JP6431593B2 - ピリジニルアミノピリミジン誘導体、その製造方法、および用途 - Google Patents
ピリジニルアミノピリミジン誘導体、その製造方法、および用途 Download PDFInfo
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- JP6431593B2 JP6431593B2 JP2017504644A JP2017504644A JP6431593B2 JP 6431593 B2 JP6431593 B2 JP 6431593B2 JP 2017504644 A JP2017504644 A JP 2017504644A JP 2017504644 A JP2017504644 A JP 2017504644A JP 6431593 B2 JP6431593 B2 JP 6431593B2
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- Prior art keywords
- methyl
- amino
- compound
- ethyl
- dimethylamino
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- 238000004519 manufacturing process Methods 0.000 title claims description 13
- LMZLTBMBIZUPOS-UHFFFAOYSA-N n-pyridin-2-ylpyrimidin-2-amine Chemical class N=1C=CC=NC=1NC1=CC=CC=N1 LMZLTBMBIZUPOS-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 202
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 78
- -1 pyrrolo [2,3-c] pyridinyl Chemical group 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 56
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 52
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 206010028980 Neoplasm Diseases 0.000 claims description 41
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 39
- 230000002829 reductive effect Effects 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- KGKINNNNQWXQSN-UHFFFAOYSA-N 5,6-difluoro-1-methylindole Chemical compound FC1=C(F)C=C2N(C)C=CC2=C1 KGKINNNNQWXQSN-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- GHKOONMJXNWOIW-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)OCC(F)(F)F)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=CC=C12)C)OCC(F)(F)F)C)C GHKOONMJXNWOIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
- SHCWQWRTKPNTEM-UHFFFAOYSA-N 2,6-dichloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1Cl SHCWQWRTKPNTEM-UHFFFAOYSA-N 0.000 claims description 4
- VOLFWQCSTMIDRS-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)Cl)OC(C)C)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)Cl)OC(C)C)C)C VOLFWQCSTMIDRS-UHFFFAOYSA-N 0.000 claims description 4
- MRCIBXJONDRDSE-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)Cl)OCC(F)(F)F)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)Cl)OCC(F)(F)F)C)C MRCIBXJONDRDSE-UHFFFAOYSA-N 0.000 claims description 4
- DHFPVOHQPNTTAD-UHFFFAOYSA-N C(=C)C(=O)NC1=C(N(CCN(C)C)C)N=C(C(=C1)NC1=NC(C2=CN(C3=C2C=CC=N3)C)=C(C=N1)Cl)OC(C)C Chemical compound C(=C)C(=O)NC1=C(N(CCN(C)C)C)N=C(C(=C1)NC1=NC(C2=CN(C3=C2C=CC=N3)C)=C(C=N1)Cl)OC(C)C DHFPVOHQPNTTAD-UHFFFAOYSA-N 0.000 claims description 3
- PLQQRQWKRUMSEF-UHFFFAOYSA-N C(=O)(C=C)NC1=C(N(CCN(C)C)C)N=C(C(NC2=NC(C3=CN=C4N(C)C=CC4=C3)=C(C=N2)Cl)=C1)OC(C)C Chemical compound C(=O)(C=C)NC1=C(N(CCN(C)C)C)N=C(C(NC2=NC(C3=CN=C4N(C)C=CC4=C3)=C(C=N2)Cl)=C1)OC(C)C PLQQRQWKRUMSEF-UHFFFAOYSA-N 0.000 claims description 3
- ZZWYZXSTVQAZJO-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)F)OCC(F)(F)F)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)F)OCC(F)(F)F)C)C ZZWYZXSTVQAZJO-UHFFFAOYSA-N 0.000 claims description 3
- ADLRXHCFFZXWDJ-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C=1C=NC(=NC=1)OC)Cl)OC(C)C)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C=1C=NC(=NC=1)OC)Cl)OC(C)C)C)C ADLRXHCFFZXWDJ-UHFFFAOYSA-N 0.000 claims description 3
- RUTOZFDWGVEMSC-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=C(C=C12)F)C)OCC(F)(F)F)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=C(C=C12)F)C)OCC(F)(F)F)C)C RUTOZFDWGVEMSC-UHFFFAOYSA-N 0.000 claims description 3
- XWZGFXITMQEERH-UHFFFAOYSA-N N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(5-fluoro-1-methylindol-3-yl)pyrimidin-2-yl]amino]-6-propan-2-yloxypyridin-3-yl]prop-2-enamide Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC=C(C=C12)F)C)OC(C)C)C)C XWZGFXITMQEERH-UHFFFAOYSA-N 0.000 claims description 3
- 238000006266 etherification reaction Methods 0.000 claims description 3
- GOWSGVZGRWKAJY-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)F)OC(C)C)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=C(C(=N1)C1=CN(C2=CC=CC=C12)C)F)OC(C)C)C)C GOWSGVZGRWKAJY-UHFFFAOYSA-N 0.000 claims description 2
- RRFVEOOXGPLTIC-UHFFFAOYSA-N CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC(=CC=C12)F)C)OC(C)C)C)C Chemical compound CN(CCN(C1=NC(=C(C=C1NC(C=C)=O)NC1=NC=CC(=N1)C1=CN(C2=CC(=CC=C12)F)C)OC(C)C)C)C RRFVEOOXGPLTIC-UHFFFAOYSA-N 0.000 claims description 2
- GPSZIUCISJPDQZ-UHFFFAOYSA-N N-[5-[[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-6-propan-2-yloxypyridin-3-yl]prop-2-enamide methanesulfonic acid Chemical compound CS(O)(=O)=O.CC(C)Oc1nc(N(C)CCN(C)C)c(NC(=O)C=C)cc1Nc1ncc(Cl)c(n1)-c1cn(C)c2ccccc12 GPSZIUCISJPDQZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
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- 125000001475 halogen functional group Chemical group 0.000 claims 3
- LLXRHAKGKJMNRR-UHFFFAOYSA-N 4-pyrimidin-5-ylpyrimidine Chemical compound C1=NC=CC(C=2C=NC=NC=2)=N1 LLXRHAKGKJMNRR-UHFFFAOYSA-N 0.000 claims 1
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- 239000013037 reversible inhibitor Substances 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
環Aはアリールまたはヘテロアリールであり;
R1は水素、ハロゲン、C1−C4アルキル、ハロC1−C4アルキル、C2−C6アルケニル、C2−C6アルキニル、および−CNからなる群から選択され;
R2はC1−C4アルキル、ハロC1−C4アルキル、C2−C6アルケニル、−(CH2)qOR7、−(CH2)qNR7R7’、および−(CH2)qC(O)R7からなる群から選択され;
R4は
各R5は独立してハロゲン、C1−C4アルキル、ハロC1−C4アルキル、C2−C6アルケニル、C2−C6アルキニル、−OR6、−C(O)R7、−C(O)NR7R7’、−OR7、−NR7R7’、−CN、または−NO2であり;
R3はハロゲン、−CN、−NO2、C1−C4アルキル、ハロC1−C4アルキル、−C(O)R6、−C(O)R7、−C(O)NR7R7’、−OR7、−OR6、−NHR7、−NR7−(C1−C4アルキル)、−NR7−(ハロC1−C4アルキル)、−NR7(CH2)nC(O)R6、−NR6R7、−NR7−ヘテロシクロアルキル(ここで該ヘテロシクロアルキルは非置換であるかまたはR7および−NR7SO2R7から選択される1〜2個の置換基で置換されている)、ならびに非置換であるかまたはハロゲン、C1−C4アルキル、ハロC1−C4アルキル、−(CH2)nOH、−NR7R7’、−OR7、および−C(O)R7から選択される1〜3個の置換基で置換されているヘテロシクロアルキルからなる群から選択され;
R6は−(CH2)qOR7、−(CH2)qNR7R7’、−(CH2)qNR7C(O)R7、−(CH2)qC(O)R7、または−(CH2)qC(O)NR7R7’であり;
R7およびR7’はそれぞれ独立して水素、C1−C4アルキル、C2−C6アルケニル、C2−C6アルキニル、もしくはハロC1−C4アルキルであるか、またはR7、R7’、およびそれらと結合している窒素原子は一緒になって環化して非置換であるかまたはハロゲン、C1−C4アルキル、ハロC1−C4アルキル、−(CH2)nOH、−NR7R7’、−OR7、および−C(O)R7から選択される1〜3個の置換基で置換されているヘテロシクロアルキルを形成し;
mは1、2、または3であり;
nは0、1、2、3、または4であり;
qは0、1、2、3、または4である]
によって示される化合物またはその医薬的に許容される塩を提供する。
R3はハロゲン、−CN、−NO2、C1−C4アルキル、ハロC1−C4アルキル、−C(O)R7、−C(O)NR7R7’、−OR7、−NHR7、−NR7−(C1−C4アルキル)、−NR7(CH2)nC(O)R6、−NR6R7、ならびに非置換であるかまたはハロゲン、C1−C4アルキル、ハロC1−C4アルキル、−(CH2)nOH、−NR7R7’、−OR7、および−C(O)R7から選択される1〜3個の置換基で置換されているヘテロシクロアルキルからなる群から選択され;
R6は−(CH2)qOR7、−(CH2)qNR7R7’、−(CH2)qC(O)R7、または−(CH2)qC(O)NR7R7’であり;
R7およびR7’はそれぞれ独立して水素、C1−C4アルキル、もしくはハロC1−C4アルキルであるか、またはR7、R7’、およびそれらと結合している窒素原子は一緒になって環化してヘテロシクロアルキルを形成し;
nは0、1、2、3、または4であり;
qは0、1、2、3、または4である。
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−6−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−6−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{5−フルオロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピロロ[2,3−b]ピリジン−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピラゾール−4−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−2’−メトキシ−(4,5’−ビピリミジン)−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;および
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−2’−アミノ−(4,5’−ビピリミジン)−2−イル]アミノ}ピリジン−3−イル}アクリルアミド
を含む。
で示される工程であって、
化合物(a)と(b)を出発物質として用い、触媒の存在下で置換反応に付して中間体2を製造し;中間体2と中間体1を置換もしくはカップリング反応に付して化合物(c)を製造し、化合物(c)のニトロ基を還元して化合物(d)を製造し、化合物(d)をアシル化して化合物(I)を製造する工程;または
中間体2と中間体1’を置換もしくはカップリング反応に付して化合物(I)を直接製造する工程
を含む製造方法も提供する。
で示される工程であって、
2,6−ジクロロ−3−ニトロピリジンを出発物質として用い、エーテル化反応に付して化合物(e)を製造し、化合物(e)のニトロ基を還元して化合物(f)を製造し、次いで化合物(f)を反応に付して化合物(g)を製造し、化合物(g)をニトロ化反応に付して化合物(h)を製造し、化合物(h)とR3Hを置換反応に付して化合物(i)を製造し、次いで化合物(i)を脱保護して中間体1を製造する工程;および
化合物(i)をBoc保護反応に付して化合物(j)を製造し、次いで化合物(j)をアセチル脱保護反応に付して化合物(k)を製造し、化合物(k)のニトロ基を還元して化合物(l)を製造し、化合物(l)をアシル化反応に付して化合物(m)を製造し、最後に化合物(m)をBoc脱保護反応に付して中間体1’を製造する工程
を含む製造方法である。
阻害率(%)=[(ブランクコントロールOD−阻害剤OD)/ブランクコントロールOD]×100%
ブランクコントロールOD:薬物の作用がなく正常に増殖した細胞のウェルのOD値。
阻害剤OD:スクリーニングされた添加化合物の作用を受けた細胞のウェルのOD値。
腫瘍容積(mm3)=0.5×(腫瘍大径×腫瘍小径2)
1H NMR(400MHz,CDCl3) δ8.29(d,J=8.3Hz,1H),7.07(d,J=8.3Hz,1H),4.15(s,3H)。
1H NMR(400MHz,DMSO−d6) δ9.90(s,1H),9.17(s,1H),4.06(s,3H),2.17(s,3H)。
1H NMR(400MHz,DMSO−d6) δ11.13(s,1H),9.53(s,1H),8.73(s,1H),4.05(s,5H),3.41−3.36(m,2H),2.83(s,3H),2.80(s,6H),2.07(s,3H)。
50mLの一つ口フラスコにN−{6−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−2−メトキシ−5−ニトロピリジン−3−イル}アセトアミド(600mg、1.93mmol)、15mLのメタノール、および0.3mLの濃塩酸を加えた。混合物を60℃で一晩反応させた。反応混合物を減圧下で蒸発乾固した。100mLのジクロロメタンおよび80mLの飽和炭酸水素ナトリウムを加えた。生じた混合物を気泡が生じなくなるまで攪拌した。有機層を分離し、無水硫酸ナトリウムで乾燥し、濾過し、減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン:メタノール=10:1)によって精製し、400mgの褐色固体を製造した。MS m/z:270[M+1]。
1H NMR(400MHz,DMSO−d6) δ11.20(s,1H),8.16(s,1H),4.06−4.02(m,5H),3.38(br s,2H),2.83(s,3H),2.80(s,3H),2.79(s,3H)。
1H NMR(400MHz,CDCl3) δ8.22(d,J=8.3Hz,1H),6.98(d,J=8.3Hz,1H),5.50(hept,J=6.2Hz,1H),1.43(d,J=6.2Hz,6H)。
MS m/z:340[M+1]。
当該化合物は中間体1aの工程6に記載の方法と同様の方法で合成した(収率38%)。MS m/z:298[M+1]。
1H NMR(400MHz,CDCl3) δ9.37(s,1H),7.63(s,1H),4.93(q,J=8.2Hz,2H),2.30(s,3H)。
当該化合物は中間体1aの工程6に記載の方法と同様の方法で合成した(収率100%)。MS m/z:338[M+1]。
MS m/z:368[M+1]。
1H NMR(400MHz,DMSO−d6) δ7.61(s,1H),7.44(s,1H),6.74(br s,2H),5.09−4.96(m,1H),3.29(t,J=5.8Hz,2H),3.19(t,J=5.7Hz,2H),2.70(s,6H),2.56(s,3H),1.45(s,9H),1.26(d,J=6.2Hz,6H)。
500mLの三つ口フラスコにtert−ブチル {5−アミノ−6−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−2−イソプロピルオキシピリジン−3−イル}カルバメート(9g、24.49mmol)、トリメチルアミン(6.83mL、49.0mmol)、および250mLのジクロロメタンを加えた。反応混合物を氷水浴中で5℃未満に冷却した。塩化アクリロイル(2.1mL、25.7mmol)を滴下した。生じた混合物を1時間反応させ続けた。反応混合物を150mLの飽和炭酸水素ナトリウム溶液および150mLの飽和食塩水で連続して洗浄し、無水硫酸ナトリウムで乾燥し、濾過した。濾液を減圧下で蒸発乾固し、5gの生成物を収率48%で製造した。MS m/z:422[M+1]。
1H NMR(400MHz,DMSO−d6) δ9.76(s,1H),8.16(s,1H),7.88(s,1H),6.44(dd,J=17.0,10.1Hz,1H),6.22(dd,J=17.0,1.9Hz,1H),5.74(dd,J=10.1,1.9Hz,1H),5.22−5.13(m,1H),3.09(t,J=6.5Hz,2H),2.77(s,3H),2.41(t,J=6.5Hz,2H),2.18(s,6H),1.45(s,9H),1.31(d,J=6.2Hz,6H)。
当該化合物は中間体1dの工程1に記載の方法と同様の方法で合成した(収率99%)。MS m/z:480[M+1]。
当該化合物は中間体1dの工程4に記載の方法と同様の方法で合成した(収率62%)。MS m/z:462[M+1]。
1H NMR(400MHz,CDCl3) δ10.11(s,1H),9.35(s,1H),6.61(s,1H),6.46(dd,J=16.9,1.7Hz,1H),6.39−6.25(m,1H),5.70(dd,J=10.0,1.8Hz,1H),4.76(q,J=8.5Hz,2H),2.96(s,2H),2.71(s,3H),2.42(s,2H),2.34(s,6H),1.53(s,9H)。
500mLの一つ口フラスコに2,4−ジクロロピリミジン(14.9g、100mmol)、1−メチル−1H−インドール(13g、100mmol)、200mLの1,2−ジクロロエタン、および塩化アルミニウム(13.9g、120mmol)を加えた。混合物を80℃で1.5時間攪拌した。反応混合物を氷浴中で室温まで冷却した。120mLのメタノールおよび400mLの水を加えて反応をクエンチした。固体が沈殿し、それを濾過した。濾過ケーキをメタノールで洗浄し、真空乾燥し、17.2gの生成物を収率71%で製造した。MS m/z:244[M+1],246。
1H NMR(400MHz,DMSO−d6) δ8.53(d,J=5.5Hz,1H),8.49(s,1H),8.42(dd,J=7.0,1.5Hz,1H),7.81(d,J=5.5Hz,1H),7.56(dd,J=7.0,1.2Hz,1H),7.33−7.26(m,2H),3.90(d,J=5.2Hz,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した(収率87%)。MS m/z:278[M+1],279,280。
1H NMR(400MHz,DMSO−d6) δ8.79(s,1H),8.74(s,1H),8.56(dd,J=7.3,1.2Hz,1H),7.62(d,J=7.6Hz,1H),7.39−7.34(m,1H),7.34−7.29(m,1H),3.97(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した(収率29%)。MS m/z:262[M+1],264。
1H NMR(400MHz,DMSO−d6) δ8.55(s,1H),8.53(d,J=5.5Hz,1H),8.10(dd,J=10.3,2.5Hz,1H),7.80(d,J=5.5Hz,1H),7.60(dd,J=8.9,4.6Hz,1H),7.17(td,J=9.1,2.6Hz,1H),3.90(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:262[M+1],264。
1H NMR(400MHz,DMSO−d6) δ8.54(d,J=5.5Hz,1H),8.49(s,1H),8.39(dd,J=8.8,5.6Hz,1H),7.81(d,J=5.5Hz,1H),7.47(dd,J=9.9,2.3Hz,1H),7.14(td,J=9.6,2.4Hz,1H),3.86(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:280[M+1],282。
1H NMR(400MHz,DMSO−d6) δ8.54(d,J=5.5Hz,1H),8.52(s,1H),8.22(dd,J=11.7,8.2Hz,1H),7.79(d,J=5.5Hz,1H),7.73(dd,J=11.2,7.0Hz,1H),3.86(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:296[M+1],297,298。
1H NMR(400MHz,CDCl3) δ8.69(dd,J=8.9,5.5Hz,1H),8.50(s,1H),8.41(s,1H),7.17−7.07(m,2H),3.90(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:314[M+1],315,316。
1H NMR(400MHz,DMSO−d6) δ8.85(s,1H),8.77(s,1H),8.39(dd,J=12.1,8.3Hz,1H),7.83(dd,J=11.0,7.1Hz,1H),3.94(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:296[M+1],297,298。
1H NMR(400MHz,CDCl3) δ8.49(s,1H),8.46(s,1H),8.46−8.42(m,1H),7.34(dd,J=8.9,4.4Hz,1H),7.14(td,J=8.9,2.6Hz,1H),3.94(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した(収率73%)。MS m/z:262[M+1],264。
1H NMR(400MHz,DMSO−d6) δ8.69(d,J=3.7Hz,1H),8.54(dd,J=7.2,1.2Hz,1H),8.39(d,J=3.0Hz,1H),7.62(d,J=7.5Hz,1H),7.41−7.30(m,2H),3.96(s,3H)。
当該化合物は中間体2aに記載の方法と同様の方法で合成した(収率77%)。MS m/z:280[M+1],282。
1H NMR(400MHz,DMSO−d6) δ8.71(d,J=3.5Hz,1H),8.45(d,J=2.8Hz,1H),8.20(dd,J=10.3,2.5Hz,1H),7.66(dd,J=8.9,4.5Hz,1H),7.30−7.16(m,1H),3.96(s,3H).
当該化合物は中間体2aに記載の方法と同様の方法で合成した。MS m/z:298[M+1],300。
1H NMR(400MHz,CDCl3) δ8.56(dd,J=11.4,8.1Hz,1H),8.36(d,J=3.3Hz,1H),8.01(d,J=2.6Hz,1H),7.19(dd,J=10.1,6.6Hz,1H),3.90(s,3H)。
50mLの三つ口フラスコに3−(2,5−ジクロロピリミジン−4−イル)−1H−ピロロ[2,3−b]ピリジン(480mg、1.8mmol)および15mLのN,N−ジメチルホルムアミドを加えた。生じた混合物を氷水浴下で5℃まで冷却した。60%水素化ナトリウム(145mg、3.6mmol)を加えた。混合物を10分間攪拌し、そこへヨウ化メチル(0.12mL、1.9mmol)を加えた。生じた混合物を5℃で15分間攪拌した。反応混合物を氷水に注ぐと、固体が沈殿し、それを吸引濾過した。濾過ケーキを乾燥し、450mgのベージュ色固体を収率89%で製造した。MS m/z:265[M+1]。
1H NMR(400MHz,DMSO−d6) δ8.94(s,1H),8.81(dd,J=8.0,1.6Hz,1H),8.78(s,1H),8.44(dd,J=4.7,1.6Hz,1H),7.38(dd,J=8.0,4.7Hz,1H),3.97(s,3H)。
当該化合物は中間体2lの工程2に記載の方法と同様の方法で合成した(収率50%)。MS m/z:279[M+1]。
1H NMR(400MHz,DMSO−d6) δ8.99(s,1H),8.75(d,J=2.1Hz,1H),8.51(d,J=2.1Hz,1H),7.68(d,J=3.5Hz,1H),6.66(d,J=3.5Hz,1H),3.90(s,3H)。
三つ口フラスコにアルゴン置換雰囲気下、2,4,5−トリクロロピリミジン(2.0g、10.9mmol)、1−メチル−4−ピラゾール−ビス(ピナコラト)ジボロン(1.75g、8.4mmol)、8.4mLの2N炭酸ナトリウム溶液、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(0.61g、0.84mmol)、および30mLのジオキサンを加えた。混合物を80℃で一晩攪拌した。反応混合物に150mLの酢酸エチルを加え、150mLの水および100mLの飽和塩化ナトリウム溶液で連続して洗浄し、無水硫酸ナトリウムで乾燥し、減圧下で蒸発乾固し、黄土色固体(1.6g)を収率83%で製造した。MS m/z:229[M+1]。
1H NMR(400MHz,DMSO−d6) δ8.82(s,1H),8.75(s,1H),8.27(s,1H),3.96(s,3H)。
当該化合物は中間体2nに記載の方法と同様の方法で合成した(収率70%)。MS m/z:257[M+1]。
1H NMR(400MHz,DMSO−d6) δ9.10(s,2H),9.05(s,1H),4.04(s,3H)。
当該化合物は中間体2nに記載の方法と同様の方法で合成した(収率44%)。MS m/z:242[M+1]。
1H NMR(400MHz,DMSO−d6) δ8.90(s,1H),8.84(s,2H),7.52(s,2H)。
1H NMR(400MHz,CDCl3) δ9.75(s,1H),9.36(s,1H),8.39(s,1H),8.38−8.33(m,1H),8.29(s,1H),7.40(s,1H),7.38−7.33(m,1H),7.33−7.27(m,2H),7.06(dd,J=16.9,10.2Hz,1H),6.39(d,J=16.9Hz,1H),5.70(d,J=10.2Hz,1H),5.29−5.20(m,1H),3.90(s,3H),3.51−3.46(m,2H),3.09(br s,2H),2.77(s,3H),2.75(s,6H),1.38(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.80(s,1H),9.73(s,1H),8.88(s,1H),8.39(d,J=5.3Hz,1H),8.11−8.03(m,1H),7.81(d,J=8.3Hz,1H),7.48(s,1H),7.42−7.40(m,1H),7.36(d,J=8.1Hz,1H),7.30(d,J=3.7Hz,1H),7.24(d,J=5.3Hz,1H),6.50(dd,J=16.9,1.9Hz,1H),5.76(dd,J=10.2,1.9Hz,1H),5.32−5.21(m,1H),3.99(s,3H),3.52(br s,2H),3.11(br s,2H),2.81(d,J=2.5Hz,9H),1.39(d,J=6.2Hz,6H)。
1H NMR(400MHz,DMSO−d6) δ10.41(s,1H),10.27(s,1H),8.68(s,1H),8.44(s,1H),8.28(t,J=8.5Hz,2H),8.18(s,1H),7.52(d,J=8.0Hz,1H),7.29−7.14(m,3H),6.98(s,1H),6.28(d,J=17.1Hz,1H),5.76(d,J=10.4Hz,1H),5.00(q,J=9.0Hz,2H),3.89(s,3H),3.61(s,2H),3.28(s,2H),2.80(s,3H),2.73(s,6H)。
1H NMR(400MHz,CDCl3) δ11.68(br s,1H),9.77(s,1H),9.48(s,1H),8.42(s,1H),8.38(d,J=8.7Hz,1H),8.33(s,1H),7.40−7.37(m,2H),7.32(dd,J=6.7,3.0Hz,2H),7.12(dd,J=16.8,10.2Hz,1H),6.43(dd,J=16.9,1.8Hz,1H),5.72(dd,J=10.2,1.8Hz,1H),4.83(q,J=8.4Hz,2H),3.93(s,3H),3.60(s,2H),3.17(s,2H),2.86(s,3H),2.85(s,6H)。
1H NMR(400MHz,CDCl3) δ9.82(s,1H),9.80(s,1H),8.93(s,1H),8.40(d,J=5.2Hz,1H),7.71(d,J=9.7Hz,1H),7.49(s,1H),7.32(dd,J=8.8,4.4Hz,1H),7.20−6.98(m,3H),6.48(d,J=16.8Hz,1H),5.76(d,J=10.5Hz,1H),5.31−5.25(m,1H),3.99(s,3H),3.43(br s,2H),2.98(br s,2H),2.71(s,6H),1.39(d,J=6.1Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.73(s,1H),9.70(s,1H),8.82(s,1H),8.39(d,J=4.9Hz,1H),7.88−7.74(m,1H),7.50(s,1H),7.25(dd,J=16.2,9.7Hz,1H),7.20−7.13(m,1H),7.05(d,J=5.0Hz,1H),6.47(d,J=16.5Hz,1H),5.76(d,J=10.3Hz,1H),5.31−5.21(m,1H),3.94(s,3H),3.54(s,2H),3.13(s,2H),2.82(s,6H),1.39(d,J=5.9Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.78(s,1H),9.46(s,1H),8.43(s,1H),8.32−8.28(m,2H),7.40(s,1H),7.08−7.03(m,2H),7.00−6.86(m,1H),6.45−6.38(m,1H),5.73(d,J=10.2Hz,1H),5.31−5.23(m,1H),3.88(s,3H),3.45(s,2H),2.99(s,2H),2.80(s,3H),2.73(s,6H),1.39(d,J=6.2Hz,6H)。
1H NMR(400MHz,DMSO−d6) δ9.93(s,1H),8.71(s,1H),8.66(s,1H),8.37(s,1H),8.25−8.15(m,1H),8.11(s,1H),7.68(dd,J=11.1,7.0Hz,1H),6.83−6.64(m,1H),6.21(d,J=16.5Hz,1H),5.73(d,J=11.9Hz,1H),5.21−5.13(m,1H),3.89(s,3H),3.36(s,4H),2.80(s,3H),2.56(s,6H),1.18(d,J=6.1Hz,6H)。
1H NMR(400MHz,MeOD) δ8.48(s,1H),8.36(s,1H),8.34(s,1H),8.02(dd,J=10.6,2.4Hz,1H),7.44(dd,J=8.9,4.4Hz,1H),7.03(td,J=9.0,2.5Hz,1H),6.47(dd,J=17.0,9.3Hz,1H),6.40(dd,J=17.0,2.5Hz,1H),5.82(dd,J=9.3,2.5Hz,1H),5.39−5.28(m,1H),3.91(s,3H),3.74(t,J=5.7Hz,2H),3.32(t,J=5.9Hz,2H),2.89(s,6H),2.80(s,3H),1.37(d,J=6.2Hz,6H)。
1H NMR(400MHz,DMSO−d6) δ10.01(s,1H),8.45(s,1H),8.35(d,J=3.9Hz,1H),8.28(d,J=2.7Hz,1H),8.26(s,1H),8.07(d,J=10.2Hz,1H),7.55(dd,J=8.9,4.6Hz,1H),7.11(td,J=9.1,2.6Hz,1H),6.90(s,1H),6.23(dd,J=17.1,1.9Hz,1H),5.72(dd,J=10.2,1.9Hz,1H),5.26−5.12(m,1H),3.92(s,3H),3.53(s,2H),3.24(s,2H),2.77(s,3H),2.71(s,6H),1.21(d,J=6.2Hz,6H)。
1H NMR(400MHz,DMSO−d6) δ10.12(s,1H),8.47−8.32(m,3H),8.23(d,J=2.8Hz,1H),8.19(s,1H),7.52(d,J=8.2Hz,1H),7.24(t,J=7.6Hz,1H),7.15(t,J=7.5Hz,1H),6.88(dd,J=16.9,10.3Hz,1H),6.23(dd,J=17.1,1.8Hz,1H),5.72(dd,J=10.2,1.7Hz,1H),5.27−5.15(m,1H),4.04(s,3H),3.91(s,3H),3.57(s,2H),3.28(s,2H),2.76(s,6H),1.26(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.70(s,1H),9.47(s,1H),8.29(d,J=3.4Hz,2H),8.23(dd,J=11.8,8.2Hz,1H),7.33(s,1H),7.14(dd,J=10.3,6.7Hz,2H),6.41(dd,J=16.9,1.8Hz,1H),5.73(dd,J=10.2,1.8Hz,1H),5.31−5.23(m,1H),3.90(s,3H),3.55(s,2H),3.13(s,2H),2.83(s,9H),1.40(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.77(s,1H),9.76(s,1H),8.82(s,1H),8.39(d,J=5.3Hz,1H),7.98(dd,J=8.7,5.2Hz,1H),7.47(s,1H),7.16(d,J=5.3Hz,1H),7.08(dd,J=9.6,2.3Hz,1H),7.03(dd,J=9.1,2.2Hz,1H),6.49(dd,J=16.9,2.0Hz,1H),5.77(dd,J=10.2,2.0Hz,1H),5.27(hept,J=6.2Hz,1H),3.94(s,3H),3.52(s,2H),3.10(s,2H),2.82(s,3H),2.80(s,6H),1.39(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.87(s,1H),9.53(s,1H),8.52−8.44(m,1H),8.28(d,J=3.7Hz,1H),8.21(s,1H),7.38(dd,J=8.1,4.9Hz,1H),7.33(dd,J=6.0,3.3Hz,2H),7.19(dd,J=16.9,10.3Hz,1H),6.43(dd,J=16.9,1.5Hz,1H),5.74(dd,J=10.3,1.5Hz,1H),4.83(q,J=8.5Hz,2H),3.93(s,3H),3.56(t,J=5.1Hz,2H),3.15(t,J=5.1Hz,2H),2.85(s,3H),2.81(s,6H)。
1H NMR(400MHz,CDCl3) δ9.85(s,2H),8.83(s,1H),8.40(d,J=5.3Hz,1H),7.71(dd,J=10.2,2.1Hz,1H),7.41(s,1H),7.31(dd,J=8.9,4.5Hz,1H),7.13(d,J=5.3Hz,2H),7.03(td,J=9.0,2.3Hz,1H),6.49(dd,J=16.9,1.8Hz,1H),5.78(dd,J=10.2,1.8Hz,1H),4.83(q,J=8.5Hz,2H),3.97(s,3H),3.49(s,2H),3.05(s,2H),2.83(s,3H),2.75(s,6H)。
1H NMR(400MHz,DMSO−d6) δ9.99(s,1H),9.88(s,1H),8.63(s,2H),8.40(s,1H),8.28(s,1H),8.19(s,1H),7.52(d,J=7.3Hz,1H),7.25(s,1H),7.10(s,1H),6.88−6.70(m,1H),6.26(d,J=16.8Hz,1H),5.75(d,J=8.6Hz,1H),5.18(br s,1H),3.92(s,3H),3.46(s,2H),3.31(s,2H),2.79(s,9H),2.38(s,3H),1.32−1.12(m,6H)。
1H NMR(400MHz,DMSO−d6) δ10.02(s,1H),9.95(s,1H),8.90(s,1H),8.71(s,1H),8.39(s,1H),8.21(s,1H),8.09(s,1H),7.69(dd,J=11.1,7.0Hz,1H),6.84(dd,J=17.0,10.2Hz,1H),6.23(dd,J=17.1,1.7Hz,1H),5.73(dd,J=10.3,1.7Hz,1H),5.17(hept,J=6.1Hz,1H),3.90(s,3H),3.61(t,J=5.6Hz,2H),3.32(d,J=5.5Hz,2H),2.79(s,6H),2.78(s,3H),2.39(s,3H),1.18(d,J=6.1Hz,6H)。
1H NMR(400MHz,DMSO−d6) δ9.99(s,2H),8.82(s,1H),8.26−8.11(m,3H),7.81(dd,J=10.6,6.9Hz,1H),7.40(d,J=6.6Hz,1H),6.82(dd,J=16.9,10.3Hz,1H),6.27(d,J=17.0Hz,1H),5.78(d,J=10.1Hz,1H),5.25−5.19(m,1H),3.91(s,3H),3.68(d,J=5.5Hz,2H),3.35(d,J=5.5Hz,2H),2.86(s,3H),2.82(s,3H),2.80(s,3H),2.36(s,3H),1.21(d,J=6.1Hz,6H)。
1H NMR(400MHz,MeOD) δ8.70(dd,J=8.0,1.0Hz,1H),8.61(s,1H),8.41(s,1H),8.40(s,1H),8.29(dd,J=4.7,1.5Hz,1H),7.14(dd,J=8.0,4.8Hz,1H),6.48(dd,J=16.9,2.6Hz,1H),6.42(dd,J=16.9,9.2Hz,1H),5.86(dd,J=9.2,2.6Hz,1H),5.38−5.32(m,1H),3.97(s,3H),3.74(t,J=5.7Hz,2H),3.33(t,J=5.7Hz,2H),2.90(s,6H),2.80(s,3H),1.41(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.69(s,1H),9.55(s,1H),8.99(d,J=1.9Hz,1H),8.71(s,1H),8.50(s,1H),7.52(s,1H),7.24(d,J=3.5Hz,1H),7.14(dd,J=16.9,10.2Hz,1H),6.63(d,J=3.5Hz,1H),6.54(dd,J=16.9,1.9Hz,1H),5.77(dd,J=10.2,1.9Hz,1H),5.26(hept,J=6.2Hz,1H),3.94(s,3H),3.52(t,J=5.2Hz,2H),3.11(t,J=5.2Hz,2H),2.81(s,3H),2.79(s,3H),1.38(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.79(s,1H),9.55(s,1H),9.12(s,1H),8.46(s,1H),8.33(s,1H),7.48(s,1H),6.50(dd,J=17.0,2.0Hz,1H),5.77(dd,J=10.0,2.0Hz,1H),5.30−5.22(m,1H),4.08(s,3H),3.57(s,2H),3.16(s,2H),2.83(s,9H),1.39(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.75(s,1H),9.50(s,1H),9.27(s,2H),8.51(s,1H),7.52(s,1H),7.17−7.03(m,1H),6.57(d,J=16.9Hz,1H),5.76(d,J=12.0Hz,1H),5.31−5.23(m,1H),4.13(s,3H),3.54(s,2H),3.12(s,2H),2.83(s,3H),2.81(s,6H),1.40(d,J=6.2Hz,6H)。
1H NMR(400MHz,CDCl3) δ9.76(s,1H),9.43(s,1H),9.09(s,2H),8.45(s,1H),7.48(s,1H),7.02(s,1H),6.52(dd,J=16.9,1.8Hz,1H),5.75(dd,J=10.3,1.8Hz,1H),5.61(s,2H),5.26(hept,J=6.2Hz,1H),3.47(br s,2H),3.05(br s,2H),2.81(s,3H),2.76(s,6H),1.39(d,J=6.2Hz,6H)。
試験例1:ヒト皮膚癌細胞(A431、野生型EGFR)、ヒト肺癌細胞(HCC827、EGFR エクソン19欠失活性化変異)、およびヒト肺癌細胞(H1975、EGFR L858R/T790M耐性変異)に対する増殖阻害効果
対数期の細胞を96ウェル培養プレートに植菌し(細胞密度:5000/ウェル、細胞懸濁液:180μL/ウェル)、37℃で5%CO2下、24時間培養した。培養後、細胞はウェルの壁に付着した。各化合物を予めDMSOに溶解し、10nMのストック溶液を製造した。試験時に、別の96細胞プレート中に、目標濃度の10倍になるまでストック溶液を完全培地で希釈した。次いで、細胞を植菌した96ウェルプレートに20μL/細胞で化合物を加え、目標濃度を達成した。各濃度についてウェルを3つ用意し、ブランクコントロールを作製した。細胞を37℃で5%CO2下、72時間培養を続けた。培養終了後、50μLの予め冷却した(4℃)50%トリクロロ酢酸、すなわち、TCAを各ウェルに加え(最終濃度=10%)、4℃で1時間置き、細胞を固定した。得られた物質を精製水で少なくとも5回洗浄し、自然に空気乾燥するか、または乾燥器内にて60℃で乾燥した。1%氷酢酸/精製水で製造した4mg/mLスルホローダミンB(SRB)溶液を各ウェルに100μL/ウェルで加え、室温で1時間染色した。上清を捨てた。残渣を1%酢酸で少なくとも5回洗浄して非特異的結合を除去し、乾燥して使用した。各ウェルに150μLの10mMトリス−HCl溶液を加え、その内容物を溶解した。510nmの波長でOD値を測定し、収集したデータに基づいて阻害率を計算した。結果を表1に示した。
ヒト肺癌H1975所持ヌードマウスの皮下移植腫瘍に対する本発明の実施例3の化合物およびAZD9291の阻害効果、ならびに対応する安全性を観察した。
試験動物:15匹のBALB/cヌードマウス、15匹のオスと0匹のメス、6週齢、18〜20g、上海ラボラトリー・アニマルリサーチセンター(Shanghai Lab. Animal Research Center)から市販されたもの
3つの試験群を確立した:それぞれ、0.5%カルボキシメチルセルロースナトリウム溶媒対照群、25mg/kgの実施例3の化合物の群、および25mg/kgのAZD9291の群。
試験方法:ヒト肺癌H1975細胞株(5×106/各マウス)をヌードマウスの背中の右側の皮下に接種した。各マウスに0.1mL接種し、腫瘍増殖を定期的に観察した。腫瘍が平均で100〜150mm3まで成長した後、腫瘍の大きさおよびマウスの体重に従ってマウスをランダムにいくつかの群に分けた。実施例3の化合物およびAZD9291を25mg/kgの投与量で胃内投与し、溶媒対照群には等量の溶媒を胃内投与し、投与を1日1回継続して12日間実施した。全実験プロセスの間、マウスの体重および腫瘍の大きさを週2回測定し、毒性反応が生じているかどうかを観察した。腫瘍容積を以下のように計算する:
腫瘍容積(mm3)=0.5×(腫瘍大径×腫瘍小径2)
Claims (13)
- 以下の一般式(I):
環Aはインドリル、ピロロ[2,3−c]ピリジニル、ピロロ[3,2−c]ピリジニル、ピロロ[2,3−b]ピリジニル、ピロロ[3,2−b]ピリジニル、ピラゾリル、またはピリミジニルであり;
R1は水素、ハロゲン、C1−C4アルキル、およびハロC1−C4アルキルからなる群から選択され;
R2はC1−C4アルキルおよびハロC1−C4アルキルからなる群から選択され;
R4は
各R5は独立してハロゲン、C1−C4アルキル、ハロC1−C4アルキル、−OR7、または−NR7R7 ’であり;
R3 は−NR6R7 であり;
R6 は−(CH2)qNR7R7 ’であり;
R7およびR7’はそれぞれ独立して水素またはC1−C4アルキルであり;
mは1、2、または3であり;
qは1、2、3、または4である]
によって示される化合物またはその医薬的に許容される塩。 - R1が水素またはハロゲンである、請求項1に記載の化合物またはその医薬的に許容される塩。
- R2がC2−C4アルキルまたはハロC2−C4アルキルである、請求項1または2に記載の化合物またはその医薬的に許容される塩。
- R2がイソプロピルまたはトリフルオロエチルである、請求項3に記載の化合物またはその医薬的に許容される塩。
- qが2である、請求項1〜5のいずれか1項に記載の化合物またはその医薬的に許容される塩。
- 各R5が独立してハロゲン、C1−C4アルキル、−OR7、または−NR7R7’であり、R7およびR7’がそれぞれ独立して水素またはC1−C4アルキルであり、mが1、2、または3である、請求項1〜6のいずれか1項に記載の化合物またはその医薬的に許容される塩。
- N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−6−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−フルオロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−6−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{5−フルオロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−(2,2,2−トリフルオロエトキシ)−5−{[4−(1−メチル−5−フルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{5−クロロ−[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[4−(1−メチル−5,6−ジフルオロ−1H−インドール−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミドメタンスルホネート;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピロロ[2,3−b]ピリジン−3−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピロロ[2,3−b]ピリジン−5−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−4−(1−メチル−1H−ピラゾール−4−イル)ピリミジン−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−2’−メトキシ−(4,5’−ビピリミジン)−2−イル]アミノ}ピリジン−3−イル}アクリルアミド;および
N−{2−{[2−(ジメチルアミノ)エチル](メチル)アミノ}−6−イソプロピルオキシ−5−{[5−クロロ−2’−アミノ−(4,5’−ビピリミジン)−2−イル]アミノ}ピリジン−3−イル}アクリルアミド
からなる群から選択される化合物またはその医薬的に許容される塩。 - 以下のスキーム:
で示される工程であって、
化合物(a)と(b)を出発物質として用い、触媒の存在下で置換反応に付して中間体2を製造し;中間体2と中間体1を置換もしくはカップリング反応に付して化合物(c)を製造し、化合物(c)のニトロ基を還元して化合物(d)を製造し、化合物(d)をアシル化して化合物(I)を製造する工程;または
中間体2と中間体1’を置換もしくはカップリング反応に付して化合物(I)を直接製造する工程
を含む、請求項1の一般式(I)によって示される化合物の製造方法。 - 中間体1および中間体1’を製造する方法が、以下のスキーム:
で示される工程であって、
2,6−ジクロロ−3−ニトロピリジンを出発物質として用い、エーテル化反応に付して化合物(e)を製造し、化合物(e)のニトロ基を還元して化合物(f)を製造し、次いで化合物(f)をアシル化反応に付して化合物(g)を製造し、化合物(g)をニトロ化反応に付して化合物(h)を製造し、化合物(h)とR3Hを置換反応に付して化合物(i)を製造し、次いで化合物(i)を脱保護して中間体1を製造する工程;および
化合物(i)をBoc保護反応に付して化合物(j)を製造し、次いで化合物(j)をアセチル脱保護反応に付して化合物(k)を製造し、化合物(k)のニトロ基を還元して化合物(l)を製造し、化合物(l)をアシル化反応に付して化合物(m)を製造し、最後に化合物(m)をBoc脱保護反応に付して中間体1’を製造する工程
を含む、請求項9に記載の製造方法。 - 請求項1〜8のいずれか1項に記載の化合物またはその医薬的に許容される塩、および医薬的に許容される担体、賦形剤、または希釈剤を含む医薬組成物。
- 哺乳類における癌を治療するための、請求項1〜8のいずれか1項に記載の化合物またはその医薬的に許容される塩を含む医薬組成物。
- 哺乳類がヒトである、請求項12に記載の医薬組成物。
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