JP2019510822A - Cdk阻害剤としてのヘテロ環置換ピリジノピリミジノン誘導体およびその用途 - Google Patents
Cdk阻害剤としてのヘテロ環置換ピリジノピリミジノン誘導体およびその用途 Download PDFInfo
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- JP2019510822A JP2019510822A JP2019502134A JP2019502134A JP2019510822A JP 2019510822 A JP2019510822 A JP 2019510822A JP 2019502134 A JP2019502134 A JP 2019502134A JP 2019502134 A JP2019502134 A JP 2019502134A JP 2019510822 A JP2019510822 A JP 2019510822A
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- pyrimidine
- methyl
- cyclopentyl
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- 108090000848 Ubiquitin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000005053 lamin Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- KOKFKKDTWBKYTQ-UHFFFAOYSA-N methyl 1-bromocyclobutane-1-carboxylate Chemical compound COC(=O)C1(Br)CCC1 KOKFKKDTWBKYTQ-UHFFFAOYSA-N 0.000 description 1
- BPVHRCYHCSMZCD-UHFFFAOYSA-N methyl 1-bromocycloheptane-1-carboxylate Chemical compound COC(=O)C1(Br)CCCCCC1 BPVHRCYHCSMZCD-UHFFFAOYSA-N 0.000 description 1
- RNWRVPVPLQMTAP-UHFFFAOYSA-N methyl 1-bromocyclohexane-1-carboxylate Chemical compound COC(=O)C1(Br)CCCCC1 RNWRVPVPLQMTAP-UHFFFAOYSA-N 0.000 description 1
- YGWINKVROAENAL-UHFFFAOYSA-N methyl 1-bromocyclopentane-1-carboxylate Chemical compound COC(=O)C1(Br)CCCC1 YGWINKVROAENAL-UHFFFAOYSA-N 0.000 description 1
- RESWQIUWQHUEAW-UHFFFAOYSA-N methyl 1-bromocyclopropane-1-carboxylate Chemical compound COC(=O)C1(Br)CC1 RESWQIUWQHUEAW-UHFFFAOYSA-N 0.000 description 1
- IOBCLXSGWMFVQJ-UHFFFAOYSA-N methyl 2-bromo-2,2-difluoroacetate Chemical compound COC(=O)C(F)(F)Br IOBCLXSGWMFVQJ-UHFFFAOYSA-N 0.000 description 1
- ARPGZMIRSBUKBU-UHFFFAOYSA-N methyl 2-bromo-2-cyanoacetate Chemical compound COC(=O)C(Br)C#N ARPGZMIRSBUKBU-UHFFFAOYSA-N 0.000 description 1
- FVRCRECNPNQSKL-UHFFFAOYSA-N methyl 2-bromo-2-cyclohexylacetate Chemical compound COC(=O)C(Br)C1CCCCC1 FVRCRECNPNQSKL-UHFFFAOYSA-N 0.000 description 1
- LELJHXRBCOPSRN-UHFFFAOYSA-N methyl 2-bromo-2-cyclopentylacetate Chemical compound COC(=O)C(Br)C1CCCC1 LELJHXRBCOPSRN-UHFFFAOYSA-N 0.000 description 1
- PNUIIPDSXRMQKT-UHFFFAOYSA-N methyl 2-bromo-2-cyclopropylacetate Chemical compound COC(=O)C(Br)C1CC1 PNUIIPDSXRMQKT-UHFFFAOYSA-N 0.000 description 1
- MRSREVPILUWLKS-UHFFFAOYSA-N methyl 2-bromo-2-methylbutanoate Chemical compound CCC(C)(Br)C(=O)OC MRSREVPILUWLKS-UHFFFAOYSA-N 0.000 description 1
- BFNLYVZMYOKODI-UHFFFAOYSA-N methyl 2-bromo-3,3,3-trifluoropropanoate Chemical compound COC(=O)C(Br)C(F)(F)F BFNLYVZMYOKODI-UHFFFAOYSA-N 0.000 description 1
- CKDTYRDFEIGXNO-UHFFFAOYSA-N methyl 2-bromo-3-methylbutanoate Chemical compound COC(=O)C(Br)C(C)C CKDTYRDFEIGXNO-UHFFFAOYSA-N 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 108700042657 p16 Genes Proteins 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- GLQWRXYOTXRDNH-UHFFFAOYSA-N thiophen-2-amine Chemical compound NC1=CC=CS1 GLQWRXYOTXRDNH-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
R1は、水素、C1〜C3のアルキル基またはC3〜C7のシクロアルキル基を表す。
R2は、C1〜C5のアルキル基、C3〜C7のシクロアルキル基、5〜6員ヘテロアリール基、フェニル基または置換フェニル基を表す。
R3,R4は、水素、C1〜C3のアルキル基、C3〜C7のシクロアルキル基、アセチル基、ハロゲン、トリフルオロメチル基、シアノ基またはCONR5R6を表す。
あるいは、R3とR4と炭素原子によりC3-C7の脂肪族環が形成される。
R5,R6は、それぞれ水素、メチル基を表す。
Xは、OまたはSを表す。
nは、0または1である。
I6とアミン(I7)を触媒反応させて目的生成物Iを得る。
化合物(I-1)6,6-ジメチル-8-イソプロピル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-2)6,6-ジメチル-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-3)6,6-ジメチル-8-シクロペンチル-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-4)8'-シクロペンチル-2'-(5-(1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロプロピル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-5)8'-シクロペンチル-2'-(5-(1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロブチル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-6)8'-シクロペンチル-2'-(5-(1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロペンチル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-7)8'-シクロペンチル-2'-(5-(1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロヘキシル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-8)8'-シクロペンチル-2'-(5-(1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロヘプチル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-9) 6-アセチル-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-10) 6-シアノ-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-11) 6-トリフルオロメチル-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-12)6,6-ジフルオロ-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-13) 6-シクロプロピル-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-14)6-シクロブチル-8-シクロペンチル-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-15)6-イソプロピル-8-メチル-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-16)6-メチル-6,8-二エチル-2-(5-(4-メチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-17)6-シクロペンチル-8-sec-ブチル-2-(5-(1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4] チアジン-7(8H)-オン
化合物(I-18)6-シクロヘキシル-8-tert-ペンチル-2-(5-(4-シクロプロピル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-19)6-シクロヘプチル-8-(3-メチル-2-ブチル) -2-(5-(4-n-プロピル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4] チアジン-7(8H)-オン
化合物(I-20)6,6-ジメチル-8-シクロペンチル-2-(5-(4-シクロブチル-1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-21)6,6-ジメチル-8-シクロペンチル-2-(5-(4-シクロペンチル-1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-22)6,6-ジメチル-8-シクロペンチル-2-(5-(4-シクロヘキシル-1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-23)6,6-ジメチル-8-シクロペンチル-2-(5-(4-シクロヘプチル-1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]チアジン-7(8H)-オン
化合物(I-24)6,6-ジメチル-8-シクロペンチル-2-(5-(4-イソプロピル-1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]チアジン-7(8H)-オン
化合物(I-25)8'-シクロペンチル-2'-(5-(4-エチル-1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロプロピル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-26)6-アセチル-8-シクロペンチル-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-27)6-シアノ-8-シクロペンチル-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-28)8'-シクロペンチル-2'-(5-(4-エチル-1-ピペラジニル)-ピリジン-2-アミノ)スピロ[シクロブチル-1,6'-ピリミジン[5,4-b][1,4]オキサジン]-7'(8'H)-オン
化合物(I-29)6,6-ジメチル-8-(2-チエニル)-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-30)6,6-ジメチル-8-(2-ピリジニル)-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-31)6,6-ジメチル-8-(2-ピリミジン)-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-32)6,6-ジメチル-8-(2-ブラニル)-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-33) N,N-ジメチル-6-ホルムアミド-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-34) 6-ホルムアミド-8-シクロペンチル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-35)6,6-ジメチル-8-フェニル-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-36)6,6-ジメチル-8-(4-クロロフェニル)-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-37)6,6-ジメチル-8-(3-ペンチル)-2-(5-(1-ピペラジニル)-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
化合物(I-38)6,6-ジメチル-8-(3-ペンチル)-2-(5-(4-エチル-1-ピペラジニル)メチル-ピリジン-2-アミノ)-6H-ピリミジン[5,4-b][1,4]オキサジン-7(8H)-オン
生物学的試験
Claims (7)
- 次の一般式(I)で示される化合物またはその薬学的に許容される塩を有することを特徴とするヘテロ環置換ピリジノピリミジノン誘導体。
R1は、水素、C1〜C3のアルキル基またはC3〜C7のシクロアルキル基を表す。
R2は、C1〜C5のアルキル基またはC3〜C7のシクロアルキル基を表す。
R3,R4は、水素、C1〜C3のアルキル基、C3〜C7のシクロアルキル基、アセチル基、ハロゲン、トリフルオロメチル基、シアノ基またはCONR5R6を表す。
あるいは、R3とR4と炭素原子によりC3-C7の脂肪族環が形成される。
R5,R6は、それぞれ水素、メチル基を表す。
Xは、OまたはSを表す。
nは、0または1である。 - 前記C1〜C3のアルキル基が、メチル基、エチル基、n-プロピル基またはイソプロピル基であり、前記C1〜C5のアルキル基が、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、1-ペンチル基、2-ペンチル基、3-ペンチル基、2-メチル-3-ブチル基、1,1-ジメチル-1-プロピル基または2,2-ジメチル-1-プロピル基であることを特徴とする請求項1に記載のヘテロ環置換ピリジノピリミジノン誘導体。
- 前記C3〜C7シクロアルキル基が、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基またはシクロヘプチル基であり、前記ハロゲンは、F、Cl、BrまたはIであることを特徴とする請求項1に記載のヘテロ環置換ピリジノピリミジノン誘導体。
- 請求項1〜4のいずれかに記載のヘテロ環置換ピリジノピリミジノン誘導体およびその薬学的に許容される塩をCDK4/6阻害剤とし、CDK4/6に関連する疾患の予防または治療に用いる用途。
- 主にCDK4/6に関連する癌をいう請求項5に記載の疾患治療用途。
- 治療有効量の請求項1〜4のいずれかに記載のヘテロ環置換ピリジノピリミジノン誘導体と、薬学的に許容される担体または賦形剤とを含むことを特徴とする医薬品組成物。
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