JP2019510821A - Cdk阻害剤としての2,4−二置換ピリミジン誘導体およびその用途 - Google Patents
Cdk阻害剤としての2,4−二置換ピリミジン誘導体およびその用途 Download PDFInfo
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- JP2019510821A JP2019510821A JP2019502133A JP2019502133A JP2019510821A JP 2019510821 A JP2019510821 A JP 2019510821A JP 2019502133 A JP2019502133 A JP 2019502133A JP 2019502133 A JP2019502133 A JP 2019502133A JP 2019510821 A JP2019510821 A JP 2019510821A
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- pyridin
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- amine
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- ZAHCXBQMKVCWDI-UHFFFAOYSA-N N1(CCNCC1)C=1C=CC(=NC=1)NC1=NC=C(C(=N1)C=1C=CC=2N(C=1)C(=NN=2)C(C)C)F Chemical compound N1(CCNCC1)C=1C=CC(=NC=1)NC1=NC=C(C(=N1)C=1C=CC=2N(C=1)C(=NN=2)C(C)C)F ZAHCXBQMKVCWDI-UHFFFAOYSA-N 0.000 description 1
- UTKNUPLTWVCBHU-UHFFFAOYSA-N OBO.CC(C)(O)C(C)(C)O Chemical compound OBO.CC(C)(O)C(C)(C)O UTKNUPLTWVCBHU-UHFFFAOYSA-N 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- NDQKGYXNMLOECO-UHFFFAOYSA-N acetic acid;potassium Chemical compound [K].CC(O)=O NDQKGYXNMLOECO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 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
- 150000001412 amines Chemical class 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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- LOXORFRCPXUORP-UHFFFAOYSA-N bromo-Cycloheptane Chemical compound BrC1CCCCCC1 LOXORFRCPXUORP-UHFFFAOYSA-N 0.000 description 1
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
- AQNQQHJNRPDOQV-UHFFFAOYSA-N bromocyclohexane Chemical compound BrC1CCCCC1 AQNQQHJNRPDOQV-UHFFFAOYSA-N 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 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
- 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
- 239000002875 cyclin dependent kinase inhibitor Substances 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
- 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
- 239000012467 final product 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
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000005053 lamin Anatomy 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
- 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
- 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
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 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
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229950003687 ribociclib Drugs 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/495—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
- A61K31/52—Purines, e.g. adenine
-
- 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
【化1】
Description
本発明のもう一つの目的は、この類の化合物を新型CDK4/6阻害剤とし、CDK4/6に関する疾患を予防または治療する医薬品を製造する用途を提供することであり、前記CDK4/6が関与する周期制御失調に起因する各種疾患とは、特に悪性腫瘍の治療をいい、乳癌、卵巣癌、前立腺癌、結腸癌、直腸癌、膵臓癌、肝癌、メラノーマ、胃癌および固形腫瘍等を含むが、これらに限定されない。
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、水素、ハロゲン、メチル基、メトキシ基またはトリフルオロメチル基を表す。
nは、0または1である。
A環は、
A環が
R3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。
R4,R5は、それぞれ水素、C1〜C3のアルキル基、C3〜C5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CONR7R8を表す。
R6は、水素またはハロゲンを表す。
R7,R8は、それぞれ水素、メチル基を表す。
Xは、CR6またはNである。
Y、Zは、CまたはNである。
化合物(I-1)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-2)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-3)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-3-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-4)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-3-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-5)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(2,3-ジメチル-2H-インダゾール-6-イル)ピリミジン-2-アミン
化合物(I-6)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(3-イソプロピル-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-7)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(3-イソプロピル-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-8)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(9-イソプロピル-8-メチル-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-9)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(9-イソプロピル-8-メチル-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-10)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(5-フルオロ-6-カルボン酸ジメチルアミド-7-イソプロピル-7H-ピロロ[2,3-d]ピリミジン-4-イル)ピリミジン-2-アミン
化合物(I-11)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(6-メチル-7-シクロペンチル-7H-ピロロ[2,3-d]ピリミジン-4-イル)ピリミジン-2-アミン
化合物(I-12)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(2-メチル-3-シクロペンチル-2H-7-アザインダゾール-6-イル)ピリミジン-2-アミン
化合物(I-13)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-3-カルバモイル-4-フルオロ-1H-インダゾール-5-イル)ピリミジン-2-アミン
化合物(I-14)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-2-カルボン酸ジメチルアミド-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-15)N-(5-(4-メチルピペラジン-1-メチル)-ピリジン-2-イル)-5-クロロ-4-(1-(3-ペンチル)-2-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-16)N-(5-(4-イソプロピルピペラジン-1-メチル)-ピリジン-2-イル)-4-(1,2-ジメチル-3-トリフルオロメチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-17)N-(5-(4-シクロプロピルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロプロピル-2-シアノ-3-イソプロピル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-18)N-(5-(4-シクロヘプチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロブチル-3-シクロプロピル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-19)N-(5-(4-シクロヘキシルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロヘキシル-3-シクロブチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-20)N-(5-(4-シクロペンチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロヘプチル-3-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-21)N-(5-(4-シクロブチルピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-シクロペンチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-22)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-2-カルボン酸ジメチルアミド-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-23)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-24)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-アセチル-1H-インドール-5-イル)ピリミジン-2-アミン
化合物(I-25)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-カルボン酸ジメチルアミド-1H-4-アザインドール-5-イル)ピリミジン-2-アミン
化合物(I-26)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-カルボン酸ジメチルアミド-1H-4-アザインドール-5-イル)ピリミジン-2-アミン
化合物(I-27)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-カルボン酸ジメチルアミド-1H-4-フルオロインドール-5-イル)ピリミジン-2-アミン
化合物(I-28)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-2-カルボン酸ジメチルアミド-1H-4-フルオロインドール-5-イル)ピリミジン-2-アミン
化合物(I-29)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(2-シクロプロピル-3-アセチル-2H-7-アザインダゾール-6-イル)ピリミジン-2-アミン
化合物(I-30)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(2-メチル-3-イソプロピル-2H-7-クロロ-インダゾール-6-イル)ピリミジン-2-アミン
化合物(I-31)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(2-メチル-3-カルボン酸ジメチルアミド-2H-7-フルオロ-インダゾール-6-イル)ピリミジン-2-アミン
化合物(I-32)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-アセチル-3-シクロプロピル-8-フルオロ-イミダゾ[1,5-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-33)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(3-トリフルオロメチル-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-34)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(3-シアノ-イミダゾ[1,2-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-35)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(3-アセチル-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-36)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(3-シクロプロピル-[1,2,4]トリアゾロ[4,3-a]ピリジン-6-イル)ピリミジン-2-アミン
化合物(I-37)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(9-シクロペンチル-8-カルボン酸ジメチルアミド-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-38)N-(5-(4-メチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(9-イソプロピル-8-アセチル-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-39)N-(5-(4-メチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(9-(3-ペンチル)-8-イソプロピル-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-40)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(9-メチル-8-カルボン酸ジメチルアミド-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-41)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(6-アセチル-7-シクロプロピル-7H-ピロロ[2,3-d]ピリミジン-4-イル)ピリミジン-2-アミン
化合物(I-42)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(5-シアノ-7-メチル-7H-ピロロ[2,3-d]ピリミジン-4-イル)ピリミジン-2-アミン
化合物(I-43)N-(5-(ピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-3-カルボン酸ジメチルアミド-1H-インダゾール-5-イル)ピリミジン-2-アミン
化合物(I-44)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-イソプロピル-3-アセチル-1H-インダゾール-5-イル)ピリミジン-2-アミン
化合物(I-45)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-3-メチル-4-フルオロ-1H-インダゾール-5-イル)ピリミジン-2-アミン
化合物(I-46)N-(5-(4-エチルピペラジン-1-メチル)-ピリジン-2-イル)-5-フルオロ-4-(1-シクロペンチル-3-トリフルオロメチル-4-アザ-1H-インダゾール-5-イル)ピリミジン-2-アミン
化合物(I-47)N-(5-(4-メチルピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(9-イソプロピル-8-メチル-9H-プリン-2-イル)ピリミジン-2-アミン
化合物(I-48)N-(5-(4-エチルピペラジン-1-イル)-ピリジン-2-イル)-5-フルオロ-4-(9-イソプロピル-8-メチル-9H-プリン-2-イル)ピリミジン-2-アミン
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2,4-二置換ピリミジン誘導体。
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、水素、ハロゲン、メチル基、メトキシ基またはトリフルオロメチル基を表す。
nは、0または1である。
A環は、
R4,R5は、それぞれ水素、C1〜C3のアルキル基、C3〜C5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CONR7R8を表す。
R6は、水素またはハロゲンを表す。
R7,R8は、それぞれ水素、メチル基を表す。
Xは、CR6またはNである。
Y、Zは、CまたはN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2,4-二置換ピリミジン誘導体。
- 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C3〜C5シクロアルキル基が、シクロプロピル基、シクロブチル基またはシクロペンチル基であり、前記ハロゲンとは、F、Cl、BrまたはIをいうことを特徴とする請求項1に記載の2,4-二置換ピリミジン誘導体。
- 請求項1〜4のいずれかに記載の2,4-二置換ピリミジ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中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2,4-二置換ピリミジン誘導体と、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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EP3746072B1 (en) * | 2018-01-29 | 2023-04-12 | Beta Pharma, Inc. | 2h-indazole derivatives as cdk4 and cdk6 inhibitors and therapeutic uses thereof |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010533716A (ja) * | 2007-07-19 | 2010-10-28 | シェーリング コーポレイション | プロテインキナーゼ阻害剤としての複素環アミド化合物 |
JP2012513396A (ja) * | 2008-12-22 | 2012-06-14 | イーライ リリー アンド カンパニー | タンパク質キナーゼ阻害剤 |
WO2016014904A1 (en) * | 2014-07-24 | 2016-01-28 | Beta Pharma, Inc. | 2-h-indazole derivatives as cyclin-dependent kinase (cdk) inhibitors and therapeutic uses thereof |
WO2016015605A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | Compounds as cdk small-molecule inhibitors and uses thereof |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010533716A (ja) * | 2007-07-19 | 2010-10-28 | シェーリング コーポレイション | プロテインキナーゼ阻害剤としての複素環アミド化合物 |
JP2012513396A (ja) * | 2008-12-22 | 2012-06-14 | イーライ リリー アンド カンパニー | タンパク質キナーゼ阻害剤 |
WO2016014904A1 (en) * | 2014-07-24 | 2016-01-28 | Beta Pharma, Inc. | 2-h-indazole derivatives as cyclin-dependent kinase (cdk) inhibitors and therapeutic uses thereof |
WO2016015605A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | Compounds as cdk small-molecule inhibitors and uses thereof |
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