JP7427098B2 - タンパク質キナ-ゼ阻害活性を有する7-アミノ-3,4-ジヒドロピリミドピリミジン-2-オン誘導体およびこれを含む治療用薬学組成物 - Google Patents
タンパク質キナ-ゼ阻害活性を有する7-アミノ-3,4-ジヒドロピリミドピリミジン-2-オン誘導体およびこれを含む治療用薬学組成物 Download PDFInfo
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- JP7427098B2 JP7427098B2 JP2022543570A JP2022543570A JP7427098B2 JP 7427098 B2 JP7427098 B2 JP 7427098B2 JP 2022543570 A JP2022543570 A JP 2022543570A JP 2022543570 A JP2022543570 A JP 2022543570A JP 7427098 B2 JP7427098 B2 JP 7427098B2
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- methyl
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- pyrimidin
- amino
- imidazol
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 41
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- 108060006633 protein kinase Proteins 0.000 title description 15
- 230000002401 inhibitory effect Effects 0.000 title description 14
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- 206010028980 Neoplasm Diseases 0.000 claims description 57
- 201000011510 cancer Diseases 0.000 claims description 52
- -1 6-methylpyridin-3-yl Chemical group 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 28
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000004122 cyclic group Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
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- 229920006395 saturated elastomer Polymers 0.000 claims description 20
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- 239000004480 active ingredient Substances 0.000 claims description 18
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- 238000011282 treatment Methods 0.000 claims description 15
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- 125000005842 heteroatom Chemical group 0.000 claims description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 5
- 150000003852 triazoles Chemical group 0.000 claims description 5
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
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- 229940035436 maltitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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- SZNYUUZOQHNEKB-UHFFFAOYSA-N n-[4-methyl-3-[1-methyl-7-[(6-methylpyridin-3-yl)amino]-2-oxo-4h-pyrimido[4,5-d]pyrimidin-3-yl]phenyl]-3-(trifluoromethyl)benzamide Chemical compound N1=C2N(C)C(=O)N(C=3C(=CC=C(NC(=O)C=4C=C(C=CC=4)C(F)(F)F)C=3)C)CC2=CN=C1NC1=CC=C(C)N=C1 SZNYUUZOQHNEKB-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000008662 sclerosing adenosis of breast Diseases 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229940034727 zelboraf Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
R1は、または水素;C1-C13アルキル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;-C(O)-(C1-C13アルキル);またはR1は、R2と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R2は、水素;C1-C13アルキル基;C3-C10シクリル基;C3-C10ヘテロシクリル基であるか;またはR2は、R1と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R3は、水素;C1-C13アルキル基;C3-C10シクリル基;またはC3-C10ヘテロシクリル基であり;
R4は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;C1-C6アルケニル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;または-C(O)-(C1-C13アルキル)であり;
Aは、C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;またはC3-C10ヘテロシクリル基であり;
nは、0~3の整数であり;
nが1以上の場合、Xは、それぞれ独立して、-CH2-、-CR5R6-、-O-、-OC(O)-、-C(O)O-、-OS(O)2-、-S(O)2O-、-NR6-、-NR6CH2-、-NR6C(O)-、-C(O)NR6-、-NR6C(O)NR6-、-S(O)2-、-NR6S(O)2-、-S(O)2NR6-からなる群より選択され、
Bは、C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;またはC3-C10ヘテロシクリル基であり;
前記C1-C6アルキル基、C1-C13アルキル基またはC3-C10シクリル基は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基またはC3-C10ヘテロシクリル基は、水素;ヒドロキシ基;ハロゲン基;カルボニル基(-(C=O)R5R6);ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルキル基;ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルコキシ基;C6-C10フェノキシ;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記R5およびR6は、それぞれ独立して、水素;C1-C6アルキル基;C1-C6アルケニル基;C1-C6アルキニル基;C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;またはR5は、R6と連結された窒素または炭素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、水素、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい3~7員(membered)飽和環を形成し、
前記C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基は、N、O、およびSからなる群より選択された1種以上のヘテロ原子を含む。
本発明者らは、上記の問題点を解決するために研究を継続した結果、癌細胞に対する優れた阻害活性を示す抗癌化合物、特に、選択的なキナ-ゼ活性抑制剤として癌の予防または治療に有用な7-アミノ-3,4-ジヒドロピリミドピリミジン-2-オン誘導体化合物、その薬学的に許容可能な塩、その水和物およびその立体異性体、またはその製造方法およびこれを有効成分として含む癌の予防または治療用薬学組成物を開発した。
R1は、または水素;C1-C13アルキル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;-C(O)-(C1-C13アルキル);またはR1は、R2と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R2は、水素;C1-C13アルキル基;C3-C10シクリル基;C3-C10ヘテロシクリル基であるか;またはR2は、R1と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R3は、水素;C1-C13アルキル基;C3-C10シクリル基;またはC3-C10ヘテロシクリル基であり;
R4は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;C1-C6アルケニル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;または-C(O)-(C1-C13アルキル)であり;
Aは、C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;またはC3-C10ヘテロシクリル基であり;
nは、0~3の整数であり;
nが1以上の場合、Xは、それぞれ独立して、-CH2-、-CR5R6-、-O-、-OC(O)-、-C(O)O-、-OS(O)2-、-S(O)2O-、-NR6-、-NR6CH2-、-NR6C(O)-、-C(O)NR6-、-NR6C(O)NR6-、-S(O)2-、-NR6S(O)2-、-S(O)2NR6-からなる群より選択され、
Bは、C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;またはC3-C10ヘテロシクリル基であり;
前記C1-C6アルキル基、C1-C13アルキル基またはC3-C10シクリル基は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基またはC3-C10ヘテロシクリル基は、水素;ヒドロキシ基;ハロゲン基;カルボニル基(-(C=O)R5R6);ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルキル基;ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルコキシ基;C6-C10フェノキシ;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記R5およびR6は、それぞれ独立して、水素;C1-C6アルキル基;C1-C6アルケニル基;C1-C6アルキニル基;C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;またはR5は、R6と連結された窒素または炭素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、水素、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい3~7員(membered)飽和環を形成し、
前記C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基は、N、O、およびSからなる群より選択された1種以上のヘテロ原子を含む。
N-イソヘキシル、-N,N-ジヘキシルを含むが、これに限定されない。
本発明の一側面において、前記化合物は、下記の化合物番号1~65からなる群より選択されるいずれか1つであることを特徴とする、化学式1で表される7-アミノ-3,4-ジヒドロピリミドピリミジン-2-オン誘導体化合物、その薬学的に許容可能な塩、その水和物およびその立体異性体から選択された化合物を提供する:
(化合物番号1)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((1-メチル-1H-ピラゾ-ル-4-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号2)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号3)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号4)
7-((1-(1-エチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号5)
7-((6-(1-エチルピペリジン-4-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号6)
7-((6-(4-アセチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号7)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号8)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号9)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号10)
7-((1-(1-エチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号11)
7-(シクロプロピルアミン)-3-(5-(5-(2,3-ジフロロフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号12)
3-(5-(5-(2,3-ジフロロフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号13)
1-メチル-3-(2-メチル-5-(5-(3-(トリフロロメチル)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号14)
7-((6-(4-アセチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号15)
7-((6-(1-エチルピペリジン-4-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号16)
7-((6-(4-エチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号17)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号18)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((4-モルホリノフェニル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号19)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号20)
7-((4-メトキシベンジル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号21)
7-(ベンジルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号22)
7-(シクロプロピルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号23)
7-(シクロペンチルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号24)
7-(シクロヘキシルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号25)
7-(ブチルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号26)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号27)
7-アミノ-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号28)
7-((6-(4-エチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号29)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号30)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号31)
7-(ベンジルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号32)
7-((4-メトキシベンジル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号33)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号34)
7-(シクロプロピルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号35)
7-(ブチルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号36)
7-(シクロペンチルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号37)
7-(シクロヘキシルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号38)
7-アミノ-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号39)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号40)
3-(5-(5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号41)
3-(5-(5,6-ジブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号42)
1-メチル-3-(2-メチル-5-(7-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号43)
3-(5-(6-ブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号44)
3-(5-(6-クロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号45)
1-メチル-3-(2-メチル-5-(6-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号46)
3-(5-(5,6-ジクロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号47)
3-(5-(5,6-ジメチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号48)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号49)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号50)
7-(シクロプロピルアミノ)-1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号51)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号52)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号53)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号54)
3-(5-((1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号55)
3-(5-((6-ブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号56)
3-(5-((6-クロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号57)
1-メチル-3-(2-メチル-5-((6-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号58)
3-(5-((6-ジブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号59)
3-(5-((6-ジクロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号60)
3-(5-((5,6-ジメチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号61)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号62)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号63)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号64)
7-(シクロプロピルアミノ)-3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;および
(化合物番号65)
1-メチル-3-(2-メチル-5-((3-(3-(トリフロロメチル)フェニル)オキセタン-3-イル)アミノ)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン。
LCMS(ESI+, m/z) : 196.95 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 4.64 (s, 2H)
LCMS(ESI+, m/z) : 376.60 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.81 - 7.67 (m, 4H), 7.42 (dt, J = 13.5, 6.5 Hz, 6H), 7.04 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 6.3 Hz, 2H), 4.72 (s, 2H), 2.19 (s, 3H), 1.13 (s, 9H).
LCMS(ESI+, m/z) : 536.25 [M+H]+
1H NMR (400 MHz, CDCl3) : 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.63 (dt, J = 6.6, 1.6 Hz, 4H), 7.46 - 7.33 (m, 6H), 7.06 (d, J = 7.6 Hz, 1H), 6.65 (dd, J = 7.5, 1.5 Hz, 1H), 6.50 (d, J = 1.6 Hz, 1H), 4.67 (s, 2H), 4.49 (s, 2H), 2.23 (s, 3H), 1.00 (s, 9H).
LCMS(ESI+, m/z) : 531.45 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.76 - 7.65 (m, 4H), 7.49 - 7.33 (m, 6H), 7.08 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.9 Hz, 2H), 6.16 (d, J = 5.4 Hz, 1H), 4.75 (s, 2H), 4.08 (s, 2H), 3.03 (d, J = 4.9 Hz, 3H), 2.14 (s, 3H), 1.10 (s, 9H).
LCMS(ESI+, m/z) : 557.20 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 1.2 Hz, 1H), 7.67 (ddt, J = 5.7, 4.0, 1.6 Hz, 4H), 7.48 - 7.32 (m, 6H), 7.26 (d, J = 1.1 Hz, 2H), 7.15 (s, 1H), 4.75 (s, 2H), 4.69 (dd, J = 14.9, 1.2 Hz, 1H), 4.50 (dd, J = 14.9, 1.0 Hz, 1H), 3.46 (s, 3H), 2.21 (s, 3H), 1.09 (s, 9H).
LCMS(ESI+, m/z) : 319.05 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.23 - 7.12 (m, 3H), 4.67 (d, J = 14.7 Hz, 1H), 4.47 (d, J = 14.7 Hz, 1H), 4.50 (s, 2H), 4.08 (d, J = 4.9 Hz, 1H), 3.35 (s, 3H), 2.15 (s, 3H).
LCMS(ESI+, m/z) : 317.0 [M+H]+
1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.14 (s, 1H), 7.79 (dd, J = 4.1, 2.4 Hz, 2H), 7.49 (d, J = 8.2 Hz, 1H), 4.86 (d, J = 14.7 Hz, 1H), 4.58 (d, J = 14.7 Hz, 1H), 3.46 (s, 3H), 2.32 (s, 3H).
LCMS(ESI+, m/z) : 165.15 [M+H]+
LCMS(ESI+, m/z) : 461.10 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.27 (s, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.28 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 7.03 (td, J = 7.5, 1.1 Hz, 1H), 4.95 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 15.0 Hz, 1H), 3.97 (s, 3H), 3.45 (s, 3H), 2.30 (s, 3H).
LCMS(ESI+, m/z) : 522.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 7.94 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 4.3 Hz, 3H), 7.67 (dd, J = 7.7, 1.7 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.39 (ddd, J = 8.8, 7.4, 1.7 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.70 (d, J = 14.2 Hz, 2H), 4.54 (d, J = 14.2 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 3.40 (s, 3H), 2.27 (s, 3H).
LCMS(ESI+, m/z) : 547.25 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.84 (d, J = 8.7 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.92 - 7.88 (m, 2H), 7.76 (dd, J = 7.7, 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (ddd, J = 8.7, 7.4, 1.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.12 (td, J = 7.6, 1.0 Hz, 1H), 4.86 (d, J = 14.1 Hz, 2H), 4.66 (d, J = 14.1 Hz, 2H), 3.99 (s, 3H), 3.40 (s, 3H), 2.73 (s, 3H), 2.73 (s, 3H), 2.36 (s, 3H).
LCMS(ESI+, m/z) : 533.05 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.45 (t, J = 1.8 Hz, 1H), 8.46 (dt, J = 8.8, 1.8 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.78 (dd, J = 8.6, 2.8 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.628 Hz, 1H), 4.87 (d, J = 14.2 Hz, 2H), 4.71 (d, J = 14.2 Hz, 2H), 4.00 (s, 3H), 3.50 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H).
LCMS(ESI+, m/z) : 673.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 8.03 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.93 - 7.89 (m, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.49 (ddd, J = 8.8, 7.4, 1.7 Hz, 1H), 7.22 (dd, J = 8.5, 1.0 Hz, 1H), 7.13 (td, J = 7.6, 1.0 Hz, 1H), 4.82 (d, J = 14.2 Hz, 2H ), 4.64 (d, J = 14.2 Hz, 2H), 4.54 (tt, J = 10.6, 4.6 Hz, 1H), 4.00 (s, 3H), 3.75 (d, J = 12.7 Hz, 2H), 3.50 (s, 3H), 3.25 (q, J = 7.3 Hz, 2H), 3.22 - 3.12 (m, 2H), 2.37 (s, 3H), 2.42-2.26 (m, 4H), 1.39 (t, J = 7.3 Hz, 3H).
LCMS(ESI+, m/z) : 630.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.25 (d, J = 2.6 Hz, 1H), 8.39 (dd, J = 8.7, 2.6 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.93 - 7.89 (m, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.63 (dd, J = 8.5, 6.3 Hz, 2H), 7.49 (ddd, J = 8.8, 7.4, 1.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.12 (td, J = 7.6, 1.0 Hz, 1H), 4.89 (d, J = 14.2 Hz, 2H), 4.68 (d, J = 14.2 Hz, 2H), 4.00 (s, 3H), 3.79 - 3.70 (m, 2H), 3.49 (s, 3H), 3.29 - 3.20 (m, 3H), 3.14 (td, J = 12.8, 2.9 Hz, 2H), 2.37 (s, 3H), 2.33 - 2.23 (m, 2H), 2.15 (tt, J = 13.1, 6.7 Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H).
LCMS(ESI+, m/z) : 645.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.79 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H), 8.13 (dd, J = 9.6, 2.7 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 6.5 Hz, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.49 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H), 7.33 (d, J = 9.7 Hz, 1H), 7.22 (dd, J = 8.4, 1.0 Hz, 1H), 7.13 (td, J = 7.6, 1.0 Hz, 1H), 4.90 (d, J = 14.1 Hz, 2H), 4.67 (d, J = 14.1 Hz, 2H), 4.00 (s, 3H), 3.79 (dd, J = 6.5, 3.8 Hz, 4H), 3.74 (dd, J = 7.1, 4.0 Hz, 2H), 3.67 (dd, J = 6.7, 4.2 Hz, 2H), 3.48 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H).
LCMS(ESI+, m/z) : 633.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.06 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.8 Hz, 2H), 7.76 (dd, J = 7.8, 1.7 Hz, 1H), 7.67 (s, 1H), 7.65 (s, 1H), 7.50 (ddd, J = 8.9, 7.5, 1.7 Hz, 1H), 7.22 (dd, J = 8.6, 1.0 Hz, 1H), 7.13 (td, J = 7.6, 1.0 Hz, 1H), 4.85 (d, J = 14.0 Hz, 2H), 4.64 (d, J = 14.0 Hz, 2H), 4.51 - 4.38 (m, 1H), 4.07 (d, J = 14.3 Hz, 2H), 4.00 (s, 3H), 3.49 (s, 3H), 2.92 - 2.77 (m, 2H), 2.38 (s, 3H), 2.16 (s, 3H), 1.97 (dtd, J = 41.7, 11.8, 4.4 Hz, 4H).
LCMS(ESI+, m/z) : 601.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 8.7 Hz, 1H), 8.14 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 7.5, 1.9 Hz, 1H), 7.90 (dd, J = 8.0, 2.0 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.59 - 7.50 (m, 3H), 4.87 (d, J = 14.3 Hz, 2H), 4.66 (d, J = 14.3 Hz, 2H), 3.41 (s, 3H), 2.74 (s, 3H), 2.73 (s, 3H), 2.35 (s, 3H).
LCMS(ESI+, m/z) : 587.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.48 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 8.9, 2.6 Hz, 1H), 8.26 (s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.86 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.62 (dd, J = 7.3, 2.1 Hz, 1H), 7.59 - 7.52 (m, 2H), 4.91 (d, J = 14.3 Hz, 2H), 4.71 (d, J = 14.3 Hz, 2H), 3.50 (s, 3H), 2.73 (s, 3H), 2.37 (s, 3H).
LCMS(ESI+, m/z) : 673.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 7.97 (d, J = 1.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.82 (ddd, J = 12.5, 7.8, 1.9 Hz, 2H), 7.70 (s, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.50 - 7.40 (m, 3H), 4.76 (d, J = 13.9 Hz, 2H), 4.53 (d, J = 13.9 Hz, 2H), 4.48 - 4.37 (m, 1H), 3.65 (d, J = 12.6 Hz, 2H), 3.39 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 3.12 - 3.01 (m, 2H), 2.30 (d, J = 13.9 Hz, 2H), 2.26 (s, 3H), 2.18 (d, J = 15.1 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H).
LCMS(ESI+, m/z) : 488.10 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.08 - 7.98 (m, 2H), 7.94 (tt, J = 3.5, 2.1 Hz, 2H), 7.73 (ddd, J = 9.5, 4.7, 1.9 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.47 - 7.28 (m, 2H), 4.82 (d, J = 14.7 Hz, 2H), 4.66 (d, J = 14.7 Hz, 2H), 3.52 (m, 1H), 3.47 (s, 3H), 2.37 (s, 3H), 1.00 (m, 2H), 0.82 - 0.69 (m, 2H).
LCMS(ESI+, m/z) : 539.30 [M+H]+
1H NMR (400 MHz, MeOD) δ 8.79 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H), 8.13 (dd, J = 9.6, 2.7 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 6.5 Hz, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.49 (ddd, J = 8.8, 7.4, 1.6 Hz, 1H), 7.33 (d, J = 9.7 Hz, 1H), 7.22 (dd, J = 8.4, 1.0 Hz, 1H), 7.13 (td, J = 7.6, 1.0 Hz, 1H), 4.90 (d, J = 14.1 Hz, 2H), 4.67 (d, J = 14.1 Hz, 2H), 4.00 (s, 3H), 3.79 (dd, J = 6.5, 3.8 Hz, 4H), 3.74 (dd, J = 7.1, 4.0 Hz, 2H), 3.67 (dd, J = 6.7, 4.2 Hz, 2H), 3.48 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H).
LCMS(ESI+, m/z) : 571.20 [M+H]+
LCMS(ESI+, m/z) : 699.20 [M+H]+
LCMS(ESI+, m/z) : 684.20 [M+H]+
LCMS(ESI+, m/z) : 685.20 [M+H]+
LCMS(ESI+, m/z) : 687.20 [M+H]+
LCMS(ESI+, m/z) : 657.20 [M+H]+
LCMS(ESI+, m/z) : 572.20 [M+H]+
LCMS(ESI+, m/z) : 616.15 [M+H]+
LCMS(ESI+, m/z) : 586.15 [M+H]+
LCMS(ESI+, m/z) : 536.15 [M+H]+
LCMS(ESI+, m/z) : 564.15 [M+H]+
LCMS(ESI+, m/z) : 578.20 [M+H]+
LCMS(ESI+, m/z) : 552.20 [M+H]+
LCMS(ESI+, m/z) : 510.15 [M+H]+
LCMS(ESI+, m/z) : 496.10 [M+H]+
LCMS(ESI+, m/z) : 631.30 [M+H]+
LCMS(ESI+, m/z) : 633.30 [M+H]+
LCMS(ESI+, m/z) : 518.20 [M+H]+
LCMS(ESI+, m/z) : 532.20 [M+H]+
LCMS(ESI+, m/z) : 562.25 [M+H]+
LCMS(ESI+, m/z) : 456.15 [M+H]+
LCMS(ESI+, m/z) : 482.20 [M+H]+
LCMS(ESI+, m/z) : 498.25 [M+H]+
LCMS(ESI+, m/z) : 510.25 [M+H]+
LCMS(ESI+, m/z) : 510.25 [M+H]+
LCMS(ESI+, m/z) : 442.10 [M+H]+
LCMS(ESI+, m/z) : 629.30 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 8.4, 2.7 Hz, 1H), 7.97 (s, 1H), 7.68 (ddd, J = 8.0, 3.3, 1.6 Hz, 5H), 7.40 (dddd, J = 18.0, 10.3, 5.6, 1.8 Hz, 7H), 7.18 - 7.09 (m, 2H), 4.75 (s, 2H), 4.63 (d, J = 14.0 Hz, 1H), 4.42 (d, J = 14.0 Hz, 1H), 3.44 (s, 3H), 2.53 (s, 3H), 2.22 (s, 3H), 1.09 (s, 9H).
LCMS(ESI+, m/z) : 391.20 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 3.7 Hz, 2H), 8.01 (dd, J = 8.4, 2.7 Hz, 1H), 7.97 (s, 1H), 7.29 (d, J = 6.7 Hz, 2H), 7.21 - 7.11 (m, 2H), 4.67 (d, J = 15.2 Hz, 3H), 4.47 (d, J = 14.0 Hz, 1H), 3.45 (s, 3H), 2.54 (s, 3H), 2.24 (s, 3H).
LCMS(ESI+, m/z) : 389.15 [M+H]+
LCMS(ESI+, m/z) : 545.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.49 (d, J = 2.5 Hz, 1H), 8.48 (dd, J = 8.7, 2.5 Hz, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 8.08 - 8.01 (m, 1H), 7.97 (s, 1H), 7.85 - 7.78 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 4.93 (d, J = 14.3 Hz, 1H), 4.70 (d, J = 14.3 Hz, 1H), 3.49 (s, 3H), 2.72 (s, 3H), 2.36 (s, 3H).
LCMS(ESI+, m/z) : 513.20 [M+H]+
LCMS(ESI+, m/z) : 633.00 [M+H]+
LCMS(ESI+, m/z) : 491.25 [M+H]+
LCMS(ESI+, m/z) : 555.10 [M+H]+
LCMS(ESI+, m/z) : 511.20 [M+H]+
LCMS(ESI+, m/z) : 491.25 [M+H]+
LCMS(ESI+, m/z) : 491.25 [M+H]+
LCMS(ESI+, m/z) : 505.25 [M+H]+
LCMS(ESI+, m/z) : 530.20 [M+H]+
LCMS(ESI+, m/z) : 468.20 [M+H]+
LCMS(ESI+, m/z) : 494.20 [M+H]+
LCMS(ESI+, m/z) : 559.20 [M+H]+
LCMS(ESI+, m/z) : 405.20 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz), 8.15-8.12 (m, 2H), 8.05 (dd, J = 8.3 Hz, J = 2.8 Hz, 1H), 7.62(d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 4.89 (d, J = 13.5 Hz, 1H), 4.50 (d, J = 13.5 Hz, 1H), 3.34 (s, 3H), 2.40 (s, 3H), 2.29 (s,3H).
LCMS(ESI+, m/z) : 376.20 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.79 (s, 1H), 8.12 (s, 1H), 8.04 (dd, J = 2.8 Hz, J = 8.4 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.47 (m, 2H), 4.97 (s, 2H), 4.59 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 3.31 (s, 3H), 2.40 (s, 3H), 1.95 (s, 3H)
LCMS(ESI+, m/z) : 203.05 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 11.03 (2H, s), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (1 H, s), 7.09 (d, J = 8.3 Hz, 1H)
LCMS(ESI+, m/z) : 221.0 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.87 (1H, s), 7.69 (1H, d), 7.57 (1H, dd)
LCMS(ESI+, m/z) : 560.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.48 (d, J = 2.5 Hz, 1H), 8.48 (dd, J = 8.9, 2.5 Hz, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.66 - 7.52 (m, 4H), 7.43 (dd, J = 8.2, 2.3 Hz, 1H), 4.83 (d, J = 14.3 Hz, 1H), 4.66 (d, J = 14.3 Hz, 1H), 3.49 (s, 3H), 2.73 (s, 3H), 2.32 (s, 3H).
LCMS(ESI+, m/z) : 528.20 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.48 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 8.9, 2.6 Hz, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.38 (dt, J = 13.1, 5.2 Hz, 3H), 6.96 (t, J = 8.6 Hz, 1H), 4.82 (d, J = 14.3 Hz, 1H), 4.66 (d, J = 14.3 Hz, 1H), 3.49 (s, 3H), 2.73 (s, 3H), 2.31 (s, 3H).
LCMS(ESI+, m/z) : 492.22 [M+H]+
LCMS(ESI+, m/z) : 570.15 [M+H]+
LCMS(ESI+, m/z) : 526.20 [M+H]+
LCMS(ESI+, m/z) : 506.25 [M+H]+
LCMS(ESI+, m/z) : 648.05 [M+H]+
LCMS(ESI+, m/z) : 560.15 [M+H]+
LCMS(ESI+, m/z) : 520.25 [M+H]+
LCMS(ESI+, m/z) : 520.20 [M+H]+
LCMS(ESI+, m/z) : 542.25 [M+H]+
LCMS(ESI+, m/z) : 451.20 [M+H]+
LCMS(ESI+, m/z) : 477.20 [M+H]+
LCMS(ESI+, m/z) : 228.10 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.08 (d, J = 5.0 Hz, 3H), 2.54 (d, J = 1.0 Hz, 3H), 1.45 - 1.20 (m, 3H).
LCMS(ESI+, m/z) : 186.0 [M+H]+
1H NMR (400 MHz, DMSO) δ 7.82 (s, 1H), 6.83 (d, J = 4.9 Hz, 1H), 5.07 (s, 1H), 4.29 (d, J = 4.3 Hz, 2H), 2.85 (d, J = 4.6 Hz, 3H), 2.42 (s, 3H).
LCMS(ESI+, m/z) : 184.10 [M+H]+
1H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 3.11 (d, J = 5.0 Hz, 3H), 2.56 (s, 3H).
LCMS(ESI+, m/z) : 353.10 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.00 - 6.84 (m, 3H), 5.60 (d, J = 6.8 Hz, 1H), 4.06 (d, J = 5.0 Hz, 2H), 3.34 (d, J = 5.5 Hz, 1H), 3.03 (d, J = 4.8 Hz, 3H), 2.55 (s, 3H), 2.06 (s, 3H).
LCMS(ESI+, m/z) : 379.0 [M+H]+
1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 1.1 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 4.70 (dd, J = 14.3, 1.1 Hz, 1H), 4.46 (d, J = 14.4 Hz, 1H), 3.45 (s, 3H), 2.58 (s, 3H), 2.17 (s, 3H).
LCMS(ESI+, m/z) : 322.10 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.70 - 7.51 (m, 4H), 5.21 (d, J = 7.1 Hz, 1H), 5.12 (d, J = 7.1 Hz, 1H), 5.04 (d, J = 6.9 Hz, 1H), 4.92 (d, J = 6.9 Hz, 1H), 4.15 (s, 1H), 1.22 (s, 9H).
LCMS(ESI+, m/z) : 218.10 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.87 - 7.76 (m, 2H), 7.62 - 7.50 (m, 2H), 4.95 (d, J = 6.5 Hz, 2H), 4.77 (d, J = 6.5 Hz, 2H).
LCMS(ESI+, m/z) : 516.20 [M+H]+
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 20.7 Hz, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 6.01 (dd, J = 8.3, 2.5 Hz, 1H), 5.02 - 4.83 (m, 4H), 4.55 - 4.46 (m, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.43 (s, 3H), 2.57 (s, 3H), 2.06 (s, 3H).
LCMS(ESI+, m/z) : 532.20 [M+H]+
LCMS(ESI+, m/z) : 576.25 [M+H]+
1H NMR (400 MHz, MeOD) δ 9.49 (d, J = 2.5 Hz, 1H), 8.46 (dd, J = 8.8, 2.6 Hz, 1H), 8.16 (s, 1H), 8.01 - 7.96 (m, 1H), 7.95 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 1H), 6.15 (dd, J = 8.3, 2.5 Hz, 1H), 5.03 - 4.94 (m, 4H), 4.59 (d, J = 14.4 Hz, 1H), 4.49 (d, J = 14.5 Hz, 1H), 3.43 (s, 3H), 2.72 (s, 3H), 2.05 (s, 3H).
実験例1.GCKおよびACK1キナ-ゼ抑制活性
本発明の化合物に対して、GCKおよびACK1の両キナ-ゼに対する阻害能を測定してIC50値を算出した。算出したIC50値は下記表1に示した。
本発明の化合物に対して、mt-NRAS(G12D)Ba/F3、OCI-AML3(mt-NRAS)細胞株における増殖抑制能を測定してGI50値を算出した。算出したGI50値は下記表2に示した。
一方、本発明による前記化学式1で表される新規化合物は、目的によって多様な形態に製剤化可能である。以下、本発明による前記化学式1で表される化合物を活性成分として含有させたいくつかの製剤化方法を例示したもので、本発明がこれに限定されるものではない。
活性成分5.0mgを篩にかけた後、ラクト-ス14.1mg、クロスポビドンUSNF0.8mgおよびマグネシウムステアレ-ト0.1mgを混合し、加圧して錠剤にした。
活性成分5.0mgを篩にかけた後、ラクト-ス16.0mgとデンプン4.0mgを混合した。ポリソルベ-ト80 0.3mgを純粋な水に溶かした後、この溶液の適量を添加した後、微粒化した。乾燥後に微粒を篩にかけた後、コルロイダルシリコンジオキシド2.7mgおよびマグネシウムステアレ-ト2.0mgと混合した。微粒を加圧して錠剤にした。
活性成分5.0mgを篩にかけた後に、ラクト-ス14.8mg、ポリビニルピロリドン10.0mg、マグネシウムステアレ-ト0.2mgと共に混合した。混合物を適当な装置を用いて硬いNo.5のゼラチンカプセルに満たした。
活性成分として100mgを含有させ、その他にも、マンニト-ル180mg、Na2HPO4・12H2O26mgおよび蒸留水2974mgを含有させて注射剤を製造した。
Claims (11)
- 下記化学式1で表される7-アミノ-3,4-ジヒドロピリミドピリミジン-2-オン誘導体化合物、その薬学的に許容可能な塩、その水和物およびその立体異性体から選択された化合物が有効成分として含まれている、癌の予防、軽減または治療用薬学組成物:
R1は、または水素;C1-C13アルキル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;-C(O)-(C1-C13アルキル);またはR1は、R2と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R2は、水素;C1-C13アルキル基;C3-C10シクリル基;C3-C10ヘテロシクリル基であるか;またはR2は、R1と連結された窒素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい4~7員(membered)飽和、不飽和または芳香族環を形成し;
R3は、水素;C1-C13アルキル基;C3-C10シクリル基;またはC3-C10ヘテロシクリル基であり;
R4は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;C1-C6アルケニル基;C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;または-C(O)-(C1-C13アルキル)であり;
Aは、C6-C10アリ-ル基;C3-C10シクリル基;C3-C10ヘテロアリ-ル基;またはC3-C10ヘテロシクリル基であり;
nは、0または1の整数であり;
nが1の場合、Xは、-NR6-であり、
Bは、C 3-C10ヘテロアリ-ル基であり;
前記C1-C6アルキル基、C1-C13アルキル基またはC3-C10シクリル基は、水素;ヒドロキシ基;ハロゲン基;C1-C13アルキル基;C1-C6アルコキシ基;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基またはC3-C10ヘテロシクリル基は、水素;ヒドロキシ基;ハロゲン基;カルボニル基(-(C=O)R5R6);ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルキル基;ハロゲンまたはC3-C10ヘテロシクリル基で置換もしくは非置換のC1-C3アルコキシ基;C6-C10フェノキシ;アミノ基(-NR5R6);ニトロ基(-N(O)2);アミド基(-(C=O)NR5R6);カルボン酸基(-C(O)OH);ニトリル基(-CN);ウレア基(-NR5(C=O)NR6-);スルホンアミド基(-NHS(O)2-);スルフィド基(-S-);スルホン基(-S(O)2-);ホスフィリル基(-P(O)R5R6);C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基からなる群より選択される1以上の置換基を含み、
前記R5およびR6は、それぞれ独立して、水素;C1-C6アルキル基;C1-C6アルケニル基;C1-C6アルキニル基;C6-C10アリ-ル基;C3-C10ヘテロアリ-ル基;C3-C10ヘテロシクリル基;またはR5は、R6と連結された窒素または炭素原子と共に、N、O、S、NH、C=N、C=O、-NHC(O)-、-NHC(O)NH-、-NHS(O)2-、またはSO2の少なくとも1種を任意に含むことができ、水素、C1-C13アルキル基、C6-C10アリ-ル基、C3-C10ヘテロアリ-ル基、ヒドロキシル基、ハライド基およびシアノ基の少なくとも1種で任意に置換されていてもよい3~7員(membered)飽和環を形成し、前記C3-C10ヘテロアリ-ル基およびC3-C10ヘテロシクリル基は、N、O、およびSからなる群より選択された1種以上のヘテロ原子を含む。 - 前記Bは、チアゾ-ル、チオフェン、ピラゾ-ル、ベンゾチオフェン、ピリダジン、ピラジン、イミダゾ-ル、オキサジアゾ-ル、トリアゾ-ル、フラン、ピリミジン、オキサゾ-ル、ピロ-ル、ピリジン、オキサジアゾ-ル、トリアジン、チアジアゾ-ル、イソキサゾ-ル、およびテトラゾ-ルからなる群より選択されたいずれか1つであり、前記Bは、置換もしくは非置換である、
請求項1に記載の薬学組成物。 - 前記R2は、水素であり、前記R3は、メチルであり、前記R4は、メチルである、
請求項1に記載の薬学組成物。 - 前記R1は、水素、C1-C6アルキル基、C3-C10シクリル基、ベンゼン、チアゾ-ル、チオフェン、ピラゾ-ル、ベンゾチオフェン、ピリダジン、ピラジン、イミダゾ-ル、オキサジアゾ-ル、トリアゾ-ル、フラン、ピリミジン、オキサゾ-ル、ピロ-ル、ピリジン、オキサジアゾ-ル、トリアジン、チアジアゾ-ル、イソキサゾ-ル、およびテトラゾ-ルからなる群より選択されたいずれか1つであり、前記R1は、置換もしくは非置換である、
請求項1に記載の薬学組成物。 - 前記化合物は、下記の化合物番号1~64からなる群より選択されるいずれか1つであることを特徴とする、請求項1に記載の薬学組成物:
(化合物番号1)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((1-メチル-1H-ピラゾ-ル-4-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号2)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号3)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号4)
7-((1-(1-エチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号5)
7-((6-(1-エチルピペリジン-4-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号6)
7-((6-(4-アセチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号7)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号8)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号9)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号10)
7-((1-(1-エチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号11)
7-(シクロプロピルアミン)-3-(5-(5-(2,3-ジフロロフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号12)
3-(5-(5-(2,3-ジフロロフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号13)
1-メチル-3-(2-メチル-5-(5-(3-(トリフロロメチル)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号14)
7-((6-(4-アセチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号15)
7-((6-(1-エチルピペリジン-4-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号16)
7-((6-(4-エチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号17)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号18)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-((4-モルホリノフェニル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号19)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号20)
7-((4-メトキシベンジル)アミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号21)
7-(ベンジルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号22)
7-(シクロプロピルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号23)
7-(シクロペンチルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号24)
7-(シクロヘキシルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号25)
7-(ブチルアミノ)-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号26)
1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号27)
7-アミノ-1-メチル-3-(2-メチル-5-(5-(2-(トリフロロメトキシ)フェニル)-1H-イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号28)
7-((6-(4-エチルピペラジン-1-イル)ピリジン-3-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号29)
7-((1-(1-アセチルピペリジン-4-イル)-1H-ピラゾ-ル-4-イル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号30)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号31)
7-(ベンジルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号32)
7-((4-メトキシベンジル)アミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号33)
3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号34)
7-(シクロプロピルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号35)
7-(ブチルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号36)
7-(シクロペンチルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号37)
7-(シクロヘキシルアミノ)-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号38)
7-アミノ-3-(5-(5-(2-メトキシフェニル)-1H-イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号39)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号40)
3-(5-(5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号41)
3-(5-(5,6-ジブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号42)
1-メチル-3-(2-メチル-5-(7-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号43)
3-(5-(6-ブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号44)
3-(5-(6-クロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号45)
1-メチル-3-(2-メチル-5-(6-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号46)
3-(5-(5,6-ジクロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号47)
3-(5-(5,6-ジメチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号48)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号49)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号50)
7-(シクロプロピルアミノ)-1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号51)
7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号52)
1-メチル-3-(2-メチル-5-(6-(トリフロロメチル)-1H-ベンゾ[d]イミダゾ-ル-2-イル)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号53)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号54)
3-(5-((1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号55)
3-(5-((6-ブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号56)
3-(5-((6-クロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号57)
1-メチル-3-(2-メチル-5-((6-メチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)フェニル)-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号58)
3-(5-((6-ジブロモ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号59)
3-(5-((6-ジクロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号60)
3-(5-((5,6-ジメチル-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-((6-メチルピリジン-3-イル)アミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号61)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-(フェニルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号62)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-7-((2,6-ジメチルピリジン-3-イル)アミノ)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;
(化合物番号63)
3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-7-(メチルアミノ)-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン;および
(化合物番号64)
7-(シクロプロピルアミノ)-3-(5-((5,6-ジフロロ-1H-ベンゾ[d]イミダゾ-ル-2-イル)アミノ)-2-メチルフェニル)-1-メチル-3,4-ジヒドロピリミド[4,5-d]ピリミジン-2(1H)-オン。 - 前記薬学的に許容可能な塩は、塩酸、臭化水素酸、硫酸、リン酸、硝酸、酢酸、グリコ-ル酸、乳酸、ピルビン酸、マロン酸、コハク酸、グルタル酸、フマル酸、リンゴ酸、マンデル酸、酒石酸、クエン酸、アスコルビン酸、パルミチン酸、マレイン酸、ヒドロキシマレイン酸、安息香酸、ヒドロキシ安息香酸、フェニル酢酸、ケイ皮酸、サリチル酸、メタンスルホン酸、ベンゼンスルホン酸およびトルエンスルホン酸から構成された群より選択される無機酸または有機酸の塩である、
請求項1に記載の薬学組成物。 - 前記癌がNRAS突然変異で誘発されることを特徴とする、請求項1に記載の薬学組成物。
- 前記薬学組成物は、NRAS突然変異を有する患者に適用される、請求項1に記載の薬学組成物。
- 前記癌は、黒色腫、大膓癌、肺癌、膀胱癌、甲状腺癌、多発性骨髄腫および血液癌からなる群より選択される1以上である、請求項1に記載の薬学組成物。
- 前記癌は、急性骨髄性白血病(AML)である、請求項1に記載の薬学組成物。
- 前記薬学組成物は、NRAS G12Dを保有した患者に投与されることを特徴とする、請求項1に記載の薬学組成物。
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KR10-2020-0005305 | 2020-01-15 | ||
PCT/KR2020/009258 WO2021145520A1 (ko) | 2020-01-15 | 2020-07-14 | 단백질 키나아제 저해 활성을 갖는 7-아미노-3,4-디히드로피리미도피리미딘-2-온 유도체 및 이를 포함하는 치료용 약학 조성물 |
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WO2021145520A1 (ko) | 2021-07-22 |
JP2023511096A (ja) | 2023-03-16 |
KR20210092358A (ko) | 2021-07-26 |
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