WO2021107657A1 - Nouveau dérivé d'oxydo-réduction de quinazoline et son utilisation en tant qu'inhibiteur de bet - Google Patents

Nouveau dérivé d'oxydo-réduction de quinazoline et son utilisation en tant qu'inhibiteur de bet Download PDF

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WO2021107657A1
WO2021107657A1 PCT/KR2020/017012 KR2020017012W WO2021107657A1 WO 2021107657 A1 WO2021107657 A1 WO 2021107657A1 KR 2020017012 W KR2020017012 W KR 2020017012W WO 2021107657 A1 WO2021107657 A1 WO 2021107657A1
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cancer
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김성욱
최재혁
이재연
박영식
김창중
거터만 조단유델
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주식회사 베노바이오
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a quinazoline derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition for preventing or treating Bromodomain Extra-Terminal (BET) protein-related diseases comprising the same as an active ingredient.
  • BET Bromodomain Extra-Terminal
  • Post-translational modification (PTM) of histones is involved in the regulation of gene expression and chromatin organization in eukaryotic cells.
  • Histone acetylation at specific lysine residues is a PTM regulated by histone acetylases and histone deacetylases.
  • Histone acetylation controls gene expression by recruiting protein complexes by direct binding of well-conserved proteins called bromodomains to acetylated lysines in histones and other proteins. There are more than 60 bromodomain containing proteins in the human genome.
  • the Bromodomain Extra-Terminal (BET) family includes BRD2, BRD3, BRD4, and BRDT, and except for BRDT, which is localized in the testis, the remaining proteins are widely expressed in various tissues.
  • BET protein family has been reported to be associated with various diseases including cancer, metabolic diseases and inflammation.
  • NUT intratesticular nuclear protein
  • BRD4 has been identified as a target in acute myeloid leukemia (AML) by an RNAi screen (Zuber et al., Nature, 478 (2011), 524-8). These findings were validated in vitro and in vivo using the BET inhibitors JQ1 and I-BET151 (Dawson et al., Nature, 478 (2011), 529-33). It is also known that BET inhibitors have broad anticancer activity in acute leukemia, multiple myeloma and other hematologic malignancies.
  • I-BET762 another BET inhibitor that is closely related to JQ1 in its chemical structure and BET binding mode, has been shown to regulate the expression of key inflammatory genes in a mouse model and protect the human body from endotoxin shock and bacteria-induced sepsis. has been reported (Nicodeme et al., Nature, 468 (2010), 1119-23). In addition, these results have been used to support the clinical evaluation of the BET inhibitor RVX-208 in clinical trials in patients with atherosclerosis, coronary artery disease, dyslipidemia, diabetes and other cardiovascular diseases (McNeill, Curr Opin Investig). Drugs, 3 (2010), 357-64 and www.clinicaltrials.gov).
  • bromodomain inhibitors Although several bromodomain inhibitors are known clinically and preclinically, the development of new bromodomain inhibitors capable of solving the problems of disease recurrence and resistance to therapeutic agents and reducing side effects is urgently required.
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • cysteine cysteine, methionine, tyrosine and tryptophan are particularly susceptible to oxidation. Accordingly, these proteinaceous substances metabolized in the human body cause various modifications such as metal binding, disulfide bond formation, methylation, and acetylation.
  • the present invention relates to diseases caused by oxidative and nitrification stress according to the "redox state" by oxidation, nitro It was completed by applying the redox chemistry technique considering the redox regulation mechanism such as S-nitrosylation. That is, the present inventors studied and developed a new bromodomain inhibitor in consideration of the redox state based on the fact that the degree of binding between signal transduction substances according to the redox state is different when the BET inhibitor recognizes the lysine residue of the histone protein. did.
  • An object of the present invention is to provide a novel quinazoline derivative compound having excellent inhibitory activity against BET protein.
  • the present invention is to provide a pharmaceutical composition for preventing or treating a BET protein-related disease comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a quinazoline derivative compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:
  • Y is -CR 5 or -NR 5 ,
  • Z is -CR 6 or -NR 6 ,
  • W is C, N, O or S
  • R 3 may be the same or different one or more selected from the group consisting of H, C 1 -C 6 alkyl, -ORa, or -SRa,
  • R 4 may be the same or different one or more selected from the group consisting of H, C 1 -C 6 alkyl, -ORa, or -SRa,
  • Ra and Rb are each independently H, alkyl, -alkyl-OH, -alkyl-SH, cycloalkyl, or heterocycloalkyl.
  • a pharmaceutical composition for preventing or treating BET protein-related diseases comprising the compound or a pharmaceutically acceptable salt thereof.
  • the BET protein-related disease is cancer; autoimmune or inflammatory diseases; metabolic diseases; And it may be any one or more selected from the group consisting of viral diseases.
  • the quinazoline derivative compound represented by Formula 1 provided in the present invention has excellent inhibitory activity against BET protein, and thus can be usefully used as a preventive or therapeutic agent for various diseases related to BET.
  • FIG. 2 is a graph showing the binding inhibitory activity of the BRD2 (BD2) protein by the compound 5 (BBC0403) of the present invention.
  • BRD4 BRD4 protein by Compound 3 (BBC0401) of the present invention.
  • BRD4 BRD4
  • BCC0401 Compound 3
  • BRD4 BRD4
  • BCC0403 Compound 5
  • the present invention relates to a novel quinazoline derivative compound, and more particularly, to a novel quinazoline derivative compound having inhibitory activity against BET protein and a pharmaceutical composition for preventing or treating BET protein-related diseases comprising the same. .
  • Alkyl is a hydrocarbon having primary, secondary, tertiary and/or quaternary carbon atoms and includes saturated aliphatic groups which may be straight-chain, branched or cyclic, or combinations thereof.
  • an alkyl group may have 1 to 20 carbon atoms (ie, C 1 -C 20 alkyl), 1 to 10 carbon atoms (ie, C 1 -C 10 alkyl), or 1 to 6 carbon atoms (ie, C 1 -C 10 alkyl). C 1 -C 6 alkyl).
  • alkyl refers to C 1 -C 6 alkyl.
  • alkyl groups examples include methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i -Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl ( t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH
  • alkyl as used throughout the specification, examples and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which are trifluoromethyl and 2,2,2-trifluoro Refers to an alkyl moiety having a substituent replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as roethyl, and the like.
  • C xy or "C x -C y”, when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to groups containing x to y carbons in the chain considered to include C 0 alkyl represents hydrogen when the group is in a terminal position, or a bond when internal to the group.
  • a (C 1 -C 6 )alkyl group contains 1 to 6 carbon atoms in the chain.
  • Alkoxy refers to a group having the formula —O-alkyl, wherein the alkyl group as defined above is attached to the parent compound through an oxygen atom.
  • the alkyl moiety of an alkoxy group may be, for example, 1 to 20 carbon atoms (ie C 1 -C 20 alkoxy), 1 to 12 carbon atoms (ie C 1 -C 12 alkoxy), 1 to 10 carbon atoms. (ie C 1 -C 10 alkoxy), or 1 to 6 carbon atoms (ie C 1 -C 6 alkoxy).
  • alkoxy groups include methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), and t-butoxy (-OC(CH 3 ) 3 or -O-tBu ), but is not limited thereto.
  • Alkenyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and includes one or more regions of unsaturation, i.e., carbon- It is a hydrocarbon with a carbon sp 2 double bond.
  • an alkenyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkenyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkenyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkenyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkenyl).
  • Alkynyl has primary, secondary, tertiary and/or quaternary carbon atoms, includes straight-chain, branched and cyclic groups, or combinations thereof, and contains one or more carbon-carbon sp triple bonds.
  • hydrocarbons with For example, an alkynyl group has 2 to 20 carbon atoms (ie, C 2 -C 20 alkynyl), 2 to 12 carbon atoms (ie, C 2 -C 12 alkynyl), 2 to 10 carbon atoms ( ie, C 2 -C 10 alkynyl), or 2 to 6 carbon atoms (ie, C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • aryl includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups wherein each atom of the ring is carbon, monocyclic, bicyclic or polycyclic.
  • the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring.
  • An aryl group can be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring is a cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocycloalkyl.
  • Aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.
  • Carbocyclylalkyl or “cycloalkylalkyl,” or “(cycloalkyl)alkyl,” as used herein, refers to an alkyl group substituted with a carbocycle group or a cycloalkyl group.
  • the terms “carbocycle”, “carbocyclyl”, “carbocyclic” or “cycloalkyl” may be monocyclic, bicyclic or polycyclic and each atom of the ring is a carbon non-aromatic refers to a saturated or unsaturated, monovalent or divalent ring.
  • a cycloalkyl group can have 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms.
  • Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused ring systems, spirocyclic ring systems or bridged ring systems. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In certain embodiments, cycloalkyl contains 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Unless otherwise specified, cycloalkyl may be substituted by one or more substituents described herein.
  • heterocyclylalkyl and “heterocycloalkyl” refer to an alkyl group substituted with a heterocycloalkyl group.
  • heterocyclyl means that the ring structure is at least 1 heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 to 4 heteroatoms.
  • heterocyclyl also refer to polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings. wherein at least one of the rings is heterocyclic, for example, the other cyclic ring can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems.
  • Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, carbonyl groups.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.
  • heterocyclos include dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4- piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, 3H-indolyl, 4H-quinolin
  • Heteroaryl refers to a substituted or unsubstituted monovalent or divalent aromatic group, monocyclic, bicyclic or polycyclic, containing one or more heteroatoms in the ring.
  • suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the ring system has at least two cyclic rings in which at least two carbons are common to two adjacent rings, wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and/or heterocyclyl.
  • Heterogroups are, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine , pyrazine, pyridazine, and pyrimidine, each of which may be substituted or unsubstituted.
  • Amino refers to the group —NH 2 .
  • Cyano refers to the group -CN.
  • Niro refers to the group —NO 2 .
  • Carboxy refers to the group -C(O)OH.
  • Aldehyde refers to the group -CHO.
  • Alkoxycarbonyl refers to the group -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein said alkyl and cycloalkyl are as defined above.
  • Acyl halide refers to a compound comprising a -C(O)-halogen group.
  • the present invention provides a quinazoline derivative compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • Y is -CR 5 or -NR 5 ,
  • Z is -CR 6 or -NR 6 ,
  • W is C, N, O or S
  • R 3 may be the same or different one or more selected from the group consisting of H, C 1 -C 6 alkyl, -ORa, or -SRa,
  • R 4 may be the same or different one or more selected from the group consisting of H, C 1 -C 6 alkyl, -ORa, or -SRa,
  • Ra and Rb are each independently H, alkyl, -alkyl-OH, -alkyl-SH, cycloalkyl, or heterocycloalkyl.
  • R 1 , and R 2 are each independently H, C 1 -C 6 alkyl, or —ORc, wherein Rc is H, C 1 -C 6 alkyl, or 3-10 membered heterocycloalkyl containing O heteroatoms.
  • R 3 can be one or more identical or different selected from the group consisting of H, C 1 -C 6 alkyl, -ORd, and -SRd,
  • R 4 may be the same or different one or more selected from the group consisting of H, C 1 -C 6 alkyl, -ORe, and -SRe,
  • Rd and Re are each independently H, C 1 -C 6 alkyl, -C 1 -C 6 alkyl-OH, -C 1 -C 6 alkyl-SH, or 3-10 membered hetero atom including a heteroatom of O cycloalkyl.
  • R 3 is H, C 1 -C 6 alkyl, , , , and At least one identical or different selected from the group consisting of R 5 and R 6 may be each independently H or C 1 -C 6 alkyl.
  • Preferred examples of the compound of Formula 1 according to the present invention are as follows, but are not limited thereto.
  • the compounds according to the invention are capable of forming pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt is not particularly limited as long as it is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion.
  • inorganic acids such as, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and the like; and acid addition salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like.
  • the present invention provides a pharmaceutical composition for preventing or treating BET (Bromodomain Extra-Terminal) protein-related diseases containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .
  • the pharmaceutical composition of the present invention is useful for preventing or treating various diseases related to the compound represented by Formula 1 contained therein by inhibiting the BET protein.
  • the BET protein-related disease is cancer; autoimmune or inflammatory diseases; metabolic diseases; or a viral disease.
  • the cancer is hematologic cancer, multiple myeloma, acute myeloid leukemia, malignant lymphoma, aplastic anemia, thymus cancer, ovarian cancer, cervical cancer, breast cancer, colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, It may be any one or more selected from the group consisting of peritoneal metastasis, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, fibrous tumor, and brain tumor, but is not limited thereto.
  • the autoimmune or inflammatory disease is rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia gravis, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune pernicious anemia and Sjogren's syndrome, allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, sepsis, sepsis syndrome, septic shock and nonalcoholic steatohepatitis It may be any one or more selected from the group consisting of, but is not limited thereto.
  • the metabolic disease is any one or more selected from the group consisting of hypertriglyceridemia, obesity, hyperlipidemia, hyperinsulinemia, hyperglycemia, arteriosclerosis, hypertension, type 2 diabetes, and insulin resistance disease may be, but is not limited thereto.
  • the viral disease is polio, acute hemorrhagic conjunctivitis, viral meningitis, hand, foot and mouth disease, hepatitis, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, cold, stomatitis herpes, foot-and-mouth disease, asthma, It may be any one or more selected from the group consisting of bronchiolitis, bronchitis, chronic obstructive pulmonary disease, pneumonia, sinusitis, otitis media, herpes simplex, herpes zoster, stomatitis, and chickenpox, but is not limited thereto.
  • a pharmaceutical formulation comprising the pharmaceutical composition.
  • the pharmaceutical preparation of the present invention may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration such as injections, preferably oral It may be in dosage form.
  • the pharmaceutical preparation may be formulated according to a conventional method by adding one or more selected from the group consisting of carriers, additives, and excipients, for example, as conventional non-toxic pharmaceutically acceptable additives in addition to the active ingredient. have.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC High performance liquid chromatography
  • TLC Thin layer chromatography
  • Ultraviolet light, iodine, and potassium permanganate were used in water for visualization.
  • the known starting materials of the present invention may be prepared by conventional synthetic methods in the art, or may be purchased from Alfa Aesar, Aldrich, and the like.
  • the intermediate compound 3 (60 mg, 237.79 umol, 1.01 eq) was reacted with 2-amino-4,6-dimethoxy-benzamide 4 (46 mg, 234.45 umol, 1 eq) to S-[2-[4- (5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl-2,6-dimethyl-phenoxylethyl]ethanethioate 5 (82 mg, 191.37 umol, 81.62% yield) was prepared.
  • Comparative Examples 1 to 3 were prepared by WUXI APPTEC (SHANGHAI) CO. BET inhibitory effect was compared with novel quinazoline compounds of the present invention purchased from LTD.
  • BRD2 (BD1, BD2, BD1+BD2)
  • BRD3 (BD1, BD2, BD1+BD2)
  • BRD4 (BD1, BD2, BD1+BD2)
  • the compound of the present invention has an excellent inhibitory effect on all proteins of BRD2 (BD1, BD2, BD1+BD2), BRD3 (BD1, BD2, BD1+BD2), and BRD4 (BD1, BD2, BD1+BD2). , can be effectively used for the treatment and prevention of BET-related diseases.

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Abstract

La présente invention concerne un nouveau composé dérivé de quinazoline et son utilisation et, plus particulièrement, un nouveau composé dérivé de quinazoline de formule chimique 1 suivante ayant une activité inhibitrice dirigée contre une protéine de bromodomaine et de domaine extra-terminal (BET), et une composition pharmaceutique pour la prévention ou le traitement de maladies associées à la protéine BET le comprenant.
PCT/KR2020/017012 2019-11-26 2020-11-26 Nouveau dérivé d'oxydo-réduction de quinazoline et son utilisation en tant qu'inhibiteur de bet WO2021107657A1 (fr)

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JP7483032B2 (ja) * 2019-11-26 2024-05-14 ベノビオ カンパニー リミテッド 新規ケルセチンレドックス誘導体及びｂｅｔ阻害剤としての用途
KR20240045472A (ko) * 2022-09-30 2024-04-08 주식회사 베노바이오 퀴나졸린염 화합물을 포함하는 관절염 치료용 조성물 및 이의 제조 방법

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KR20140088893A (ko) * 2011-11-01 2014-07-11 리스버로직스 코퍼레이션 치환된 퀴나졸리논을 위한 경구 즉시 방출 제형
US20130281398A1 (en) * 2012-04-19 2013-10-24 Rvx Therapeutics Inc. Treatment of diseases by epigenetic regulation
KR20160038008A (ko) * 2013-07-31 2016-04-06 제니쓰 에피제네틱스 코포레이션 브로모도메인 억제제로서 신규 퀴나졸리논
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