JP5721821B2 - モルホリノピリミジンおよび治療におけるそれらの使用 - Google Patents
モルホリノピリミジンおよび治療におけるそれらの使用 Download PDFInfo
- Publication number
- JP5721821B2 JP5721821B2 JP2013513758A JP2013513758A JP5721821B2 JP 5721821 B2 JP5721821 B2 JP 5721821B2 JP 2013513758 A JP2013513758 A JP 2013513758A JP 2013513758 A JP2013513758 A JP 2013513758A JP 5721821 B2 JP5721821 B2 JP 5721821B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- methylmorpholin
- methylsulfonimidoyl
- pyrimidin
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
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- 238000002560 therapeutic procedure Methods 0.000 title description 3
- DUIMWXDLDBNUFD-UHFFFAOYSA-N 4-pyrimidin-2-ylmorpholine Chemical class C1COCCN1C1=NC=CC=N1 DUIMWXDLDBNUFD-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 241
- -1 3-methylmorpholin-4-yl Chemical group 0.000 claims description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims description 102
- 239000001257 hydrogen Substances 0.000 claims description 102
- 150000003839 salts Chemical class 0.000 claims description 81
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 79
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- 206010028980 Neoplasm Diseases 0.000 claims description 61
- 238000011282 treatment Methods 0.000 claims description 59
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 201000011510 cancer Diseases 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 108091000080 Phosphotransferase Proteins 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 102000020233 phosphotransferase Human genes 0.000 claims description 14
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 8
- OHUHVTCQTUDPIJ-JYCIKRDWSA-N ceralasertib Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-JYCIKRDWSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- OHUHVTCQTUDPIJ-MUWSIPGASA-N imino-methyl-[1-[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 OHUHVTCQTUDPIJ-MUWSIPGASA-N 0.000 claims description 6
- JESNSKPPMWEWAT-JKGBWWFKSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CC1 JESNSKPPMWEWAT-JKGBWWFKSA-N 0.000 claims description 5
- HQFFRTPOWLGAIX-FZAOIFNZSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C HQFFRTPOWLGAIX-FZAOIFNZSA-N 0.000 claims description 4
- AORKOLDGMLWWPG-RZQXLCLMSA-N 6-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=C(F)C=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CC1 AORKOLDGMLWWPG-RZQXLCLMSA-N 0.000 claims description 4
- PSIPSQLSHTYKJT-RZQXLCLMSA-N 6-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=C(F)C=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C PSIPSQLSHTYKJT-RZQXLCLMSA-N 0.000 claims description 4
- OOEYPUFPMHMEAP-IZPCHGGPSA-N imino-[1-[2-(1h-indol-4-yl)-6-[(3r)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]-methyl-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3C=CC=2)=N1 OOEYPUFPMHMEAP-IZPCHGGPSA-N 0.000 claims description 4
- DTTJKLNXNZAVSM-RNHBAAACSA-N imino-methyl-[1-[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-c]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)S(C)(=N)=O)=NC(C=2C=3C=CNC=3C=NC=2)=N1 DTTJKLNXNZAVSM-RNHBAAACSA-N 0.000 claims description 4
- FEFZJKWFEQKDHO-KHXSAUHESA-N imino-methyl-[[6-[(3r)-3-methylmorpholin-4-yl]-2-(1h-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]methyl]-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C[S@](C)(=N)=O)=NC(C=2C=3C=CNC=3N=CC=2)=N1 FEFZJKWFEQKDHO-KHXSAUHESA-N 0.000 claims description 4
- LRIFUSYFLXZCKX-JKGBWWFKSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C LRIFUSYFLXZCKX-JKGBWWFKSA-N 0.000 claims description 4
- LRIFUSYFLXZCKX-YSVRNHBLSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C LRIFUSYFLXZCKX-YSVRNHBLSA-N 0.000 claims description 4
- YIASZZUGUQHGBB-RZCFMFBHSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[4-(methylsulfonimidoyl)oxan-4-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@@](C)(=N)=O)CCOCC1 YIASZZUGUQHGBB-RZCFMFBHSA-N 0.000 claims description 4
- YXSYJGJKBNBZLQ-BRRNQIAESA-N 1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@](C)(=N)=O)=NC(N2C3=CC=CC=C3N=C2N)=N1 YXSYJGJKBNBZLQ-BRRNQIAESA-N 0.000 claims description 3
- YXSYJGJKBNBZLQ-OSXTUODASA-N 1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(N2C3=CC=CC=C3N=C2N)=N1 YXSYJGJKBNBZLQ-OSXTUODASA-N 0.000 claims description 3
- WUJFVGIVMGNTPV-FZAOIFNZSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@@](C)(=N)=O)CC1 WUJFVGIVMGNTPV-FZAOIFNZSA-N 0.000 claims description 3
- WUJFVGIVMGNTPV-RZQXLCLMSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CC1 WUJFVGIVMGNTPV-RZQXLCLMSA-N 0.000 claims description 3
- HQFFRTPOWLGAIX-RZQXLCLMSA-N 4-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=C(F)C=CC=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C HQFFRTPOWLGAIX-RZQXLCLMSA-N 0.000 claims description 3
- FGTJUHKILGGMAK-FZAOIFNZSA-N 5-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC(F)=CC=C2N1C(N=C(C=1)C(C)(C)[S@@](C)(=N)=O)=NC=1N1CCOC[C@H]1C FGTJUHKILGGMAK-FZAOIFNZSA-N 0.000 claims description 3
- FGTJUHKILGGMAK-RZQXLCLMSA-N 5-fluoro-n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[2-(methylsulfonimidoyl)propan-2-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC(F)=CC=C2N1C(N=C(C=1)C(C)(C)[S@](C)(=N)=O)=NC=1N1CCOC[C@H]1C FGTJUHKILGGMAK-RZQXLCLMSA-N 0.000 claims description 3
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- OOEYPUFPMHMEAP-ONSXPEOJSA-N imino-[1-[2-(1h-indol-4-yl)-6-[(3r)-3-methylmorpholin-4-yl]pyrimidin-4-yl]cyclopropyl]-methyl-oxo-$l^{6}-sulfane Chemical compound C[C@@H]1COCCN1C1=CC(C2(CC2)[S@@](C)(=N)=O)=NC(C=2C=3C=CNC=3C=CC=2)=N1 OOEYPUFPMHMEAP-ONSXPEOJSA-N 0.000 claims description 3
- JESNSKPPMWEWAT-YSVRNHBLSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@@](C)(=N)=O)CC1 JESNSKPPMWEWAT-YSVRNHBLSA-N 0.000 claims description 3
- YIASZZUGUQHGBB-JTJFVBHCSA-N n-methyl-1-[4-[(3r)-3-methylmorpholin-4-yl]-6-[4-(methylsulfonimidoyl)oxan-4-yl]pyrimidin-2-yl]benzimidazol-2-amine Chemical compound CNC1=NC2=CC=CC=C2N1C(N=1)=NC(N2[C@@H](COCC2)C)=CC=1C1([S@](C)(=N)=O)CCOCC1 YIASZZUGUQHGBB-JTJFVBHCSA-N 0.000 claims description 3
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- 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
- 210000003905 vulva Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
R2は、
nは、0または1であり;
R2A、R2C、R2EおよびR2Fは、各々独立して、水素またはメチルであり;
R2BおよびR2Dは、各々独立して、水素またはメチルであり;
R2Gは、−NHR7および−NHCOR8より選択され;
R2Hは、フルオロであり;
R3は、メチルであり;
R4およびR5は、各々独立して、水素またはメチルであり、またはR4およびR5は、それらが結合している原子と一緒になって、環Aを形成し;
環Aは、C3−6シクロアルキル、またはOおよびNより選択される1個のヘテロ原子を含有する飽和4〜6員複素環式環であり;
R6は、水素であり;
R7は、水素またはメチルであり;
R8は、メチルである)
を有する化合物、またはその薬学的に許容しうる塩を提供する。
R2は、
nは、0または1であり;
R2A、R2C、R2EおよびR2Fは、各々独立して、水素またはメチルであり;
R2BおよびR2Dは、各々独立して、水素またはメチルであり;
R2Gは、−NH2、−NHMeおよび−NHCOMeより選択され;
R2Hは、フルオロであり;
R3は、メチルであり;
R4およびR5は、各々独立して、水素またはメチルであり、またはR4およびR5は、それらが結合している原子と一緒になって、環Aを形成し;
環Aは、C3−6シクロアルキル、またはOおよびNより選択される1個のヘテロ原子を含有する飽和4〜6員複素環式環であり;そして
R6は、水素である)
を有する化合物、またはその薬学的に許容しうる塩を提供する。
(b)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
(c)H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
(d)H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);および
(e)N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984)。
C1−6アルキルについて:C1−3アルキル、ブチル、2−メチルプロピル、tert−ブチル、ペンチル、2,2−ジメチルプロピル、3−メチルブチルおよびヘキシル;
C3−6シクロアルキルについて:シクロプロピル、シクロブチル、シクロペンチルおよびシクロヘキシル;
C3−6シクロアルキルC1−3アルキルについて:シクロプロピルメチル、シクロプロピルエチル、シクロブチルメチル、シクロペンチルメチルおよびシクロヘキシルメチル;
アリールについて:フェニル;
アリールC1−3アルキルについて:ベンジルおよびフェネチル;
カルボシクリルについて:アリール、シクロヘキセニルおよびC3−6シクロアルキル;
ハロについて:フルオロ、クロロ、ブロモおよびヨード;
C1−3アルコキシについて:メトキシ、エトキシ、プロポキシおよびイソプロポキシ;
C1−6アルコキシについて:C1−3アルコキシ、ブトキシ、tert−ブトキシ、ペンチルオキシ、1−エチルプロポキシおよびヘキシルオキシ;
C1−3アルカノイルについて:アセチルおよびプロパノイル;
C1−6アルカノイルについて:アセチル、プロパノイルおよび2−メチルプロパノイル;
ヘテロアリールについて:ピリジニル、イミダゾリル、ピリミジニル、チエニル、ピロリル、ピラゾリル、チアゾリル、チアゾリル、トリアゾリル、オキサゾリル、イソオキサゾリル、フラニル、ピリダジニルおよびピラジニル;
ヘテロアリールC1−3アルキルについて:ピロリルメチル、ピロリルエチル、イミダゾリルメチル、イミダゾリルエチル、ピラゾリルメチル、ピラゾリルエチル、フラニルメチル、フラニルエチル、チエニルメチル、チエニルエチル、ピリジニルメチル、ピリジニルエチル、ピラジニルメチル、ピラジニルエチル、ピリミジニルメチル、ピリミジニルエチル、ピリミジニルプロピル、ピリミジニルブチル、イミダゾリルプロピル、イミダゾリルブチル、1,3,4−トリアゾリルプロピルおよびオキサゾリルメチル;
ヘテロシクリルについて:ヘテロアリール、ピロリジニル、ピペリジニル、ピペラジニル、アゼチジニル、モルホリニル、ジヒドロ−2H−ピラニル、テトラヒドロピリジンおよびテトラヒドロフラニル;
飽和ヘテロシクリルについて:オキセタニル、ピロリジニル、ピペリジニル、ピペラジニル、アゼチジニル、モルホリニル、テトラヒドロピラニルおよびテトラヒドロフラニル。
一つの側面において、nは、0である。
一つの側面において、R1は、モルホリン−4−イルおよび3−メチルモルホリン−4−イルより選択される。
一つの側面において、R2は、
R2Aは、水素である。
R2Bは、水素である。
R2Cは、水素である。
R2Dは、水素である。
R2Eは、水素である。
R2Fは、水素である。
本発明の一つの側面において、R2Gは、−NHR7および−NHCOR8より選択される。
本発明の一つの側面において、R4およびR5は、水素である。
本発明の一つの側面において、環Aは、C3−6シクロアルキル、または、OおよびNより選択される1個のヘテロ原子を含有する飽和4〜6複素環式環である。
一つの側面において、R6は、水素である。
一つの側面において、R7は、水素またはメチルである。
一つの側面において、R12は、メチルである。
R1が、モルホリン−4−イルおよび3−メチルモルホリン−4−イルより選択され;
nが、0または1であり;
R2Aが、水素であり;
R2Bが、水素であり;
R2Cが、水素であり;
R2Dが、水素であり;
R2Eが、水素であり;
R2Fが、水素であり;
R2Gが、−NHR7および−NHCOR8より選択され;
R2Hが、フルオロであり;
R3が、メチルであり;
R4およびR5が、それらが結合している原子と一緒になって、環Aを形成し;
環Aが、C3−6シクロアルキル、または、OおよびNより選択される1個のヘテロ原子を含有する飽和4〜6複素環式環であり;
R6が、水素であり;
R7が、水素またはメチルであり;そして
R8が、メチルである、式(I)を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R1が、モルホリン−4−イルおよび3−メチルモルホリン−4−イルより選択され;
nが、0または1であり;
R2Aが、水素であり;
R2Bが、水素であり;
R2Cが、水素であり;
R2Dが、水素であり;
R2Eが、水素であり;
R2Fが、水素であり;
R2Gが、−NH2、−NHMeおよび−NHCOMeより選択され;
R2Hが、フルオロであり;
R3が、メチルであり;
R4およびR5が、それらが結合している原子と一緒になって、環Aを形成し;
環Aが、C3−6シクロアルキル、または、OおよびNより選択される1個のヘテロ原子を含有する飽和4〜6複素環式環であり;
R6が、水素である、式(I)を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R1が、モルホリン−4−イルおよび3−メチルモルホリン−4−イルより選択され;
nが、0または1であり;
R2Aが、水素であり;
R2Bが、水素であり;
R2Cが、水素であり;
R2Dが、水素であり;
R2Eが、水素であり;
R2Fが、水素であり;
R2Gが、−NHR7および−NHCOR8より選択され;
R2Hが、フルオロであり;
R3が、メチルであり;
R4およびR5が、それらが結合している原子と一緒になって、環Aを形成し;
環Aが、シクロプロピル環、シクロブチル環、シクロペンチル環、オキセタニル環、テトラヒドロフリル環、テトラヒドロピラニル環、アゼチジニル環、ピロリジニル環またはピペリジニル環であり;
R6が、水素であり;
R7が、水素またはメチルであり;そして
R8が、メチルである、式(I)を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R1が、モルホリン−4−イルおよび3−メチルモルホリン−4−イルより選択され;
nが、0または1であり;
R2Aが、水素であり;
R2Bが、水素であり;
R2Cが、水素であり;
R2Dが、水素であり;
R2Eが、水素であり;
R2Fが、水素であり;
R2Gが、−NH2、−NHMeおよび−NHCOMeより選択され;
R2Hが、フルオロであり;
R3が、メチルであり;
R4およびR5が、それらが結合している原子と一緒になって、環Aを形成し;
環Aが、シクロプロピル環、シクロブチル環、シクロペンチル環、オキセタニル環、テトラヒドロフリル環、テトラヒドロピラニル環、アゼチジニル環、ピロリジニル環またはピペリジニル環であり;そして
R6が、水素である、式(I)を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R2は、
nは、0または1であり;
R2Aは、水素であり;
R2Bは、水素であり;
R2Cは、水素であり;
R2Dは、水素であり;
R2Eは、水素であり;
R2Fは、水素であり;
R2Gは、−NHR7および−NHCOR8より選択され;
R2Hは、フルオロであり;
R3は、メチル基であり;
R6は、水素であり;
R7は、水素またはメチルであり;そして
R8は、メチルである)
を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R2は、
nは、0または1であり;
R2Aは、水素であり;
R2Bは、水素であり;
R2Cは、水素であり;
R2Dは、水素であり;
R2Eは、水素であり;
R2Fは、水素であり;
R2Gは、−NH2、−NHMeおよび−NHCOMeより選択され;
R2Hは、フルオロであり;
R3は、メチル基であり;そして
R6は、水素である)
を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R2は、
nは、0または1であり;
R2Aは、水素であり;
R2Bは、水素であり;
R2Cは、水素であり;
R2Dは、水素であり;
R2Eは、水素であり;
R2Fは、水素であり;
R2Gは、−NHR7であり;
R2Hは、フルオロであり;
R3は、メチル基であり;
R6は、水素であり;そして
R7は、水素である)
を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
R2は、
nは、0であり;
R2Aは、水素であり;
R2Bは、水素であり;
R2Cは、水素であり;
R2Dは、水素であり;
R2Eは、水素であり;
R2Fは、水素であり;
R2Gは、−NHR7であり;
R2Hは、フルオロであり;
R3は、メチル基であり;
R6は、水素であり;そして
R7は、メチルである)
を有する部分集合の化合物またはそれらの薬学的に許容しうる塩を提供する。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[((R)−S−メチルスルホンイミドイル)メチル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール;
1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−(S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−c]ピリジン;
N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((R)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−インドール;
4−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;および
6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
のいずれか一つより選択される化合物または化合物の組み合わせ、またはその薬学的に許容しうる塩を提供する。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[(R)−(S−メチルスルホンイミドイル)メチル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−(R)−(S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;および
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−(S)−(S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
のいずれか一つより選択される化合物または化合物の組み合わせ、またはその薬学的に許容しうる塩を提供する。
次の検定は、ATRキナーゼ阻害剤としての本発明の化合物の作用を測定するのに用いることができる。
in vitro 酵素検定に用いるためのATRは、HeLa核抽出物(CILBiotech, Mons, Belgium)から、次の緩衝液(25mMのHEPES(pH7.4)、2mMのMgCl2、250mMのNaCl、0.5mMのEDTA、0.1mMのNa3VO4、10%v/vグリセロールおよび0.01%v/v Tween 20)中に入っているATRのアミノ酸400−480(Tibbetts RS et al, 1999, Genes Dev. 13:152-157)へ上昇したウサギ多クローン性抗血清での免疫沈降によって得た。ATR−抗体複合体は、核抽出物から、プロテインA−Sepharoseビーズ(Sigma,#P3476)と一緒に1時間インキュベート後、遠心分離によってビーズを回収することによって単離した。96ウェルプレートのウェル中において、10μLのATR含有 Sepharose ビーズを、1μgの基質グルタチオンS−トランスフェラーゼ−p53N66(グルタチオンS−トランスフェラーゼに融合したp53のNH2末端66アミノ酸を、大腸菌(E.coli)中で発現させた)と一緒に、ATR検定緩衝液(50mMのHEPES(pH7.4)、150mMのNaCl、6mMのMgCl2、4mMのMnCl2、0.1mMのNa3VO4、0.1mMのDTTおよび10%(v/v)グリセロール)中において阻害剤の存在下または不存在下の37℃でインキュベートした。穏やかに振とうしながら10分後、ATPを3μMの最終濃度へと加え、そして反応を、37℃で更に1時間続けた。その反応を、100μLのPBSの添加によって止め、そして反応を、白色不透明グルタチオン被覆96ウェルプレート(NUNC #436033)に移し、4℃で一晩インキュベートした。次に、このプレートを、PBS/0.05%(v/v)Tween 20で洗浄し、吸取乾燥させ、そして標準的なELISA(Enzyme-Linked ImmunoSorbent Assay)技法により、ホスホセリン15p53(16G78)抗体(Cell Signaling Technology,#9286)で分析した。リン酸化したグルタチオンS−トランスフェラーゼ−p53N66基質の検出は、ヤギ抗マウス西洋ワサビペルオキシダーゼ結合二次抗体(Pierce,#31430)との組合せで行った。増強された化学発光溶液(NEN,Boston,MA)を用いて、シグナルを生じ、そして化学発光検出は、TopCount(Packard,Meriden,CT)プレートリーダーによって行った。
ATMおよびATRは、DNA損傷への明瞭な且つ重複した応答を有する。それらは、互いに関与すべきであり、そして応答は協調しているべきである。どちらの経路も、電離放射線によって活性化されることがありうるが、しかしながら、ATRだけは、UVによって活性化される。UV処理は、高処理量細胞検定に用いるのに実用的でないので、UV模擬4NQ0(Sigma)を、ATR DNA損傷応答経路を活性化させるのに選択した。
化合物の増強作用因子(PF50)は、ATR阻害剤との組合せで用いられた場合の化学療法薬の作用の倍増の尺度である。具体的には、これは、化学療法薬、典型的に、カルボプラチンの存在下における対照細胞成長のIC50を、この試剤および目的のATR阻害剤の存在下における細胞成長のIC50で割った比率として計算する。この目的のために、HT29細胞を、96ウェルプレートの各々のウェル中において80μlの容量中に、指数関数的成長を検定時間の間中確実にする適当な密度(典型的に、1000〜1500個細胞)で播種し、37℃で一晩インキュベートした。引き続き、細胞は、DMSOビヒクルを投与するかまたは一定濃度(典型的に、1μM、0.3μMおよび0.1μM)の試験化合物で処理した。37℃で1時間インキュベーション後、それら細胞を、化学療法薬の既知の感受性に基づくその10ポイント用量反応(典型的に、カルボプラチンについて30〜0.001ug/ml)で更に処理した。細胞を37℃で5日間成長させ、その時間後、細胞成長を、スルホローダミンB(SRB)検定(Skehan, P et al, 1990 New colorimetric cytotoxic assay for anticancer-drug screening. J. Natl. Cancer Inst. 82, 1107-1112.)を用いて評価した。具体的には、基剤を除去し、そして細胞を、100μlの氷冷10%(w/v)トリクロロ酢酸で固定した。次に、それらプレートを、4℃で20分間インキュベート後、水で4回洗浄した。次に、各々のウェルを、100μLの1%酢酸中の0.4%(w/v)SRBで20分間染色後、1%酢酸で更に4回洗浄した。次に、プレートを室温で2時間乾燥させ、そして各々のウェル中への100μLの Tris Base pH8.5の添加によって染料を可溶化した。プレートを振とう後、光学濃度を564nm(OD564)で測定した。PF50を計算するために、化学療法薬の用量反応曲線について得られたOD564値を、ビヒクル単独で処理された細胞から得られた値の百分率として表した。同様に、ATR阻害剤の包含の対照とするために、一定のATR阻害剤濃度との組合せで調べられた化学療法薬からの値を、ATR阻害剤単独の該当する濃度で処理された細胞から得られた値の百分率として表した。これら内部制御曲線から、IC50値を計算し、そしてPF50を、上記のように、これら値の比率として決定した。化合物は、ATR阻害剤のそれらだけで最小発育阻害を示す濃度でPF50値を用いて比較する。IC50値は、用量反応4パラメーターロジスティックモデル#203を用いて、XLfit(IDBS, Surrey UK)で計算した。上部(最大)および下部(最小)曲線適合は、フリーであったので、それぞれ、100%〜0%へ固定されることはなかった。
検定は、AlphaScreen 技術(Gray et al., Analytical Biochemistry, 2003, 313: 234-245)を用いて、リコンビナントmTORによるリン酸化を阻害する試験化合物の能力を決定した。
この検定は、レーザー走査によって生じる画像の特徴を速やかに定量するのに用いることができるプレートリーダーである Acumen Explorer技術(Acumen Bioscience Limited)を用いて評価されるように、Akt中のセリン473のリン酸化を阻害する試験化合物の能力を決定する。
(ii)細胞分裂抑制薬であって、抗エストロゲン(例えば、タモキシフェン、トレミフェン(toremifene)、ラロキシフェン(raloxifene)、ドロロキシフェン(droloxifene)およびヨードキシフェン(iodoxyfene));エストロゲン受容体ダウンレギュレーター(例えば、フルヴェストラント(fulvestrant));抗アンドロゲン(例えば、ビカルタミド(bicalutamide)、フルタミド、ニルタミド(nilutamide)および酢酸シプロテロン);LHRHアンタゴニストまたはLHRHアゴニスト(例えば、ゴセレリン、ロイプロレリン(leuprorelin)およびブセレリン(buserelin));プロゲストゲン(例えば、酢酸メゲストロール);アロマターゼ阻害剤(例えば、アナストロゾール(anastrozole)、レトロゾール(letrozole)、ボラゾール(vorazole)およびエクセメスタン(exemestane)として);およびフィナステリドなどの5α−レダクターゼの阻害剤などのもの;
(iii)抗浸潤薬(例えば、4−(6−クロロ−2,3−メチレンジオキシアニリノ)−7−[2−(4−メチルピペラジン−1−イル)エトキシ]−5−テトラヒドロピラン−4−イルオキシキナゾリン(AZD0530;国際特許出願WO01/94341号)およびN−(2−クロロ−6−メチルフェニル)−2−{6−[4−(2−ヒドロキシエチル)ピペラジン−1−イル]−2−メチルピリミジン−4−イルアミノ}チアゾール−5−カルボキサミド(ダサチニブ(dasatinib)、BMS−354825;J. Med. Chem., 2004, 47, 6658-6661)のようなc−Srcキナーゼファミリー阻害剤;およびマリマスタト(marimastat)のようなメタロプロテイナーゼ阻害剤、およびウロキナーゼプラスミノーゲンアクチベーター受容体機能の阻害剤);
(iv)増殖因子機能の阻害剤:例えば、このような阻害剤には、増殖因子抗体および増殖因子受容体抗体(例えば、抗erbB2抗体トラスツズマブ(trastuzumab)[HerceptinTM]および抗erbB1抗体セツキシマブ(cetuximab)[C225])が含まれる;このような阻害には、更に、例えば、チロシンキナーゼ阻害剤、例えば、上皮増殖因子ファミリーの阻害剤(例えば、N−(3−クロロ−4−フルオロフェニル)−7−メトキシ−6−(3−モルホリノプロポキシ)キナゾリン−4−アミン(ゲフィチニブ(gefitinib),ZD1839)、N−(3−エチニルフェニル)−6,7−ビス(2−メトキシエトキシ)キナゾリン−4−アミン(エルロチニブ(erlotinib),OSI−774)および6−アクリルアミド−N−(3−クロロ−4−フルオロフェニル)−7−(3−モルホリノプロポキシ)キナゾリン−4−アミン(CI1033)などのEGFRファミリーチロシンキナーゼ阻害剤、およびラパチニブ(lapatinib)などのerbB2チロシンキナーゼ阻害剤);肝細胞増殖因子ファミリーの阻害剤;イマチニブ(imatinib)などの血小板由来増殖因子ファミリーの阻害剤;セリン/トレオニンキナーゼの阻害剤(例えば、ファルネシルトランスフェラーゼ阻害剤などのRas/Rafシグナリング阻害剤、例えば、ソラフェニブ(sorafenib)(BAY43−9006));およびMEKおよび/またはAktキナーゼによる細胞シグナリングの阻害剤が含まれる;
(v)抗血管新生薬であって、血管内皮増殖因子の作用を阻害するものなど[例えば、抗血管内皮細胞増殖因子抗体ベヴァシズマブ(bevacizumab)(AvastinTM);およびVEGF受容体チロシンキナーゼ阻害剤であって、4−(4−ブロモ−2−フルオロアニリノ)−6−メトキシ−7−(1−メチルピペリジン−4−イルメトキシ)キナゾリン(ZD6474;WO01/32651号中の実施例2)、4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピロリジン−1−イルプロポキシ)キナゾリン(AZD2171;WO00/47212号中の実施例240)、ヴァタラニブ(vatalanib)(PTK787;WO98/35985号)およびSU11248(スニチニブ(sunitinib);WO01/60814号)などのもの;および他の機構によって働く化合物(例えば、リノマイド(linomide)、インテグリンαvβ3機能の阻害剤、およびアンギオスタチン(angiostatin)];
(vi)血管損傷薬であって、コンブレタスタチンA4(combretastatin A4);および国際特許出願WO99/02166号、WO00/40529号、WO00/41669号、WO01/92224号、WO02/04434号およびWO02/08213号に開示された化合物などのもの;
(vii)アンチセンス療法、例えば、抗rasアンチセンス薬であるISIS2503などの、上に挙げられた標的に向けられているもの;
(viii)遺伝子治療アプローチであって、異常p53または異常BRCA1またはBRCA2などの異常遺伝子を置き換えるアプローチ;シトシンデアミナーゼ、チミジンキナーゼまたは細菌ニトロレダクターゼ酵素を用いたものなどのGDEPT(遺伝子に支配される酵素プロドラッグ療法(gene-directed enzyme pro-drug therapy))アプローチ;および多剤耐性遺伝子治療などの、化学療法または放射線療法への患者耐性を増加させるアプローチを含めたもの;および
(ix)免疫療法アプローチであって、インターロイキン2、インターロイキン4または顆粒球−マクロファージコロニー刺激因子などのサイトカインでのトランスフェクションなどの、患者腫瘍細胞の免疫原性を増加させる ex-vivo および in-vivo アプローチ;T細胞アネルギーを減少させるアプローチ;サイトカインでトランスフェクションされた樹状細胞などのトランスフェクションされた免疫細胞を用いたアプローチ;サイトカインでトランスフェクションされた腫瘍細胞系を用いたアプローチ;および抗イディオタイプ抗体を用いたアプローチを含めたもの。
ここで、本発明を、次の実施例で詳しく説明するが、ここにおいて、概して、
(i)操作は、室温(RT)で、すなわち、17〜25℃の範囲内で、そして特に断らない限り、N2またはArなどの不活性ガスの雰囲気下で行った;
(ii)概して、反応経過は、質量分析計(LCMS)に通常はカップリングした薄層クロマトグラフィー(TLC)および/または分析高速液体クロマトグラフィー(HPLC)で追跡した。与えられている反応時間は、必ずしも、達成可能な最小値ではない;
(iii)必要な場合、有機溶液を、無水MgSO4またはNa2SO4上で乾燥させ、処理手順は、伝統的な相分離技術を用いて、または(xiii)に記載のようにSCXを用いることによって行い、蒸発は、真空中のロータリーエバポレーションによってかまたは、Genevac HT−4/EZ−2または Biotage V10中で行った;
(iv)示されている場合の収率は、必ずしも、達成可能な最大値ではなく、そしてより多い量の反応生成物が必要とされるならば、必要な時に反応を繰り返した;
(v)概して、式(I)の最終生成物の構造は、核磁気共鳴(NMR)および/または質量スペクトル技法によって確認した;エレクトロスプレー質量スペクトルデータは、正・負双方のイオンデータを獲得する Waters ZMDまたは Waters ZQ LC/質量分析計を用いて得たが、概して、親構造に関するイオンのみを報告している;プロトンNMR化学シフト値は、300MHzの磁場強度で操作する Bruker DPX300スペクトロメーターか、400MHzで操作する Bruker DRX400か、500MHzで操作する Bruker DRX500かまたは700MHzで操作する Bruker AV700を用いて、δスケールで測定した。特に断らない限り、NMRスペクトルは、d6−ジメチルスルホキシド中において400MHzで得た。次の略語を用いた:s,一重線;d,二重線;t,三重線;q,四重線;m,多重線;br,幅広;qn,五重線;
(vi)特に断らない限り、不斉炭素および/または硫黄原子を含有する化合物は、分割しなかった;
(vii)中間体は、必ずしも完全に精製しなかったが、それらの構造および純度は、TLC、分析HPLCおよび/またはNMR分析および/または質量分析によって評価した;
(viii)特に断らない限り、フラッシュカラムクロマトグラフィー(FCC)は、Merck Kieselgel シリカ(Art. 9385)上または逆相シリカ(Fluka シリカゲル90C18)上または Silicycle カートリッジ(40〜63μmシリカ、4〜330g重量)上または Grace resolv カートリッジ(4〜120g)上または RediSep Rf 1.5 Flash カラム上または RediSep Rf 高性能 Gold Flash カラム(150〜415g重量)上または RediSep Rf Gold C18 Reversed-phase カラム(20〜40μmシリカ)上において、手動でかまたは自動で、Isco Combi Flash Companion システムまたは類似のシステムを用いて行った;
(ix)分取逆相HPLC(RP HPLC)は、C18逆相シリカ上において、例えば、Waters‘Xterra’または‘XBridge’分取逆相カラム(5μmシリカ、19mm直径、100mm長さ)上、または Phenomenex“Gemini”または‘AXIA’分取逆相カラム(5μmシリカ、110A、21.1mm直径、100mm長さ)上において、漸減極性混合物を溶離剤として、例えば、溶媒Aとしての[0.1〜5%ギ酸または1〜5%水性水酸化アンモニウム(d=0.88)を含有]および溶媒Bとしてのアセトニトリルまたは3:1のMeOH:MeCNを用いて行った;典型的な手順は、次の通りであると考えられる。溶媒Aおよび溶媒Bのそれぞれ85:15(または、適宜、別の比率)の混合物〜5:95の溶媒Aおよび溶媒Bの混合物の25mL/分で9.5分間にわたる溶媒勾配;
(x)次の分析HPLC法を用いた;概して、逆相シリカを、約1mL/分の流速で用い、そして検出は、エレクトロスプレー質量分析および254nmの波長でのUV吸光度によった。分析HPLCは、C18逆相シリカ上、Phenomenex“Gemini”分取逆相カラム(5μmシリカ、110A、2mm直径、50mm長さ)上において、漸減極性混合物を溶離剤として、例えば、溶媒Aとしての水(0.1%ギ酸または0.1%アンモニアを含有)および溶媒Bとしてのアセトニトリルまたは3:1のMeOH:MeCNの漸減極性混合物を用いて行った。典型的な分析HPLC法は、次の通りであると考えられる。溶媒Aおよび溶媒Bのそれぞれ95:5の混合物〜5:95の溶媒Aおよび溶媒Bの混合物の約1mL/分で4分間にわたる溶媒勾配;
(xi)特定の化合物を、酸付加塩、例えば、一塩酸塩または二塩酸塩として得た場合、その塩の化学量論は、その化合物中の塩基性基の数および性状に基づき、概して、その塩の正確な化学量論は、例えば、元素分析データによって決定しなかった;
(xii)反応が、マイクロ波の使用に言及している場合、次のマイクロ波反応器の一つを用いた。Biotage Initiator、Personal Chemistry Emrys Optimizer、Personal Chemistry Smithcreator またはCEMExplorer;
(xii)化合物は、強陽イオン交換(SCX)クロマトグラフィーにより、Isolute SPEフラッシュSCX−2カラムまたはSCX−3カラム(International Sorbent Technology Limited, Mid Glamorgan, UK)を用いて精製した;
(xiv)次の分取キラルHPLC法を用いた;概して、10〜350ml/分の流速、そして検出は、254nmの典型的な波長でのUV吸光度によった。約1〜100mg/mlの試料濃度を、イソヘキサンまたはヘプタンと混合されてよいMeOH、EtOHまたはiPAなどの適する溶媒混合物中において、0.5〜100mlの注入容量および10〜150分の実験時間および25〜35℃の典型的なオーブン温度で用いた;
(xv)次の分析キラルHPLC法を用いた;概して、1ml/分の流速、そして検出は、254nmの典型的な波長でのUV吸光度によった。約1mg/mlの試料濃度を、EtOHなどの適する溶媒混合物中において、約10μlの注入容量および10〜60分の実験時間および25〜35℃の典型的なオーブン温度で用いた;
(xvi)次の分取キラルSFC(超臨界流体クロマトグラフィー)法を用いた;概して、約70ml/分の流速、そして検出は、254nmの典型的な波長でのUV吸光度によった。約100mg/mlの試料濃度を、MeOHなどの適する溶媒混合物中において、約0.5mlの注入容量および10〜150分の実験時間および25〜35℃の典型的なオーブン温度で用いた;
(xvii)概して、実施例は、ACD Name Ver 10.06を用いて命名し、中間体化合物は、CambridgeSoft による ChemDraw Ultra 11.0.2の「Structure to Name」部分を用いて命名した;
(xviii)上述のものに加えて、次の略語を用いた。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[((R)−S−メチルスルホンイミドイル)メチル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン
1H NMR (400 MHz, CDCl3) 1.40 (3H, d), 3.17 (3H, s), 3.39 (1H, tt), 3.62 (1H, td), 3.77 (1H, dd), 3.85 (1H, d), 4.08 (1H, dd), 4.18 (1H, d), 4.37 - 4.48 (2H, q), 4.51 (1H, s), 6.59 (1H, s), 7.35 (1H, t), 7.46 (1H, d), 8.06 (1H, d), 8.42 (1H, d), 10.16 (1H, s);m/z:(ES+)MH+,387.19。
1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.34 (1H, td), 3.55 (1H, td), 3.70 (1H, dd), 3.81 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.37 (1H, br s), 7.15 (1H, s);m/z:(ESI+)MH+,272.43。
1H NMR (400 MHz, CDCl3) 1.35 (3H, d), 3.33 (1H, td), 3.55 (1H, td), 3.69 (1H, dd), 3.80 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s), 4.36 (1H, br s), 7.15 (1H, s);m/z:(ESI+)MH+,272.43。
1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 2.65 (1H, br s), 3.25 - 3.32 (1H, m), 3.51 - 3.57 (1H, m), 3.67 - 3.70 (1H, m), 3.78 (1H, d), 3.98 - 4.09 (2H, m), 4.32 (1H, br s), 4.59 (2H, s), 6.44 (1H, s);m/z:(ESI+)MH+,244.40。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.13 (3H, s), 3.27 - 3.34 (1H, m), 3.51 - 3.57 (1H, m), 3.66 - 3.70 (1H, m), 3.79 (1H, d), 3.99 - 4.03 (2H, m), 4.34 (1H, br s), 5.09 (2H, d), 6.52 (1H, s);m/z:(ESI+)MH+,322.83。
1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 - 4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s);m/z:(ESI+)MH+354.31。
1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98 - 4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s);m/z:(ESI+)MH+,354.31。
1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.07 (3H, s), 3.11 - 3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.92 - 4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s);m/z:(ES+)MH+,274.36。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H, s)。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, d), 3.29 (1H, td), 3.54 (1H, td), 3.68 (1H, dd), 3.73 - 3.82 (2H, m), 3.94 (1H, dd), 4.00 (2H, dd), 4.33 (1H, s), 6.42 (1H, s)。
1HNMR (400 MHz, CDCl3) 1.33 (3H, d), 2.61 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6.41 (1H, s)。キラルHPLC:(HP1100 System 5,20μm Chiralpak AD−H(250mmx4.6mm)カラムを50/50/0.1のヘキサン/EtOH/TEAで溶離する)Rf,12.192 98.2%。
1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 2.64 (3H, d), 3.14 - 3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88 - 3.96 (2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4.33 (1H, s), 6.81 (1H, s);m/z:(ESI+)MH+,290.43。
1H NMR (400 MHz, CDCl3) 1.29 (3H, dd), 2.56 (3H, s), 3.15 - 3.33 (1H, m), 3.46 (1H, tt), 3.55 - 3.83 (3H, m), 3.85 - 4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s)。キラルHPLC:(HP1100 System 6,20μm Chiralpak AD(250mmx4.6mm)カラムを50/50/0.1のイソヘキサン/EtOH/TEAで溶離する)Rf,7.197 >99%。
1H NMR (400 MHz, CDCl3) 1.28 (3H, d), 2.58 (3H, s), 3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88 - 4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s)。キラルHPLC:(HP1100 System 6,20μm Chiralpak AD(250mmx4.6mm)カラムを50/50/0.1のイソヘキサン/EtOH/TEAで溶離する)Rf,16.897 >99%。
1H NMR (400 MHz, DMSO-d6) 1.22 (3H, d), 3.17 - 3.27 (1H, m), 3.44 (1H, td), 3.59 (1H, dd), 3.62 (3H, s), 3.74 (1H, d), 3.95 (1H, dd), 4.04 (1H, br s), 4.28 (1H, s), 5.08 (2H, q), 6.96 (1H, s);m/z:(ESI+)MH+,401.12および403.13。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.21 - 3.38 (1H, m), 3.42 (3H, d), 3.45 - 3.57 (1H, m), 3.61 - 3.70 (1H, m), 3.78 (1H, d), 4.01 (1H, dd), 3.90 -4.15 (1H, br s), 4.30 (1H, s), 4.64 (1H, dd), 4.84 (1H, dd), 6.49 (1H, d);m/z:(ESI+)MH+,541.35。
1H NMR (400 MHz, DMSO-d6) 6.59 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.55 (1H, t), 7.65 (1H, dd), 7.70 (1H, ddd), 7.87 - 7.93 (2H, m), 8.13 (1H, d), 12.42 (1H, s), 13.32 (1H, s)。
1H NMR (400 MHz, DMSO-d6) 6.58 (1H, d), 7.06 (1H, dd), 7.45 (1H, d), 7.64 (1H, d), 8.13 (1H, d), 12.44 (1H, s);m/z:(ES+)(MH+MeCN)+,176.03。
1H NMR (400 MHz, DMSO-d6) 6.40 - 6.45 (1H, m), 7.33 (1H, d), 7.57 - 7.63 (1H, m), 8.09 (1H, t), 12.02 (1H, s);m/z:(ES+)MH+,198.92。
1H NMR (400 MHz, DMSO-d6) 6.43 (1H, dd), 7.33 (1H, d), 7.55 - 7.66 (1H, m), 8.09 (1H, d), 12.03 (1H, s);m/z:(ES+)MH+,199.22。
1H NMR (400 MHz, CDCl3) 2.38 (3H, s), 6.64 (1H, d), 7.28 (2H, d), 7.36 (1H, d), 7.78 (1H, d), 8.06 (2H, d), 8.22 (1H, d);m/z:(ES+)MH+,353.23。
1H NMR (400 MHz, CDCl3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.22 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, m), 8.42 (1H, d);m/z:(ES+)MH+,399.40。
1H NMR (400 MHz, CDCl3) 1.36 (12H, s), 2.35 (3H, s), 7.01 (1H, d), 7.23 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, d), 8.42 (1H, d);m/z:(ES+)MH+,399.40。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン、および、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.51 (3H, m), 1.70 - 1.82 (1H, m), 3.11 (3H, s), 3.28 (1H, m, 水ピークで不鮮明), 3.48 - 3.60 (1H, m), 3.68 (1H, dd), 3.75 - 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.51 - 7.67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s);m/z:(ES+)MH+,413.12。キラルHPLC:(HP1100 System 4,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを50/25/25/0.1のイソヘキサン/EtOH/MeOH/TEAで溶離する)Rf,9.013 >99%。
実施例2.02:4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン(326mg,0.79mmol)を、DCM(3ml)中に溶解させた。シリカゲル(0.5g)を加え、その混合物を真空中で濃縮した。得られた粉末を、シリカ上のフラッシュクロマトグラフィーにより、DCM中の0〜5%MeOHの勾配で溶離して精製した。純粋な画分を蒸発乾固させ、そして残留物を、EtOAc/n−ヘプタンから結晶化して、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン(256mg,79%)を白色結晶性固体として得た。
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.39 - 1.60 (3H, m), 1.71 - 1.81 (1H, m), 3.10 (3H, d), 3.21 - 3.29 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.54 - 7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s)。DSC(Mettler-Toledo DSC820、試料は、孔付きアルミニウムパン中において30℃〜350℃へ10℃/分の加熱速度で実験した)ピーク,224.11℃。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 - 1.58 (3H, m), 1.70 - 1.80 (1H, m), 3.10 (3H, d), 3.23 - 3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 - 7.61 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s);m/z:(ES+)MH+,413.12。キラルHPLC:(HP1100 System 4,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを50/25/25/0.1のイソヘキサン/EtOH/MeOH/TEAで溶離する)Rf,15.685 >99%。
実施例2.01:4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン(66.5mg)を、EtOH/水からの結晶化によって精製して、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン(0.050g)を得た。
1H NMR (400 MHz, CDCl3) 1.40 (3H, d), 1.59 (2H, s), 1.81 (2H, s), 2.41 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.59 - 3.67 (1H, m), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.54 (1H, s), 6.91 (1H, s), 7.34 (1H, t), 7.43 (1H, t), 8.05 (1H, d), 8.41 (1H, d), 9.14 (1H, s)。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.43 (3H, d), 3.46 - 3.59 (1H, m), 3.62 - 3.71 (1H, m), 3.79 (1H, d), 3.90 - 4.50 (2H, br s), 4.21 (1H, s), 4.66 (1H, dd), 4.86 (1H, dd), 6.50 (1H, d);m/z:(ES+)MH+,401.01,402.93。
1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 1.39 - 1.48 (2H, m), 1.69 - 1.77 (2H, m), 3.12 (3H, s), 3.22 - 3.36 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.78 (1H, d), 3.90 - 4.10 (1H, br s), 4.00 (1H, dd), 4.33 (1H, br s), 6.79 (1H, d);m/z:(ES+)MH+,331.08,333.00。
1H NMR (400 MHz, DMSO-d6) 1.21 (3H, d), 1.39 (3H, m), 1.62 - 1.71 (1H, m), 3.01 (3H, s), 3.43 (1H, tt), 3.58 (1H, dd), 3.72 (1H, d), 3.82 (1H, d), 3.93 (1H, dd), 4.01 (1H, s), 4.38 (1H, s), 6.96 (1H, d);m/z:(ES+)MH+,331.46および333.43。
1H NMR (400 MHz, CDCl3) 1.37 (3H, d), 1.56 (2H, m), 1.83 (2H, q), 2.37 (4H, s), 3.16 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.85 (1H, d), 4.01 - 4.19 (2H, m), 4.49 (1H, s), 6.95 (1H, d), 7.28 (2H, d, CDCL3ピークで不鮮明), 7.44 (1H, t), 7.82 (1H, d), 8.02 - 8.11 (3H, m), 8.52 (1H, d);m/z:(ES+)MH+,567.11。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.42 (1H, dd), 1.47 - 1.58 (2H, m), 1.68 - 1.80 (1H, m), 3.10 (3H, s), 3.24 - 3.31 (1H, m), 3.51 (1H, t), 3.66 (1H, dd), 3.80 (1H, d), 3.83 - 3.88 (1H, m), 4.00 (1H, dd), 4.20 (1H, s), 4.57 (1H, s), 6.99 (1H, d), 7.22 (1H, dd), 7.53 - 7.63 (1H, m), 7.94 (1H, d), 8.34 (1H, t), 11.80 (1H, s);m/z:(ES+)MH+,413.47。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.41 - 1.59 (3H, m), 1.76 (1H, dt), 3.10 (3H, d), 3.31 (1H, d), 3.52 (1H, t), 3.67 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.58 (1H, s), 7.00 (1H, d), 7.22 (1H, dd), 7.54 - 7.63 (1H, m), 7.95 (1H, d), 8.33 (1H, d), 11.75 (1H, s);m/z:(ES+)MH+,413.19。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.43 (1H, dd), 1.46 - 1.58 (2H, m), 1.69 - 1.77 (1H, m), 3.10 (3H, s), 3.27 (1H, td), 3.51 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.85 (1H, s), 4.01 (1H, dd), 4.19 (1H, d), 4.59 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54 - 7.63 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s);m/z:(ES+)MH+,413.50。キラルHPLC:(Kronlab プレプシステム,20μm Chiralpak OJ(250mmx4.6mm)カラムを50/25/25/0.1のヘキサン/EtOH/MeOH/TEAで溶離する)Rf,9.684 99.4%。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.38 - 1.46 (1H, dd), 1.51 (2H, m), 1.72 - 1.81 (1H, m), 3.10 (3H, s), 3.26 (1H, td), 3.51 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.84 (1H, s), 3.94 - 4.04 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.53 - 7.63 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s);m/z:(ES+)MH+,413.53。キラルHPLC:(Kronlab プレプシステム,20μm Chiralpak OJ(250mmx4.6mm)カラムを50/25/25/0.1のヘキサン/EtOH/MeOH/TEAで溶離する)Rf,18.287 99.3%。
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.61 (3H, m), 1.70 - 1.81 (1H, m), 3.10 (3H, d), 3.53 (1H, dd), 3.68 (1H, dd), 3.77 - 3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.58 (1H, s), 7.01 (1H, d), 7.23 (1H, dd), 7.55 - 7.61 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s)。m/z:(ES+)MH+,413.19。キラルHPLC:(HP1100 System 4,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを50/25/25/0.1のイソヘキサン/EtOH/MeOH/TEAで溶離する)Rf,9.023 88.0%,15.796 12.0%。
1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 1.43 (2H, q), 1.72 (2H, q), 2.35 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd), 4.32 (1H, s), 6.79 (1H, s);m/z:(ES+)MH+,331.18および333.15。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, t), 1.39 - 1.6 (3H, m), 1.7 - 1.8 (1H, m), 3.10 (3H, s), 3.26 (1H, d), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 3.97 - 4.02 (1H, m), 4.19 (1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.22 (1H, dd), 7.53 - 7.61 (1H, m), 7.95 (1H, d), 8.33 (1H, d), 11.75 (1H, s);m/z:(ES+)MH+,413.08。
1H NMR (400 MHz, CDCl3) 1.36 (3H, d), 1.52 (2H, dd), 1.80 (2H, dd), 2.24 - 2.46 (3H, s), 3.10 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.84 (1H, d), 3.99 - 4.18 (2H, m), 4.47 (1H, s), 6.91 (1H, s), 7.23 - 7.3 (3H, m, CDCl3で不鮮明), 7.45 (1H, d), 7.81 (1H, d), 8.08 (3H, dd), 8.51 (1H, d);m/z:(ES+)MH+,567.4。
1H NMR (400 MHz, DMSO-d6) 1.19 - 1.31 (3H, m), 1.37 - 1.58 (3H, m), 1.75 (1H, ddd), 2.34 (3H, s), 3.04 (3H, d), 3.2 - 3.27 (1H, m), 3.46 - 3.54 (1H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.82 (1H, s), 3.99 (1H, dd), 4.16 (1H, d), 4.54 (1H, s), 7.04 (1H, s), 7.42 (2H, d), 7.54 (1H, d), 8.01 (3H, dd), 8.10 (1H, d), 8.49 (1H, d);m/z:(ES+)MH+,567.00。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.38 - 1.47 (1H, m), 1.47 - 1.57 (2H, m), 1.75 (1H, dd), 3.11 (1H, s), 3.28 (1H, dd), 3.52 (1H, dd), 3.67 (1H, dd), 3.81 (1H, d), 3.98 - 4.04 (1H, m), 4.18 (1H, s), 4.58 (1H, s), 7.00 (1H, s), 7.22 (1H, d), 7.59 (1H, d), 7.95 (1H, d), 8.34 (1H, d), 8.41 (3H, s), 11.83 (1H, s);m/z:(ES+)MH+,413.11。
1H NMR (400 MHz, CDCl3) 1.39 (3H, d), 1.53 - 1.61 (2H, m), 1.78 - 1.84 (2H, m), 2.43 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.63 (1H, td), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.53 (1H, s), 6.92 (1H, s), 7.34 (1H, dd), 7.41 - 7.47 (1H, m), 8.06 (1H, d), 8.43 (1H, d), 9.60 (1H, s);m/z:(ES+)MH+,413.12。キラルHPLC:(HP1100 System 4,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを50/25/25/0.1のヘプタン/EtOH/MeOH/TEAで溶離する)Rf,8.113 98.9%。
m/z:(ES+)MH+,162.88。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.44 (1H, dd), 1.47 - 1.58 (2H, m), 1.76 (1H, dt), 3.11 (3H, s), 3.26 (1H, dd), 3.52 (1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.85 (1H, d), 4.02 (1H, dd), 4.20 (1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.23 (1H, dd), 7.57 - 7.62 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.81 (1H, s);m/z:(ES+)MH+,413.12。Mpt.(Buchi Melting Point B−545)222℃。キラルHPLC:(HP1100 System 7,5μm Chiralcel OJ(250mmx4.6mm)カラムを50/50/0.1のヘプタン/(50/50のEtOH/MeOH)/TEAで溶離する)Rf,9.836 99.8%。
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.47 (2H, dq), 1.55 - 1.66 (1H, m), 1.69 - 1.89 (1H, m), 3.01 (3H, s), 3.04 (3H, d), 3.30 - 3.39 (1H, m), 3.52 (1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.95 (1H, s), 4.01 (1H, dd), 4.09 (1H, d), 4.51 (1H, s), 6.77 (1H, s), 6.97 (1H, t), 7.08 (1H, t), 7.25 (1H, d), 8.08 (1H, d), 8.67 (1H, d);m/z:(ES+)MH+,442.09。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを70/30/0.1のイソヘキサン/IPA/TEAで溶離する)Rf,12.219 >99%。
1H NMR (400 MHz, DMSO-d6) 1.33 (3H, t), 1.45 - 1.61 (2H, m), 1.61 - 1.68 (1H, m), 1.80 - 1.89 (1H, m), 3.07 (3H, s), 3.09 (3H, d), 3.39 (1H, dd), 3.58 (1H, td), 3.72 (1H, dd), 3.86 (1H, d), 4.01 (1H, s), 4.06 (1H, dd), 4.15 (1H, d), 4.55 (1H, s), 6.82 (1H, s), 7.03 (1H, t), 7.14 (1H, t), 7.31 (1H, d), 8.14 (1H, d), 8.73 (1H, d);m/z:(ES+)MH+,442.09。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを70/30/0.1のイソヘキサン/IPA/TEAで溶離する)Rf,25.093 >99%。
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.52 (3H, m), 1.72 - 1.86 (1H, m), 3.02 (3H, s), 3.03 (3H, d), 3.26 - 3.33 (1H, m), 3.52 (1H, t), 3.66 (1H, d), 3.80 (1H, d), 4.01 (2H, m), 4.12 (1H, s, メタノールピークで不鮮明), 4.51 (1H, s), 6.77 (1H, s), 6.98 (1H, t), 7.09 (1H, t), 7.25 (1H, d), 8.08 (1H, d), 8.71 (1H, d);m/z:(ES+)MH+,442.16。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを70/30/0.1のイソヘキサン/IPA/TEAで溶離する)Rf,11.984 97.9%。
1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87 - 7.00 (2H, m), 7.05 - 7.25 (2H, m), 7.49 (1H, s)。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール、および、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール
1H NMR (400 MHz, DMSO-d6) 1.33 (3H, d), 1.49 (1H, dd), 1.52 - 1.63 (2H, m), 1.75 - 1.84 (1H, m), 3.16 (3H, s), 3.53 - 3.62 (1H, m), 3.72 (1H, dd), 3.79 - 3.89 (2H, m), 4.06 (1H, dd), 4.23 (1H, d), 4.65 (1H, s), 6.96 (1H, s), 7.25 (1H, t), 7.37 (1H, s), 7.50 (1H, t), 7.59 (1H, d), 8.09 - 8.13 (1H, m), 11.27 (1H, s);m/z:(ES+)MH+,412.24。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを50/50/0.1のヘキサン/EtOH/TEAで溶離する)Rf,8.690 >99%。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.41 - 1.46 (1H, m), 1.50 (2H, td), 1.75 (1H, dd), 3.11 (3H, s), 3.52 (1H, dd), 3.64 - 3.70 (1H, m), 3.73 - 3.83 (2H, m), 4.01 (1H, d), 4.20 (1H, d), 4.56 (1H, s), 6.89 (1H, s), 7.19 (1H, t), 7.32 (1H, s), 7.44 (1H, s), 7.53 (1H, d), 8.04 - 8.08 (1H, m), 11.22 (1H, s);m/z:(ES+)MH+,412.24。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを50/50/0.1のヘキサン/EtOH/TEAで溶離する)Rf,36.980 >99%。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.39 - 1.56 (3H, m), 1.69 - 1.78 (1H, m), 3.10 (3H, d), 3.52 (1H, td), 3.66 (1H, dd), 3.72 - 3.83 (2H, m), 4.00 (1H, dd), 4.20 (1H, d), 4.57 (1H, s), 6.89 (1H, d), 7.18 (1H, t), 7.31 (1H, t), 7.43 (1H, t), 7.53 (1H, d), 8.05 (1H, dd), 11.21 (1H, s);m/z:(ES+)MH−,412.55。キラルHPLC:(HP1100 System 4,5μm Chiralpak AS−H(250mmx4.6mm)カラムを50/50/0.1のヘプタン/EtOH/TEAで溶離する)Rf,4.511 >99%。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.28 (1H, dd), 3.42 (3H, d), 3.46 - 3.57 (1H, m), 3.61 - 3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, d), 4.85 (1H, dd), 6.49 (1H, d);m/z:(ES+)MH+,400.94および402.85。キラルHPLC:(HP1100 System 4,5μm Chiralpak AD−H(250mmx4.6mm)カラムを50/50のヘプタン/EtOHで溶離する)Rf,4.367 12.5%,6.053 87.5%。
1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 3.31 (1H, t), 3.42 (3H, d), 3.47 - 3.57 (1H, m), 3.62 - 3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, dd), 4.86 (1H, dd), 6.49 (1H, d);m/z:(ES+)MH+,400.94および402.86。キラルHPLC:(HP1100 System 4,5μm Chiralpak AD−H(250mmx4.6mm)カラムを50/50のヘプタン/EtOHで溶離する)Rf,4.365 73.5%,6.067 26.4%。
1H NMR (400 MHz, CDCl3) 1.31 (3H, t), 1.43 (2H, h), 1.67 - 1.75 (2H, m), 2.33 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd + broad s), 4.33 (1H, s), 6.78 (1H, s);m/z:(ES+)MH+,331.04および332.99。キラルHPLC:(HP1100 System 4,5μm Chiralpak AD−H(250mmx4.6mm)カラムを70/30/0.1のヘプタン/IPA/TEAで溶離する)Rf,5.948 89.5%。
1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.49 (2H, m), 1.50 - 1.58 (1H, m), 1.71 - 1.84 (1H, m), 3.02 (3H, s), 3.52 (1H, t), 3.67 (1H, d), 3.80 (1H, d), 3.93 (1H, s), 4.01 (1H, d), 4.09 (1H, s), 4.48 (1H, s), 6.87 (1H, s), 6.97 (1H, dd), 7.07 (1H, dd), 7.18 (1H, d), 7.65 (2H, s), 8.08 (1H, d);m/z:(ES+)MH+,428.10。キラルHPLC:(HP1100 System 3,20μm Chiralpak IA(250mmx4.6mm)カラムを50/50/0.2/0.1のヘキサン/IPA/AcOH/TEAで溶離する)Rf,5.653 93.8%。
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.44 (2H, s), 1.50 - 1.58 (1H, m), 1.72 - 1.82 (1H, m), 3.01 (3H, s), 3.47 - 3.57 (1H, m), 3.63 - 3.70 (1H, m), 3.78 (1H, s), 3.94 (1H, s), 3.97 - 4.05 (1H, m), 4.04 - 4.13 (1H, m), 4.43 - 4.55 (1H, m), 6.88 (1H, s), 6.98 (1H, d), 7.07 (1H, s), 7.18 (1H, d), 7.66 (2H, s), 8.07 (1H, d)。m/z:(ES+)MH+,428.10。キラルHPLC:(HP1100 System 4,20μm Chiralpak IA(250mmx4.6mm)カラムを50/50/0.2/0.1のヘキサン/IPA/AcOH/TEAで溶離する)Rf,7.031 96.9%。
4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.50 (2H, dd), 1.60 (1H, d), 1.80 (1H, s), 3.01 (3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.51 (1H, d), 3.66 (1H, d), 3.80 (1H, d), 3.99 (1H, s), 4.02 (1H, s), 4.08 (1H, s), 4.50 (1H, s), 6.79 (1H, s), 6.96 (2H, dd), 7.92 (1H, d), 8.79 (1H, d);m/z:(ES+)MH+,460.08。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを70/30/0.1のヘプタン/IPA/TEAで溶離する)Rf,10.697 >99%。
1H NMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.50 (2H, d), 1.59 (1H, d), 1.79 (1H, s), 3.02 (3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.52 (1H, t), 3.67 (1H, d), 3.80 (1H, d), 3.98 (1H, s), 4.01 (1H, d), 4.08 (1H, s), 4.50 (1H, s), 6.79 (1H, s), 6.96 (2H, dd), 7.92 (1H, d), 8.79 (1H, d);m/z:(ES+)MH+,460.08。キラルHPLC:(HP1100 System 4,20μm Chiralpak AS(250mmx4.6mm)カラムを70/30/0.1のヘプタン/IPA/TEAで溶離する)Rf,18.427 99.8%。
1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88 - 6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s);m/z:(ES−)M−H−,151.19。
1H NMR (400 MHz, DMSO-d6) 7.01 - 7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s);m/z:(ES+)MH+,171.20。
1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67 - 6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d);m/z:(ES+)MH+,166.00。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−(S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−c]ピリジン
1HNMR (400 MHz, DMSO-d6) 1.29 (3H, d), 1.40 - 1.60 (3H, m), 1.76 (1H, d), 3.11 (3H, s), 3.12 - 3.21 (1H, m), 3.53 (1H, t), 3.68 (1H, d), 3.80 (2H, d), 4.01 (1H, d), 4.20 (1H, s), 4.58 (1H, s), 6.95 (1H, d), 7.28 (1H, s), 7.71 (1H, s), 8.83 (1H, s), 9.08 (1H, s), 11.75 (1H, s);m/z:(ES+)MH+,413.16。
1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40 - 1.61 (3H, m), 1.68 (9H, s), 1.76 (1H, dd), 3.09 (3H, d), 3.24 (1H, m), 3.52 (1H, t), 3.67 (1H, dd), 3.79 (2H, d), 4.00 (1H, dd), 4.19 (1H, s), 4.56 (1H, s), 7.00 (1H, d), 7.57 (1H, d), 8.00 (1H, d), 9.25 (1H, s), 9.37 (1H, s);m/z:(ES+)MH+,513.19。
N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.76 (6H, d), 2.78 (3H, d), 3.03 (3H, d), 3.33 - 3.41 (1H, m), 3.47 - 3.58 (1H, m), 3.68 (1H, dd), 3.81 (1H, d), 3.89 (1H, s), 4.02 (1H, dd), 4.12 (1H, d), 4.53 (1H, s), 6.80 (1H, s), 6.98 (1H, dd), 7.08 (1H, t), 7.24 (1H, d), 8.10 (1H, d), 8.69 (1H, d);m/z:(ES+)MH+,444.18。キラルHPLC:(HP1100 System 5,20μm Chiralcel OJ(250mmx4.6mm)カラムを80/20/0.1のイソヘキサン/EtOH/TEAで溶離する)Rf,21.886 >99%。
1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.76 (6H, d), 2.78 (3H, d), 3.03 (3H, d), 3.33 - 3.39 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.81 (1H, d), 3.88 (1H, s), 4.02 (1H, dd), 4.12 (1H, d), 4.53 (1H, s), 6.80 (1H, s), 6.92 - 7.01 (1H, m), 7.08 (1H, td), 7.24 (1H, d), 8.10 (1H, d), 8.69 (1H, d);m/z:(ES+)MH+,444.15。キラルHPLC:(HP1100 System 5,20μm Chiralcel OJ(250mmx4.6mm)カラムを80/20/0.1のイソヘキサン/EtOH/TEAで溶離する)Rf,34.353 99.4%。
1H NMR (400 MHz, DMSO-d6) 1.19 (3H, d), 1.49 (6H, dd), 2.17 (3H, t), 3.19 (1H, dd), 3.37 - 3.48 (1H, m), 3.57 (1H, dd), 3.71 (1H, d), 3.92 (1H, d), 4.03 (1H, s), 4.41 (1H, s), 6.70 (1H, s);m/z:(ES+)MH+,318.09および320.04。
1H NMR (400 MHz, DMSO-d6) 1.20 (3H, dd), 1.83 (6H, d), 3.20 (1H, dd), 3.41 (1H, dddd), 3.56 (1H, d), 3.59 (3H, d), 3.72 (1H, d), 3.94 (1H, dd), 4.07 (1H, s), 4.45 (1H, s), 6.93 (1H, d);m/z:(ES+)MH+,429.4および431.5。
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((R)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 2.19 - 2.35 (2H, m), 2.65 - 2.75 (5H, m), 3.02 (2H, d), 3.24 (2H, dd), 3.33 - 3.39 (1H, m), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (1H, d), 3.87 - 3.97 (2H, m), 4.03 (1H, dd), 4.06 (1H, s), 4.16 (1H, d), 4.53 (1H, s), 6.90 (1H, s), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H, dd), 8.06 (1H, d), 8.39 (1H, q);m/z:(ES+)MH+,486.53。キラルHPLC:(HP1100 System 4,20μm Chiralpak OJ(250mmx4.6mm)カラムを50/50/0.1のヘキサン/EtOH/TEAで溶離する)Rf,8.874 >99%。
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 2.19 - 2.36 (2H, m), 2.61 - 2.76 (5H, m), 3.02 (3H, d), 3.18 - 3.27 (2H, m), 3.36 (1H, dd), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (1H, d), 3.93 (2H, dd), 4.00 - 4.08 (2H, m), 4.17 (1H, d), 4.52 (1H, s), 6.91 (1H, s), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H, d), 8.06 (1H, d), 8.39 (1H, q);m/z:(ES+)MH+,486.57。キラルHPLC:(HP1100 System 4,20μm Chiralpak OJ(250mmx4.6mm)カラムを50/50/0.1のヘキサン/EtOH/TEAで溶離する)Rf,12.742 >99%。
1H NMR (400 MHz, DMSO-d6) 1.84 - 1.96 (1H, m), 2.02 (1H, td), 2.09 (3H, d), 2.27 - 2.45 (2H, m), 3.14 (1H, d), 3.10 - 3.26 (3H, m), 3.24 (1H, d), 3.33 - 3.41 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H, d), 3.78 - 3.87 (1H, m), 3.87 - 3.97 (2H, m), 4.07 (1H, d), 4.32 - 4.48 (1H, m), 6.76 (1H, s);m/z:(ES+)MH+,360.11および362.06。
1H NMR (400 MHz, DMSO-d6) 1.34 (3H, dd), 2.49 (1H, td), 2.63 (2H, ddd), 2.75 - 2.82 (1H, m), 3.26 (3H, d), 3.29 - 3.41 (3H, m), 3.49 (1H, s), 3.51 - 3.60 (1H, m), 3.63 - 3.73 (1H, m), 3.80 (1H, d), 3.98 - 4.11 (4H, m), 6.68 (1H, d);m/z:(ES−)M−H−,469.04および471.03。
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−インドール
1H NMR (500 MHz, DMSO-d6) 1.28 (3H, d), 2.19 - 2.36 (2H, m), 2.72 (3H, d), 2.84 (2H, t), 3.18 (1H, t), 3.20 - 3.29 (2H, m), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (2H, d), 3.95 (2H, t), 4.03 (1H, dd), 4.29 (1H, d), 4.59 (1H, s), 6.87 (1H, d), 7.20 (1H, t), 7.27 (1H, t), 7.41 - 7.49 (1H, m), 7.54 (1H, dd), 8.11 (1H, dd), 11.24 (1H, s);m/z:(ES+)MH+,456.54。
1H NMR (400 MHz, CDCl3) 1.34 (3H, d), 1.84 - 1.94 (1H, m), 2.10 (3H, s), 2.24 - 2.37 (2H, m), 2.44 (1H, ddd), 3.30 (1H, td), 3.41 (1H, ddd), 3.51 - 3.64 (2H, m), 3.65 - 3.73 (1H, m), 3.75 - 3.82 (1H, m), 3.90 - 4.08 (4H, m), 4.36 (1H, s), 6.46 (1H, s);m/z:(ES+)MH+,360.15および362.11。
1H NMR (400 MHz, DMSO-d6) 1.20 (3H, d), 2.19 - 2.31 (2H, m), 2.72 - 2.84 (2H, m), 3.11 - 3.28 (3H, m), 3.40 - 3.45 (1H, m), 3.46 (3H, s), 3.53 - 3.61 (1H, m), 3.74 (1H, d), 3.94 (3H, d), 4.12 (1H, s), 4.47 (1H, s), 7.05 (1H, s);m/z:(ES+)MH+,471.04および473.00。
4−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、4−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.77 (6H, d), 2.79 (3H, s), 3.05 (3H, d), 3.35 (1H, dd), 3.47 - 3.59 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.93 (1H, s), 4.03 (1H, dd), 4.12 (1H, d), 4.53 (1H, s), 6.83 (1H, s), 6.90 - 7.01 (2H, m), 7.92 - 7.96 (1H, m), 8.81 (1H, q);m/z:(ES+)MH+,462.53。キラルHPLC:(Gilson プレプ,50mm 20μm Chiralcel OJカラムを75/25/0.1のヘプタン/(50/50のEtOH/MeOH)/TEAで溶離する)Rf,10.163 >99%。
1H NMR (400 MHz, DMSO-d6) 1.33 (3H, d), 1.79 (6H, d), 2.83 (3H, s), 3.09 (3H, d), 3.38 (1H, dd), 3.59 (1H, td), 3.73 (1H, dd), 3.86 (1H, d), 3.97 (1H, s), 4.06 (1H, dd), 4.16 (1H, d), 4.59 (1H, s), 6.88 (1H, s), 6.94 - 7.05 (2H, m), 7.94 - 8.02 (1H, m), 8.86 (1H, q);m/z:(ES+)MH+,462.53。キラルHPLC:(Gilson プレプ,50mm 20μm Chiralcel OJカラムを75/25/0.1のヘプタン/(50/50のEtOH/MeOH)/TEAで溶離する)Rf,14.239 >99%。
1H NMR (400 MHz, CDCl3) 1.32 (3H, t), 1.59 (3H, s), 1.64 (3H, s), 2.23 (3H, d), 3.22 - 3.36 (1H, m), 3.48 - 3.59 (1H, m), 3.69 (1H, dd), 3.73 - 3.81 (1H, m), 4.00 (1H, dd), 4.05 (1H, d), 4.31 (1H, s), 6.45 (1H, d);m/z:(ES+)MH+,318.02および319.98。
1H NMR (400 MHz, DMSO-d6) 1.18 (3H, d), 1.83 (6H, s), 3.20 - 3.24 (1H, m), 3.36 - 3.48 (1H, m), 3.53 - 3.65 (4H, m), 3.68 - 3.79 (1H, m), 3.94 (1H, dd), 4.03 - 4.07 (1H, m), 4.43 - 4.47 (1H, m), 6.94 (1H, s);m/z:(ES−)M−H−,427.26。
6−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、5−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、5−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、6−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.32 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.02 (3H, d), 3.33 - 3.40 (1H, m), 3.55 (1H, td), 3.69 (1H, dd), 3.83 (1H, d), 3.92 (1H, s), 3.97 - 4.15 (2H, m), 4.53 (1H, d), 6.84 (1H, s), 6.91 - 6.95 (1H, m), 7.21 (1H, dd), 7.89 (1H, dd), 8.66 (1H, q);m/z:(ES+)MH+,462.51。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,5.56 98.9%。
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.32 -3.36 (1H, m), 3.54 (1H, td), 3.68 (1H, dd), 3.81 (1H, d), 3.91 (1H, s), 3.97 - 4.15 (2H, m), 4.53 (1H, d), 6.72 - 6.84 (2H, m), 7.04 (1H, dd), 8.06 (1H, dd), 8.86 (1H, q);m/z:(ES+)MH+,462.53。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,10.29 96.3%。
1H NMR (400 MHz, DMSO-d6) 1.30 (3H, d), 1.76 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.31 - 3.39 (1H, m), 3.54 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.92 (1H, s), 3.97 - 4.18 (2H, m), 4.52 (1H, d), 6.73 - 6.84 (2H, m), 7.04 (1H, dd), 8.07 (1H, dd), 8.86 (1H, q);m/z:(ES+)MH+,462.53。キラルSFC:(Berger Minigram,5μm Chiralcel OD−H(250mmx4.6mm)カラムを85/15/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,10.94 98.9%。
1H NMR (400 MHz, DMSO-d6) 1.14 (3H, d), 1.58 (6H, d), 2.60 (3H, s), 2.83 (3H, d), 3.16 - 3.25 (1H, m), 3.35 (1H, td), 3.50 (1H, dd), 3.64 (1H, d), 3.72 (1H, s), 3.79 - 3.98 (2H, m), 4.34 (1H, d), 6.65 (1H, s), 6.69 - 6.77 (1H, m), 7.03 (1H, dd), 7.71 (1H, dd), 8.48 (1H, q);m/z:(ES+)MH+,462.53。キラルSFC:(Berger Minigram,5μm Chiralcel OD−H(250mmx4.6mm)カラムを85/15/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,7.47 88.4%。
1H NMR (400 MHz, DMSO-d6) 6.66 - 6.79 (2H, m), 6.81 - 6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s);m/z:(ES+)MH+,151.19。
1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd);m/z:(ES+)MH+,171.34。
1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38 - 6.44 (2H, m), 6.67 (1H, dd), 6.79 - 6.84 (1H, m);m/z:(ES+)MH+,166.31。
6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン、および、6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.4 - 1.54 (2H, m), 1.57 - 1.64 (1H, m), 1.77 - 1.82 (1H, m), 3.00 - 3.04 (6H, m), 3.33- 3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.93 - 4.13 (3H, m), 4.49 - 4.51 (1H, m), 6.80 (1H, s), 6.93 (1H, ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q);m/z:(ES+)MH+,460.50。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,7.70 99.9%。
1H NMR (400 MHz, DMSO-d6) 1.50 (3H, d), 1.61 - 1.77 (2H, m), 1.76 - 1.89 (1H, m), 1.94 - 2.06 (1H, m), 3.24 (3H, s), 3.27 (3H, d), 3.52 - 3.56 (1H, m), 3.75 (1H, td), 3.89 (1H, dd), 4.03 (1H, d), 4.15 - 4.37 (3H, m), 4.70 - 4.74 (1H, m), 6.94 - 7.06 (2H, m), 7.27 (1H, dd), 8.28 (1H, dd), 9.07 (1H, q);m/z:(ES+)MH+,460.50。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,10.59 99.8%。
1H NMR (400 MHz, DMSO-d6) 1.31 (3H, d), 1.44 - 1.54 (2H, m), 1.57 - 1.64 (1H, m), 1.77 - 1.82 (1H, m), 3.00 - 3.04 (6H, m), 3.33 - 3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.93 - 4.13 (3H, m), 4.49 - 4.51 (1H, m), 6.80 (1H, s), 6.93 (1H, ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q);m/z:(ES+)MH+,460.50。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,12.72 97.4%。
1H NMR (400 MHz, DMSO-d6) 1.27 (3H, d), 1.43 - 1.51 (2H, m), 1.55 - 1.63 (1H, m), 1.72 - 1.83 (1H, m), 3.03 (3H, s), 3.06 (3H, d), 3.28 - 3.37 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.79 (1H, d), 3.93 - 4.14 (3H, m), 4.46 - 4.49 (1H, m), 6.72 - 6.82 (2H, m), 7.05 (1H, dd), 8.05 (1H, dd), 8.84 (1H, q);m/z:(ES+)MH+,460.50。キラルSFC:(Berger Minigram,5μm Chiralcel OJ−H(250mmx4.6mm)カラムを90/10/0.5のCO2/MeOH/N,NDMEAで溶離する)Rf,25.03 99.5%。
1H NMR (400 MHz, DMSO-d6) 1.18 (3H, d), 1.25 - 1.50 (3H, m), 1.59 - 1.71 (1H, m), 3.01 (3H, s), 3.19 (1H, t), 3.39 - 3.46 (1H, m), 3.52 - 3.61 (1H, m), 3.72 (1H, d), 3.86 (1H, s), 3.93 (1H, dd), 4.01 - 4.05 (1H, m), 4.38 (1H, s), 6.95 (1H, s);m/z:(ES+)MH+,331.39。
Claims (13)
- 式(I):
R2は、
nは、0または1であり;
R2A、R2C、R2EおよびR2Fは、各々独立して、水素またはメチルであり;
R2BおよびR2Dは、各々独立して、水素またはメチルであり;
R2Gは、−NHR7および−NHCOR8より選択され;
R2Hは、フルオロであり;
R3は、メチルであり;
R4およびR5は、各々独立して、水素またはメチルであり、またはR4およびR5は、それらが結合している原子と一緒になって、環Aを形成し;
環Aは、C3−6シクロアルキル、またはOおよびNより選択される1個のヘテロ原子を含有する飽和4〜6員複素環式環であり;
R6は、水素であり;
R7は、水素またはメチルであり;
R8は、メチルである)
を有する化合物、またはその薬学的に許容しうる塩。 - R4およびR5が、それらが結合している原子と一緒になって、環Aを形成し、そして環Aが、C3−6シクロアルキル、またはOおよびNより選択される1個のヘテロ原子を含有する飽和4〜6員複素環式環である、請求項1に記載の化合物。
- 環Aが、シクロプロピル環、テトラヒドロピラニル環またはピペリジニル環である、請求項1または請求項2に記載の化合物。
- R2Aが、水素であり;R2Bが、水素であり;R2Cが、水素であり;R2Dが、水素であり;R2Eが、水素であり;そしてR2Fが、水素である、請求項1〜3のいずれか1項に記載の化合物。
- R1が、3−メチルモルホリン−4−イルである、請求項1〜4のいずれか1項に記載の化合物。
- 式(I)の化合物が、
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[((R)−S−メチルスルホンイミドイル)メチル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−インドール;
1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−(S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−c]ピリジン;
N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((R)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[4−((S)−S−メチルスルホンイミドイル)テトラヒドロ−2H−ピラン−4−イル]ピリミジン−2−イル}−1H−インドール;
4−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
4−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[1−メチル−1−((R)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[1−メチル−1−((S)−S−メチルスルホンイミドイル)エチル]−6−[(3R)−3−メチルモルホリン−4−イル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;
5−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン;および
6−フルオロ−N−メチル−1−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ベンゾイミダゾール−2−アミン
より選択される、請求項1に記載の化合物またはその薬学的に許容しうる塩。 - 式(I)の化合物が、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((S)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジンである、請求項1に記載の化合物またはその薬学的に許容しうる塩。
- 式(I)の化合物が、4−{4−[(3R)−3−メチルモルホリン−4−イル]−6−[1−((R)−S−メチルスルホンイミドイル)シクロプロピル]ピリミジン−2−イル}−1H−ピロロ[2,3−b]ピリジンである、請求項1に記載の化合物またはその薬学的に許容しうる塩。
- 癌の処置に用いるための、請求項1〜10のいずれか一項に記載の式(I)の化合物またはその薬学的に許容しうる塩。
- 請求項1〜10のいずれか一項に記載の式(I)の化合物またはその薬学的に許容しうる塩を、薬学的に許容しうるアジュバント、希釈剤または担体と一緒に含む医薬組成物。
- ATRキナーゼの阻害に感受性である腫瘍の予防または処置に用いるための薬剤の製造における、請求項1〜10のいずれか1項に記載の式(I)の化合物またはその薬学的に許容しうる塩の使用。
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