JP2014517017A - 化合物、その医薬組成物、及び癌治療用のidh1突然変異阻害薬としてのその使用 - Google Patents
化合物、その医薬組成物、及び癌治療用のidh1突然変異阻害薬としてのその使用 Download PDFInfo
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- JP2014517017A JP2014517017A JP2014515055A JP2014515055A JP2014517017A JP 2014517017 A JP2014517017 A JP 2014517017A JP 2014515055 A JP2014515055 A JP 2014515055A JP 2014515055 A JP2014515055 A JP 2014515055A JP 2014517017 A JP2014517017 A JP 2014517017A
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- Prior art keywords
- alkyl
- alkylene
- compound
- methyl
- nmr
- Prior art date
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- 201000011510 cancer Diseases 0.000 title claims abstract description 42
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- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 title claims abstract description 36
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 title claims abstract description 34
- 230000035772 mutation Effects 0.000 title claims abstract description 28
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- 238000011282 treatment Methods 0.000 title abstract description 37
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- 238000000034 method Methods 0.000 claims abstract description 94
- -1 CF 3 Chemical group 0.000 claims description 170
- 125000002947 alkylene group Chemical group 0.000 claims description 99
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 98
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 74
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 229920006395 saturated elastomer Polymers 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical group 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 16
- 229910052717 sulfur Chemical group 0.000 claims description 16
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 15
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- 125000001424 substituent group Chemical group 0.000 claims description 15
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- 125000002619 bicyclic group Chemical group 0.000 claims description 14
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 12
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
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- HWXBTNAVRSUOJR-UHFFFAOYSA-N 2-hydroxyglutaric acid Chemical compound OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
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- 230000001419 dependent effect Effects 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
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- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 6
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 6
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- 239000003937 drug carrier Substances 0.000 claims description 6
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- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 455
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 437
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 402
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 67
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- 239000011734 sodium Substances 0.000 description 58
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 56
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- 239000012267 brine Substances 0.000 description 51
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
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- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 13
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Classifications
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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Abstract
Description
イソクエン酸+NAD+(NADP+)→α−KG+CO2+NADH(NADPH)+H+。
したがって、突然変異体IDH1およびその新活性の阻害は、癌のための潜在的な療法的治療である。したがって、アルファヒドロキシル新活性を有するIDH1突然変異体の阻害剤が必要とされ続けている。
(I)
の化合物またはその薬学的に許容可能な塩が記載され、式中:
Xは、CR4またはNであり;
Yは、−N(R5)−またはCH(R5)−であり;
Zは、−O−、−S−、−C(R)2−またはN(R7)であり;
Wは、C(R1)(R1)またはN(R7)であり;但し、ZとWとの両方が同時にN(R7)であることはなく;
Vは、NまたはC(R)であり;
各Rは、水素、メチルまたはCF3から独立して選択され;
各R1は、水素、アルコキシ、または場合によりOH若しくはSHで置換されているアルキルから独立して選択され;
または2個のR1が、それらが結合している炭素原子と一緒になって、3〜7員シクロアルキル、または4〜7員飽和ヘテロシクリル環を形成し、ここで前記シクロアルキルまたはヘテロシクリルは、場合によりメチル、ハロまたはCF3で置換されており;
R2は、フェニル、3〜7員シクロアルキル、C2〜C4アルキル、またはCF3から選択され、ここでフェニルまたはシクロアルキルは、場合により、メチル、CF3またはフルオロから選択される単一置換基で置換されており;
各R3は、−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C1〜C4フルオロアルキル、−C(O)−O−(C1〜C4アルキル)、−フェニル、−ヘテロアリール、C3〜C7シクロアルキル、−CH2−N(C1〜C4アルキル)2、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、場合によりハロまたはOHで置換されている−C1〜C4アルキルから独立して選択されるか、または2個のR3が一緒になって3〜8飽和環または縮合フェニルを形成し、ここで前記飽和環または縮合フェニルは、場合により1〜2個のメチルで置換されており;
R4は、水素、−CN、ハロ、C1〜C4アルコキシ、−CH2NH(C1〜C4アルキル)、C2〜C4アルケニル、C2〜C4アルキニル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、C1〜C4フルオロアルキル、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、または5員ヘテロアリールから選択され;
R5は、C1〜C4アルキル、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−Q、−C(O)−O−(C0〜C2アルキレン)−Q、−C(O)−(C1〜C2アルキレン)−O−(C0〜C2アルキレン)−Q、−C(O)−C(O)−Q、−S(O)2−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)C(O)O−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)N(R6)−(C2〜C6アルキニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C2〜C6アルケニル)、C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−C(O)C(O)N(R)(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−S(O)0〜2−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)C(O)N(R6)(C1〜C6アルキル)、−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2−(C1〜C6アルキル)、またはC(O)−(C1〜C4アルキレン)−N(R6)S(O)2Qから選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、C(O)CF3、CN、−OHまたはCO2Hで置き換えられており;
各R6は、水素及びメチルから独立して選択され;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、場合により−OHで置換されているC1〜C4アルキル、C1〜C4アルコキシ、−(C1〜C4アルキレン)−OC(O)O−(C1〜C4アルキル)、−C(O)O−(C1〜C4アルキル)、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;
各R7は、独立して−G−L−Mであり;
Gは、結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここで場合により炭化水素鎖の1個、2個または3個のメチレン単位は、独立して、−NR8−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
Lは、共有結合であるか、或いは二価C1〜8飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでLの1個、2個、または3個のメチレン単位は、場合により、及び独立して、シクロプロピレン、−NR8−、−N(R8)C(O)−、−C(O)N(R8)−、−N(R8)SO2−、SO2N(R8)−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
MはEであるか、或いは窒素、酸素、または硫黄から独立して選択される0〜3個のヘテロ原子を有する3〜10員単環式または二環式飽和環、部分的に不飽和の環、または芳香環であり、且つ前記環は、−D−E、オキソ、NO2、ハロゲン、CN、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルから独立して選択される1〜4個の基で置換されており;
Dは、共有結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでDの1個または2個のメチレン単位は、場合により、及び独立して、−NR8−、−S−、−O−、−C(O)−、−SO−、またはSO2−に置き換えられており;
Eは、水素、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、ここで前記アルキル、アルケニルまたはアルキニルは、場合によりオキソ、ハロゲン、またはCNで置換されており;
各R8は、独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、またはフェニルか、窒素、酸素、若しくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜7員ヘテロシクリルか、または窒素、酸素、若しくは硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員単環式ヘテロアリール環から選択される場合により置換されている基であり;及び
mは、0、1、2または3である。
用語「ハロ」または「ハロゲン」は、フッ素、塩素、臭素またはヨウ素の任意のラジカルを指す。
それぞれのRbは、水素、および−C1〜C4アルキルから独立して選択され;または
2つのRbは、それらが結合している窒素原子と一緒になってN、S、およびOから選択される1つの追加のヘテロ原子を場合により含む4から8員ヘテロシクリルを形成し、
それぞれのRb’は、C3〜C7カルボシリル(carbocylyl)、フェニル、ヘテロアリール、およびヘテロシクリルから独立して選択され、前記フェニル、シクロアルキル、ヘテロアリールまたは複素環置換基上の1つ以上の置換可能な位置は、−(C1〜C4アルキル)、−(C1〜C4フルオロアルキル)、−OH、−O−(C1〜C4アルキル)、−O−(C1〜C4フルオロアルキル)、ハロ、−NH2、−NH(C1〜C4アルキル)、または−N(C1〜C4アルキル)2の1つ以上により場合によりさらに置換されている。
構造式I:
(I)
の化合物またはその薬学的に許容可能な塩が提供され、式中:
Xは、CR4またはNであり;
Yは、−N(R5)−またはCH(R5)−であり;
Zは、−O−、−S−、−C(R)2−またはN(R7)であり;
Wは、C(R1)(R1)またはN(R7)であり;但し、ZとWとの両方が同時にN(R7)であることはなく;
Vは、NまたはC(R)であり;
各Rは、水素、メチルまたはCF3から独立して選択され;
各R1は、水素、アルコキシ、または場合によりOH若しくはSHで置換されているアルキルから独立して選択され;
または2個のR1が、それらが結合している炭素原子と一緒になって、3〜7員シクロアルキル、または4〜7員飽和ヘテロシクリル環を形成し、ここで前記シクロアルキルまたはヘテロシクリルは、場合によりメチル、ハロまたはCF3で置換されており;
R2は、フェニル、3〜7員シクロアルキル、C2〜C4アルキル、またはCF3から選択され、ここでフェニルまたはシクロアルキルは、場合により、メチル、CF3またはフルオロから選択される単一置換基で置換されており;
各R3は、−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C1〜C4フルオロアルキル、−C(O)−O−(C1〜C4アルキル)、−フェニル、−ヘテロアリール、C3〜C7シクロアルキル、−CH2−N(C1〜C4アルキル)2、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、場合によりハロまたはOHで置換されている−C1〜C4アルキルから独立して選択されるか、または2個のR3が一緒になって3〜8飽和環または縮合フェニルを形成し、ここで前記飽和環または縮合フェニルは、場合により1〜2個のメチルで置換されており;
R4は、水素、−CN、ハロ、C1〜C4アルコキシ、−CH2NH(C1〜C4アルキル)、C2〜C4アルケニル、C2〜C4アルキニル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、C1〜C4フルオロアルキル、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、または5員ヘテロアリールから選択され;
R5は、C1〜C4アルキル、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−Q、−C(O)−O−(C0〜C2アルキレン)−Q、−C(O)−(C1〜C2アルキレン)−O−(C0〜C2アルキレン)−Q、−C(O)−C(O)−Q、−S(O)2−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)C(O)O−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)N(R6)−(C2〜C6アルキニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C2〜C6アルケニル)、C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−C(O)C(O)N(R)(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−S(O)0〜2−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)C(O)N(R6)(C1〜C6アルキル)、−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2−(C1〜C6アルキル)、またはC(O)−(C1〜C4アルキレン)−N(R6)S(O)2Qから選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、C(O)CF3、CN、−OHまたはCO2Hで置き換えられており;
各R6は、水素及びメチルから独立して選択され;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、場合により−OHで置換されているC1〜C4アルキル、C1〜C4アルコキシ、−(C1〜C4アルキレン)−OC(O)O−(C1〜C4アルキル)、−C(O)O−(C1〜C4アルキル)、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;
各R7は、独立して−G−L−Mであり;
Gは、結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここで場合により炭化水素鎖の1個、2個または3個のメチレン単位は、独立して、−NR8−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
Lは、共有結合であるか、或いは二価C1〜8飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでLの1個、2個、または3個のメチレン単位は、場合により、及び独立して、シクロプロピレン、−NR8−、−N(R8)C(O)−、−C(O)N(R8)−、−N(R8)SO2−、SO2N(R8)−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
MはEであるか、或いは窒素、酸素、または硫黄から独立して選択される0〜3個のヘテロ原子を有する3〜10員単環式または二環式飽和環、部分的に不飽和の環、または芳香環であり、且つ前記環は、−D−E、オキソ、NO2、ハロゲン、CN、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルから独立して選択される1〜4個の基で置換されており;
Dは、共有結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでDの1個または2個のメチレン単位は、場合により、及び独立して、−NR8−、−S−、−O−、−C(O)−、−SO−、またはSO2−に置き換えられており;
Eは、水素、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、ここで前記アルキル、アルケニルまたはアルキニルは、場合によりオキソ、ハロゲン、またはCNで置換されており;
各R8は、独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、またはフェニルか、窒素、酸素、若しくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜7員ヘテロシクリルか、または窒素、酸素、若しくは硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員単環式ヘテロアリール環から選択される場合により置換されている基であり;及び
mは、0、1、2または3である。
(I)
の化合物またはその薬学的に許容可能な塩が提供され、式中:
Xは、CR4またはNであり;
Yは、−N(R5)−またはCH(R5)−であり;
Zは、−O−、−S−、−C(R)2−またはN(R7)であり;
Wは、C(R1)(R1)またはN(R7)であり;但し、(1)Zが−C(R)2−のとき、WはC(R1)(R1)ではなく;且つ(2)ZとWとの両方が同時にN(R7)であることはなく;
Vは、NまたはC(R)であり;
各Rは、水素、メチルまたはCF3から独立して選択され;
各R1は、水素、アルコキシ、または場合によりOH若しくはSHで置換されているアルキルから独立して選択され;
または2個のR1が、それらが結合している炭素原子と一緒になって、3〜7員シクロアルキル、または4〜7員飽和ヘテロシクリル環を形成し、ここで前記シクロアルキルまたはヘテロシクリルは、場合によりメチル、ハロまたはCF3で置換されており;
R2は、フェニル、3〜7員シクロアルキル、またはC2〜C4アルキルから選択され、ここでフェニルまたはシクロアルキルは、場合により、メチル、CF3またはフルオロから選択される単一置換基で置換されており;
各R3は、場合によりハロで置換されている−C1〜C4アルキル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、−C1〜C4フルオロアルキル、−C(O)−O−(C1〜C4アルキル)、−フェニル、−ヘテロアリール、C3〜C7シクロアルキル、−CH2−N(C1〜C4アルキル)2、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)から独立して選択されるか、または2個のR3が一緒になって3〜8飽和環または縮合フェニルを形成し、ここで前記飽和環または縮合フェニルは、場合により1〜2個のメチルで置換されており;
R4は、水素、−CN、ハロ、C1〜C4アルコキシ、−CH2NH(C1〜C4アルキル)、C2〜C4アルケニル、C2〜C4アルキニル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、C1〜C4フルオロアルキル、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、及び5員ヘテロアリールから選択され;
R5は、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−Q、−C(O)−O−(C1〜C2アルキレン)−Q、−C(O)−(C1〜C2アルキレン)−O−(C0〜C2アルキレン)−Q、−C(O)−C(O)−Q、−S(O)2−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)N(R6)−(C2〜C6アルキニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C2〜C6アルケニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−C(O)C(O)N(R)(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−S(O)0〜2−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、)、−C(O)−(C1〜C4アルキレン)−C(O)C(O)N(R6)(C1〜C6アルキル)、−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2−(C1〜C6アルキル)、及び−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2Qから選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により、−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、またはC(O)CF3で置き換えられており;
各R6は、水素及びメチルから独立して選択され;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、C1〜C4アルキル、C1〜C4アルコキシ、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;
各R7は、独立して−G−L−Mであり;
Gは、結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここで場合により炭化水素鎖の1個、2個または3個のメチレン単位は、独立して、−NR8−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
Lは、共有結合であるか、或いは二価C1〜8飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでLの1個、2個、または3個のメチレン単位は、場合により、及び独立して、シクロプロピレン、−NR8−、−N(R8)C(O)−、−C(O)N(R8)−、−N(R8)SO2−、SO2N(R8)−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
MはEであるか、或いは窒素、酸素、または硫黄から独立して選択される0〜3個のヘテロ原子を有する3〜10員単環式または二環式飽和環、部分的に不飽和の環、または芳香環であり、且つ前記環は、−D−E、オキソ、NO2、ハロゲン、CN、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルから独立して選択される1〜4個の基で置換されており;
Dは、共有結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでDの1個または2個のメチレン単位は、場合により、及び独立して、−NR8−、−S−、−O−、−C(O)−、−SO−、またはSO2−に置き換えられており;
Eは、水素、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、ここで前記アルキル、アルケニルまたはアルキニルは、場合によりオキソ、ハロゲン、またはCNで置換されており;
各R8は、独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、またはフェニルか、窒素、酸素、若しくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜7員ヘテロシクリルか、または窒素、酸素、若しくは硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員単環式ヘテロアリール環から選択される場合により置換されている基であり;及び
mは、0、1、2または3である。
から選択される。
、−C(O)−CH3、−SO2CH3、−CH2CH2OH、−(CH2)1〜4−SH、または(CH2)1〜4−OHから独立して選択される。
(II)
により示され、式中:
各R1は同じであり、水素及びメチルから選択され;
R2は、場合により単一のフルオロまたは単一のメチルで置換されているフェニル、シクロヘキシル、シクロペンチル、シクロブチル、場合により単一のメチルで置換されているシクロプロピル、イソプロピル及びメチルから選択され;
R3aは、水素及びメチルから選択され;
R3bは、水素、メチル、エチル、イソブチル、イソプロピル、シクロプロピル、フェニル、−C(O)−O−CH2CH3、−C(O)−O−CH3、及び−CH2−O−CH3から選択され、ここでメチル、エチル、イソブチル、及びイソプロピルの各々は、場合によりフルオロで置換されており;
R3cは、水素及びメチルから選択され;
R3dは、水素、フェニル及びメチルから選択され;及び
R5は、構造式Iと同様に定義される。
(III)
により示され、式中:
WまたはZの一方はN(R7)であり、且つWまたはZの他方はC(R1)(R1)であり
各R1は同じであり、水素及びメチルから選択され;
R2は、場合により単一のフルオロまたは単一のメチルで置換されているフェニル、シクロヘキシル、シクロペンチル、シクロブチル、場合により単一のメチルで置換されているシクロプロピル、イソプロピル及びメチルから選択され;
R3aは、水素及びメチルから選択され;
R3bは、水素、メチル、エチル、イソブチル、イソプロピル、フェニル、C3〜C7シクロアルキル、−C(O)−O−CH2CH3、−C(O)−O−CH3、及び−CH2−O−CH3から選択され;
R3cは、水素及びメチルから選択され;
R3dは、水素、フェニル及びメチルから選択され;及び
R5は、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、及び−(C0〜C4アルキレン)−O−(C1〜C4アルキル)から選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により、−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、またはC(O)CF3で置き換えられており;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、C1〜C4アルキル、C1〜C4アルコキシ、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;及び
R7は、構造式Iと同様に定義される。
本明細書に記載の方法において使用される化合物は、対象に投与する前に、薬学的に許容可能な担体またはアジュバントと一緒に、薬学的に許容可能な組成物に配合することができる。別の実施形態において、そのような薬学的に許容可能な組成物は、疾患または病徴のモジュレーションを達成するために有効な量の追加の治療剤、例として本明細書に記載のものをさらに含む。
突然変異体IDH1活性を阻害する方法において、その阻害が必要とされる対象に、構造式IまたはIIの化合物、本明細書の実施形態のいずれか1つに記載の化合物、または薬学的に許容可能なその塩を接触させることを含む方法が提供される。一実施形態において、治療すべき癌は、IDH1突然変異が対象中のα−ケトグルタル酸のR(−)−2−ヒドロキシグルタル酸へのNAPH依存性還元を触媒する酵素の新たな能力をもたらすIDH1の突然変異体アレルを特徴とする。この実施形態の一態様において、突然変異体IDH1は、R132X突然変異を有する。この実施形態の一態様において、R132X突然変異は、R132H、R132C、R132L、R132V、R132SおよびR132Gから選択される。別の態様において、R132X突然変異は、R132HまたはR132Cである。さらに別の態様において、R132X突然変異は、R132Hである。
一部の実施形態において、本明細書に記載の方法は、それが必要とされる対象に、第2の治療、例えば、追加の癌治療剤または追加の癌治療を同時投与する追加のステップを含む。例示的な追加の癌治療剤としては、例えば、化学療法、標的療法、抗体療法、免疫療法、およびホルモン療法が挙げられる。追加の癌治療としては、例えば、外科手術、および放射線治療が挙げられる。これらの治療のそれぞれの例は、以下に提供される。
anhy. − 無水
aq. − 水性
min − 分
mL − ミリリットル
mmol − ミリモル
mol − モル
MS − 質量分析
NMR − 核磁気共鳴
TLC − 薄層クロマトグラフィー
HPLC − 高速液体クロマトグラフィー
Hz − ヘルツ
δ − 化学シフト
J − カップリング定数
s − 一重線
d − 二重線
t − 三重線
q − 四重線
m − 多重線
br − 幅広
qd − 四重二重線
dquin − 二重五重線
dd − 二重二重線
dt − 二重三重線
CHCl3 − クロロホルム
DCM − ジクロロメタン
DMF − ジメチルホルムアミド
Et2O − ジエチルエーテル
EtOH − エチルアルコール
EtOAc − 酢酸エチル
MeOH − メチルアルコール
MeCN − アセトニトリル
PE − 石油エーテル
THF − テトラヒドロフラン
AcOH − 酢酸
HCl − 塩酸
H2SO4 − 硫酸
NH4Cl − 塩化アンモニウム
KOH − 水酸化カリウム
NaOH − 水酸化ナトリウム
K2CO3 − 炭酸カリウム
Na2CO3 − 炭酸ナトリウム
TFA − トリフルオロ酢酸
Na2SO4 − 硫酸ナトリウム
NaBH4 − 水素化ホウ素ナトリウム
NaHCO3 − 重炭酸ナトリウム
LiHMDS − リチウムヘキサメチルジシリルアミド
NaHMDS − ナトリウムヘキサメチルジシリルアミド
LAH − 水素化アルミニウムリチウム
NaBH4 − 水素化ホウ素ナトリウム
LDA − リチウムジイソプロピルアミド
Et3N − トリエチルアミン
DMAP − 4−(ジメチルアミノ)ピリジン
DIPEA − N,N−ジイソプロピルエチルアミン
NH4OH − 水酸化アンモニウム
EDCI − 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
HOBt − 1−ヒドロキシベンゾトリアゾール
HATU − O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラ−メチルウロニウム
BINAP − 2,2’−ビス(ジフェニルホスファニル)−1,1’−ビナフチル
(実施例)
構造式I及びIIの化合物を調製する間の共通の合成中間体として、場合により置換されているジメチルシクロプロピルピラノピリジン5を使用し、それ自体は、以下のスキーム1に従い合成した。
スキーム1:
以下のスキーム2に従い中間体5から式IIの様々な化合物(式中、各R1はメチルであり、且つR2はシクロプロピルである)を調製した。
スキーム2:
一般式
の様々な8−置換−6−ヒドロキシ−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル中間体を、以下に記載するとおり調製した。これらの中間体を、スキーム1における8−シクロプロピル−6−ヒドロキシ−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(3)の代替として使用して、式I及び式IIのさらなる化合物を生成した。
実施例1ステップA及びBに記載される方法により、イソ酪酸クロリド及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値247.1、実測値247.0。1H NMR (クロロホルム−d)δ4.64 (s, 2H), 2.89 (quin, J = 7.0 Hz, 1H), 2.84 (s, 2H), 1.38 − 1.45 (m, 6H), 1.33 (s, 6H).
ジメチルシクロプロピルピラノピリジンの実験手順(ステップA及びB)に記載される方法により、塩化プロピオニル及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値233.1、実測値233.1。
実施例1ステップA及びBに記載される方法により、シクロブタンカルボニルクロリド及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値259.1、実測値259.2。1H NMR (クロロホルム−d)δ 4.54 (s, 2H), 3.43 − 3.55 (m, 1H), 2.80 (s, 2H), 2.46 − 2.62 (m, 2H), 2.30 − 2.42 (m, 2H), 2.03 − 2.18 (m, 2H), 1.30 (s, 6H).
実施例1ステップA及びBに記載される方法により、シクロペンタンカルボニルクロリド及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値273.1、実測値273.1。
実施例1ステップA及びBに記載される方法により、シクロヘキサンカルボニルクロリド及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値287.2、実測値287.0。1H NMR (クロロホルム−d) δ 4.64 (s, 2H), 2.84 (s, 2H), 2.42 − 2.57 (m, 1H), 1.86 − 2.02 (m, 4H), 1.80 (d, J = 13.3 Hz, 1H), 1.71 (d, J = 12.0 Hz, 2H), 1.54 − 1.65 (m, 1H), 1.34 − 1.41 (m, 2H), 1.33 (s, 6H).
実施例1ステップA及びBに記載される方法により、3−フルオロベンゾイルクロリド及び2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値299.1、実測値299.0。
実施例1ステップA及びBに記載される方法により、シクロヘキサンカルボニルクロリド及びジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値259.1、実測値258.9。1H NMR (クロロホルム−d) δ12.97 (br. s., 1H), 4.63 (s, 2H), 3.94 (t, J = 5.8 Hz, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.31 − 2.54 (m, 1H), 1.87 − 2.04 (m, 4H), 1.79 (d, J = 13.1 Hz, 1H), 1.70 (d, J = 11.0 Hz, 2H), 1.54 − 1.66 (m, 1H), 1.24 − 1.43 (m, 2H).
実施例1ステップA及びBに記載される方法により、シクロペンタンカルボニルクロリド及びジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値245.1、実測値245.1。1H NMR (クロロホルム−d)δ 4.61 − 4.68 (m, 2H), 3.90 − 3.98 (m, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.79 − 2.91 (m, 1H), 2.10 − 2.19 (m, 2H), 1.96 − 2.06 (m, 2H), 1.86 − 1.95 (m, 2H), 1.78 − 1.85 (m, 2H).
実施例1ステップA及びBに記載される方法により、イソブチリルクロリド及びジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値219.1、実測値219.1。1H NMR (クロロホルム−d)δ 4.62 (s, 2H), 3.90 − 3.98 (m, 2H), 2.98 (t, J = 5.8 Hz, 2H), 2.86 (spt, J = 6.9 Hz, 1H), 1.39 (d, J = 6.8 Hz, 6H).
実施例1ステップA及びBに記載される方法により、4−メチルベンゾイルクロリド及びジヒドロ−2H−ピラン−4(3H)−オンから
を調製した。MS(ES)M+H 予測値267.1、実測値267.1。1H NMR (DMSO−d6) δ7.34 (s, 4H), 4.31 (s, 2H), 3.87 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.38 (s, 3H).
3−ヒドロキシ−1−イソプロピル−5,6,7,8−テトラヒドロイソキノリン−4−カルボニトリル中間体を、スキーム3に従い調製した。これらの中間体もまた、スキーム1における8−シクロプロピル−6−ヒドロキシ−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(3)の代替として使用して、本発明のさらなる化合物を生成した。
スキーム3:
表題化合物を、上記で2つの位置異性体生成物の混合物としてステップJ及びステップKに記載される方法により、イソブチリルクロリド及び4,4−ジメチルシクロヘキサノンから調製した。MS(ES)M+H 予測値245.2、実測値245.0。
スキーム1のステップDにおける(R)−2−イソプロピルピペラジンの代替として有用な様々な置換ピペラジン中間体を使用して、式I及び式IIの他の化合物を合成した。
スキーム4A:
スキーム4B:
1,4−ジ−tert−ブチル2−メチルピペラジン−1,2,4−トリカルボキシレート(26;Rb=Me)。DMF(10mL)中の1,4−ビス(tert−ブトキシカルボニル)−ピペラジン−2−カルボン酸(25;3.6g、11mmol)の混合物に、K2CO3(2g、18mmol)を添加した。得られた懸濁液を0℃に冷却し、ヨードメタン(1.5mL、12mmol)で処理した。次に混合物を室温に加温させて6時間撹拌した。水(200mL)でクエンチした後、混合物を酢酸エチル(100mL)で抽出し、有機層をブラインで洗浄し、無水Na2SO4で乾燥し、ろ過し、真空濃縮して、3.6gの表題化合物を白色固体として得た。
スキーム4c:
5−フェニルピペラジン−2,3−ジオン 34。200mLのEtOH中の33(1.9g、14mmol)の溶液に、シュウ酸ジエチル(2.04g、14mmol)を添加した。得られた混合物を還流させながら2時間撹拌した。室温に冷却した後、混合物をブラインでクエンチし、EtOAcで抽出した。有機層を真空濃縮して、2.15gの34を帯黄色の油として得た。MS(ES)M+H 予測値191.1、実測値191。
スキーム4d:
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE1を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ 7.45 − 7.59 (m, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.86 (br. s., 1H), 4.48 (d, J = 13.6 Hz, 1H), 4.15 − 4.24 (m, 1H), 4.11 (dt, J = 13.1, 2.0 Hz, 1H), 3.55 (br. s., 1H), 3.28 (dd, J = 13.1, 3.8 Hz, 1H), 3.06 − 3.23 (m, 2H), 2.84 − 2.96 (m, 2H), 2.58 − 2.74 (m, 2H), 1.78 − 1.87 (m, 4H), 1.44 − 1.53 (m, 3H), 1.15 − 1.23 (m, 6H). LC−MS : m/z 393.0 (M+H)+.
1H NMR (クロロホルム−d)δ 7.53 (dd, J = 1.8, 0.8 Hz, 1H), 7.06 (dd, J = 3.4, 0.9 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 3.98 (br. s., 4H), 3.61 − 3.78 (m, 4H), 3.08 − 3.23 (m, 1H), 2.92 (t, J = 6.8 Hz, 2H), 2.42 (s, 2H), 1.56 − 1.62 (m, 2H), 1.16 − 1.22 (m, 6H), 0.98 − 1.05 (m, 6H). LC−MS : m/z 406.9 (M+H)+.
1H NMR (クロロホルム−d)δ 8.23 (s, 1H), 4.71 (s, 2H), 4.13 − 4.25 (m, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.51 (br. s., 1H), 3.22 (dd, J = 13.1, 3.5 Hz, 1H), 3.05 (td, J = 12.5, 3.3 Hz, 1H), 2.94 (t, J = 5.8 Hz, 2H), 2.57 (s, 3H), 2.42 (tt, J = 11.2, 3.6 Hz, 1H), 1.81 − 1.88 (m, 2H), 1.75 (d, J = 11.0 Hz, 1H), 1.62 − 1.71 (m, 3H), 1.43 (d, J = 6.8 Hz, 3H), 1.26 − 1.40 (m, 4H). LC−MS : m/z 450.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.75 (s, 1H), 7.47 (s, 1H), 6.55 − 6.64 (m, 1H), 4.72 (s, 3H), 4.14 − 4.41 (m, 3H), 3.95 (t, J = 5.6 Hz, 2H), 3.49 (br. s., 1H), 3.26 (dd, J = 13.1, 3.3 Hz, 1H), 3.09 (td, J = 12.5, 3.3 Hz, 1H), 2.95 (t, J = 5.5 Hz, 2H), 2.33 − 2.51 (m, 1H), 1.85 (d, J = 12.5 Hz, 2H), 1.77 (d, J = 10.8 Hz, 1H), 1.65 − 1.72 (m, 2H), 1.60 (d, J = 12.0 Hz, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.30 − 1.39 (m, 3H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ 4.89 (br. s., 1H), 4.69 (s, 2H), 4.12 − 4.26 (m, 2H), 3.90 − 3.97 (m, 2H), 3.66 − 3.83 (m, 3H), 3.47 − 3.66 (m, 1H), 3.33 − 3.41 (m, 3H), 2.99 − 3.28 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.63 − 2.80 (m, 1H), 2.52 − 2.63 (m, 1H), 2.41 (tt, J = 11.1, 3.7 Hz, 1H), 1.84 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.62 − 1.71 (m, 3H), 1.26 − 1.41 (m, 7H). LC−MS : m/z 427.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.72 (br. s., 1H), 7.40 − 7.49 (m, 1H), 6.51 − 6.66 (m, 1H), 4.70 (s, 2H), 4.45 − 4.64 (m, 2H), 4.27 (br. s., 1H), 3.87 − 4.16 (m, 3H), 3.54 − 3.75 (m, 1H), 3.11 (dd, J = 13.3, 3.0 Hz, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 11.1, 3.5 Hz, 1H), 2.17 − 2.34 (m, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.70 − 1.77 (m, 2H), 1.54 − 1.65 (m, 3H), 1.29 − 1.39 (m, 3H), 0.84 − 1.07 (m, 4H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.70 − 7.80 (m, 1H), 7.39 − 7.54 (m, 1H), 6.60 (s, 1H), 4.72 (s,3H), 4.13 − 4.42 (m, 3H), 3.95 (t, J = 5.6 Hz, 2H), 3.50 (br. s., 1H), 3.26 (d, J = 12.5 Hz, 1H), 3.04 − 3.17 (m, 1H), 2.95 (t, J = 5.5 Hz, 2H), 2.43 (t, J = 11.2 Hz, 1H), 1.85 (d, J = 12.3 Hz, 2H), 1.56 − 1.80 (m, 5H), 1.44 (d, J = 6.8 Hz, 3H), 1.25 − 1.37 (m, 3H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ 5.21 − 5.32 (m, 1H), 4.72 − 4.84 (m, 1H), 4.69 (s, 2H), 4.11 − 4.28 (m, 2H), 4.02 − 4.09 (m, 1H), 3.78 − 4.01 (m, 4H), 3.32 (dd, J = 13.6, 4.5 Hz, 1H), 3.02 − 3.18 (m, 1H), 2.82 − 2.97 (m, 4H), 2.69 − 2.79 (m, 2H), 2.36 − 2.46 (m, 1H), 2.13 − 2.20 (m, 3H), 1.85 (d, J = 11.8 Hz, 2H), 1.76 (d, J = 9.5 Hz, 1H), 1.66 (br. s., 1H), 1.60 (d, J = 11.8 Hz, 2H), 1.27 − 1.41 (m, 4H), 1.14 − 1.22 (m, 3H). LC−MS : m/z 501.0 (M+H)+.
1H NMR (クロロホルム−d)δ 7.21 (dd, J = 5.1, 1.1 Hz, 1H), 6.87 − 6.99 (m, 2H), 4.91 (br. s., 1H), 4.69 (s, 2H), 4.22 (d, J = 13.6 Hz, 1H), 4.13 (d, J = 13.3 Hz, 1H), 3.86 − 3.98 (m, 4H), 3.77 (d, J = 13.3 Hz, 1H), 3.50 − 3.67 (m, 1H), 3.11 − 3.23 (m, 1H), 2.88 − 3.05 (m, 3H), 2.33 − 2.48 (m, 1H), 1.84 (d, J = 12.3 Hz, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.62 − 1.69 (m, 3H), 1.26 − 1.38 (m, 7H). LC−MS : m/z 465.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.79 (br. s., 1H), 7.40 − 7.52 (m, 1H), 6.49 − 6.70 (m, 1H), 5.39 (br. s., 0.5H), 4.79 (br. s., 0.5H), 4.65 − 4.74 (m, 2H), 4.21 (dq, J = 10.7, 7.1 Hz, 2H), 4.03 − 4.16 (m, 2H), 3.81 − 4.03 (m, 3H), 3.39 (d, J = 11.5 Hz, 1H), 3.03 − 3.17 (m, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.34 − 2.47 (m, 1H), 1.50 − 1.84 (m, 10H), 1.09 − 1.39 (m, 3H). LC−MS : m/z 493.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.77 (s, 1H), 7.47 (s, 1H), 6.60 (s, 1H), 4.72 (s, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.87 (br. s., 4H), 3.69 (br. s., 4H), 2.95 (t, J = 5.4 Hz, 2H), 2.44 (t, J = 10.9 Hz, 1H), 1.86 (d, J = 12.5 Hz, 2H), 1.57 − 1.81 (m, 5H), 1.31 − 1.42 (m, 3H). LC−MS : m/z 420.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.74 (s, 1H), 7.45 − 7.54 (m, 1H), 6.54 − 6.64 (m, 1H), 4.53 − 5.02 (m, 2H), 4.11 − 4.41 (m, 3H), 3.89 − 4.08 (m, 2H), 3.51 (m, 1H), 3.21 (dd, J = 13.1, 3.5 Hz, 1H), 3.01 − 3.15 (m, 1H), 2.94 (t, J = 5.8 Hz, 2H), 2.43 (tt, J = 11.1, 3.5 Hz, 1H), 1.73 − 1.96 (m, 6H), 1.53 − 1.65 (m, 2H), 1.29 − 1.43 (m, 4H), 0.85 − 1.03 (m, 3H). LC−MS : m/z 449.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 (br. s., 1H), 7.11 (d, J = 3.5 Hz, 1H), 6.51 (br. s., 1H), 5.34 (br. s., 1H), 4.70 (s, 3H), 4.53 (d, J = 13.6 Hz, 1H), 4.16 − 4.31 (m, 2H), 4.12 (d, J = 7.0 Hz, 1H), 3.86 − 4.05 (m, 3H), 3.50 (d, J = 10.0 Hz, 1H), 3.23 (br. s., 1H), 2.93 (t, J = 5.5 Hz, 2H), 2.41 (br. s., 1H), 1.84 (d, J = 11.5 Hz, 2H), 1.75 (d, J = 9.5 Hz, 1H), 1.65 (br. s., 3H), 1.29 − 1.38 (m, 4H), 1.20 (t, J = 7.2 Hz, 3H). LC−MS : m/z 495.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.69 (br. s., 1H), 7.46−7.51 (m, 1H), 5.39 (br. s., 0.5H), 4.80 (br. s., 0.5H), 4.72 (d, J = 3.5 Hz, 2H), 4.25 (dq, J = 9.7, 7.3 Hz, 2H), 4.01 − 4.15 (m, 2H), 3.93 (br. s., 1H), 3.40 (d, J = 11.8 Hz, 1H), 3.03 − 3.18 (m, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.54 − 2.57 (s, 3H), 2.34 − 2.47 (m, 1H), 1.50 − 1.84 (m, 10H), 1.09 − 1.39 (m, 3H). LC−MS : m/z 507.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.53 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 4.9, 2.9 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.59 − 4.83 (m, 3H), 4.08 − 4.38 (m, 3H), 3.88 − 3.99 (m, 2H), 3.46 (br. s., 1H), 3.23 (d, J = 10.8 Hz, 1H), 3.07 (td, J = 12.5, 3.4 Hz, 1H), 2.87 − 2.97 (m, 2H), 2.41 (tt, J = 11.0, 3.5 Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.74 (d, J = 11.0 Hz, 1H), 1.68 (br. s., 1H), 1.53 − 1.61 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.27 − 1.39 (m, 4H). LC−MS : m/z 451.0 (M+H)+.
1H NMR (クロロホルム−d)δ 7.44 − 7.59 (m, 1H), 7.05 (d, J = 3.3 Hz, 1H), 6.52 (dd, J = 3.3, 1.8 Hz, 1H), 4.72 (s, 3H), 4.48 (br. s., 1H), 4.23 − 4.38 (m, 2H), 3.87 − 4.04 (m, 2H), 3.47 (br. s., 1H), 3.30 (dd, J = 13.2, 3.6 Hz, 1H), 3.16 (td, J = 12.4, 3.3 Hz, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.43 (tt, J = 10.9, 3.6 Hz, 1H), 1.89 − 2.08 (m, 1H), 1.74 − 1.88 (m, 4H), 1.52 − 1.64 (m, 2H), 1.21 − 1.44 (m, 5H), 0.83 − 1.04 (m, 3H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (クロロホルム−d)δ 8.57 (dd, J = 5.0, 0.8 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.39 (dd, J = 14.1, 7.8 Hz, 1H), 7.22 (d, J = 6.8 Hz, 1H), 4.89 (br. s., 0.5H), 4.69 (s, 2H), 4.53 (d, J = 13.8 Hz, 0.5H), 4.09 − 4.24 (m, 2.5H), 3.89 − 4.07 (m, 3H), 3.54 (t, J = 11.0 Hz, 1H), 3.09 − 3.23 (m, 1H), 2.78 − 3.05 (m, 2.5H), 2.29 − 2.47 (m, 1H), 1.83 (d, J = 12.5 Hz, 4H), 1.75 (d, J = 10.0 Hz, 2H), 1.62 − 1.70 (m, 2H), 1.46 − 1.62 (m, 2H), 1.12 − 1.40 (m, 3H). LC−MS : m/z 460.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.83 (s, 1H), 4.70 (s, 3H), 4.12 − 4.32 (m, 3H), 3.85 − 3.99 (m, 2H), 3.53 (br. s., 1H), 3.30 (dd, J = 13.1, 3.5 Hz, 1H), 3.14 (td, J = 12.5, 3.5 Hz, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.36 − 2.47 (m, 4H), 1.80 − 1.89 (m, 2H), 1.75 (d, J = 11.3 Hz, 1H), 1.53 − 1.63 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.26 − 1.41 (m, 5H). LC−MS : m/z 450.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.28 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 4.70 (s, 2H), 4.14 − 4.25 (m, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.44 (br. s., 1H), 3.22 (d, J = 10.8 Hz, 1H), 3.00 − 3.09 (m, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.35 − 2.47 (m, 4H), 1.84 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 11.3 Hz, 1H), 1.63 − 1.70 (m, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.27 − 1.35 (m, 4H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (クロロホルム−d)δ 4.89 (br. s., 1H), 4.70 (s, 2H), 4.13 − 4.27 (m, 2H), 3.80 − 4.08 (m, 7H), 3.42 − 3.67 (m, 1H), 3.12 − 3.42 (m, 2H), 2.99 − 3.10 (m, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.0, 3.6 Hz, 1H), 1.98 − 2.24 (m, 2H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.63 − 1.70 (m, 3H), 1.28 − 1.43 (m, 7H). LC−MS : m/z 439.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.19 − 7.26 (m, 2H), 6.86 − 6.95 (m, 2H), 4.92 (br. s., 1H), 4.69 (s, 2H), 4.22 (d, J = 10.8 Hz, 1H), 4.11 (d, J = 12.8 Hz, 1H), 3.81 − 4.03 (m, 4H), 3.71 − 3.81 (m, 2H), 3.34 − 3.51 (m, 1H), 3.09 − 3.34 (m, 1H), 2.87 − 3.04 (m, 3H), 2.40 (tt, J = 11.0, 3.6 Hz, 1H), 1.83 (d, J = 12.5 Hz, 2H), 1.74 (d, J = 14.6 Hz, 2H), 1.59 − 1.68 (m, 3H), 1.26 − 1.37 (m, 5H). LC−MS : m/z 489.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.24 (t, J = 8.0 Hz, 1H), 6.73 − 6.89 (m, 3H), 4.91 (br. s., 1H), 4.68 (s, 2H), 4.21 (d, J = 13.8 Hz, 1H), 4.10 (d, J = 12.3 Hz, 2H), 3.92 (t, J = 5.0 Hz, 2H), 3.72 − 3.83 (m, 4H), 3.44 (t, J = 11.2 Hz, 1H), 3.07 − 3.23 (m, 1H), 2.96 − 3.07 (m, 1H), 2.90 (t, J = 5.5 Hz, 2H), 2.39 (tt, J = 11.0, 3.5 Hz, 1H), 1.72 − 1.86 (m, 4H), 1.61 − 1.67 (m, 2H), 1.51 − 1.61 (m, 2H), 1.25 − 1.34 (m, 5H). LC−MS : m/z 489.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.05 (dd, J = 3.5, 0.8 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.88 (br. s., 1H), 4.71 (s, 2H), 4.49 (d, J = 13.1 Hz, 1H), 4.27 (d, J = 12.0 Hz, 1H), 4.18 (dt, J = 13.1, 2.1 Hz, 1H), 3.87 − 4.05 (m, 2H), 3.55 (br. s., 1H), 3.34 (dd, J = 13.1, 3.8 Hz, 1H), 3.17 (td, J = 12.5, 3.4 Hz, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.43 (tt, J = 11.1, 3.7 Hz, 1H), 1.85 (d, J = 12.8 Hz, 2H), 1.54 − 1.79 (m, 5H), 1.46 (d, J = 6.8 Hz, 3H), 1.31 − 1.42 (m, 3H). LC−MS : m/z 435.2 (M+H)+.
1H NMR (クロロホルム−d)δ 4.88 (br. s., 1H), 4.70 (s, 2H), 4.52 (d, J = 13.6 Hz, 1H), 4.23 (d, J = 13.1 Hz, 1H), 3.90 − 3.97 (m, 2H), 3.52 − 3.82 (m, 1H), 3.00 − 3.30 (m, 3H), 2.80 − 2.97 (m, 4H), 2.56 − 2.78 (m, 2H), 2.37 − 2.46 (m, 1H), 2.11 − 2.21 (m, 3H), 1.84 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 14.6 Hz, 2H), 1.52 − 1.63 (m, 2H), 1.26 − 1.42 (m, 7H). LC−MS : m/z 443.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.46 (dd, J = 5.0, 1.0 Hz, 1H), 7.32 (dd, J = 3.6, 1.1 Hz, 1H), 7.06 (dd, J = 5.0, 3.8 Hz, 1H), 4.77 (br. s., 1H), 4.70 (s, 2H), 4.37 (d, J = 13.6 Hz, 1H), 4.12 − 4.28 (m, 2H), 3.91 − 3.98 (m, 2H), 3.53 (t, J = 11.4 Hz, 1H), 3.28 (dd, J = 13.1, 3.5 Hz, 1H), 3.12 (td, J = 12.5, 3.3 Hz, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 11.1, 3.6 Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 10.8 Hz, 1H), 1.68 (br. s., 1H), 1.55 − 1.59 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.27 − 1.40 (m, 5H). LC−MS : m/z 451.0 (M+H)+.
1H NMR (クロロホルム−d)δ 8.47 (d, J = 6.8 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 6.89 (t, J = 6.0 Hz, 1H), 4.60 − 4.87 (m, 3H), 4.23 (d, J = 12.8 Hz, 2H), 3.88 − 4.08 (m, 3H), 3.55 − 3.76 (m, 1H), 3.32 (d, J = 11.3 Hz, 1H), 3.08 (br. s., 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H), 2.42 (tt, J = 11.0, 3.6 Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.57 − 1.79 (m, 5H), 1.45 (d, J = 5.3 Hz, 3H), 1.27 − 1.38 (m, 3H). LC−MS : m/z 499.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.47 − 7.56 (m, 1H), 7.07 (d, J = 3.3 Hz, 1H), 6.52 (dd, J = 3.3, 1.8 Hz, 1H), 4.87 (br. s., 2H), 4.73 (s, 2H), 4.31 (d, J = 13.1 Hz, 2H), 3.96 (t, J = 5.8 Hz, 2H), 3.23 (dd, J = 12.9, 4.1 Hz, 2H), 2.96 (t, J = 5.6 Hz, 2H), 2.39 − 2.52 (m, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.60 − 1.80 (m, 5H), 1.57 (d, J = 6.8 Hz, 6H), 1.30 − 1.43 (m, 3H). LC−MS : m/z 449.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.79 (br. s., 1H), 7.32 (br. s., 1H), 4.79 (br. s., 1H), 4.71 (s, 2H), 4.35 (d, J = 6.5 Hz, 1H), 4.11 − 4.27 (m, 2H), 3.91 − 3.99 (m, 2H), 3.86 (s, 3H), 3.55 (br. s., 1H), 3.21 − 3.28 (m, 1H), 3.03 − 3.14 (m, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.0, 3.6 Hz, 1H), 1.75 (d, J = 10.3 Hz, 2H), 1.69 (br. s., 1H), 1.54 − 1.62 (m, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.27 − 1.41 (m, 5H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.47 − 7.57 (m, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H), 4.70 (s, 2H), 3.87 − 4.11 (m, 6H), 3.66 − 3.78 (m, 4H), 2.93 (t, J = 5.8 Hz, 2H), 2.42 (tt, J = 11.0, 3.6 Hz, 1H), 1.80 − 1.89 (m, 2H), 1.53 − 1.78 (m, 5H), 1.27 − 1.41 (m, 3H). LC−MS : m/z 421.0 (M+H)+.
1H NMR (クロロホルム−d)δ 8.54 (br. s., 2H), 7.72 (br. s., 1H), 7.34 (dd, J = 7.7, 4.9 Hz, 1H), 4.89 (br. s., 1H), 4.69 (s, 3H), 4.53 (d, J = 14.3 Hz, 1H), 4.02 − 4.31 (m, 3H), 3.89 − 3.97 (m, 2H), 3.72 − 3.80 (m, 3H), 3.37 − 3.63 (m, 1H), 3.17 (t, J = 13.7 Hz, 2H), 2.89 − 3.05 (m, 3H), 2.41 (tt, J = 11.1, 3.5 Hz, 1H), 1.28 − 1.37 (m, 7H). LC−MS : m/z 480.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.44 − 7.59 (m, 1H), 7.03 (br. s., 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 4.70 (s, 2H), 4.21 − 4.58 (m, 4H), 3.85 − 4.04 (m, 2H), 3.60 (br. s., 1H), 3.08 − 3.28 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 11.0, 3.7 Hz, 1H), 2.18 − 2.32 (m, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.54 − 1.75 (m, 5H), 1.06 (br. s., 3H), 0.80 − 0.95 (m, 3H). LC−MS : m/z 463.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 (s, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.46 − 6.58 (m, 1H), 4.88 (br. s., 1H), 4.72 (s, 2H), 4.50 (d, J = 13.1 Hz, 1H), 4.28 (d, J = 12.5 Hz, 1H), 4.19 (d, J = 12.8 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.56 (br. s., 1H), 3.34 (dd, J = 13.2, 3.6 Hz, 1H), 3.10 − 3.26 (m, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.43 (t, J = 11.3 Hz, 1H), 1.85 (d, J = 12.3 Hz, 2H), 1.55 − 1.77 (m, 5H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 − 1.42 (m, 3H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ 8.88 (br. s., 1H), 7.74 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.22 − 7.28 (m, 2H), 6.59 (br. s., 1H), 4.72 (s, 3H), 4.08 − 4.37 (m, 3H), 3.95 (t, J = 5.6 Hz, 2H), 3.50 (t, J = 11.4 Hz, 1H), 3.29 (d, J = 11.5 Hz, 1H), 3.04 − 3.18 (m, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.0, 3.5 Hz, 1H), 1.85 (d, J = 12.5 Hz, 2H), 1.55 − 1.79 (m, 5H), 1.43 (d, J = 6.5 Hz, 3H), 1.30 − 1.39 (m, 3H). LC−MS : m/z 484.1 (M+H)+.
1H NMR (クロロホルム−d)δ 5.97 (s, 1H), 4.72 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.80 (br. s., 4H), 3.67 (br. s., 4H), 2.95 (t, J = 5.6 Hz, 2H), 2.40 − 2.48 (m, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.85 (d, J = 12.5 Hz, 2H), 1.61 − 1.76 (m, 5H), 1.30 − 1.42 (m, 3H). LC−MS : m/z 448.9 (M+H)+.
1H NMR (クロロホルム−d)δ 8.87 (br. s., 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.14 − 7.27 (m, 3H), 6.55 (br. s., 1H), 4.72 (s, 2H), 4.06 (br. s., 2H), 3.94 (t, J = 5.6 Hz, 2H), 3.80 (br. s., 2H), 3.56 (br. s., 4H), 2.93 (t, J = 5.6 Hz, 2H), 2.36 − 2.48 (m, 1H), 1.80 − 1.89 (m, 2H), 1.53 − 1.79 (m, 5H), 1.29 − 1.41 (m, 3H). LC−MS : m/z 469.9 (M+H)+.
1H NMR (クロロホルム−d)δ 8.81 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 4.88 − 5.04 (m, 1H), 4.70 (s, 2H), 4.57 (br. s., 1H), 4.13 − 4.41 (m, 2H), 3.89 − 3.97 (m, 2H), 3.55 − 3.77 (m, 1H), 3.36 (br. s., 1H), 3.18 (br. s., 1H), 2.93 (t, J = 5.8 Hz, 2H), 2.41 (tt, J = 11.1, 3.7 Hz, 1H), 1.80 − 1.91 (m, 2H), 1.74 (d, J = 10.8 Hz, 1H), 1.63 − 1.68 (m, 2H), 1.41 − 1.45 (m, 3H), 1.26 − 1.40 (m, 5H). LC−MS : m/z 452.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.47 − 7.54 (m, 1H), 7.04 − 7.09 (m, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.66 − 4.76 (m, 2H), 4.58 (br. s., 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.27 (dd, J = 13.3, 1.5 Hz, 1H), 4.05 (d, J = 13.3 Hz, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.36 − 3.59 (m, 3H), 2.93 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 11.2, 3.5 Hz, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.52 − 1.79 (m, 5H), 1.29 (d, J = 6.5 Hz, 6H). LC−MS : m/z 435.2 (M+H)+.
1H NMR (クロロホルム−d)δ 7.87 − 7.94 (m, 1H), 7.77 − 7.84 (m, 1H), 7.53 − 7.60 (m, 1H), 7.37 − 7.46 (m, 2H), 5.26 − 5.38 (m, 1H), 4.69 (s, 2H), 4.17 (d, J = 14.1 Hz, 3H), 3.90 − 3.96 (m, 2H), 3.49 (t, J = 11.7 Hz, 1H), 3.28 (d, J = 11.8 Hz, 1H), 3.08 (t, J = 11.5 Hz, 1H), 2.88 − 2.96 (m, 2H), 2.40 (tt, J = 11.0, 3.6 Hz, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.73 (d, J = 11.3 Hz, 1H), 1.60 − 1.69 (m, 3H), 1.56 (br. s., 1H), 1.43 (dd, J = 3.9, 1.9 Hz, 3H), 1.28 − 1.36 (m, 3H). LC−MS : m/z 501.1 (M+H)+.
1H NMR (クロロホルム−d)δ 5.29 (d, J = 2.0 Hz, 0.5H), 4.76 (s, 0.5H), 4.71 (s, 2H), 4.15 (d, J = 7.0 Hz, 2H), 4.06 (d, J = 7.0 Hz, 1H), 3.83 − 4.00 (m, 2H), 3.72 − 3.83 (m, 2H), 3.63 − 3.71 (m, 4H), 3.36 − 3.41 (m, 3H), 3.25 − 3.36 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.58 − 2.74 (m, 3H), 1.85 (d, J = 11.8 Hz, 3H), 1.47 − 1.75 (m, 4H), 1.27 − 1.42 (m, 3H), 1.18 (t, J = 7.2 Hz, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.27 − 7.35 (m, 1H), 6.93 − 7.08 (m, 3H), 4.69 (s, 2H), 4.55 (d, J = 13.6 Hz, 1H), 4.22 (d, J = 12.8 Hz, 1H), 4.02 − 4.17 (m, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.75 (br. s., 2H), 3.12 − 3.35 (m, 1H), 3.02 − 3.12 (m, 1H), 2.91 (t, J = 5.6 Hz, 3H), 2.33 − 2.47 (m, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.67 (br. s., 1H), 1.50 − 1.61 (m, 2H), 1.26 − 1.40 (m, 7H). LC−MS : m/z 477.1 (M+H)+.
1H NMR (クロロホルム−d)δ 9.02 (d, J = 6.8 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.00 (t, J = 6.9 Hz, 1H), 4.93 (br. s., 1H), 4.71 (s, 2H), 4.49 (d, J = 13.1 Hz, 1H), 4.14 − 4.32 (m, 2H), 3.87 − 4.00 (m, 2H), 3.65 (br. s., 1H), 3.32 (dd, J = 13.1, 3.5 Hz, 1H), 3.17 (td, J = 12.5, 3.4 Hz, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.0, 3.7 Hz, 1H), 1.84 (d, J = 12.3 Hz, 2H), 1.75 (d, J = 9.8 Hz, 1H), 1.56 − 1.62 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.28 − 1.42 (m, 5H). LC−MS : m/z 385.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.34 (d, J = 1.5 Hz, 1H), 6.34 (d, J = 1.5 Hz, 1H), 4.62 − 4.85 (m, 3H), 4.13 − 4.42 (m, 3H), 3.94 (t, J = 5.8 Hz, 2H), 3.51 (br. s., 1H), 3.32 (d, J = 10.0 Hz, 1H), 3.06 − 3.21 (m, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.42 (t, J = 11.3 Hz, 1H), 2.29 (s, 3H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.5 Hz, 3H), 1.43 (d, J = 6.5 Hz, 3H), 1.27 − 1.38 (m, 5H). LC−MS : m/z 449.0 (M+H)+.
1H NMR (クロロホルム−d)δ 8.74 (br. s., 1H), 7.78 (s, 1H), 7.36 − 7.43 (m, 1H), 7.25 − 7.32 (m, 2H), 6.51 − 6.67 (m, 1H), 4.72 (s, 2H), 3.95 (t, J = 5.8 Hz, 3H), 3.84 (br. s., 2H), 3.70 (br. s., 5H), 2.94 (t, J = 5.6 Hz, 2H), 2.43 (tt, J = 11.0, 3.6 Hz, 1H), 1.81 − 1.89 (m, 2H), 1.55 − 1.81 (m, 5H), 1.30 − 1.41 (m, 3H). LC−MS : m/z 470.2 (M+H)+.
1H NMR (クロロホルム−d)δ 8.78 (br. s., 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.39 − 7.47 (m, 1H), 7.20 − 7.26 (m, 2H), 4.71 (s, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.88 (br. s., 4H), 3.69 (br. s., 4H), 2.93 (t, J = 5.6 Hz, 2H), 2.34 − 2.48 (m, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.74 (d, J = 10.8 Hz, 1H), 1.67 (br. s., 2H), 1.53 − 1.60 (m, 2H), 1.28 − 1.38 (m, 3H). LC−MS : m/z 469.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.38 (d, J = 1.5 Hz, 1H), 6.36 (d, J = 1.5 Hz, 1H), 4.72 (s, 2H), 3.96 (t, J = 5.8 Hz, 2H), 3.85 − 3.93 (m, 4H), 3.68 − 3.81 (m, 4H), 2.95 (t, J = 5.6 Hz, 2H), 2.38 − 2.50 (m, 1H), 2.32 (s, 3H), 1.86 (d, J = 12.3 Hz, 2H), 1.56 − 1.81 (m, 5H), 1.29 − 1.44 (m, 3H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.27 − 7.37 (m, 1H), 7.21 − 7.26 (m, 1H), 7.03 − 7.15 (m, 2H), 4.91 (br. s., 1H), 4.69 (s, 2H), 4.18 − 4.27 (m, 1H), 4.14 (d, J = 13.3 Hz, 1H), 3.86 − 4.04 (m, 2H), 3.71 − 3.86 (m, 3H), 3.53 (t, J = 11.2 Hz, 1H), 3.17 (t, J = 14.7 Hz, 1H), 2.87 − 3.04 (m, 3H), 2.40 (tt, J = 11.1, 3.7 Hz, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.0 Hz, 1H), 1.65 (br. s., 4H), 1.27 − 1.37 (m, 6H). LC−MS : m/z 477.1 (M+H)+.
1H NMR (クロロホルム−d)δ 8.54 (br. s., 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60 (br. s., 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 4.72 (s, 2H), 3.70 − 3.97 (m, 10H), 2.95 (t, J = 5.6 Hz, 2H), 2.38 − 2.52 (m, 1H), 1.85 (d, J = 12.5 Hz, 2H), 1.55 − 1.80 (m, 5H), 1.30 − 1.41 (m, 3H). LC−MS : m/z 469.9 (M+H)+.
1H NMR (クロロホルム−d)δ 8.71 − 8.79 (m, 1H), 8.64 (dd, J = 4.0, 1.8 Hz, 1H), 8.43 (s, 1H), 6.96 (dd, J = 6.9, 4.1 Hz, 1H), 4.70 (s, 3H), 4.11 − 4.41 (m, 3H), 3.88 − 3.98 (m, 2H), 3.57 (br. s., 1H), 3.43 (dd, J = 13.1, 3.5 Hz, 1H), 3.26 (t, J = 11.5 Hz, 1H), 2.86 − 2.98 (m, 2H), 2.41 (tt, J = 11.0, 3.7 Hz, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.74 (d, J = 11.3 Hz, 1H), 1.69 (br. s., 1H), 1.54 − 1.63 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.26 − 1.38 (m, 4H). LC−MS : m/z 486.2 (M+H)+.
1H NMR (クロロホルム−d)δ 8.20 − 8.26 (m, 1H), 7.86 − 7.93 (m, 1H), 4.81 − 5.04 (m, 1H), 4.70 (s, 3H), 4.15 − 4.34 (m, 2H), 3.87 − 3.97 (m, 2H), 3.55 − 3.76 (m, 1H), 3.30 − 3.37 (m, 1H), 3.09 − 3.24 (m, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 11.0, 3.7 Hz, 1H), 1.81 − 1.87 (m, 2H), 1.75 (d, J = 10.8 Hz, 2H), 1.54 − 1.63 (m, 2H), 1.43 (d, J = 6.5 Hz, 3H), 1.27 − 1.38 (m, 4H). LC−MS : m/z 436.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.48 − 7.60 (m, 1H), 7.07 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.3, 1.8 Hz, 1H), 4.74 (s, 2H), 3.85 − 4.14 (m, 6H), 3.67 − 3.83 (m, 4H), 2.87 − 3.06 (m, 3H), 1.76 − 1.99 (m, 5H), 1.62 − 1.75 (m, 3H). LC−MS : m/z 406.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 (d, J = 1.0 Hz, 1H), 7.07 (d, J = 3.3 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.87 (br. s., 2H), 4.74 (s, 2H), 4.28 (d, J = 12.8 Hz, 2H), 3.97 (t, J = 5.8 Hz, 2H), 3.22 (dd, J = 12.9, 4.4 Hz, 2H), 2.91 − 3.03 (m, 3H), 1.80 − 1.96 (m, 5H), 1.56 (d, J = 6.8 Hz, 6H), 1.33 (br. s., 3H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.71 − 7.80 (m, 1H), 7.47 (t, J = 1.6 Hz, 1H), 6.54 − 6.67 (m, 1H), 4.72 (s, 3H), 4.14 − 4.42 (m, 3H), 3.89 − 4.01 (m, 2H), 3.50 (br. s., 1H), 3.27 (dd, J = 12.9, 3.4 Hz, 1H), 3.10 (td, J = 12.5, 3.5 Hz, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 1.44 (d, J = 6.8 Hz, 3H), 1.15 − 1.24 (m, 6H). LC−MS : m/z 395.0 (M+H)+.
1H NMR (クロロホルム−d)δ 7.38 (br. s., 1H), 7.22 − 7.33 (m, 5H), 7.18 (d, J = 6.5 Hz, 1H), 5.26 (br. s., 1H), 4.58 − 4.76 (m, 2H), 4.15 (br. s., 1H), 3.86 − 4.05 (m, 3H), 3.78 (br. s., 3H), 3.47 − 3.61 (m, 1H), 2.88 − 3.03 (m, 2H), 2.62 − 2.77 (m, 1H), 2.30 − 2.43 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.85 (br. s., 3H). LC−MS : m/z 471.1 (M+H)+.
1H NMR (クロロホルム−d)δ 9.18 (br. s., 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.36 − 7.50 (m, 2H), 7.14 − 7.34 (m, 2H), 4.74 (s, 2H), 3.83 − 4.01 (m, 6H), 3.73 (br. s., 4H), 2.96 (br. s., 2H), 2.75 − 2.89 (m, 1H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 430.4 (M+H)+.
1H NMR (クロロホルム−d)δ 7.51 (dd, J = 1.8, 0.8 Hz, 1H), 7.37 (br. s., 2H), 7.25 (t, J = 7.4 Hz, 2H), 7.13 − 7.20 (m, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 5.20 (br. s., 1H), 4.55 − 4.74 (m, 2H), 4.31 (br. s., 2H), 3.78 − 4.08 (m, 5H), 3.61 (br. s., 1H), 2.89 − 3.01 (m, 2H), 2.57 − 2.77 (m, 1H), 1.09 − 1.19 (m, 3H), 0.81 (d, J = 6.3 Hz, 3H). LC−MS : m/z 456.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.48 − 7.63 (m, 2H), 7.29 − 7.33 (m, 1H), 4.73 (s, 2H), 3.96 (t, J = 5.8 Hz, 4H), 3.62 − 3.74 (m, 6H), 2.96 (t, J = 5.8 Hz, 2H), 2.83 (dt, J = 13.4, 6.5 Hz, 1H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 459.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.47 (d, J = 1.8 Hz, 1H), 7.33 − 7.38 (m, 1H), 7.26 − 7.31 (m, 1H), 4.72 (s, 2H), 3.99 − 4.09 (m, 1H), 3.86 − 3.98 (m, 3H), 3.70 − 3.81 (m, 2H), 3.56 − 3.70 (m, 2H), 3.43 − 3.52 (m, 1H), 3.33 − 3.42 (m, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H). LC−MS : m/z 459.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.50 (s, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.50 (br. s., 1H), 4.65 − 4.95 (m, 4H), 4.29 (br. s., 1H), 4.17 (d, J = 13.6 Hz, 1H), 3.94 (t, J = 5.6 Hz, 2H), 3.59 (dd, J = 13.6, 3.3 Hz, 2H), 2.92 (t, J = 5.5 Hz, 2H), 2.81 (dt, J = 13.4, 6.6 Hz, 1H), 1.43 (br. s., 3H), 1.31 (d, J = 6.5 Hz, 3H), 1.18 (d, J = 6.5 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H). LC−MS : m/z 408.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 (dd, J = 1.8, 0.8 Hz, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.88 (br. s., 1H), 4.72 (s, 2H), 4.49 (d, J = 13.3 Hz, 1H), 4.29 (d, J = 12.0 Hz, 1H), 4.14 − 4.24 (m, 1H), 3.92 − 4.03 (m, 2H), 3.55 (br. s., 1H), 3.35 (dd, J = 13.1, 3.8 Hz, 1H), 3.19 (td, J = 12.4, 3.5 Hz, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.72 − 2.88 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.15 − 1.25 (m, 6H). LC−MS : m/z 395.0 (M+H)+.
1H NMR (クロロホルム−d)δ 7.25 − 7.34 (m, 1H), 6.39 (d, J = 1.8 Hz, 1H), 4.72 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.80 (br. s., 4H), 3.68 (br. s., 4H), 2.95 (t, J = 5.6 Hz, 2H), 2.82 (dt, J = 13.4, 6.7 Hz, 1H), 2.42 (s, 3H), 1.16 − 1.25 (m, 6H). LC−MS : m/z 394.9 (M+H)+.
1H NMR (クロロホルム−d)δ 7.52 − 7.58 (m, 1H), 7.37 − 7.44 (m, 2H), 7.24 − 7.35 (m, 2H), 7.07 (dd, J = 3.5, 0.8 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.88 (br. s., 2H), 4.70 (s, 2H), 4.31 (d, J = 13.1 Hz, 2H), 4.05 (t, J = 5.9 Hz, 2H), 3.25 (dd, J = 12.9, 4.1 Hz, 2H), 3.07 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H), 1.59 (d, J = 7.0 Hz, 6H). LC−MS : m/z 456.9 (M+H)+.
1H NMR (クロロホルム−d)δ 4.77 − 4.89 (m, 2H), 4.65 (d, J = 10.3 Hz, 0.5H), 4.40 (d, J = 10.3 Hz, 0.5H), 4.27 − 4.36 (m, 1H), 4.07 − 4.26 (m, 1H), 3.64 − 3.87 (m, 2.5H), 3.39 − 3.58 (m, 1H), 3.36 (d, J = 3.8 Hz, 3H), 2.90 − 3.09 (m, 2.5H), 2.76 (s, 2H), 2.52 − 2.74 (m, 2H), 2.19 − 2.30 (m, 0.5H), 2.10 (dt, J = 10.4, 6.7 Hz, 0.5H), 1.67 − 1.74 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.05 − 1.17 (m, 2H), 0.97 − 1.04 (m, 5H), 0.84 − 0.92 (d, J = 6.8 Hz, 1.5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 441.2 (M+H)+.
1H NMR (クロロホルム−d)δ 4.83 (s, 2H), 4.69 (br. s., 0.5H), 4.58 (d, J = 12.8 Hz, 0.5H), 4.05 − 4.22 (m, 2H), 3.90 (br. s., 0.5H), 3.67 − 3.81 (m, 2.5H), 3.42 − 3.54 (m, 0.5H), 3.36 (s, 3H), 2.88 − 3.18 (m, 2.5H), 2.76 (s, 2H), 2.51 − 2.74 (m, 2H), 1.66 − 1.80 (m, 3H), 1.31 (d, J = 1.5 Hz, 6H), 1.09 − 1.17 (m, 2H), 0.99 − 1.04 (m, 2H), 0.90 (dt, J = 18.1, 7.5 Hz, 3H). LC−MS : m/z 427.0 (M+H)+.
1H NMR (クロロホルム−d)δ 4.76 − 4.89 (m, 2H), 4.64 (d, J = 9.2 Hz, 0.5H), 4.39 (d, J = 10.3 Hz, 0.5H), 4.32 (d, J = 13.6 Hz, 1H), 4.10 − 4.24 (m, 1H), 3.74 (d, J = 13.6 Hz, 0.5H), 3.39 − 3.54 (m, 1H), 2.90 − 3.08 (m, 2.5H), 2.80 − 2.89 (m, 2H), 2.76 (s, 2H), 2.59 − 2.72 (m, 2H), 2.20 − 2.33 (m, 0.5H), 2.04 − 2.13 (m, 0.5H), 1.67 − 1.75 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.05 − 1.19 (m, 2H), 0.96 − 1.05 (m, 5H), 0.88 (d, J = 6.8 Hz, 1.5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 457.2 (M+H)+.
1H NMR (クロロホルム−d)δ 4.76 − 4.89 (m, 2H), 4.66−4.68 (m, 0.5H), 4.32−4.43 (m, 1.5H), 4.18 (t, J = 9.0 Hz, 1H), 3.73 (d, J = 13.3 Hz, 0.5H), 3.38 − 3.51 (m, 1H), 2.89 − 3.12 (m, 2.5H), 2.76 (s, 2H), 2.10 − 2.43 (m, 3H), 1.64 − 1.75 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.06 − 1.18 (m, 3H), 0.96 − 1.05 (m, 5H), 0.79 − 0.91 (m, 3H), 0.59 (d, J = 7.5 Hz, 2H), 0.13 − 0.29 (m, 2H). LC−MS : m/z 437.3 (M+H)+.
1H NMR (クロロホルム−d)δ 7.28 (d, J = 2.0 Hz, 1H), 6.32 − 6.40 (m, 1H), 4.83 (s, 2H), 3.85 − 4.82 (m, 4H), 3.34 (br. s., 1H), 3.13 (dd, J = 13.2, 3.6 Hz, 1H), 2.90 − 3.04 (m, 1H), 2.77 (s, 2H), 2.37 − 2.40 (m, 3H), 1.83 − 1.96 (m, 1H), 1.66 − 1.79 (m, 2H), 1.29 − 1.35 (m, 6H), 1.08 − 1.15 (m, 2H), 0.98 − 1.04 (m, 2H), 0.84 − 0.94 (m, 3H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (クロロホルム−d) δ7.20 (dd, J = 5.1, 1.1 Hz, 1H), 6.87 − 6.99 (m, 2H), 4.82 (s, 2H), 4.69 (br. s., 0.5H), 4.46 − 4.64 (m, 0.5H), 4.01 − 4.17 (m, 2H), 3.87 − 3.94 (m, 1H), 3.77 (d, J = 13.1 Hz, 1H), 3.39 − 3.56 (m, 1H), 3.01 − 3.14 (m, 1H), 2.81 − 3.01 (m, 2H), 2.72 − 2.79 (m, 2H), 1.66 − 1.84 (m, 3H), 1.30 (d, J = 2.5 Hz, 6H), 1.10 (d, J = 4.0 Hz, 2H), 0.98 − 1.05 (m, 2H), 0.82 − 0.94 (m, 3H). LC−MS : m/z 465.1 (M+H)+.
1H NMR (クロロホルム−d) δ7.16 − 7.26 (m, 1H), 6.85 − 6.99 (m, 2H), 4.75 − 4.88 (m, 2H), 4.64 − 4.65 (m, 0.5H), 4.40 (d, J = 10.5 Hz, 0.51H), 4.24 − 4.33 (m, 1H), 4.08 − 4.18 (m, 1H), 3.79 − 4.05 (m, 3H), 3.32 − 3.50 (m, 1H), 2.92 − 3.04 (m, 1H), 2.78 − 2.90 (m, 1H), 2.75 (s, 2H), 2.06 − 2.275 (m, 1H), 1.62 − 1.71 (m, 1H), 1.31 (d, J = 3.0 Hz, 6H), 0.93 − 1.19 (m, 7H), 0.76 − 0.90 (m, 3H). LC−MS : m/z 479.1 (M+H)+.
1H NMR (クロロホルム−d) δ7.24 − 7.34 (m, 1H), 6.35 (br. s., 1H), 4.78 − 4.92 (m, 2H), 4.13−4.56 (m, 3H), 3.87 (d, J = 12.3 Hz, 0.5H), 3.46−3.54 (m, 1H), 2.92 − 3.16 (m, 2.5H), 2.78 (s, 2H), 2.35 − 2.48 (m, 3H), 2.18 − 2.32 (m, 1H), 1.69 − 1.77 (m, 1H), 1.33 (d, J = 2.3 Hz, 6H), 1.00 − 1.21 (m, 6H), 0.79 − 0.98 (m, 4H). LC−MS : m/z 463.1 (M+H)+.
1H NMR (クロロホルム−d)δ 7.65 − 7.76 (m, 1H), 7.40 − 7.48 (m, 1H), 6.46 − 6.60 (m, 1H), 4.83 (s, 2H), 3.98 − 4.52 (m, 4H), 3.98 (br. s., 1H), 3.40 (br. s., 1H), 3.13 (dd, J = 13.1, 3.8 Hz, 1H), 2.92 − 3.05 (m, 1H), 2.77 (s, 2H), 1.66 − 1.96 (m, 3H), 1.29 − 1.38 (m, 6H), 1.08 − 1.15 (m, 2H), 0.98 − 1.04 (m, 2H), 0.85 − 0.96 (m, 3H). LC−MS : m/z 435.2 (M+H)+.
1H NMR (クロロホルム−d) δ8.46 − 8.57 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.27 − 7.32 (m, 1H), 4.82 (s, 2H), 4.63 − 4.65 (m, 0.5H), 4.40 (d, J = 10.3 Hz, 0.5H), 4.23 − 4.34 (m, 1H), 4.09 − 4.19 (m, 1H), 3.72 − 3.80 (m, 2.5H), 3.39 − 3.55 (m, 1H), 2.92 − 3.04 (m, 1H), 2.79 − 2.91 (m, 1.5H), 2.75 (s, 2H), 2.07 − 2.30 (m, 1H), 1.66 − 1.73 (m, 1H), 1.29 − 1.33 (m, 6H), 0.96 − 1.16 (m, 7H), 0.88 (d, J = 6.8 Hz, 1.5H), 0.79 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 474.2 (M+H)+.
1H NMR (クロロホルム−d) δ7.27 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.0 Hz, 1H), 4.52 − 5.22 (m, 3H), 3.98 − 4.28 (m, 3H), 3.41 (br. s., 1H), 3.15 (dd, J = 12.9, 3.4 Hz, 1H), 2.97 (td, J = 12.5, 3.5 Hz, 1H), 2.77 (s, 2H), 2.35 − 2.45 (m, 3H), 1.66 − 1.75 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.31 (s, 6H), 1.09 − 1.15 (m, 2H), 0.98 − 1.04 (m, 2H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.16 − 7.24 (m, 1 H), 6.85 − 6.99 (m, 2 H), 4.89 (br. s., 0.5 H), 4.82 (s, 2 H), 4.51 − 4.54 (m, 0.5 H), 4.10 − 4.22 (m, 0.5 H), 3.97 − 4.12 (m, 2 H), 3.88 − 3.97 (m, 2 H), 3.74 (d, J = 13.3 Hz, 0.5 H), 3.52 (t, J = 11.9 Hz, 0.5 H), 2.99 − 3.22 (m, 1.5 H), 2.82 − 2.96 (m, 1 H), 2.76 (s, 2 H), 1.68 − 1.75 (m, 1 H), 1.26 − 1.36 (m, 9 H), 1.07 − 1.15 (m, 2 H), 0.95 − 1.04 (m, 2 H). LC−MS : m/z 451.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.25 − 7.32 (m, 2H), 6.84 − 7.02 (m, 3H), 4.76 − 4.89 (m, 2H), 4.67 (d, J = 10.5 Hz, 0.5H), 4.42 (d, J = 10.5 Hz, 0.5H), 4.29 − 4.38 (m, 3H), 4.10 − 4.25 (m, 1H), 3.87 (d, J = 13.6 Hz, 0.5H), 3.59 (d, J = 10.3 Hz, 0.5H), 3.48 (td, J = 12.8, 3.0 Hz, 0.5H), 2.84 − 3.10 (m, 4.5H), 2.71 − 2.79 (m, 2H), 2.29 (dt, J = 10.3, 6.7 Hz, 0.5H), 2.05 − 2.18 (m, 0.5H), 1.67 − 1.76 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 1.07 − 1.18 (m, 2H), 0.96 − 1.05 (m, 5H), 0.89 − 0.96 (m, 1.5H), 0.83 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 503.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.46 − 8.62 (m, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.19 (dd, J = 6.9, 4.4 Hz, 1H), 4.76 − 4.92 (m, 2H), 4.61 − 4.64 (m, 0.5H), 4.37 (d, J = 10.5 Hz, 0.5H), 4.24 − 4.34 (m, 1H), 4.02 − 4.19 (m, 2H), 3.99 (d, J = 5.3 Hz, 1H), 3.79 − 3.95 (m, 1H), 3.31 − 3.43 (m, 0.5H), 2.87 − 3.02 (m, 1.5H), 2.82 (dd, J = 12.9, 3.4 Hz, 1H), 2.72 − 2.78 (m, 2H), 1.99 − 2.27 (m, 2H), 1.64 − 1.75 (m, 1H), 1.31 (d, J = 3.0 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.79 (dd, J = 12.8, 6.8 Hz, 3H). LC−MS : m/z 474.3 (M+H)+.
1H NMR (クロロホルム−d)δ8.23 (d, J = 9.0 Hz, 1H), 7.89 (s, 1H), 4.76 − 4.96 (m, 3H), 4.61 − 4.64 (m, 0.5H), 4.36 − 4.51 (m, 1.5H), 4.15 − 4.32 (m, 1H), 3.44 − 3.60 (m, 0.5H), 3.02 − 3.20 (m, 2.5H), 2.77 (s, 2H), 2.19 − 2.34 (m, 1H), 1.66 − 1.74 (m, 1H), 1.29 − 1.35 (m, 6H), 0.82 − 1.18 (m, 10H). LC−MS : m/z 450.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.48 (s, 1H), 7.37 − 7.44 (m, 2H), 7.30 − 7.36 (m, 2H), 7.27 (br. s., 1H), 7.23 − 7.26 (m, 1H), 6.99 (br. s., 1H), 6.41 − 6.49 (m, 1H), 5.87 (t, J = 4.1 Hz, 1H), 4.76 − 4.88 (m, 2H), 4.59 (d, J = 13.1 Hz, 1H), 4.47 (d, J = 11.0 Hz, 1H), 4.20 (d, J = 12.0 Hz, 1H), 3.85 (dd, J = 13.8, 4.5 Hz, 1H), 3.60 (br. s., 1H), 3.42 − 3.52 (m, 1H), 2.75 (s, 2H), 1.67 − 1.75 (m, 1H), 1.31 (d, J = 1.8 Hz, 6H), 1.06 − 1.20 (m, 2H), 1.02 (dd, J = 8.0, 3.5 Hz, 2H). LC−MS : m/z 483.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.78 − 4.90 (m, 2H), 4.28 − 4.46 (m, 1.5H), 4.12 − 4.24 (m, 1H), 3.81 − 4.09 (m, 4.5H), 3.40 − 3.60 (m, 1H), 3.24 − 3.36 (m, 1H), 2.92 − 3.07 (m, 2H), 2.76 (s, 2H), 2.22 − 2.34 (m, 1H), 1.98 − 2.21 (m, 3H), 1.69 − 1.76 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 0.95 − 1.19 (m, 6H), 0.77 − 0.92 (m, 4H). LC−MS : m/z 453.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.45 − 7.60 (m, 1H), 7.37 (dd, J = 5.0, 3.0 Hz, 1H), 7.11 − 7.22 (m, 1H), 4.77 − 4.90 (m, 2H), 4.10 − 4.55 (m, 3H), 3.85 (d, J = 10.8 Hz, 0.5H), 3.50 (br. s., 1H), 3.07 (d, J = 11.0 Hz, 2H), 2.87 − 3.03 (m, 0.5H), 2.76 (s, 2H), 2.20 − 2.33 (m, 1H), 1.65 − 1.77 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 0.93 − 1.18 (m, 8H), 0.78 − 0.93 (m, 2H). LC−MS : m/z 465.2 (M+H)+.
1H NMR (クロロホルム−d) δ7.47 − 7.53 (m, 1H), 7.36 (dd, J = 4.9, 2.9 Hz, 1H), 7.18 (dd, J = 5.0, 1.0 Hz, 1H), 4.83 (s, 2H), 4.16 (d, J = 12.5 Hz, 3H), 3.42 (br. s., 1H), 3.14 (d, J = 11.0 Hz, 1H), 2.92 − 3.05 (m, 1H), 2.77 (s, 2H), 1.64 − 2.02 (m, 4H), 1.29 − 1.35 (m, 6H), 1.07 − 1.15 (m, 2H), 0.98 − 1.05 (m, 2H), 0.77 − 0.98 (m, 3H). LC−MS : m/z 451.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.79 (br. s., 1H), 7.46 (s, 1H), 6.63 (br. s., 1H), 5.39 (br. s., 1H), 4.83 (s, 2H), 4.66 (d, J = 11.5 Hz, 1H), 4.01 − 4.21 (m, 3H), 3.73 (s, 3H), 3.28 (d, J = 11.0 Hz, 1H), 3.03 (td, J = 12.3, 3.5 Hz, 1H), 2.77 (s, 2H), 1.63 − 1.80 (m, 1H), 1.29 − 1.39 (m, 6H), 1.14 (dd, J = 8.0, 4.0 Hz, 2H), 1.03 (dt, J = 5.1, 2.7 Hz, 2H). LC−MS : m/z 465.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.18 − 7.27 (m, 2H), 6.79 − 6.96 (m, 2H), 4.76 − 4.88 (m, 2H), 4.64 − 4.66 (m, 0.5H), 4.41 (d, J = 10.5 Hz, 0.5H), 4.20 − 4.34 (m, 1H), 4.03 − 4.17 (m, 1H), 3.81 − 3.91 (m, 3.5H), 3.71 − 3.81 (m, 1.5H), 3.51 − 3.71 (m, 1H), 3.29 − 3.42 (m, 0.5H), 2.89 − 3.01 (m, 1.5H), 2.71 − 2.84 (m, 3H), 2.06 − 2.25 (m, 1H), 1.66 − 1.71 (m, 1H), 1.30 (d, J = 2.8 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.84 (dd, J = 16.6, 6.8 Hz, 3H). LC−MS : m/z 503.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.45 − 7.51 (m, 1H), 7.37 − 7.44 (m, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.20 − 7.27 (m, 2H), 6.99 (br. s., 1H), 6.46 (br. s., 1H), 5.87 (br. s., 1H), 4.75 − 4.89 (m, 2H), 4.60 (d, J = 13.1 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.20 (d, J = 11.8 Hz, 1H), 3.85 (dd, J = 13.8, 4.3 Hz, 1H), 3.60 (br. s., 1H), 3.38 − 3.52 (m, 1H), 2.70 − 2.81 (m, 2H), 1.68 − 1.73 (m, 1H), 1.29 − 1.33 (m, 6H), 1.07 − 1.19 (m, 2H), 1.02 (dd, J = 7.9, 3.4 Hz, 2H). LC−MS : m/z 483.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.46 − 8.61 (m, 2H), 7.62 − 7.73 (m, 1H), 7.28 − 7.33 (m, 1H), 4.82 (s, 2H), 4.70 (d, J = 11.8 Hz, 0.5H), 4.58 (d, J = 13.3 Hz, 0.5H), 4.01 − 4.21 (m, 2H), 3.68 − 3.88 (m, 3H), 3.38 − 3.59 (m, 0.5H), 2.81 − 3.11 (m, 2.5H), 2.76 (s, 2H), 1.66 − 1.92 (m, 3H), 1.29 − 1.35 (m, 6H), 1.06 − 1.16 (m, 2H), 0.97 − 1.05 (m, 2H), 0.80 − 0.97 (m, 3H). LC−MS : m/z 460.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.24 (s, 1H), 7.89 (s, 1H), 5.13 (br. s., 0.5H), 4.80 − 4.98 (m, 3H), 4.49 − 4.69 (m, 0.5H), 4.20 (d, J = 13.1 Hz, 2H), 3.49 − 3.56 (m, 0.5H), 3.22 (dd, J = 13.3, 3.8 Hz, 1.5H), 2.99 − 3.12 (m, 1H), 2.77 (s, 2H), 1.60 − 1.87 (m, 3H), 1.32 (s, 6H), 1.10 − 1.17 (m, 2H), 0.99 − 1.05 (m, 2H), 0.80 − 0.98 (m, 3H). LC−MS : m/z 436.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.22 − 7.28 (m, 1H), 6.78 − 6.89 (m, 3H), 4.83 (s, 2H), 4.73 (br. s., 0.5H), 4.60 − 4.63 (m, 0.5H), 3.96 − 4.16 (m, 2H), 3.87 (br. s., 0.5H), 3.81 (d, J = 2.3 Hz, 3H), 3.77 (s, 2H), 3.68 − 3.75 (m, 1H), 3.31 − 3.46 (m, 0.5H), 2.97 − 3.15 (m, 1H), 2.79 − 2.95 (m, 1H), 2.76 (s, 2H), 1.66 − 1.81 (m, 3H), 1.28 − 1.36 (m, 6H), 1.11 (d, J = 2.5 Hz, 2H), 0.96 − 1.04 (m, 2H), 0.88 (td, J = 7.3, 3.1 Hz, 3H). LC−MS : m/z 489.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.18 − 7.28 (m, 1H), 6.71 − 6.88 (m, 3H), 4.73 − 4.89 (m, 2H), 4.41 (d, J = 10.3 Hz, 0.5H), 4.40 − 4.42 (m, 0.5H), 4.02 − 4.30 (m, 2H), 3.69 − 3.87 (m, 6H), 3.48 − 3.51 (m, 0.5H), 3.33 (t, J = 11.7 Hz, 0.5H), 2.88 − 3.00 (m, 1H), 2.64 − 2.81 (m, 3H), 2.04 − 2.22 (m, 1H), 1.64 − 1.75 (m, 1H), 1.30 (d, J = 3.5 Hz, 6H), 0.94 − 1.16 (m, 7H), 0.75 − 0.88 (m, 3H). LC−MS : m/z 503.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.20 − 7.26 (m, 2H), 6.81 − 6.96 (m, 2H), 4.82 (s, 2H), 4.71 (br. s., 0.5H), 4.60 (d, J = 13.1 Hz, 0.5H), 3.97 − 4.18 (m, 2H), 3.81 − 3.92 (m, 4H), 3.69 − 3.79 (m, 2H), 3.33 − 3.47 (m, 0.5H), 2.97 − 3.12 (m, 1H), 2.79 − 2.96 (m, 1.5H), 2.71 − 2.78 (m, 2H), 1.63 − 1.81 (m, 3H), 1.30 (d, J = 2.8 Hz, 6H), 1.06 − 1.14 (m, 2H), 0.96 − 1.03 (m, 2H), 0.83 − 0.92 (m, 3H). LC−MS : m/z 489.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.84 (s, 1H), 4.77 − 4.89 (m, 2H), 4.14 − 4.45 (m, 3H), 3.99 (d, J = 12.5 Hz, 0.5H), 3.43 − 3.77 (m, 1H), 2.99 − 3.22 (m, 2.5H), 2.77 (s, 2H), 2.37 − 2.47 (m, 3H), 2.20 − 2.31 (m, 1H), 1.66 − 1.75 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 0.96 − 1.18 (m, 7H), 0.77 − 0.96 (m, 3H). LC−MS : m/z 464.1 (M+H)+.
1H NMR (クロロホルム−d)δ5.16 − 5.35 (m, 1H), 4.83 (s, 2H), 4.62 (dt, J = 13.6, 2.0 Hz, 1H), 4.11 (dd, J = 12.7, 2.1 Hz, 1H), 3.71 − 3.91 (m, 3H), 3.61 − 3.70 (m, 2H), 3.34 − 3.41 (m, 3H), 3.27 (br. s., 1H), 3.21 (dd, J = 13.4, 4.4 Hz, 1H), 3.04 (td, J = 12.0, 3.5 Hz, 1H), 2.72 − 2.79 (m, 3H), 2.60 − 2.71 (m, 1H), 1.57 − 1.78 (m, 1H), 1.27 − 1.39 (m, 6H), 1.10 − 1.18 (m, 2H), 0.96 − 1.10 (m, 2H). LC−MS : m/z 457.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.71 − 7.80 (m, 1H), 7.41 − 7.52 (m, 1H), 6.59 (dd, J = 1.9, 0.9 Hz, 1H), 4.85 (s, 2H), 4.69 (br. s., 1H), 4.30 (br. s., 1H), 4.00 − 4.17 (m, 2H), 3.47 (br. s., 1H), 3.18 (dd, J = 13.1, 3.5 Hz, 1H), 3.01 (td, J = 12.5, 3.4 Hz, 1H), 2.79 (s, 2H), 1.69 − 1.77 (m, 1H), 1.40 − 1.50 (m, 3H), 1.33 (s, 6H), 1.08 − 1.19 (m, 2H), 0.98 − 1.07 (m, 2H). LC−MS : m/z 421.2 (M+H)+.
1H NMR (クロロホルム−d) δ8.44 − 8.63 (m, 1H), 7.67 (td, J = 7.7, 1.5 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 7.16 − 7.25 (m, 1H), 4.82 (s, 2H), 4.68 (br. s., 0.5H), 4.57 (d, J = 13.3 Hz, 0.5H), 3.85 − 4.18 (m, 5H), 3.32 − 3.52 (m, 0.5H), 2.95 − 3.09 (m, 1H), 2.78 − 2.93 (m, 1.5H), 2.75 (s, 2H), 1.62 − 1.82 (m, 3H), 1.28 − 1.34 (m, 6H), 1.05 − 1.13 (m, 2H), 0.94 − 1.03 (m, 2H), 0.81 − 0.92 (m, 3H). LC−MS : m/z 460.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.83 (s, 2H), 4.17 − 4.41 (m, 4H), 3.38 − 3.51 (m, 1H), 2.87 − 3.06 (m, 2H), 2.77 (s, 2H), 2.13 (dt, J = 10.5, 6.5 Hz, 1H), 1.65 − 1.74 (m, 1H), 1.28 − 1.39 (m, 9H), 1.06 − 1.19 (m, 2H), 0.96 − 1.06 (m, 6H), 0.84 − 0.94 (m, 2H), 0.79 (d, J = 6.8 Hz, 4H), 0.54 − 0.68 (m, 2H). LC−MS : m/z 481.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.71 (br. s., 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.38 − 7.51 (m, 1H), 4.77 − 4.92 (m, 2H), 4.07 − 4.65 (m, 3H), 3.55 − 3.67 (m, 1H), 2.95 − 3.34 (m, 3H), 2.77 (s, 2H), 2.21 − 2.38 (m, 1H), 1.65 − 1.76 (m, 1H), 1.31 (s, 6H), 0.95 − 1.16 (m, 8H), 0.80 (br. s., 2H). LC−MS : m/z 460.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.63 (br. s., 1H), 7.34 − 7.45 (m, 5H), 7.29 − 7.32 (m, 1H), 6.53 (br. s., 1H), 4.74 − 4.90 (m, 2H), 4.46 (br. s., 2H), 4.18 (d, J = 11.3 Hz, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.58 (br. s., 1H), 3.43 (br. s., 1H), 2.76 (s, 2H), 1.70 − 1.72 (m, 1H), 1.33 (d, J = 3.5 Hz, 6H), 1.15 (dd, J = 7.8, 4.5 Hz, 1H), 1.03 (d, J = 7.8 Hz, 3H). LC−MS : m/z 483.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.84 (s, 2H), 4.78 (br. s., 1H), 4.13 (d, J = 12.5 Hz, 3H), 3.75 (t, J = 6.4 Hz, 2H), 3.33 − 3.43 (m, 3H), 3.01 (br. s., 2H), 2.78 (s, 2H), 2.49 − 2.74 (m, 2H), 1.67 − 1.82 (m, 1H), 1.36 − 1.52 (m, 6H), 1.32 (s, 6H), 1.09 − 1.18 (m, 2H), 0.99 − 1.05 (m, 2H). LC−MS : m/z 427.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 − 7.37 (m, 1H), 7.19 − 7.26 (m, 1H), 6.99 − 7.15 (m, 2H), 4.75 − 4.88 (m, 2H), 4.64 (d, J = 10.5 Hz, 0.5H), 4.40 (d, J = 10.3 Hz, 0.5H), 4.22 − 4.34 (m, 1H), 4.06 − 4.21 (m, 1H), 3.71 − 3.80 (m, 2H), 3.50 − 3.54 (m, 0.5H), 3.32 − 3.46 (m, 1.5H), 2.93 − 3.01 (m, 1H), 2.81 − 2.89 (m, 1H), 2.75 (s, 2H), 2.24 (dt, J = 9.7, 6.6 Hz, 0.5H), 2.10 (dt, J = 10.4, 6.7 Hz, 0.5H), 1.66 − 1.72 (m, 1H), 1.31 (d, J = 3.0 Hz, 6H), 1.06 − 1.19 (m, 2H), 0.94 − 1.05 (m, 5H), 0.87 (d, J = 6.8 Hz, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 491.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.75 (s, 1H), 7.42 − 7.53 (m, 1H), 6.59 (dd, J = 1.8, 0.8 Hz, 1H), 4.85 (s, 2H), 4.68 (br. s., 1H), 4.28 (br. s., 1H), 4.01 − 4.16 (m, 2H), 3.46 (br. s., 1H), 3.18 (dd, J = 12.9, 3.4 Hz, 1H), 3.01 (td, J = 12.5, 3.4 Hz, 1H), 2.79 (s, 2H), 1.68 − 1.80 (m, 1H), 1.39 − 1.49 (m, 3H), 1.33 (s, 6H), 1.09 − 1.18 (m, 2H), 0.99 − 1.07 (m, 2H). LC−MS : m/z 421.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.71 (br. s., 1H), 7.45 (t, J = 1.6 Hz, 1H), 6.40 − 6.64 (m, 1H), 4.86 (s, 2H), 4.53−4.56 (m, 2H), 4.27 (s, 1H), 3.48 (s, 1H), 3.00 − 3.24 (m, 3H), 2.78 (s, 2H), 2.24 (m, 1H), 1.26 − 1.36 (m, 9H), 1.04 − 1.16 (m, 2H), 0.79 − 0.98 (m, 6H), 0.63 − 0.79 (m, 2H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.50 (d, J = 1.3 Hz, 1H), 7.02 (br. s., 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 4.77 − 4.89 (m, 2H), 4.20 − 4.54 (m, 4H), 3.58 (br. s., 1H), 3.00 − 3.21 (m, 2H), 2.77 (s, 2H), 2.18 − 2.34 (m, 1H), 1.65 − 1.76 (m, 1H), 1.32 (d, J = 1.8 Hz, 6H), 0.92 − 1.19 (m, 8H), 0.79 − 0.92 (m, 2H). LC−MS : m/z 449.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.87 (s, 2H), 4.55 (d, J = 13.6 Hz, 2H), 4.28 (dd, J = 12.9, 1.9 Hz, 1H), 3.64 − 3.91 (m, 3H), 3.39 (d, J = 4.3 Hz, 3H), 2.88 − 3.18 (m, 3H), 2.79 (s, 2H), 2.47 − 2.76 (m, 1H), 1.28 − 1.37 (m, 6H), 1.07 (d, J = 6.5 Hz, 3H), 0.86 − 0.92 (m, 3H), 0.78 − 0.86 (m, 2H), 0.65 − 0.76 (m, 2H). LC−MS : m/z 455.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.21 (br. s., 1H), 6.90 − 6.96 (m, 2H), 4.90 (br. s., 0.5H), 4.81 (br. s., 2H), 4.59 (br. s., 1H), 4.34 (d, J = 13.3 Hz, 0.5H), 4.20 (br. s., 0.5H), 3.81 − 4.07 (m, 3H), 3.64 (d, J = 11.5 Hz, 1H), 3.33 − 3.58 (m, 1H), 3.21 (d, J = 11.3 Hz, 0.5H), 2.75 (br. s., 2H), 1.69 (br. s., 1H), 1.25 − 1.43 (m, 8H), 0.99 − 1.17 (m, 8H). LC−MS : m/z 465.0 (M+H)+.
1H NMR (クロロホルム−d) δ4.87 (br. s., 0.5H), 4.83 (s, 2H), 4.55 − 4.58 (m, 0.5H), 3.98 − 4.18 (m, 2.5H), 3.65 − 3.81 (m, 2.5H), 3.42 − 3.57 (m, 1H), 3.36 (s, 3H), 2.90 − 3.20 (m, 2.5H), 2.73 − 2.81 (m, 2H), 2.49 − 2.73 (m, 2H), 1.47 − 1.74 (m, 4H), 1.31 (s, 6H), 1.07 − 1.16 (m, 2H), 0.99 − 1.04 (m, 2H), 0.89 − 0.97 (m, 6H). LC−MS : m/z 455.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.78 − 4.88 (m, 2H), 4.62 − 4.64 (m, 0.5H), 4.30 − 4.47 (m, 1.5H), 4.13 − 4.26 (m, 1H), 3.96 − 4.09 (m, 2H), 3.79 (d, J = 13.3 Hz, 0.5H), 3.39 − 3.55 (m, 3H), 2.88 − 3.08 (m, 2.5H), 2.71 − 2.82 (m, 3H), 2.08 − 2.34 (m, 2H), 1.77 − 2.06 (m, 2H), 1.67 − 1.74 (m, 1H), 1.63 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 1.07 − 1.18 (m, 2H), 0.97 − 1.05 (m, 5H), 0.84 − 0.90 (m, 1.5H), 0.79 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 467.1 (M+H)+.
1H NMR (クロロホルム−d) δ8.81 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 4.44 − 4.83 (m, 4H), 4.09 − 4.24 (m, 2H), 3.54 − 3.56 (m, 0.5H), 3.25 (dd, J = 13.2, 3.6 Hz, 1.5H), 3.09 (td, J = 12.4, 3.3 Hz, 1H), 2.77 (s, 2H), 1.89 − 2.05 (m, 1H), 1.65 − 1.75 (m, 2H), 1.31 (s, 6H), 1.08 − 1.18 (m, 2H), 0.95 − 1.04 (m, 4H), 0.79 (br. s., 1H). LC−MS : m/z 452.1 (M+H)+.
1H NMR (クロロホルム−d)δ5.88 − 5.96 (m, 1H), 4.83 (s, 2H), 4.65 (br. s., 1H), 3.99 − 4.29 (m, 3H), 3.39 (br. s., 1H), 3.14 (dd, J = 12.9, 3.4 Hz, 1H), 2.96 (td, J = 12.5, 3.4 Hz, 1H), 2.77 (s, 2H), 2.31 − 2.37 (m, 3H), 2.22 − 2.28 (m, 3H), 1.64 − 1.75 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.31 (s, 6H), 1.09 − 1.16 (m, 2H), 0.97 − 1.04 (m, 2H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.34 (d, J = 1.5 Hz, 1H), 6.30 − 6.37 (m, 1H), 4.75 − 4.92 (m, 2H), 3.40 − 4.42 (m, 5H), 3.00 − 3.21 (m, 2H), 2.69 − 2.82 (m, 2H), 2.17 − 2.33 (m, 4H), 1.67 − 1.76 (m, 1H), 1.32 (d, J = 1.8 Hz, 6H), 0.72 − 1.19 (m, 10H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.57 − 7.69 (m, 1H), 7.32 − 7.42 (m, 5H), 7.27 − 7.31 (m, 1H), 6.51 (br. s., 1H), 5.67 (br. s., 1H), 4.73 − 4.88 (m, 2H), 4.43 (br. s., 2H), 4.16 (d, J = 11.8 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.50 − 3.63 (m, 1H), 3.40 (br. s., 1H), 2.68 − 2.81 (m, 2H), 1.66 − 1.74 (m, 1H), 1.30 (d, J = 3.8 Hz, 6H), 1.03 − 1.17 (m, 2H), 1.01 (m, 2H). LC−MS : m/z 483.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.24 (d, J = 1.8 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 4.82 (s, 2H), 3.79 − 3.84 (m, 2H), 3.74 − 3.79 (m, 4H), 2.70 − 2.82 (m, 2H), 2.40 (s, 3H), 1.70 (td, J = 8.2, 4.0 Hz, 1H), 1.60 (s, 6H), 1.31 (s, 6H), 1.12 (dt, J = 7.3, 3.7 Hz, 2H), 0.97 − 1.03 (m, 2H). LC−MS : m/z 449.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.51 (d, J = 1.0 Hz, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.50 (dd, J = 3.4, 1.9 Hz, 1H), 4.84 (s, 3H), 4.46 (d, J = 12.8 Hz, 1H), 4.00 − 4.22 (m, 2H), 3.50 (d, J = 10.8 Hz, 1H), 3.25 (dd, J = 13.1, 3.5 Hz, 1H), 3.09 (td, J = 12.4, 3.5 Hz, 1H), 2.78 (s, 2H), 1.67 − 1.77 (m, 1H), 1.41 − 1.50 (m, 3H), 1.26 − 1.38 (m, 6H), 1.13 (dd, J = 6.3, 4.3 Hz, 2H), 0.97 − 1.06 (m, 2H). LC−MS : m/z 421.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.45 − 7.53 (m, 1H), 6.95 (dd, J = 3.4, 0.6 Hz, 1H), 6.47 (dd, J = 3.5, 1.8 Hz, 1H), 4.82 (s, 2H), 3.95 − 4.04 (m, 2H), 3.87 − 3.95 (m, 2H), 3.82 (s, 2H), 2.76 (s, 2H), 1.68 − 1.76 (m, 1H), 1.59 (s, 6H), 1.32 (s, 6H), 1.09 − 1.15 (m, 2H), 0.97 − 1.03 (m, 2H). LC−MS : m/z 435.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.52 (d, J = 1.3 Hz, 1H), 7.05 (d, J = 3.3 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.85 (s, 3H), 4.48 (d, J = 13.8 Hz, 1H), 4.15 (d, J = 12.8 Hz, 1H), 4.08 (dt, J = 13.1, 2.0 Hz, 1H), 3.53 (br. s., 1H), 3.26 (dd, J = 12.9, 3.6 Hz, 1H), 3.10 (td, J = 12.4, 3.5 Hz, 1H), 2.79 (s, 2H), 1.70 − 1.77 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.34 (s, 6H), 1.11 − 1.18 (m, 2H), 0.97 − 1.07 (m, 2H). LC−MS : m/z 421.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.80 (br. s., 1H), 7.37 − 7.51 (m, 1H), 6.64 (br. s., 1H), 5.38 (br. s., 1H), 4.78 − 4.89 (m, 2H), 4.69 (br. s., 1H), 4.00 − 4.27 (m, 4H), 3.29 (br. s., 1H), 3.03 (td, J = 12.2, 3.4 Hz, 1H), 2.68 − 2.86 (m, 2H), 1.64 − 1.79 (m, 1H), 1.18 − 1.35 (m, 9H), 1.14 (br. s., 2H), 0.94 − 1.08 (m, 2H). LC−MS : m/z 479.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.54 − 7.72 (m, 1H), 7.33−7.44 (m, 5H), 7.27−7.29(m,1H), 6.51 (br. s., 1H), 5.67 (br. s., 1H), 4.74 − 4.87 (m, 2H), 4.43 (br. s., 2H), 4.16 (d, J = 12.0 Hz, 1H), 3.72 − 3.87 (m, 1H), 3.50 − 3.64 (m, 1H), 3.33 − 3.46 (m, 1H), 2.68 − 2.79 (m, 2H), 1.68 − 1.75 (m, 1H), 1.30 (d, J = 3.5 Hz, 6H), 1.03 − 1.17 (m, 2H), 0.98 − 1.02 (m, 2H). LC−MS : m/z 483.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.39 (br. s., 1H), 7.58 (br. s., 1H), 7.27 − 7.40 (m, 1H), 6.88 (br. s., 1H), 4.77 − 4.89 (m, 2H), 4.10 − 4.55 (m, 3H), 3.52 − 3.85 (m, 1H), 3.21 (br. s., 2H), 2.77 (s, 2H), 2.54 (s, 3H), 2.21 − 2.35 (m, 2H), 1.67 − 1.78 (m, 1H), 1.29 − 1.38 (m, 6H), 0.67 − 1.20 (m, 10H). LC−MS : m/z 513.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.45 − 7.55 (m, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.84 (s, 2H), 3.95 (br. s., 4H), 3.60 − 3.70 (m, 4H), 2.79 (s, 2H), 1.68 − 1.77 (m, 1H), 1.32 (s, 6H), 1.14 (quin, J = 3.7 Hz, 2H), 0.98 − 1.06 (m, 2H). LC−MS : m/z 407.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.85 − 4.96 (m, 0.5H), 4.82 (s, 2H), 4.53 − 4.65 (m, 1H), 4.32 (d, J = 13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.88 − 4.07 (m, 1H), 3.69 − 3.77 (m, 2H), 3.65 (dd, J = 13.4, 3.6 Hz, 0.5H), 3.40 − 3.55 (m, 1.5H), 3.34 − 3.39 (m, 3H), 3.20 (dd, J = 13.4, 3.6 Hz, 0.5H), 2.72 − 2.85 (m, 2.5H), 2.53 − 2.64 (m, 1.5H), 1.66 − 1.74 (m, 1H), 1.51 − 1.58 (m, 1H), 1.41 − 1.48 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 1.19 − 1.27 (m, 3H), 1.16 (d, J = 6.5 Hz, 1H), 1.10 (dd, J = 9.5, 5.0 Hz, 2H), 0.97 − 1.03 (m, 2H). LC−MS : m/z 427.0 (M+H)+.
1H NMR (クロロホルム−d)δ8.47 (s, 1H), 8.52 (s, 1H), 7.57 (s, 1H), 4.76 − 4.92 (m, 2H), 4.28 − 4.54 (m, 2H), 4.02 − 4.16 (m, 1H), 3.50 − 3.61 (m, 1H), 2.90 − 3.15 (m, 2H), 2.76 (s, 2H), 2.41 (s, 3H), 2.19 − 2.33 (m, 1H), 1.92 − 2.06 (m, 1H), 1.67 − 1.78 (m, 1H), 1.29 − 1.38 (m, 6H), 0.96 − 1.18 (m, 8H), 0.81 − 0.91 (m, 2H). LC−MS : m/z 474.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.82 (s, 2H), 3.85 − 3.94 (m, 2H), 3.76 (s, 2H), 3.69 − 3.75 (m, 2H), 2.77 − 2.85 (m, 2H), 2.76 (s, 2H), 2.56 − 2.67 (m, 2H), 2.15 (s, 3H), 1.68 − 1.74 (m, 1H), 1.51 (s, 6H), 1.31 (s, 6H), 1.08 − 1.14 (m, 2H), 0.96 − 1.03 (m, 2H). LC−MS : m/z 443.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.50 (s, 1H), 7.03 − 7.10 (m, 1H), 6.50 (dd, J = 3.5, 1.8 Hz, 1H), 4.84 (s, 2H), 4.38 − 4.56 (m, 2H), 4.23 − 4.32 (m, 1H), 3.89 − 3.98 (m, 1H), 3.54 (d, J = 8.8 Hz, 1H), 3.33 − 3.50 (m, 2H), 2.78 (s, 2H), 1.92 − 2.10 (m, 1H), 1.32 (s, 6H), 1.25 (s, 3H), 1.09 − 1.17 (m, 2H), 0.99 − 1.03 (m, 2H). LC−MS : m/z 422.9 (M+H)+.
1H NMR (クロロホルム−d)δ7.62 − 7.82 (m, 1H), 7.38 − 7.50 (m, 1H), 6.56 (s, 1H), 4.76 − 5.04 (m, 2.5H), 4.31 − 4.60 (m, 2H), 3.97 (d, J = 13.6 Hz, 1H), 3.37 − 3.51 (m, 2.5H), 2.76 (s, 2H), 1.65 − 1.79 (m, 1H), 1.31 (d, J = 3.5 Hz, 6H), 1.20 − 1.28 (m, 6H), 1.05 − 1.15 (m, 2H), 0.96 − 1.04 (m, 2H). LC−MS : m/z 435.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.69 − 7.74 (m, 1H), 7.43 (t, J = 1.6 Hz, 1H), 6.52 − 6.56 (m, 1H), 4.82 (s, 2H), 3.87 − 3.92 (m, 2H), 3.83 − 3.87 (m, 2H), 3.80 (s, 2H), 2.76 (s, 2H), 2.22 (t, J = 7.7 Hz, 1H), 1.59 (s, 6H), 1.32 (s, 6H), 1.12 (quin, J = 3.7 Hz, 2H), 0.98 − 1.05 (m, 2H). LC−MS : m/z 435.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.47 − 7.53 (m, 1H), 7.02 − 7.09 (m, 1H), 6.50 (dd, J = 3.4, 1.9 Hz, 1H), 4.83 (s, 2H), 4.38 − 4.56 (m, 2H), 4.22 − 4.31 (m, 1H), 3.88 − 3.98 (m, 1H), 3.34 − 3.61 (m, 3H), 2.77 (s, 2H), 1.67 − 1.76 (m, 1H), 1.32 (s, 6H), 1.25 (s, 3H), 1.08 − 1.14 (m, 2H), 0.98 − 1.04 (m, 2H). LC−MS : m/z 421.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.73 (d, J = 6.8 Hz, 1H), 8.64 (br. s., 1H), 8.43 (s, 1H), 6.87 − 7.04 (m, 1H), 4.78 − 4.90 (m, 2H), 4.35 − 4.62 (m, 2.5H), 4.16 (d, J = 12.5 Hz, 0.5H), 3.55 − 3.97 (m, 2H), 3.06 − 3.29 (m, 2H), 2.76 (s, 2H), 2.21 − 2.38 (m, 1H), 1.64 − 1.75 (m, 1H), 1.28 − 1.36 (m, 6H), 0.96 − 1.21 (m, 8H), 0.69 − 0.84 (m, 2H). LC−MS : m/z 500.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.52 (s, 1H), 7.04 (br. s., 1H), 6.52 (dd, J = 3.4, 1.6 Hz, 1H), 4.68 − 4.81 (m, 2H), 4.37 − 4.68 (m, 4H), 3.63 (br. s., 1H), 3.10 − 3.32 (m, 2H), 2.83 − 2.91 (m, 1H), 2.80 (s, 2H), 1.72 (br. s., 1H), 1.30 − 1.36 (m, 6H), 1.16 − 1.25 (m, 6H), 1.06 (br. s., 3H), 0.91 (br. s., 3H). LC−MS : m/z 451.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.28 (d, J = 2.0 Hz, 1H), 6.28 − 6.42 (m, 1H), 4.72 (s, 3H), 3.93 − 4.37 (m, 3H), 3.43 (br. s., 1H), 3.20 (dd, J = 13.1, 3.5 Hz, 1H), 2.96 − 3.10 (m, 1H), 2.80 − 2.89 (m, 1H), 2.78 (s, 2H), 2.40 (s, 3H), 1.84 − 1.98 (m, 1H), 1.76 (dt, J = 14.2, 7.0 Hz, 1H), 1.30 (s, 6H), 1.15 − 1.23 (m, 6H), 0.85 − 0.95 (m, 3H). LC−MS : m/z 451.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.74 (br. s., 1H), 7.47 (t, J = 1.8 Hz, 1H), 6.47 − 6.68 (m, 1H), 4.69 − 4.79 (m, 2H), 4.30 − 4.58 (m, 3H), 3.50 − 4.03 (m, 2H), 3.14 (dd, J = 13.3, 3.3 Hz, 2H), 2.83 − 2.90 (m, 1H), 2.80 (s, 2H), 2.26 (br. s., 1H), 1.28 − 1.34 (m, 6H), 1.17 − 1.25 (m, 6H), 1.07 (br. s., 2H), 0.91 (br. s., 4H). LC−MS : m/z 451.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.21 (dd, J = 5.0, 1.3 Hz, 1H), 6.89 − 6.99 (m, 2H), 4.70 (s, 2.5H), 4.61 (d, J = 12.5 Hz, 0.5H), 4.13 − 4.34 (m, 2H), 3.78 − 4.07 (m, 3H), 3.39 − 3.60 (m, 0.5H), 2.88 − 3.18 (m, 2.5H), 2.74 − 2.87 (m, 3H), 1.77 − 1.86 (m, 1H), 1.72 (dd, J = 14.9, 7.7 Hz, 1H), 1.29 (d, J = 2.5 Hz, 6H), 1.16 − 1.21 (m, 6H), 0.83 − 0.96 (m, 3H). LC−MS : m/z 467.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.72 (s, 1H), 7.46 (t, J = 1.8 Hz, 1H), 6.57 (d, J = 1.0 Hz, 1H), 4.72 (s, 3H), 4.10 − 4.39 (m, 3H), 3.29 − 3.58 (m, 1H), 3.20 (dd, J = 13.2, 3.4 Hz, 1H), 3.07 (td, J = 12.4, 3.0 Hz, 1H), 2.74 − 2.88 (m, 3H), 1.75 − 1.97 (m, 2H), 1.30 (s, 6H), 1.16 − 1.23 (m, 6H), 0.86 − 0.99 (m, 3H). LC−MS : m/z 437.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.17 − 7.24 (m, 1H), 6.83 − 7.04 (m, 2H), 4.67 − 4.75 (m, 2H), 4.38 − 4.57 (m, 1.5H), 4.17 − 4.32 (m, 1H), 3.81 − 4.10 (m, 3H), 3.46 − 3.47 (m, 1H), 2.79 − 3.53 (m, 3.5H), 2.76 (s, 2H), 2.10 − 2.30 (m, 1H), 1.29 (d, J = 2.3 Hz, 6H), 1.13 − 1.22 (m, 6H), 0.97 − 1.08 (m, 3H), 0.79 − 0.91 (m, 3H). LC−MS : m/z 481.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 (d, J = 2.0 Hz, 1H), 6.37 (br. s., 1H), 4.69 − 4.79 (m, 2H), 4.26 − 4.67 (m, 3H), 3.90 (d, J = 9.8 Hz, 0.5H), 3.52 (br. s., 1H), 2.99 − 3.22 (m, 2.5H), 2.86 (quin, J = 6.7 Hz, 1H), 2.80 (s, 2H), 2.42 (s, 3H), 2.20 − 2.33 (m, 1H), 1.31 − 1.36 (m, 6H), 1.15 − 1.26 (m, 6H), 1.09 (br. s., 2H), 0.84 − 1.02 (m, 4H). LC−MS : m/z 465.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.19 − 7.25 (m, 1H), 6.89 − 7.01 (m, 2H), 5.24 − 5.40 (m, 1H), 4.63 − 4.82 (m, 3H), 3.98 − 4.24 (m, 5H), 3.77 − 3.93 (m, 2H), 3.25 − 3.36 (m, 1H), 2.94 − 3.10 (m, 1H), 2.74 − 2.89 (m, 3H), 1.29 (d, J = 4.8 Hz, 6H), 1.14 − 1.22 (m, 9H). LC−MS : m/z 511.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.79 (br. s., 1H), 7.46 (s, 1H), 6.63 (br. s., 1H), 5.39 (br. s., 0.5H), 4.80 (br. s., 0.5H), 4.72 (d, J = 3.5 Hz, 2H), 4.21 (dq, J = 10.7, 7.1 Hz, 2H), 4.01 − 4.15 (m, 2H), 3.93 (br. s., 1H), 3.40 (d, J = 11.8 Hz, 1H), 3.03 − 3.18 (m, 1H), 2.76 − 2.89 (m, 3H), 1.11 − 1.34 (m, 15H). LC−MS : m/z 481.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 4.56 − 4.83 (m, 3H), 4.03 − 4.32 (m, 3H), 3.47 (br. s., 1H), 3.18 − 3.31 (m, 1H), 3.07 (td, J = 12.6, 3.1 Hz, 1H), 2.83 − 2.92 (m, 1H), 2.81 (s, 2H), 2.36 − 2.46 (m, 3H), 1.38 − 1.46 (m, 3H), 1.30 − 1.37 (m, 6H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 437.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.24 (s, 1H), 4.73 (s, 2H), 4.12 − 4.29 (m, 2H), 3.49 (s, 1H), 3.23 (dd, J = 13.1, 3.5 Hz, 1H), 3.01 − 3.14 (m, 1H), 2.77 − 2.91 (m, 3H), 2.57 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.31 (s, 6H), 1.16 − 1.23 (m, 6H). LC−MS : m/z 438.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.25 (d, J = 7.0 Hz, 1H), 7.93 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 12.0 Hz, 1H), 4.71 (s, 2H), 4.66 (d, J = 9.8 Hz, 0.5H), 4.60 (d, J = 14.1 Hz, 1H), 4.49 (d, J = 10.3 Hz, 0.5H), 4.33 (d, J = 12.8 Hz, 1H), 3.57 (t, J = 11.7 Hz, 1H), 3.12 − 3.32 (m, 2H), 2.81 − 2.89 (m, 1H), 2.74 − 2.81 (m, 2H), 2.19 − 2.34 (m, 1H), 1.30 (s, 6H), 1.18 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H), 1.00 − 1.09 (m, 3H), 0.80 − 0.94 (m, 3H). LC−MS : m/z 452.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.89 (br. s., 0.5H), 4.72 (s, 2H), 4.52 (d, J = 12.0 Hz, 0.5H), 4.02 − 4.32 (m, 2.5H), 3.74 (d, J = 13.1 Hz, 0.5H), 3.59 (t, J = 11.3 Hz, 0.5H), 3.01 − 3.30 (m, 2.5H), 2.84 (quin, J = 6.6 Hz, 3H), 2.79 (s, 2H), 2.56 − 2.73 (m, 2H), 2.16 (s, 3H), 1.30 − 1.44 (m, 9H), 1.20 (d, J = 6.3 Hz, 6H). LC−MS : m/z 431.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.55 (d, J = 5.0 Hz, 2H), 7.73 (d, J = 6.5 Hz, 1H), 7.33 (dd, J = 7.5, 5.0 Hz, 1H), 4.62 − 4.75 (m, 2.5H), 4.37 − 4.57 (m, 1.5H), 4.16 − 4.33 (m, 1H), 3.72 − 3.87 (m, 2.5H), 3.42 − 3.61 (m, 1H), 2.91 − 3.12 (m, 2.5H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 2.77 (s, 2H), 2.08 − 2.37 (m, 1H), 1.30 (d, J = 2.3 Hz, 6H), 1.15 − 1.24 (m, 6H), 1.03 (dd, J = 13.4, 6.4 Hz, 3H), 0.89 (dd, J = 10.3, 6.8 Hz, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 476.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.54 (d, J = 2.8 Hz, 1H), 7.61 − 7.77 (m, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.15 − 7.24 (m, 1H), 4.58 − 4.74 (m, 2.5H), 4.49 (dt, J = 13.6, 2.0 Hz, 1H), 4.40 (d, J = 10.3 Hz, 0.5H), 4.18 − 4.34 (m, 1H), 3.87 − 4.15 (m, 3H), 3.33 − 3.51 (m, 0.5H), 2.96 − 3.06 (m, 1.5H), 2.85 − 2.94 (m, 1H), 2.82 (quin, J = 6.7 Hz, 1H), 2.76 (s, 2H), 2.09 − 2.30 (m, 1H), 1.29 (d, J = 2.3 Hz, 6H), 1.17 (dd, J = 10.4, 6.7 Hz, 6H), 1.01 (dd, J = 9.9, 6.7 Hz, 3H), 0.80 (dd, J = 12.7, 6.9 Hz, 3H). LC−MS : m/z 476.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.89 (br. s., 0.5H), 4.71 (s, 2H), 4.53 (d, J = 12.8 Hz, 0.5H), 4.09 − 4.31 (m, 2.5H), 3.66 − 3.82 (m, 2.5H), 3.50 − 3.63 (m, 0.5H), 3.37 (s, 3H), 3.01 − 3.29 (m, 2.5H), 2.81 − 2.88 (m, 1H), 2.76 − 2.81 (m, 2H), 2.53 − 2.74 (m, 2H), 1.30 − 1.44 (m, 9H), 1.19 (d, J = 6.5 Hz, 6H). LC−MS : m/z 415.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.23 (dd, J = 5.0, 1.3 Hz, 1H), 6.86 − 7.07 (m, 2H), 4.93 (br. s., 0.5H), 4.73 (s, 2H), 4.57 (d, J = 13.3 Hz, 0.5H), 4.09 − 4.35 (m, 2.5H), 3.90 − 4.05 (m, 2H), 3.79 (d, J = 12.8 Hz, 0.5H), 3.57 (t, J = 12.0 Hz, 0.5H), 3.13 − 3.32 (m, 1.5H), 3.00 (q, J = 11.7 Hz, 1H), 2.82 − 2.88 (m, 1H), 2.75 − 2.82 (m, 2H), 1.28 − 1.39 (m, 9H), 1.14 − 1.24 (m, 6H). LC−MS : m/z 453.0 (M+H)+.
1H NMR (クロロホルム−d)δ5.29 (dd, J = 4.3, 2.0 Hz, 1H), 4.74 − 4.86 (m, 1H), 4.63 − 4.74 (m, 2H), 4.25 (dd, J = 12.8, 2.0 Hz, 3H), 3.97 − 4.21 (m, 2H), 3.62 − 3.89 (m, 3H), 3.37 − 3.40 (m, 2H), 3.33 − 3.37 (m, 1H), 3.11 (ddd, J = 12.9, 10.7, 4.5 Hz, 1H), 2.76 − 2.87 (m, 3H), 2.60 − 2.71 (m, 1H), 1.29 (d, J = 3.5 Hz, 6H), 1.09 − 1.23 (m, 9H). LC−MS : m/z 473.3 (M+H)+.
1H NMR (クロロホルム−d) δ7.46 (s, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.29 − 7.35 (m, 2H), 7.22 − 7.25 (m, 1H), 6.95 − 7.02 (m, 1H), 6.45 (br. s., 1H), 5.91 (t, J = 4.4 Hz, 1H), 4.68 − 4.75 (m, 2H), 4.57 − 4.67 (m, 2H), 4.27 (d, J = 10.5 Hz, 1H), 3.96 (dd, J = 13.8, 4.5 Hz, 1H), 3.56 − 3.67 (m, 1H), 3.50 − 3.56 (m, 1H), 2.83 (dt, J = 13.2, 6.6 Hz, 1H), 2.76 (s, 2H), 1.29 (s, 6H), 1.21 (d, J = 6.5 Hz, 3H), 1.13 − 1.19 (m, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.42 − 7.51 (m, 3H), 7.31 − 7.38 (m, 2H), 7.24 − 7.28 (m, 1H), 7.00 (br. s., 1H), 6.47 (br. s., 1H), 5.94 (t, J = 4.4 Hz, 1H), 4.72 (d, J = 6.3 Hz, 2H), 4.58 − 4.69 (m, 2H), 4.30 (d, J = 10.3 Hz, 1H), 3.98 (dd, J = 13.9, 4.1 Hz, 1H), 3.46 − 3.73 (m, 2H), 2.81 − 2.90 (m, 1H), 2.78 (s, 2H), 1.32 (s, 6H), 1.23 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.5 Hz, 3H). LC−MS : m/z 485.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.52 (br. s., 1H), 7.12 (d, J = 3.5 Hz, 1H), 6.52 (br. s., 1H), 5.34 (t, J = 3.1 Hz, 1H), 4.76 (s, 1H), 4.72 (d, J = 3.8 Hz, 2H), 4.53 (d, J = 13.3 Hz, 1H), 4.15 − 4.34 (m, 2H), 3.42 − 3.57 (m, 1H), 3.23 (br. s., 1H), 2.75 − 2.91 (m, 3H), 1.30 (d, J = 4.5 Hz, 6H), 1.10 − 1.23 (m, 6H).
1H NMR (クロロホルム−d)δ7.75 (s, 1H), 7.47 (t, J = 1.8 Hz, 1H), 6.55 − 6.64 (m, 1H), 4.74 (s, 3H), 4.12 − 4.42 (m, 3H), 3.49 (br. s., 1H), 3.26 (dd, J = 12.9, 3.9 Hz, 1H), 3.10 (td, J = 12.5, 3.4 Hz, 1H), 2.86 (quin, J = 6.7 Hz, 1H), 2.81 (s, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.32 (s, 6H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 423.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.97 (s, 1H), 4.72 (s, 2H), 4.51 − 4.66 (m, 1.5H), 4.29 − 4.49 (m, 2H), 3.99 (d, J = 14.1 Hz, 0.5H), 3.62 − 3.77 (m, 1H), 3.08 − 3.28 (m, 2H), 2.81 − 2.93 (m, 1H), 2.79 (s, 2H), 2.41 − 2.49 (m, 3H), 2.20 − 2.32 (m, 1H), 1.28 − 1.36 (m, 6H), 1.18 − 1.22 (m, 6H), 0.83 − 1.08 (m, 6H). LC−MS : m/z 466.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.24 (dd, J = 8.5, 7.8 Hz, 1H), 6.77 − 6.88 (m, 3H), 4.92 (br. s., 1H), 4.70 (s, 2H), 4.16 − 4.24 (m, 1H), 4.09 (t, J = 11.9 Hz, 1H), 3.80 (s, 3H), 3.56 − 3.76 (m, 2H), 3.44 (br. s., 1H), 3.19 (dd, J = 13.3, 3.3 Hz, 1H), 2.92 − 3.10 (m, 1H), 2.70 − 2.92 (m, 4H), 1.29 (d, J = 1.8 Hz, 9H), 1.17 (d, J = 6.8 Hz, 6H). LC−MS : m/z 477.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.47 (d, J = 6.5 Hz, 1H), 7.58 (br. s., 1H), 7.30 (br. s., 1H), 6.89 (br. s., 1H), 4.62 − 4.92 (m, 3H), 4.23 (d, J = 12.8 Hz, 2H), 3.99 (br. s., 1H), 3.65 (br. s., 1H), 3.32 (d, J = 11.8 Hz, 1H), 3.08 (br. s., 1H), 2.75 − 2.91 (m, 3H), 2.53 (br. s., 3H), 1.41 − 1.51 (m, 3H), 1.31 (s, 6H), 1.19 (dd, J = 6.7, 1.6 Hz, 6H). LC−MS : m/z 487.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.27 − 7.30 (m, 1H), 7.20 − 7.25 (m, 1H), 6.85 − 6.96 (m, 2H), 4.60 − 4.79 (m, 2.5H), 4.37 − 4.57 (m, 1.5H), 4.17 − 4.28 (m, 1H), 3.57 − 3.92 (m, 6H), 3.38 (t, J = 11.4 Hz, 0.5H), 2.77 − 3.07 (m, 3.5H), 2.76 (d, J = 2.5 Hz, 2H), 2.09 − 2.27 (m, 1H), 1.29 (d, J = 1.8 Hz, 6H), 1.13 − 1.22 (m, 6H), 1.01 (dd, J = 6.4, 1.6 Hz, 3H), 0.85 (dd, J = 17.1, 6.8 Hz, 3H). LC−MS : m/z 505.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.46 (dd, J = 5.0, 1.0 Hz, 1H), 7.33 (dd, J = 3.8, 1.0 Hz, 1H), 7.07 (dd, J = 5.0, 3.8 Hz, 1H), 4.78 (br. s., 1H), 4.72 (s, 2H), 4.38 (d, J = 13.1 Hz, 1H), 4.07 − 4.28 (m, 2H), 3.43 − 3.63 (m, 1H), 3.28 (dd, J = 13.1, 3.5 Hz, 1H), 3.12 (td, J = 12.5, 3.5 Hz, 1H), 2.84 (dt, J = 13.3, 6.7 Hz, 1H), 2.79 (s, 2H), 1.42 − 1.51 (m, 3H), 1.30 (s, 6H), 1.15 − 1.22 (m, 6H). LC−MS : m/z 439.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.61 (br. s., 1H), 7.39 (br. s., 3H), 7.34 (t, J = 7.5 Hz, 3H), 6.51 (br. s., 1H), 5.71 (br. s., 1H), 4.52 − 4.74 (m, 4H), 4.24 (d, J = 10.8 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.56 (d, J = 11.8 Hz, 1H), 3.50 (d, J = 10.0 Hz, 1H), 2.81 (dt, J = 13.3, 6.7 Hz, 1H), 2.75 (s, 2H), 1.27 − 1.31 (m, 6H), 1.19 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.63 (br. s., 1H), 7.32 − 7.46 (m, 5H), 7.25 − 7.31 (m, 1H), 6.53 (br. s., 1H), 5.73 (br. s., 1H), 4.60 − 4.81 (m, 4H), 4.26 (d, J = 11.0 Hz, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.41 − 3.70 (m, 2H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 2.77 (s, 2H), 1.31 (d, J = 2.0 Hz, 6H), 1.19 − 1.24 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H). LC−MS : m/z 485.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.51 − 7.58 (m, 1H), 7.37 (dd, J = 4.9, 2.9 Hz, 1H), 7.18 − 7.23 (m, 1H), 4.59 − 4.87 (m, 3H), 4.09 − 4.39 (m, 3H), 3.48 (br. s., 1H), 3.24 (d, J = 12.0 Hz, 1H), 3.07 (td, J = 12.5, 3.3 Hz, 1H), 2.84 (dt, J = 13.3, 6.7 Hz, 1H), 2.79 (s, 2H), 1.43 (d, J = 6.8 Hz, 3H), 1.30 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). LC−MS : m/z 439.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 − 7.38 (m, 1H), 7.20 − 7.30 (m, 1H), 7.03 − 7.14 (m, 2H), 4.62 − 4.78 (m, 2H), 4.40 − 4.56 (m, 1.5H), 4.20 − 4.32 (m, 1H), 3.55 − 3.92 (m, 3H), 3.32 − 3.47 (m, 1H), 2.88 − 3.10 (m, 2H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 2.76 (s, 2H), 2.10 − 2.32 (m, 1.5H), 1.30 (d, J = 2.5 Hz, 6H), 1.14 − 1.23 (m, 6H), 1.02 (dd, J = 9.0, 6.5 Hz, 3H), 0.88 (dd, J = 6.9, 4.9 Hz, 1.5H), 0.81 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 493.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.76 (s, 1H), 7.47 (s, 1H), 6.60 (d, J = 1.0 Hz, 1H), 4.74 (s, 3H), 4.13 − 4.42 (m, 3H), 3.50 (br. s., 1H), 3.26 (dd, J = 13.1, 3.0 Hz, 1H), 3.10 (td, J = 12.4, 3.3 Hz, 1H), 2.86 (quin, J = 6.7 Hz, 1H), 2.81 (s, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.32 (s, 6H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 423.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.28 − 7.33 (m, 1H), 6.91 − 7.09 (m, 3H), 4.62 − 4.79 (m, 2.5H), 4.37 − 4.55 (m, 1.5H), 4.12 − 4.32 (m, 1H), 3.66 − 3.84 (m, 3H), 3.33 − 3.47 (m, 1H), 2.96 − 3.11 (m, 1H), 2.78 − 2.91 (m, 2H), 2.76 (d, J = 3.3 Hz, 2H), 2.06 − 2.28 (m, 1H), 1.29 (d, J = 2.3 Hz, 6H), 1.15 − 1.22 (m, 6H), 1.01 (dd, J = 6.4, 2.1 Hz, 3H), 0.85 (d, J = 7.0 Hz, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 493.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.36 (s, 1H), 6.35 (s, 1H), 4.73 (s, 3H), 4.14 − 4.44 (m, 3H), 3.43 − 3.63 (m, 1H), 3.33 (dd, J = 13.1, 3.5 Hz, 1H), 3.17 (td, J = 12.3, 3.3 Hz, 1H), 2.76 − 2.92 (m, 3H), 2.30 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.32 (s, 7H), 1.21 (d, J = 6.8 Hz, 6H). LC−MS : m/z 437.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.28 − 7.36 (m, 1H), 7.21 − 7.26 (m, 1H), 7.03 − 7.14 (m, 2H), 4.71 (s, 3H), 4.01 − 4.26 (m, 2H), 3.70 − 3.95 (m, 3H), 3.10 − 3.37 (m, 2H), 2.98 (d, J = 13.6 Hz, 1H), 2.75 − 2.88 (m, 3H), 1.27 − 1.33 (m, 9H), 1.18 (d, J = 6.8 Hz, 6H). LC−MS : m/z 465.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.24 (t, J = 7.8 Hz, 1H), 6.82 − 6.88 (m, 2H), 6.76 − 6.82 (m, 1H), 4.61 − 4.78 (m, 2.5H), 4.35 − 4.54 (m, 1.5H), 4.14 − 4.28 (m, 1H), 3.72 − 3.86 (m, 5.5H), 3.31 − 3.54 (m, 1H), 2.95 − 3.08 (m, 1.5H), 2.71 − 2.86 (m, 4H), 2.07 − 2.30 (m, 1H), 1.29 (d, J = 2.5 Hz, 6H), 1.14 − 1.22 (m, 6H), 1.00 (dd, J = 6.5, 2.0 Hz, 3H), 0.75 − 0.87 (m, 3H). LC−MS : m/z 505.3 (M+H)+.
1H NMR (クロロホルム−d)δ6.79 − 6.89 (m, 2H), 6.69 − 6.78 (m, 1H), 4.92 (br. s., 0.5H), 4.73 (s, 2H), 4.57 (d, J = 13.8 Hz, 0.5H), 4.05 − 4.30 (m, 2.5H), 3.63 − 3.86 (m, 2.5H), 3.46 − 3.62 (m, 0.5H), 3.11 − 3.26 (m, 1.5H), 2.92 − 3.08 (m, 1H), 2.85 (quin, J = 6.7 Hz, 1H), 2.80 (s, 2H), 1.29 − 1.38 (m, 9H), 1.20 (d, J = 6.8 Hz, 6H). LC−MS : m/z 483.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.52 (d, J = 1.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.88 (br. s., 1H), 4.74 (s, 2H), 4.50 (d, J = 13.6 Hz, 1H), 4.27 (d, J = 13.1 Hz, 1H), 4.19 (dd, J = 13.1, 2.0 Hz, 1H), 3.56 (br. s., 1H), 3.35 (dd, J = 13.1, 3.8 Hz, 1H), 3.18 (td, J = 12.4, 3.5 Hz, 1H), 2.79 − 2.90 (m, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.32 (s, 6H), 1.18 − 1.23 (m, 6H). LC−MS : m/z 423.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.95 − 8.03 (m, 2H), 7.65 − 7.73 (m, 1H), 7.51 − 7.59 (m, 2H), 4.95 − 5.08 (m, 0.5H), 4.74 (s, 2H), 4.64 (d, J = 13.6 Hz, 0.5H), 4.35 (d, J = 13.1 Hz, 0.5H), 4.25 (d, J = 13.3 Hz, 0.5H), 4.08 − 4.19 (m, 1H), 3.92 (br. s., 0.5H), 3.64 (td, J = 12.8, 3.3 Hz, 0.5H), 3.49 (d, J = 13.3 Hz, 0.5H), 3.30 − 3.43 (m, 1H), 3.03 − 3.27 (m, 1.5H), 2.76 − 2.92 (m, 3H), 1.51 (d, J = 6.8 Hz, 1.5H), 1.43 (d, J = 6.8 Hz, 1.5H), 1.32 (s, 6H), 1.16 − 1.24 (m, 6H). LC−MS : m/z 461.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.17 − 7.29 (m, 2H), 6.83 − 7.00 (m, 2H), 4.93 (br. s., 0.5H), 4.71 (s, 2H), 4.57 (d, J = 13.3 Hz, 0.5H), 4.22 (d, J = 10.3 Hz, 1H), 4.11 (d, J = 12.8 Hz, 1.5H), 3.81 − 3.89 (m, 3H), 3.67 − 3.78 (m, 2.5H), 3.46 (t, J = 11.7 Hz, 0.5H), 3.07 − 3.26 (m, 1.5H), 2.88 − 3.05 (m, 1H), 2.73 − 2.87 (m, 3H), 1.30 (s, 9H), 1.18 (d, J = 6.8 Hz, 6H). LC−MS : m/z 477.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.73 (s, 1H), 7.41 − 7.54 (m, 1H), 6.58 (s, 1H), 4.73 (s, 3H), 4.12 − 4.41 (m, 3H), 3.50 (br. s., 1H), 3.22 (dd, J = 13.2, 3.4 Hz, 1H), 3.04 − 3.15 (m, 1H), 2.75 − 2.93 (m, 3H), 1.78 − 2.02 (m, 2H), 1.32 (s, 6H), 1.15 − 1.24 (m, 6H), 0.87 − 1.03 (m, 3H). LC−MS : m/z 437.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.86 − 7.95 (m, 1H), 7.82 (dd, J = 6.5, 2.3 Hz, 1H), 7.57 (s, 1H), 7.36 − 7.48 (m, 2H), 4.71 (s, 3H), 4.15 − 4.20 (m, 3H), 3.49 (t, J = 11.7 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.09 (t, J = 11.3 Hz, 1H), 2.73 − 2.91 (m, 3H), 1.44 (d, J = 6.0 Hz, 3H), 1.28 − 1.35 (m, 6H), 1.16 − 1.19 (m, 6H),. LC−MS : m/z 489.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.70 (br. s., 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 7.4, 4.9 Hz, 1H), 4.72 (s, 3H), 4.03 − 4.33 (m, 3H), 3.50 (br. s., 1H), 3.25 (d, J = 10.3 Hz, 1H), 3.09 (t, J = 12.2 Hz, 1H), 2.73 − 2.93 (m, 3H), 1.45 (d, J = 6.5 Hz, 3H), 1.30 (s, 6H), 1.19 (d, J = 6.5 Hz, 6H). LC−MS : m/z 434.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.21 − 7.35 (m, 3H), 7.12 − 7.21 (m, 1H), 4.93 (br. s., 0.5H), 4.73 (s, 2H), 4.57 (d, J = 12.8 Hz, 0.5H), 4.11 − 4.25 (m, 2.5H), 3.67 − 3.84 (m, 3H), 3.51 (t, J = 11.3 Hz, 0.5H), 3.09 − 3.25 (m, 1.5H), 2.89 − 3.06 (m, 1H), 2.75 − 2.88 (m, 3H), 1.30 − 1.34 (m, 9H), 1.20 (d, J = 6.8 Hz, 6H). LC−MS : m/z 481.2 (M+H)+.
1H NMR (クロロホルム−d) δ8.24 (s, 1H), 7.93 (s, 1H), 4.62 − 5.21 (m, 4H), 4.27 (br. s., 1H), 4.19 (d, J = 13.1 Hz, 1H), 3.34 − 3.66 (m, 2H), 3.18 (br. s., 1H), 2.73 − 2.92 (m, 3H), 1.39 − 1.50 (m, 3H), 1.31 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). LC−MS : m/z 424.2 (M+H)+.
1H NMR (クロロホルム−d)δ9.03 (d, J = 7.0 Hz, 1H), 7.98 (br. s., 1H), 7.84 (br. s., 1H), 7.44 (t, J = 7.8 Hz, 1H), 6.98 − 7.08 (m, 1H), 4.94 (br. s., 1H), 4.73 (s, 2H), 4.49 (d, J = 11.5 Hz, 1H), 4.16 − 4.32 (m, 2H), 3.66 (br. s., 1H), 3.32 (dd, J = 13.1, 3.3 Hz, 1H), 3.17 (td, J = 12.4, 3.3 Hz, 1H), 2.71 − 2.93 (m, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.31 (s, 6H), 1.17 − 1.21 (m, 6H). LC−MS : m/z 473.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.47 − 7.57 (m, 1H), 7.05 (d, J = 3.5 Hz, 1H), 6.47 − 6.59 (m, 1H), 4.88 (br. s., 1H), 4.73 (s, 2H), 4.50 (d, J = 13.1 Hz, 1H), 4.27 (d, J = 13.8 Hz, 1H), 4.19 (d, J = 13.3 Hz, 1H), 3.56 (br. s., 1H), 3.35 (dd, J = 13.2, 3.6 Hz, 1H), 3.18 (td, J = 12.5, 3.4 Hz, 1H), 2.74 − 2.94 (m, 3H), 1.42 − 1.54 (m, 3H), 1.30 − 1.37 (m, 6H), 1.17 − 1.24 (m, 6H). LC−MS : m/z 423.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.94 (s, 1H), 4.72 (s, 3H), 4.12 − 4.41 (m, 3H), 3.50 (br. s., 1H), 3.31 (dd, J = 12.9, 3.1 Hz, 1H), 3.15 (td, J = 12.4, 3.0 Hz, 1H), 2.71 − 2.93 (m, 3H), 2.45 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.28 − 1.38 (m, 6H), 1.20 (d, J = 6.5 Hz, 6H). LC−MS : m/z 438.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.82 (s, 1H), 8.01 (s, 1H), 4.96 (br. s., 1H), 4.72 (s, 2H), 4.56 (br. s., 1H), 4.19 (d, J = 13.1 Hz, 2H), 3.64 (br. s., 1H), 3.38 (br. s., 1H), 3.19 (br. s., 1H), 2.71 − 2.91 (m, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.30 (s, 6H), 1.19 (d, J = 6.5 Hz, 6H). LC−MS : m/z 440.1 (M+H)+.
1H NMR (クロロホルム−d)δ5.94 (s, 1H), 4.55 − 4.84 (m, 3H), 4.12 − 4.31 (m, 3H), 3.42 (br. s., 1H), 3.17 − 3.29 (m, 1H), 2.98 − 3.11 (m, 1H), 2.73 − 2.89 (m, 3H), 2.31 − 2.39 (m, 3H), 2.22 − 2.30 (m, 3H), 1.35 − 1.42 (m, 3H), 1.30 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). LC−MS : m/z 451.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.47 (s, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.28 − 7.36 (m, 2H), 7.21 − 7.26 (m, 1H), 6.98 (br. s., 1H), 6.46 (br. s., 1H), 5.92 (t, J = 4.4 Hz, 1H), 4.70 (d, J = 6.3 Hz, 2H), 4.55 − 4.67 (m, 2H), 4.27 (d, J = 10.0 Hz, 1H), 3.96 (dd, J = 13.8, 4.0 Hz, 1H), 3.48 − 3.74 (m, 2H), 2.83 (dt, J = 13.3, 6.7 Hz, 1H), 2.76 (s, 2H), 1.30 (s, 6H), 1.21 (d, J = 6.8 Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.46 (dd, J = 8.8, 1.8 Hz, 1H), 7.32 − 7.38 (m, 1H), 7.20 − 7.30 (m, 1H), 5.07 (d, J = 4.0 Hz, 0.5H), 4.65 − 4.80 (m, 2.5H), 4.21 − 4.38 (m, 1H), 4.06 − 4.21 (m, 1H), 3.68 (td, J = 12.8, 3.3 Hz, 1H), 3.23 − 3.41 (m, 2H), 3.07 − 3.23 (m, 1H), 2.75 − 2.91 (m, 3H), 1.44 − 1.50 (m, 1.5H), 1.32 (s, 7.5H), 1.21 (dt, J = 6.7, 3.2 Hz, 6H). LC−MS : m/z 501.2 (M+H)+.
1H NMR (クロロホルム−d)δ8.48 − 8.61 (m, 2H), 7.70 (br. s., 1H), 7.32 (dd, J = 7.8, 5.0 Hz, 1H), 4.89 (br. s., 0.5H), 4.71 (s, 2H), 4.53 (d, J = 13.1 Hz, 0.5H), 4.05 − 4.31 (m, 2.5H), 3.68 − 3.87 (m, 2.5H), 3.57 (t, J = 11.3 Hz, 0.5H), 3.17 (t, J = 13.2 Hz, 1.5H), 2.92 − 3.09 (m, 1H), 2.71 − 2.89 (m, 3H), 1.37 (d, J = 6.0 Hz, 1.5H), 1.30 (s, 7.5H), 1.19 (d, J = 6.8 Hz, 6H). LC−MS : m/z 448.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.71 (br. s., 1H), 7.39 − 7.49 (m, 2H), 7.36 (d, J = 9.3 Hz, 1H), 7.25 (br. s., 2H), 7.19 (d, J = 7.5 Hz, 1H), 6.52 − 6.62 (m, 1H), 5.37 (br. s., 1H), 4.91 − 5.16 (m, 1H), 4.59 − 4.73 (m, 2H), 4.21 (br. s., 2H), 3.82 (br. s., 2H), 3.57 (br. s., 1H), 2.77 − 2.87 (m, 2H), 2.67 − 2.77 (m, 1H), 1.29 − 1.30 (m, 6H), 1.16 (d, J = 6.5 Hz, 3H), 0.83 (br. s., 3H). LC−MS : m/z 499.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.61 (br. s., 1H), 7.44 (br. s., 1H), 7.39 (br. s., 2H), 7.27 − 7.36 (m, 3H), 6.51 (br. s., 1H), 5.71−5.79 (br. s., 1H), 4.45 − 4.74 (m, 4H), 4.24 (d, J = 10.8 Hz, 1H), 3.91 (d, J = 10.3 Hz, 1H), 3.56 (d, J = 11.8 Hz, 1H), 3.50 (d, J = 9.8 Hz, 1H), 2.81 (dt, J = 13.2, 6.6 Hz, 1H), 2.75 (s, 2H), 1.29 (s, 6H), 1.19 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 5.8 Hz, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.38−7.54 (m, 2H), 7.22 − 7.28 (m, 3H), 7.18 (d, J = 6.5 Hz, 1H), 6.36 (d, J = 1.5 Hz, 1H), 5.37 (br. s., 1H), 4.91 − 5.14 (m, 1H), 4.60 − 4.73 (m, 2H), 4.05 (br. s., 2H), 3.79 (br. s., 2H), 3.58 (br. s., 1H), 2.77 − 2.86 (m, 2H), 2.68 − 2.77 (m, 1H), 2.37 (s, 3H), 1.29 − 1.31 (m, 6H), 1.17 (d, J = 6.5 Hz, 3H), 0.89 − 0.92 (m, 3H). LC−MS : m/z 485.1 (M+H)+.
1H NMR (クロロホルム−d)δ8.57 (d, J = 4.8 Hz, 1H), 7.65 − 7.76 (m, 1H), 7.40 (dd, J = 14.4, 7.9 Hz, 1H), 7.23 (dd, J = 6.8, 5.3 Hz, 1H), 4.71 (s, 2H), 4.52 (br. s., 1H), 3.94 − 4.24 (m, 5H), 3.06 − 3.27 (m, 2H), 2.95 (dd, J = 13.1, 3.0 Hz, 1H), 2.73 − 2.90 (m, 3H), 1.29 (s, 9H), 1.18 (d, J = 6.5 Hz, 6H). LC−MS : m/z 448.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.90 (br. s., 0.5H), 4.72 (s, 2H), 4.54 (d, J = 13.1 Hz, 0.5H), 4.12 − 4.37 (m, 2.5H), 3.81 − 4.08 (m, 4.5H), 3.59 (q, J = 11.5 Hz, 0.5H), 3.12 − 3.35 (m, 2.5H), 2.95 − 3.10 (m, 1H), 2.76 − 2.90 (m, 3H), 2.04 − 2.25 (m, 2H), 1.39 − 1.48 (m, 1.5H), 1.30 (s, 7.5H), 1.20 (d, J = 6.8 Hz, 6H). LC−MS : m/z 427.2 (M+H)+.
1H NMR (クロロホルム−d) δ7.24 (d, J = 5.0 Hz, 1H), 6.99 (dd, J = 5.3, 3.5 Hz, 1H), 6.95 (br. s., 1H), 4.73 (s, 2H), 3.98 (s, 2H), 3.83 (br. s., 2H), 3.68 (d, J = 18.3 Hz, 4H), 3.60 (d, J = 4.8 Hz, 2H), 2.75 − 2.90 (m, 3H), 1.32 (s, 6H), 1.21 (d, J = 6.5 Hz, 6H). LC−MS : m/z 439.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.48 − 7.57 (m, 1H), 7.07 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.74 (s, 2H), 3.99 (br. s., 4H), 3.69 − 3.85 (m, 4H), 2.77 − 2.96 (m, 3H), 1.32 (s, 6H), 1.22 (d, J = 6.5 Hz, 6H). LC−MS : m/z 409.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.51 (s, 1H), 7.07 (dd, J = 3.4, 0.6 Hz, 1H), 6.51 (dd, J = 3.5, 1.8 Hz, 1H), 4.72 (s, 2H), 4.60 (br. s., 1H), 4.47 (d, J = 11.3 Hz, 1H), 4.29 (dt, J = 13.2, 1.4 Hz, 1H), 4.07 (d, J = 13.1 Hz, 1H), 3.51 (t, J = 10.8 Hz, 2H), 2.84 (dt, J = 13.3, 6.7 Hz, 1H), 2.79 (s, 2H), 2.20 − 2.25 (m, 1H), 1.31 (s, 6H), 1.20 (d, J = 2.5 Hz, 3H), 1.18 (d, J = 2.5 Hz, 3H). LC−MS : m/z 423.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.69 − 7.83 (m, 1H), 7.39 − 7.52 (m, 1H), 6.59 (dd, J = 1.8, 0.8 Hz, 1H), 4.73 (s, 3H), 4.13 − 4.42 (m, 3H), 3.50 (d, J = 6.8 Hz, 1H), 3.25 (dd, J = 13.2, 3.4 Hz, 1H), 3.08 (td, J = 12.5, 3.5 Hz, 1H), 2.80 (s, 2H), 2.46 (tt, J = 11.2, 3.6 Hz, 1H), 1.82 − 1.90 (m, 2H), 1.56 − 1.79 (m, 6H), 1.43 − 1.48 (m, 3H), 1.29 − 1.39 (m, 8H). LC−MS : m/z 463.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.76 (s, 1H), 7.41 − 7.52 (m, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.73 (s, 3H), 4.13 − 4.43 (m, 3H), 3.51 (br. s., 1H), 3.25 (dd, J = 12.8, 3.0 Hz, 1H), 3.09 (td, J = 12.5, 3.4 Hz, 1H), 2.75 − 2.85 (m, 2H), 2.46 (tt, J = 11.1, 3.7 Hz, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.59 − 1.73 (m, 6H), 1.45 (d, J = 6.8 Hz, 3H), 1.29 − 1.40 (m, 8H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.90 (br. s., 0.5H), 4.71 (s, 2H), 4.53 (d, J = 12.5 Hz, 0.5H), 4.04 − 4.33 (m, 2.5H), 3.68 − 3.84 (m, 2.5H), 3.49 − 3.64 (m, 0.5H), 3.38 (s, 3H), 2.99 − 3.27 (m, 2.5H), 2.64 − 2.84 (m, 3H), 2.52 − 2.62 (m, 1H), 2.44 (tt, J = 11.0, 3.5 Hz, 1H), 1.84 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.60 − 1.68 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H), 1.29 (s, 9H). LC−MS : m/z 455.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.19 − 7.26 (m, 1H), 6.87 − 7.04 (m, 2H), 4.94 (br. s., 0.5H), 4.72 (s, 2H), 4.57 (d, J = 12.8 Hz, 0.5H), 4.09 − 4.34 (m, 2.5H), 3.88 − 3.99 (m, 2H), 3.79 (d, J = 12.0 Hz, 0.5H), 3.51 − 3.67 (m, 0.5H), 3.11 − 3.31 (m, 1.5H), 2.91 − 3.08 (m, 1H), 2.79 (s, 2H), 2.45 (tt, J = 11.1, 3.6 Hz, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.77 (d, J = 10.3 Hz, 1H), 1.54 − 1.72 (m, 6H), 1.30 − 1.36 (m, 10H). LC−MS : m/z 493.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.64 (br. s., 1H), 7.39 − 7.47 (m, 3H), 7.36 (t, J = 7.7 Hz, 2H), 7.25 − 7.32 (m, 1H), 6.53 (br. s., 1H), 5.76 (br. s., 1H), 4.45 − 4.75 (m, 4H), 4.25 (d, J = 11.3 Hz, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.39 − 3.66 (m, 2H), 2.71 − 2.81 (m, 2H), 2.44 (t, J = 11.0 Hz, 1H), 1.74 − 1.91 (m, 3H), 1.67 (d, J = 8.5 Hz, 2H), 1.29 − 1.43 (m, 11H). LC−MS : m/z 525.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.52 (s, 1H), 7.05 (d, J = 3.3 Hz, 1H), 6.46 − 6.63 (m, 1H), 4.89 (br. s., 1H), 4.73 (s, 2H), 4.50 (d, J = 13.1 Hz, 1H), 4.26 (d, J = 13.3 Hz, 1H), 4.18 (d, J = 13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J = 12.8, 3.0 Hz, 1H), 3.12 − 3.24 (m, 1H), 2.80 (s, 2H), 2.37 − 2.55 (m, 1H), 1.86 (d, J = 11.8 Hz, 2H), 1.56 − 1.77 (m, 6H), 1.48 (d, J = 6.5 Hz, 3H), 1.34 − 1.42 (m, 2H), 1.32 (s, 6H). LC−MS : m/z 463.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.45 − 7.58 (m, 1H), 7.04 (d, J = 3.5 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 4.87 (br. s., 1H), 4.71 (s, 2H), 4.49 (d, J = 13.8 Hz, 1H), 4.25 (d, J = 13.8 Hz, 1H), 4.17 (dd, J = 13.1, 2.0 Hz, 1H), 3.54 (br. s., 1H), 3.32 (dd, J = 13.1, 3.8 Hz, 1H), 3.16 (td, J = 12.4, 3.5 Hz, 1H), 2.79 (s, 2H), 2.45 (tt, J = 11.0, 3.8 Hz, 1H), 1.79 − 1.91 (m, 3H), 1.54 − 1.79 (m, 5H), 1.43 − 1.52 (m, 3H), 1.27 − 1.36 (m, 8H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.53 (dd, J = 1.6, 0.9 Hz, 1H), 7.07 (dd, J = 3.4, 0.6 Hz, 1H), 6.52 (dd, J = 3.5, 1.8 Hz, 1H), 4.73 (s, 2H), 3.99 (br. s., 4H), 3.61 − 3.80 (m, 4H), 2.81 (s, 2H), 2.39 − 2.53 (m, 1H), 1.82 − 1.90 (m, 2H), 1.55 − 1.80 (m, 6H), 1.34 − 1.45 (m, 2H), 1.30 − 1.33 (m, 6H). LC−MS : m/z 448.9 (M+H)+.
1H NMR (クロロホルム−d)δ7.73 − 7.84 (m, 1H), 7.39 − 7.54 (m, 2H), 7.13 − 7.26 (m, 3H), 6.53 − 6.66 (m, 1H), 4.75 (br. s., 1H), 4.68 (s, 2H), 4.18 − 4.41 (m, 3H), 3.52 (br. s., 1H), 3.30 (dd, J = 12.9, 3.6 Hz, 1H), 3.12 (td, J = 12.5, 3.4 Hz, 1H), 2.90 (s, 2H), 1.44 − 1.53 (m, 3H), 1.37 (s, 6H). LC−MS : m/z 475.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.72 (br. s., 1H), 7.44 − 7.51 (m, 1H), 6.52 − 6.61 (m, 1H), 4.46 − 4.70 (m, 4H), 4.31 (br. s., 1H), 4.04 (br. s., 0.5H), 3.81 (br. s., 0.5H), 3.57 (br. s., 0.5H), 3.46 (quin, J = 8.2 Hz, 1H), 3.03 − 3.26 (m, 2H), 2.71 − 2.83 (m, 2H), 2.32 − 2.46 (m, 2H), 2.21 − 2.31 (m, 3H), 1.98 − 2.12 (m, 1H), 1.84 − 1.95 (m, 1H), 1.29 (d, J = 2.0 Hz, 6H), 0.99 − 1.14 (m, 2H), 0.85 − 0.99 (m, 4H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.20 (d, J = 5.0 Hz, 1H), 6.88 − 7.01 (m, 2H), 4.41 − 4.65 (m, 4H), 4.19 − 4.35 (m, 1H), 3.83 − 4.07 (m, 2.5H), 3.38 − 3.61 (m, 2H), 2.87 − 3.17 (m, 2.5H), 2.68 − 2.83 (m, 2H), 2.30 − 2.48 (m, 2H), 2.19 − 2.29 (m, 2H), 1.98 − 2.16 (m, 1H), 1.23 − 1.30 (m, 6H), 0.99 − 1.11 (m, 3H), 0.85 (dd, J = 19.6, 6.8 Hz, 3H). LC−MS : m/z 493.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.70 − 7.80 (m, 1H), 7.47 (t, J = 1.6 Hz, 1H), 6.64 (dd, J = 1.8, 0.8 Hz, 1H), 4.75 (s, 4H), 4.22 (d, J = 13.1 Hz, 2H), 3.16 (dd, J = 13.1, 4.3 Hz, 2H), 2.93 − 3.08 (m, 1H), 2.81 (s, 2H), 1.89 − 1.98 (m, 2H), 1.80 − 1.87 (m, 3H), 1.54 (d, J = 7.0 Hz, 6H), 1.33 (s, 6H), 1.26 − 1.31 (m, 3H). LC−MS : m/z 463.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.47 − 7.58 (m, 1H), 7.01 − 7.10 (m, 1H), 6.51 (dd, J = 3.3, 1.8 Hz, 1H), 4.88 (br. s., 1H), 4.74 (s, 2H), 4.49 (d, J = 13.3 Hz, 1H), 4.24 (d, J = 13.8 Hz, 1H), 4.11 − 4.18 (m, 1H), 3.55 (br. s., 1H), 3.32 (dd, J = 13.1, 3.8 Hz, 1H), 3.16 (td, J = 12.4, 3.5 Hz, 1H), 2.95 − 3.05 (m, 1H), 2.80 (s, 2H), 1.87 − 1.96 (m, 2H), 1.77 − 1.86 (m, 4H), 1.63 − 1.74 (m, 2H), 1.44 − 1.51 (m, 3H), 1.30 − 1.36 (m, 6H). LC−MS : m/z 449.1 (M+H)+.
1H NMR (DMSO−d6) δ7.72 (br. s., 1H), 7.39 − 7.55 (m, 1H), 6.55 (s, 1H), 4.45 − 4.74 (m, 4H), 4.27 (br. s., 1H), 4.02 (d, J = 12.0 Hz, 0.5H), 3.55 (br. s., 1H), 3.12 (dd, J = 13.4, 3.4 Hz, 2.5H), 2.71 − 2.82 (m, 2H), 2.55 (q, J = 7.5 Hz, 2H), 2.11 − 2.39 (m, 1H), 1.27 − 1.32 (m, 6H), 1.23 (t, J = 7.4 Hz, 3H), 1.06 (br. s., 2H), 0.82 − 0.98 (m, 4H). LC−MS : m/z 437.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.61 − 4.75 (m, 2.5H), 4.52 (d, J = 13.3 Hz, 1H), 4.44 (d, J = 10.3 Hz, 0.5H), 4.25 − 4.36 (m, 1H), 3.79 − 3.89 (m, 0.5H), 3.69 − 3.78 (m, 2H), 3.56 (d, J = 9.8 Hz, 0.5H), 3.41 − 3.52 (m, 0.5H), 3.34 − 3.40 (m, 3H), 2.92 − 3.18 (m, 2.5H), 2.51 − 2.81 (m, 6H), 2.03 − 2.32 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 1.25 (t, J = 7.4 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.90 (d, J = 6.8 Hz, 1.5H), 0.84 (d, J = 6.8 Hz, 1.5H).
1H NMR (クロロホルム−d)δ7.79 (br. s., 1H), 7.46 (s, 1H), 6.63 (br. s., 1H), 5.39 (br. s., 0.5H), 4.80 (br. s., 0.5H), 4.72 (d, J = 3.5 Hz, 2H), 4.21 (dq, J = 10.7, 7.1 Hz, 2H), 4.01 − 4.15 (m, 2H), 3.93 (br. s., 1H), 3.40 (d, J = 11.8 Hz, 1H), 3.03 − 3.18 (m, 1H), 2.76 − 2.89 (m, 3H), 1.11 − 1.34 (m, 15H). LC−MS : m/z 481.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.79 (br. s., 1H), 7.46 (s, 1H), 6.63 (br. s., 1H), 5.39 (br. s., 0.5H), 4.80 (br. s., 0.5H), 4.72 (d, J = 3.5 Hz, 2H), 4.21 (dq, J = 10.7, 7.1 Hz, 2H), 4.01 − 4.15 (m, 2H), 3.93 (br. s., 1H), 3.40 (d, J = 11.8 Hz, 1H), 3.03 − 3.18 (m, 1H), 2.76 − 2.89 (m, 3H), 1.11 − 1.34 (m, 15H). LC−MS : m/z 481.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.91 (s, 0.5H), 4.83 (s, 2H), 4.56 (d, J = 13.6 Hz, 0.5H), 4.18 (d, J = 13.3 Hz, 2H), 4.07 (d, J = 11.0 Hz, 1H), 3.58 − 3.84 (m, 5H), 3.54 (d, J = 6.5 Hz, 1H), 3.33 − 3.41 (m, 4H), 3.30 (s, 3H), 2.99 − 3.20 (m, 2H), 2.94 (d, J = 11.0 Hz, 1H), 1.62 − 1.76 (m, 1H), 1.31 (s, 6H), 1.13 (br. s., 2H), 0.94 − 1.08 (m, 2H). LC−MS : m/z 443.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.82 (br. s., 1H), 7.43 (t, J = 1.5 Hz, 1H), 6.65 (br. s., 1H), 4.84 (s, 2H), 4.07 (d, J = 12.5 Hz, 3H), 3.77 (br. s., 1H), 3.59 − 3.73 (m, 1H), 3.35 (s, 4H), 3.01 (td, J = 12.5, 3.3 Hz, 2H), 2.68 − 2.84 (m, 3H), 1.70 (td, J = 8.2, 3.9 Hz, 1H), 1.27 − 1.37 (m, 6H), 1.08 − 1.17 (m, 2H), 0.95 − 1.08 (m, 2H). LC−MS : m/z 451.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.50 − 4.75 (m, 3.5H), 4.39 − 4.50 (m, 0.5H), 4.24 − 4.37 (m, 1H), 3.84 (d, J = 13.6 Hz, 0.5H), 3.68 − 3.79 (m, 2H), 3.53 − 3.62 (m, 0.5H), 3.40 − 3.52 (m, 1.5H), 3.37 (d, J = 3.3 Hz, 3H), 2.95 − 3.22 (m, 2.5H), 2.53 − 2.83 (m, 4H), 2.32 − 2.48 (m, 2H), 2.19 − 2.31 (m, 2H), 1.99 − 2.19 (m, 2H), 1.85 − 1.96 (m, 1H), 1.29 (d, J = 2.5 Hz, 6H), 1.00 − 1.11 (m, 3H), 0.87 − 0.94 (m, 1.5H), 0.80 − 0.87 (m, 1.5H). LC−MS : m/z 455.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.17 − 7.37 (m, 2H), 6.43 (br. s., 0.5H), 5.40 (br. s., 0.5H), 4.83 (s, 2H), 4.67 (d, J = 13.1 Hz, 1H), 4.05 (d, J = 11.0 Hz, 1H), 3.84 − 3.98 (m, 1H), 3.81 (d, J = 13.8 Hz, 1H), 3.72 (s, 3H), 3.27 (d, J = 11.5 Hz, 1H), 2.90 − 3.07 (m, 1H), 2.77 (s, 2H), 2.43 (br. s., 3H), 1.64 − 1.79 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 1.14 (dd, J = 8.0, 3.8 Hz, 2H), 0.92 − 1.08 (m, 2H). LC−MS : m/z 479.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.80 (br. s., 1H), 7.46 (s, 1H), 6.64 (br. s., 1H), 5.42 (br. s., 1H), 4.64 − 4.86 (m, 3H), 4.19 (d, J = 10.3 Hz, 2H), 3.73 (s, 3H), 3.38 (d, J = 11.3 Hz, 1H), 3.06 − 3.22 (m, 2H), 2.70 − 2.92 (m, 3H), 1.24 − 1.34 (m, 6H), 1.20 (d, J = 6.5 Hz, 6H). LC−MS : m/z 467.4 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE2を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ 4.82 (br. s., 1H), 4.70 (s, 2H), 4.23 (d, J = 19.3 Hz, 2H), 3.99 − 4.18 (m, 3H), 3.90 − 3.97 (m, 2H), 3.59 − 3.80 (m, 1H), 3.08 − 3.30 (m, 2H), 2.93 (t, J = 5.6 Hz, 2H), 2.37 − 2.48 (m, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.69 (br. s., 1H), 1.55 − 1.64 (m, 3H), 1.46 (d, J = 6.0 Hz, 1H), 1.35 − 1.41 (m, 1H), 1.32 (d, J = 7.8 Hz, 3H), 1.27 − 1.29 (m, 1H). LC−MS : m/z 417.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.88 (br. s., 0.5H), 4.65 − 4.75 (m, 2H), 4.50 (d, J = 13.1 Hz, 0.5H), 4.06 − 4.29 (m, 2.5H), 3.88 − 3.99 (m, 2H), 3.52 − 3.78 (m, 1H), 3.00 − 3.29 (m, 2.5H), 2.93 (t, J = 5.8 Hz, 2H), 2.33 − 2.48 (m, 1H), 2.10 − 2.18 (m, 3H), 1.79 − 1.89 (m, 2H), 1.55 − 1.76 (m, 5H), 1.35 − 1.41 (m, 2H), 1.24 − 1.34 (m, 6H). LC−MS : m/z 397.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.70 (s, 2H), 4.45 (d, J = 11.8 Hz, 1H), 4.24 (br. s., 1H), 4.05 − 4.21 (m, 2H), 3.89 − 3.98 (m, 2H), 3.56 − 3.81 (m, 1H), 3.39 (d, J = 10.5 Hz, 1H), 3.21 (br. s., 1H), 3.00 − 3.16 (m, 1H), 2.86 − 2.97 (m, 2H), 2.41 (tt, J = 11.1, 3.6 Hz, 1H), 1.80 − 1.89 (m, 2H), 1.54 − 1.79 (m, 6H), 1.40 − 1.45 (m, 1H), 1.27 − 1.38 (m, 4H), 0.95 − 1.08 (m, 2H), 0.73 − 0.85 (m, 2H). LC−MS : m/z 409.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.32 − 7.39 (m, 2H), 7.24 − 7.32 (m, 3H), 4.71 (s, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.77 − 3.86 (m, 4H), 3.57 − 3.67 (m, 4H), 3.46 − 3.53 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.1, 3.5 Hz, 1H), 1.85 (d, J = 12.5 Hz, 2H), 1.76 (d, J = 14.8 Hz, 2H), 1.61 − 1.69 (m, 2H), 1.58 (d, J = 12.0 Hz, 1H), 1.24 − 1.42 (m, 3H). LC−MS : m/z 445.1 (M+H)+.
1H NMR (クロロホルム−d)δ5.27 − 5.53 (m, 1H), 4.70 (s, 3H), 4.23 (br. s., 4H), 4.16 (br. s., 2H), 3.93 (t, J = 5.4 Hz, 1H), 3.48 (br. s., 3H), 3.24 (br. s., 1H), 3.08 (br. s., 1H), 2.93 (t, J = 5.4 Hz, 2H), 2.42 (br. s., 1H), 1.84 (d, J = 11.0 Hz, 2H), 1.75 (d, J = 10.0 Hz, 1H), 1.66 (br. s., 4H), 1.30 − 1.39 (m, 6H). LC−MS : m/z 413.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.81 − 4.96 (m, 0.5H), 4.66 − 4.75 (m, 2H), 4.50 (d, J = 13.6 Hz, 0.5H), 4.06 − 4.33 (m, 2.5H), 3.87 − 4.03 (m, 2H), 3.51 − 3.79 (m, 1H), 2.96 − 3.23 (m, 2.5H), 2.86 − 2.95 (m, 2H), 2.41 (tt, J = 11.1, 3.6 Hz, 1H), 2.14 (d, J = 9.5 Hz, 3H), 1.80 − 1.89 (m, 2H), 1.54 − 1.75 (m, 5H), 1.32 − 1.41 (m, 3H), 1.25 − 1.31 (m, 3H) . LC−MS : m/z 383.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.71 (s, 2H), 3.95 (t, J = 5.8 Hz, 2H), 3.85 (br. s., 2H), 3.80 (br. s., 2H), 3.73 (br. s., 2H), 3.66 (br. s., 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.43 (tt, J = 11.1, 3.7 Hz, 1H), 1.73 − 1.90 (m, 3H), 1.55 − 1.72 (m, 4H), 1.23 − 1.43 (m, 4H), 1.00 − 1.07 (m, 2H), 0.76 − 0.84 (m, 2H). LC−MS : m/z 395.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.89 (br. s., 1H), 4.70 (s, 2H), 4.12 − 4.25 (m, 2H), 3.89 − 3.98 (m, 2H), 3.74 (d, J = 12.8 Hz, 1H), 2.98 − 3.28 (m, 2H), 2.88 − 2.97 (m, 2H), 2.20 − 2.48 (m, 3H), 1.80 − 1.88 (m, 2H), 1.60 − 1.77 (m, 6H), 1.26 − 1.42 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). LC−MS : m/z 411.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.83 (s, 2H), 4.60 (d, J = 9.8 Hz, 1H), 4.28 − 4.49 (m, 1H), 4.04 − 4.28 (m, 1H), 3.84 (d, J = 9.8 Hz, 1H), 3.12 (td, J = 13.2, 3.0 Hz, 1H), 2.91 − 3.05 (m, 2H), 2.77 (s, 2H), 2.12−2.29 (m, 1H), 1.64 − 1.82 (m, 2H), 1.32 (d, J = 2.3 Hz, 6H), 1.06 − 1.19 (m, 2H), 0.96 − 1.05 (m, 8H), 0.87 − 0.94 (m, 2H), 0.71 − 0.84 (m, 2H). LC−MS : m/z 423.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.83 (s, 2H), 4.40 (d, J = 10.3 Hz, 1H), 4.33 (d, J = 13.1 Hz, 1H), 4.10 − 4.24 (m, 1H), 3.73 (d, J = 13.3 Hz, 1H), 3.28 − 3.58 (m, 1H), 2.84 − 3.10 (m, 2H), 2.76 (s, 2H), 2.40 (d, J = 7.3 Hz, 1H), 1.70 (td, J = 7.9, 4.0 Hz, 2H), 1.31 (d, J = 2.3 Hz, 6H), 1.18 (t, J = 7.3 Hz, 3H), 0.93 − 1.06 (m, 6H), 0.64 − 0.92 (m, 4H). LC−MS : m/z 411.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.89 (m, 2H), 4.64 − 4.67 (m, 0.5H), 4.41 (d, J = 10.5 Hz, 0.5H), 4.33 (dd, J = 13.3, 1.8 Hz, 1H), 4.14 − 4.24 (m, 1H), 3.74 (d, J = 13.6 Hz, 0.5H), 3.36 − 3.55 (m, 1H), 2.90 − 3.07 (m, 2.5H), 2.76 (s, 2H), 2.29 − 2.43 (m, 2.5H), 2.08 − 2.20 (m, 0.5H), 1.64 − 1.76 (m, 3H), 1.31 (d, J = 2.5 Hz, 6H), 0.95 − 1.18 (m, 10H), 0.87 (d, J = 6.8 Hz, 1.5H), 0.81 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 425.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.83 (s, 2H), 4.38 (d, J = 10.3 Hz, 1H), 4.32 (d, J = 13.3 Hz, 1H), 4.03 − 4.25 (m, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.35 − 3.58 (m, 1H), 2.86 − 3.12 (m, 2H), 2.76 (s, 2H), 2.24 (d, J = 7.3 Hz, 1H), 2.09 − 2.18 (m, 3H), 1.67 − 1.76 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 0.94 − 1.06 (m, 6H), 0.86 − 0.94 (m, 2H), 0.83 (d, J = 6.8 Hz, 2H). LC−MS : m/z 397.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.33 − 7.39 (m, 2H), 7.26 − 7.31 (m, 3H), 4.72 (s, 2H), 3.77 − 3.86 (m, 4H), 3.57 − 3.68 (m, 4H), 3.43 − 3.54 (m, 2H), 2.74 − 2.92 (m, 3H), 1.31 (s, 6H), 1.19 (d, J = 6.8 Hz, 6H). LC−MS : m/z 433.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.23 − 7.42 (m, 5H), 4.95 (br. s., 0.5H), 4.71 (s, 2H), 4.59 (d, J = 13.3 Hz, 0.5H), 4.20 − 4.23 (m, 1H), 4.08 − 4.23 (m, 1.5H), 3.80 (br. s., 2H), 3.72 (d, J = 13.6 Hz, 0.5H), 3.48 (t, J = 10.9 Hz, 0.5H), 3.13 − 3.21 (m, 1H), 2.92 − 3.08 (m, 1H), 2.86 (t, J = 11.2 Hz, 0.5H), 2.77 (s, 2H), 2.39 − 2.53 (m, 1H), 1.85 (d, J = 12.3 Hz, 2H), 1.54 − 1.63 (m, 6H), 1.29 − 1.43 (m, 11H). LC−MS : m/z 487.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.83 (s, 2H), 4.31 − 4.45 (m, 2H), 4.16 − 4.27 (m, 3H), 4.09 (d, J = 8.5 Hz, 1H), 3.40 (br. s., 1H), 2.90 − 3.08 (m, 2H), 2.76 (s, 2H), 2.12 − 2.28 (m, 1H), 2.03 − 2.10 (m, 3H), 1.67 − 1.76 (m, 1H), 1.33 (dd, J = 11.7, 1.4 Hz, 12H), 1.07 − 1.18 (m, 2H), 0.97 − 1.06 (m, 5H), 0.82 (d, J = 6.8 Hz, 3H). LC−MS : m/z 497.5 (M+H)+.
1H NMR (クロロホルム−d)δ4.78 − 4.91 (m, 2H), 4.62 − 4.65 (m, 0.5H), 4.29 − 4.44 (m, 1.5H), 4.10 − 4.26 (m, 1H), 3.79 (d, J = 13.8 Hz, 0.5H), 3.68 − 3.74 (m, 3H), 3.40 − 3.58 (m, 1H), 2.91 − 3.15 (m, 2.5H), 2.78 (s, 2H), 2.64 − 2.74 (m, 4H), 2.07 − 2.34 (m, 1H), 1.69 − 1.76 (m, 1H), 1.33 (d, J = 2.5 Hz, 6H), 1.07 − 1.20 (m, 2H), 0.99 − 1.06 (m, 5H), 0.89 − 0.95 (m, 1.5H), 0.82 (d, J = 7.0 Hz, 1.5H). LC−MS : m/z 469.4 (M+H)+.
表題化合物を、化合物412のLiOH/メタノール−H2O加水分解から調製した。1H NMR (METHANOL−d4) δ4.80 − 4.92 (m, 2H), 4.50 − 4.53 (m, 0.5H), 4.23 − 4.45 (m, 1.5H), 4.10 − 4.22 (m, 1H), 3.97 (d, J = 14.1 Hz, 0.5H), 3.42 − 3.55 (m, 0.5H), 2.91 − 3.20 (m, 2.5H), 2.58 − 2.87 (m, 6H), 2.07 − 2.32 (m, 1H), 1.81 − 1.92 (m, 1H), 1.26 − 1.38 (m, 6H), 1.09 − 1.17 (m, 2H), 1.02 − 1.09 (m, 3H), 1.00 (d, J = 6.5 Hz, 2H), 0.92 (d, J = 6.8 Hz, 1H), 0.82 (d, J = 6.8 Hz, 2H). LC−MS : m/z 455.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.75 − 4.90 (m, 2H), 4.63 − 4.68 (m, 0.5H), 4.29 − 4.44 (m, 1.5H), 4.11 − 4.27 (m, 1H), 3.71 − 3.83 (m, 3H), 3.42 − 3.67 (m, 4H), 2.93 − 3.15 (m, 2H), 2.71 − 2.84 (m, 2H), 2.06 − 2.33 (m, 1H), 1.66 − 1.78 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 1.06 − 1.18 (m, 2H), 0.97 − 1.05 (m, 5H), 0.81 − 0.94 (m, 3H). LC−MS : m/z 455.3 (M+H)+.
表題化合物を、化合物409のLiOH/メタノール−H2O加水分解から調製した。1H NMR (METHANOL−d4) δ4.82 − 4.90 (m, 2H), 4.25 − 4.46 (m, 2H), 4.10 − 4.25 (m, 1H), 3.85 (d, J = 14.1 Hz, 1H), 3.39 − 3.65 (m, 2H), 2.93 − 3.22 (m, 3H), 2.78 (s, 2H), 2.09 − 2.21 (m, 1H), 1.82 − 1.90 (m, 1H), 1.32 (s, 6H), 0.97 − 1.17 (m, 7H), 0.84 − 0.94 (m, 3H). LC−MS : m/z 441.5 (M+H)+.
1H NMR (クロロホルム−d)δ4.52 − 4.69 (m, 3.5H), 4.26 − 4.49 (m, 1.5H), 4.16 (d, J = 12.5 Hz, 0.5H), 3.90 (d, J = 10.0 Hz, 0.5H), 3.37 − 3.66 (m, 2H), 2.99 − 3.29 (m, 2.5H), 2.70 − 2.83 (m, 2H), 2.37 (dt, J = 19.6, 10.1 Hz, 2H), 2.20 − 2.31 (m, 2.5H), 1.98 − 2.11 (m, 1H), 1.84 − 1.96 (m, 1H), 1.73 − 1.83 (m, 1H), 1.29 (d, J = 2.3 Hz, 6H), 0.89 − 1.11 (m, 7H), 0.77 − 0.87 (m, 3H). LC−MS : m/z 437.3 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE3を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.77 − 4.89 (m, 2H), 4.51 − 4.68 (m, 0.5H), 4.28 − 4.43 (m, 1.5H), 4.21 (d, J = 11.0 Hz, 1H), 4.00 (d, J = 13.6 Hz, 0.5H), 3.66 − 3.83 (m, 1H), 3.52 − 3.64 (m, 3.5H), 3.38 − 3.50 (m, 1H), 2.91 − 3.21 (m, 2.5H), 2.73 − 2.80 (m, 2H), 2.64 − 2.71 (m, 2H), 1.97 − 2.29 (m, 2H), 1.67 − 1.75 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 0.98 − 1.20 (m, 7H), 0.81 − 0.91 (m, 3H). LC−MS : m/z 456.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.83 (d, J = 10.0 Hz, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 5.06 (dd, J = 16.3, 7.8 Hz, 1H), 4.86 − 4.97 (m, 1H), 4.79 − 4.85 (m, 2H), 4.53 − 4.56 (m, 0.5H), 4.26 − 4.41 (m, 1.5H), 4.12 − 4.24 (m, 1H), 3.70 (d, J = 13.3 Hz, 0.5H), 3.40 − 3.58 (m, 1H), 2.95 − 3.16 (m, 2.5H), 2.76 (s, 2H), 2.09 − 2.27 (m, 1H), 1.67 − 1.75 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.90 − 1.19 (m, 8.5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 463.2 (M+H)+.
1H NMR (クロロホルム−d)δ6.93 − 7.16 (m, 1H), 6.86 (s, 1H), 4.73 − 5.03 (m, 4H), 4.12 − 4.42 (m, 3H), 3.82 (br. s., 0.5H), 3.50 − 3.65 (m, 1H), 2.95 − 3.19 (m, 2.5H), 2.68 − 2.82 (m, 2H), 2.32 − 2.43 (m, 3H), 2.12 − 2.25 (m, 1H), 1.67 − 1.78 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 1.07 − 1.19 (m, 3.5H), 0.92 − 1.05 (m, 5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 477.3 (M+H)+.
1H NMR (クロロホルム−d)δ8.28 (br. s., 1H), 7.98 (br. s., 1H), 4.99 − 5.22 (m, 2H), 4.75 − 4.92 (m, 2H), 4.57 (d, J = 12.8 Hz, 0.5H), 4.26 − 4.44 (m, 1.5H), 4.19 (dd, J = 19.1, 13.3 Hz, 1H), 3.79 (d, J = 13.3 Hz, 0.5H), 3.45 − 3.65 (m, 1H), 2.92 − 3.16 (m, 2.5H), 2.70 − 2.85 (m, 2H), 2.11 − 2.41 (m, 1H), 1.67 − 1.80 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.90 − 1.19 (m, 8.5H), 0.82 (d, J = 6.5 Hz, 1.5H). LC−MS : m/z 464.0 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE4を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.78 − 4.90 (m, 2H), 4.58 − 4.60 (m, 0.5H), 4.11 − 4.41 (m, 4.5H), 3.73 (dd, J = 18.6, 4.3 Hz, 4H), 3.60 (d, J = 13.6 Hz, 1H), 3.35 − 3.52 (m, 0.5H), 3.27 − 3.29 (m, 0.5H), 2.92 − 3.10 (m, 2H), 2.76 (s, 2H), 2.22 − 2.35 (m, 0.5H), 2.13 (dt, J = 10.8, 6.5 Hz, 0.5H), 1.66 − 1.75 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.97 − 1.18 (m, 7H), 0.88 − 0.92 (m, 1.5H), 0.84 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 457.3 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE5を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.76 − 4.90 (m, 2H), 4.61 (d, J = 10.3 Hz, 0.5H), 4.27 − 4.42 (m, 1.5H), 4.09 − 4.23 (m, 1H), 3.34 − 3.70 (m, 6H), 2.93 − 3.11 (m, 3H), 2.76 (s, 2H), 2.20 − 2.33 (m, 2H), 1.67 − 1.75 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.07 − 1.17 (m, 2H), 0.98 − 1.05 (m, 5H), 0.88 − 0.92 (m, 1.5H), 0.83 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 450.4 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップE6を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.75 − 4.90 (m, 2H), 4.54 − 4.57 (m, 0.5H), 4.25 − 4.41 (m, 2H), 4.05 − 4.23 (m, 2.5H), 3.87 (d, J = 13.6 Hz, 0.5H), 3.58 (q, J = 6.9 Hz, 2H), 3.42 (t, J = 11.7 Hz, 1H), 2.90 − 3.11 (m, 2.5H), 2.76 (s, 2H), 2.07 − 2.33 (m, 1H), 1.66 − 1.75 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 1.20 − 1.28 (m, 3H), 0.97 − 1.19 (m, 7H), 0.79 − 0.93 (m, 3H). LC−MS : m/z 441.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.77 − 4.89 (m, 2H), 4.53 − 4.56 (m, 0.5H), 4.28 − 4.41 (m, 2H), 4.10 − 4.28 (m, 2.5H), 3.89 (d, J = 13.6 Hz, 0.5H), 3.58 − 3.60 (m, 0.5H), 3.31 − 3.49 (m, 2.5H), 2.92 − 3.12 (m, 2.5H), 2.70 − 2.84 (m, 2H), 2.10 − 2.31 (m, 1H), 1.65 − 1.77 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 0.95 − 1.17 (m, 8H), 0.79 − 0.92 (m, 3H), 0.50 − 0.64 (m, 2H), 0.18 − 0.31 (m, 2H). LC−MS : m/z 467.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.89 (m, 2H), 4.54 − 4.56 (m, 0.5H), 4.25 − 4.40 (m, 2H), 4.04 − 4.24 (m, 2.5H), 3.89 (d, J = 13.6 Hz, 0.5H), 3.36 − 3.62 (m, 3H), 2.89 − 3.10 (m, 2.5H), 2.72 − 2.81 (m, 2H), 2.08 − 2.30 (m, 1H), 1.60 − 1.70 (m, 3H), 1.31 (d, J = 2.5 Hz, 6H), 1.05 − 1.18 (m, 2H), 0.98 − 1.04 (m, 5H), 0.91 − 0.97 (m, 3H), 0.82 − 0.90 (m, 3H). LC−MS : m/z 455.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.79 − 4.91 (m, 2H), 4.55 − 4.57 (m, 0.5H), 4.11 − 4.40 (m, 5.5H), 3.76 − 3.97 (m, 4.5H), 3.44 (t, J = 12.5 Hz, 1H), 2.92 − 3.14 (m, 2.5H), 2.73 − 2.82 (m, 2H), 2.13 − 2.31 (m, 1H), 2.00 − 2.11 (m, 2H), 1.68 − 1.78 (m, 1H), 1.33 (d, J = 2.5 Hz, 6H), 1.08 − 1.19 (m, 2H), 0.98 − 1.07 (m, 5H), 0.83 − 0.95 (m, 3H). LC−MS : m/z 483.5 (M+H)+.
1H NMR (クロロホルム−d)δ7.43 (s, 1H), 6.30 − 6.49 (m, 2H), 4.76 − 4.91 (m, 2H), 4.48 − 4.67 (m, 2.5H), 4.08 − 4.38 (m, 4.5H), 3.76 (d, J = 13.3 Hz, 0.5H), 3.30 − 3.58 (m, 1H), 2.87 − 3.16 (m, 2.5H), 2.67 − 2.84 (m, 2H), 2.07 − 2.33 (m, 1H), 1.62 − 1.79 (m, 1H), 1.31 (d, J = 1.5 Hz, 6H), 1.06 − 1.18 (m, 2H), 0.93 − 1.06 (m, 5H), 0.80 − 0.90 (m, 3H). LC−MS : m/z 493.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.11 − 7.26 (m, 1H), 6.66 − 6.77 (m, 2.5H), 6.56 − 6.65 (m, 0.5H), 4.83 (s, 2H), 4.67 − 4.78 (m, 2H), 4.53 − 4.57 (m, 0.5H), 4.26 − 4.40 (m, 1.5H), 4.07 − 4.25 (m, 1H), 3.89 (d, J = 13.6 Hz, 0.5H), 3.51 − 3.60 (m, 0.5H), 3.42 − 3.49 (m, 0.5H), 2.86 − 3.14 (m, 2.5H), 2.76 (s, 2H), 2.05 − 2.23 (m, 1H), 1.64 − 1.78 (m, 1H), 1.31 (d, J = 3.5 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.83 − 0.95 (m, 1.5H), 0.76 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 507.4 (M+H)+.
1H NMR (クロロホルム−d)δ8.38 (br. s., 1H), 8.28 (br. s., 1H), 7.19 − 7.46 (m, 2H), 4.72 − 4.98 (m, 4H), 4.54 − 4.57 (m, 0.5H), 4.26 − 4.42 (m, 1.5H), 4.12 − 4.25 (m, 1H), 3.85 (d, J = 13.3 Hz, 0.5H), 3.45 − 3.62 (m, 1H), 2.90 − 3.17 (m, 2.5H), 2.72 − 2.82 (m, 2H), 2.09 − 2.35 (m, 1H), 1.66 − 1.76 (m, 1H), 1.32 (d, J = 3.8 Hz, 6H), 0.91 − 1.19 (m, 8.5H), 0.76 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 490.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.60 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 4.90 − 5.13 (m, 2H), 4.80 − 4.90 (m, 2H), 4.56 − 4.59 (m, 0.5H), 4.27 − 4.40 (m, 1.5H), 4.18 (d, J = 12.8 Hz, 1H), 3.82 (d, J = 13.3 Hz, 0.5H), 3.41 − 3.63 (m, 1H), 2.89 − 3.12 (m, 2.5H), 2.78 (s, 2H), 2.08 − 2.34 (m, 1H), 1.65 − 1.81 (m, 1H), 1.33 (d, J = 3.0 Hz, 6H), 0.96 − 1.19 (m, 7H), 0.88 − 0.95 (m, 1.5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 541.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.70 − 7.87 (m, 2H), 5.19 − 5.47 (m, 2H), 4.76 − 4.91 (m, 2H), 4.55 − 4.58 (m, 0.5H), 4.26 − 4.43 (m, 1.5H), 4.18 (t, J = 13.1 Hz, 1H), 3.84 (d, J = 13.6 Hz, 0.5H), 3.43 − 3.67 (m, 1H), 2.90 − 3.16 (m, 2.5H), 2.77 (s, 2H), 2.16 (td, J = 6.8, 3.5 Hz, 1H), 1.67 − 1.78 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 0.97 − 1.19 (m, 7H), 0.89 − 0.96 (m, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 464.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.62 − 7.74 (m, 2H), 5.32 − 5.50 (m, 2H), 4.75 − 4.91 (m, 2H), 4.56 − 4.59 (m, 0.5H), 4.32 (t, J = 11.3 Hz, 1.5H), 4.17 (d, J = 10.8 Hz, 1H), 3.69 (d, J = 13.8 Hz, 0.5H), 3.35 − 3.58 (m, 1H), 2.92 − 3.14 (m, 2.5H), 2.70 − 2.83 (m, 2H), 2.08 − 2.26 (m, 1H), 1.71 (dd, J = 7.5, 4.5 Hz, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.94 − 1.18 (m, 8.5H), 0.78 − 0.91 (m, 1.5H). LC−MS : m/z 464.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.62 (d, J = 7.8 Hz, 1H), 7.17 − 7.30 (m, 2H), 7.05 − 7.14 (m, 2H), 6.57 (br. s., 1H), 4.85 − 5.00 (m, 2H), 4.81 (br. s., 2H), 4.57 (d, J = 10.0 Hz, 0.5H), 4.34 (d, J = 10.0 Hz, 0.5H), 4.23 (dd, J = 18.9, 13.7 Hz, 1H), 4.13 (d, J = 12.5 Hz, 0.5H), 4.03 (d, J = 12.5 Hz, 0.5H), 3.63 (d, J = 13.6 Hz, 0.5H), 3.31 − 3.52 (m, 1H), 2.89 − 3.08 (m, 1.5H), 2.62 − 2.86 (m, 3H), 2.06 − 2.32 (m, 1H), 1.66 − 1.75 (m, 1H), 1.30 (d, J = 3.5 Hz, 6H), 0.91 − 1.16 (m, 8.5H), 0.82 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 512.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 − 7.38 (m, 2H), 4.79 − 5.11 (m, 4H), 4.55 − 4.58 (m, 0.5H), 4.23 − 4.39 (m, 1.5H), 4.15 (dd, J = 9.9, 7.7 Hz, 1H), 3.87 (d, J = 13.6 Hz, 0.5H), 3.58 − 4.61 (m, 0.5H), 3.35 − 3.52 (m, 0.5H), 2.83 − 3.12 (m, 2.5H), 2.71 − 2.82 (m, 2H), 2.04 − 2.15 (m, 4H), 1.66 − 1.75 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.96 − 1.16 (m, 7H), 0.85 − 0.93 (m, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 477.5 (M+H)+.
1H NMR (クロロホルム−d)δ7.42 (dd, J = 7.0, 2.3 Hz, 1H), 6.10 (t, J = 2.5 Hz, 1H), 4.76 − 5.15 (m, 3H), 4.55 − 4.58 (m, 0.5H), 4.29 (t, J = 14.3 Hz, 1.5H), 4.14 (t, J = 10.3 Hz, 1H), 3.85 (d, J = 13.6 Hz, 0.5H), 3.56 − 3.58 (m, 0.5H), 3.33 − 3.50 (m, 0.5H), 2.83 − 3.12 (m, 2.5H), 2.69 − 2.81 (m, 2H), 2.26 − 2.35 (m, 3H), 2.08 − 2.25 (m, 1H), 1.65 − 1.75 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.94 − 1.20 (m, 7H), 0.88 (d, J = 6.8 Hz, 1.5H), 0.81 (d, J = 6.8 Hz, 1.5H). LC−MS : m/z 477.5 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップF1を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.68 − 4.91 (m, 4H), 4.06 − 4.34 (m, 6H), 3.87 − 4.00 (m, 2H), 3.58 − 3.69 (m, 3H), 3.37 − 3.45 (m, 4H), 3.09 (t, J = 12.5 Hz, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.38 − 2.48 (m, 1H), 1.86 (d, J = 11.5 Hz, 2H), 1.77 (d, J = 9.0 Hz, 1H), 1.63 − 1.70 (m, 3H), 1.29 − 1.44 (m, 4H), 1.20 (t, J = 7.2 Hz, 3H). LC−MS : m/z 501.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.69 (s, 2H), 4.41 (br. s., 1H), 4.08 − 4.25 (m, 4H), 4.01 (d, J = 13.3 Hz, 1H), 3.93 (td, J = 5.8, 1.0 Hz, 2H), 3.18 − 3.40 (m, 2H), 3.05 (td, J = 12.4, 3.5 Hz, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.35 − 2.46 (m, 1H), 1.79 − 1.89 (m, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.54 − 1.70 (m, 4H), 1.31 − 1.41 (m, 2H), 1.30 (d, J = 3.0 Hz, 3H), 1.27 − 1.29 (m, 3H), 1.23 − 1.26 (m, 1H). LC−MS : m/z 413.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.69 (s, 2H), 4.41 (br. s., 1H), 3.97 − 4.25 (m, 5H), 3.88 − 3.96 (m, 2H), 3.20 − 3.41 (m, 2H), 3.06 (td, J = 12.4, 3.8 Hz, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.41 (tt, J = 10.9, 3.9 Hz, 1H), 1.84 (d, J = 12.8 Hz, 2H), 1.71 − 1.77 (m, 1H), 1.53 − 1.71 (m, 6H), 1.26 − 1.41 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H). LC−MS : m/z 427.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 − 7.43 (m, 6H), 5.11 − 5.22 (m, 2H), 4.63 − 4.73 (m, 2H), 4.45 (br. s., 1H), 4.09 − 4.27 (m, 2H), 4.04 (d, J = 13.3 Hz, 1H), 3.93 (td, J = 5.8, 1.0 Hz, 2H), 3.36 (td, J = 12.7, 3.3 Hz, 1H), 3.25 (dd, J = 13.1, 3.8 Hz, 1H), 3.05 (td, J = 12.4, 3.5 Hz, 1H), 2.91 (t, J = 5.8 Hz, 2H), 2.33 − 2.49 (m, 1H), 1.78 − 1.88 (m, 2H), 1.74 (d, J = 10.5 Hz, 1H), 1.48 − 1.70 (m, 6H), 1.25 − 1.40 (m, 7H). LC−MS : m/z 475.3 (M+H)+.
1H NMR (クロロホルム−d)δ7.04 − 7.16 (m, 2H), 6.86 − 6.98 (m, 2H), 4.74 (s, 2H), 3.92 − 4.03 (m, 2H), 3.82 (s, 5H), 3.69 − 3.79 (m, 6H), 2.97 (t, J = 5.6 Hz, 2H), 2.84 (dt, J = 13.3, 6.7 Hz, 1H), 1.22 (d, J = 6.5 Hz, 6H). LC−MS : m/z 437.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.74 − 4.90 (m, 2H), 4.20 − 4.33 (m, 3H), 4.14 (d, J = 12.0 Hz, 2H), 3.85 (br. s., 1H), 3.55 − 3.65 (m, 2H), 3.39 (s, 3H), 3.20 (d, J = 6.3 Hz, 1H), 2.97 − 3.11 (m, 2H), 2.76 (s, 2H), 2.12 (dt, J = 10.4, 6.6 Hz, 1H), 1.68 − 1.74 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 0.94 − 1.17 (m, 7H), 0.86 (d, J = 6.8 Hz, 3H). LC−MS : m/z 457.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.77 − 4.88 (m, 2H), 4.29 (d, J = 13.3 Hz, 1H), 4.14 (d, J = 13.3 Hz, 4H), 3.83 (br. s., 1H), 3.11 − 3.24 (m, 1H), 2.95 − 3.10 (m, 2H), 2.72 − 2.81 (m, 2H), 2.11 (dq, J = 17.1, 6.7 Hz, 1H), 1.65 − 1.73 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.27 (t, J = 7.0 Hz, 3H), 1.05 − 1.17 (m, 2H), 0.94 − 1.04 (m, 5H), 0.83 − 0.88 (m, 3H). LC−MS : m/z 427.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.77 − 4.89 (m, 2H), 4.29 (d, J = 13.1 Hz, 1H), 4.01 − 4.16 (m, 4H), 3.82 (br. s., 1H), 3.10 − 3.26 (m, 1H), 2.93 − 3.10 (m, 2H), 2.73 − 2.81 (m, 2H), 2.07 − 2.18 (m, 1H), 1.62 − 1.74 (m, 3H), 1.31 (d, J = 2.5 Hz, 6H), 1.05 − 1.19 (m, 2H), 0.93 − 1.03 (m, 8H), 0.82 − 0.89 (m, 3H). LC−MS : m/z 441.3 (M+H)+.
1H NMR (クロロホルム−d)δ6.98 − 7.05 (m, 2H), 6.84 − 6.91 (m, 2H), 4.78 − 4.89 (m, 2H), 4.35 (d, J = 13.6 Hz, 1H), 4.20 (d, J = 11.8 Hz, 2H), 3.91 − 4.03 (m, 1H), 3.80 (s, 3H), 3.40 (dt, J = 12.9, 6.7 Hz, 1H), 3.15 (d, J = 12.8 Hz, 2H), 2.77 (s, 2H), 2.18 − 2.27 (m, 1H), 1.68 − 1.77 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 1.09 − 1.22 (m, 2H), 0.92 − 1.06 (m, 8H). LC−MS : m/z 505.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.90 (m, 2H), 4.30 (d, J = 13.3 Hz, 1H), 4.15 (d, J = 12.5 Hz, 2H), 3.78 − 3.97 (m, 3H), 3.17 (d, J = 11.5 Hz, 1H), 2.97 − 3.10 (m, 2H), 2.76 (s, 2H), 2.12 (dt, J = 10.3, 6.7 Hz, 1H), 1.95 (dt, J = 13.3, 6.7 Hz, 1H), 1.66 − 1.74 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.07 − 1.18 (m, 2H), 0.92 − 1.03 (m, 11H), 0.86 (d, J = 6.8 Hz, 3H). LC−MS : m/z 455.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.87 (br. s., 1H), 4.68 − 4.84 (m, 3H), 4.12 − 4.29 (m, 2H), 3.92 − 4.12 (m, 2H), 3.69 − 3.82 (m, 3H), 3.48 − 3.68 (m, 1H), 3.35 (td, J = 13.6, 4.3 Hz, 1H), 3.00 − 3.14 (m, 1H), 2.75 − 2.88 (m, 3H), 1.29 (d, J = 3.5 Hz, 6H), 1.19 (td, J = 7.0, 4.0 Hz, 9H). LC−MS : m/z 477.1 (M+H)+.
1H NMR (クロロホルム−d)δ4.73 − 4.88 (m, 2H), 4.71 (d, J = 3.8 Hz, 2H), 4.14 − 4.39 (m, 4H), 3.97 − 4.13 (m, 2H), 3.50 − 3.69 (m, 3H), 3.42 (s, 1.5H), 3.31 − 3.37 (m, 1.5H), 3.08 (t, J = 12.2 Hz, 1H), 2.75 − 2.91 (m, 3H), 1.24 − 1.36 (m, 9H), 1.13 − 1.23 (m, 6H). LC−MS : m/z 489.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.72 − 4.92 (m, 2H), 4.71 (d, J = 3.5 Hz, 2H), 4.00 − 4.27 (m, 6H), 3.60 (d, J = 13.1 Hz, 1H), 3.28 − 3.47 (m, 1H), 3.08 (d, J = 11.5 Hz, 1H), 2.80 − 2.88 (m, 1H), 2.75 − 2.80 (m, 2H), 1.62 − 1.75 (m, 2H), 1.29 (d, J = 4.0 Hz, 7H), 1.14 − 1.22 (m, 10H). LC−MS : m/z 473.3 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップF2を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.75 − 4.91 (m, 2H), 4.30 (d, J = 12.5 Hz, 1H), 4.07 − 4.21 (m, 2H), 3.80 − 3.98 (m, 3H), 3.18 (br. s., 1H), 2.96 − 3.10 (m, 2H), 2.76 (s, 2H), 2.11 (dt, J = 10.4, 6.5 Hz, 1H), 1.67 − 1.73 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.07 − 1.20 (m, 3H), 0.94 − 1.05 (m, 5H), 0.87 (d, J = 6.8 Hz, 3H), 0.50 − 0.63 (m, 2H), 0.28 (q, J = 4.7 Hz, 2H). LC−MS : m/z 453.4 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップG1を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.32 (d, J = 7.5 Hz, 1H), 3.67 − 3.75 (m, 1H), 3.61 − 3.67 (m, 4H), 3.49 − 3.55 (m, 4H), 3.17 (quin, J = 6.7 Hz, 1H), 2.89 (d, J = 6.3 Hz, 2H), 2.64 (d, J = 6.0 Hz, 2H), 1.93 − 2.04 (m, 2H), 1.79 − 1.85 (m, 4H), 1.61 − 1.76 (m, 4H), 1.33 − 1.47 (m, 2H), 1.19 (d, J = 6.8 Hz, 6H), 1.08 − 1.17 (m, 2H). LC−MS : m/z 410.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.29 (d, J = 6.8 Hz, 1H), 4.17 (d, J = 12.5 Hz, 4H), 3.74 (br. s., 1H), 3.07 − 3.27 (m, 3H), 2.89 (br. s., 2H), 2.66 (br. s., 2H), 2.00 (d, J = 10.5 Hz, 2H), 1.71 (br. s., 7H), 1.34 − 1.49 (m, 8H), 1.08 − 1.26 (m, 9H). LC−MS : m/z 438.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.30 − 7.36 (m, 2H), 6.97 − 7.02 (m, 2H), 6.40 (s, 1H), 4.70 (s, 2H), 4.36 (dt, J = 6.5, 3.2 Hz, 1H), 4.13 − 4.31 (m, 2H), 3.85 − 4.01 (m, 3H), 3.31 − 3.51 (m, 2H), 3.17 (td, J = 12.3, 3.5 Hz, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.42 (tt, J = 11.1, 3.7 Hz, 1H), 1.80 − 1.88 (m, 2H), 1.76 (d, J = 10.8 Hz, 1H), 1.65 − 1.71 (m, 2H), 1.53 − 1.62 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.26 − 1.35 (m, 3H). LC−MS : m/z 478.2 (M+H)+.
1H NMR (クロロホルム−d)δ5.90 (ddt, J = 17.1, 10.5, 5.4 Hz, 1H), 5.23 (dq, J = 17.1, 1.6 Hz, 1H), 5.14 (dd, J = 10.3, 1.3 Hz, 1H), 4.99 (dd, J = 4.0, 2.3 Hz, 1H), 4.79 (dt, J = 13.6, 2.0 Hz, 1H), 4.65 − 4.74 (m, 3H), 4.22 − 4.30 (m, 1H), 3.86 − 4.19 (m, 6H), 3.64 − 3.75 (m, 1H), 3.50 − 3.60 (m, 1H), 3.37 (dd, J = 13.4, 4.4 Hz, 1H), 3.09 − 3.20 (m, 1H), 2.91 (t, J = 5.8 Hz, 2H), 2.35 − 2.45 (m, 1H), 1.84 (d, J = 12.0 Hz, 2H), 1.75 (d, J = 9.5 Hz, 1H), 1.64 − 1.72 (m, 2H), 1.54 − 1.60 (m, 1H), 1.28 − 1.41 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H). LC−MS : m/z 482.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.69 (s, 2H), 4.16 − 4.27 (m, 2H), 4.12 (d, J = 12.8 Hz, 1H), 3.88 − 3.97 (m, 2H), 3.81 (d, J = 12.5 Hz, 1H), 3.28 − 3.41 (m, 4H), 3.15 (br. s., 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.40 (tt, J = 11.1, 3.5 Hz, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.68 (br. s., 1H), 1.53 − 1.62 (m, 2H), 1.27 − 1.37 (m, 7H), 1.15 − 1.19 (m, 3H). LC−MS : m/z 412.2 (M+H)+.
1H NMR (クロロホルム−d)δ5.91 (ddt, J = 17.1, 10.4, 5.6 Hz, 1H), 5.09 − 5.25 (m, 2H), 4.69 (s, 2H), 4.51 (br. s., 1H), 4.17 − 4.26 (m, 2H), 4.13 (d, J = 13.1 Hz, 1H), 3.89 − 3.98 (m, 4H), 3.78 − 3.89 (m, 1H), 3.28 − 3.39 (m, 2H), 3.04 − 3.22 (m, 1H), 2.92 (t, J = 5.8 Hz, 2H), 2.40 (tt, J = 11.1, 3.7 Hz, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.63 − 1.70 (m, 3H), 1.52 − 1.63 (m, 2H), 1.32 − 1.42 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H). LC−MS : m/z 424.3 (M+H)+.
1H NMR (クロロホルム−d)δ8.07 − 8.16 (m, 1H), 6.93 − 7.16 (m, 3H), 6.63 (d, J = 3.8 Hz, 1H), 4.70 (s, 2H), 4.33 − 4.44 (m, 1H), 4.27 (d, J = 13.3 Hz, 1H), 4.17 (d, J = 13.1 Hz, 1H), 3.88 − 4.03 (m, 3H), 3.35 − 3.54 (m, 2H), 3.13 − 3.27 (m, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.34 − 2.49 (m, 1H), 1.85 (d, J = 12.5 Hz, 2H), 1.76 (d, J = 10.0 Hz, 1H), 1.54 − 1.64 (m, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.27 − 1.38 (m, 4H). LC−MS : m/z 477.9 (M+H)+.
1H NMR (クロロホルム−d)δ7.25 (s, 1H), 7.10 (d, J = 8.3 Hz, 2H), 6.34 (br. s., 1H), 4.70 (s, 2H), 4.36 (dd, J = 6.4, 3.1 Hz, 1H), 4.11 − 4.31 (m, 2H), 3.87 − 4.02 (m, 3H), 3.31 − 3.51 (m, 2H), 3.17 (td, J = 12.2, 3.5 Hz, 1H), 2.93 (t, J = 5.8 Hz, 2H), 2.41 (tt, J = 11.1, 3.6 Hz, 1H), 2.30 (s, 3H), 1.84 (d, J = 12.8 Hz, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.64 − 1.71 (m, 3H), 1.54 − 1.60 (m, 1H), 1.36 (d, J = 6.5 Hz, 3H), 1.26 − 1.34 (m, 3H). LC−MS : m/z 474.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.09 − 7.22 (m, 2H), 6.87 (d, J = 7.3 Hz, 1H), 6.32 (s, 1H), 4.70 (s, 2H), 4.37 (dt, J = 6.5, 3.2 Hz, 1H), 4.14 − 4.31 (m, 2H), 3.93 (td, J = 5.8, 1.3 Hz, 3H), 3.33 − 3.51 (m, 2H), 3.18 (td, J = 12.3, 3.8 Hz, 1H), 2.93 (t, J = 5.8 Hz, 2H), 2.37 − 2.47 (m, 1H), 2.33 (s, 3H), 1.85 (d, J = 12.5 Hz, 2H), 1.76 (d, J = 10.3 Hz, 1H), 1.60 − 1.72 (m, 4H), 1.37 (d, J = 6.8 Hz, 3H), 1.26 − 1.35 (m, 3H). LC−MS : m/z 474.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.27 (br. s., 1H), 7.25 (br. s., 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.35 (br. s., 1H), 4.70 (s, 2H), 4.35 (br. s., 1H), 4.10 − 4.31 (m, 2H), 3.87 − 4.00 (m, 3H), 3.79 (s, 3H), 3.31 − 3.50 (m, 2H), 3.18 (br. s., 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.37 − 2.46 (m, 1H), 1.84 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.69 (br. s., 1H), 1.54 − 1.63 (m, 2H), 1.36 (d, J = 6.5 Hz, 3H), 1.26 − 1.35 (m, 4H). LC−MS : m/z 490.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.72 (s, 2H), 4.31 (d, J = 7.8 Hz, 1H), 4.14 − 4.28 (m, 4H), 3.95 (t, J = 5.6 Hz, 2H), 3.72 (dtd, J = 10.7, 7.1, 3.6 Hz, 1H), 3.15 (dd, J = 12.7, 4.1 Hz, 2H), 2.89 − 3.02 (m, 3H), 1.94 − 2.04 (m, 2H), 1.77 − 1.93 (m, 7H), 1.60 − 1.76 (m, 5H), 1.40 (d, J = 6.8 Hz, 7H), 1.09 − 1.23 (m, 3H). LC−MS : m/z 466.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.67 − 4.75 (m, 2H), 4.28 (d, J = 12.8 Hz, 3H), 4.13 − 4.23 (m, 2H), 3.94 (t, J = 5.6 Hz, 2H), 3.63 − 3.84 (m, 1H), 3.17 (dd, J = 12.7, 4.1 Hz, 2H), 2.93 (t, J = 5.5 Hz, 2H), 2.81 (dt, J = 13.4, 6.7 Hz, 1H), 1.90 − 2.05 (m, 3H), 1.67 − 1.76 (m, 3H), 1.34 − 1.43 (m, 8H), 1.15 − 1.23 (m, 8H).. LC−MS : m/z 439.9 (M+H)+.
1H NMR (クロロホルム−d)δ4.72 (s, 2H), 4.34 (d, J = 7.3 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.64 − 3.85 (m, 5H), 3.54 (d, J = 5.0 Hz, 4H), 2.95 (t, J = 5.4 Hz, 2H), 2.82 (dt, J = 13.1, 6.4 Hz, 1H), 1.99 (d, J = 9.8 Hz, 2H), 1.70 − 1.77 (m, 2H), 1.31 − 1.50 (m, 3H), 1.27 (br. s., 1H), 1.08 − 1.24 (m, 8H). LC−MS : m/z 412.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.32 − 7.41 (m, 2H), 6.97 − 7.10 (m, 2H), 6.43 (s, 1H), 4.73 (s, 2H), 3.97 (t, J = 5.8 Hz, 2H), 3.74 − 3.81 (m, 4H), 3.64 − 3.73 (m, 4H), 2.96 (t, J = 5.6 Hz, 2H), 2.84 (dt, J = 13.3, 6.7 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H). LC−MS : m/z 424.3 (M+H)+.
1H NMR (クロロホルム−d)δ5.17 (br. s., 1H), 4.75 − 4.89 (m, 2H), 4.24 (d, J = 13.3 Hz, 1H), 4.08 − 4.20 (m, 3H), 3.94 (d, J = 11.0 Hz, 1H), 3.59 (br. s., 1H), 3.52 (br. s., 2H), 3.01 − 3.30 (m, 3H), 2.71 − 2.80 (m, 2H), 2.55 (br. s., 2H), 2.14 (m, 1H), 1.65 − 1.74 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.27 (t, J = 7.2 Hz, 3H), 0.94 − 1.18 (m, 7H), 0.81 − 0.91 (m, 3H). LC−MS : m/z 498.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.89 (m, 2H), 4.36 (br. s., 1H), 4.24 (d, J = 13.1 Hz, 1H), 4.12 (d, J = 11.5 Hz, 1H), 3.92 (d, J = 11.0 Hz, 1H), 3.58 − 3.76 (m, 1H), 3.30 (br. s., 2H), 3.22 (br. s., 1H), 3.03 − 3.19 (m, 2H), 2.70 − 2.82 (m, 2H), 2.09 − 2.19 (m, 1H), 1.66 − 1.74 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.07 − 1.20 (m, 5H), 0.95 − 1.04 (m, 5H), 0.89 (d, J = 6.5 Hz, 3H). LC−MS : m/z 426.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.89 (m, 2H), 4.38 (br. s., 1H), 4.24 (d, J = 13.3 Hz, 1H), 4.12 (d, J = 11.8 Hz, 1H), 3.91 (d, J = 12.5 Hz, 1H), 3.64 (d, J = 9.5 Hz, 1H), 3.04 − 3.32 (m, 5H), 2.75 (s, 2H), 2.08 − 2.20 (m, 1H), 1.66 − 1.73 (m, 1H), 1.48 − 1.56 (m, 2H), 1.28 − 1.37 (m, 10H), 1.05 − 1.17 (m, 2H), 0.95 − 1.02 (m, 5H), 0.85 − 0.93 (m, 6H). LC−MS : m/z 468.5 (M+H)+.
1H NMR (クロロホルム−d)δ7.22 − 7.40 (m, 5H), 4.76 − 4.91 (m, 2H), 4.69 (br. s., 1H), 4.45 (br. s., 2H), 4.24 (d, J = 13.1 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.94 (d, J = 11.8 Hz, 1H), 3.58 − 3.77 (m, 1H), 3.04 − 3.33 (m, 3H), 2.69 − 2.82 (m, 2H), 2.10 − 2.17 (m, 1H), 1.65 − 1.76 (m, 1H), 1.31 (d, J = 3.3 Hz, 6H), 1.05 − 1.17 (m, 2H), 0.93 − 1.02 (m, 5H), 0.83 − 0.93 (m, 3H). LC−MS : m/z 488.5 (M+H)+.
1H NMR (クロロホルム−d)δ7.22 − 7.36 (m, 2H), 6.91 − 7.07 (m, 2H), 6.44 (s, 1H), 4.73 − 4.92 (m, 2H), 4.29 (d, J = 13.3 Hz, 1H), 4.16 (d, J = 12.5 Hz, 1H), 4.00 (d, J = 12.5 Hz, 1H), 3.80 (d, J = 9.0 Hz, 1H), 3.31 (td, J = 12.5, 3.1 Hz, 1H), 3.07 − 3.24 (m, 2H), 2.76 (s, 2H), 2.18 − 2.29 (m, 1H), 1.67 − 1.74 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 1.05 − 1.18 (m, 2H), 0.98 − 1.04 (m, 5H), 0.94 (d, J = 6.8 Hz, 3H). LC−MS : m/z 492.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.74 − 4.89 (m, 2H), 4.24 (d, J = 13.3 Hz, 1H), 4.07 − 4.19 (m, 2H), 3.94 − 4.06 (m, 1H), 3.88 (d, J = 12.5 Hz, 1H), 3.58 − 3.72 (m, 1H), 3.03 − 3.28 (m, 3H), 2.70 − 2.80 (m, 2H), 2.09 − 2.18 (m, 1H), 1.65 − 1.73 (m, 1H), 1.31 (d, J = 1.8 Hz, 6H), 1.15 (dd, J = 6.4, 3.1 Hz, 6H), 1.07 − 1.13 (m, 2H), 0.94 − 1.03 (m, 5H), 0.83 − 0.92 (m, 3H). LC−MS : m/z 440.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.28 − 7.34 (m, 2H), 7.17 − 7.25 (m, 3H), 4.73 − 4.88 (m, 2H), 4.36 (br. s., 1H), 4.19 (d, J = 13.3 Hz, 1H), 4.08 (d, J = 11.5 Hz, 1H), 3.85 (d, J = 12.3 Hz, 1H), 3.44 − 3.59 (m, 3H), 3.01 − 3.21 (m, 3H), 2.84 (t, J = 6.8 Hz, 2H), 2.75 (s, 2H), 2.04 − 2.12 (m, 1H), 1.65 − 1.73 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.04 − 1.17 (m, 2H), 0.97 − 1.02 (m, 2H), 0.90 − 0.95 (m, 3H), 0.74 − 0.82 (m, 3H). LC−MS : m/z 502.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.44 − 7.63 (m, 4H), 6.78 (br. s., 1H), 4.74 − 4.91 (m, 2H), 4.30 (d, J = 13.3 Hz, 1H), 4.17 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 12.0 Hz, 1H), 3.84 (d, J = 8.3 Hz, 1H), 3.35 (t, J = 11.5 Hz, 1H), 3.05 − 3.24 (m, 2H), 2.76 (s, 2H), 2.20 − 2.32 (m, 1H), 1.63 − 1.76 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 1.07 − 1.15 (m, 2H), 0.99 − 1.05 (m, 5H), 0.93 (d, J = 6.8 Hz, 3H). LC−MS : m/z 499.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.20 − 7.26 (m, 2H), 6.80 − 6.86 (m, 2H), 6.29 (s, 1H), 4.75 − 4.90 (m, 2H), 4.28 (d, J = 13.3 Hz, 1H), 4.16 (d, J = 12.3 Hz, 1H), 3.99 (q, J = 6.9 Hz, 3H), 3.78 (d, J = 9.3 Hz, 1H), 3.29 (td, J = 12.5, 3.1 Hz, 1H), 3.09 − 3.23 (m, 2H), 2.73 − 2.80 (m, 2H), 2.16 − 2.23 (m, 1H), 1.67 − 1.73 (m, 1H), 1.37 − 1.43 (m, 3H), 1.31 (d, J = 2.5 Hz, 6H), 1.06 − 1.18 (m, 2H), 0.98 − 1.04 (m, 5H), 0.95 (d, J = 6.8 Hz, 3H). LC−MS : m/z 518.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.21 − 7.26 (m, J = 8.5 Hz, 2H), 7.03 − 7.15 (m, J = 8.0 Hz, 2H), 6.29 − 6.46 (m, 1H), 4.74 − 4.91 (m, 2H), 4.28 (d, J = 13.3 Hz, 1H), 4.11 − 4.20 (m, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.80 (d, J = 9.5 Hz, 1H), 3.29 (td, J = 12.5, 3.1 Hz, 1H), 3.08 − 3.22 (m, 2H), 2.76 (s, 2H), 2.29 (s, 3H), 2.16 − 2.23 (m, 1H), 1.66 − 1.72 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.07 − 1.18 (m, 2H), 0.98 − 1.03 (m, 5H), 0.94 (d, J = 6.8 Hz, 3H). LC−MS : m/z 488.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.25 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.30 (br. s., 1H), 4.75 − 4.89 (m, 2H), 4.28 (d, J = 13.1 Hz, 1H), 4.16 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 12.5 Hz, 1H), 3.78 (s, 4H), 3.25 − 3.35 (m, 1H), 3.09 − 3.24 (m, 2H), 2.72 − 2.81 (m, 2H), 2.18 − 2.26 (m, 1H), 1.67 − 1.76 (m, 1H), 1.31 (d, J = 2.0 Hz, 6H), 1.07 − 1.19 (m, 2H), 1.01 (d, J = 6.3 Hz, 5H), 0.95 (d, J = 6.8 Hz, 3H). LC−MS : m/z 503.9 (M+H)+.
1H NMR (クロロホルム−d)δ5.81 − 5.98 (m, 1H), 5.23 (dd, J = 17.1, 1.3 Hz, 1H), 5.14 (dd, J = 10.3, 1.3 Hz, 1H), 4.99 (br. s., 1H), 4.65 − 4.84 (m, 4H), 4.22 − 4.30 (m, 1H), 4.01 − 4.18 (m, 2H), 3.92 (t, J = 5.3 Hz, 2H), 3.63 − 3.77 (m, 1H), 3.56 (d, J = 11.3 Hz, 1H), 3.39 (dd, J = 13.4, 4.1 Hz, 1H), 3.09 − 3.22 (m, 1H), 2.75 − 2.87 (m, 3H), 1.29 (d, J = 2.8 Hz, 6H), 1.15 − 1.22 (m, 9H). LC−MS : m/z 470.4 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップG2を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.69 (s, 2H), 4.38 − 4.61 (m, 1H), 4.17 − 4.29 (m, 2H), 4.13 (d, J = 13.1 Hz, 1H), 3.89 − 4.00 (m, 2H), 3.77 − 3.87 (m, 1H), 3.20 − 3.40 (m, 2H), 3.04 − 3.19 (m, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.81 − 2.88 (m, 3H), 2.40 (tt, J = 11.0, 3.6 Hz, 1H), 1.84 (d, J = 12.8 Hz, 2H), 1.52 − 1.75 (m, 5H), 1.24 − 1.41 (m, 6H). LC−MS : m/z 398.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.70 (s, 3H), 4.10 − 4.28 (m, 3H), 4.07 (br. s., 2H), 3.89 − 3.97 (m, 2H), 3.84 (dt, J = 12.8, 2.9 Hz, 1H), 3.27 − 3.40 (m, 2H), 3.11 (td, J = 12.2, 3.6 Hz, 1H), 2.88 − 2.95 (m, 2H), 2.41 (tt, J = 11.1, 3.7 Hz, 1H), 2.25 (t, J = 2.5 Hz, 1H), 1.81 − 1.88 (m, 2H), 1.75 (d, J = 10.3 Hz, 1H), 1.63 − 1.71 (m, 2H), 1.52 − 1.63 (m, 2H), 1.27 − 1.44 (m, 6H). LC−MS : m/z 422.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.69 (s, 3H), 4.05 − 4.29 (m, 3H), 3.93 (td, J = 5.8, 1.3 Hz, 2H), 3.69 − 3.86 (m, 1H), 3.31 (td, J = 12.1, 3.4 Hz, 2H), 3.11 (br. s., 1H), 2.85 − 2.95 (m, 2H), 2.68 (dt, J = 7.0, 3.4 Hz, 1H), 2.33 − 2.46 (m, 1H), 1.80 − 1.87 (m, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.63 − 1.70 (m, 2H), 1.58 (d, J = 12.0 Hz, 2H), 1.29 − 1.41 (m, 3H), 1.28 (d, J = 6.5 Hz, 3H), 0.69 − 0.80 (m, 2H), 0.42 − 0.57 (m, 2H). LC−MS : m/z 424.4 (M+H)+.
1H NMR (クロロホルム−d)δ4.70 (s, 2H), 4.53 (br. s., 1H), 4.07 − 4.27 (m, 3H), 3.88 − 3.98 (m, 2H), 3.78 − 3.86 (m, 1H), 3.17 − 3.38 (m, 4H), 3.12 (t, J = 10.9 Hz, 1H), 2.92 (t, J = 5.6 Hz, 2H), 2.40 (tt, J = 11.0, 3.6 Hz, 1H), 1.80 − 1.88 (m, 2H), 1.75 (d, J = 10.5 Hz, 1H), 1.45 − 1.70 (m, 6H), 1.26 − 1.41 (m, 6H), 0.91 − 0.96 (m, 3H). LC−MS : m/z 426.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.75 − 4.90 (m, 2H), 4.45 (br. s., 1H), 4.23 (d, J = 13.3 Hz, 1H), 4.11 (d, J = 11.5 Hz, 1H), 3.92 (d, J = 12.8 Hz, 1H), 3.65 (d, J = 9.8 Hz, 1H), 3.03 − 3.31 (m, 3H), 2.83 (s, 3H), 2.75 (s, 2H), 2.09 − 2.22 (m, 1H), 1.66 − 1.74 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.88 (d, J = 6.8 Hz, 3H). LC−MS : m/z 412.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.72 − 4.90 (m, 2H), 4.55 (br. s., 1H), 4.25 (d, J = 13.3 Hz, 1H), 4.13 (d, J = 12.3 Hz, 1H), 4.05 (br. s., 2H), 3.93 (d, J = 12.8 Hz, 1H), 3.64 (d, J = 8.5 Hz, 1H), 3.18 − 3.33 (m, 1H), 3.02 − 3.18 (m, 2H), 2.76 (s, 2H), 2.20 − 2.28 (m, 1H), 2.15 (dt, J = 10.0, 6.7 Hz, 1H), 1.31 (d, J = 3.0 Hz, 6H), 0.97 − 1.06 (m, 6H), 0.84 − 0.96 (m, 4H). LC−MS : m/z 436.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.74 − 4.86 (m, 3H), 4.26 (d, J = 13.3 Hz, 1H), 4.13 (d, J = 12.3 Hz, 1H), 3.93 (d, J = 12.3 Hz, 1H), 3.65 (d, J = 8.8 Hz, 1H), 3.41 − 3.50 (m, 2H), 3.33 − 3.40 (m, 3H), 3.01 − 3.29 (m, 4H), 2.76 (s, 2H), 2.08 − 2.19 (m, 1H), 1.64 − 1.74 (m, 1H), 1.28 − 1.36 (m, 6H), 0.95 − 1.03 (m, 6H), 0.88 (d, J = 7.0 Hz, 4H). LC−MS : m/z 456.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.96 (br. s., 1H), 4.76 − 4.88 (m, 2H), 4.25 (d, J = 13.3 Hz, 1H), 4.12 (d, J = 12.0 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 3.61 − 3.79 (m, 3H), 3.43 (br. s., 2H), 3.18 − 3.31 (m, 1H), 3.03 − 3.18 (m, 2H), 2.70 − 2.81 (m, 2H), 2.12 − 2.23 (m, 1H), 1.66 − 1.74 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 1.07 − 1.18 (m, 2H), 0.95 − 1.05 (m, 5H), 0.89 (d, J = 6.8 Hz, 3H). LC−MS : m/z 442.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.88 (m, 2H), 4.29 (d, J = 13.3 Hz, 1H), 4.11 (d, J = 12.8 Hz, 1H), 3.49 − 3.71 (m, 2H), 3.37 (td, J = 12.6, 3.1 Hz, 1H), 3.16 (dd, J = 13.3, 3.5 Hz, 1H), 3.02 (td, J = 12.2, 3.4 Hz, 1H), 2.82 (s, 6H), 2.76 (s, 2H), 2.08 − 2.24 (m, 1H), 1.63 − 1.73 (m, 1H), 1.31 (s, 6H), 1.06 − 1.19 (m, 2H), 0.97 − 1.04 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). LC−MS : m/z 426.3 (M+H)+.
1H NMR (クロロホルム−d)δ4.74 − 4.92 (m, 2H), 4.47 (br. s., 1H), 4.25 (d, J = 13.3 Hz, 1H), 4.13 (d, J = 11.8 Hz, 1H), 3.93 (d, J = 12.8 Hz, 1H), 3.67 (d, J = 9.5 Hz, 1H), 3.03 − 3.28 (m, 5H), 2.69 − 2.80 (m, 2H), 2.08 − 2.18 (m, 1H), 1.82 (br. s., 1H), 1.66 − 1.74 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.06 − 1.19 (m, 2H), 0.94 − 1.02 (m, 5H), 0.85 − 0.93 (m, 3H), 0.43 − 0.55 (m, 2H), 0.19 (q, J = 4.8 Hz, 2H). LC−MS : m/z 452.2 (M+H)+.
1H NMR (クロロホルム−d)δ4.76 − 4.88 (m, 2H), 4.66 (br. s., 1H), 4.23 (d, J = 13.3 Hz, 1H), 4.11 (d, J = 11.5 Hz, 1H), 3.88 (d, J = 12.0 Hz, 1H), 3.54 − 3.75 (m, 1H), 2.97 − 3.25 (m, 3H), 2.75 (s, 2H), 2.66 (tt, J = 7.0, 3.6 Hz, 1H), 2.09 − 2.18 (m, 1H), 1.66 − 1.75 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 1.00 − 1.18 (m, 4H), 0.97 (d, J = 6.5 Hz, 3H), 0.82 − 0.90 (m, 3H), 0.69 − 0.78 (m, 2H), 0.42 − 0.54 (m, 2H). LC−MS : m/z 438.4 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップHを用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.70 (s, 2H), 4.09 − 4.25 (m, 3H), 3.94 (t, J = 5.9 Hz, 2H), 3.70 (d, J = 12.8 Hz, 1H), 3.43 (t, J = 12.0 Hz, 1H), 3.28 (d, J = 12.0 Hz, 1H), 3.14 (t, J = 10.8 Hz, 1H), 2.89 − 2.95 (m, 5H), 2.42 (t, J = 10.7 Hz, 1H), 1.84 (d, J = 12.3 Hz, 2H), 1.75 (d, J = 10.0 Hz, 1H), 1.68 (br. s., 1H), 1.59 (d, J = 12.3 Hz, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.28 − 1.37 (m, 4H). LC−MS : m/z 419.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.66 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.18 (t, J = 4.3 Hz, 1H), 4.71 (s, 2H), 3.94 (t, J = 5.6 Hz, 2H), 3.73 − 3.83 (m, 4H), 3.18 − 3.33 (m, 4H), 2.92 (t, J = 5.5 Hz, 2H), 2.81 (dt, J = 13.2, 6.6 Hz, 1H), 1.18 (d, J = 6.5 Hz, 6H). LC−MS : m/z 433.1 (M+H)+.
1H NMR (クロロホルム−d)δ7.58 (dd, J = 3.8, 1.3 Hz, 1H), 7.53 (dd, J = 5.0, 1.3 Hz, 1H), 7.04 (dd, J = 5.0, 3.8 Hz, 1H), 4.73 − 4.88 (m, 2H), 4.15 (d, J = 13.6 Hz, 1H), 3.86 − 4.03 (m, 2H), 3.61 − 3.73 (m, 1H), 3.37 − 3.50 (m, 1H), 2.99 (dd, J = 13.8, 4.0 Hz, 1H), 2.89 (td, J = 12.5, 3.8 Hz, 1H), 2.64 − 2.78 (m, 2H), 2.04 − 2.15 (m, 1H), 1.64 − 1.72 (m, 1H), 1.30 (d, J = 6.3 Hz, 6H), 0.92 − 1.12 (m, 10H). LC−MS : m/z 501.2 (M+H)+.
1H NMR (クロロホルム−d)δ7.72 (d, J = 8.3 Hz, 2H), 7.19 − 7.31 (m, 2H), 4.71 − 4.87 (m, 2H), 4.05 − 4.18 (m, 1H), 3.79 − 3.95 (m, 2H), 3.63 (dt, J = 9.7, 3.0 Hz, 1H), 3.29 − 3.45 (m, 1H), 2.96 (dd, J = 13.7, 3.9 Hz, 1H), 2.73 − 2.85 (m, 1H), 2.70 (d, J = 3.3 Hz, 2H), 2.40 (s, 3H), 2.07 (dq, J = 9.8, 6.7 Hz, 1H), 1.65 − 1.71 (m, 1H), 1.29 (d, J = 7.8 Hz, 6H), 1.05 − 1.13 (m, 1H), 0.97 − 1.04 (m, 3H), 0.94 (d, J = 6.5 Hz, 6H). LC−MS : m/z 509.0 (M+H)+.
1H NMR (クロロホルム−d)δ7.35 (d, J = 4.0 Hz, 1H), 6.86 (d, J = 4.0 Hz, 1H), 4.74 − 4.89 (m, 2H), 4.05 − 4.16 (m, 1H), 3.97 (dt, J = 12.8, 1.6 Hz, 1H), 3.79 − 3.91 (m, 1H), 3.64 (dt, J = 9.3, 3.5 Hz, 1H), 3.37 − 3.49 (m, 1H), 3.12 (dd, J = 13.8, 4.0 Hz, 1H), 3.00 (td, J = 12.5, 4.0 Hz, 1H), 2.66 − 2.81 (m, 2H), 2.06 − 2.15 (m, 1H), 1.64 − 1.72 (m, 1H), 1.30 (d, J = 8.5 Hz, 6H), 1.08 − 1.16 (m, 1H), 1.00 − 1.07 (m, 3H), 0.97 (d, J = 3.0 Hz, 3H), 0.97 (d, J = 10.5 Hz, 3H). LC−MS : m/z 535.0 (M+H)+.
1H NMR (クロロホルム−d)δ4.77 − 4.90 (m, 2H), 4.22 − 4.33 (m, 1H), 4.04 − 4.14 (m, 1H), 3.80 (dt, J = 14.3, 1.6 Hz, 1H), 3.56 (d, J = 10.3 Hz, 1H), 3.32 − 3.44 (m, 1H), 3.09 − 3.19 (m, 2H), 2.90 − 2.98 (m, 3H), 2.76 (s, 2H), 2.14 − 2.20 (m, 1H), 1.68 − 1.76 (m, 1H), 1.32 (d, J = 3.8 Hz, 6H), 1.01 − 1.17 (m, 4H), 0.97 (d, J = 3.8 Hz, 3H), 0.99 (d, J = 4.0 Hz, 3H). LC−MS : m/z 433.4 (M+H)+.
1H NMR (クロロホルム−d)δ7.60 (ddd, J = 9.3, 4.3, 1.4 Hz, 2H), 7.10 (dd, J = 5.0, 3.8 Hz, 1H), 4.72 (s, 2H), 4.27 − 4.41 (m, 1H), 4.16 (d, J = 12.8 Hz, 1H), 4.06 (dd, J = 13.2, 2.1 Hz, 1H), 3.77 − 3.89 (m, 1H), 3.45 (td, J = 12.3, 3.3 Hz, 1H), 3.28 (dd, J = 13.1, 3.5 Hz, 1H), 3.14 (td, J = 12.3, 3.5 Hz, 1H), 2.85 (quin, J = 6.7 Hz, 1H), 2.78 (s, 2H), 1.31 (d, J = 3.0 Hz, 6H), 1.26 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 4.0 Hz, 3H), 1.21 (d, J = 4.0 Hz, 3H). LC−MS : m/z 475.2 (M+H)+.
適切なピラノピリジン(pyraonpyridine)及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップI1−1を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.76 − 4.88 (m, 2H), 4.13 (dd, J = 12.8, 2.3 Hz, 1H), 3.97 − 4.07 (m, 1H), 3.45 − 3.62 (m, 2H), 3.36 (s, 3H), 3.12 − 3.24 (m, 1H), 2.98 − 3.10 (m, 2H), 2.89 (t, J = 11.3 Hz, 1H), 2.75 (s, 2H), 2.51 (dd, J = 11.5, 8.0 Hz, 2H), 2.28 − 2.37 (m, 1H), 2.12 − 2.25 (m, 1H), 1.64 − 1.72 (m, 1H), 1.30 (s, 6H), 1.09 − 1.17 (m, 2H), 1.01 − 1.06 (m, 3H), 0.96 − 1.00 (m, 2H), 0.93 (d, J = 7.0 Hz, 3H). LC−MS : m/z 413.3 (M+H)+.
適切なピラノピリジン及び置換ピペラジン中間体を使用して、本発明の以下の化合物を、スキーム2のステップI2を用いて作製した化合物と同等の方法で作製した。
1H NMR (クロロホルム−d)δ4.70 (s, 2H), 4.09 − 4.24 (m, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.68 − 3.83 (m, 3H), 3.45 − 3.59 (m, 1H), 3.39 (br. s., 2H), 3.07 (br. s., 1H), 2.73 − 3.02 (m, 5H), 2.41 (tt, J = 11.1, 3.6 Hz, 1H), 1.86 (d, J = 12.5 Hz, 2H), 1.76 (d, J = 10.0 Hz, 1H), 1.70 (br. s., 1H), 1.54 − 1.64 (m, 2H), 1.29 − 1.42 (m, 4H), 1.10 − 1.24 (m, 3H). LC−MS : m/z 412.6 (M+H)+.
76μlアッセイ緩衝液(150mM NaCl、10mM MgCl2、20mMトリス pH7.5、0.03%ウシ血清アルブミン)の量で、標準的な384ウェルプレートにおいて以下のとおりアッセイを実施した。25ulの基質混合物(8uM NADPH、2mM aKG)に対し、DMSO中、1μlの試験化合物を添加した。プレートを短時間遠心し、次に25μlの酵素混合物を添加し(0.2μg/ml IDH1 R132H)、続いて短時間遠心し、100RPMで振盪した。反応物を室温で50分間インキュベートし、次に25μlの検出混合物(30μMレサズリン、36μg/ml)を添加し、混合物を室温で5分間、さらにインキュベートした。Ex544 Em590 c/o590での蛍光分光法により、レサズリンからレゾルフィンへの変換を検出した。
T125フラスコにおいて、10%FBS、1×ペニシリン/ストレプトマイシン及び500ug/mLのG418を含有するDMEM中で細胞(例えば、HT1080またはU87MG)を成長させる。トリプシンにより細胞を回収し、10%FBS含有DMEM中100ul/ウェルにおいて5000細胞/ウェルの密度で96ウェル白色底面プレートに播種する。カラム1及び12には細胞を播かない。細胞を5%CO2において37Cで一晩インキュベートする。翌日、化合物を2×濃度で構成し、各細胞ウェルに100ulを添加する。DMSOの終濃度は0.2%であり、DMSO対照ウェルは列Gに播く。次にプレートをインキュベーターに48時間置く。48時間目に各ウェルから100ulの培地を抜き取り、LC−MSにより2−HG濃度を分析する。細胞プレートをインキュベーターに戻し、さらに24時間置く。化合物の添加後72時間目に、10mL/プレートのPromega Cell Titer Glo試薬を解凍して混合する。細胞プレートをインキュベーターから取り出し、室温に平衡化させる。次に培地の各ウェルに100ulの試薬を添加する。次に細胞プレートをオービタルシェーカーに10分間置き、次に室温で20分間静置する。次にプレートの積分時間500msでのルミネセンスを読み取る。
以下の5に例示するコア1の合成:
ステップA1:5−(シクロプロパンカルボニル)−2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オン(2)
撹拌子を備えた500mLの三つ口丸底フラスコに、2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オン(6g、46.8mmol)及び120mLの乾燥トルエンを装入した。溶液を窒素パージし、0℃に冷却した。撹拌しながら、LDAの溶液(THF/n−ヘプタン中2M溶液、24.5mL、15.6mmol)を滴下して添加し、反応混合物の撹拌を0℃で5分間継続させた後、シクロプロパンカルボニルクロリド(2.8mL、31.2mmol)を添加した。0℃でさらに20分間撹拌した後、pHが7を上回るまで、反応混合物を1NのHClでクエンチした。H2Oと塩化メチレンに分配した後、次に有機層をブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。フラッシュカラムクロマトグラフィー(10%酢酸エチル/石油エーテル)により、6gの粗製の表題化合物を帯黄色の油として得て、これを次のステップにさらなる精製なしに直接使用した。MS(ES)M+H 予測値197.1、実測値197.3。
70mLのEtOH中の5−(シクロプロパンカルボニル)−2,2−ジメチルジヒドロ−2H−ピラン−4(3H)−オン(2)(6g、30.6mmol)及び2−シアノアセトアミド(4.1g、49.0mmol)の溶液に、ジエチルアミン(2.1mL、20.4mmol)を添加した。LC−MSによって生成物が完全に形成されたことが示されるまで、反応混合物を室温で72時間撹拌した。次に反応混合物を還流温度に加熱し、その間、十分なEtOHを添加して清澄な溶液とした。再び室温に冷却した後、EtOH溶液から生成物を析出させ、真空ろ過及び風乾後、白色固体として3.3gの表題化合物を得た。MS(ES)M+H 予測値245.1、実測値245。1H NMR (クロロホルム−d) δ 4.74 (s, 2H), 2.82 (s, 2H), 1.68 − 1.78 (m, 1H), 1.34 (s, 6H), 1.30 − 1.32 (m, 2H), 1.24 − 1.26 (m, 2H)
250mLの丸底フラスコに、8−シクロプロピル−6−ヒドロキシ−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(3)(3.7g、15.16mmol)、DMAP(185mg、1.52mmol)、トリエチルアミン(2.74mL、19.7mmol)及び150mLの塩化メチレンを装入した。反応混合物をドライアイス−アセトン浴で0℃に冷却した後、トリフルオロメタンスルホン酸無水物(3.3mL、19.7mmol)をシリンジで滴下して添加した。得られた混合物を0℃で30分間撹拌した後、室温まで加温させてさらに2時間撹拌した。TLCによって出発物質が生成物に完全に変換されたことが示された後、反応混合物を真空濃縮し、フラッシュカラムクロマトグラフィー(1:10酢酸エチル/石油エーテル)により精製することで、4.9gの表題化合物を白色固体として得た。1H NMR (クロロホルム−d) δ 4.91 (s, 2H), 2.88 (s, 2H), 1.73 − 1.84 (m, 1H), 1.34 (s, 6H), 1.23 − 1.27 (m, 2H), 1.17 − 1.22 (m, 2H)
封管に、2mLのEtOH中の5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イルトリフルオロメタン−スルホネート(600mg、1.60mmol)、(R)−2−イソプロピルピペラジン(170mg、1.33mmol)、及びトリエチルアミン(0.24mL、1.73mmol)を装入した。反応混合物を還流温度で一晩加熱した。それを減圧濃縮した後、反応混合物をフラッシュカラムクロマトグラフィー(1:10メタノール/塩化メチレン)により精製することで、428mgの表題化合物を得た。MS(ES)M+H 予測値355.2、実測値355.2。1H NMR (クロロホルム−d) δ 4.84 (s, 2H), 4.33 (d, J = 13.1 Hz, 1H), 4.19 (d, J = 14.3 Hz, 1H), 3.47 − 3.55 (m, 1H), 3.35 − 3.47 (m, 1H), 2.94 − 3.21 (m, 3H), 2.77 (s, 2H), 1.98 − 2.14 (m, 1H), 1.64 − 1.77 (m, 1H), 1.31 (s, 6H), 1.14 − 1.21 (m, 3H), 1.08 − 1.14 (m, 5H), 0.98 − 1.07 (m, 2H)
ステップB:エチル4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−1−(2−(チオフェン−2−イル)アセチル)ピペラジン−2−カルボキシレート
化合物番号421
5mLのアンバーガラスバイアルに、エチル4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)ピペラジン−2−カルボキシレート(31mg、0.08mmol)、2−(チオフェン−2−イル)酢酸(48mg、0.34mmol)、EDCI(68.8mg、0.36mmol)、HOBt(48.6mg、0.36mmol)、トリエチルアミン(36.8mg、0.36mmol)及び1mLの塩化メチレンを添加した。得られた反応混合物を室温で一晩撹拌した。混合物を1NのHCl水溶液でクエンチし、EtOAcで3回抽出した。混合有機層を飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC分離(DCM:アセトン/70:1)により精製することで、21mgの表題化合物を白色固体として得た。MS(ES)M+H 予測値509.2、実測値509.3。1H NMR (クロロホルム−d) δ: 7.22 − 7.26 (m, 1H), 6.89 − 7.01 (m, 2H), 5.24 − 5.38 (m, 0.5H), 4.79 − 4.89 (m, 2H), 4.61 − 4.73 (m, 1H), 4.00 − 4.28 (m, 4.5H), 3.74 − 3.93 (m, 2H), 3.19 − 3.29 (m, 1H), 2.92 − 3.05 (m, 1H), 2.72 − 2.85 (m, 2H), 1.68 − 1.78 (m, 1H), 1.29 − 1.36 (m, 6H), 1.12 − 1.23 (m, 5H), 0.99 − 1.08 (m, 2H)
化合物番号440
15mLの塩化メチレン中の(R)−8−シクロプロピル−6−(3−シクロプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(250mg、0.7mmol)の溶液に、トリエチルアミン(0.2mL、1.4mmol)及びメチル3−クロロ−3−オキソプロパノエート(191mg、1.4mmol)を添加した。得られた反応混合物を室温で一晩撹拌させた。反応混合物をDCMで希釈し、次にブラインで洗浄した。有機層を無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC分離(DCM/アセトン:70:1)により精製することで、200mgの表題化合物を黄色の油として得た。1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.62 − 4.65 (m, 0.5H), 4.26 (d, J = 13.1 Hz, 1H), 4.16 (d, J = 12.5 Hz, 1H), 4.03 (d, J = 9.3 Hz, 0.5H), 3.71 − 3.85 (m, 3.5H), 3.60 − 3.70 (m, 0.5H), 2.93 − 3.58 (m, 5H), 2.78 (s, 2H), 1.66 − 1.75 (m, 1H), 1.36 − 1.44 (m, 1H), 1.32 (d, J = 3.0 Hz, 6H), 1.13 (t, J = 3.6 Hz, 2H), 0.97 − 1.07 (m, 2H), 0.31 − 0.64 (m, 4H)
LC−MS : m/z 453.2 (M+H)+
構成要素1:(R)−2−イソプロピルピペラジンの合成
ステップD:(R)−2−イソプロピルピペラジン
フラスコに、THF(5mL)中の(R)−3−イソプロピルピペラジン−2,5−ジオン(154mg、1mmol)を添加し、LAH(THF中2.5M溶液)(2.5mL、6mmol)をN2下0℃で滴下して添加した。得られた混合物を65℃に加熱し、一晩撹拌させた。次に反応混合物を室温に冷却し、続いて0.23mLのH2O、0.23mLの10%NaOH及び0.46mLのH2Oを添加した。反応混合物をろ過し、ケークをEtOAcで洗浄した。有機相を濃縮することで、粗生成物を固体として得た(86mg)。1H NMR (クロロホルム−d) δ 0.91 (d, 3H, J = 6.8 Hz), 0.93 (d, 3H, J = 6.6 Hz), 1.48−1.57 (m, 1H), 1.75 (br, 2H), 2.31〜2.45 (m, 2H), 2.67−2.83 (m, 2H), 2.90 (d, 1H, J = 11.5 Hz), 2.99−3.02 (m, 2H)
ステップ1:水(1250ml)中の(R)−6−シクロプロピル−2−(4−(3−メトキシプロパノイル)−3−メチルピペラジン−1−イル)−5−(2−ビニルキナゾリン−5−イル)ニコチノニトリル(100g、0.87mol)の溶液に、NaHCO3(175g、2.08mol)を室温で添加し、続いてTHF(1250mL)中(Boc)2Oの溶液を添加した。得られた反応混合物を一晩加熱還流した。一晩撹拌した後、減圧下で反応混合物を濃縮してTHFを除去した。EtOAc(1250mL)を残渣に添加し、得られた混合物を5℃に冷却し、次にNaHSO4飽和水溶液でpH3に調整した。層を分離し、水層をEtOAcで抽出した(1000mL×3)。混合EtOAc層を水及びブラインで洗浄し、Na2SO4で乾燥して減圧濃縮することで、(R)−2−(tert−ブトキシカルボニルアミノ)−2−シクロプロピル酢酸(165g、収率88%、ee>99%)を得た。1H NMR (MeOD 400MHz) δ 3.16−3.14 (d, J = 8.8, 1H), 1.11 (s, 9H), 0.73−0.78 (m, 1H), 0.28−0.2 (m, 3H), 0.18−0.15 (m, 1H)
ステップF1:2−シクロプロピルピラジン
20mL無水THF中の2−クロロピラジン(1.14g、10mmol)及び50mg Fe(acac)3の溶液に、−40℃で1分間かけてシクロプロピルマグネシウムクロリド(10mL、1M)を添加した。次に溶液を−40℃で0.5時間撹拌し、0℃に加温した。THFを減圧除去し、100mLの水及び100mLのEAを添加した。EA層を水(2回)及びブラインで洗浄することで、フラッシュカラムクロマトグラフィー(EA:PE=1:10)による精製後、生成物(0.8g)を得た。1H NMR (クロロホルム−d) δ 8.48 (d, J = 2.5 Hz, 1H), 8.37 (br. s., 1H), 8.29 (t, J = 3.0 Hz, 1H), 2.05 (dt, J = 6.2, 3.0 Hz, 1H), 0.95 − 1.19 (m, 4H).
50mLメタノール中の2−シクロプロピルピラジン(0.8g)の溶液に、5mLのAcOH及び50mgのPd/Cを添加した。反応混合物をH2(60psi)下室温で一晩撹拌した。混合物をろ過し、ろ液を濃縮乾固して生成物(0.85g)を得て、これをさらなる精製なしに使用した。1H NMR (DMSO) δ: 3.53 (dd, J = 13.9, 3.1 Hz, 1H), 3.32 − 3.48 (m, 2H), 2.99 − 3.18 (m, 3H), 2.38 − 2.62 (m, 1H), 0.73 − 0.89 (m, 1H), 0.50 − 0.63 (m, 2H), 0.23 − 0.42 (m, 2H)
ステップG1:2−(tert−ブトキシカルボニルアミノ)−4,4,4−トリフルオロブタン酸
5mLのH2O及び5mLのTHF中の2−アミノ−4,4,4−トリフルオロブタン酸(450mg、3mmol)の溶液に、NaHCO3(504mg、mmol)を添加し、続いてTHF(3mL)中のジ−tert−ブチルジカーボネート(650mg、3mmol)の溶液を添加した。得られた混合物を80℃で一晩撹拌した。THFを除去した後、混合物を水に注入し、塩化メチレンで抽出した。混合有機層を無水Na2SO4で乾燥して真空濃縮した。723mgの表題化合物を粗生成物として得て、続く反応でさらなる精製なしに使用した。MS(ES)M+H 予測値201.1、実測値201.3。1H NMR (クロロホルム−d) δ 5.25 (d, J = 7.8 Hz, 1H), 4.40 − 4.67 (m, 1H), 2.60 − 2.90 (m, 2H), 1.46 (s, 9H).
25mLの丸底フラスコに、5mL塩化メチレン中の2−(tert−ブトキシカルボニルアミノ)−4,4,4−トリフルオロブタン酸(723mg、2.8mmol)、Et3N(560mg、5.6mmol)、イソブチルカルボノクロリダート(380mg、2.8mmol)を添加した。得られた反応混合物を0℃で0.5時間撹拌した。次にメチル2−アミノアセテート(352mg、2.8mmol)を添加し、得られた混合物を室温で一晩撹拌した。飽和NaHCO3、ブラインで洗浄した後、混合有機層を無水Na2SO4で乾燥して真空濃縮した。900mgの表題化合物を粗生成物として得て、続く反応でさらなる精製なしに使用した。MS(ES)M+H 予測値272.1、実測値272.0。1H NMR (クロロホルム−d) δ 7.11 (br. s., 1H), 5.28 (br. s., 1H), 4.44 − 4.67 (m, 1H), 3.84 − 4.07 (m, 2H), 3.69 − 3.83 (s, 3H), 2.72 − 2.95 (m, 1H), 2.42 − 2.64 (m, 1H), 1.38 − 1.50 (m, 9H)
5mLの1,2−ジクロロベンゼン中のメチル2−(2−(tert−ブトキシカルボニルアミノ)−4,4,4−トリフルオロブタンアミド)アセテート(900mg、2.7mmol)の混合物を、一晩180℃に加熱した。混合物を冷却してMTBE(5mL)を添加した。帯黄褐色の沈殿物が形成された。ろ過ケークをMTBEで洗浄して風乾することで、200mgの表題化合物を得た。1H NMR (DMSO−d6) δ 8.28 (d, J = 9.3 Hz, 2H), 4.00 − 4.26 (m, 1H), 3.68 − 3.87 (m, 2H), 2.66 − 2.88 (m, 2H).
フラスコに、THF(5mL)中の3−(2,2,2−トリフルオロエチル)ピペラジン−2,5−ジオン(200mg、1mmol)を添加し、LAH(2.5mL、6mmol、(THF中2.5M溶液))をN2下0℃で滴下して添加し、次に混合物を一晩65℃に加熱した。反応の完了後、混合物を冷却し、0.23mLのH2Oを添加し、続いて0.23mLの10%NaOH及び0.46mLのH2Oを添加した。混合物をろ過し、ケークをEtOAcで洗浄した。有機相を濃縮することで、粗生成物(140mg固体)を得た。1H NMR (クロロホルム−d) δ 2.75 − 3.02 (m, 7H), 2.52 (dd, J = 11.7, 9.9 Hz, 1H), 2.10 − 2.17 (m, 2H).
Hidaka,Hiroyoshi;欧州特許出願公開第1074545号明細書;(2001);(A1)に記載される手順による
0597ステップH1:1,4−ビス(tert−ブトキシカルボニル)ピペラジン−2−カルボン酸
室温のNa2CO3(40g、380mmol、200mLの水中)の水溶液に、ピペラジン−2−カルボン酸二塩酸塩(10g、50mmol)を添加し、続いてテトラヒドロフラン(200mL)中のジ−tert−ブチルジカーボネート(41g、183mmol)を添加した。反応混合物を室温で20時間撹拌し、次に揮発分を減圧除去した。次に得られた混合物をジエチルエーテル(100mL)で抽出した。水層を、それが弱酸性(pH=4)になるまで3.0M HClで処理し、次に酢酸エチル(150mL)で抽出した。有機層をブラインで洗浄し、無水Na2SO4で乾燥し、ろ過し、濃縮して、16gの表題化合物を白色固体として得た。1H NMR (クロロホルム−d) δ 12.9 (1 H, s), , 2.70−4.50 (m, 7H), 1.33 (m, 18H).
表題化合物を、ステップH1に記載される方法により(S)−ピペラジン−2−カルボン酸二塩酸塩から調製した。
10mLのDMF中の(S)−1,4−ビス(tert−ブトキシカルボニル)ピペラジン−2−カルボン酸(0.5g、1.38mmol)の混合物に、K2CO3(0.6g、4.4mmol)を添加した。得られた懸濁液を0℃に冷却し、ブロモエタン(1mL、9.34mmol)で処理した。反応混合物を室温に加温させて、24時間撹拌した。水(10mL)でクエンチした後、混合物を酢酸エチル(20mL)で抽出し、有機層をブラインで洗浄し、無水Na2SO4で乾燥し、ろ過し、真空濃縮することで、0.48gの表題化合物を白色固体として得て、これを次のステップにさらなる精製なしに直接使用した。
室温のメタノール(4mL)中の(S)−1,4−ジ−tert−ブチル2−エチルピペラジン−1,2,4−トリカルボキシレート(1.2g、4.5mmol)の溶液に、HCl溶液(5mL、EtOAc中4.0M)を添加した。反応混合物を室温で一晩撹拌し、次に濃縮することで、1gの2−(メトキシメチル)ピペラジンを塩酸塩として得て、これを次のステップでさらなる精製なしに使用した。1H NMR (クロロホルム−d) δ 4.18 (m, 2H), 3.43 (dd, 1H), 3.13 (dd, 1H), 2.96 (m, 1H), 2.70 (m, 4H), 1.27 (t, 3H).
ステップI:2−(ジフルオロメチル)ピペラジン
40mLのEtOH中の1,4−ジベンジル−2−(ジフルオロメチル)ピペラジン(Synthetic Communications,2011,vol.41,#14 p.2031−2035に記載される手順により合成した)(80mg、0.253mmol)の溶液に、Pd(OH)2/C(15mg)を添加した。得られた混合物を50Psi下室温で2日間水素化した。反応混合物をろ過し、ろ液を濃縮して、表題化合物を得た(これをさらなる精製なしに直接使用した)。1H NMR (クロロホルム−d) δ 5.67 (td, 1H), 2.62−3.13 (m, 7H).
ステップJ1:6−フルオロ−2−メチル−1,4−ジトシル−1,4−ジアゼパン
2−メチル−1,4−ジトシル−1,4−ジアゼパン−6−オール、及び6−フルオロ−2−メチル−1,4−ジトシル−1,4−ジアゼパンを、Synthesis 2003,2,p.223−226に記載される手順に従い調製した。1H NMR (クロロホルム−d) δ 7.62 − 7.75 (m, 4H), 7.30 − 7.37 (m, 4H), 5.00−4.84(m, 1H), 4.09 − 4.37 (m, 2H), 3.73 − 3.95 (m, 1H), 3.37 − 3.62 (m, 2H), 3.12 − 3.32 (m, 1H), 3.05 (ddd, J = 13.6, 7.2, 4.0 Hz, 1H), 2.43 − 2.46 (m, 6H), 1.05 − 1.14 (m, 3H)
HOAc−HBr(3mL、30wt%)中の6−フルオロ−2−メチル−1,4−ジトシル−1,4−ジアゼパン(84mg、0.19mmol)の懸濁液を、圧力管においてマイクロ波照射を用いて100℃に3分間加熱した。溶媒を真空除去し、残渣をEt2Oと共に粉砕し、Et2Oで洗浄して表題化合物を得て、これをさらなる精製なしに直接使用した。
ステップK1:(R)−2−(tert−ブトキシカルボニルアミノ)−2,3,4,4,4−ペンタジュウテリオ−3−(トリジュウテリオメチル)ブタン酸
水(6.4mL)中のD−バリン(d8)(500mg、4.27mmol)の溶液に、NaHCO3(717mg、8.53mmol)を添加し、続いてTHF(6.4mL)中のジ−tert−ブチルジカーボネート(932mg)の溶液を添加した。混合物を撹拌し、還流させながら16時間加熱し、次に真空濃縮してTHFを除去した。次にEtOAc(4.5mL)を添加し、混合物を10℃に冷却し、次にNaHSO4飽和水溶液(3.3mL)でpH3に調整した。層を分離し、水層をEtOAc(4mL×3)で抽出した。混合EtOAc層を水(2mL×1)及びブラインで洗浄し、MgSO4で乾燥して真空濃縮することで、所望の化合物(924mg、99%)を得た。
1H NMR (クロロホルム−d) δ: 5.00 (br. s., 1H), 1.45 (s, 9H)
5℃のCH2Cl2(12.3mL)中の(R)−2−(tert−ブトキシカルボニルアミノ)−2,3,4,4,4−ペンタジュウテリオ−3−(トリジュウテリオメチル)ブタン酸(924g、4.25mol)及びEt3N(430mg、4.25mmol)の撹拌混合物に、イソブチルクロロホルメート(580mg、4.25mmol)を30分かけて添加した。添加が完了したところで混合物を0〜5℃で30分間撹拌した。別のフラスコにおいて、グリシンメチルエステル塩酸塩(534mg、4.25mmol)、Et3N(430mg、4.25mmol)、及びCH2Cl2(12.3mL)の混合物を30分間撹拌し、次にこの混合物を上記の混合物に0.5時間かけて添加した。添加の完了後、混合物を室温で16時間撹拌し、次に水(3×15mL)及びブラインで洗浄し、乾燥させて真空濃縮することで、生成物(1.12g、91%)を得た。
1,2−ジクロロベンゼン(9mL)中の(R)−メチル2−(2−(tert−ブトキシカルボニルアミノ)−2,3,4,4,4−ペンタジュウテリオ−3−(トリジュウテリオメチル)ブタン−アミノ)アセテート(999mg、3.46mmol)の溶液を175〜180℃で18時間加熱し、形成されたMeOHを全て留去させた。大気圧で窒素流を用いて6mLの溶媒を留去した後、混合物を50℃に冷却し、MTBE(5mL)を慎重に添加した。混合物を室温に冷却してろ過した。得られた固体をMTBE(0.2mL)で洗浄し、100℃で真空乾燥することで、生成物(320mg、59%)を得た。1H NMR (DMSO−d6) δ: 8.18 (br. s., 1H), 8.01 (br. s., 1H), 3.81 (d, J = 17.8 Hz, 1H), 3.61 (dd, J = 17.8, 3.0 Hz, 1H)
乾燥THF(5mL)中の(R)−3−ジュウテリオ−3−(ペルジュウテリオプロパン−2−イル)ピペラジン−2,5−ジオン(160mg、1mmol)の溶液に、LiAlH4(228mg、6mmol)を添加した。混合物を還流させながら12時間撹拌した。0℃に冷却した後、水(0.5mL)を慎重に添加し、混合物を室温で30分間撹拌した。固体をろ去し、ろ液を真空濃縮することで生成物を得て(120mg、88%)、これを次のステップにさらなる精製なしに直接使用した。
表題化合物を、ステップK4に記載される方法により、LiAlD4と共に(R)−3−ジュウテリオ−3−(ペルジュウテリオプロパン−2−イル)ピペラジン−2,5−ジオンから調製した。
表題化合物を、ステップK2に記載される方法により、グリシンメチルエステル塩酸塩(d2)と共に(R)−2−(tert−ブトキシカルボニルアミノ)−2,3,4,4,4−ペンタジュウテリオ−3−(トリジュウテリオメチル)ブタン酸から調製した。
表題化合物を、ステップK3に記載される方法により、(R)−メチル2−(2−(tert−ブトキシカルボニルアミノ)−2,3,4,4,4−ペンタジュウテリオ−3−(トリジュウテリオメチル)ブタン−アミド)−2,2−ジジュウテリオアセテートから調製した。
表題化合物を、ステップK4に記載される方法により、(R)−3,3,6−トリジュウテリオ−6−(ペルジュウテリオプロパン−2−イル)ピペラジン−2,5−ジオンから調製した。
表題化合物を、ステップK4に記載される方法により、LiAlD4と共に(R)−3,3,6−トリジュウテリオ−6−(ペルジュウテリオプロパン−2−イル)ピペラジン−2,5−ジオンから調製した。
ステップL1:メチル2−(オキセタン−3−イリデン)アセテート
米国特許出願公開第20100075983号明細書に記載される手順により表題化合物を合成した。1H NMR (400 MHz, CDCl3) δ = 5.66 (dd, J = 4.7, 2.3 Hz, 1H), 5.51 (dd, J = 6.5, 2.9 Hz, 2H), 5.31 (dt, J = 5.2, 2.7 Hz, 2H), 3.72 (s, 3H).
メタノール(25mL)中のメチル2−(オキセタン−3−イリデン)アセテート(641.0mg、5mmol)の溶液に、室温で25mgのPd/C(10%)を添加し、得られた混合物をH2雰囲気下で一晩撹拌した。セライトパッドでPd/Cを除去した後、残渣を減圧乾燥し、次に溶離液として酢酸エチル/石油エーテル(1:1、V/V)を使用したシリカゲル上でのカラムクロマトグラフィーに供することで、淡黄色の液体を得た。収率:586.1mg(90.1%)。1H NMR (400 MHz, CDCl3) δ = 4.94 − 4.78 (m, 2H), 4.42 (t, J = 6.3 Hz, 2H), 3.67 (s, 3H), 3.44 − 3.29 (m, 1H), 2.74 (d, J = 7.9 Hz, 2H).
テトラヒドロフラン(10mL)及び水(3mL)の混合物中のメチル2−(オキセタン−3−イル)アセテート(130.1mg、1.00mmol)の溶液に、水酸化リチウム一水和物(44.1mg、1.05mmol)を、ドライアイス−アセトン浴を使用して−10℃で添加した。得られた溶液を室温に加温させて一晩撹拌した。テトラヒドロフラン及び水を除去した後、得られた白色固体をいかなるさらなる精製もなしに次の反応ステップで直接使用した。収率:121.4mg(99.5%)。1H NMR (400 MHz, D2O) δ 4.83 − 4.73 (m, 1H), 4.33 (t, J = 6.4 Hz, 1H), 4.33 (t, J = 6.4 Hz, 1H), 3.18 (dt, J = 14.7, 7.3 Hz, 1H), 2.48 (d, J = 8.0 Hz, 1H).
ステップM1:((ブタ−3−エン−1−イルオキシ)メチル)ベンゼン
3−ブテン−1−オール(5.00g)、トリエチルアミン(0.46g)、水酸化ナトリウム(4.10g)及びヘキサン(50mL)の混合物を50℃で0.5時間撹拌し、次に臭化ベンジル(12.9g)を混合物に60℃未満で滴下して添加した。混合物を還流状態に加温させて3時間還流した。混合物を氷冷した水に注ぎ、混合物をヘキサンで抽出した。有機層を水、ブラインで洗浄し、Na2SO4で乾燥して真空濃縮した。シリカゲル上でのクロマトグラフィー(石油エーテルから石油エーテル:酢酸エチル=10:1)により残渣を精製することで、表題化合物を油として得た(6g)。1H NMR (CHLOROFORM− δ) d: 7.30 − 7.43 (m, 5H), 5.78 − 5.95 (m, 1H), 5.03 − 5.19 (m, 2H), 4.56 (s, 2H), 3.57 (t, J = 6.8 Hz, 2H), 2.42 (qt, J = 6.7, 1.3 Hz, 2H)
トルエン(200mL)中の[(ブタ−3−エン−1−イルオキシ)メチル]ベンゼン(10.6g)の溶液に、氷冷下でm−クロロ過安息香酸を水と共に(69〜75%、20.0g)添加し、次に混合物を室温に加温させた。室温で18時間撹拌した後、混合物をろ過した。ろ液をヘキサンで希釈し、5%重炭酸ナトリウム水溶液(200mL)、3%重炭酸ナトリウム水溶液(200mL)、水(200mL)、ブライン中のチオ硫酸ナトリウム五水和物(8.1g)の溶液で洗浄し、Na2SO4で乾燥して真空濃縮した。残渣をシリカゲル上でのクロマトグラフィー(ヘキサン:酢酸エチル=20:1から4:1)により精製することで、表題化合物を油として得た(10.2g)。1H NMR (クロロホルム−d) δ: 7.31 − 7.42 (m, 5H), 4.56 (s, 2H), 3.60 − 3.69 (m, 2H), 3.10 (td, J = 4.5, 1.9 Hz, 1H), 2.77 − 2.85 (m, 1H), 2.56 (dd, J = 5.0, 2.8 Hz, 1H), 1.88 − 2.00 (m, 1H), 1.74 − 1.86 (m, 1H)
米国特許出願公開第2010/94000号明細書を参照のこと。
乾燥t−BuOH(13mL)中のKOBu−t(1.12g、10mmol)及びヨウ化トリメチルオキソスルホニウム(2.2g、10mmol)の混合物を、50℃で1時間、磁気撹拌した。次に、乾燥t−BuOH(10mL)中の2−(2−(ベンジルオキシ)エチル)オキシラン(0.9g、5mmol)の溶液を滴下して添加し、3日間撹拌した。溶媒を慎重に減圧除去し、残留懸濁液に水(30mL)を添加した。混合物をn−ヘキサンで抽出し、無水MgSO4で乾燥して濃縮し、粗生成物を得て、これをカラムクロマトグラフィーにより精製することで、生成物を無色の油として得た(0.4g)。1H NMR (クロロホルム−d) δ: 7.29 − 7.45 (m, 5H), 5.03 (dd, J = 7.2, 5.6 Hz, 1H), 4.70 (td, J = 8.0, 5.8 Hz, 1H), 4.47 − 4.61 (m, 3H), 3.48 − 3.63 (m, 2H), 2.64 − 2.77 (m, 1H), 2.35 − 2.49 (m, 1H), 2.09 − 2.22 (m, 1H), 1.93 − 2.09 (m, 1H)
Journal of Organic Chemistry,2000,67(26),9488−9491を参照のこと。
MeOH(15mL)中の2−(2−(ベンジルオキシ)エチル)オキセタン(0.3g、14.2mmol)の溶液に、10%Pd/C(20mg)を添加した。反応混合物を水素でパージし、水素雰囲気下で2日間撹拌した。黒色の懸濁液をセライトプラグに通過させてMeOHで溶出し、次に有機層を濃縮することで、所望の生成物を無色の油として得た(0.10g、62%)。1H NMR (クロロホルム−d) d: 5.12 (qd, J = 7.3, 4.6 Hz, 1H), 4.72 (td, J = 8.0, 6.0 Hz, 1H), 4.60 (dt, J = 9.1, 6.0 Hz, 1H), 3.88 (ddd, J = 11.0, 7.0, 4.5 Hz, 1H), 3.79 (ddd, J = 11.0, 6.7, 4.6 Hz, 1H), 2.66 − 2.80 (m, 1H), 2.56 (br. s., 1H), 2.40 − 2.52 (m, 1H), 2.07 (dtd, J = 14.4, 7.2, 4.5 Hz, 1H), 1.93 (ddt, J = 14.4, 7.2, 4.5 Hz, 1H).
硫酸(1mL)及び水(3mL)を、氷冷しながら水(3mL)中の酸化クロム(VI)の溶液に連続的に添加した。この溶液を、氷冷して内部温度を20℃未満に保ちながらアセトン(10mL)中の2−ヒドロキシメチルオキセタン(40mg)の溶液に滴下して添加し、混合物を室温で2時間撹拌した。次に2−プロパノールを添加して反応をクエンチし、この溶液を酢酸エチルで希釈してセライトでろ過した。ろ液をブラインで洗浄し、水層を酢酸エチルで2回抽出した。有機層を共に合わせて無水硫酸マグネシウムで乾燥した後、溶媒を蒸発させて生成物を得て、これをさらなる精製なしに次のステップに使用した(30mg)。1H NMR (400 MHz, methanol−d4) δ 5.26 ‐ 5.15 (m, 1H), 4.69 (ddd, J = 8.3, 7.8, 5.9 Hz, 1H), 4.58 (dt, J = 9.2, 5.9 Hz, 1H), 2.88 ‐ 2.70 (m, 3H), 2.51 (ddt, J = 11.2, 9.1, 7.3 Hz, 1H).
ステップN:2−(メトキシカルボニルアミノ)酢酸
H2O(1mL)中の2−アミノ酢酸(2.0g、26.2mmol)の溶液に、メチルカルボノクロリダート(1.6g、16.6mmol)及びNaOH(2.6mL、10Nを部分量ずつ添加した。15分後、連続的に撹拌しながらNa2CO3(1.3g)を添加した。次に、4mLの濃塩酸で溶液を酸性化し、酢酸エチルで抽出し、Na2SO4で乾燥して濃縮した。残渣を酢酸エチルで希釈し、室温で一晩撹拌した。混合物をろ過して331mgの白色固体を得て、これを次のステップにさらなる精製なしに直接使用した。
化合物番号422
(R)−3−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−N−メチル−3−オキソプロパンアミド
NH3/MeOH(1.5mL、1M)中の(R)−メチル3−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−シクロプロピルピペラジン−1−イル)−3−オキソプロパノエート(40mg、0.09mmol)の溶液を30℃で一晩撹拌した。次に、反応混合物を濃縮し、分取TLC分離(DCM/メタノール:20:1)により精製することで、33mgの表題化合物を無色の油として得た。1H NMR (クロロホルム−d) δ 7.68 (br. s., 0.5H), 7.50 (br. s., 0.5H), 4.76 − 4.91 (m, 2H), 4.53 − 4.71 (m, 0.5H), 4.26 − 4.46 (m, 1.5H), 4.17 (d, J = 11.5 Hz, 1H), 3.88 (d, J = 13.8 Hz, 0.5H), 3.61 (d, J = 10.5 Hz, 0.5H), 3.27 − 3.53 (m, 2.5H), 2.90 − 3.15 (m, 2.5H), 2.80 − 2.87 (m, 3H), 2.77 (s, 2H), 2.05 − 2.35 (m, 1H), 1.66 − 1.78 (m, 1H), 1.32 (d, J = 3.0 Hz, 6H), 0.95 − 1.16 (m, 7H), 0.75 − 0.92 (m, 3H)
LC−MS : m/z 454.4 (M+H)+
(R)−8−シクロプロピル−6−(4−(3−ヒドロキシプロパノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル
10mLのテトラヒドロフラン中の(R)−メチル3−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−シクロプロピルピペラジン−1−イル)−3−オキソプロパノエート(43mg、0.09mmol)及びNaBH4(7mg、0.18mmol)の溶液に、BF3.OEt2(0.02mL、0.18mmol)を滴下して添加した。次に、混合物を室温で一晩撹拌した。溶液を水及びブラインで洗浄した。有機層を無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC(DCM/アセトン:70:1)により精製することで、14mgの表題化合物を無色の油として得た。1H NMR (クロロホルム−d) δ 4.77 − 4.91 (m, 2H), 4.64 (d, J = 10.0 Hz, 0.5H), 4.28 − 4.46 (m, 1.5H), 4.10 − 4.26 (m, 1H), 3.90 (br. s., 2H), 3.63 − 3.83 (m, 1H), 3.37 − 3.54 (m, 1H), 2.91 − 3.11 (m, 2H), 2.72 − 2.88 (m, 2H), 2.56 − 2.66 (m, 2H), 2.11 − 2.36 (m, 1H), 1.67 − 1.77 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.78 − 0.93 (m, 3H)
LC−MS : m/z 427.1 (M+H)+
(R)−8−シクロプロピル−6−(4−(3−フルオロプロパノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル
乾燥DCM(10mL)中の(R)−8−シクロプロピル−6−(4−(3−ヒドロキシプロパノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(106mg、0.4mmol)の溶液に、−78℃でDASTを添加した。混合物をこの温度で2時間撹拌し、次に水(0.5mL)でクエンチした。有機相を1N HCl(2×5mL)、ブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC(PE/EA:5:1)により精製することで、75mgの表題化合物を無色の油として得た。1H NMR (クロロホルム−d) δ 4.80 − 4.93 (m, 3H), 4.71 − 4.80 (m, 1H), 4.66 (d, J = 10.3 Hz, 0.5H), 4.41 (d, J = 10.3 Hz, 0.5H), 4.33 (d, J = 13.6 Hz, 1H), 4.12 − 4.25 (m, 1H), 3.75 (d, J = 13.6 Hz, 0.5H), 3.39 − 3.52 (m, 1H), 2.96 − 3.08 (m, 2H), 2.95 (s, 0.5H), 2.81 − 2.87 (m, 1H), 2.62 − 2.81 (m, 3H), 2.20 − 2.35 (m, 0.5H), 2.05 − 2.20 (m, 0.5H), 1.66 − 1.76 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 1.08 − 1.18 (m, 2H), 0.95 − 1.06 (m, 5H), 0.89 (d, J = 6.8 Hz, 2H), 0.82 (d, J = 6.8 Hz, 2H)
LC−MS : m/z 429.5 (M+H)
(R)−エチル−4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−4−オキソブタノエート
20mLの塩化メチレン中の(R)−8−シクロプロピル−6−(3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(500mg、1.4mmol)の溶液に、トリエチルアミン(0.4mL、2.8mmol)及びメチル4−クロロ−4−オキソブタノエート(0.35mL、2.8mmol)を添加した。得られた反応混合物を室温で一晩撹拌した。反応混合物をDCMで希釈し、次にブラインで洗浄した。有機層を無水Na2SO4で乾燥して真空濃縮した。粗生成物をフラッシュカラムクロマトグラフィー(DCM/アセトン:70:1)により精製することで、368mgの(R)−メチル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−4−オキソブタノエートを淡黄色の油として得た。H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.28 − 4.50 (m, 2H), 4.02 − 4.28 (m, 1H), 3.70 − 3.84 (m, 3H), 3.40 − 3.70 (m, 4H), 2.91 − 3.18 (m, 2H), 2.76 (s, 2H), 2.05 − 2.32 (m, 1H), 1.61 − 1.81 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 0.95 − 1.18 (m, 7H), 0.78 − 0.95 (m, 3H)
LC−MS:m/z 455.2(M+H)+
(R)−6−(4−(3−(1,3,4−オキサジアゾル−2−イル)プロパノイル)−3−イソプロピルピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル
5mLの無水エタノール中の(R)−メチル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−4−オキソブタノエート(40mg、0.1mmol)の溶液に、ヒドラジン水和物(10mg、0.2mmol)を添加した。得られた混合物を4時間加熱還流した。TLCによって反応の完了が示された後、混合物を減圧蒸発させた。得られた残渣、オルトギ酸トリメチル(11mg)、4−メチルベンゼンスルホン酸(5mg)及びMeOH(5mL)の混合物を還流させながら一晩加熱した。LC−MSによって反応の完了が示された後、混合物を蒸発させた。分取TLC分離(DCM/アセトン:70:1)により残渣を精製することで、表題化合物を得た。1H NMR (400 MHz, CHLOROFORM−d) δ 8.34 (d, J = 4.2 Hz, 1 H) , 4.83 (s, 2 H) , 4.62 (d, J = 10.2 Hz, 0.5 H), 4.27 − 4.39 (m, 1.5 H), 4.11 − 4.23 (m, 1 H) , 3.78 (d, J = 14.6 Hz, 0.5 H) , 3.43 − 3.55 (m, 1 H), 3.27 (t, J = 7.2 Hz, 2 H) , 2.98 − 3.07 (m, 2 H), 2.89 − 2.98 (m, 2.5 H) , 2.77 (s, 2 H) , 2.12 (m, 1 H) , 1.65 − 1.75 (m, 1 H), 1.32 (d, J = 2.6 Hz, 6 H) , 0.96 − 1.04 (m, 6 H), 0.87 − 0.93 (m, 2 H) , 0.79 (d, J = 6.8 Hz, 2 H)
LC−MS: m/z 479.3 (M+H)+
8−シクロプロピル−6−((R)−4−((1R,2R)−2−(ヒドロキシメチル)シクロプロパンカルボニル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル
MeOH/THF(5mL/5mL)中のトランス−メチル2−((R)−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−カルボニル)シクロプロパンカルボキシレート(120mg、0.4mmol)の溶液に、LiBH4(53mg,2.4mmol)をいくつかの部分量ずつ添加した。混合物を室温で2時間撹拌した。水(0.5mL)を添加して反応をクエンチし、次にEA(20mL)を添加した。有機相を水、ブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC(PE/EA:2:1)により精製することで、66mgの表題化合物を無色の油として得た。1H NMR (クロロホルム−d) δ 4.69 − 4.97 (m, 2H), 4.58 (d, J = 10.0 Hz, 0.5H), 4.27 − 4.47 (m, 1.5H), 4.00 − 4.27 (m, 1.5H), 3.61 − 3.91 (m, 1.5H), 3.35 − 3.61 (m, 1.5H), 2.89 − 3.18 (m, 2.5H), 2.78 (d, J = 17.3 Hz, 2H), 2.27 (ddd, J = 13.2, 6.7, 3.4 Hz, 0.5H), 2.12 (dt, J = 6.7, 3.3 Hz, 0.5H), 1.62 − 1.92 (m, 2H), 1.19 − 1.38 (m, 6H), 0.96 − 1.17 (m, 7H), 0.69 − 0.96 (m, 4H)
LC−MS : m/z 453.6 (M+H)+
((1R,2R)−2−((R)−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−カルボニル)シクロプロピル)メチルメチルカーボネート
DMF(4mL)中の8−シクロプロピル−6−((R)−4−((1R,2R)−2−(ヒドロキシメチル)シクロプロパンカルボニル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(100mg、0.22mmol)の溶液に、0℃でNaH(16.3mg、65%、0.44mmol)を添加した。混合物を0℃で30分間撹拌した。炭酸ジメチル(30mg、0.33mmol)を添加した。得られた混合物を室温で2時間撹拌した。水(20mL)を慎重に添加して反応をクエンチした。水相をDCM(3×10mL)で抽出した。混合有機相を水、ブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取TLC(PE/EA:3:1)により精製することで、30mgの表題化合物を無色の油として得た。1H NMR (クロロホルム−d) δ 4.74 − 4.94 (m, 2H), 4.57 (dd, J = 10.2, 4.4 Hz, 0.5H), 4.13 − 4.42 (m, 4H), 3.84 − 4.01 (m, 1H), 3.74 − 3.84 (m, 3.5H), 3.38 − 3.61 (m, 0.5H), 2.92 − 3.13 (m, 2.5H), 2.77 (s, 2H), 2.27 (dt, J = 10.7, 5.5 Hz, 0.5H), 2.13 (dt, J = 10.5, 6.5 Hz, 0.5H), 1.65 − 1.93 (m, 4H), 1.32 (d, J = 2.5 Hz, 6H), 0.97 − 1.19 (m, 7H), 0.76 − 0.94 (m, 4H)
LC−MS : m/z 511.6 (M+H)
エチル4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−1−(2−(チオフェン−2−イル)アセチル)ピペラジン−2−カルボキシレート
1H NMR (クロロホルム−d) d: 7.22 − 7.26 (m, 1H), 6.89 − 7.01 (m, 2H), 5.24 − 5.38 (m, 0.5H), 4.79 − 4.89 (m, 2H), 4.61 − 4.73 (m, 1H), 4.00 − 4.28 (m, 4.5H), 3.74 − 3.93 (m, 2H), 3.19 − 3.29 (m, 1H), 2.92 − 3.05 (m, 1H), 2.72 − 2.85 (m, 2H), 1.68 − 1.78 (m, 1H), 1.29 − 1.36 (m, 6H), 1.12 − 1.23 (m, 5H), 0.99 − 1.08 (m, 2H)
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.91 (m, 2H), 4.65 − 4.68 (m, 0.5H), 4.42 (d, J = 10.5 Hz, 0.5H), 4.34 (d, J = 13.6 Hz, 1H), 4.12 − 4.27 (m, 1H), 3.61 − 3.75 (m, 0.5H), 3.44 − 3.60 (m, 0.5H), 3.14 − 3.43 (m, 2.5H), 2.94 − 3.10 (m, 2.5H), 2.77 (s, 2H), 2.14 (dq, J = 17.2, 6.7 Hz, 1H), 1.67 − 1.75 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.96 − 1.18 (m, 7H), 0.77 − 0.92 (m, 3H)
LC−MS : m/z 465.2 (M+H)+
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(4−メトキシブタノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.75 − 4.90 (m, 2H), 4.64 − 4.66 (m, 0.5H), 4.40 (d, J = 10.3 Hz, 0.5H), 4.33 (d, J = 13.6 Hz, 1H), 4.07 − 4.25 (m, 1H), 3.78 (d, J = 13.6 Hz, 0.5H), 3.38 − 3.57 (m, 3H), 3.34 (s, 3H), 2.89 − 3.07 (m, 2.5H), 2.69 − 2.82 (m, 2H), 2.35 − 2.54 (m, 2H), 2.10 − 2.31 (m, 1H), 1.87 − 2.04 (m, 2H), 1.66 − 1.75 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 0.96 − 1.16 (m, 7H), 0.75 − 0.92 (m, 3H)
LC−MS : m/z 455.2 (M+H)+
8−シクロプロピル−6−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素3、ステップB)
1H NMR (クロロホルム−d) δ 4.78 − 4.91 (m, 2H), 4.25 (d, J = 12.8 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 3.69 − 4.10 (m, 4H), 3.61 − 3.75 (m, 3H), 2.50 − 3.24 (m, 7H), 1.67 − 1.76 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 1H), 1.09 − 1.17 (m, 2H), 0.96 − 1.05 (m, 2H), 0.29 − 0.64 (m, 4H)
LC−MS : m/z 439.2 (M+H)+
8−シクロプロピル−6−(3−シクロプロピル−4−(フラン−3−カルボニル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素3、ステップB)
1H NMR (クロロホルム−d) δ 7.64 − 7.77 (m, 1H), 7.37 − 7.50 (m, 1H), 6.55 (s, 1H), 4.84 (s, 2H), 4.14 − 4.30 (m, 3H), 3.67 − 4.00 (m, 21H), 3.15 (dd, J = 12.8, 3.5 Hz, 1H), 2.98 (td, J = 12.5, 3.3 Hz, 1H), 2.78 (s, 2H), 1.67 − 1.79 (m, 1H), 1.41 − 1.57 (m, 1H), 1.32 (d, J = 2.3 Hz, 6H), 1.10 − 1.19 (m, 2H), 0.95 − 1.06 (m, 2H), 0.60 (td, J = 8.5, 3.8 Hz, 1H), 0.42 − 0.54 (m, 1H), 0.38 (br. s., 1H)
LC−MS : m/z 447.2 (M+H)+
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(イソオキサゾール−3−カルボニル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 8.48 (d, J = 1.5 Hz, 1 H), 6.69 (d, J = 1.5 Hz, 1 H) , 4.83 (s, 2 H), 4.68 (d, J = 13.0 Hz, 0.5 H) , 4.33 − 4.53 (m, 2 H), 4.12 − 4.32 (m, 1.5 H) ,3.53 (td, J = 12.9, 3.2 Hz, 0.5 H) ,3.01 − 3.22 (m, 2.5 H) ,2.77 (d, J = 3.0 Hz, 2 H), 2.16 − 2.36 (m, 1 H), 1.64 − 1.77 (m, 1 H) ,1.32 (s, 6 H), 1.04 − 1.15 (m, 3 H), 1.02 (dd, J = 7.9, 2.6 Hz, 2 H) ,0.93 (t, J = 6.4 Hz, 3 H), 0.81 (d, J = 6.7 Hz, 2 H)
LC−MS: m/z 450.2 (M+H)+
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(4−オキソペンタノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 4.75 − 4.89 (m, 2 H) ,4.46 − 4.69 (m, 0.5 H), 4.24 − 4.40 (m, 2 H), 4.06 − 4.23 (m, 1 H), 3.81 (d, J = 13.8 Hz, 0.5 H), 3.52 − 3.60 (m, 0.5 H), 3.37 − 3.51 (m, 1 H), 2.89 − 3.12 (m, 2.5 H), 2.79 − 2.84 (m, 2 H), 2.76 (s, 2 H), 2.55 − 2.71 (m, 2 H), 2.23 (s, 3 H), 1.64 − 1.77 (m, 1 H), 1.27 − 1.37 (s, 6 H), 1.06 − 1.19 (m, 2 H), 0.94 − 1.05 (m, 4 H), 0.85 − 0.94 (m, 2 H), 0.80 (d, J = 6.8 Hz, 2 H)
LC−MS: m/z 453.0 (M+H)+
8−シクロプロピル−6−(3−シクロプロピル−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素3、ステップB)
1H NMR (クロロホルム−d) δ 4.78 − 4.90 (m, 2H), 4.66 (br. s., 0.5H), 4.26 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 12.5 Hz, 1H), 4.07 (d, J = 8.5 Hz, 0.5H), 3.67 − 3.84 (m, 1.5H), 3.30 (q, J = 9.8 Hz, 2H), 3.03 − 3.15 (m, 1.5H), 2.90 − 3.03 (m, 1H), 2.71 − 2.84 (m, 2H), 1.68 − 1.78 (m, 1H), 1.37 − 1.47 (m, 1H), 1.32 (d, J = 3.0 Hz, 6H), 1.10 − 1.19 (m, 2H), 0.98 − 1.07 (m, 2H), 0.28 − 0.71 (m, 4H)
LC−MS : m/z 463.1 (M+H)+
(R)−メチル3−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−3−オキソプロピルカルバメート(構成要素12、ステップB)
1H NMR (クロロホルム−d) δ 5.50 (br. s., 1H), 4.75 − 4.91 (m, 2H), 4.60 − 4.65 (m, 0.5H), 4.24 − 4.41 (m, 1.5H), 4.08 − 4.22 (m, 1H), 3.60 − 3.80 (m, 3.5H), 3.33 − 3.50 (m, 3H), 2.91 − 3.04 (m, 2.5H), 2.70 − 2.82 (m, 2H), 2.50 − 2.63 (m, 2H), 2.05 − 2.34 (m, 1H), 1.65 − 1.78 (m, 1H), 1.31 (d, J = 2.8 Hz, 6H), 0.95 − 1.19 (m, 7H), 0.70 − 0.91 (m, 3H)
LC−MS : m/z 484.1 (M+H)+
(R)−8−シクロプロピル−6−(4−(3−メトキシプロパノイル)−3−メチルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.96 (m, 2.5H), 4.51 (d, J = 13.6 Hz, 0.5H), 4.20 (br. s., 0.5H), 3.93 − 4.14 (m, 2H), 3.65 − 3.83 (m, 2.5H), 3.46 − 3.65 (m, 0.5H), 3.37 (s, 3H), 3.06 − 3.24 (m, 1.5H), 2.88 − 3.06 (m, 1H), 2.55 − 2.80 (m, 4H), 1.66 − 1.76 (m, 1H), 1.24 − 1.39 (m, 9H), 1.09 − 1.19 (m, 2H), 0.97 − 1.05 (m, 2H)
LC−MS : m/z 413.2 (M+H)+
8−シクロプロピル−6−((3R)−4−(3−ヒドロキシブタノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 4.83 (s, 2 H) 4.63 (m, 0.5 H) , 4.28 − 4.47 (m, 2 H), 4.04 − 4.28 (m, 2 H) , 3.63 − 3.78 (m, 0.5 H) , 3.43 (td, J = 8.2, 3.4 Hz, 1 H), 2.90 − 3.08 (m, 2.5 H) , 2.76 (s, 2 H) , 2.44 − 2.62 (m, 1 H) , 2.21 − 2.43 (m, 1.5 H) , 1.58 − 1.78 (m, 1 H), 1.28 − 1.38 (m, 6 H), 1.18 − 1.28 (m, 5 H), 0.94 − 1.07 (m, 4 H), 0.88 (t, J = 6.2 Hz, 2 H) , 0.74 − 0.84 (m, 2 H)
LC−MS: m/z 441.2 (M+H)+
(R)−8−シクロプロピル−6−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素2、ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.63 − 4.65 (m, 0.5H), 4.24 (d, J = 12.5 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 4.05 (d, J = 8.8 Hz, 0.5H), 3.69 − 3.88 (m, 3H), 3.36 (s, 3H), 2.94 − 3.24 (m, 3H), 2.75 − 2.82 (m, 2H), 2.50 − 2.67 (m, 2H), 1.66 − 1.76 (m, 1H), 1.31 (d, J = 3.0 Hz, 7H), 1.10 − 1.18 (m, 2H), 0.98 − 1.06 (m, 2H), 0.33 − 0.63 (m, 4H)
LC−MS : m/z 439.1 (M+H)+
(R)−8−シクロプロピル−6−(3−シクロプロピル−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素2、ステップB)
1H NMR (クロロホルム−d) δ 4.84 (s, 2H), 4.66 (br. s., 0.5H), 4.26 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.07 (d, J = 8.5 Hz, 0.5H), 3.67 − 3.92 (m, 1.5H), 3.21 − 3.38 (m, 2H), 3.06 − 3.18 (m, 1.5H), 2.94 − 3.01 (m, 1H), 2.78 (s, 2H), 1.68 − 1.80 (m, 1H), 1.38 − 1.49 (m, 1H), 1.32 (d, J = 3.3 Hz, 6H), 1.10 − 1.20 (m, 2H), 0.99 − 1.08 (m, 2H), 0.27 − 0.79 (m, 4H)
LC−MS : m/z 463.0 (M+H)+
((R)−8−シクロプロピル−6−(3−ジュウテリオ−4−(3−メトキシプロパノイル)−3−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.75 − 4.91 (m, 2H), 4.65 (d, J = 11.3 Hz, 0.5H), 4.32 (ddd, J = 13.3, 5.3, 1.5 Hz, 1H), 4.18 (d, J = 14.1 Hz, 1H), 3.62 − 3.85 (m, 3H), 3.27 − 3.48 (m, 4.5H), 2.90 − 3.04 (m, 2H), 2.73 − 2.79 (m, 2H), 2.52 − 2.70 (m, 2H), 1.64 − 1.76 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 1.08 − 1.16 (m, 2H), 0.95 − 1.05 (m, 2H)
LC−MS : m/z 449.6 (M+H)+
(R)−8−シクロプロピル−3,3−ジメチル−6−(2,2,3,5,5−ペンタジュウテリオ−4−(3−メトキシプロパノイル)−3−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.89 (m, 2 H), 4.16 (dd, J = 12.7, 7.4 Hz, 1 H), 3.64 − 3.80 (m, 2 H), 3.36 (d, J = 3.5 Hz, 3 H), 2.88 − 3.05 (m, 1 H), 2.76 (s, 2 H), 2.49 − 2.74 (m, 2 H), 1.64 − 1.76 (m, 1 H), 1.31 (d, J = 2.5 Hz, 6 H), 0.96 − 1.18 ppm (m, 4 H)
LC−MS : m/z 453.6(M+H)+
メチル5−((R)−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−2−メチル−5−オキソペンタノエート
1H NMR (クロロホルム−d) δ 4.77 − 4.91 (m, 2H), 4.62 − 4.70 (m, 0.5H), 4.28 − 4.49 (m, 1.5H), 4.07 − 4.25 (m, 1H), 3.63 − 3.79 (m, 3.5H), 3.34 − 3.54 (m, 1H), 2.88 − 3.11 (m, 2.5H), 2.72 − 2.83 (m, 2H), 2.49 − 2.62 (m, 1H), 2.33 − 2.46 (m, 1H), 2.19 − 2.30 (m, 1H), 1.81 − 1.98 (m, 2H), 1.64 − 1.78 (m, 1H), 1.29 − 1.37 (m, 6H), 1.21 (d, J = 7.0 Hz, 3H), 0.95 − 1.17 (m, 7H), 0.76 − 0.89 (m, 3H)
LC−MS : m/z 497.2 (M+H)+
(R)−8−シクロプロピル−6−(2,2,3,3,5,6,6−ヘプタジュウテリオ−4−(3−メトキシプロパノイル)−5−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.82 (s, 2H), 3.65 − 3.80 (m, 2H), 3.36 (d, J = 3.5 Hz, 3H), 2.74 − 2.80 (m, 2H), 2.49 − 2.74 (m, 2H), 1.63 − 1.74 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 0.96 − 1.20 (m, 4H)
LC−MS : m/z 454.6 (M+H) +
(R)−8−シクロプロピル−3,3−ジメチル−6−(2,2,5−トリジュウテリオ−4−(3−メトキシプロパノイル)−5−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.64 (d, J = 13.8 Hz, 0.5H), 4.25 − 4.38 (m, 1H), 3.66 − 3.84 (m, 2.5H), 3.31 − 3.40 (m, 3H), 2.86 − 3.08 (m, 2H), 2.73 − 2.80 (m, 2H), 2.49 − 2.73 (m, 2H), 1.64 − 1.75 (m, 1H), 1.31 (d, J = 2.3 Hz, 6H), 0.96 − 1.19 (m, 4H)
LC−MS : m/z 451.6 (M+H) +
(R)−8−シクロプロピル−6−(3−ジュウテリオ−3−(ペルジュウテリオプロパン−2−イル)−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.32 (d, J = 13.1 Hz, 0.5H), 4.19 (br. s., 2H), 3.64 (br. s., 1.5H), 3.32 (d, J = 9.8 Hz, 2H), 2.94 − 3.05 (m, 2H), 2.77 (s, 2H), 1.66 − 1.77 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.97 − 1.19 (m, 4H)
LC−MS : m/z 473.6 (M+H) +
(R)−メチル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−ジュウテリオ−2−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−4−オキソブタノエート(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.62 (d, J = 10.8 Hz, 0.5H), 4.31 (dd, J = 12.7, 6.7 Hz, 1H), 4.11 − 4.24 (m, 1H), 3.78 (d, J = 13.6 Hz, 0.5H), 3.70 (d, J = 3.8 Hz, 3H), 3.45 (m., 0.5H), 2.88 − 3.11 (m, 2.5H), 2.76 (s, 2H), 2.60 − 2.74 (m, 4H), 1.65 − 1.76 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 0.99 − 1.17 (m, 4H)
LC−MS : m/z 477.6 (M+H) +
(R)−メチル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2,2,3,3,5,5,6−ヘプタジュウテリオ−6−(ペルジュウテリオプロパン−2−イル)ピペラジン−1−イル)−4−オキソブタノエート(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.82 (s, 2H), 3.70 (d, J = 3.5 Hz, 3H), 2.76 (s, 2H), 2.57 − 2.74 (m, 4H), 1.66 − 1.76 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 0.96 − 1.18 (m, 4H)
LC−MS : m/z 483.7 (M+H) +
(R)−8−シクロプロピル−6−(2,2,3,3,5,6,6−ヘプタジュウテリオ−5−(ペルジュウテリオプロパン−2−イル)−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 3.14 − 3.42 (m, 2H), 2.77 (s, 2H), 1.68 − 1.76 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.97 − 1.18 (m, 4H)
LC−MS : m/z 479.7 (M+H) +
(R)−8−シクロプロピル−3,3−ジメチル−6−(2,2,3,5,5−ペンタジュウテリオ−3−(1,1,1,3,3,3−ヘキサジュウテリオプロパン−2−イル)−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素11、ステップB)
1H NMR (クロロホルム−d) δ 4.75 − 4.93 (m, 2H), 4.10 − 4.27 (m, 1H), 3.22 − 3.47 (m, 2H), 2.90 − 3.07 (m, 1H), 2.77 (s, 2H), 1.72 (dt, J = 8.0, 3.9 Hz, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.98 − 1.20 (m, 4H)
LC−MS : m/z 477.6 (M+H) +
(R)−8−シクロプロピル−3,3−ジメチル−6−(2,2,3,5,5−ペンタジュウテリオ−3−(1,1,1,3,3,3−ヘキサジュウテリオプロパン−2−イル)−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素9、ステップB)
1H NMR (クロロホルム−d) δ 4.74 − 4.94 (m, 2H), 3.15 − 3.43 (m, 2H), 2.78 (s, 2H), 1.69 − 1.76 (m, 1H), 1.33 (d, J = 2.8 Hz, 6H), 0.99 −1.20 (m, 4H)
LC−MS : m/z 479.6 (M+H) +
8−シクロプロピル−6−((3R)−3−シクロプロピル−4−(3−ヒドロキシブタノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素2、ステップB)
1H NMR (クロロホルム−d) δ 4.84 (s, 2H), 4.62 − 4.65 (m, 0.5H), 4.13 − 4.35 (m, 3H), 4.03 (d, J = 8.3 Hz, 0.5H), 3.61 − 3.83 (m, 1H), 2.91 − 3.19 (m, 3H), 2.78 (s, 2H), 2.30 − 2.58 (m, 2H), 1.67 − 1.77 (m, 1H), 1.29 − 1.35 (m, 7H), 1.19 − 1.27 (m, 3H), 1.13 (m, 2H), 0.98 − 1.07 (m, 2H), 0.38 − 0.68 (m, 4H)
LC−MS : m/z 439.0 (M+H)+
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(2−(メチルチオ)アセチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.90 (m, 2H), 4.58 − 4.61 (m, 0.5H), 4.28 − 4.43 (m, 1.5H), 4.20 (d, J = 11.5 Hz, 1H), 3.73 (d, J = 13.6 Hz, 0.5H), 3.27 − 3.53 (m, 3H), 3.07 − 3.13 (m, 1H), 2.89 − 3.04 (m, 1H), 2.69 − 2.84 (m, 2H), 2.05 − 2.33 (m, 4H), 1.65 − 1.73 (m, 1H), 1.32 (d, J = 2.5 Hz, 6H), 0.95 − 1.19 (m, 7H), 0.77 − 0.93 (m, 3H)
LC−MS : m/z 443.5 (M+H)+
(R)−8−シクロプロピル−6−(3−イソプロピル−4−(2−(メチルスルホニル)アセチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.90 (m, 2H), 4.62 − 4.65 (m, 0.5H), 4.27 − 4.45 (m, 2H), 4.12 − 4.26 (m, 2H), 3.81 − 4.10 (m, 1H), 3.51 − 3.66 (m, 1H), 3.11 − 3.20 (m, 4H), 2.99 − 3.11 (m, 1.5H), 2.68 − 2.86 (m, 2H), 2.10 − 2.37 (m, 1H), 1.71 (dddd, J = 10.0, 7.6, 5.1, 2.4 Hz, 1H), 1.32 (d, J = 3.0 Hz, 6H), 0.97 − 1.18 (m, 7H), 0.87 (dd, J = 6.7, 3.6 Hz, 3H)
LC−MS : m/z 475.6 (M+H)+
(R)−8−シクロプロピル−6−(4−(3−(フラン−2−イル)プロパノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 7.31 ( s, 1 H), 6.28 (d, J = 3.01 Hz, 1 H), 6.04 (d, J = 3.0 Hz, 1 H) ,4.82 (s, 2 H) ,4.64 (m, 0.5 H) ,4.40 (d, J = 10.3 Hz, 0.5 H), 4.30 (t, J = 13.9 Hz, 1 H) 4.09 − 4.19 (m, 1 H) , 3.73 (d, J = 13.5 Hz, 0.5 H), 3.35 − 3.51 (m, 1 H) , 2.97 − 3.07 (m, 2.5 H), 2.88 − 2.97 (m, 2 H) , 2.76 (S, 2 H), 2.68 − 2.74 (m, 1 H) , 2.09 (m, 1 H), 1.70 (tt, J = 7.9, 4.1 Hz, 2 H), 1.31 (d, J = 2.2 Hz, 6 H), 0.95 − 1.18 (m, 6 H), 0.86 (d, J = 6.8 Hz, 2 H), 0.79 (d, J = 6.8 Hz, 2 H)
LC−MS: m/z 477.3 (M+H)+
8−シクロプロピル−6−((3R)−3−イソプロピル−4−(2−(メチルスルフィニル)アセチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 4.72 − 4.90 (m, 2 H), 4.50 − 4.67 (m,0.5 H), 4.26 − 4.45 (m, 1.5 H) , 4.04 − 4.25 (m, 1.5 H), 3.71 − 3.85 (m, 0.5 H), 3.58 − 3.71 (m, 0.5 H) , 3.40 − 3.58 (m, 0.5 H), 2.92 − 3.17 (m, 3 H), 2.71 − 2.85 (m, 5 H), 2.22 − 2.37 (m, 1 H) , 2.13 (dd, J = 10.8, 5.2 Hz, 1 H) , 1.61 − 1.77 (m, 1 H) , 1.27 − 1.41 (m, 6 H), 1.05 − 1.16 (m, 3 H) , 0.95 − 1.05 (m, 4 H), 0.75 − 0.94 (m, 3 H)
LC−MS: m/z 459.3 (M+H)+
(1R,2R)−メチル2−((R)−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−カルボニル)シクロプロパンカルボキシレート)(ステップB)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.57 (d, J = 10.0 Hz, 0.5H), 4.27 − 4.40 (m, 1.5H), 4.13 − 4.25 (m, 1.5H), 3.76 − 3.84 (m, 0.5H), 3.67 − 3.76 (m, 3H), 3.52 (d, J = 1.8 Hz, 0.5H), 2.93 − 3.18 (m, 2.5H), 2.77 (s, 2H), 2.31 − 2.40 (m, 1H), 2.17 − 2.27 (m, 1H), 1.65 − 1.76 (m, 1H), 1.43 − 1.50 (m, 1H), 1.27 − 1.37 (m, 6H), 1.08 − 1.19 (m, 2H), 0.97 − 1.06 (m, 5H), 0.84 − 0.94 (m, 2H), 0.80 (dd, J = 6.7, 4.6 Hz, 1H)
LC−MS : m/z 481.6 (M+H) +
(R)−6−(4−(2−(1,3,4−オキサジアゾル−2−イル)アセチル)−3−イソプロピルピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 8.44 (s, 1 H) , 4.73 − 4.93 (m, 2 H), 4.60 (d, J = 11.8 Hz, 0.5 H), 4.26 − 4.41 (m, 1.5 H), 3.96 − 4.25 (m, 3 H), 3.78 (d, J = 13.5 Hz, 0.5 H), 3.43 − 3.61 (m, 1 H), 2.89 − 3.17 (m, 2.5 H), 2.77 (s, 2 H), 2.06 − 2.25 (m, 1 H) , 1.63 − 1.77 (m, 1 H) , 1.32 (d, J = 3.0 Hz, 6 H) , 0.95 − 1.11 (m, 6 H) , 0.72 − 0.95 (m, 4 H)
LC−MS: m/z 465.5 (M+H)+
(R)−8−シクロプロピル−6−(4−(3−エトキシプロパノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.84 (s, 2H), 4.66 (d, J = 9.8 Hz, 0.5H), 4.41 (d, J = 10.5 Hz, 0.5H), 4.34 (d, J = 13.3 Hz, 1H), 4.11 − 4.23 (m, 1H), 3.70 − 3.89 (m, 3H), 3.48 − 3.63 (m, 3H), 3.28 − 3.48 (m, 1H), 2.92 − 3.13 (m, 2H), 2.82 (s, 3H), 2.74 − 2.80 (m, 2H), 2.56 − 2.73 (m, 2H), 2.19 (dt, 2H), 1.71 (dt, J = 7.8, 3.6 Hz, 1H), 1.33 (d, J = 2.0 Hz, 6H), 1.24 − 1.30 (m, 3H), 0.97 − 1.08 (m, 4H), 0.79 − 0.92 (m, 4H)
LC−MS : m/z 455.6 (M+H)+
6−(4−(シクロプロパンカルボニル)−3−(ジフルオロメチル)ピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素7、ステップB)
1H NMR (クロロホルム−d) δ 5.91−6.31(m, 1H),4.90 − 5.04 (m, 0.5H), 4.76 − 4.90 (m, 2H), 4.68 (d, J = 13.3 Hz, 0.5H), 4.16 − 4.34 (m, 1.5H), 4.04 − 4.16 (m, 1H), 3.91 (d, J = 13.3 Hz, 0.5H), 3.55 − 3.82 (m, 2.5H), 3.28 − 3.45 (m, 3.5H), 3.01 − 3.22 (m, 1.5H), 2.89 − 3.01 (m, 0.5H), 2.68 − 2.89 (m, 3H), 2.56 − 2.68 (m, 1H), 1.67 − 1.76 (m, 1H), 1.32 (d, J = 4.3 Hz, 6H), 1.09 − 1.18 (m, 2H), 0.96 − 1.09 (m, 2H)
LC−MS : m/z 449.2 (M+H)+
(1R,2R)−エチル2−((R)−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−カルボニル)シクロプロパンカルボキシレート(ステップB)
1H NMR (クロロホルム−d) δ 4.77 − 4.89 (m, 2H), 4.57 (d, J = 10.3 Hz, 0.5H), 4.28 − 4.41 (m, 1.5H), 4.14 − 4.22 (m, 3H), 3.95 − 4.12 (m, 0.5H), 3.77 (t, J = 10.2 Hz, 0.5H), 3.44 − 3.60 (m, 1H), 3.05 − 3.14 (m, 1H), 2.96 − 3.05 (m, 0.5H), 2.77 (s, 2H), 2.08 − 2.38 (m, 3H), 1.67 − 1.77 (m, 1H), 1.46 (ddd, J = 8.9, 5.9, 3.3 Hz, 1H), 1.35 − 1.43 (m, 1H), 1.27 − 1.34 (m, 9H), 1.09 − 1.18 (m, 2H), 0.95 − 1.06 (m, 5H), 0.76 − 0.93 (m, 4H)
LC−MS : m/z 495.6 (M+H) +
(R)−8−シクロプロピル−6−(3−シクロプロピル−4−(2−(オキセタン−3−イル)アセチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素10、ステップB)
1H NMR (400 MHz, CDCl3) δ = 4.91 (ddd, J = 8.0, 6.3, 1.9 Hz, 2H), 4.83 (s, 2H), 4.40 (dd, J = 7.9, 4.5 Hz, 2H), 4.24 (d, J = 12.8 Hz, 1H), 4.16 (d, J = 7.2 Hz, 1H), 3.97 (s, 1H), 3.71 (t, J = 10.0 Hz, 2H), 3.41 (dt, J = 14.0, 6.3 Hz, 1H), 3.32 − 2.87 (m, 3H), 2.79 (d, J = 11.3 Hz, 4H), 1.77 − 1.57 (m, 2H), 1.38 − 1.28 (m, 6H), 1.14 (dd, J = 7.1, 3.8 Hz, 2H), 1.02 (ddd, J = 9.4, 6.6, 2.8 Hz, 2H), 0.58 (s, 1H), 0.40 (d, J = 4.9 Hz, 2H).
LC−MS: m/z 451.6 (M+H)+
(R)−N−ブチル−5−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−2,5−ジオキソペンタンアミド(ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 6.81 − 6.95 (m, 1 H), 4.83 (s, 2 H), 4.56 (m, 0.5 H), 4.24 − 4.38 (m, 1.5 H), 4.07 − 4.24 (m, 1 H) , 3.77 (d, J = 13.3 Hz, 0.5 H), 3.39 − 3.56 (m, 1 H), 3.30 (qd, J = 6.8, 3.6 Hz, 2 H), 3.15 − 3.26 (m, 2 H), 2.98 − 3.10 (m, 1.5 H) , 2.91 − 2.98 (m, 1 H), 2.70 − 2.80 (m, 4 H) , 2.00 − 2.15 (m, 1 H) , 1.65 − 1.76 (m, 1 H) , 1.48 − 1.57 (m, 2 H), 1.31 − 1.42 (m, 6 H), 1.25 − 1.31 (m, 3 H) , 0.88 − 1.05 (m, 10 H), 0.80 (d, J = 6.8 Hz, 2 H)
LC−MS: m/z 538.5 (M+H)+
8−シクロプロピル−6−(4−(3−メトキシプロパノイル)−3−(2,2,2−トリフルオロエチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素4、ステップB)
1H NMR (クロロホルム−d) δ 5.24 (br. s., 0.5H), 4.69 − 4.73 (m, 0.5H), 4.51 (br, 0.5H), 3.96 − 4.15 (m, 2H), 3.88 (d, J = 13.8 Hz, 0.5H), 3.64 − 3.83 (m, 2H), 3.46 − 3.58 (m, 0.5H), 2.88 − 3.17 (m, 2.5H), 2.56 − 2.80 (m, 5H), 1.73 (br. s., 1H), 1.33 (s, 6H), 1.02 − 1.16 (m, 4H)
LC−MS : m/z 481.6 (M+H)+
8−シクロプロピル−3,3−ジメチル−6−(3−(2,2,2−トリフルオロエチル)−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素4、ステップB)
1H NMR (クロロホルム−d) δ 5.28 (br. s., 0.5H), 4.71 − 4.75 (m, 0.5H), 4.32 (br, 0.5H), 3.95 − 4.16 (m, 2H), 3.75 (d, J = 13.3 Hz, 0.5H), 3.55 − 3.70 (m, 0.5H), 3.16 − 3.35 (m, 2H), 2.88 − 3.16 (m, 3H), 2.66 − 2.86 (m, 3H), 1.73 (dd, J = 8.4, 3.9 Hz, 1H), 1.32 − 1.39 (m, 6H), 1.03 − 1.17 (m, 4H)
LC−MS : m/z 505.5 (M+H)+
8−シクロプロピル−6−((3R)−3−イソプロピル−4−(2−(オキセタン−2−イル)アセチル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素11、ステップB)
1H NMR (400 MHz, CHLOROFORM−d) δ 5.20 − 5.31 (m, 1 H), 4.78 − 4.90 (m, 2 H), 4.67 − 4.78 (m, 1 H), 4.48 − 4.62 (m, 0.5 H),4.29 − 4.47 (m, 1.5 H), 4.08 − 4.26 (m, 1 H) , 3.84 (d, J = 15.6 Hz, 0.5 H), 3.39 − 3.61 (m, 1 H), 2.91 − 3.10 (m, 3.5 H), 2.81 − 2.91 (m, 1.5 H), 2.72 − 2.81 (m, 2.5 H), 2.40 − 2.64 (m, 1 H) , 1.91 − 2.15 (m, 2 H) , 1.72 (m, 1 H), 1.33 (m, 6 H), 0.96 − 1.17 (m, 6 H), 0.76 − 0.96 (m, 4 H)
LC−MS: m/z 453.3(M+H)+
(R)−6−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素2、ステップC)
1H NMR (クロロホルム−d) δ 4.84 (s, 2H), 3.49 − 4.54 (m, 5H), 2.99 − 3.17 (m, 2H), 2.78 (s, 2H), 1.66 − 1.78 (m, 2H), 1.32 (d, J = 2.5 Hz, 6H), 1.11 − 1.19 (m, 2H), 0.89 − 1.09 (m, 6H), 0.72 − 0.82 (m, 2H), 0.61 (br. s., 1H), 0.34 − 0.54 (m, 3H)
LC−MS : m/z 421.4 (M+H)+
6−(4−(シクロプロパンカルボニル)−3−(ジフルオロメチル)ピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素7、ステップC)
1H NMR (クロロホルム−d) δ 5.91−6.34 (m, 1H),4.94 (d, J = 15.6 Hz, 0.5H), 4.76 − 4.88 (m, 2H), 4.63 (d, J = 13.6 Hz, 0.5H), 4.51(br,0.5H),4.13 − 4.33 (m, 2H), 4.01 − 4.13 (m, 0.5H), 3.73 (t, J = 11.0 Hz, 0.5H), 3.35 (d, J = 13.8 Hz, 0.5H), 3.06 − 3.30 (m, 1.5H), 2.99 (t, J = 12.0 Hz, 0.5H),2.78 (s, 2H), 1.74 − 1.83 (m, 1H), 1.67 − 1.74 (m, 1H), 1.32 (d, J = 4.3 Hz, 6H), 1.11 − 1.18 (m, 2H), 0.94 − 1.11 (m, 4H), 0.82 − 0.90 (m, 2H)
LC−MS : m/z 431.2 (M+H)+
(S)−エチル1−アセチル−4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)ピペラジン−2−カルボキシレート(構成要素6、ステップC)
1H NMR (クロロホルム−d) δ 5.24 (dd, J = 4.1, 1.9 Hz, 0.5H), 4.77 − 4.91 (m, 2H), 4.67 (dt, J = 13.4, 2.0 Hz, 1H), 4.42 − 4.50 (m, 0.5H), 4.11 − 4.27 (m, 2H), 4.01 − 4.10 (m, 0.5H), 3.69 − 3.90 (m, 1.5H), 3.19 − 3.45 (m, 1.5H), 2.95 − 3.11 (m, 1H), 2.68 − 2.84 (m, 2H), 2.05 − 2.32 (m, 3.5H), 1.66 − 1.75 (m, 1H), 1.31 (d, J = 3.3 Hz, 6H), 1.12 − 1.23 (m, 5H), 0.97 − 1.07 (m, 2H)
LC−MS : m/z 427.5 (M+H)+
6−(4−(シクロプロパンカルボニル)−3−(2,2,2−トリフルオロエチル)ピペラジン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素4、ステップC)
1H NMR (クロロホルム−d) δ 5.20 (br. s., 0.5H), 4.85 (s, 2H), 4.64 (d, J = 13.3 Hz, 1H), 4.19 (d, J = 13.3 Hz, 0.5H), 3.94 − 4.14 (m, 2H), 3.32 − 3.64 (m, 2H), 2.92 − 3.22 (m, 3H), 2.68 − 2.88 (m, 3H), 2.54 − 2.68 (m,0.5H), 1.69 − 1.74 (m, 1H), 1.33 (s, 6H), 1.11 − 1.15 (m, 2H), 1.01 − 1.08 (m, 4H), 0.84 (br. s., 2H)
LC−MS : m/z 463.3 (M+H)+
6−(4−(シクロプロパンカルボニル)−6−フルオロ−3−メチル−1,4−ジアゼパン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素8、ステップC)
1H NMR (クロロホルム−d) δ 4.87 (s, 2H), 4.42−4.83 (m, 4H), 4.29 (m, 1H), 4.11 (br. s., 1H), 3.04−3.15 (m, 2H), 2.80 (s, 2H), 1.71 − 1.76 (m, 1H), 1.65−1.63 (m, 1H), 1.34 (s, 6H), 1.27 (m, 1.5H), 1.17 − 1.20 (m,1.5H), 1.03 − 1.09 (m, 4H), 0.80 − 0.98 (m, 4H)
LC−MS : m/z 427.3 (M+H)+
6−(4−(シクロプロパンカルボニル)−5−メチル−1,4−ジアゼパン−1−イル)−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(構成要素5、ステップC)
1H NMR (クロロホルム−d) δ 4.76 − 4.91 (m, 2H), 4.67 (dt, J = 10.1, 6.5 Hz, 0.5H), 4.16 − 4.42 (m, 3.5H), 3.35 − 3.52 (m, 1H), 3.05 − 3.30 (m, 1.5H), 2.90 − 3.05 (m, 0.5H), 2.71 − 2.84 (m, 2H), 2.19 − 2.49 (m, 1H), 1.62 − 1.92 (m, 4H), 1.21 − 1.42 (m, 8H), 1.06 − 1.21 (m, 4H), 0.88 − 1.06 (m, 3H), 0.73 − 0.88 (m, 2H)
LC−MS : m/z 409.2 (M+H)+
(R)−8−シクロプロピル−6−(4−(4−ヒドロキシブタノイル)−3−イソプロピルピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(ステップB)
1H NMR (クロロホルム−d) δ 4.77 − 4.91 (m, 2H), 4.65 (d, J = 10.8 Hz, 0.5H), 4.36 − 4.48 (m, 0.5H), 4.32 (dd, J = 13.3, 1.8 Hz, 1H), 4.10 − 4.24 (m, 1H), 3.65 − 3.84 (m, 2.5H), 3.36 − 3.58 (m, 1H), 2.89 − 3.11 (m, 2.5H), 2.69 − 2.83 (m, 2H), 2.47 − 2.63 (m, 2H), 2.21 − 2.34 (m, 1H), 1.90 − 1.98 (m, 1H), 1.66 − 1.76 (m, 1H), 1.32 (d, J = 2.8 Hz, 6H), 0.95 − 1.17 (m, 7H), 0.75 − 0.93 (m, 3H)
LC−MS : m/z 441.2 (M+H)+
(R)−8−シクロプロピル−6−(3−シクロプロピル−4−(3−ヒドロキシプロパノイル)ピペラジン−1−イル)−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル
1H NMR (クロロホルム−d) δ 4.85 (s, 2H), 4.63 − 4.67 (m, 0.5H), 4.26 (d, J = 12.8 Hz, 1H), 4.17 (dd, J = 12.7, 2.1 Hz, 1H), 4.05 (d, J = 9.0 Hz, 0.5H), 3.91 (br. s., 2H), 3.74 (br. s., 1H), 2.90 − 3.38 (m, 3H), 2.79 (s, 2H), 2.47 − 2.66 (m, 2H), 1.69 − 1.78 (m, 1H), 1.33 − 1.41 (m, 7H), 1.10 − 1.19 (m, 2H), 0.98 − 1.09 (m, 2H), 0.44 − 0.69 (m, 4H)
LC−MS : m/z 425.4 (M+H)+
(R)−イソプロピル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−4−オキソブタノエート(ステップB)
1H NMR (クロロホルム−d) δ 5.02 (dq, J = 12.4, 6.2 Hz, 1H), 4.75 − 4.91 (m, 2H), 4.62 (d, J = 11.3 Hz, 0.5H), 4.26 − 4.43 (m, 1.5H), 4.07 − 4.26 (m, 1H), 3.79 (d, J = 13.6 Hz, 0.5H), 3.38 − 3.60 (m, 1H), 2.91 − 3.13 (m, 2.5H), 2.71 − 2.81 (m, 2H), 2.56 − 2.71 (m, 4H), 2.07 − 2.39 (m, 1H), 1.66 − 1.77 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 1.21 − 1.27 (m, 6H), 0.97 − 1.18 (m, 7H), 0.74 − 0.94 (m, 3H)
LC−MS : m/z 497.3 (M+H)+
(R)−2−ヒドロキシエチル4−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−イソプロピルピペラジン−1−イル)−4−オキソブタノエート(ステップB)
1H NMR (クロロホルム−d) δ 4.76 − 4.90 (m, 2H), 4.59 (d, J = 10.8 Hz, 0.5H), 4.09 − 4.38 (m, 4.5H), 3.68 − 3.90 (m, 2.5H), 3.36 − 3.60 (m, 1H), 2.89 − 3.15 (m, 2.5H), 2.63 − 2.83 (m, 6H), 2.07 − 2.36 (m, 1H), 1.67 − 1.74 (m, 1H), 1.31 (d, J = 2.5 Hz, 6H), 0.95 − 1.16 (m, 7H), 0.86 − 0.94 (m, 1.5H), 0.80 (d, J = 6.8 Hz, 1.5H)
LC−MS : m/z 449.7 (M+H)+
(R)−メチル3−(4−(5−シアノ−8−シクロプロピル−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−6−イル)−2−シクロプロピルピペラジン−1−イル)−3−オキソプロパノエート(構成要素2、ステップC)
1H NMR (クロロホルム−d) δ 4.83 (s, 2H), 4.62 − 4.65 (m, 0.5H), 4.26 (d, J = 13.1 Hz, 1H), 4.16 (d, J = 12.5 Hz, 1H), 4.03 (d, J = 9.3 Hz, 0.5H), 3.71 − 3.85 (m, 3.5H), 3.60 − 3.70 (m, 0.5H), 2.93 − 3.58 (m, 5H), 2.78 (s, 2H), 1.66 − 1.75 (m, 1H), 1.36 − 1.44 (m, 1H), 1.32 (d, J = 3.0 Hz, 6H), 1.13 (t, J = 3.6 Hz, 2H), 0.97 − 1.07 (m, 2H), 0.31 − 0.64 (m, 4H)
LC−MS : m/z 453.2 (M+H)+
コア合成1:
ステップA:tert−ブチル3−(シクロプロパンカルボニル)−4−オキソピペリジン−1−カルボキシレート
撹拌子を備えた500mLの三つ口丸底フラスコに、tert−ブチル4−オキソピペリジン−1−カルボキシレート(9.3g、46.8mmol)及び120mLの乾燥トルエンを装入した。溶液を窒素パージし、0℃に冷却した。撹拌しながらLDAの溶液(THF/n−ヘプタン中2M溶液、24.5mL、15.6mmol)を滴下して添加し、反応混合物の撹拌を0℃で5分間継続させた後、激しく撹拌しながらシクロプロパンカルボニルクロリド(2.8mL、31.2mmol)を添加した。0℃でさらに20分間撹拌した後、反応混合物をPH<7まで1NのHClでクエンチした。H2Oと塩化メチレンに分配した後、次に混合有機層をブラインで洗浄し、無水Na2SO4で乾燥させて真空濃縮した。フラッシュカラムクロマトグラフィー(10%酢酸エチル/石油エーテル)により、9gの表題化合物を帯黄色の油として得て、これをさらなる精製なしに次のステップに直接使用した。LC−MS:m/z 268.3(M+H)。
70mLのEtOH中のtert−ブチル3−(シクロプロパンカルボニル)−4−オキソピペリジン−1−カルボキシレート(8.2g、30.6mmol)及び2−シアノアセトアミド(4.1g、49.0mmol)の溶液に、ジエチルアミン(2.1mL、20.4mmol)を添加した。LC−MSによって生成物が完全に形成されたことが示されるまで、反応混合物を室温で72時間撹拌した。次に反応混合物を還流温度に加熱し、その間、十分なEtOHを添加して清澄な溶液とした。再び室温に冷却した後、EtOH溶液から生成物を析出させ、真空ろ過及び風乾後、5.3gの表題化合物を白色固体として得て、これをさらなる精製なしに次のステップに直接使用した。LC−MS:m/z 316.5(M+H)。
250mL丸底フラスコに、8−シクロプロピル−6−ヒドロキシ−3,3−ジメチル−3,4−ジヒドロ−1H−ピラノ[3,4−c]ピリジン−5−カルボニトリル(4.8g、15.2mmol)、DMAP(185mg、1.52mmol)、トリエチルアミン(2.74mL、19.7mmol)及び150mLの塩化メチレンを装入した。反応混合物をドライアイス−アセトン浴で0℃に冷却した後、トリフルオロメタンスルホン酸無水物(3.3mL、19.7mmol)をシリンジで滴下して添加した。得られた混合物を0℃で30分間撹拌した後、それを室温に加温させてさらに2時間撹拌した。TLCによって出発物質が生成物に完全に変換されたことが示された後、反応混合物を真空濃縮し、フラッシュカラムクロマトグラフィー(1:10酢酸エチル/石油エーテル)により精製することで、6.5gの表題化合物をオフホワイト色の固体として得た。1H NMR (クロロホルム−d) δ 4.74 (br. s., 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H), 1.96 (br. s., 1H), 1.51 (s, 9H), 1.16 − 1.28 (m, 4H)
封管に、2mLのCH3CN中の上記のtert−ブチル5−シアノ−8−シクロプロピル−6−ヒドロキシ−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(715mg、1.60mmol)、(R)−2−シクロプロピルピペラジン(cyclepropylpiperazine)(202mg、1.60mmol)、及びジエチルアミン(0.24mL、1.73mmol)を装入した。反応混合物を還流させながら一晩加熱した。それを減圧濃縮した後、反応混合物をフラッシュカラムクロマトグラフィー(1:10メタノール/塩化メチレン)により精製することで、610mgの表題化合物を得た。MS(ES)M+H 予測値424.5、実測値424.5。1H NMR (クロロホルム−d) δ 4.62 (br. s., 2H), 4.25 (d, J = 13.1 Hz, 1H), 4.05 − 4.15 (m, 1H), 3.58 − 3.72 (m, 2H), 3.24 − 3.38 (m, 2H), 3.16 (dd, J = 13.3, 10.5 Hz, 1H), 3.00 (td, J = 12.0, 3.1 Hz, 1H), 2.91 (t, J = 5.5 Hz, 2H), 2.26 (td, J = 9.8, 2.8 Hz, 1H), 1.88 (br. s., 1H), 1.50 (s, 9H), 1.08 − 1.16 (m, 2H), 1.04 (d, J = 6.5 Hz, 2H), 0.60 − 0.67 (m, 2H), 0.47 − 0.57 (m, 1H), 0.36 − 0.46 (m, 1H)
塩化メチレン(30mL)中の(R)−tert−ブチル5−シアノ−8−シクロプロピル−6−(3−シクロプロピルピペラジン−1−イル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(30mg、0.08mmol)、3−メトキシプロパン酸(4.23g、10mmol)及びDIPEA(2.6g、20mmol)の溶液に、HATU(4.18g、11mmol)を添加した。反応混合物を室温で2時間撹拌した。有機相を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取HPLC(PE:EA/80:20)により精製することで、4.5gの表題化合物を白色固体として得た。MS(ES)M+H 予測値510.6、実測値510.5。1H NMR (クロロホルム−d) δ 4.55 − 4.73 (m, 2H), 4.27 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 12.5 Hz, 1H), 4.06 (d, J = 7.5 Hz, 0.5H), 3.83 (d, J = 12.3 Hz, 0.5H), 3.57 − 3.77 (m, 5H), 3.38 (s, 3H), 3.20 − 3.33 (m, 1H), 3.08 (d, J = 12.8 Hz, 1H), 2.89 − 3.04 (m, 3H), 2.69 (br. s., 1H), 2.64 (br. s., 1H), 1.90 (br. s., 1H), 1.71 (br. s., 1H), 1.47 − 1.57 (m, 9H), 1.10 − 1.19 (m, 2H), 1.05 (d, J = 7.0 Hz, 2H), 0.58 (br. s., 1H), 0.51 (br. s., 1H), 0.34 − 0.47 (m, 2H)
塩化メチレン(30mL)中の(R)−tert−ブチル5−シアノ−8−シクロプロピル−6−(3−シクロプロピルピペラジン−1−イル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(4.23g、10mmol)及びDIPEA(2.6g、20mmol)の溶液に、シクロプロパンカルボニルクロリド(1.76g、15mmol)を添加した。反応混合物を室温で0.5時間撹拌した。有機相を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取HPLC(PE:EA/80:20)により精製することで、4.1gの表題化合物を白色固体として得た。MS(ES)M+H 予測値492.6、実測値492.5。1H NMR (クロロホルム−d) δ 4.55 − 4.73 (m, 2H), 4.28 (d, J = 12.5 Hz, 1H), 4.18 (d, J = 12.3 Hz, 1H), 4.02 (br. s., 1H), 3.59 − 3.72 (m, 3H), 3.36 − 3.58 (m, 0.5H), 3.16 (br. s., 1.5H), 3.00 (br. s., 1H), 2.93 (t, J = 5.6 Hz, 2H), 1.89 (br. s., 1H), 1.65 − 1.77 (m, 1H), 1.44 − 1.55 (m, 9H), 1.14 (br. s., 2H), 0.95 − 1.09 (m, 4H), 0.85 − 0.95 (m, 1H), 0.70 − 0.83 (m, 2H), 0.60 (br. s., 1H), 0.31 − 0.54 (m, 3H)
表題化合物を、方法E1を用いて3,3,3−トリフルオロプロパン酸から調製した。MS(ES)M+H 予測値534.6、実測値534.6。1H NMR (クロロホルム−d) δ 4.54 − 4.73 (m, 2H), 4.26 (d, J = 12.8 Hz, 1H), 4.17 (d, J = 12.5 Hz, 1H), 4.06 (d, J = 8.0 Hz, 1H), 3.75 − 3.87 (m, 1H), 3.57 − 3.75 (m, 2.5H), 3.29 (q, J = 9.3 Hz, 2H), 3.07 (d, J = 11.8 Hz, 1.5H), 2.86 − 3.02 (m, 3H), 1.89 (br. s., 1H), 1.46 − 1.56 (m, 9H), 1.36 − 1.44 (m, 1H), 1.13 (br. s., 2H), 1.05 (d, J = 6.8 Hz, 2H), 0.60 (br. s., 1H), 0.52 (br. s., 1H), 0.36 − 0.48 (m, 2H)
表題化合物を、方法E1を用いてナトリウム3−ヒドロキシプロパノエートから調製した。LC−MS:m/z 496.6(M+H)。
MeOH(10mL)中の(R)−tert−ブチル5−シアノ−8−シクロプロピル−6−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(2.55g 5mmol)の溶液に、1N HCl/MeOH溶液(50mL)を添加した。反応が完了するまで混合物を室温で撹拌した。溶媒を真空除去することで、粗生成物を淡黄色の油として得て(2.3g)、これを次のステップでさらなる精製なしに使用した。LC−MS:m/z 410.6(M+H)。
表題化合物を、方法F1を用いて(R)−tert−ブチル5−シアノ−6−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−8−シクロプロピル−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレートから調製した。LC−MS:m/z 392.6(M+H)。
表題化合物を、方法F1を用いて(R)−tert−ブチル5−シアノ−8−シクロプロピル−6−(3−シクロプロピル−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレートから調製した。LC−MS:m/z 434.5(M+H)。
表題化合物を、方法F1を用いて(R)−tert−ブチル5−シアノ−8−シクロプロピル−6−(3−シクロプロピル−4−(3−ヒドロキシプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレートから調製した。LC−MS:m/z 396.6(M+H)。
化合物番号478
塩化メチレン(10mL)中の(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル(111mg、0.25mmol)及びEt3N(0.1mL、0.75mmol)の溶液に、塩化アセチル(30mg、0.375mmol)を添加した。混合物を室温で1時間撹拌した。TLCによって出発物質が生成物に完全に変換されたことが示された後、反応混合物を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗製物を分取HPLC(PE:EA/80:20)により精製することで、78mgの表題化合物をオフホワイト色の油として得た。
1H NMR (クロロホルム−d)δ 4.70 − 4.89 (m, 4H), 4.29 (d, J = 13.1 Hz, 1H), 4.18 (d, J = 12.5 Hz, 1H), 3.78 − 3.93 (m, 1H), 3.59 − 3.77 (m, 4H), 3.36 (s, 3H), 3.19 − 3.31 (m, 1H), 3.09 (d, J = 12.8 Hz, 1H), 2.86 − 3.04 (m, 3H), 2.56 − 2.74 (m, 2H), 2.17 − 2.27 (m, 3H), 1.89 − 2.07 (m, 2H), 1.43 (d, J = 3.5 Hz, 0.5H), 1.32 (br. s., 0.5H), 0.99 − 1.23 (m, 4H), 0.56 (br. s., 1H), 0.50 (br. s., 1H), 0.28 − 0.46 (m, 2H); LC−MS : m/z 452.6 (M+H)
化合物番号488
塩化メチレン(10mL)中の(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル(111mg、0.25mmol)、プロピオル酸(26mg、0.375mmol)及びDIPEA(97mg、0.75mmol)の溶液に、HATU(142mg、0.375mmol)を添加した。反応混合物を室温で2時間撹拌した。有機相を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取HPLC(PE:EA/80:20)により精製することで、55mgの表題化合物を白色の油として得た。
1H NMR (クロロホルム−d)δ 4.98 (s, 1H), 4.73 − 4.93 (m, 1H), 4.32 (d, J = 12.8 Hz, 1H), 4.22 (d, J = 12.8 Hz, 1H), 3.97 − 4.15 (m, 2H), 3.80 − 3.97 (m, 1H), 3.62 − 3.80 (m, 3H), 3.38 (s, 3H), 3.20 − 3.32 (m, 1H), 2.88 − 3.17 (m, 4H), 2.69 (br. s., 1H), 2.44 − 2.66 (m, 1H), 1.83 − 1.97 (m, 1H), 1.39 (d, J = 7.0 Hz, 1H), 0.99 − 1.24 (m, 4H), 0.58 (br. s., 1H), 0.52 (br. s., 1H), 0.42 (br. s., 2H); LC−MS : m/z 461.2 (M+H)
化合物番号479
表題化合物を、方法G1を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びメタンスルホニルクロリドから調製した。
1H NMR (クロロホルム−d)δ 4.40 − 4.56 (m, 2H), 4.31 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.5 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 3.81 (br. s., 1H), 3.70 (t, J = 5.9 Hz, 2H), 3.47 − 3.62 (m, 2H), 3.36 (s, 3H), 3.27 (s, 1H), 3.03 − 3.21 (m, 3H), 2.99 (d, J = 11.8 Hz, 1H), 2.93 (s, 3H), 2.55 − 2.77 (m, 2H), 1.78 − 1.90 (m, 1H), 1.29 − 1.46 (m, 1H), 1.10 − 1.21 (m, 2H), 0.99 − 1.10 (m, 2H), 0.56 (br. s., 1H), 0.50 (br. s., 1H), 0.29 − 0.48 (m, 2H); LC−MS : m/z 488.6 (M+H)
化合物番号484
表題化合物を、方法G1を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び2−クロロエタノールから調製した。
1H NMR (クロロホルム−d)δ 4.62 − 4.65 (d, J = 8.3 Hz,1H), 4.24 (d, J = 13.1 Hz, 1H), 4.14 (d, J = 12.5 Hz, 1H), 4.04 (d, J = 8.3 Hz, 0.5H), 3.60 − 3.90 (m, 7H), 3.36 (s, 3H), 3.23 (br. s., 1H), 3.06 (d, J = 12.8 Hz, 1H), 2.89 − 3.02 (m, 3H), 2.74 − 2.89 (m, 4H), 2.43 − 2.73 (m, 3H), 1.78 − 1.89 (m, 1H), 1.34 (br. s., 1H), 1.08 − 1.19 (m, 2H), 0.93 − 1.06 (m, 2H), 0.56 (br. s., 1H), 0.49 (br. s., 1H), 0.40 (d, J = 5.5 Hz, 2H); LC−MS : m/z 454.6 (M+H)
(R)−7−アクリロイル−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル
表題化合物を、方法G1を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び塩化アクリロイルから調製した。
1H NMR (クロロホルム−d)δ 6.67 (dd, J = 16.7, 10.7 Hz, 1H), 6.38 (d, J = 16.8 Hz, 1H), 5.80 (d, J = 10.5 Hz, 1H), 4.75 − 5.05 (m, 2H), 4.30 (d, J = 12.8 Hz, 0.5H), 4.20 (d, J = 12.5 Hz, 1H), 4.00 − 4.13 (m, 1H), 3.80 (d, J = 11.0 Hz, 4H), 3.55 − 3.75 (m, 2H), 3.37 (s, 3H), 3.10 (d, J = 12.0 Hz, 1H), 3.01 (br. s., 3H), 2.69 (br. s., 1H), 2.64 (br. s., 1H), 1.99 (br. s., 1H), 1.83 (br. s., 1H), 0.95 − 1.19 (m, 4H), 0.57 (br. s., 2H), 0.51 (br. s., 1H), 0.41 (br. s., 1H); LC−MS : m/z 464.6 (M+H)
化合物番号498
表題化合物を、方法G1を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−ヒドロキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び塩化アクリロイルから調製した。
1H NMR (クロロホルム−d)δ 6.67 (dd, J = 16.7, 10.7 Hz, 1H), 6.37 (dd, J = 16.8, 1.8 Hz, 1H), 5.80 (dd, J = 10.5, 1.5 Hz, 1H), 4.71 − 4.96 (m, 2H), 4.29 (d, J = 12.8 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 3.90 (br. s., 3H), 3.76 − 3.87 (m, 1H), 3.62 − 3.76 (m, 1H), 3.49 (br. s., 1H), 3.20 − 3.33 (m, 1H), 3.06 − 3.20 (m, 1H), 2.85 − 3.06 (m, 3H), 2.41 − 2.66 (m, 2H), 1.88 (br. s., 1H), 1.34 (br. s., 1H), 0.98 − 1.18 (m, 4H), 0.59 (br. s., 1H), 0.50 (br. s., 1H), 0.43 (d, J = 6.3 Hz, 2H); LC−MS : m/z 450.6 (M+H)
化合物番号500
表題化合物を、方法G2を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−ヒドロキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びプロピオル酸から調製した。
1H NMR (クロロホルム−d) δ 4.98 (s, 1H), 4.72 − 4.94 (m, 1H), 4.28 − 4.39 (m, 1H), 4.21 (d, J = 12.8 Hz, 1H), 3.98 − 4.15 (m, 2H), 3.82 − 3.98 (m, 2H), 3.61 − 3.82 (m, 2H), 3.37 − 3.53 (m, 1H), 3.09 − 3.35 (m, 2H), 2.90 − 3.08 (m, 3H), 2.41 − 2.69 (m, 2H), 1.82 − 1.96 (m, 1H), 1.72 (br. s., 1H), 1.30 − 1.40 (m, 1H), 1.01 − 1.24 (m, 4H), 0.60 (br. s., 1H), 0.52 (br. s., 1H), 0.44 (d, J = 6.0 Hz, 2H); LC−MS : m/z 448.5 (M+H)
化合物番号502
表題化合物を、方法G2を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びメタクリル酸から調製した。
1H NMR (クロロホルム−d) δ 5.26 (s, 1H), 5.09 (s, 1H), 4.67 − 4.86 (m, 2H), 4.25 (d, J = 12.8 Hz, 1H), 4.15 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 8.3 Hz, 1H), 3.58 − 3.72 (m, 5H), 3.32 (s, 3H), 3.23 (br. s., 1H), 3.02 − 3.16 (m, 1H), 2.83 − 3.02 (m, 3H), 2.51 − 2.73 (m, 2H), 1.86 − 2.07 (m, 4H), 1.30 (br. s., 1H), 0.94 − 1.17 (m, 4H), 0.53 (br. s., 1H), 0.46 (br. s., 1H), 0.21 − 0.42 (m, 2H); LC−MS : m/z 478.6 (M+H)
化合物番号501
表題化合物を、方法G2を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びナトリウム3−ヒドロキシプロパノエートから調製した。
1H NMR (クロロホルム−d) δ 4.70 − 4.91 (m, 1H), 4.65 (s, 1H), 4.30 (d, J = 12.8 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 4.00 − 4.11 (m, 1H), 3.87 − 3.96 (m, 2H), 3.65 − 3.86 (m, 5H), 3.36 (s, 3H), 3.26 (br. s., 1H), 3.04 − 3.19 (m, 1H), 2.89 − 3.04 (m, 3H), 2.45 − 2.74 (m, 5H), 1.89 − 2.01 (m, 1H), 1.31 (br. s., 1H), 0.98 − 1.21 (m, 4H), 0.53 − 0.74 (m, 1H), 0.50 (br. s., 1H), 0.17 − 0.46 (m, 2H); LC−MS : m/z 482.6 (M+H)
化合物番号480
表題化合物を、方法G1を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び塩化アセチルから調製した。
1H NMR (クロロホルム−d)δ 4.77 (q, J = 16.9 Hz, 2H), 4.66 (s,0.5H), 4.30 (d, J = 12.8 Hz, 1H), 4.20 (d, J = 12.3 Hz, 1.5H), 3.76 − 3.91 (m, 1H), 3.62 − 3.76 (m, 2H), 3.23 − 3.31 (m, 0.5H), 3.17 (dd, J = 11.3, 6.5 Hz, 1.5H), 2.88 − 3.07 (m, 3H), 2.15 − 2.26 (m, 4H), 1.89 − 2.00 (m, 1H), 1.77 − 1.89 (m, 1H), 1.30 − 1.55 (m, 1H), 1.10 − 1.20 (m, 2H), 0.89 − 1.10 (m, 4H), 0.69 − 0.82 (m, 2H), 0.59 (br. s., 1H), 0.24 − 0.54 (m, 3H); LC−MS : m/z 434.6 (M+H)
化合物番号481
表題化合物を、方法G1を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びメタンスルホニルクロリドから調製した。
1H NMR (クロロホルム−d)δ 4.48 (d, J = 2.8 Hz, 2H), 4.33 (d, J = 12.5 Hz, 1H), 4.22 (d, J = 12.3 Hz, 1H), 3.95 − 4.12 (m, 1H),3.43 − 3.64 (m, 3H), 3.27 (d, J = 7.3 Hz, 1H), 3.15 (s, 1H), 2.98 − 3.12 (m, 3H), 2.92 (s, 3H), 1.88 − 1.97 (m, 1H), 1.79 − 1.87 (m, 1H), 1.20 − 1.27 (m, 1H), 1.12 − 1.18 (m, 2H), 0.91 − 1.08 (m, 4H), 0.71 − 0.84 (m, 2H), 0.35 − 0.65 (m, 4H); LC−MS : m/z 470.6 (M+H)
化合物番号489
表題化合物を、方法G1を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び塩化アクリロイルから調製した。
1H NMR (クロロホルム−d)δ 6.67 (dd, J = 16.4, 10.7 Hz, 1H), 6.28 − 6.48 (m, 1H), 5.80 (d, J = 10.5 Hz, 1H), 4.72 − 5.02 (m, 2H), 4.46 (d, J = 6.3 Hz, 1H), 4.33 (d, J = 12.8 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 3.74 − 4.03 (m, 3H), 3.19 (br. s., 2H), 3.02 (br. s., 3H), 2.00 (br. s., 1H), 1.70 (br. s., 1H), 1.37 − 1.52 (m, 1H), 1.16 (br. s., 2H), 0.93 − 1.11 (m, 4H), 0.72 − 0.87 (m, 2H), 0.62 (br. s., 1H), 0.45 − 0.55 (m, 2H), 0.29 − 0.45 (m, 1H); LC−MS : m/z 446.6 (M+H)
化合物番号491
表題化合物を、方法G2を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びプロピオル酸から調製した。
1H NMR (クロロホルム−d)δ 4.98 (s, 0.5H), 4.71 − 4.91 (m, 1.5H), 4.53 (br. s., 1H), 4.34 (d, J = 12.5 Hz, 1H), 4.24 (d, J = 12.3 Hz, 1H), 3.97 − 4.16 (m, 2H), 3.81 − 3.97 (m, 1H), 3.55 − 3.78 (m, 1H), 3.14 − 3.35 (m, 2H), 2.90 − 3.13 (m, 3H), 1.86 − 1.99 (m, 1H), 1.30 − 1.58 (m, 2H), 1.13 − 1.23 (m, 2H), 1.03 − 1.13 (m, 3H), 1.00 (br. s., 1H), 0.71 − 0.84 (m, 2H), 0.61 (br. s., 1H), 0.45 − 0.55 (m, 2H), 0.22 − 0.45 (m, 1H); LC−MS : m/z 444.5 (M+H)
化合物番号493
表題化合物を、方法G1を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び2−クロロエタンスルホニルクロリドから調製した。
1H NMR (クロロホルム−d)δ 6.52 (dd, J = 16.6, 9.8 Hz, 1H), 6.38 (d, J = 16.6 Hz, 1H), 6.11 (d, J = 9.8 Hz, 1H), 4.39 − 4.50 (m, 3H), 4.34 (d, J = 12.8 Hz, 1H), 4.24 (d, J = 12.3 Hz, 1H), 3.58 − 3.85 (m, 1H), 3.51 (dtd, J = 18.9, 12.5, 5.8 Hz, 2.5H), 3.13 − 3.38 (m, 1.5H), 3.07 (t, J = 5.8 Hz, 3H), 1.77 − 1.88 (m, 1H), 1.31 − 1.50 (m, 2H), 1.13 − 1.22 (m, 2H), 0.95 − 1.11 (m, 4H), 0.76 − 0.86 (m, 2H), 0.62 (br. s., 1H), 0.29 − 0.56 (m, 3H); LC−MS : m/z 482.6 (M+H)
化合物番号494
表題化合物を、方法G1を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及びメチルカルボノクロリダートから調製した。
1H NMR (クロロホルム−d)δ 4.61 − 4.77 (m, 2H), 4.50 (br. s., 0.5H), 4.30 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.5 Hz, 1H), 3.86 − 4.06 (m, 0.5H), 3.78 (s, 3H), 3.63 − 3.77 (m, 3H), 3.50 (br. s., 1H), 3.18 (br. s., 1H), 2.84 − 3.09 (m, 3H), 1.91 (br. s., 1H), 1.36 − 1.51 (m, 1H), 1.22 − 1.35 (m, 1H), 1.12 − 1.20 (m, 2H), 0.94 − 1.10 (m, 4H), 0.73 − 0.85 (m, 2H), 0.62 (br. s., 1H), 0.33 − 0.56 (m, 3H); LC−MS : m/z 450.6 (M+H)
化合物番号497
表題化合物を、方法G2を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び2−シアノ酢酸から調製した。
1H NMR (クロロホルム−d)δ 4.70 − 4.91 (m, 1H), 4.67 (s, 1H), 4.33 (d, J = 12.5 Hz, 1H), 4.22 (d, J = 11.5 Hz, 1H), 3.94 − 4.15 (m, 0.5H), 3.70 − 3.94 (m, 2.5H), 3.60 − 3.69 (m, 1H), 3.43 − 3.60 (m, 1H), 3.12 − 3.34 (m, 1H), 2.99 − 3.12 (m, 2H), 2.89 − 2.99 (m, 1H), 1.87 − 1.96 (m, 2H), 1.69 (br. s., 1H), 1.12 − 1.22 (m, 2H), 0.91 − 1.11 (m, 4H), 0.71 − 0.83 (m, 2H), 0.59 (br. s., 1H), 0.29 − 0.54 (m, 3H); LC−MS : m/z 459.6 (M+H)
化合物番号499
表題化合物を、方法G2を用いて(R)−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び(E)−ブタ−2−エン酸から調製した。
1H NMR (クロロホルム−d)δ 6.85 − 7.03 (m, 1H), 6.23 − 6.43 (m, 1H), 4.70 − 4.99 (m, 2H), 4.53 (br. s., 1H), 4.26 − 4.37 (m, 1H), 4.20 (d, J = 12.5 Hz, 1H), 3.90 − 4.06 (m, 1H), 3.68 − 3.90 (m, 2H), 3.39 − 3.66 (m, 1H), 3.09 − 3.39 (m, 1H), 2.99 (br. s., 3H), 1.84 − 2.03 (m, 4H), 1.61 − 1.79 (m, 1H), 1.36 − 1.51 (m, 1H), 1.10 − 1.20 (m, 2H), 0.92 − 1.10 (m, 4H), 0.74 − 0.85 (m, 2H), 0.60 (br. s., 1H), 0.27 − 0.54 (m, 3H); LC−MS : m/z 460.6 (M+H)
化合物番号490
表題化合物を、方法G1を用いて(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3,3,3−トリフルオロプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−4−カルボニトリル及び塩化アクリロイルから調製した。
1H NMR (クロロホルム−d)δ 6.66 (dd, J = 16.1, 10.8 Hz, 1H), 6.37 (d, J = 16.8 Hz, 1H), 5.68 − 5.97 (m, 1H), 4.72 − 5.01 (m, 2H), 4.44 (t, J = 6.1 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.3 Hz, 1H), 3.76 − 3.98 (m, 3H), 3.72 (br. s., 1H), 3.30 (d, J = 8.8 Hz, 2H), 3.05 − 3.20 (m, 2H), 3.01 (br. s., 2H), 1.99 (br. s., 1H), 1.37 (br. s., 1H), 0.95 − 1.24 (m, 4H), 0.60 (br. s., 1H), 0.52 (br. s., 1H), 0.36 − 0.48 (m, 2H); LC−MS : m/z 488.5 (M+H)
ステップH:tert−ブチル5−シアノ−8−シクロプロピル−6−(2−フルオロ−4−(メトキシカルボニル)フェニル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート
DMF(150mL)中の2−フルオロ−4−(メトキシカルボニル)フェニルボロン酸(400mg、2mmol)の溶液に、tert−ブチル5−シアノ−8−シクロプロピル−6−(トリフルオロメチルスルホニルオキシ)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(896mg、2mmol)、ジクロロ−ビス(トリフェニルホスフィン)パラジウム(II)(140mg、0.2mmol)及び炭酸カリウム(420mg、6mmol)を添加し、混合物を窒素下90℃で10時間撹拌した。混合物を酢酸エチル及び水で希釈した。有機層を分離し、ブラインで洗浄し、硫酸マグネシウムで乾燥して真空濃縮した。フラッシュカラムクロマトグラフィー(10%酢酸エチル/石油エーテル)により、表題化合物をオフホワイト色の固体として得て(780mg)、これをさらなる精製なしに次のステップに直接使用した。LC−MS:m/z 352.5(M+H)。
MeOH(5mL)中のtert−ブチル5−シアノ−8−シクロプロピル−6−(2−フルオロ−4−(メトキシカルボニル)フェニル)−3,4−ジヒドロ−2,7−ナフチリジン−2(1H)−カルボキシレート(270mg 0.5mmol)の溶液に、1NのHCl/MeOH溶液(20mL)を添加した。反応が完了するまで混合物を室温で撹拌した。溶媒を真空除去することで、粗生成物を淡黄色の油として得て(240mg)、これをさらなる精製なしに次のステップに使用した。LC−MS:m/z 352.5(M+H)。
塩化メチレン(10mL)中のメチル4−(4−シアノ−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−3−イル)−3−フルオロベンゾエート塩酸塩(97mg、0.25mmol)及びEt3N(0.1mL、0.75mmol)の溶液に、2−クロロエタンスルホニルクロリド(62mg、0.375mmol)を添加した。混合物を室温で3時間撹拌した。TLCによって出発物質が生成物に完全に変換されたことが示された後、反応混合物を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗製物を分取HPLC分離(PE:EA/80:20)により精製することで、55mgの表題化合物をオフホワイト色の油として得た。
1H NMR (クロロホルム−d)δ 7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.87 (dd, J = 10.4, 1.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 6.55 (dd, J = 16.6, 9.8 Hz, 1H), 6.41 (d, J = 16.6 Hz, 1H), 6.15 (d, J = 9.5 Hz, 1H), 4.59 (s, 2H), 3.97 (s, 3H), 3.59 (t, J = 5.9 Hz, 2H), 3.20 (t, J = 5.8 Hz, 2H), 1.88 − 2.01 (m, 1H), 1.24 − 1.31 (m, 2H), 1.08 − 1.18 (m, 2H); LC−MS : m/z 442.5 (M+H)
塩化メチレン(10mL)中の(メチル4−(4−シアノ−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,7−ナフチリジン−3−イル)−3−フルオロベンゾエート塩酸塩(97mg,0.25mmol)、プロピオル酸(26mg、0.375mmol)及びDIPEA(97mg、0.75mmol)の溶液に、HATU(142mg、0.375mmol)を添加した。反応混合物を室温で2時間撹拌した。有機相を1NのHCl水溶液(1×20mL)、飽和NaHCO3及びブラインで洗浄し、無水Na2SO4で乾燥して真空濃縮した。粗生成物を分取HPLC(PE:EA/80:20)により精製することで、52mgの表題化合物をオフホワイト色の油として得た。
1H NMR (クロロホルム−d)δ 7.95 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 10.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 5.14 (s, 0.5H), 4.98 (s, 1.5H), 4.14 (t, J = 5.8 Hz, 1.5H), 3.86 − 4.06 (m, 3.5H), 3.28 (s, 1H), 3.03 − 3.24 (m, 2H), 2.02 − 2.12 (m, 1H), 1.21 − 1.29 (m, 2H), 1.10 − 1.19 (m, 2H); LC−MS : m/z 404.4 (M+H)
1H NMR (クロロホルム−d) δ 6.50 (dd, J = 16.6, 9.8 Hz, 1H), 6.36 (d, J = 16.6 Hz, 1H), 6.09 (d, J = 9.8 Hz, 1H), 4.41 (s, 2H), 3.62 − 3.76 (m, 4H), 3.49 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 5.9 Hz, 2H), 2.46 − 2.66 (m, 4H), 2.36 (s, 3H), 1.65 − 1.86 (m, 1H), 1.09 − 1.20 (m, 2H). LC−MS : m/z 388.2 (M+H)
ステップA:tert−ブチル4−(シクロプロパンカルボニル)−3−オキソピペリジン−1−カルボキシレート
−70℃で、THF(20mL)中のtert−ブチル3−オキソピペリジン−1−カルボキシレート(5.5g、27.6mmol)の溶液に、LDA(11mL、16.8mmol)を徐々に添加した。混合物を−70℃で20分間撹拌した後、シクロプロパンカルボニルクロリド(1.58ml、16.2mmol)を添加した。得られた混合物をさらに10分間撹拌し、0℃に加温させて、次に水(10mL)中の飽和NH4Clでクエンチした。次にEA(30mL)を添加し、有機相を分離し、乾燥し、濃縮することで淡色の油を得て、これをフラッシュカラム(PE:EA=5:1)で精製して4gの表題化合物11を得て、これを次のステップにさらなる精製なしに直接使用した。
EtOH(7ml)中の化合物11(3g、11.6mmol)の溶液に、Et2NH(1mL)及び2−シアノアセトアミド(1.47g、17.5mmol)を添加した。混合物を室温で2日間撹拌した。得られた沈殿物をろ過し、乾燥させることで1gの表題化合物12を得て、これをさらなる精製なしに次のステップに使用した。1H NMR (クロロホルム−d) δ: 4.58 (br. s., 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.76 (br. s., 2H), 1.49 (s, 9H), 0.92 − 1.05 (m, 4H).
−40℃で、Et3NをDCM(10ml)中の12の溶液に徐々に添加した。次に同じ温度でトリフリン酸無水物を添加した。反応物を−30℃から0℃までさらに3時間撹拌した。TLCを使用して、出発物質が完全に消費されたことを観測した。次に水(10mL)を反応物に添加し、有機相を分離し、濃縮し、PTLC(EA:PE=1:2)により精製することで、600mgの表題化合物13を得た。1H NMR (クロロホルム−d) δ 4.78 (br. s., 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.8 Hz, 2H), 2.01 (br. s., 1H), 1.51 (s, 9H), 1.19 − 1.31 (m, 4H).
化合物13(100mg、0.223mmol)及びシクロプロピルピペラジン(170mg、1.35mmol)の溶液を封管において80℃に加熱し、同じ温度でさらに12時間撹拌した。得られた溶液を濃縮し、PTLC(EA:PE=1:1)により精製することで、80mgの表題化合物14を得た。1H NMR (クロロホルム−d) δ 4.62 (br. s., 2H), 4.28 (d, 1H), 4.07 − 4.18 (m, 1H), 3.58 − 3.72 (m, 2H), 3.24 − 3.38 (m, 2H), 3.16 (dd, 10.5 Hz, 1H), 3.00 (td, J = 12.0, 3.1 Hz, 1H), 2.89 (t, J = 5.3 Hz, 2H), 2.26 (td, J = 9.8, 2.8 Hz, 1H), 1.88 (br. s., 1H), 1.52 (s, 9H), 1.08 − 1.16 (m, 2H), 1.04 (d, J = 6.5 Hz, 2H), 0.65 − 0.69 (m, 2H), 0.49 − 0.59 (m, 1H), 0.38 − 0.47 (m, 1H).
DCM(2mL)中の14(60mg、0.141mmol)、3−メトキシプロパン酸(22mg、0.17mmol)、HATU(8mg)の溶液を、室温で2時間撹拌した。反応物を水で洗浄し、濃縮し、PTLC(EA:PE=2:3)により精製することで、50mgの表題化合物15を得た。1H NMR (クロロホルム−d) δ: 4.65 (br. s., 2H), 3.99 − 4.29 (m, 3H), 3.58 − 3.88 (m, 4H), 3.32 − 3.48 (m, 3H), 2.84 (t, J = 5.3 Hz, 2H), 2.58 (t, J = 6.3 Hz, 2H), 2.01 (br. s., 1H), 1.81 (m, 1H), 1.47 − 1.54 (m, 9H), 1.06 − 1.15 (m, 2H), 1.02 (dt, J = 7.7, 2.9 Hz, 2H)
HCl.MTBE(1N、5mL)中の5(50mg)の溶液を2時間撹拌した。得られた溶液を濃縮して濃厚な油を得て、これをDCM(2mL)に溶解し、アクリル酸塩化物(17mg)及びEt3N(20mg)で処理してさらに10分間撹拌した。反応物からPTLC(PE:EA=1:1)を用いて表題化合物を単離して、10mgの化合物番号483を得た。1H NMR (クロロホルム−d)δ 6.68 (dd, J = 16.8, 10.5 Hz, 1H), 6.38 (d, J = 16.8 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 4.91 (br. s., 1H), 4.78 (br. s., 1H), 4.29 (d, J = 11.8 Hz, 1H), 4.18 (d, J = 12.3 Hz, 2H), 3.84 (br. s., 2H), 3.53 − 3.79 (m, 3H), 3.37 (s, 3H), 2.91 (br. s., 3H), 2.63 (d, J = 6.5 Hz, 2H), 2.01 (br. m, H), 1.08 − 1.20 (m, 2H), 1.04 (br. s., 2H), 0.58 (br. s., 2H), 0.41 (br. s., 2H); LC−MS : m/z 464.8 (M+H)+
(R)−6−アクリロイル−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−2,6−ナフチリジン−4−カルボニトリル
1H NMR (クロロホルム−d)δ 6.68 (dd, J = 16.8, 10.5 Hz, 1H), 6.38 (d, J = 16.8 Hz, 1H), 5.80 (d, J = 10.8 Hz, 1H), 4.91 (br. s., 1H), 4.78 (br. s., 1H), 4.29 (d, J = 11.8 Hz, 1H), 4.18 (d, J = 12.3 Hz, 2H), 3.84 (br. s., 2H), 3.53 − 3.79 (m, 3H), 3.37 (s, 3H), 2.91 (br. s., 3H), 2.63 (d, J = 6.5 Hz, 2H), 2.01 (br. m, H), 1.08 − 1.20 (m, 2H), 1.04 (br. s., 2H), 0.58 (br. s., 2H), 0.41 (br. s., 2H); LC−MS : m/z 464.8 (M+H)+
(R)−6−アクリロイル−3−(4−(シクロプロパンカルボニル)−3−シクロプロピルピペラジン−1−イル)−1−シクロプロピル−5,6,7,8−テトラヒドロ−2,6−ナフチリジン−4−カルボニトリル
3−メトキシプロパン酸の代わりにシクロプロパンカルボニルクロリドであることを除き、化合物番号483と同じ手順を用いて表題化合物を合成した(ステップE)。
1H NMR (クロロホルム−d)δ 6.69 (dd, J = 16.8, 10.5 Hz, 1H), 6.39 (d, J = 16.6 Hz, 1H), 5.81 (d, J = 11.0 Hz, 1H), 4.92 (br. s., 1H), 4.79 (br. s., 1H), 4.32 (d, J = 12.8 Hz, 1H), 4.22 (d, J = 12.3 Hz, 2H), 3.85 (br. s., 4H), 2.92 (br. s., 2H), 2.02 (br. s., 2H), 1.23 − 1.38 (m, 4H), 1.11 − 1.23 (m, 2H), 0.97 − 1.10 (m, 4H), 0.73 − 0.97 (m, 4H), 0.31 − 0.60 (m, 2H). LC−MS : m/z 446.9 (M+H)+
(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−6−(メチルスルホニル)−5,6,7,8−テトラヒドロ−2,6−ナフチリジン−4−カルボニトリル
1H NMR (クロロホルム−d)δ 4.51 (s, 2H), 4.30 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 12.5 Hz, 1H), 3.73 (t, J = 5.8 Hz, 3H), 3.61 (br. m., 5H), 3.38 (s, 3H), 2.86 − 3.05 (m, 6H), 2.65 (m, 2H), 1.87 − 2.11 (m, 2H), 1.04 − 1.23 (m,4H), 0.37 − 0.64 (m, 4H). LC−MS : m/z 462.9 (M+H)+
(R)−1−シクロプロピル−3−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−6−プロピオロイル−5,6,7,8−テトラヒドロ−2,6−ナフチリジン−4−カルボニトリル
アクリル酸塩化物の代わりにプロピオル酸であることを除き、化合物番号483と同じ手順を用いて表題化合物を合成した(ステップF)。
1H NMR (クロロホルム−d)δ 5.00 (d, J = 4.0 Hz, 1H), 4.86 (s, 1H), 4.25 − 4.50 (m, 1H), 4.20 (d, J = 12.8 Hz, 1H), 4.02 − 4.15 (m, 2H), 3.78 − 4.02 (m, 2H), 3.57 − 3.78 (m, 3H), 3.33 − 3.41 (m, 3H), 3.10 − 3.19 (m, 1H), 2.85 − 3.10 (m, 3H), 2.46 − 2.75 (m, 2H), 2.11 − 2.26 (m, 1H), 1.87 − 2.11 (m, 1H), 0.97 − 1.24 (m, 4H), 0.59 (br. s., 1H), 0.52 (br. s., 1H), 0.22 − 0.48 (m, 2H). LC−MS: m/z 462.7 (M+H)+
(R)−tert−ブチル8−シアノ−5−シクロプロピル−7−(3−シクロプロピル−4−(3−メトキシプロパノイル)ピペラジン−1−イル)−3,4−ジヒドロ−2,6−ナフチリジン−2(1H)−カルボキシレート
1H NMR (クロロホルム−d) δ: 5.45 (d, J = 3.3 Hz, 1H), 5.29 − 5.40 (m, 1H), 5.24 (dd, J = 16.6, 3.0 Hz, 1H), 4.82 (s, 2H), 4.29 (d, J = 12.5 Hz, 1H), 4.19 (d, J = 12.5 Hz, 1H), 4.06 (br. s., 1H), 3.86 (br. s., 2H), 3.57 − 3.79 (m, 3H), 3.32 − 3.48 (m, 3H), 3.27 (br. s., 1H), 3.10 (d, J = 13.6 Hz, 1H), 2.86 − 3.05 (m, 3H), 2.69 (br. s., 1H), 2.64 (br. s., 1H), 2.01 (dd, J = 7.5, 3.8 Hz, 1H), 1.58 − 1.84 (m, 2H), 1.38 − 1.51 (m, 1H), 1.30 − 1.38 (m, 2H), 1.27 (br. s., 2H), 0.97 − 1.20 (m, 4H), 0.89 (t, J = 6.5 Hz, 1H), 0.58 (br. s., 1H), 0.52 (br. s., 1H), 0.42 (br. s., 2H). LC−MS: m/z 482.2 (M+H)+
Claims (35)
- 構造式I
(I)
を有する化合物またはその薬学的に許容可能な塩であって、式中:
Xは、CR4またはNであり;
Yは、−N(R5)−または−CH(R5)−であり;
Zは、−O−、−S−、−C(R)2−またはN(R7)であり;
Wは、C(R1)(R1)またはN(R7)であり;但し、ZとWとの両方が同時にN(R7)であることはなく;
Vは、NまたはC(R)であり;
各Rは、水素、メチルまたはCF3から独立して選択され;
各R1は、水素、アルコキシ、または場合によりOH若しくはSHで置換されているアルキルから独立して選択され;
または2個のR1が、それらが結合している炭素原子と一緒になって、3〜7員シクロアルキル、または4〜7員飽和ヘテロシクリル環を形成し、ここで前記シクロアルキルまたはヘテロシクリルは、場合によりメチル、ハロまたはCF3で置換されており;
R2は、フェニル、3〜7員シクロアルキル、C2〜C4アルキル、またはCF3から選択され、ここでフェニルまたはシクロアルキルは、場合により、メチル、CF3またはフルオロから選択される単一置換基で置換されており;
各R3は、−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C1〜C4フルオロアルキル、−C(O)−O−(C1〜C4アルキル)、−フェニル、−ヘテロアリール、C3〜C7シクロアルキル、−CH2−N(C1〜C4アルキル)2、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、場合によりハロまたはOHで置換されている−C1〜C4アルキルから独立して選択されるか、または2個のR3が一緒になって3〜8飽和環または縮合フェニルを形成し、ここで前記飽和環または縮合フェニルは、場合により1〜2個のメチルで置換されており;
R4は、水素、−CN、ハロ、C1〜C4アルコキシ、−CH2NH(C1〜C4アルキル)、C2〜C4アルケニル、C2〜C4アルキニル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、C1〜C4フルオロアルキル、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、または5員ヘテロアリールから選択され;
R5は、C1〜C4アルキル、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−Q、−C(O)−O−(C0〜C2アルキレン)−Q、−C(O)−(C1〜C2アルキレン)−O−(C0〜C2アルキレン)−Q、−C(O)−C(O)−Q、−S(O)2−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)C(O)O−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)N(R6)−(C2〜C6アルキニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C2〜C6アルケニル)、C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−C(O)C(O)N(R)(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−S(O)0〜2−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)C(O)N(R6)(C1〜C6アルキル)、−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2−(C1〜C6アルキル)、またはC(O)−(C1〜C4アルキレン)−N(R6)S(O)2Qから選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、C(O)CF3、CN、−OHまたはCO2Hで置き換えられており;
各R6は、水素及びメチルから独立して選択され;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、場合により−OHで置換されているC1〜C4アルキル、C1〜C4アルコキシ、−(C1〜C4アルキレン)−OC(O)O−(C1〜C4アルキル)、−C(O)O−(C1〜C4アルキル)、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;
各R7は、独立して−G−L−Mであり;
Gは、結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここで場合により炭化水素鎖の1個、2個または3個のメチレン単位は、独立して、−NR8−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
Lは、共有結合であるか、或いは二価C1〜8飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでLの1個、2個、または3個のメチレン単位は、場合により、及び独立して、シクロプロピレン、−NR8−、−N(R8)C(O)−、−C(O)N(R8)−、−N(R8)SO2−、SO2N(R8)−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
MはEであるか、或いは窒素、酸素、または硫黄から独立して選択される0〜3個のヘテロ原子を有する3〜10員単環式または二環式飽和環、部分的に不飽和の環、または芳香環であり、且つ前記環は、−D−E、オキソ、NO2、ハロゲン、CN、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルから独立して選択される1〜4個の基で置換されており;
Dは、共有結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでDの1個または2個のメチレン単位は、場合により、及び独立して、−NR8−、−S−、−O−、−C(O)−、−SO−、またはSO2−に置き換えられており;
Eは、水素、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、ここで前記アルキル、アルケニルまたはアルキニルは、場合によりオキソ、ハロゲン、またはCNで置換されており;
各R8は、独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、またはフェニルか、窒素、酸素、若しくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜7員ヘテロシクリルか、または窒素、酸素、若しくは硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員単環式ヘテロアリール環から選択される場合により置換されている基であり;及び
mは、0、1、2または3である
化合物。 - Xが、CR4またはNであり;
Yが、−N(R5)−またはCH(R5)−であり;
Zが、−O−、−S−、−C(R)2−またはN(R7)であり;
Wが、C(R1)(R1)またはN(R7)であり;但し、(1)Zが−C(R)2−のとき、WはC(R1)(R1)ではなく;且つ(2)ZとWとの両方が同時にN(R7)であることはなく;
Vが、NまたはC(R)であり;
各Rが、水素、メチルまたはCF3から独立して選択され;
各R1が、水素、アルコキシ、または場合によりOH若しくはSHで置換されているアルキルから独立して選択され;
または2個のR1が、それらが結合している炭素原子と一緒になって、3〜7員シクロアルキル、または4〜7員飽和ヘテロシクリル環を形成し、ここで前記シクロアルキルまたはヘテロシクリルは、場合によりメチル、ハロまたはCF3で置換されており;
R2が、フェニル、3〜7員シクロアルキル、またはC2〜C4アルキルから選択され、ここでフェニルまたはシクロアルキルは、場合により、メチル、CF3またはフルオロから選択される単一置換基で置換されており;
各R3が、場合によりハロで置換されている−C1〜C4アルキル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、−C1〜C4フルオロアルキル、−C(O)−O−(C1〜C4アルキル)、−フェニル、−ヘテロアリール、C3〜C7シクロアルキル、−CH2−N(C1〜C4アルキル)2、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)から独立して選択されるか、または2個のR3が一緒になって3〜8飽和環または縮合フェニルを形成し、ここで前記飽和環または縮合フェニルは、場合により1〜2個のメチルで置換されており;
R4が、水素、−CN、ハロ、C1〜C4アルコキシ、−CH2NH(C1〜C4アルキル)、C2〜C4アルケニル、C2〜C4アルキニル、−(C1〜C4アルキル)−O−(C1〜C4アルキル)、C1〜C4フルオロアルキル、C(O)−N−(C1〜C4アルキル)2、−C(O)−NH−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、または5員ヘテロアリールから選択され;
R5が、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−Q、−C(O)−O−(C1〜C2アルキレン)−Q、−C(O)−(C1〜C2アルキレン)−O−(C0〜C2アルキレン)−Q、−C(O)−C(O)−Q、−S(O)2−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)N(R6)−(C2〜C6アルキニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C2〜C6アルケニル)、−C(O)−(C0〜C2アルキレン)−N(R6)−(C0〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−C(O)C(O)N(R)(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−S(O)0〜2−(C1〜C4アルキル)、−S(O)2−(C1〜C4アルキル)、)、−C(O)−(C1〜C4アルキレン)−C(O)C(O)N(R6)(C1〜C6アルキル)、−C(O)−(C1〜C4アルキレン)−N(R6)S(O)2−(C1〜C6アルキル)、またはC(O)−(C1〜C4アルキレン)−N(R6)S(O)2Qから選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により、−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、またはC(O)CF3で置き換えられており;
各R6が、水素及びメチルから独立して選択され;
Qが、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、C1〜C4アルキル、C1〜C4アルコキシ、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;
各R7が、独立して−G−L−Mであり;
Gが、結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここで場合により炭化水素鎖の1個、2個または3個のメチレン単位は、独立して、−NR8−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
Lが、共有結合であるか、或いは二価C1〜8飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでLの1個、2個、または3個のメチレン単位は、場合により、及び独立して、シクロプロピレン、−NR8−、−N(R8)C(O)−、−C(O)N(R8)−、−N(R8)SO2−、SO2N(R8)−、−O−、−C(O)−、−OC(O)−、−C(O)O−、−S−、−SO−、−SO2−、−C(=S)−、−C(=NR8)−、−N=N−、またはC(=N2)−に置き換えられており;
MがEであるか、或いは窒素、酸素、または硫黄から独立して選択される0〜3個のヘテロ原子を有する3〜10員単環式または二環式飽和環、部分的に不飽和の環、または芳香環であり、且つ前記環は、−D−E、オキソ、NO2、ハロゲン、CN、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルから独立して選択される1〜4個の基で置換されており;
Dが、共有結合であるか、或いは二価C1〜C6飽和または不飽和直鎖状または分枝状炭化水素鎖であり、ここでDの1個または2個のメチレン単位は、場合により、及び独立して、−NR8−、−S−、−O−、−C(O)−、−SO−、または−SO2−により置換されており;
Eが、水素、C1〜C6アルキル、C2〜C6アルケニル、またはC2〜C6アルキニルであり、ここで前記アルキル、アルケニルまたはアルキニルは、場合によりオキソ、ハロゲン、またはCNで置換されており;
各R8が、独立して、水素、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、またはフェニルか、窒素、酸素、若しくは硫黄から独立して選択される1〜2個のヘテロ原子を有する4〜7員ヘテロシクリルか、または窒素、酸素、若しくは硫黄から独立して選択される1〜4個のヘテロ原子を有する5〜6員単環式ヘテロアリール環から選択される場合により置換されている基であり;及び
mが、0、1、2または3であり;
但し:
Xが−C(CN)−であり、Yが−N(R5)−であり、mが0であり、R2がフェニルまたはC2〜C4アルキルであり、且つZが−O−または−S−である場合、各R1が同時にメチルであることはなく;及び
Xが−C(CN)−であり、Yが−N(R5)−であり、mが0であり、R2がフェニルまたはC2〜C4アルキルであり、且つZが−CH2−である場合、各R1が同時に水素であることはない、
請求項1に記載の化合物。 - Xが−C(CN)−である、請求項1に記載の化合物。
- 各R1が同じであり、メチル及び水素から選択される、請求項1または2に記載の化合物。
- Zが−O−である、請求項3に記載の化合物。
- Zが−C(CH3)2−であり、各R1が水素である、請求項3に記載の化合物。
- Zが−CH2−である、請求項3に記載の化合物。
- Zが−N(R7)−である、請求項3に記載の化合物。
- Yが−N(R5)−である、請求項1〜8のいずれか一項に記載の化合物。
- R2が、場合により単一のフルオロまたは単一のメチルで置換されているフェニル、シクロヘキシル、シクロペンチル、シクロブチル、場合により単一のメチルで置換されているシクロプロピル、イソプロピル、エチル及びメチルから選択される、請求項1〜9のいずれか一項に記載の化合物。
- R2が、シクロヘキシル、シクロブチル、シクロプロピル、エチル及びイソプロピルから選択される、請求項10に記載の化合物。
- R2がシクロヘキシルであり;Zが−O−であり;且つ各R1が水素である、請求項11に記載の化合物。
- R2が、シクロブチル、シクロプロピル、エチル及びイソプロピルから選択され;Zが−O−であり;且つ各R1がメチルである、請求項11に記載の化合物。
- R5が、−C(O)−(C1〜C4アルキル)、−C(O)−(CH2)0〜2−Q、−C(O)−(CH2)1〜2−O−(CH2)0〜2−Q、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−N(R6)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(CH2)0〜2−N(R6)−(C2〜C6アルケニル)、−C(O)−(CH2)1〜2−O−(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(CH2)0〜4−C(O)−O−(C1〜C4アルキル)、及び−C(O)−(CH2)1〜2−S−(C1〜C4アルキル)から選択される、請求項1〜13のいずれか一項に記載の化合物。
- R5が、−C(O)−(C0〜C2アルキレン)−C(O)N(R6)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−C(O)−(C1〜C6アルキル)、−C(O)−(C0〜C2アルキレン)−N(R6)C(O)O−(C1〜C6アルキル)である、請求項1〜14のいずれか一項に記載の化合物。
- 各R7が、
、または(CH2)1〜4−SHから独立して選択される、請求項1〜15のいずれか一項に記載の化合物。 - R7が、
、−C(O)−CH3、−SO2CH3及び−CH2CH2OHから独立して選択される、請求項1〜15のいずれか一項に記載の化合物。 - 構造式II:
(II)
を有する請求項1に記載の化合物であって、
式中:
各R1は同じであり、水素及びメチルから選択され;
R2は、場合により単一のフルオロまたは単一のメチルで置換されているフェニル、シクロヘキシル、シクロペンチル、シクロブチル、場合により単一のメチルで置換されているシクロプロピル、イソプロピル及びメチルから選択され;
R3aは、水素及びメチルから選択され;
R3bは、水素、メチル、エチル、イソブチル、イソプロピル、フェニル、−C(O)−O−CH2CH3、−C(O)−O−CH3、及び−CH2−O−CH3から選択され;
R3cは、水素及びメチルから選択され;
R3dは、水素、フェニル及びメチルから選択され;及び
R5は、請求項1にあるとおり定義される、
化合物。 - 各R1がメチルであり;且つ
R2が、エチル、イソプロピル、シクロプロピル及びシクロブチルから選択される、
請求項18に記載の化合物。 - R3a、R3c及びR3dが同時に水素であり;且つ
R3bが、(R)−メチル、(R)−エチル、(R)−イソプロピル、及びC(O)−O−CH2CH3から選択される、
請求項19に記載の化合物。 - 各R1が水素であり;且つ
R2がシクロヘキシルである、
請求項18に記載の化合物。 - R3a、R3c及びR3dが同時に水素であり;且つ
R3bが(R)−メチルである、
請求項120に記載の化合物。 - R5が、−C(O)−(CH2)0〜2−OCH3、−C(O)−CH2−OCH2CH3、−C(O)−フラニル、−C(O)−NH−CH2−CH=CH2、−C(O)−(CH2)1〜2−C(O)−OCH3、−C(O)−(CH2)2−SCH3、−C(O)−シクロプロピル、−C(O)−CH2−シクロプロピル、−C(O)−CH2CH3、−C(O)−(CH2)2CH3、−C(O)−CH2Cl、−C(O)−NH−CH3、−C(O)−CH2−チエニル、−C(O)−NH−(CH2)2−C(O)−OCH3、−C(O)−CH2−ピリジニル、−C(O)−(CH2)2−O−フェニル、−C(O)−CH2−ピラゾリル、及び−C(O)−オキサゾリルから選択される、請求項18〜22のいずれか一項に記載の化合物。
- 構造式(III)
(III)
を有する請求項1に記載の化合物であって、式中:
WまたはZの一方はN(R7)であり、且つWまたはZの他方はC(R1)(R1)であり;
各R1は同じであり、水素及びメチルから選択され;
R2は、場合により単一のフルオロまたは単一のメチルで置換されているフェニル、シクロヘキシル、シクロペンチル、シクロブチル、場合により単一のメチルで置換されているシクロプロピル、イソプロピル及びメチルから選択され;
R3aは、水素及びメチルから選択され;
R3bは、水素、メチル、エチル、イソブチル、イソプロピル、フェニル、C3〜C7シクロアルキル、−C(O)−O−CH2CH3、−C(O)−O−CH3、及び−CH2−O−CH3から選択され;
R3cは、水素及びメチルから選択され;
R3dは、水素、フェニル及びメチルから選択され;及び
R5は、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、−C(O)−(C1〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−C(O)−(C1〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、−C(O)−(C1〜C2アルキレン)−O−(C1〜C4アルキル)、−C(O)−O−(C1〜C4アルキレン)−O−(C1〜C4アルキル)、−(C0〜C4アルキレン)−O−C(O)−(C1〜C4アルキル)、−(C0〜C4アルキレン)−C(O)−O−(C1〜C4アルキル)、及び−(C0〜C4アルキレン)−O−(C1〜C4アルキル)から選択され、ここで:
R5に存在する任意のアルキレン部分が、場合によりOHまたはFで置換されており;
R5に存在する任意の末端メチル部分が、場合により、−CH2OH、CF3、−CH2F、−CH2Cl、C(O)CH3、またはC(O)CF3で置き換えられており;
Qは、アリール、ヘテロアリール、カルボシクリル及びヘテロシクリルから選択され;及びQは、C1〜C4アルキル、C1〜C4アルコキシ、−CN、フルオロ、クロロ、及びブロモから独立して選択される最大3個の置換基で場合により置換されており;及び
R7は、構造式Iと同様に定義される、
化合物。 - ZがN(R7)であり、且つWがCH2である、請求項24に記載の化合物。
- WがN(R7)であり、且つZがCH2である、請求項24に記載の化合物。
- R7が、C(O)C1〜C4アルキル、C(O)C2〜C4アルケニル、C(O)C2〜C4アルキニル、S(O)2C1〜C4アルキルまたはS(O)2C2〜C4アルケニルである、請求項24〜26のいずれか一項に記載の化合物。
- 式(II)の化合物において以下の立体配置
を有する、請求項1に記載の化合物。 - R5が、−C(O)−(C1〜C4アルキル)、−C(O)−(C0〜C2アルキレン)−Q、及び−C(O)−(C1〜C2アルキレン)−O−(C1〜C4アルキル)から選択される、請求項24〜28のいずれか一項に記載の化合物。
- 請求項1に記載の化合物と、薬学的に許容可能な担体とを含む医薬組成物。
- 第2の治療剤をさらに含む、請求項30に記載の組成物。
- 患者におけるα−ケトグルタレートからR(−)−2−ヒドロキシグルタレートへのNAPH依存性の還元を触媒する酵素の新しい能力をもたらすIDH1突然変異の存在によって特徴付けられる癌の治療方法であって、それを必要とする前記患者に請求項30に記載の組成物を投与するステップを含む、方法。
- 前記IDH1突然変異がIDH1 R132H突然変異である、請求項32に記載の方法。
- 前記癌が、神経膠腫(膠芽腫)、急性骨髄性白血病、肉腫、黒色腫、非小細胞肺癌、胆管癌、胆管癌、軟骨肉腫、骨髄異形成症候群(MDS)、骨髄増殖性新生物(MPN)、または結腸癌から選択される、請求項33に記載の方法。
- 前記それを必要とする患者に第2の治療剤を投与するステップをさらに含む、請求項32〜34のいずれか一項に記載の方法。
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JP2018524383A (ja) * | 2015-07-21 | 2018-08-30 | バイエル・ファルマ・アクティエンゲゼルシャフト | Midh1阻害剤としての縮合イミダゾール |
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CA2839616A1 (en) | 2012-12-20 |
ES2618637T3 (es) | 2017-06-21 |
AU2012269473B2 (en) | 2017-04-20 |
AU2012269473A1 (en) | 2014-01-09 |
CN103764658A (zh) | 2014-04-30 |
US9662327B2 (en) | 2017-05-30 |
CN103764658B (zh) | 2017-06-09 |
CA2839616C (en) | 2019-08-06 |
JP6196615B2 (ja) | 2017-09-13 |
US20140206673A1 (en) | 2014-07-24 |
EP2721033B1 (en) | 2016-12-07 |
EP2721033A1 (en) | 2014-04-23 |
WO2012171506A1 (en) | 2012-12-20 |
JP2017178968A (ja) | 2017-10-05 |
US20170210749A1 (en) | 2017-07-27 |
CN102827170A (zh) | 2012-12-19 |
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