Ltd. Nouveau dérivé d'amide pouvant inhiber la croissance de cellules cancéreuses
WO2013013640A1 (fr) * 2011-07-27 2013-01-31 上海医药集团股份有限公司 Dérivé de quinazoline, procédé de préparation pour cela, produit intermédiaire, composition et son application
WO2017117680A1 (fr) * 2016-01-06 2017-07-13 Trillium Therapeutics Inc. Nouveaux dérivés de quinazoline fluorés utilisés comme inhibiteurs du récepteur du facteur de croissance épidermique (egfr)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100511700B1 (ko) * 1997-08-01 2005-09-02 와이어쓰 홀딩스 코포레이션 치환된 퀴나졸린 유도체, 이를 포함하는 약제학적 조성물 및 이의 제조방법
WO2007055514A1 (fr) * 2005-11-08 2007-05-18 Hanmi Pharm. Co., Ltd. Dérivés de quinazoline en tant qu'inhibiteurs multiplex et méthode de synthèse desdits dérivés
WO2008150118A2 (fr) * 2007-06-05 2008-12-11 Hanmi Pharm. Co., Ltd. Nouveau dérivé d'amide pouvant inhiber la croissance de cellules cancéreuses
WO2013013640A1 (fr) * 2011-07-27 2013-01-31 上海医药集团股份有限公司 Dérivé de quinazoline, procédé de préparation pour cela, produit intermédiaire, composition et son application
WO2017117680A1 (fr) * 2016-01-06 2017-07-13 Trillium Therapeutics Inc. Nouveaux dérivés de quinazoline fluorés utilisés comme inhibiteurs du récepteur du facteur de croissance épidermique (egfr)

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