WO2019177375A1 - Dérivés de pyrimidine substitués en positions 2, 4 et 5, leur procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif - Google Patents

Dérivés de pyrimidine substitués en positions 2, 4 et 5, leur procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif Download PDF

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WO2019177375A1
WO2019177375A1 PCT/KR2019/002915 KR2019002915W WO2019177375A1 WO 2019177375 A1 WO2019177375 A1 WO 2019177375A1 KR 2019002915 W KR2019002915 W KR 2019002915W WO 2019177375 A1 WO2019177375 A1 WO 2019177375A1
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substituted
amino
cancer
alkyl
unsubstituted
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PCT/KR2019/002915
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Korean (ko)
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WO2019177375A8 (fr
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정명호
김주빈
전현호
이윤호
이화
강세인
조서현
강주희
김환
김현경
서경아
손정범
김남두
석지윤
이선화
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포로노이바이오 주식회사
보로노이 주식회사
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Publication of WO2019177375A1 publication Critical patent/WO2019177375A1/fr
Publication of WO2019177375A8 publication Critical patent/WO2019177375A8/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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

  • 2,4,5-substituted pyrimidine derivatives 2,4,5-substituted pyrimidine derivatives, a preparation method thereof and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.
  • Targeted therapies are generally designed to target the molecules that are characteristic of cancer cells and to have an effect.
  • the molecular targets are the si gnal transduct ion pathway and angiogens of cancer cells. Genes involved in cell matrix, cell cycle regulators, and apoptosis.
  • Currently used as important target therapeutics in therapy include 1 signaling pathway inhibitors, including tyrosine kinase inhibitors' and angiogenesis inhibitors 1 .
  • EGFR epidermal growth factor receptor
  • NSCLC species
  • breast cancer glioma, squamous cell carcinoma of the head and neck, colorectal cancer, rectal carcinoma, head and neck cancer, gastric cancer and prostate cancer
  • EGFR-tyrosine kinase It is known that activation leads to continuous cell proliferation, invasion of surrounding tissues, distant metastasis, angiogenesis and increased cell survival.
  • the EGFR is one of the ErbB tyrosine kinase receptors family (EGFR, HER-2, ErbB-3, ErbB-4), and the extra race 11 uar ligand-binding domain. It is a transmembrane tyrosine kinase (t ransmembr ane tyrosine kinase) with an intrace 1 lu lar domain including the tyros ine kinase domain.
  • Tyrosine kinase in the body is activated and the signal stimulated by EGFR is the phosphatidyl inosi tol 3-kinase (PI3K) / AKT / inT0R, RAS / RAF / MAPK, JAK / STAT signaling pathway.
  • PI3K phosphatidyl inosi tol 3-kinase
  • EGFR is particularly overexpressed in more than half of non-sma 11 cell 1 ungcancers (NSCLCs), and many studies have been conducted as targets for treatment.
  • EGFR tyrosine kinase inhibitors have been developed to inhibit EGFR tyrosine kinase activity.
  • Representative agents include zephytinib (IRESSAä), erlotinib (TARCEVAä) and lapatinib (TYKERBä, TYVERBä).
  • the EGFR mutation is classified into a sensitizing mutation and a resi stant mutation.
  • Deletion of exon 19 and L858R point mutation of exon 21 are the most important susceptibility mutations. It accounts for about 85 to 90%, and exon 19 del mutations are known to be more susceptible to TKI.
  • the T790M point mutation of exon 20 is the most important resistance mutation and is known to be found in more than 50% of acquired resistant patients (Clin Cancer Res 2006; 12: 6494-6501.).
  • somatic mutations identified thus far include point mutations in exon 19 or insertion into exon 20, as well as point mutations in which a single nucleic acid residue is modified in the expressed protein (eg, L858R, G719S, G719C, G719A,
  • EGFR T790M mutations were found in approximately 50% (24/48) of patient-derived tumors that acquired resistance to zephytinib or erlotinib (Kosaka et al CCR 2006; Balak et a 1 CCR). 2006 and Engelman et al Science 2007).
  • This secondary genetic modification is caused at a position similar to a 'gatekeeper' residue and its associated secondary allele in a patient treated with a kinase inhibitor (eg, T315I in ABL in imatinib resistant CML).
  • EGFR_dell9 or EGFR_L858R are the major causes of non-small cell lung cancer and head and neck cancer, and their therapeutic drugs, Iresa and Taceva, have been developed and are currently used in clinical practice.
  • Iresa and Taceva therapeutic drugs
  • acqui red resistance to EGFR secondary mutations based on the structure of the drug was observed, which was found to be a major cause of drug resistance.
  • EGFR first generation inhibitors are used for an average of about 10 months, the acquisition resistance of the T790M mutation located in the gatekeeper of the EGFR kinase may occur, preventing the EGFR first generation inhibitors from taking effect.
  • EGFR_deU9_T790M or EGFR_L858R_T790M double mutations occur, preventing the existing therapeutic from showing efficacy.
  • / ⁇ 1 is unsubstituted or substituted Unsubstituted or substituted 5 to 15 membered heteroaryl containing one or more heteroatoms selected from the group consisting of 0 and £,
  • Cycloalkyl or 0 and at least one selected being the one or more heteroatoms from the group comprising unsubstituted or substituted 3 to 10 membered heterocycloalkyl or heterocycloalkyl of 3 to 10 atoms of atoms consisting of (: ⁇ 3 alkyl ,
  • ⁇ , 11 11 and 12 12 are independently hydrogen or alkyl of straight or branched chain, wherein one or more substituents may be substituted with one or more amines substituted with the alkylshon unsubstituted or straight or branched ⁇ -5 alkyl.
  • Or groups 1 () and 11 together with the atoms to which they are attached, form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl comprising at least one hetero atom selected from the group consisting of 0 and 3;
  • said substituted heterocycloalkyl may be substituted with at least one substituted with one or more linear or branched- 5 alkyl and unsubstituted or straight or branched- 5 alkyl. And it may be substituted with one or more selected from the group consisting of 5 to 10 atoms of heterocycloalkyl containing one or more hetero atoms selected from the group consisting of S).
  • a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by the formula (1), its optical isomer or pharmaceutically acceptable salt thereof as an active ingredient.
  • a health functional food for preventing or improving cancer containing the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cancer comprising the step of administering a pharmaceutical composition or nutraceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof Prophylactic or therapeutic methods are provided.
  • a use of a pharmaceutical composition or nutraceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer are provided.
  • the 2,4,5-substituted pyrimidine derivatives according to the present invention exhibit a high inhibitory effect against EGFR (epidermal growth factor receptor) wild type or mutation, it can be usefully used for the treatment of cancer expressing EGFR wild type or EGFR mutation. It is excellent in inhibiting lung cancer cell line proliferation, and in particular, it can be usefully used for the treatment of lung cancer.
  • EGFR epidermal growth factor receptor
  • One aspect of the present invention provides a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • yo 1 o, yo 11 and yo 12 are independently hydrogen or alkyl of straight or branched chain, wherein said alkyl is unsubstituted or substituted with one or more amines substituted with one or more of -5 alkyl of straight or branched chain.
  • the compound represented by Formula 1 may be a compound represented by Formula 13 below.
  • hetero atom selected from the group consisting of unsubstituted or substituted (: 6-14 aryl, linear or branched ⁇ -10 alkoxy- 3 alkyl, unsubstituted or substituted- 10 cycloalkyl or 0 and Unsubstituted or substituted 3 to 10 membered heterocycloalkyl or 3 to 10 membered heterocycloalkyl- 3 alkyl containing one or more
  • And 1 are independently hydrogen, straight or branched chain, 0 1-5 alkyl or 1 %-; ? Alkyl, 2 is hydrogen or 1 %- :? Alkyl, wherein 3 , 4 , V 15 and 6 are independently hydrogen or linear or branched -5 alkyl, and 1 and 1 are unsubstituted or substituted 5-8 membered heterocyclo together with the atoms to which they are attached Alkyl may be formed, wherein the heterocycloalkyl may further include one or more, wherein the substituted heterocycloalkyl may be linear or branched- 5 alkyl and non- 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • And 1 are independently hydrogen, linear or branched 0 1-3 alkyl or 1 ; 14 (: ⁇ 3 alkyl, 2 is hydrogen or alkyl, and V 13 , 4 , V 15 and 6 are independent Or hydrogen or a straight or branched chain ( -3 alkyl), or and may form an unsubstituted or substituted 5 to 8 membered heterocycloalkyl together with the atoms to which they are attached, wherein the heterocycloalkyl And may further include one or more silver, wherein the substituted heterocycloalkyl is selected from the group consisting of 0 and one or more substituted with one or more linear or branched alkyl and unsubstituted or linear or branched ( ⁇ -3 alkyl). It may be substituted with one or more selected from the group consisting of 5 or 6 membered heterocycloalkyl containing one or more heteroatoms selected. In addition, in the formula 1 ⁇ 1,
  • At least one hetero atom selected from the group consisting of unsubstituted or substituted phenyl, straight or branched chain 0 1-3 alkoxy ⁇ -2 alkyl, unsubstituted or substituted (: 3-5 cycloalkyl or 0 and One 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • . And 1 are independently hydrogen, straight or from 0 1-3 14 alkyl or ethyl branched
  • 2 is hydrogen or ethyl
  • the 3, 4, and 6 V 15 are independently hydrogen or straight or branched Or- 3 alkyl of the chain,.
  • And 1 together with the four atoms to which they are attached may form an unsubstituted or substituted piperazine or piperidine, wherein the substituted piperazine and piperidine are methyl, ethyl and non- It may be substituted with one or more selected from the group consisting of piperazinyl substituted with one or more -3 alkyl of a ring or a straight or branched chain.
  • Examples of the compound represented by the above formula according to the present invention include the following compounds:
  • ⁇ 18-6> 1 (5-((5- (3,6-dihydro-la-pyran-4-yl)) 4-((2,4-dimethoxyphenyl) amino) pyrimidine-2 Sun) amino)-2-((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide, 2, 2, 2-trifluoroacetic acid salt;
  • It may be prepared by a method for preparing a compound represented by the formula (13) comprising the step (step 4) of preparing a compound represented by the formula (13) by reacting the compound represented by the formula (23) and the compound represented by the formula (33).
  • Step 1 of Scheme 1 ⁇ 1 is a step of preparing a compound represented by Chemical Formula 5 by reacting a compound represented by Chemical Formula 73 with a compound represented by Chemical Formula 83.
  • halogen of the compound represented by Chemical Formula 7 ⁇ 1 and Chemical Formula 83 The primary amine of the compound represented by the reaction is a step of preparing a compound represented by the formula (53).
  • Step 1 reaction of Scheme 13 is not particularly limited as long as it is a condition capable of combining amine and commonly known halogen and amine.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (Ya00, Dimethylsulphoxide (3 ⁇ 4 ⁇ 0), Methylene chloride, Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenyl Propionate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandel Late
  • Step 2 of Scheme 13 is a step of preparing a compound represented by Chemical Formula 43 by reacting a compound represented by Chemical Formula 53 with a compound represented by Chemical Formula 6, specifically, halogen and Chemical Formula 6 of the compound represented by Chemical Formula 53. Hydrogen of the compound represented by C is reacted to prepare a compound represented by Chemical Formula 43.
  • the step 2 reaction of the above scheme is not particularly limited as long as the halogen and hydrogen are substituted.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (large; Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (10, dimethyl sulfoxide (01 0), methylene chloride, dichloroethane, water, acetonasulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropione Yate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate
  • Step 3 of Scheme 13 A nitro of a compound represented by the formula (43) is hydrogenated in the presence of a catalyst to form a primary amine, thereby preparing a compound represented by the formula (23).
  • the reaction of Step 3 of Scheme 13 is not limited as long as the hydrogenation may occur, and the catalyst may be used without limitation if the catalyst is also a commonly used catalyst.
  • 311 uses 2 ⁇ 23 ⁇ 40, but is not limited thereto. It is not.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran pear); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide ( ⁇ , Dimethylsulphoxide (E)), Methylene chloride, Dichloroethane, Water, Acetonasesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenylpropionate Phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, aceto
  • Step 4 of Scheme 13 is a step of preparing a compound represented by Chemical Formula 13 by reacting the compound represented by Chemical Formula 23 with the compound represented by Chemical Formula 33, specifically, with the primary amine of the compound represented by Chemical Formula 23; Halogen of the compound represented by Formula 33 reacts to form an amine bond.
  • the compound represented by step is prepared.
  • Step 4 The reaction of Scheme 13 is If conditions capable of forming a bond to a halogen with an amine, Nu bond are not particularly limited.
  • the base conditions were used, and as the base
  • Imethylaminopyridine show! 5 ) organic bases such as pyridine, triethylamine, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene 81]) or sodium carbonate, sodium bicarbonate, hydroxide
  • organic bases such as pyridine, triethylamine, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene 81]
  • sodium carbonate sodium bicarbonate
  • hydroxide sodium carbonate
  • inorganic bases such as sodium, potassium hydroxide, and kerosene, which may be used alone or in mixtures and used in equivalent or excessive amounts.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethyl formamide (A), Dimethyl sulfoxide (!
  • the compound represented by Formula 1 may be a compound represented by Formula 113 below.
  • alkyl may be substituted one or more by unsubstituted or straight-chain or branched (amine) alkyl groups at least one substituted with ( ⁇ 5 alkyl), Or ⁇ and 1 () together with the atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 3 to 10 atoms comprising one or more hetero atoms selected from the group consisting of 0 and 3,
  • Substituted heterocycloalkyl is a straight or branched chain of- 5 alkyl, and 3 to 10 atoms of unsubstituted or straight or branched chain 0 1-5 alkyl containing one or more hetero atoms selected from the group consisting of 0 and.
  • 16 may be substituted with one or more selected).
  • 1 ⁇ 1 o and 11 are independently hydrogen or straight or branched -3 alkyl, wherein said alkyl may be substituted one or more with amines substituted one or more by unsubstituted or straight or branched -3 alkyl Or 2 9 and ⁇ together with the atoms to which they are attached may form an unsubstituted or substituted heterocycloalkyl of 3 to 8 atoms comprising one or more hetero atoms selected from the group consisting of 0 and , the substituted heterocycloalkyl is a straight-chain or branched-one 3 Al kilo-5 alkyl, and 0, and 3 to 8 which is unsubstituted or straight or branched chain of atoms including one or more heteroatoms selected from the group consisting of It may be substituted with one or more selected from the group consisting of at least substituted heterocycloalkyl.
  • 1 is an unsubstituted or substituted 5 to 9 membered heteroaryl containing one or more- ⁇ - ⁇ 4 or ⁇ atoms,
  • ⁇ is an unsubstituted or substituted 5 or 6 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of straight or branched chain ( ⁇ -3 alkyl, unsubstituted or substituted phenyl or 0 and -3 alkyl,
  • 17 are independently straight or branched ( -3 alkyl or unsubstituted or amine substituted with one or more methyl; hydrogen or straight or branched ( ⁇ -3 alkoxy); 3 is -10 or- ⁇ 11 ego,
  • ⁇ 9 ,. And 1 are independently hydrogen or a straight or branched chain ( ⁇ -3 alkyl), wherein the alkyl may be substituted one or more with an amine unsubstituted or substituted with one or more methyl,
  • Examples of the compound represented by Formula 113 according to the present invention include the following compounds:
  • Step 1 Reacting the compound represented by Chemical Formula 7 3 with the compound represented by Chemical Formula 813 to prepare a compound represented by Chemical Formula (Step 1); Preparing a compound represented by Chemical Formula 413 by reacting the compound represented by Chemical Formula 51) with the compound represented by Chemical Formula Example (step 2); Reacting the compound represented by Chemical Formula 413 to prepare a compound represented by Chemical Formula (Step 3); And
  • It may be prepared by a method for preparing a compound represented by the formula including the step (step 4) of reacting the compound represented by the formula and the compound represented by the formula (Step 4).
  • X 13 , X 23 and the table are independently halogen. 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • Step 1 in the reaction scheme is a step of preparing a compound represented by Chemical Formula 513 by reacting the compound represented by Chemical Formula 713 with the compound represented by Chemical Formula 813, specifically, the halogen of the compound represented by Chemical Formula 713 and Chemical Formula 813.
  • the primary amine of the compound to be reacted is a step in which the compound represented by the formula
  • the reaction of Step 1 in Scheme 113 is not particularly limited as long as it is a condition capable of combining amine and commonly known halogen and amine.
  • the reaction was carried out in the presence of a base and a metal ligand, and the reaction was carried out in the presence of a base and a metal ligand.
  • the base is not limited to 13 ⁇ 411 (: 11 ⁇ 1 (a base commonly used in 1 63 1011, ⁇ -dimethylaminopyridine?) , Organic bases such as pyridine, triethylamine,, -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7 -undecene) or sodium carbonate, sodium bicarbonate, sodium hydroxide, hydroxide There are inorganic bases, such as potassium and arsenic, which can be used alone or in combination and used in equivalent or excessive amounts.
  • the metal ligand may be used palladium, nickel, copper ligand and the like.
  • Me (1 2 (Buk)) 3 was used as the palladium ligand, but this is only one example, but is not limited thereto.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (03 ⁇ 4), Dimethylsulphoxide (03 ⁇ 40), Methylene chloride, Dichloroethane, Water, Acetonazenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Ethyl acetate, Phenyl acetate, Phenylpropy Oneates, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate,.
  • Step 2 of Scheme 11 is a step of preparing a compound represented by Chemical Formula by reacting a compound represented by Chemical Formula 5 with a compound represented by Chemical Formula. Specifically, halogen of the compound represented by Chemical Formula 5) 3 and Hydrogen of the compound represented by Chemical Formula 613 is reacted to prepare a compound represented by Chemical Formula.
  • the step 2 reaction in the above scheme is not particularly limited as long as it is a condition under which halogen and hydrogen are substituted.
  • Reaction solvents are isopropanol, methanol, ethanol, propanol and butane 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • Lower alcohols including 21 ol; Tetrahydrofuran pear); Dioxane; Ether solvents including ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (ya), dimethyl sulfoxide (), methylene chloride, dichloroethane, water, acetonizensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropionate Phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, maleat, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, aceto Nitrile, and the like, which may be used alone or in combination.
  • Step 3 in the reaction scheme is a step of preparing a compound represented by the formula (D) by reacting the compound represented by the formula (VII). Is a step of preparing a compound.
  • Step 3 of the reaction scheme is not limited as long as the hydrogenation can occur conditions, the catalyst can also be used without limitation if the catalyst is also commonly used, in the present invention (1: 1 2 ⁇ 23 ⁇ 40 rule was used, but not limited to It is not.
  • the reaction solvent is a lower alcohol containing isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran); Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (Ya00, Dimethylsulfoxide) ), Methylene chloride, dichloroethane, water, acetonizensulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropionate, phenylbutyrate, cyclate, lactate, hydroxy Butyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2 -sulfonate, mandelate, ace
  • Step 4 in the reaction scheme is a step of preparing a compound represented by Chemical Formula 11) by reacting the compound represented by Chemical Formula 213 with the compound represented by Chemical Formula 313, specifically, the primary amine of the compound represented by Chemical Formula 213. And a halogen of the compound represented by Formula 313 react to form an amine bond, thereby preparing a compound represented by Formula 113.
  • Step 4 reaction of the above reaction scheme is not particularly limited as long as it is a condition that can combine the halogen and the amine to form an amine bond.
  • the base was gawa-dimethylaminopyridine, pyridine, triethylamine, gawa-diisopropylethylamine, 1,8-diazabicyclo [5. 4 . 0] -7 -undesendae 311) or other organic base or sodium carbonate, sodum bicarbonate, sodium hydroxide, hydroxyl 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • inorganic bases such as potassium sulphate and kerosene, which can be used alone or in mixture and used in equivalent or excessive amounts.
  • Reaction solvents include lower alcohols including isopropanol, methanol, ethanol, propanol and butanol; Tetrahydrofuran (large; Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Dimethylformamide (night 00, dimethyl sulfoxide (night 60), methylene chloride, dichloroethane, water, acetonasulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, ethyl acetate, phenylacetate, phenylpropy One Nate, Phenylbutyrate, Citrate, Lactate, Hydroxybutyrate, Glycolate, Maleate, Tartrate, Methanesulfonate, Propanesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Mandelate
  • the compound represented by Chemical Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid (near 01) is useful.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes.
  • Non-toxic organic acids such as dioate, 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. Obtained from the same organic acid.
  • Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, the derivative of formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like
  • the precipitate produced by adding acid may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure and dried to crystallize in an organic solvent.
  • Bases can also be used to make pharmaceutically acceptable metal salts.
  • Alkali or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt.
  • Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention includes not only the compound represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may inhibit EGFR (epidermal growth factor receptor) wild type or EGFR mutation.
  • EGFR epidermal growth factor receptor
  • the EGFR mutation is EGFR Del 19, EGFR L858R, EGFR
  • the compound is ABLKF317I) -phosphoryl at ed, ABLKF317L) -phosphorylated, BLK, BTK, EGFR, EGFR (E746-A750de 1), EGFR (G719C), EGFR (G719S), EGFR (L747-E749de 1, A750P), EGFR (L747-S752de 1, P753S), EGFR (L747-T751del, Sins), EGFRCL858R), EGFR (L858R, T790M),
  • EGFR L861Q may exhibit inhibitory activity against one or more protein kinases selected from the group consisting of.
  • the cancer may be a mutation expressed for EGFR.
  • the cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma , Ovarian epithelial cancer, Ovarian germ cell cancer, Breast cancer, Brain cancer, Pituitary adenoma, Multiple myeloma, Gallbladder cancer, Biliary cancer, Colorectal cancer, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroidal melanoma, Bartoenvelope cancer, Bladder cancer , Peritoneal cancer, Parathyroid cancer, Adrenal cancer, Paranasal sinus cancer, Non-small cell lung cancer, Snow cancer, Astrocytoma, Small cell lung cancer, Pediatric brain
  • the compound represented by the formula (1) of the present invention not only shows an excellent inhibitory effect even in EGFR wild type in Ba / F3 cell line, but also shows a high inhibitory effect against EGFR single, double or triple mutations (see Experimental Examples la and lb).
  • the compound represented by the formula (1) of the present invention shows excellent proliferation inhibitory ability against lung cancer cell lines A549, PC9, PC9GR, H1975 cells (see Experimental Examples la and lb). Therefore, the compound represented by Formula 1 according to the present invention
  • EGFR ep i derma 1 growth factor receptor
  • the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations, oral and parenteral, during clinical administration. When formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one compound and at least one excipient such as starch, calcium carbonate, sucrose
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.
  • simple diluents such as water and liquid paraffin
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives can be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions.
  • compositions comprising an effective salt may be administered parenterally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a parenteral formulation in the form of a solution or a suspension, which is prepared in the form of an ampule or a vial unit It may be prepared in a dosage form.
  • the composition may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically valuable substances, and conventional methods of mixing, It may be formulated according to the granulation or coating method.
  • Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols.
  • Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylylcellulose and / or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or Disintegrants or boiling mixtures such as sodium salts and the like and / or absorbents, colorants, flavors, and sweeteners.
  • a pharmaceutical composition for the prevention or treatment of cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be administered as a separate treatment or in combination with other anticancer agents in use. Can be used.
  • Another aspect of the present invention provides a health functional food for preventing or improving cancer containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may inhibit EGFR (epidermal growth factor receptor) wild type or EGFR mutation.
  • EGFR epidermal growth factor receptor
  • the EGFR mutations include EGFR Del 19, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R / T790M, EGFR L858R / T790M / C797S, EGFR DeU9 / T790M / C797S, EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGV H, At least one selected from the group consisting of EGFR FQEA and HER2 YVMA.
  • the compound is ABLKF317I) -phosphorylated, ABLKF317L)-phosphorylatecl, BLK, BTK, EGFR, EGFR (E746-A750del), EGFR (G719C), EGFR (G719S), EGFR (L747_E749de 1, A750P), EGFR (L747-S752de 1 , P753S), 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • protein kinases selected from the group consisting of EGFR (L861Q), seedlings, seedlings, 7903 ⁇ 40, $ 832, and 1 ⁇ 2.
  • the cancer may be a mutation expressed in the yakyo.
  • the cancer includes pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, cleft lip cancer, myxocarcinoma, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma , Ovarian epithelial cancer, Ovarian germ cell cancer, Breast cancer, Brain cancer, Pituitary adenoma, Multiple myeloma, Gallbladder cancer, Biliary cancer, Colon cancer, Chronic myeloid leukemia, Chronic lymphocytic leukemia, Retinoblastoma, Choroidal melanoma, Battery swelling cancer, Bladder cancer , Peritoneal Cancer, Parathyroid Cancer, Adrenal Cancer, Paranasal Sinus Cancer, Non-Small Cell Lung Cancer, Snow Cancer, Astrocytoma, Small Cell Lung Cancer, Pediatric Brain Cancer,
  • Compound represented by the formula (1) according to the present invention by showing a high inhibitory ability against wild wild type, mutant, can be added to health supplements, such as food, beverages as a dietary supplement for the prevention or improvement of cancer .
  • the compound represented by Chemical Formula 1 according to the present invention may be added to foods or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the compound in the health food is 0. It can be added from 1 to 90 parts by weight.
  • the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
  • the health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and various flavoring agents or natural carbohydrates as in the general beverage. Water and the like may be included as additional components.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, toll and erythritol.
  • natural flavoring agents tautin, stevia extract (e.g., Rebaudioside Shaw, glycyrrhin, etc.
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the ratio of the natural carbohydrate is generally about 1 to 100 urine of the composition of the present invention. Preferably about 5-12 ⁇ .
  • Compound is pyosa are various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents and mogul agents (cheese, chocolate, etc., X pectic acid and its salts, alginic acid and its salts, organic acid, protective colloidal. It may contain a thickener, a regulator, a stabilizer, a preservative, a glycerin, an alcohol, a carbonation agent used in a carbonated beverage, and the like.
  • the compound represented by the formula (1) of the present invention may contain the flesh for the production of natural fruit juice and fruit juice beverage and vegetable beverage.
  • cancer comprising a step of administering a pharmaceutical composition or a nutraceutical composition containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.
  • a method of prevention or treatment Provides a method of prevention or treatment.
  • Another aspect of the present invention provides a use of a pharmaceutical composition or a nutraceutical composition containing a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of cancer.
  • MPLC Medium Pressure Liquid Chromatography
  • Mobile phase A used water containing 0.1% formic acid and mobile phase B used acetonitrile containing 0.1% formic acid.
  • Mobile phase A used water containing 0.035% trifluoroacetic acid and mobile phase B used methanol containing 0.035% trifluoroacetic acid.
  • the Initiator of Biotage a snap cap react vial was used. Commercial reagents used were used without further purification.
  • the room temperature refers to a temperature of about 20 to 25 ° C. Concentration under reduced pressure or solvent distillation was carried out using a rotary evaporator.
  • Example la-l> ⁇ (5-((5- (3,6-dihydro-2min-pyran-4-yl) -4-((2- (isopropylsulfonyl) phenyl) amino) pyri) Preparation of midin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide 2019/177375 1 »(: 1/10 ⁇ 019/002915
  • Step 1 Preparation of 5-ro- (2- (isopropylsulfonyl) phenyl) pyrimidin-4 amine
  • step 4 5- (3,6-dihydro-2min-pyran-4-yl)-#-(2- (isopropylsulfonyl) phenyl)--(2-methoxy-4- Preparation of 4-methylpiperazin-1-yl) -5-nitrophenyl) pyrimidine-2,4-diamine
  • Example 1 15 (111/2): 648.5 [3 ⁇ 4! +1] + , 1, [(): 1.18
  • Examples 13-2 to 13-11 were prepared in the same manner as in Example 13-1, and Example 1 3
  • the chemical structures of -1 to 13-11 are shown in Table 1 below, compound names, yields, and 1 ⁇ 1 ⁇ analysis results in Table 2 below.
  • Step 1 Preparation of 3- (5-bromo-2-chloropyrimidin-4-yl)-1 min-indole After dissolving indole (10.3 ⁇ , 87.77_ 0 1) in ash 100.0 1) under nitrogen, a methyl magnesium bromide solution (29.31111, 87.77_ 0 1, 3M nyoah) below was slowly added dropwise over 20 minutes. After stirring the mixed solution at room temperature for 100 minutes,! 'Five times that becomes soluble in (40.01) - bromo - 2,4 - a furnace dikeul pyrimidine (10.0 ⁇ , 43.88_1 0 1) at room temperature. The reaction solution was heated to 60 ° : and stirred for 1 hour.
  • the reaction mixture was cooled to room temperature and the reaction was terminated by adding methanol, followed by extraction with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from nucleic acid / ethyl acetate to give the title compound as a solid (7.4 ⁇ 54%).
  • a target compound was prepared in a similar manner to Step 2 of Example 13-1.
  • step 4 5- (3, 6-dihydro-2min-pyran-4-day)--(4 ⁇ Preparation of Fluo-2--2-Methoxy-5-nitrophenyl) -4- (1-methyl-1 min-indol-3-yl) pyrimidin-2-amine Performed analogously to step 3 of Example-1 above Target compound
  • a target compound was carried out similarly to step 4 of Example 13-1.
  • step 6 -( 5- (3,6-dihydro-2min-pyran-4-yl)-4- (1-methyl-1min-phosphoryl-3-yl) pyrimidine- Preparation of 2-yl) -6-methoxy-4- (4-methylpiperazin-1-yl) benzene-1,3-diamine
  • the desired compound was carried out similarly to the step 5 of Example 13-1.
  • Step 7 (5-((5_ (3,6-dihydro-2min-pyran-4-yl)) 4- (1-methyl-1min_ indole-3-yl) pyridine Preparation of midin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide
  • the desired compound was carried out similarly to the step 6 of Example 13-1.
  • Example 13-13 to 1-ch-16 were prepared in the same manner as in Example -12, and the chemical structures of Examples -12 to 13-16 are shown in Table 3, below. , And The analysis results are summarized in Table 4 below.
  • Step 1 Preparation of 5-Bromo-2-chloro- (2-methoxyethyl) pyrimidine-4-amine
  • Triethylamine (1.1 1, 7.46
  • a target compound was carried out similarly to step 2 of Example 13-1.
  • the target compound (96%) was prepared in the same manner as in Step 3 of Example 13-1.
  • step 5 -(5- (3,6-dihydro-2min-pyran-4-yl)-4-((2-methoxyethyl) amino) pyrimidine _ 2- I)--(2_ (dimethylamino) ethyl) _5-methoxy- _methylbenzene-1,2,4-triamine
  • a target compound (43%) was prepared in a similar manner to Step 5 of Example 13-1.
  • step 6 ⁇ (5-((5- (3,6-dihydro-2 min-pyran-4-yl)) 4-((2-methoxyethyl) amino) pyrimidine ⁇ 2 -Yl) amino) ⁇ 2-((2- (dimethylamino) ethyl) (methyl) amino) -4 -methoxyphenyl) acrylamide, Preparation of 2,2,2-trifluoroacetic acid salt
  • the target compound (2%) was prepared in a similar manner to Step 6 of Example 1 3 _1, except that the show 01 ′:-apparatus was used instead of the chromatography used in Step 6 of Example 13-1. Prepared.
  • Example 11-1-1 (5-((4-((2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidin-2-yl) amino) -4-methoxy- 2- (4-methylpiperazin-! - - Manufacturing trifluoroacetic acid salt-yl) carbonyl Fe) acrylamide-2, 2, 2
  • Step 1 Preparation of 5-morpholinpyrimidine-2, 4 (1 min, 3 min) -dione 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • 5-bromouracil (12. , 62.8 _01) were placed in morpholine (1081111, 1.2411101), heated with microwave for 10 minutes at 1001 :, and the reaction was terminated by lowering the temperature to room temperature. The resulting suspension was diluted with methanol and then filtered to obtain the target compound (11.0, 89%).
  • the reaction mixture was adjusted to 7 by addition of solid sodium bicarbonate.
  • the reaction mixture was filtered through celite and washed several times with ethyl acetate.
  • the filtrate was concentrated under reduced pressure to provide the target compound-(5 -amino-2-mesocies-4_ (4-methylpiperazin-1 -yl) phenyl) -7-(2- (isopropylsulfonyl) phenyl)- 5-Mofolinopyrimidine-2,4-diamine (62.411, 97%) was obtained and used in the next reaction without purification.
  • Example 113-1 Compound-(5-Amino-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl)-(2- (isopropylsulfonyl) phenyl) obtained in Step 6 above Dissolve 5, morpholinopyrimidine-2,4-diamine (62.41, 0.11_01) in 1'fold (15). 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • the filtrate was purified using a concentrated liquid under reduced pressure ⁇ 61) -150, and then purified by the target compound (5-((4-((2- (isopropylsulfonyl) phenyl) amino) -5-morpholinopyrimidine-2 -Yl) amino) -4 -methoxy- 2- (4-methylpiperazin-1 -yl) phenyl) acrylamide trifluoroacetic acid salt (20.3
  • step 4 of Example 1 2-((2-chloro-5-morpholinopyrimidin-4-yl) amino) -VII-dimethylbenzenesulfonamide was substituted for 2-chloro-methyl-5-morpho.
  • a target compound (64%) was obtained by the same method except that nopyrimidine-4-amine was used.
  • Step 4 #-(5-Amino-2-methoxy-4- (4-methylpiperazin-1-yl) phenyl)-#-methyl-5-morpholinopyrimidine-2,4-diamine Produce
  • step 5 (4-4-methoxy-5- (4- (methylamino) -5-morpholinopyrimidin-2-yl) amino) -2- (4-methylpiperazin- Preparation of trifluoroacetic acid salt of 1-yl) phenyl) acrylamide
  • step 7 of the first embodiment? 1) 33 )-1 1 33 was used in the same manner to obtain the target compound (3%).
  • Example 11-16 was prepared by the method similar to that of Example 1.15 Chemical structure of -15 and 11 3 -16 In Table 11, the compound names and the analysis results are summarized in Table 12 below.
  • A549 is cultured after 10% FBS (HyClone) is added to DMEM (Invitrogen), and other cancer cells use RPMI-1640 (Invi trogen) added with 10% FBS.
  • Ba / F3 cells use RPMI-1640 with 10% FBS and 5 ng / ml IL-3 (R & D Systems).
  • Transduced Ba / F3 cells are cultured by adding 1 ug / mlpuromycin (Invi trogen) to the same medium. Cells are dispensed in 3000-5000 cells per well of a white clear bottom 96 well plate (Corning) 24 hours before compound treatment.
  • Compound is dimethyl sulfoxide 2019/177375 1 »(: 1/10 ⁇ 019/002915
  • 59 dilutions (3 dilutions, 12 concentrations in total) were injected in 0.5 increments, with a final concentration of 0.3 nM-50 uM.
  • the viable cell was measured for 10 minutes at room temperature using Cel ITi ter-Glo luminescent cell -viability reagent (Pr omega) 72 hours after compound treatment, and then the luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each test was repeated three times. The results were calculated as the percentage of cellular equipment compared to the control (GraphPad Prism version 5.0 program was used to graph and calculate the IC 50 value.
  • WT wild type (Wi Id Type)
  • Table 13 the example compounds of all compounds represented by the general formula la of the present invention in Ba / F3 cell line not only show excellent inhibitory ability in the EGFR wild type, but also EGFR single , It can be seen that it shows a high inhibitory ability against double or triple mutations.
  • Example compound of the compound represented by the chemical formula of the present invention in 8 cells / 3 cell line also shows a high inhibitory ability against exon 20 insertion mutation.
  • the example compound of the 3 ⁇ 4 compound represented by the general formula la of the present invention can be seen to exhibit excellent proliferation inhibitory ability against lung cancer cell lines PC9GR, H1975, PC9, A549, U87 cells. Therefore, the compound represented by the formula la according to the present invention exhibits high inhibitory ability against ep i derma 1 growth factor receptor (EGFR) wild type or mutation, and therefore, EGFR Del 19, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R / T790M, EGFR L858R / T790M / C797S, EGFR De 1 19 / T790M / C797S, EGFR NPH, EGFR SVD,
  • EGFR mutations such as EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA, HER2 YVMA, etc. can be useful for the treatment of cancers, and can be useful for the treatment of lung cancer.
  • the inhibitory activity against Ba / F3 and lung cancer cell proliferation expressing the EGFR mutation of the compound represented by the formula lb according to the present invention was evaluated by the same method as Experimental example la.
  • Example compound of the compound represented by the chemical formula of the present invention in 8 cells / 3 cell line also shows a high inhibitory ability against exon 20 insertion mutation.
  • the example compound of the compound represented by the formula lb of the present invention can be seen to exhibit excellent proliferation inhibitory ability against lung cancer cell lines PC9GR, H1975, PC9, A549 cells. Therefore, the compound represented by the formula lb according to the present invention shows a high inhibitory ability against EGFR (epidermal growth factor receptor) wild type or mutation, as well as EGFR wild type, EGFR Dell9, EGFR L858R, EGFR Dell9 / T790M, EGFR L858R Treatment of cancers with EGFR mutations such as / T790M, EGFR L858R / T790M / C797S, EGFR De 1 19 / T790M / C797S, EGFR NPH, EGFR SVD, EGFR NPG, EGFR H, EGFR ASV, EGFR FQEA, HER2 YVMA It can be usefully used for, and excellent in inhibiting lung cancer cell
  • Example 1 3 -2 selected from Example compounds of the present invention, Ask your company to measure the enzyme (L) 36 selectivity. The experiment was conducted using an analytical panel. At this time, the concentration of the drug to be treated in the enzyme was set at 1 to 0, and the control percentage (% (: 01 01 ' 1) was determined by the same method as in Equation 1 below, and the results are shown in Table 19 below.
  • the positive control refers to a compound that exhibits a control percentage of 0%, and the negative control indicates a control percentage of 100%.
  • the enzyme selectivity of the present invention was determined to have activity against the enzyme if the control percentage for each enzyme is ⁇ 35% (ie less than 35%).
  • the compound according to the present invention is Show 81 he 3171) _1) ⁇ 1031) 110 1 6 (1 , Show 81 he 3171) -1) 11031) 110 1 Root, seedling, seedling, seedling 6 746-Show 75 (1 ⁇ 26 ”, Table 0 1 719 (:), Table Drawing), Table 6- Mausoleum (1 47- £ 749 Line, Sho-A), Grave Line, 757535) Table 0 1? (1747- when), £ 0?
  • the control percentage is smaller than 35%, indicating that the compound according to the present invention has inhibitory activity against the enzymes listed above, from which the enzymes listed above Therefore, the derivative compound according to the present invention has a show 811 3171)-a first line, a show 81 '' _ 3171 / ) -1) 110313110 316 (1, One(, ! , Ticket mausoleum, £ &?
  • compositions for the treatment or prophylaxis of £ 0 seedlings (58 ⁇ 0, seedlings 0 1 ⁇ 8581 ?, 179), £ 1 (1861, £ 0? 79), £ 1 ⁇ 82, or ⁇ 2 kinase-related diseases in 2019/177375 1 »(: 1 ⁇ 1 ⁇ 2019/002915
  • the 2, 4, 5-substituted pyrimidine derivatives according to the present invention can be usefully used for the treatment of cancer.

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Abstract

La présente invention concerne des dérivés de pyrimidine substitués en positions 2, 4 et 5, leur procédé de préparation et une composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif. Le composé selon l'invention présente une forte capacité inhibitrice vis-à-vis du récepteur du facteur de croissance épidermique (EGFR) de type sauvage ou mutant, et par conséquent, ledit composé peut être utilisé de manière efficace dans le traitement d'un cancer exprimant EGFR de type sauvage ou une mutation d'EGFR. Le composé a une excellente aptitude à inhiber la prolifération des lignées cellulaires du cancer du poumon et peut être particulièrement utile pour le traitement du cancer du poumon.
PCT/KR2019/002915 2018-03-13 2019-03-13 Dérivés de pyrimidine substitués en positions 2, 4 et 5, leur procédé de préparation et composition pharmaceutique pour la prévention ou le traitement du cancer les contenant en tant que principe actif WO2019177375A1 (fr)

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EP3746424A4 (fr) * 2018-01-31 2021-08-25 Dizal (Jiangsu) Pharmaceutical Co., Ltd Inhibiteurs de erbb/btk
WO2021185298A1 (fr) * 2020-03-18 2021-09-23 南京药石科技股份有限公司 Inhibiteur de la tyrosine kinase egfr et son utilisation
CN114630819A (zh) * 2019-11-19 2022-06-14 韩国化学研究院 用于预防或治疗癌症的苯甲酰胺衍生物、其制备方法以及包含其作为活性成分的药物组合物
US11466000B2 (en) 2019-03-19 2022-10-11 Voronoi Inc. Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
WO2023011358A1 (fr) * 2021-08-02 2023-02-09 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Nouveaux sels pharmaceutiques et formes polymorphes d'un inhibiteur d'erbb et btk

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KR102383200B1 (ko) * 2019-10-18 2022-04-06 한국화학연구원 피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
KR102467444B1 (ko) * 2019-11-11 2022-11-15 서울대학교산학협력단 이소-엑시구아민 A(iso-exiguamine A) 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 IDO-1 관련 질환의 예방 또는 치료용 약학적 조성물
TW202227425A (zh) * 2020-09-18 2022-07-16 南韓商沃若諾伊生物公司 雜芳基衍生物、彼之製法、及包含彼作為活性成份之藥學組成物
WO2023014022A1 (fr) * 2021-08-05 2023-02-09 한국화학연구원 Dérivé de pyrimidine, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter le cancer le comprenant en tant que principe actif

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