JP5968983B2 - Syk阻害剤としての縮合複素芳香族ピロリジノン - Google Patents
Syk阻害剤としての縮合複素芳香族ピロリジノン Download PDFInfo
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- JP5968983B2 JP5968983B2 JP2014239677A JP2014239677A JP5968983B2 JP 5968983 B2 JP5968983 B2 JP 5968983B2 JP 2014239677 A JP2014239677 A JP 2014239677A JP 2014239677 A JP2014239677 A JP 2014239677A JP 5968983 B2 JP5968983 B2 JP 5968983B2
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- JP
- Japan
- Prior art keywords
- pyrrolo
- dihydro
- compound
- pyrimidin
- aminocyclohexylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- -1 heteroaromatic pyrrolidinones Chemical class 0.000 title claims description 296
- 239000003112 inhibitor Substances 0.000 title description 8
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- 125000001424 substituent group Chemical group 0.000 claims description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 229920006395 saturated elastomer Polymers 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 67
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 60
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 50
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 238000011282 treatment Methods 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 36
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000002950 monocyclic group Chemical group 0.000 claims description 22
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
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- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
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- JRTCSSCKQPIELQ-UHFFFAOYSA-N 2-(cyclohexylamino)-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(NC3CCCCC3)N=2)=C1 JRTCSSCKQPIELQ-UHFFFAOYSA-N 0.000 claims description 4
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- VPNLOOYVNORYBV-UONOGXRCSA-N 2-[[(1r,2s)-2-aminocyclohexyl]amino]-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(N[C@H]3[C@H](CCCC3)N)N=2)=C1 VPNLOOYVNORYBV-UONOGXRCSA-N 0.000 claims description 4
- NANBZQDYUFCFNV-LSDHHAIUSA-N 2-[[(1r,2s)-2-aminocyclohexyl]amino]-4-(3-methylanilino)spiro[6h-pyrrolo[3,4-d]pyrimidine-7,1'-cyclopropane]-5-one Chemical compound CC1=CC=CC(NC=2C3=C(C4(CC4)NC3=O)N=C(N[C@H]3[C@H](CCCC3)N)N=2)=C1 NANBZQDYUFCFNV-LSDHHAIUSA-N 0.000 claims description 4
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- FVJOLSXHWBIDLU-UHFFFAOYSA-N 2-(3-aminopiperidin-1-yl)-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(N=2)N2CC(N)CCC2)=C1 FVJOLSXHWBIDLU-UHFFFAOYSA-N 0.000 claims description 3
- IUAAVEWTWOMZRH-UHFFFAOYSA-N 2-(3-aminopyrrolidin-1-yl)-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(N=2)N2CC(N)CC2)=C1 IUAAVEWTWOMZRH-UHFFFAOYSA-N 0.000 claims description 3
- MOVFMVAKMICKFT-UHFFFAOYSA-N 2-[(2-amino-2-methylpropyl)amino]-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(NCC(C)(C)N)N=2)=C1 MOVFMVAKMICKFT-UHFFFAOYSA-N 0.000 claims description 3
- DCEDMRYXIHJASG-UHFFFAOYSA-N 2-[2-(aminomethyl)piperidin-1-yl]-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CC1=CC=CC(NC=2C=3C(=O)NCC=3N=C(N=2)N2C(CCCC2)CN)=C1 DCEDMRYXIHJASG-UHFFFAOYSA-N 0.000 claims description 3
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- UCFAUSQCVJRLNA-LSDHHAIUSA-N 2-[[(1r,2s)-2-(methylamino)cyclohexyl]amino]-4-(3-methylanilino)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound CN[C@H]1CCCC[C@H]1NC(N=C1NC=2C=C(C)C=CC=2)=NC2=C1C(=O)NC2 UCFAUSQCVJRLNA-LSDHHAIUSA-N 0.000 claims description 3
- HWJURIDHSVIDIZ-NWDGAFQWSA-N 2-[[(1r,2s)-2-aminocyclohexyl]amino]-4-(1,5-dimethylpyrazol-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one Chemical compound C1=NN(C)C(C)=C1C1=NC(N[C@H]2[C@H](CCCC2)N)=NC2=C1C(=O)NC2 HWJURIDHSVIDIZ-NWDGAFQWSA-N 0.000 claims description 3
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- NAMMXOIUVLUSKX-UHFFFAOYSA-N methyl 2-chloro-4-methyl-6-(1-methylpyrazol-4-yl)pyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(Cl)N=C1C1=CN(C)N=C1 NAMMXOIUVLUSKX-UHFFFAOYSA-N 0.000 description 2
- QMRKTYUCYOUYKF-UHFFFAOYSA-N methyl 4-chloro-2-(4-ethylpiperazin-1-yl)-6-(3-methylanilino)pyrimidine-5-carboxylate Chemical compound C1CN(CC)CCN1C1=NC(Cl)=C(C(=O)OC)C(NC=2C=C(C)C=CC=2)=N1 QMRKTYUCYOUYKF-UHFFFAOYSA-N 0.000 description 2
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- COLKJWHUCOXCHV-MOPGFXCFSA-N methyl 4-cyano-2-(1h-indazol-6-ylamino)-6-[[(1r,2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexyl]amino]pyridine-3-carboxylate Chemical compound C1=C(C#N)C(C(=O)OC)=C(NC=2C=C3NN=CC3=CC=2)N=C1N[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C COLKJWHUCOXCHV-MOPGFXCFSA-N 0.000 description 2
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- WDHIRWRYFLZTKU-UHFFFAOYSA-N methyl 4-cyano-6-(3-methylanilino)-2-[2-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]piperidin-1-yl]pyrimidine-5-carboxylate Chemical compound N1=C(N2C(CCCC2)CNC(=O)OC(C)(C)C)N=C(C#N)C(C(=O)OC)=C1NC1=CC=CC(C)=C1 WDHIRWRYFLZTKU-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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Description
Podolanczuk et al., Blood (2009) 113:3154−60を参照のこと。他の障害としては、急性脊髄性白血病、B細胞慢性リンパ性白血病、B細胞リンパ腫(例えば、マントル細胞リンパ腫)、及びT細胞リンパ腫(例えば、末梢T細胞リンパ腫)などの血液悪性疾患;ならびに肺癌、膵癌、及び結腸癌などの上皮性癌が挙げられる。例えば、Cynthia K. Hahn et al., Cancer Cell (2009) 16:281−294; D. H. Chu et al., Immnol. Rev. (1998) 165:167−180; A. L. Feldman et al., Leukemia (2008) 22:1139−43; A. Rinaldi et al., Br. J. Haematol. (2006) 132:303−316; B. Streubel et
al., Leukemia (2006) 20:313−18; Maike B
uchner et al., Cancer Research (2009) 69(13):5424−32; A. D. Baudot et al., Oncogene (2009) 28:3261−73; and Anurag Singh et al., Cancer Cell (2009) 15:489−500を参照のこと。
Gは、N及びC(R5)から選択され;
L1及びL2は、各々独立して、NH及び結合から選択され;
R1及びR2は、各々独立して、水素、ハロ、C1−3アルキル、及びC1−3ハロアルキルから選択されるか、又は、R1及びR2は、それらが結合する原子と共にC3−6シクロアルキルを形成し;
R3は、独立して、ハロ、オキソ、NO2、CN、R6、及びR7から選択される1〜5つの置換基で、各々、随意に置換される、C2−6アルキル、C3−8シクロアルキル、C2−5ヘテロシクリル、及びC1−9ヘテロアリールから選択され;
R4は、独立して、ハロ、オキソ、CN、R6、及びR7から選択される1〜5つの置換基で、各々、随意に置換される、C3−8シクロアルキル、C2−5ヘテロシクリル、C6−14アリール、及びC1−9ヘテロアリールから選択され;
R5は、水素、ハロ、CN、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C2−5ヘテロシクリル、C1−5ヘテロアリール、及びR10から選択され、ここで、前記アルキル、アルケニル、アルキニル部分が、独立して、ハロ、CN、オキソ、及びR10から選択される1〜5つの置換基で、各々、随意に置換され、ならびに前記ヘテロシクリル部分が3〜6環原子を有し、ならびに前記ヘテロアリール部分が5又は6環原子を有し、ならびに前記ヘテロシクリル及びヘテロアリール部分が、独立して、ハロ、NO2、CN、C1−4アルキル、C2−4アルケニル、C2−4アルキニル、C1−4
ハロアルキル、及びR10から選択される1〜4つの置換基で、各々、随意に置換され;
各R6は、独立して、−OR8、−N(R8)R9、−NR8C(O)R9、−C(O)R8、−C(O)OR8、−C(O)N(R8)R9、−C(O)N(R8)OR9、−C(O)N(R8)S(O)2R9、−N(R8)S(O)2R9、−S(O)nR8、及び−S(O)2N(R8)R9から選択され;
各R7が、独立して、ハロ、オキソ、−NO2、−CN、C1−6アルキル、C1−6ハロアルキル、及びR10から選択される1〜5つの置換基で、各々、随意に置換される、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル(CH2)m−、C6−14アリール−(CH2)m−、C2−5ヘテロシクリル(CH2)m−、及びC1−9ヘテロアリール−(CH2)m−から独立して選択され;
各R8及びR9は、独立して、水素又はハロ、オキソ、−NO2、−CN、C1−6アルキル、C1−6ハロアルキル、及びR10から選択される1〜5つの置換基で、各々、随意に置換される、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル(CH2)m−、C6−14アリール−(CH2)m−、C2−5ヘテロシクリル(CH2)m−、及びC1−9ヘテロアリール−(CH2)m−から独立して選択され;
各R10は、独立して、−OR11、−N(R11)R12、−N(R11)C(O)R12、−C(O)R11、−C(O)OR11、−C(O)N(R11)R12、−C(O)N(R11)OR12、−C(O)N(R11)S(O)2R12、−NR11S(O)2R12、−S(O)nR11、及び−S(O)2N(R11)R12から選択され;
各R11及びR12は、独立して、水素及びC1−6アルキルから選択され;
各nは、独立して、0、1及び2から選択され;ならびに
各mは、独立して、0、1、2、3、及び4から選択され;
式中、前述したヘテロアリール部分の各々は、独立して、N、O、及びSから選択される1〜4つのヘテロ原子を有し、ならびに前述したヘテロシクリル部分の各々は、飽和又は部分的に不飽和であり、及び独立して、N、O、及びSから選択される1つ又は2つのヘテロ原子を有する。
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−フルオロフェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−クロロフェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
4−(1H−インダゾール−6−イルアミノ)−2−((1R,2S)−2−アミノシクロヘキシルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−(トリフルオロメチル)フェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
シス−2−(2−アミノシクロヘキシルアミノ)−4−(3−(トリフルオロメチル)フェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(1−メチル−1H−ピラゾール−4−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(4−エチルピペラジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
シス−2−(2−ヒドロキシシクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノピペリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−メチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−イソブチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−フェニル−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(ベンゾ[b]チオフェン−3−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−エチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−ベンジル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(イミダゾ[1,2−a]ピリジン−3−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−プロピル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−(2−メトキシエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
4−(1H−インダゾール−6−イルアミノ)−6−((1R,2S)−2−アミノシクロヘキシルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(4−フルオロ−3−メチルフェニルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−クロロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(ピラゾロ[1,5−a]ピリジン−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
2−(2−(アミノメチル)ピペリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−(メチルスルホニル)フェニルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロペンチルアミノ)−4−(3−(メチルスルホニル)フェニルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−4−メチル−2−(4−(3−(メチルスルホニル)フェニルアミノ)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)ペンタンアミド;
(R)−4−メチル−2−(4−(1−メチル−1H−ピラゾール−4−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)ペンタンアミド;
2−((1R,2S)−2−(ジメチルアミノ)シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−(メチルアミノ)シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2’−((1R,2S)−2−アミノシクロヘキシルアミノ)−4’−(m−トリルアミノ)スピロ[シクロプロパン−1,7’−ピロロ[3,4−d]ピリミジン]−5’(6’H)−オン;
2−(2−アミノエチルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(2−アミノ−2−メチルプロピルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(5−オキソ−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−2−イルアミノ)アセトアミド;
2−((2−アミノエチル)(メチル)アミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(ピロリジン−2−イルメチルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノピロリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1,5−ジメチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1H−インドール−2−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1H−ピラゾール−5−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノプロピル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(ベンゾフラン−3−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(イミダゾ[1,2−a]ピリジン−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(ベンゾ[b]チオフェン−3−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1S,2R)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−6−(2−アミノ−3−エトキシプロピルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−6−(2−アミノ−3−エトキシプロピルアミノ)−7−フルオロ−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(2−アミノ−3,3,3−トリフルオロプロピルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−4−メチル−2−(3−オキソ−4−(m−トリルアミノ)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)ペンタンアミド;
6−(シス−4−アミノテトラヒドロフラン−3−イルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−エチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−エチル−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−シクロプロピル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−(ジフルオロメチル)−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−シクロプロピル−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
シス−6−(2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(シス−2−アミノ−4,4−ジフルオロシクロペンチルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(シス−2−アミノ−3,3−ジフルオロシクロヘキシルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(シス−2−アミノ−3,3−ジフルオロシクロヘキシルアミノ)−4−(1−(ジフルオロメチル)−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(シス−2−アミノ−3,3−ジフルオロシクロヘキシルアミノ)−4−(1−シクロプロピル−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(4−(1−(ジフルオロメチル)−1H−ピラゾール−4−イル)−7−フルオロ−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(4−(1−シクロプロピル−1H−ピラゾール−4−イル)−7−フルオロ−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(4−(ベンゾフラン−3−イル)−7−フルオロ−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−3−オキソ−4−(ピラゾロ[1,5−a]ピリジン−3−イル)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−クロロ−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−3−オキソ−4−(m−トリルアミノ)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−7−カルボニトリル;
(R)−6−(2−アミノ−3−メトキシプロピルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−6−(2−アミノ−3−メトキシプロピルアミノ)−3−オキソ−4−(m−トリルアミノ)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−7−カルボニトリル;
(R)−6−(2−アミノ−3−メトキシプロピルアミノ)−7−フルオロ−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
7−アクリロイル−6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−ヨ−ド−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−(1H−ピラゾール−4−イル)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−(シス−2−アミノ−3,3−ジフルオロシクロヘキシルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−(1−メチル−1H−ピラゾール−5−イル)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−4−アミノテトラヒドロ−2H−ピラン−3−イルアミノ)−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
tert−ブチル(1S,2R)−2−(3−オキソ−7−フェニル−4−(m−トリルアミノ)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)シクロヘキシルカルバマ−ト;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−メチル−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(m−トリルアミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−メチル−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−6−(2−アミノ−3−メトキシプロピルアミノ)−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(ピラゾロ[1,5−a]ピリジン−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(1−(ジフルオロメチル)−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(ベンゾフラン−3−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(S)−6−(3−アミノピロリジン−1−イル)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(S)−6−(3−アミノピペリジン−1−イル)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(1−イソプロピル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
7−フルオロ−4,6−ビス(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−ブロモ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−(4−フルオロフェニル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
(R)−6−(2−アミノ−3−メトキシプロピルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(チオフェン−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(4−メチルチオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(4−メチルチオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(チオフェン−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−N,4−ジメチルペンタンアミド;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(5−メチルチオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−4−(4−メチルチオフェン−2−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−3−オキソ−4−(チオフェン−3−イル)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−4−(5−メチルチオフェン−2−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(2−アミノチアゾール−5−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−4−(フラン−2−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−4−(フラン−3−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−4−(5−メチルフラン−2−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(4−(5−シアノチオフェン−2−イル)−7−フルオロ−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(4−(4−シアノチオフェン−2−イル)−7−フルオロ−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−3−オキソ−4−(チアゾール−5−イル)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
(R)−2−(7−フルオロ−4−(イソチアゾール−5−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−1,1−ジメチル−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(1−メチル−1H−ピラゾール−3−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(2−メチルチアゾール−5−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(5−メチルチオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−1−メチル−4−(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−3−オキソ−4−(チオフェン−2−イル)−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(チオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(チアゾール−5−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(チオフェン−2−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(4−(トリフルオロメチル)−1H−イミダゾール−1−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((1R,2S)−2−アミノシクロヘキシルアミノ)−7−フルオロ−4−(4−メチル−1H−イミダゾール−1−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(3−メチルイソチアゾール−5−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−7−フルオロ−4−(2−メチルチアゾール−5−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
(R)−2−(7−フルオロ−4−(2−メチルチアゾール−5−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)−4−メチルペンタンアミド;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(5−クロロチオフェン−2−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;
6−((3R,4R)−3−アミノテトラヒドロ−2H−ピラン−4−イルアミノ)−4−(1−シクロプロピル−1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン;ならびに上述した化合物のいずれかの立体異性体及びそれらの薬剤的に許容できる塩。
ヘキサン、シクロペンタネシクロヘキサン、ビ(シクロヘキサン)などから由来するものが挙げられる。
記環を含む一般的に特定の数の炭素原子を有する。シクロアルキル基と同様に、前記二環式シクロアルケニル基は孤立、スピロ、縮合又は架橋環を含み得る。同様に、いずれかの環原子で前記シクロアルケニル基は親基又は親基質に結合され得、及び、結合又は置換基が原子価の条件に反しない限り、1つ以上の水素以外の置換基を含み得る。シクロアルケニル基としては、例えば、シクロブテニル(いわゆるシクロブテン−1−イル及びシクロブテン−3−イル)、シクロペンテニル、シクロヘキセニル、ビシクロ[2.2.1]ヘプタ−2−エニルなどのような、上述のシクロアルキル基の部分的に不飽和の類似体が挙げられる。
、イソチアゾリル、チアゾリル、1,2,3−トリアゾリル、1,3,4−トリアゾリル、1−オキサ−2,3−ジアゾリル、1−オキサ−2,4−ジアゾリル、1−オキサ−2,5−ジアゾリル、1−オキサ−3,4−ジアゾリル、1−チア−2,3−ジアゾリル、1−チア−2,4−ジアゾリル、1−チア−2,5−ジアゾリル、1−チア−3,4−ジアゾリル、テトラゾリル、ピリジニル、ピリダジニル、ピリミジニル、及びピラジニルのような単環式基が挙げられる。
レオマーを指す。例えば、化合物がS,R,Z立体化学的配置を有するならば、その立体異性体はR,S,Z配置を有する反対の鏡像異性体、及びS,S,Z配置、R,R,Z配置、S,R,E配置、R,S,E配置、S,S,E配置及びR,R,E配置を有するジアステレオマーを含むだろう。化合物の立体化学的配置が特定されないならば、そのとき「立体異性体」は、化合物のあり得る立体化学的配置のいずれか1つを指す。
Ac(アセチル);ACN(アセトニトリル);AIBN(アゾ−ビス−イソブチロニトリル);API(活性医薬成分);aq(水溶液);Boc(tert−ブトキシカルボニル);BSA(ウシ血清アルブミン);Cbz(カルボベンジルオキシ);dba(ジベンジリデンアセトン); DCC(1,3−ジシクロヘキシルカルボジイミド);DCM(ジクロロメタン);DIPEA(N,N−ジイソプロピルエチルアミン、ヒューニッヒ塩基);DMA(N,N−ジメチルアセトアミド);DMAP(4−ジメチルアミノピリジン);DMARD(疾患修飾性抗リウマチ薬);DME(1,2−ジメトキシエタン
);DMF(N,N−ジメチルホルムアミド);DMSO(ジメチルスルホキシド);dppf(1,1’−ビス(ジフェニルホスフィノ)フェロセン);DTT(ジチオスレイトール);EDA(エトキシル化ドデシルアルコール、Brj(登録商標)35);EDCI(N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド);EDTA(エチレンジアミン四酢酸);ee(鏡像体過剰率);eq(当量);Et(エチル);
Et3N(トリエチル−アミン); EtOAc(酢酸エチル);EtOH(エタノール
);FAM(5−カルボキシフルオレセイン);HATU(2−(3H−[1,2,3]トリアゾロ[4,5−b]ピリジン−3−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロリン酸塩(V));HEPES(4−(2−ヒドロキシエチル)ピペラジン−1−エタンスルホン酸);HOAc(酢酸);HOBt(1H−ベンゾ[d][
1,2,3]トリアゾール−1−オール);IC50(50%阻害濃度);IPA(イソプロパノール);IPAc(イソプロピルアセタート);IPE(イソプロピルエーテル);LDA(リチウムジイソプロピルアミド);LiHMDS(リチウムビス(トリメチルシリル)アミド);mCPBA(m−クロロペルオキシ安息香酸);Me(メチル);MeOH(メタノール);MTBE(メチルtert−ブチル エーテル);MOI(感染多重度);mp(融点);NaOt−Bu(ナトリウム tert−ブトキシド);NBS(N−ブロモスクシンイミド);NCS(N−クロロスクシンイミド);NIS(N−ヨードスクシンイミド);PE(石油エーテル);Ph(フェニル);pIC50(−log10(IC50)、IC50がモル(M)単位で与えられたとき);Pr(プロピル);i−Pr(イソプロピル);PTFE(ポリテトラフルオロエチレン);RT(室温、おおよそ20°C〜25°C);SYK(脾臓チロシンキナーゼ);TCEP(トリ
ス(2−カルボキシエチル)ホスフィン);TFA(トリフルオロ酢酸);TFAA(2,2,2−トリフルオロ酢酸無水物);THF(テトラヒドロフラン);及びトリス緩衝液(2−アミノ−2−ヒドロキシメチル−プロパン−1,3−ジオール バッファー)。
エタン−1−イルを表し、それぞれ、ハロ、オキソ、−NO2、−CN、R6、及びR7から独立して選択される、1〜5つ、1〜4つ、又は1〜2つの置換基で任意に置換される化合物である。
NO2、−CN、R6、R7から独立して選択される1〜4の置換基で任意に置換され;並びにR4が、C1−9ヘテロアリール、又はさらに詳細には、単環式C2−4ヘテロアリールであり、それぞれ、ハロ、オキソ、−CN、R6、及びR7から独立して選択される、1〜5つ、又は1〜4つの置換基で任意に置換される化合物である。
ダゾリル、イソオキサゾリル、オキサゾリル、イソチアゾリル、及びチアゾリルから選択され、又はさらに詳細には、チオフェンイル、ピラゾリル、イソチアゾリル、及びチアゾリルから選択される、単環式C2−4ヘテロアリールであり、それぞれ、ハロ、−CN、R6、及びR7から独立して選択される1〜3つの置換基で任意に置換される化合物である。
が、任意の置換基を有さない上記の実施形態が含まれる。
加熱すると、状態変化、一般的には二次(「ガラス転移」)を特徴とする、固体から液体特性への変化が起こる。用語「結晶」は、物質が分子レベルで規則正しい内部構造を有し、明確なピークを持つ特有のX線回折パターンを生じる固相を指す。また、このような物質も、十分に加熱すると液体の特性を示すが、固体から液体への変化は、相変化、一般的には一次(「融点」)を特徴とする。
、「プロ成分」を持つ薬理的に活性な化合物に存在する適切な官能基の置換により調整してもよい。プロドラッグとしては、例えば、エステル、エーテル、又は、カルボン酸、水酸基、若しくはアミノ官能基をそれぞれ有する式1の化合物のアミド誘導体が挙げられる。プロドラッグに関する更なる議論については、例えば、“Pro drugs as Novel Delivery Systems” ACS Symposium Series 14 (1975)、T. Higuchi及びV. Stella著、並びにBioreversible Carriers in Drug Design (1987)、E. B. Rocheら著を参照のこと。
って更に富化されてもよい。立体異性体を分離するための技術に関する更なる議論については、Stereochemistry of Organic Compounds (1994)、E. L. Eliel及びS. H. Wilen著を参照のこと。
and others編の複数巻からなるシリーズ、Compendium of Organic Synthetic Methods (1974 et seq.)を含む、多くの論文に見出すことができる。出発物質及び試薬は、商業的な供給元からを入手するか、又は文献の方法を使って調製し得る。反応スキームの幾つかでは、化学変換によって生ずる微量の生成物(例えば、エステルの加水分解からのアルコール、二塩基酸の脱炭酸からのCO2など)を省略し得る。くわえて、幾つかの例では、反応中間体を、分離又は精製すること無しに(すなわち、そのままで)、それに続く工程で使用し得る。
範囲などに対するいかなる参照は、「範囲」という語が明示的に使用されるか否かのいずれにせよ、その示された端点を含む。
換し、中間体1−3を得る。2番目の置換を、高温(例えば、90℃又は還流条件)にて、極性非プロトン有機溶媒(例えば、DMA又はDMF)中で、ヒンダード塩基(例えば、Et3N又はDIPEA)の存在下において実施する。
)の存在下における反応を介して、3−5に変換する。上記のように、3−5のニトリル基の還元及びそれに続く環化によって、化合物2−8を得る。
NBH3又はNaBH(OAc)3)の存在下において、MeOH中で、2,4−ジメトキシベンジルアミンと反応させ、還元的アミノ化を介して、直ちに又は約50℃の加熱のいずれかで、5−3に環化するアミノ中間体を得る。中間体5−3を酸(例えば、TFA)で約60℃にて処理することによって、化合物5−4を得る。
2000)に見い出され得る。
らびにヒドロキシプロピルメチルセルロースが挙げられる。また、錠剤は、ラクトース(一水和物、噴霧乾燥した一水和物、無水物など)、マンニトール、キシリトール、デキストロース、スクロース、ソルビトール、微結晶性セルロース、デンプン及びリン酸水素カルシウム二水和物などの賦形剤も含有し得る。
Pharmaceutical Dosage Forms: Tablets, Vol. 1−3 (2d ed., 1990); and D. K. Parikh
& C. K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997)を参照のこと。
を占め得る。
On−line (2001) 25(2):1−14を参照のこと。
Sci. 88(10):955-958 (1999)を参照のこと。
として、鼻腔内又は吸入によって投与され得る。吸入器を使用して、API単独か、APIとラクトースなどの希釈剤の粉末配合か、又はAPIとホスファチジルコリンなどのリン脂質を含む混合成分粒子を含む乾燥粉末を投与し得る。鼻腔内使用に関して、粉末は、生物接着剤(bioadhesive agent)、例えば、キトサン又はシクロデキストリンを含み得る。加圧容器、ポンプ、スプレー、アトマイザー又はネブライザーを使用して、API、APIの分散、可溶化又は放出延長するための1つ以上の薬剤(例えば、含水エタノール又は無水エタノール)、高圧ガスとしての役割をする1つ以上の溶媒(1,1,1,2−テトラフルオロエタン又は1,1,1,2,3,3,3−ヘプタフルオロプロパンなど)、及びソルビタントリオレート、オレイン酸もしくはオリゴ乳酸のような有意の界面活性剤を含む溶液又は懸濁液から、エアロゾルスプレーを作り出し得る。電気流体力学を使用するアトマイザーを使用して、細かいミストを作り出し得る。
〜約100μLで変わり得る。典型的な製剤は、1つ以上の式1の化合物、プロピレングリコール、滅菌水、エタノール及び塩化ナトリウムを含み得る。プロピレングリコールの代わりに使用され得る代替的な溶媒としては、グリセロール及びポリエチレングリコールが挙げられる。
ているが、医師は、その質量がこの体重範囲から外れる患者(例えば、乳幼児)に対して適切な投与量をに決定することができるであろう。
減少性紫斑病);肺の炎症(慢性閉塞性肺疾患)ならびに血栓症を含む、免疫系及び炎症にかかわり得る。また、式1の化合物を使用して、例えば、急性脊髄性白血病、B細胞慢性リンパ性白血病、B細胞リンパ腫(例えば、マントル細胞リンパ腫)、及びT細胞リンパ腫(例えば、末梢T細胞リンパ腫)などの血液悪性疾患、ならびに肺癌(小細胞肺癌及び非小細胞肺癌)、膵癌、及び結腸癌などの上皮性癌(すなわち、上皮性悪性腫瘍)を含む異常な細胞増殖に関連する障害、疾患、及び病を治療し得る。
治療するための薬理活性組成物又は治療の1つ以上と組み合わせ得る。例えば、具体的に上記で名前を挙げた化合物を含む、式1の化合物、及びそれらの薬剤的に許容できる複合体、塩、溶媒和物及び水和物は、例えば、関節リウマチ及び変形性関節症を含む関節炎を治療するため、又は、例えば急性脊髄性白血病、B細胞慢性リンパ性白血病、B細胞リンパ腫などの血液悪性疾患、ならびにT細胞リンパ腫、及び肺癌、膵癌、及び結腸癌などの上皮性悪性腫瘍を含む癌を治療するための化合物又は治療の1つ以上と組み合わせて、同時に、連続的に、又は別々に投与され得る。そのような組み合わせは、例えば、より少ない副作用、十分な治療を受けられていない患者集団を治療する能力の改善、又は相乗的な活性といった、著しい治療上の利点を提供し得る。
1の化合物を、カルシウムチャネル遮断剤、スタチン、フィブラート、ベータ遮断剤、ACE阻害剤、及び血小板凝集阻害剤などの心臓血管剤の1つ以上と組み合わせ得る。
3を超えるその関連したサブタイプを含む、インターフェロンが挙げられる。他のサイトカインとしては、顆粒球コロニー刺激因子(CSF)(フィルグラスチム)及び顆粒球マクロファージCSF(サルグラモスチム)が挙げられる。他の免疫調節剤としては、カルメット−ゲラン桿菌、レバミゾール、及びオクトレオチド;トラスツズマブ(trastruzumab)及びリツキシマブなどの腫瘍抗原に対するモノクローナル抗体;ならびに腫瘍に対する免疫応答を誘導する癌ワクチンが挙げられる。
トロジェン)のBamHI/XbaI部位にクローニングする。Met−Ala−Lys−SYK(356−635)−HHHHHHをコードする組換えプラスミドをシーケンシングして、大腸菌DH10Bac株に形質転換する。組換えバクミドDNAを単離し、Sf9昆虫細胞にトランスフェクションする。トランスフェクションの72時間後に、組換えウイルスを集める。約0.01の感染の多重度(MOI)でSf9細胞を感染することによって、高い力価のウィルスストックを調製する。Sf9細胞の懸濁液(10L)を組換えウイルス(MOI=5)で感染し、WaveBioreactor(GE−ヘルスケア)中で、48時間、インキュベーションする。細胞を集め、−80℃にて保存する。
チルスルホキシド)、CD3OD(ジューテロメタノール)、及びTHF−d8(ジューテロテトラヒドロフラン)。「アンモニア」とは、溶液比重0.88を有する水の中のアンモニアの濃縮溶液を指す。
媒B[水/アセトニトリル(20/80)(v/v)中に10mMのNH4HCO3]内の勾配にある。 前記分取HPLC条件では、塩基性と指示がない限り、酸性の条件を用
いる。分取薄層クロマトグラフィー(TLC)では、典型的には、シリカゲル60F254プレート上で行った。 クロマトグラフィーによる単離後、前記溶媒を取り除き、及び
遠心エバポレーター[例えばGeneVac(商標)]、ロータリーエバポレータ、真空フラスコ、凍結乾燥器などの中で乾燥させることにより、前記生成物を得る。不活性(例えば窒素)又は反応性(例えばH2)雰囲気内の反応を、典型的には、約1気圧(14.7psi)以上の圧力で実施した。
を白色固体として得た(1.2g、62%)。[M+H]C25H35N5O4における計算値470;実測値、470。
(m, 10 H), 2.32 (s, 3 H), 3.16 (m, 2 H), 3.92 (br s, 1 H), 4.14 (s, 2 H), 6.88 (d, J=7.07 Hz, 1 H), 7.13 (br s, 1 H), 7.22 (t, J=7.45 Hz, 1 H), 7.34 - 7.55 (m, 1 H), 7.70 (br s, 1 H), 8.01 (br s, 1 H), 8.58 (br s, 1 H)。[M+H]C19H24N6Oにおける計算値353;実測値、353。
ルオロフェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン
(br s, 8 H), 2.33 (s, 1 H), 3.57 (m, 1 H), 4.21 (br s, 2 H), 6.94 (s, 1 H), 7.07 (s, 1 H), 7.14 - 7.31 (m, 1 H), 7.43 (m, 1 H), 7.71 (d, J=8.59 Hz, 2 H), 8.01 (s, 1 H), 8.14 (br s, 1 H), 8.84 (s, 1 H), 12.99 (br s,
1 H)。[M+H]C19H22N8Oにおける計算値379;実測値、379。
ロヘキシルアミノ)−4−メチル−6−(m−トリルアミノ)ピリミジン−5−カルボキシラートと同様の方法で調製し、CCl4(10mL)中の1−ブロモピロリジン−2,5−ジオン(53.0mg、0.298mmol)及び安息香酸ペルオキシ無水物(48.1mg、0.199mmol)と合わせ、得られた混合物を70℃で18時間撹拌した。反応を中止した。混合物を減圧下で濃縮し、水とEtOAcの間で分離した。有機抽出物を乾燥し、減圧下で濃縮し、表題化合物を得、これをさらに精製することなく次の工程に用いた。[M+H]C25H31BrN5O4における計算値603;実測値、604。
(s, 1 H), 7.77 (d, J = 8.30 Hz, 1 H), 8.03 (s, 1 H), 8.37 (s, 1 H), 8.65
(s, 1 H), 8.82 (s, 1 H)。[M+H]C17H16N6Oにおける計算値321;実測値、321。
4で乾燥させ、濾過した。濾液を減圧下で濃縮し、残渣をIPEで洗浄し、表題化合物を無色固体として得た(3.43g、85%)。1H NMR (400 MHz, CDCl3)δppm 1.31 (t, J=6.8Hz, 3H,), 3.58 (s, 2H), 4.24 (q, J=6.8 Hz, 2H), 4.67 (s, 2H), 7.73 - 7.78 (m, 2H), 7.86 - 7.91 (m, 2H)。
4.45 (q, J=7.2Hz, 2H), 4.98 (s, 2H), 7.78 - 7.81 (m, 2H), 7.91 - 7.93 (m,
2H), 8.19 (br s, 1H), 8.96 (br s, 1H)。
(q, J=7.2Hz, 2H), 5.05 (s, 2H), 7.76 - 7.80 (m, 2H), 7.89 - 7.93 (m, 2H)。
3H), 4.52 (q, J=7.2Hz, 2H), 5.20 (s, 2H), 6.97 - 6.98 (m, 1H), 7.23 - 7.27 (m, 1H), 7.33 (br s, 1H), 7.45 - 7.47 (m, 1H), 7.73 - 7.78 (m, 2H), 7.89 - 7.94 (m, 2H), 10.67 (br s, 1H)。
1H), 7.16 - 7.49 (m, 3H), 7.74 - 7.75 (m, 2H), 7.90 - 7.91 (m, 2H), 10.68 - 10.81 (m, 1H)。[M+H]C34H41N6O6における計算値629;実測値、629。
9mg、0.174mmol)及びヒドラジン水和物(36.5mg、0.729mmol)の混合物を65℃で12時間撹拌した。冷却後、混合物を減圧下で濃縮し、残渣を水で処理し、EtOAcで抽出した。合わせた有機層をNaHCO3水溶液、水、及びブラインで洗浄し、SiO2、を通して濾過し、濾液を減圧下で濃縮した。残渣をEtOAc/ヘキサンから再結晶化し、濾過し、表題化合物を得た(34.8mg)。濾液を濃縮し、IPEと共に粉砕し、表題化合物(合計 65.1mg、83%)の第2バッチを得た(20.3mg)。1H NMR (400 MHz, DMSO-d6)δppm 1.24 - 1.79 (m, 17H), 2.32 (s, 3H), 3.84 (br s, 1H), 4.06 (br s, 1H), 4.14 (s, 2H), 6.55 - 6.70 (m, 1H), 6.87 - 7.04 (m, 2H), 7.20 - 7.24 (m, 1H), 7.40 - 7.48 (m, 1H), 7.68 - 7.80 (m, 1H), 8.01 - 8.06 (m, 1H), 8.56 - 8.59 (m, 1H)。[M+H]C24H33N6O3における計算値453;実測値、453。
(m, 10H), 2.37 (s, 3H), 3.24 (br s, 1H), 4.07 (br s, 1H), 4.20 (s, 2H
), 5.55 (br s, 1H), 5.89 (br s, 1H), 6.89 - 6.91 (m, 1H), 7.22 - 7.24 (m, 1H), 7.53 - 7.63 (m, 2H), 8.49 (br s, 1H)。[M+H]C19H25N6Oにおける計算値353;実測値、353。
の溶液に、ブチルリチウム(100mL、160mmol)を−78℃でゆっくりと添加した。混合物を−78℃で15分間撹拌した。この混合物にTHF(50mL)中の2,4,6−トリクロロピリミジン(20.06g、109mmol)の溶液を−78℃でゆっくりと添加した。混合物を1時間撹拌した。ドライアイスを添加し、混合物を室温で1時間撹拌した。混合物に1N HClを添加し、次いでこれをEtOAcで抽出した。有機層をNaHCO3水溶液で塩基性にし、EtOAcで洗浄した。水層を1N HClで酸性にし、EtOAcで抽出した。有機層を1N HCl、水、及びブラインで洗浄し、無水MgSO4で乾燥させ、次いで濾過した。濾液を減圧下で濃縮した。残渣をヘキサンで洗浄し、所望の生成物を薄褐色固体として得た(12.28g、49%)。1H NMR (500 MHz, CDCl3)δppm 7.65 (br s, 1H)。
検出されず。[M+H]C12H10Cl2N3O2における計算値298;実測値、298。
MHz, CDCl3)δppm 2.38 (s, 3H), 4.00 (s, 3H), 7.02 - 7.03 (m, 1H), 7.27 -
7.33 (m, 2H), 7.44 - 7.46 (m, 1H), 10.30 (br s, 1H)。[M+H]C13H12Cl2N3O2における計算値312;実測値、312。
(br s, 6H), 3.82 - 3.97 (m, 7H), 6.92 - 6.93 (m, 1H), 7.21 - 7.22 (m, 1H
), 7.37 - 7.42 (m, 2H), 10.45 (s, 1H)。[M+H]C19H25ClN5O2における計算値390;実測値、390。
混合物を90℃で3時間撹拌した。水を添加し、得られた混合物をEtOAcで抽出した。有機層を、NaHCO3水溶液、水、及びブラインで洗浄し、無水Na2SO4で乾燥させ、次いで、SiO2を通して濾過した。濾液を減圧下で濃縮し、残渣をカラムクロマトグラフィー(SiO2 ヘキサン/EtOAc=5/1)により精製し、表題化合物を黄色の油状物として得た(51.1mg、34%)。1H NMR (500 MHz, CDCl3)δppm 1.12 (t, J=7.5Hz, 3H), 2.35 (s, 3H), 2.44 - 2.49 (m, 6H), 3.81 - 3.98 (m, 7H), 6.95 - 6.96 (m, 1H), 7.23 - 7.26 (m, 1H), 7.37 - 7.47 (m, 2H), 10.46
(s, 1H)。[M+H]C20H25N6O2における計算値381;実測値、381。
NMR (500 MHz, CDCl3)δppm 1.19 (br s, 3H), 2.36 (s, 3H), 2.5 (br s, 6H), 4.08 (br s, 4H), 4.23 (s, 2H), 5.50 (s, 1H), 6.91 - 6.92 (m, 1H), 7.22
- 7.26 (m, 1H), 7.49 - 7.54 (m, 2H), 8.44 (s, 1H)。[M+H]C19H25N6Oにおける計算値353;実測値、353。
−5−カルボキシラート(500.5mg、1.603mmol)、シアン化亜鉛(II)(100.7mg、0.857mmol)及びテトラキス(トリフェニルホスフィン)パラジウム(187.3mg、0.162mmol)の混合物を電子レンジで120℃で1時間撹拌し、冷却後、NaHCO3飽和水溶液を添加し、混合物をEtOAcで抽出した。有機層を、NaHCO3水溶液、水、及びブラインで洗浄し、無水Na2SO4で乾燥させ、次いで、SiO2を通して濾過した。濾液を減圧下で濃縮し、残渣をカラムクロマトグラフィー(SiO2、ヘキサン/EtOAc=4/1)により精製し、黄色固体(182.5mg)を得、これをIPEで洗浄し、表題化合物を得た(117.5mg)。1H NMR (500 MHz, CDCl3)δppm 2.41 (s, 3H), 4.12 (s, 3H), 7.10 - 7.12 (m, 1H), 7.31 - 7.35 (m, 2H), 7.42 - 7.43 (m, 1H), 10.65 (br s, 1H)。[M+H]C15H12N5O2における計算値294;実測値、294。
7.46 - 7.51 (m, 2H), 10.62 (br s, 1H)。[M+H]C20H24N5O2における計算値366;実測値、366。
5.2mg)。1H NMR (500 MHz, DMSO-d6)δppm 1.14 - 1.17 (m, 1H), 1.24 - 1.34 (m, 4H), 1.62 - 1.63 (m, 1H), 1.73 - 1.78 (m, 2H), 1.89 - 1.97 (m, 2H), 2.33 (s, 3H), 3.74 - 3.83 (m, 1H), 4.12 - 4.17 (m, 2H), 6.86 - 6.88 (m,
1H), 7.20 - 7.23 (m, 1H), 7.42 - 7.52 (m, 2H), 7.76 (s, 1H), 8.00 - 8.05
(m, 1H), 8.53 - 8.57 (m, 1H)。[M+H]C19H24N5Oにおける計算値338;実測値、338
。
), 8.58 - 8.59 (m, 1H)。[M+H]C19H24N5O2における計算値354;実測値、354。
2.30 (s, 3 H), 2.57 - 3.07 (m, 3 H), 4.16 (s, 2 H), 4.26 - 4.86 (m, 2 H
), 6.88 (d, J=5.6 Hz, 1 H), 7.23 (s, 1 H), 7.42 - 7.55 (m, 1 H), 7.59 (s, 1 H), 8.08 (s, 1 H), 8.55 (s, 1 H)。[M+H]C18H22N6Oにおける計算値339;実測値、339。
3 H), 7.77 (s, 1H)。[M+H]C7H4ClINO2における計算値332;実測値、332。
)δppm 3.99 (s, 3 H), 8.44 (s, 1H)。
NMR (500 MHz, CDCl3)δppm 2.40 (s, 3 H), 3.99 (s, 3H), 6.92 (s, 1H), 7.05 - 7.14 (m, 4H), 7.33 (t, J=7.81 Hz, 1H)。
tOAcですすぎ、乾燥し、表題化合物を黄色固体として得た(250mg、79%)。1H NMR (500 MHz, CDCl3)δppm 1.23 - 1.77 (m, 17 H), 2.34 (s, 3 H), 3.94 (br s, 3 H), 3.98 (br s, 1H), 4.80 (s, 1H), 6.15 (s, 1 H), 6.91 (d, J=5.37 Hz, 1 H), 7.21 (t, J=7.81 Hz, 1H), 7.29 (s, 1H), 7.47 - 7.55 (m, 1 H),
10.64 (br s, 1 H)。
δppm 1.03 - 2.10 (m, 17 H), 2.34 (s, 3 H), 3.81 - 4.29 (m, 4 H), 5.03 (s, 1 H), 5.32 (s, 1 H), 5.81 (s, 1 H), 6.20 (s, 1 H), 6.81 (s, 1 H), 7.18 (s, 1 H), 7.49 (s, 1 H), 7.64 (s, 1 H), 8.77 (s, 1 H)。[M+H]C25H33N5O3における計算値452;実測値、452。
δppm 1.19 - 1.77 (m, 8 H), 2.29 (s, 3 H), 3.20 (br s, 1 H), 3.99 (br s, 1 H), 4.19 (s, 2 H), 6.06 (s, 1 H), 6.75 (d, J=7.32 Hz, 2 H), 7.14 (t, J=7.81 Hz, 1 H), 7.48 (d, J=7.32 Hz, 1 H), 7.60 (s, 1 H), 7.90 (s, 1 H), 8.87 (s, 1 H)。[M+H]C20H25N5Oにおける計算値352;実測値、352。
ジン−5−オン
− 1.94 (m, 6 H) 3.93 (s, 3 H) 4.14 - 4.30 (m, 2 H) 4.29 - 4.58 (m, 1 H
) 7.51 (d, J=6.83 Hz, 1 H) 7.71 (br s, 2 H)8.29 (s, 1 H) 8.34 - 8.69 (m,
1 H) 9.11 (d, J=17.09 Hz, 1 H)。[M+H]C16H21N7Oにおける計算値328;実測値、328。
δppm 0.92 (d, J=1.00 Hz, 6 H), 0.87 - 1.00 (m, 6 H), 1.45 - 1.70 (m, 2 H), 1.46 - 1.70 (m, 2 H), 1.70 - 2.00 (m, 6 H), 2.22 (spt, J=13.70 Hz, 1 H),
3.64 (br s, 1 H), 4.02 (d, J=6.83 Hz, 2 H), 4.30 (s, 2 H), 4.63 (d, J=3.91 Hz, 1 H), 8.54 (s, 1 H), 9.12 (br s, 1 H)。[M+H]C19H27N7Oにおける計算値370;実測値、370。
し、濃縮し、NaHCO3飽和水溶液で中和し、EtOAcに抽出した。有機相を無水Na2SO4で乾燥させ、溶媒を真空下で除去し、表題化合物を淡白色フィルムとして得た。1H NMR(400 MHz,CD3OD)δppm 1.40 - 1.95(m ,8 H), 3.27(br s ,1 H) , 4.18 - 4.54(m, 3 H) , 7.35 - 7.59(m, 3 H), 8.12(br s , 2 H)。[M+H]C18H21N5Oにおける計算値324;実測値、324。
;実測値、380。
1.47 - 1.55 (m, 3 H), 1.54 - 1.99 (m, 8 H), 3.64 (br s, 1 H), 4.26 (q, J=7.32 Hz, 2 H), 4.30 (s, 2 H), 4.63 (br s, 1 H), 8.54 (br s, 1 H), 9.14
(s, 1 H)。[M+H]C17H23N7Oにおける計算値342;実測値、342。
2 H), 4.61 (br s, 1 H), 5.40 (s, 2 H), 7.22 - 7.41 (m, 5 H), 8.58 (s, 1
H), 9.16 (br s, 1 H)。[M+H]C22H25N7Oにおける計算値404;実測値、404。
(500 MHz, CD3OD)δppm 1.47 - 1.73 (m, 2 H), 1.74 - 2.03 (m, 6 H), 3.68 (br s, 1 H), 4.27 - 4.54 (m, 2 H), 4.58 - 4.75 (m, 1 H), 7.52 - 7.79 (m, 1 H), 8.00 - 8.12 (m, 1 H), 8.14 (t, J=7.57 Hz, 1 H), 10.23 (br s, 1 H), 10.81 (d, J=5.86 Hz, 1 H)。[M+H]C19H21N7Oにおける計算値364;実測値、364。
2−イル)−1H−ピラゾールの代わりに1−プロピル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾールを用いて、実施例14と同様の方法で表題化合物のTFA塩を調製した。1H NMR (500 MHz, CD3OD)δppm 0.92 (t, J=1.00 Hz, 3 H), 1.43 - 1.70 (m, 2 H), 1.69 - 2.14 (m, 8 H), 3.62 (br s, 1 H), 4.18 (t, J=6.83 Hz, 2 H), 4.24 - 4.41 (m, 2 H), 4.63 (br
s, 1 H), 8.56 (br s, 1 H), 9.13 (br s, 1 H)。[M+H]C18H25N7Oにおける計算値356;実測値、356。
(m, 8 H), 3.13 (br s, 1H), 3.94 - 4.07 (m, 1 H), 4.21 (s, 2 H), 6.02 - 6.14 (m, 1 H), 6.70 (br s, 1 H), 7.13 (d, J=8.30 Hz, 1 H), 7.63 (d, J=8.30 Hz, 1 H), 7.94 (d, J=2.93 Hz, 2 H), 8.23 (s, 1 H), 9.08 (s, 1 H), 12.84
(br s, 1 H)。[M+H]C20H23N7Oにおける計算値378;実測値、378。
Hz, 3 H), 3.80 - 3.82 (m, 3 H), 3.83 (br s, 1 H), 4.01 - 4.09 (m, 1 H), 6.48 (s, 1 H), 6.62 (d, J=7.81 Hz, 1 H), 7.06 (t, J=9.03, 1 H), 7.39 (d, J=4.39 Hz, 1 H), 7.50 - 7.68 (m, 1 H), 10.41 (br s, 1 H)。
1.14 - 1.95 (m, 8 H), 2.28 (s, 3 H), 3.73 (br s, 1 H), 4.30 (s, 2H), 4.38 (s, 1 H), 6.17 (s, 1 H), 7.00 (t, J=9.03 Hz, 1 H), 7.41 - 7.54 (m, 2 H)。
6.73 (d, J=6.35 Hz, 1 H), 6.79 (d, J=7.32 Hz, 1 H), 7.17 (t, J=7.57 Hz, 1 H), 7.43 (d, J=7.81 Hz, 1 H), 7.46 (s, 1 H), 7.76 (br s, 2 H), 8.29 (s, 1 H), 8.79 (s, 1 H)。[M+H]C20H24FN5Oにおける計算値370;実測値、370。
クロロ−3−ヨードピリジン(5.00g、20.88mmol)の溶液を反応混合物に−78℃で滴下し、得られた混合物を−78℃で2時間撹拌した。ドライアイスを反応混合物に添加し、これを室温まで温め、一晩撹拌した。得られた混合物をH2Oで反応停止処理し、有機相をH2Oで洗浄した。合わせた水相を濃HClで酸性にし、EtOAcで抽出した。有機相を合わせ、ブラインで洗浄し、MgSO4で乾燥させ、蒸発させ、粗2−クロロ−4−ヨードニコチン酸を得、これをDMF(70mL)中、炭酸カリウム(5.77g、41.8mmol)及びヨードメタン(1.567mL、25.06mmol)と合わせた。混合物を室温で1時間撹拌し、次いでこれにEt2O及びH2Oを添加した。有機相をH2O及びブラインで洗浄し、MgSO4で乾燥させ、蒸発させた。残渣をSiO2上クロマトグラフィーにより精製し、表題化合物を白色固体として得た(3.23g、52.0%)。1H NMR (500 MHz, CDCl3)δppm 4.01 (s, 3 H), 7.68 - 7.76 (m, 1 H), 7.97 - 8.11 (m, 1 H)。[M+H]C7H5ClINO2における計算値298;実測値、298。
(s, 1 H), 8.79 (d, J=4.88 Hz, 1 H)。[M+H]C12H10N4O2における計算値243;実測値、243。
;実測値、277。
MHz, DMSO-d6)δppm 122 - 1.61 (m, 8 H), 3.63 (s, 3 H), 4.19 (s, 2 H), 6.46 (br s, 1 H), 7.98 (s, 1 H), 8.29 (s, 1 H), 8.85 (s, 1 H)。[M+H]C17H22N6Oにおける計算値327;実測値、327。
), 5.43 (t, J=4.0 Hz, 1 H), 6.49 (d, J=4.0 Hz, 1 H)。
ol)を一晩室温で撹拌した。次いで、反応混合物を6N HClで氷浴中で反応停止処理した。混合物を濃縮し、乾固した。残渣をEtOAc(500mL)で処理し、激しく45℃で30分間撹拌した。濾過後、濾液を濃縮し、表題化合物を得、さらに精製することなく用いた(4.4g)。1H NMR (400 MHz, CDCl3)δppm 1.79-1.84 (m, 1 H), 2.00 (s, 6 H), 3.56-3.67 (m, 2 H), 3.88-3.97 (m, 2 H), 5.09-5.14 (m, 2 H)。
(m, 1 H)。
(150mg、0.352mmol)及びSELECTFLUOR(登録商標)(150mg、0.422mmol)の溶液を室温で一晩撹拌した。次いで、水を添加し、混合物をCHCl3(3×)で抽出した。有機相を合わせ、ブラインで洗浄し、MgSO4で乾燥させ、蒸発させた。残渣を分取HPLCにより精製し、表題化合物を得た(15mg、9.60%)。[M+H]C22H29FN6O3における計算値445;実測値、445。
(1−メチル−1H−ピラゾール−4−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン
2 H), 4.45 (br s, 1 H), 6.77 (d, J=6.35 Hz, 1 H), 7.93 (br s, 3 H), 8.30
(s, 1 H), 8.36 (s, 1 H), 8.84 (s, 1 H)。[M+H]C17H21FN6Oにおける計算値345
;実測値、345。
る計算値361;実測値、361。
−ジメトキシフェニル)メタンアミン(34.2mL、228mmol)の混合物を室温で2時間撹拌した。トリアセトキシヒドロホウ酸ナトリウム(22.98g、108mmol)を混合物に添加し、これを室温で2時間撹拌した。次に、HCl(2N、120mL)を添加し、得られた固体(17.3g)を濾過により単離した。DMF(200mL)中の固体、N1−((エチルイミノ)メチレン)−N3,N3−ジメチルプロパン−1,3−ジアミン 塩酸塩(10.35g、54mmol)及び1H−ベンゾ[d][1,2,3]トリアゾール−1−オール 水和物(8.27g、54mmol)の混合物を室温で2時間撹拌した。次に、水を添加し、混合物をEtOAc(2×300mL)で抽出した。有機相を合わせ、NaHCO3飽和水溶液(300mL)、H2O(300mL)、及びブライン(300mL)で洗浄し、無水Na2SO4で乾燥させ、濾過した。濾液を減圧下で濃縮し、残渣をEtOAcで洗浄し、表題化合物を薄黄色固体(6.7g、16.7%)として得た。[M+H]C16H13Cl2FN2O3における計算値371;実測値、371。
4.68 (d, J=1.95 Hz, 2 H), 5.36 (br s, 1 H), 6.36 - 6.54 (m, 2 H), 7.15 - 7.21 (m, 1 H), 8.26 (br s, 1 H), 9.02 (br s, 1 H)。[M+H]C31H39FN6O5におけ
る計算値595;実測値、595。
tert−ブチル(1S,2R)−2−(2−(2,4−ジメトキシベンジル)−7−フルオロ−4−(1−メチル−1H−ピラゾール−4−イル)−3−オキソ−2,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)シクロヘキシルカルバマート(2.4g、4.04mmol)及びTFA(5mL、64.9mmol)の溶液を80℃で30分間撹拌した。得られた懸濁液をEtOAc(5mL)で希釈し、濾過した。濾液を真空下で蒸発させた。残渣をH2O(300mL)及びEtOAc(100mL)で希釈し、濾過した。沈殿物をEtOAcで洗浄し、乾燥し、表題化合物をTFA塩(900mg)として得た。濾液をEtOAc(200mL)で抽出した。水相NaHCO3飽和水溶液で中和し、EtOAc(2×400mL)及びTHF(2×200mL)で抽出した。有機相を合わせ、MgSO4で乾燥させ、蒸発させた。残渣をEtOAcで洗浄し、表題化合物の第1収集物(400mg)を遊離塩基として得た。上記で得られたTFA塩をNaHCO3飽和水溶液(20mL)で希釈し、及び室温で一晩撹拌した。得られた懸濁液を濾過し、固体をEtOAcで洗浄し、表題化合物の第2収集物(700mg)を遊離塩基として得た(1.1g、79%)。
測値、345。
018mmol)の混合物を85℃で3時間撹拌した。反応後、混合物を濾過し、濾液をEtOAc及びH2Oで希釈した。水相をEtOAcで抽出した。有機相を合わせ、ブラインで洗浄し、MgSO4で乾燥させ、蒸発させた。残渣をSiO2上でクロマトグラフィーにより精製し、表題化合物を得た(53mg、46.1%)。1H NMR (500 MHz, CDCl3)δppm 1.17 - 2.03 (m, 17 H), 3.74 - 3.81(m, 3 H), 3.84 - 3.89 (m, 3 H
), 4.04 (br s, 1 H), 4.26 (br s, 2 H), 4.46 (br s, 1 H), 4.71 (br s, 2 H), 6.36 - 6.55 (m, 2 H), 6.83 (d, J=5.86 Hz, 1 H), 7.18 - 7.31 (m, 2 H), 8.42 (br s, 1 H), 8.47 - 8.57 (m, 1 H), 9.42 (br s, 1 H)。
4.46 (br s, 2 H), 6.61 (br s, 1 H), 7.09 (d, J=6.35 Hz, 1 H), 7.49 (d, J=7.32, 1 H), 8.36 (br s, 1 H), 8.59 (d, J= 7.81 Hz, 1 H), 8.83 (d, J=6.83 Hz, 1 H), 9.56 (br s, 1 H)。[M+H]C20H21FN6Oにおける計算値381;実測値、381。
N−エチル−N−イソプロピルプロパン−2−アミン(0.4mL、2.296mmol)の混合物を0℃で3時間撹拌した。水(50mL)混合物に添加し、これをEtOAc(2×40mL)で抽出した。有機層をNaHCO3飽和水溶液(20mL)、水(20mL)及びブライン(20mL)で洗浄し、無水Na2SO4で乾燥させ、次いで、濾過した(DM1020)。濾液を減圧下で濃縮し、残渣をカラムクロマトグラフィー(SiO2、ヘキサン/EtOAc=4/1)により精製し、表題化合物を透明油状物として得た(310.5mg)。1H NMR (500 MHz, CDCl3)δppm 1.34-1.74 (m, 15H), 2.35-2.37 (m, 3H), 3.03-3.21 (m, 2H), 3.60-3.71 (m, 1H), 3.90 (s, 3H), 4.43-5.04 (m, 3H), 6.94-6.98 (m, 1H), 7.23-7.46 (m, 3H), 10.13-10.43 (m, 1H)。[M+H]C24H33ClN5O4における計算値490;実測値、490。
おける計算値481;実測値、481。
(m, 2H), 1.67-1.69 (m, 3H), 2.31 (s, 3H), 3.06 (br s, 1H), 3.24 (br s, 2H), 4.16 (s, 2H), 4.67 (br s, 1H), 5.08 (br s, 1H), 6.77 (br s, 1H), 6.87 (d, 1H, J=7.0Hz), 7.23-7.25 (m, 1H), 7.53 (br s, 2h), 8.07 (s, 1H), 8.55 (s, 1H)。[M+H]C24H33N6O3における計算値453;実測値、453.5。
(m, 1H), 2.94 (br s, 1H), 4.17 (s, 2H), 4.68-4.79 (m, 2H), 6.88 (d, 1H, J=7.5 Hz), 7.22- 7.25(m, 1H), 7.49-7.50 (m, 1H), 7.60 (s, 1H), 8.06 (s, 1H), 8.58 (s, 1H)。[M+H]C19H25N6Oにおける計算値353;実測値、353.5。
(s, 3H), 4.07 (s, 3H), 7.10 (s, 1H), 7.57-7.60 (m, 1H), 7.70-7.72 (m, 1H), 7.91-7.93 (m, 1H), 8.25-8.26 (m, 1H), 10.73 (s, 1H)。
コチナート
), 3.95-3.97 (m, 4H), 4.16-4.17 (m, 1H), 4.77 (s, 1H), 6.24 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.61 (m, 1H), 7.77-7.78 (m, 1H), 8.41 (s, 1H), 10.99 (s, 1H), 1H 検出されず。
m, 1H), 6.03-6.05 (m, 1H), 6.29 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.60 (m, 1H), 7.71-7.72 (m, 1H), 8.53 (s, 1H), 11.01 (s, 1H)。
)フェニルアミノ)ニコチナート(165.0mg、0.451mmol)、Et3N(0.15mL、1.076mmol)、及びtert−ブチル(1S,2R)−2−アミノシクロペンチルカルバマート(142.0mg、0.709mmol)の混合物を60℃で12時間撹拌した。NaHCO3飽和水溶液(20mL)を混合物に添加し、次いでこれを、EtOAc(2×30mL)で抽出した。有機層をNaHCO3飽和水溶液(20mL)、水(20mL)及びブライン(20mL)で洗浄し、無水Na2SO4で乾燥させ、及び濾過した(DM1020)。濾液を減圧下で濃縮した。残渣をカラムクロマトグラフィー(SiO2、ヘキサン/EtOAc=1/1)により精製し、次いで、IPEと共に粉砕し、表題化合物を得た(147mg)。
(m, 1H), 2.19-2.20 (m, 1H), 3.32 (s, 3H), 3.74 (br s, 1H), 4.23-4.28 (m, 2H), 4.45 (br s, 1H), 6.22 (s, 1H), 7.34-7.35 (m, 1H), 7.51-7.58 (m, 3H), 7.73 (br s, 3H), 8.13 (s, 1H), 8.82 (s, 1H), 9.26 (s, 1H)。
化し、表題化合物を白色固体として得た(18.8mg、27%)。1H-NMR (DMSO-d6)δppm 0.87-0.94 (m, 6H), 1.54-1.63 (m, 2H), 1.76 (br s, 1H), 3.32 (s, 3H
), 4.24 (s, 2H), 4.50 (br s, 1H), 6.17 (s, 1H), 7.00-7.04 (m, 2H), 7.22
(br s, 1H), 7.47-7.57 (m, 2H), 8.01 (br s, 1H), 8.06 (s, 1H), 8.45 (br
s, 1H), 9.23 (s, 1H)。[M+H]C20H26N5O4Sにおける計算値432;実測値、432.5。
、水(20mL)及びブライン(20mL)で洗浄し、無水Na2SO4で乾燥させ、濾過した。濾液を減圧下で濃縮し、残渣をカラムクロマトグラフィー(DM1020、EtOAc/MeOH=15/1−10/1)により精製し、表題化合物を白色固体として得た(10.2mg、54%)。1H-NMR (DMSO-d6)δppm 0.88-0.95 (m, 6H), 1.52-1.60 (m, 2H), 1.73-1.76 (m, 1H), 3.88 (s, 3H), 4.21 (s, 2H), 4.48 (br s, 1H), 6.43 (s, 1H), 6.90 (s, 1H), 7.03 (br s, 1H), 7.42 (s, 1H), 8.01 (s, 1H), 8.41 (s, 1H), 8.92 (s, 1H)。[M+H]C17H23N6O2における計算値343;実測
値、343。
NMR (400 MHz, DMSO-d6)δppm 1.44 -1.57 (m, 4 H), 1.85 (br s, 4 H), 2.32
(s, 3 H), 2.64 - 2.87 (2s, 6 H), 4.20 (d, J=4.55 Hz, 2 H), 6.91 (d, J=7.07 Hz, 1 H), 7.00 (s, 1 H), 7.13 (s, 1 H), 7.17 - 7.34 (m, 2 H), 8.19 (br
s, 1 H), 8.68 (br s, 1 H)。[M+H]C21H28N6Oにおける計算値381;実測値、381。
応を中止し、混合物を逆相分取HPLCにより精製し、表題化合物のTFA塩を得た(5mg、27%)。1H NMR (400 MHz, DMSO-d6)δppm 1.35-1.79 (m, 8 H), 2.32 (s,
3 H), 4.20 (br s, 2 H), 6.52 (br s, 2 H), 6.91 (d, J=7.33 Hz, 1 H), 7.24
(t, J=7.71 Hz, 2 H), 8.03 (br s, 1 H), 8.16 (br s, 2 H), 8.40 (br s, 1 H), 8.66 (br s, 1 H)。[M+H]C20H26N6Oにおける計算値367;実測値、367。
1 H), 1.42 (m, 6 H), 1.63 (m, 3 H), 1.86 (m, 2 H), 2.33 (s, 3 H), 3.62 (br s, 1 H), 4.18 (br s, 1 H), 6.91 (d, J=7.33 Hz, 1 H), 7.24 (t, J=7.71 Hz, 1 H), 7.36 - 7.56 (m, 1 H), 7.60 (br s, 1 H), 7.73 (br s, 2 H), 8.33 (br s, 1 H), 8.65 (br s, 1 H)。[M+H]C21H26N6Oにおける計算値379;実測値、379
。
ルアミノ)ピリミジン−5−カルボキシラート(0.44g、1.45mmol)及び二酸化セレン(0.32g、2.89mmol)の混合物を100℃で24時間加熱した。次いで、反応混合物を冷却し、濾過した。濾液を濃縮し、乾燥して、褐色の泡状物(0.459g)を得、これをDCM(6mL)及びMeOH(3mL)中の(2,4−ジメトキシフェニル)メタンアミン(0.217mL、1.446mmol)に分散させた。得られた混合物を室温で30分間撹拌した。水素化シアノほう素ナトリウム(0.227g、3.62mmol)を添加し、室温で20時間撹拌した。固相を濾過し、MeOHで洗浄し、表題化合物を黄色固体(0.537g、85%)として得た。[M+H]C23H24N4O3Sにおける計算値437;実測値、437。
(br s, 2 H) 8.18 (d, J=13.67 Hz, 1 H) 8.54 - 8.82 (m, 1 H)。[M+H]C15H18N6Oにおける計算値299;実測値、299。
題化合物のTFA塩を調製した。1H NMR (500 MHz, CD3OD)δppm 1.14 - 1.53 (m, 6 H), 2.37 (br s, 3 H), 3.62 (br s, 2 H), 4.12 - 4.47 (m, 2 H), 6.77 - 7.15
(m, 1 H), 7.13 - 7.40 (m, 1 H), 7.40 - 7.79 (m, 2 H)。[M+H]C17H22N6Oにお
ける計算値327;実測値、327。
(d, J=7.32 Hz, 1 H), 7.23 (t, J=7.81 Hz, 1 H), 7.55 (d, J=7.81 Hz, 2 H)。[M+H]C16H20N6Oにおける計算値313;実測値、313。
1.91 - 2.26 (m, 3 H), 2.38 (br s, 3 H), 3.19 (br s, 1 H), 3.63 (d, J=7.32 Hz, 1 H), 3.71 - 4.03 (m, 2 H), 4.15 - 4.51 (m, 2 H), 6.74 - 7.16 (m, 1 H), 7.13 - 7.76 (m, 3 H)。[M+H]C18H22N6Oにおける計算値339;実測値、339。
(m, 2 H)。[M+H]C17H20N6Oにおける計算値325;実測値、325。
して得た(0.179g、83%)。[M+H]C9H11ClN2O2Sにおける計算値247;実測値、247。
をDCM(10mL)に溶解した。溶液を氷浴中で冷やし、及びm−クロロペルオキシ安息香酸(0.134g、0.778mmol)を添加した。反応物を室温まで30分間にわたって撹拌しながら温めた。m−クロロペルオキシ安息香酸(0.159g、0.519mmol)の別のアリコートを反応混合物に添加し、及びさらに45分間撹拌した。次いで、反応混合物をDCM(10mL)で希釈し、及びNaHCO3飽和水溶液(10mL)で反応停止処理した。有機相をNaHCO3飽和水溶液(5mL)及びブライン(5mL)で洗浄し、及び無水Na2SO4で乾燥させた。溶媒を真空下で除去し、表題化合物を黄色の油状物として得た(173mg、98%)。[M+H]C14H18N4O4Sにおける計算値339;実測値、339。
で24時間加熱した。次いで混合物を冷却し、濾過した。濾液を濃縮し、乾燥して、褐色の泡状物(0.1g、0.206mmol)を得、これをDCM(2mL)及びMeOH(1mL)中、酢酸ナトリウム(0.051g、0.617mmol)及び(2,4−ジメトキシフェニル)メタンアミン(0.031mL、0.206mmol)と合わせた。混合物を室温で30分間撹拌し、その後、水素化シアノほう素ナトリウム(0.032g、0.514mmol)を添加した。反応混合物を室温で20時間撹拌し、次いで、セライトのパッドを通して濾過し、これをMeOHですすいだ。濾液を逆相分取HPLCにより精製し、画分を真空下で濃縮し、表題化合物を黄褐色固体として得た。[M+H]C31H41N7O5における計算値592;実測値、592。
), 1.67 - 2.02 (m, 6 H), 2.66 - 2.72 (m, 3 H), 3.67 (br s, 1 H), 3.85 (s, 3 H), 4.29 (s, 2 H), 4.50 - 4.64 (m, 1 H), 8.64 (br s, 1 H)。[M+H]C17H23N7Oにおける計算値342;実測値、342。
H), 7.08 (t, J=7.57 Hz, 1 H), 7.25 (t, J=7.57 Hz, 1 H), 7.47 (d, J=8.30 H
z, 1 H), 7.58 - 7.79 (m, 2 H)。[M+H]C20H22N6Oにおける計算値363;実測値、363。
密閉管中に置き、90℃で4時間加熱し、その後、セライトのパッドを通して濾過し、これをMeOHですすいだ。濾液を逆相分取HPLCで精製し、画分を真空下で濃縮し、表題化合物を褐色油状物として得た(0.190g、34%)。[M+H]C22H26N4O4における
計算値411;実測値、411。
濾過し、これをMeOHですすいだ。濾液を逆相分取HPLCで精製した。画分を回収し、濃縮し、真空下で表題化合物を黄褐色固体として得た(1.7mg、1%)。[M+H]C30H37N5O5における計算値548;実測値、548。
NMR (500 MHz, CD3OD)δppm 2.11 - 2.26 (m, 2 H), 2.30 - 2.45 (m, 3 H), 2.92 - 3.09 (m, 4 H), 4.39 (s, 2 H), 6.98 (d, J=8.34 Hz, 1 H), 7.16 - 7.35 (m, 1 H), 7.51 (s, 1 H), 7.65 (d, J=8.59 Hz, 1 H)。[M+H]C16H19N5Oにおける計
算値298;実測値、298。
いた。バイアルを窒素でパージし、密封し、120℃で1時間加熱した。混合物をセライトのパッドを通して濾過し、これをMeOHですすいだ。溶媒を真空下で除去し、残渣をMeOHで希釈し、精密濾過フリットを通過させ、分取HPLCで精製した。画分を回収し、真空下で濃縮し、表題化合物を黄褐色の油状物として得た。a黄褐色oil(36.3mg、48%)。[M+H]C35H39FN4O6における計算値632;実測値、632。
H), 7.56 (d, J=7.81 Hz, 1 H), 8.31 (d, J=6.83 Hz, 1 H), 9.08 (s, 1 H)。[M+H]C21H21FN4O2における計算値381;実測値、381。
)δppm 1.50 - 1.75 (m, 3 H), 1.74 - 1.98 (m, 5 H), 3.78 (br s, 1 H), 4.58
(br s, 3 H), 7.57 (t, J = 6.35 Hz, 1 H), 7.93 - 8.21 (m, 2 H), 8.78 (br s, 1 H), 9.45 (d, J=6.35 Hz, 1 H)。[M+H]C20H21FN6Oにおける計算値381;実測値、381。
ける計算値397;実測値、397。
1%)。[M+H]C27H34ClFN4O5における計算値550;実測値、550
NMR (500 MHz, CD3OD)δppm 1.56 - 2.01 (m, 8 H), 3.85 (br s, 1 H), 3.94 (br s, 3 H), 4.45 (br s, 2 H), 4.67 (br s, 1 H), 8.31 (br s, 1 H), 8.81 (br s, 1 H)。[M+H]C17H21FN6Oにおける計算値345;実測値、345。
計算値245;実測値、245。
−イルアミノ)プロパン−2−イルカルバマート(109mg、0.239mmol)の溶液に、TFA/DCM溶液(1/1、10mL)を添加した。混合物を室温で2時間撹拌した。溶媒を除去した後、得られた粗物質をMeOH/DCM(1/1、5mL)の溶液中で再構成し、及び逆相分取HPLCで精製した。画分を回収し、ACNを回転蒸発で除去した。得られた水溶液をNaHCO3飽和水溶液で中和し、EtOAc(2×200mL)で洗浄し、Na2SO4で乾燥させ、濾過した。有機相を回転蒸発で除去して乾固し、表題化合物を得た(11mg、13%)。1H NMR (400 MHz, DMSO-d6)δppm 1.08 - 1.18 (m, 3 H), 1.25 - 1.44 (m, 4 H), 2.26 - 2.32 (m, 3 H), 4.07 - 4.17
(m, 3 H), 4.19 - 4.29 (m, 2 H), 6.03 (s, 1 H), 6.78 (d, J=7.83 Hz, 1 H),
7.06 (br s, 1 H), 7.12 - 7.22 (m, 1 H), 7.48 (s, 1 H), 7.60 (d, J=7.83 Hz, 1 H), 7.66 - 7.75 (m, 2 H), 7.99 (s, 1 H), 8.83 - 8.97 (m, 1 H)。[M+H]C19H25N5O2における計算値356;実測値、356。
、474。
4.40 (s, 2 H), 6.80 (d, J=7.58 Hz, 1 H), 7.07 - 7.25 (m, 2 H), 7.38 (s, 1 H), 7.54 (d, J=7.58 Hz, 1 H), 7.92 (br s, 2 H), 8.28 (s, 1 H), 8.83 (s, 1 H)。[M+H]C19H24FN5O2における計算値374;実測値、374。
(400 MHz, CDCl3)δppm 3.91-3.95 (m, 1 H), 4.06-4.14 (m, 1 H), 4.45-4.51
(m, 1 H), 4.63-4.67 (m, 1 H), 7.30-7.39 (m, 5 H)。
(m, 2 H), 1.91 - 2.15 (m, 1 H), 2.22 - 2.40 (m, 3 H), 3.47 - 3.66 (m, 1 H), 3.66 - 3.86 (m, 1 H), 4.14 - 4.27 (m, 1 H), 4.33 - 4.46 (m, 1 H), 4.74 - 4.89 (m, 1 H), 5.96 - 6.13 (m, 1 H), 6.71 - 6.86 (m, 1 H), 7.08 - 7.26
(m, 1 H), 7.38 - 7.70 (m, 2 H), 8.79 - 9.07 (m, 1 H)。[M+H]C17H18F3N5Oに
おける計算値366;実測値、366。
,3−ジヒドロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)ペンタンアミド
(m, 1 H), 1.61 (t, J=7.33 Hz, 2 H), 1.69 - 1.83 (m, 1 H), 2.24 - 2.34 (m,
3 H), 4.21 (s, 1 H), 4.37 (s, 1 H), 6.00 - 6.17 (m, 1 H), 6.69 - 6.80 (m, 1 H), 6.96 (br s, 1 H), 7.04 (d, J=7.83 Hz, 1 H), 7.10 - 7.26 (m, 2 H), 7.49 (s, 1 H), 7.58 (d, J=7.33 Hz, 1 H), 7.95 (s, 1 H), 8.82 - 8.97 (m,
1 H)。[M+H]C20H25N5O2における計算値368;実測値、368。
.54mg、0.133mmol)を添加した。混合物を室温で一晩撹拌した。さらにアミンを添加し、室温でさらに1日撹拌した。反応混合物をMeOH(10mL)で希釈し、及び逆相分取HPLCにより精製した。画分を回収し、ACNを回転蒸発で除去した。得られた水溶液をNaHCO3飽和水溶液で中和し、及びEtOAc(2×200mL)で洗浄し、Na2SO4で乾燥させ、濾過した。有機相を回転蒸発で除去して乾固し、表題化合物を得た(35.5mg、73%)。[M+H]C19H21N5O3における計算値368;実測値、368。
における計算値273.5;実測値、273.5。
;実測値、441。
c]ピリジン−6−イルアミノ)シクロヘキシルカルバマート(50mg、0.113mmol)の溶液に、DCM/TFA(1/1、2mL)を添加した。混合物を室温で2時間撹拌した。溶媒を除去した後、得られた粗物質をMeOH(5.0mL)中で再構成し、及び分取HPLCにより精製した。画分を回収し、溶媒を回転蒸発で除去して乾固し、表題化合物をTFA塩(10.5mg、27%)として得た。1H NMR (500 MHz, DMSO-d6)δppm 1.31 - 1.55 (m, 6 H), 1.58 - 1.86 (m, 8 H), 4.20 - 4.31 (m, 3 H),
6.56 (s, 1 H), 6.84 (d, J=7.32 Hz, 1 H), 7.56 - 7.76 (m, 2 H), 8.10 (s, 1 H), 8.38 (s, 1 H), 8.96 (s, 1 H)。[M+H]C18H24N6Oにおける計算値341;実測値、341。
る計算値459;実測値、459。
1H−ピラゾール−4−イル)−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン
(m, 2 H), 3.47 - 3.60 (m, 2 H), 3.69 (br s, 1 H), 4.18 (q, J=7.32 Hz, 2 H), 4.33 - 4.52 (m, 3 H), 6.74 (d, J=6.83 Hz, 1 H), 7.77 (br s, 3 H), 8.26 - 8.44 (m, 2 H), 8.88 (s, 1 H)。[M+H]C18H23FN6Oにおける計算値359;実測値、359。
測値、245。
4.35 (s, 2 H), 6.65 (s, 1 H), 8.35 (s, 1 H), 8.96 (s, 1 H)。[M+H]C19H24N6Oにおける計算値353;実測値、353。
−イルアミノ)シクロヘキシルカルバマート(36mg、0.057mmol)の溶液を60℃で2時間加熱した。溶媒を除去した後、残渣をMeOH(2mL)で希釈し。及び分取HPLCにより精製した。画分を回収し、回転蒸発で除去して乾固し、表題化合物をTFA塩として得た(18.7mg、86%)。1H NMR (500 MHz, DMSO-d6)δppm 1.40 - 1.52 (m, 2 H), 1.58 - 1.76 (m, 3 H), 1.75 - 1.94 (m, 3 H), 3.67 (br s, 1 H), 4.44 (d, J=4.88 Hz, 2 H), 4.53 (br s, 1 H), 6.86 (d, J=6.83 Hz, 1 H), 7.71 (br s, 2 H), 7.79 - 8.12 (m, 1 H), 8.53 (s, 2 H), 9.41 (s, 1 H
)。[M+H]C17H19F3N6Oにおける計算値381;実測値、381。
(500 MHz, DMSO-d6)δppm 0.94 - 1.11 (m, 4 H), 1.47 (d, J=6.35 Hz, 2 H), 1.56 - 1.97 (m, 6 H), 3.60 - 3.85 (m, 2 H), 4.28 - 4.53 (m, 3 H), 6.74 (d, J=6.35 Hz, 1 H), 7.70 (br s, 2 H), 8.25 (s, 1 H), 8.38 (s, 1 H), 8.94 (s, 1 H)。[M+H]C19H23FN6Oにおける計算値371;実測値、371。
H), 1.58 (br s, 2 H), 1.76 (br s, 2 H), 3.71 - 3.90 (m, 11 H), 4.33 (br
s, 2 H), 4.51 (br s, 2 H), 6.43 - 6.72 (m, 3 H), 6.87 (br s, 1 H), 7.07 (br s, 1 H)。[M+H]C27H34ClFN4O5における計算値549;実測値、549。
5;実測値、595。
(m, 2 H), 4.20-4.24 (m, 1 H), 4.42 (s, 2 H), 5.62 (s, 2 H), 7.17-7.28
(m, 5 H)。
J=7.2, 14.0 Hz, 2 H), 3.49 (s, 2 H), 3.85 (quintet J=7.0 Hz, 1 H), 4.43 (s, 2 H), 7.25-7.34 (m, 5 H);1H NMR of (1R,3r,5S) (400 MHz, CDCl3)δppm 1.99 (dd, J=7.6, 15.6 Hz, 2 H), 2.23 (d, J=16.6 Hz, 2 H), 3.55 (s, 2 H), 4.08 (t, J=7.2 Hz, 1 H), 4.49 (s, 2 H), 7.27-7.35 (m, 5 H)。
Cl3)δppm 1.65-1.79 (m, 2 H), 2.01-2.07 (m, 1 H), 2.30-2.37 (m, 1 H), 3.49-3.54 (m 1 H), 3.97-4.06 (m, 2 H), 4.11-4.13 (br, 1 H), 4.33-4.40 (m, 2 H), 7.18-7.27 (m, 5 H)。
Hz, 1 H), 7.25-7.36 (m, 5 H)。
(400 MHz, CDCl3)δppm 1.99-2.08 (m. 2 H), 2.23-2.30 (m, 2 H), 3.75-3.80
(m, 2 H), 3.99-4.04 (m, 1 H), 4.49 (s, 2 H), 7.26-7.35 (m, 5 H)。
)δppm 1.45 (br, 18 H), 2.15-2.19 (m, 2 H), 2.47-2.52 (m, 2 H), 4.22 (br, 2 H), 4.87 (br, 2 H)。
;実測値137。
, 7.93 (br s, 2 H), 8.41 (d, J=7.32 Hz, 2 H), 8.87 (s, 1 H)。[M+H]C16H17F3N6Oにおける計算値367;実測値、367。
), 4.23-4.28 (m, 1H)。
), 3.80 (br, 1 H), 4.05-4.16 (m, 2 H), 5.12 (s, 4 H), 5.4 (s, 1 H), 6.4
(s, 1 H), 7.33-7.37 (m, 10 H)。
H)。
H), 4.20-4.26 (m, 1 H)。[M+H]C6H12F2N2における計算値151;実測値、151。
縮し、DMF(1mL)で再構成した。残渣を分取HPLCにより精製し、適切な画分を回収し、過剰アセトニトリルを蒸発させた。残渣を炭酸ナトリウム飽和水溶液で処理した、EtOAc(3×20mL)で抽出した。有機層を合わせ、硫酸ナトリウムで乾燥させ、濃縮し、表題化合物を無色残渣として得た(13.7mg、10%)。[M+H]C22H24ClF3N4O3における計算値485;実測値、485。
2.33 (t, J=1.77 Hz, 1 H), 2.63 - 2.72 (m, 1 H), 4.11 (br s, 1 H), 4.40 - 4.50 (m, 2 H), 4.62 (br s, 1 H), 6.93 (d, J=5.31 Hz, 1 H), 7.74 - 8.14 (m, 1 H), 8.45 (s, 1 H), 8.56 (s, 1 H), 9.40 (s, 1 H)。[M+H]C17H17F5N6Oにおける計算値417;実測値、417。
6.10 (m, 1 H), 6.83 (d, J=6.06 Hz, 1 H), 8.22 (s, 1 H), 8.39 (s, 2 H), 8.84 - 9.05 (m, 1 H)。[M+H]C19H21F3N6Oにおける計算値407;実測値、407。
NMR (500 MHz, DMSO-d6)δppm 0.82 - 1.00 (m, 6 H), 1.45 - 1.60 (m, 1 H), 1.67 - 1.83 (m, 2 H), 3.87 (s, 3 H), 4.36 (s, 2 H), 4.50 - 4.64 (m, 1 H),
6.88 - 7.02 (m, 2 H), 7.44 (s, 1 H), 8.28 (s, 2 H), 8.83 (s, 1 H)。[M+H
]C17H21FN6O2における計算値361;実測値、361。
)δppm 1.63 (br s, 1 H), 1.75 - 1.92 (m, 3 H), 2.00 - 2.29 (m, 2 H), 2.33
(dt, J=3.73, 1.80 Hz, 1 H), 2.62 - 2.74 (m, 1 H), 4.34 - 4.46 (m, 2 H), 4.57 (br s, 1 H), 4.81 (d, J=5.56 Hz, 2 H), 5.08 - 5.30 (m, 2 H), 5.93 - 6.10 (m, 1 H), 6.83 (d, J=6.06 Hz, 1 H), 8.22 (s, 1 H), 8.39 (s, 2 H), 8.84 - 9.05 (m, 1 H)。[M+H]C17H19F3N6O2における計算値397;実測値、397。
0.70 - 1.07 (m, 7 H), 1.15 - 1.35 (m, 1 H), 1.48 - 1.64 (m, 1 H), 1.67 - 1.93 (m, 2 H), 4.25 - 4.43 (m, 2 H), 4.54 (d, J=9.60 Hz, 1 H), 4.79 (d, J=5.81 Hz, 1 H), 5.11 - 5.31 (m, 1 H), 5.91 - 6.16 (m, 1 H), 6.80 - 7.07 (m, 2 H), 7.42 (br s, 1 H), 8.25 (s, 1 H), 8.34 - 8.43 (m, 1 H), 8.83 - 8.97 (m, 1 H)。[M+H]C19H23FN6O2における計算値387;実測値、387。
−メチルペンタンアミド
1.57 - 1.91 (m, 3 H), 4.42 (s, 2 H), 4.63 - 4.77 (m, 1 H), 6.99 - 7.17 (m, 2 H), 7.24 - 7.42 (m, 3 H), 7.62 (d, J=7.83 Hz, 1 H), 8.32 - 8.48 (m, 2
H), 9.28 (s, 1 H)。[M+H]C21H21FN4O3における計算値397;実測値、397。
8.27 (s, 1 H), 8.47 (d, J=8.84 Hz, 1 H), 8.72 (d, J=6.82 Hz, 1 H), 9.30
(s, 1 H)。[M+H]C20H21FN6O2における計算値397;実測値、397。
7.83 (br s, 3 H), 7.39 - 7.57 (m, 2 H), 7.12 - 7.32 (m, 1 H), 6.84 (d, J=7.6 Hz, 1 H), 6.22 (d, J=6.8 Hz, 1 H), 4.19 - 4.43 (m, 3 H), 3.71 (br s, 1 H), 2.32 (s, 3 H), 1.37 - 1.99 (m, 8 H)。[M+H]C20H24ClN5Oにおける計算値386;実測値、386。
した。有機層を合わせ、濃縮し、表題化合物を油状物として得、さらに精製することなく用いた(10.9g、28%)。
3 H), 1.47 (s, 9 H)。
をH2雰囲気下で室温で一晩撹拌した。濾過後、粗生成物をアミノ−保護シリカゲルクロマトグラフィーによりEtOAc及び石油エーテル(EtOAc/PE=1/1)で溶出して精製し、表題化合物を得た(740mg、19.4%)。1H NMR (400 MHz, CD3OD
)δppm 5.00 (s, 1 H), 3.67-3.66 (m, 1 H), 3.51-3.47 (m, 1 H), 3.42-3.38
(m, 1 H), 3.35 (s, 1 H), 2.82-2.78 (m, 2 H), 1.46 (s, 9 H)。[M+H]C9H20N2O3における計算値205;実測値、205。
H31N5O4における計算値442;実測値、442。
6.93 (d, J=7.3 Hz, 1 H), 4.43 (s, 2 H), 3.71 - 3.80 (m, 1 H), 3.60 - 3.70
(m, 1 H), 3.44 - 3.60 (m, 3 H), 3.29 (s, 3 H), 2.33 (s, 3 H)。[M+H]C19H22N6O2における計算値367;実測値、367。
(s, 1 H), 7.85 (br s, 3 H), 7.60 (s, 1 H), 7.51 (s, 1 H), 7.27 (t, J=7.8 Hz, 1 H), 7.08 (dd, J=16.5, 10.5 Hz, 1 H), 6.93 (d, J=7.6 Hz, 1 H), 6.19 (dd, J=16.7, 2.0 Hz, 1 H), 5.68 - 5.90 (m, 1 H), 4.50 - 4.80 (m, 3 H), 3.65 (br s, 1 H), 2.34 (s, 3 H), 1.78 - 2.01 (m, 2 H), 1.75 (s, 3 H), 1.43 - 1.58 (m, 3 H)。[M+H]C23H27N5O2における計算値406;実測値、406。
(m, 1 H), 2.36 (s, 3 H), 1.87 (d, J=5.6 Hz, 4 H), 1.66 (br s, 4 H)。[M+H]C20H24IN5Oにおける計算値478;実測値、478。
1 H), 8.97 (s, 1 H), 8.19 (s, 1 H), 8.06 (br s, 1 H), 7.75 (br s, 4 H), 7.42 - 7.58 (m, 2 H), 7.21 (t, J=8.1 Hz, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 5.55 (d, J=6.6 Hz, 1 H), 4.25 (s, 3 H), 3.77 (br s, 1 H), 2.32 (s, 3 H),
1.63 - 1.89 (m, 4 H), 1.36 - 1.63 (m, 4 H)。[M+H]C23H27N7Oにおける計算値418;実測値、418。
物を室温まで冷却し、EtOAc(30mL)で希釈し、水(2×10mL)及びブライン(20mL)で洗浄した。有機層を回収し、Na2SO4で乾燥させ、及び濃縮し、濃褐色油状物を得、これを表題化合物及び異性体(328mg、119%)に含めた。粗生成物をさらに精製することなく用いた。[M+H]C21H23F2N5O2における計算値416;実測値、416。
(d, J=7.3 Hz, 1 H), 6.15 (s, 1 H), 4.45 (br s, 1 H), 4.24 (d, 2 H), 4.15
(br s, 1 H), 2.29 (s, 3 H), 2.01 - 2.25 (m, 2 H), 1.74 - 1.89 (m, 3 H),
1.60 (d, J=10 Hz, 1 H)。[M+H]C20H23F2N5Oにおける計算値388;実測値、388。
における計算値532;実測値、532。
Hz, 3 H), 3.89 - 4.00 (m, 1 H), 4.02 - 4.21 (m, 1 H), 5.23 - 5.58 (m, 1 H), 6.29 - 6.47 (m, 1 H), 6.85 (d, J=7.58 Hz, 1 H), 7.23 (td, J=7.77, 4.93 Hz, 1 H), 7.47 - 7.56 (m, 2 H), 7.58 (dd, J=9.35, 1.77 Hz, 1 H), 7.64 - 7.83 (m, 2 H), 8.21 (d, J=2.27 Hz, 1 H), 9.04 (s, 1 H)。[M+H]C24H29N7Oにおけ
る計算値432;実測値、432。
R,4R)−テトラヒドロ−2H−ピラン−3,4−ジアミン塩酸塩(303.0mg、1.989mmol)、及びDIPEA(868μL、4.97mmol)を添加した。得られた黄色懸濁液、塩基を添加して溶液として、50℃で12時間撹拌した。反応混合物を室温まで冷却し、EtOAc(30mL)で希釈し、及び、水(20mL)及びブライン(20mL)で洗浄した。有機層を回収し、Na2SO4で乾燥し、及び濃縮し、黄色の油状物を得、これは表題化合物を含んだ(350mg、55.4%)。粗生成物をさらに精製することなく次の工程に用いた。[M+H]C20H23N5O3における計算値382;実測値、382。
3.76 (br s, 1 H), 3.53 - 3.72 (m, 2 H), 2.31 (s, 3 H), 1.99 (qd, J=12.6,
4.7 Hz, 1 H), 1.70 - 1.80 (m, 1 H)。[M+H]C19H23N5O2における計算値354;実測値、354。
ミノ)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オンに対応する画分を収集した。1H NMR (400 MHz, DMSO-d6)δppm 8.91 (s, 1 H), 7.94 - 8.15 (m, 4 H), 7.52 (s, 1 H), 7.43 (d, J=8.3 Hz, 1 H), 7.18 (t, J=7.8 Hz, 1 H), 7.03 (d,
J=8.3 Hz, 1 H), 6.79 (d, J=7.6 Hz, 1 H), 6.21 (s, 1 H), 4.44 (br s, 1 H), 4.20 - 4.30 (m, 2 H), 3.84 - 3.95 (m, 2 H), 3.67 - 3.81 (m, 1 H), 3.62
(dd, J=11.6, 1.8 Hz, 1 H), 3.50 (td, J=11.2, 2.4 Hz, 1 H), 2.30 (s, 3 H), 1.98 - 2.13 (m, 1 H), 1.71 - 1.82 (m, 1 H)。[M+H]C19H23N5O2における計算値354;実測値、354。
;実測値、428。
l)を添加し、混合物をさらに2分脱気した。容器にキャップをし、反応混合物を100℃で撹拌しながら一晩加熱した。反応混合物を室温まで冷却し、EtOAc(5mL)で希釈し、水(5mL)及びブライン(5mL)で洗浄した。有機層を回収し、Na2SO4で乾燥させ、濃縮し、表題化合物を褐色粘着性の油状物として得、これを精製することなく用いた(45mg)。[M+H]C26H35N5O3における計算値466;実測値、466。
(m, 2 H)。[M+H]C21H27N5Oにおける計算値366;実測値、366。
合物を残渣まで濃縮し、これをDMF(1mL)で希釈し、分取HPLCで精製した。適切な画分を回収し、凍結乾燥し、表題化合物のTFA塩を白色固体として得た(2.6mg、73%)。1H NMR (400 MHz, DMSO-d6)δppm 8.81 (s, 1 H), 8.25 (s, 1 H),
7.57 (s, 1 H), 7.40 (d, J=8.1 Hz, 1 H), 7.04 - 7.28 (m, 2 H), 6.79 (d, J=7.3 Hz, 1 H), 6.62 - 6.76 (m, 2 H), 4.26 - 4.46 (m, 3 H), 3.85 - 3.96 (m,
2 H), 2.32 (s, 3 H), 1.94 - 2.13 (m, 1 H), 1.59 - 1.70 (m, 1 H), 1.07 - 1.28 (m, 4 H)。[M+H]C19H22FN5O2における計算値372;実測値、372。
る計算値505;実測値、505。
ロ−1H−ピロロ[3,4−c]ピリジン−6−イルアミノ)シクロヘキシルカルバマートを用いて、調製40と同様の方法で表題化合物を調製した。[M+H]C23H32N6O3における
計算値441;実測値、441。
びヘキサン(50〜100%EtOAc勾配)で溶出して精製し、表題化合物を薄黄色残渣として得た(36.5mg、20%)。[M+H]C21H28N6O5における計算値445;実測値、445。
(m, 1 H), 1.80-1.82 (s, 1 H), 3.40 (td, J=11.47, 2.44 Hz, 1 H), 3.53 (dd, J=11.23, 1.95 Hz, 1 H), 3.67 (dd, J=11.47, 2.20 Hz, 1 H), 3.71-3.73 (m, 1 H), 3.75 (s, 3 H), 3.77-3.79 (m, 1 H), 3.81 (s, 3 H), 4.09-4.11 (m, 1 H
), 4.33 (s, 2 H), 4.50 (s, 2 H), 6.48 (dd, J=8.30, 2.44 Hz, 1 H), 6.58 (d, J=2.44, 1 H), 6.90 (br s, 1 H), 7.06 (d, J=8.30 Hz, 1 H)。[M+H]C21H24ClFN4O4における計算値451;実測値、451。
1 H), 4.59 (s, 2 H), 6.50 (dd, J=8.30, 1.95 Hz, 1 H), 6.60 (d, J=2.44, 1 H), 7.04-7.08 (m, 2 H), 7.16 (d, J=5.86 Hz, 1 H), 7.48-7.51 (m, 1 H), 7.93 (br s, 1 H), 8.37 (d, J=9.27 Hz, 1 H), 8.79 (d, J=6.83 Hz, 1 H), 9.36 (s, 1 H)。[M+H]C28H29FN6O4における計算値533;実測値、533。
2.09-2.12 (m, 1 H), 3.60-3.63 (m, 1 H), 3.76-3.77 (m, 1 H), 3.88-3.98 (m, 3 H), 4.44 (d, J=6.35 Hz, 2 H), 4.54-4.55 (m, 1 H), 7.17 (d, J=5.86 Hz, 1 H), 7.89 (br s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 9.43 (s, 1 H)。[M+H]C16H17F3N6O2における計算値383;実測値、383。
ン−6−イル)ピロリジン−3−イルカルバマート
(s, 2 H), 8.02 (br s, 2 H), 8.26 (d, J=0.51 Hz, 1 H), 8.39 (s, 1 H), 8.85 (s, 1 H); )。 [M+H]C15H17FN6Oにおける計算値317;実測値、317。
), 8.04 (br s, 3 H), 8.36 (s, 1 H), 8.51 (s, 1 H), 8.90 (s, 1 H)。[M+H]C16H19FN6Oにおける計算値331;実測値、331。
(d, J=6.83 Hz, 2 H), 8.15 (s, 1 H), 8.88 (s, 1 H)。[M+H]C19H25FN6Oにおける計算値373;実測値、373。
δppm 6.11 (dd, J=9.3 Hz, 1.5 Hz, 1 H), 6.95 (d, J=9.3 Hz, 1 H), 9.54 (s, 1
H)。[M+H]C7H3Cl2FN2O2における計算値237;実測値、237。
(400 MHz, DMSO-d6)δppm 3.92 (s, 3 H), 3.96 (s, 3 H), 4.53 (s, 2 H), 8.17 (s, 1 H), 8.49 (s, 1 H), 8.50 (s, 1 H), 8.81 (s, 1 H), 8.92 (s, 1 H
)。[M+H]C15H13FN6Oにおける計算値313;実測値、313。
7.65 (d, J=7.81 Hz, 1 H), 7.68 - 7.83 (m, 3 H), 7.87 (br s, 2 H), 8.39 (s, 1 H), 8.58 - 9.00 (m, 1 H), 9.62 - 9.86 (m, 1 H)。[M+H]C21H22FN7Oにおけ
る計算値408;実測値、408。
。油状物をIPAc(12mL)に再溶解し、約75℃まで加熱し、マレイン酸(423mg)を添加した。固体の沈殿がすぐに起こり、濃混合物をIPAc(5mL)で希釈した、スラリーを室温まで冷却し、20分間静置した。固体を濾過し、IPAc(10mL)で洗浄し、乾燥して、表題化合物のマレイン酸塩を白色結晶性固体として得た(730mg、44%)。1H NMR (300 MHz, DMSO-d6)δppm 1.34-1.42 (m, 2 H), 1.50 (s,
9 H), 1.50-1.64 (m, 6 H), 3.22 (m, 1 H), 3.83 (br s, 1 H), 6.02 (s, 2 H), 6.86 (d, J=7.5 Hz, 1 H), 7.68 (br s, 3 H)。
、氷浴を除去し、混合物を室温で16時間撹拌し、EtOH中の表題化合物を得た。
), 4.72 (s, 2 H), 6.71 (d, J=7.58 Hz, 1 H), 7.22 (d, J=6.32 Hz, 1 H)。
下で保持する速度で、ナスフラスコに移した。添加後、反応容器をDMA(1mL)ですすいだ。すすいだ物をナスフラスコに添加し、得られた水溶液スラリーを氷浴中で10分間撹拌し、次いで、撹拌しながら室温まで温めた。内部温度が22℃に達したら、混合物を濾過した。ケーキ状濾過物を脱イオンH2O(2×5mL)ですすぎ、吸引して風乾した. 固体を氷酢酸(3mL)で再懸濁し、室温で1時間撹拌した。イソプロパノール(1mL)を添加し、混合物を室温で撹拌した。脱イオン水(3.4mL)を添加し、再結晶を起こさせた。沈殿が起こったが、ある固体は粘着性であり、それで混合物を40℃油浴で撹拌しながら20分間加熱した。混合物を撹拌しながら室温まで冷却させ、次いで濾過した。ケーキ状濾過物をHOAc/H2O/IPA(2.1mL)の3:3:1混合物ですすぎ、すぐに吸引して風乾し、次いで、真空オーブンで60℃で乾燥し、表題化合物を黄褐色固体として得た(352mg、62%)。1H NMR (400 MHz, DMSO-d6)δppm 1.35 (s, 9 H), 1.53 (s, 9 H), 1.65 (m, 3 H), 1.76 (m, 3 H), 3.94 (s, 3 H), 4.03 (br s, 1 H), 4.38 ( br s, 1 H), 4.67 (s, 2 H), 5.12 ( br s, 1 H),
5.77 ( br s, 1 H), 8.25 (br s, 1 H), 8.96 (br s, 1 H)。[M+H]C27H37FN6O5における計算値545;実測値、545。
4.41 - 4.60 (m, 1 H), 6.75 (d, J=6.57 Hz, 1 H), 7.96 (br s, 3 H), 8.22 - 8.31 (m, 1 H), 8.34 (s, 1 H), 8.84 (s, 1 H)。[M+H]C17H21FN6Oにおける計算値345;実測値345。
2 H), 3.81-3.83 (m, 2 H), 4.41-4.43 (m, 2 H), 4.49-5.10 (m, 1 H), 7.12-7.13 (m, 1 H), 7.52-7.54 (m, 1 H), 7.90-7.97 (m, 3 H), 8.48 (s, 1 H), 8.88
(s, 1 H)。[M+H]C16H17FN4O2Sにおける計算値349;実測値、349。
H), 4.42 (d, J=11.62 Hz, 2 H), 6.46 (s, 1 H), 7.20-7.22 (m, 3 H), 8.46
(s, 1 H), 8.85 (s, 1 H)。[M+H]C17H19FN4O2Sにおける計算値363;実測値、363。
算値361;実測値、361。
2 H), 7.01 (d, J=5.86 Hz, 1 H), 7.15 (dd, J=5.37, 3.91 Hz, 1 H), 7.64 (dd, J=4.88, 0.98 Hz, 1 H), 7.75 (br s, 2 H), 8.50 (s, 1 H), 8.95 - 9.07 (m, 1 H)。[M+H] C17H19FN4OSにおける計算値347;実測値、347。
.76mL、24.25mmol)の混合物を100℃で3日間撹拌した。溶媒を除去し、得られた残渣をさらに精製することなく次の工程に用いた。[M+H]C23H27ClFN3O5における計算値480;実測値480。
で溶解し、分取HPLCにより水(0.05%TFA)及びACN(40〜70%勾配、0.035%TFA)で溶出して精製した。回収した画分を合わせ、溶媒を回転蒸発で除去して乾固し、表題化合物を得た。[M+H]C26H30FN5O5における計算値 512;実測値512。
m, 1 H), 7.93 (d, J=4.39 Hz, 1 H), 8.30 (s, 1 H), 8.83 (s, 1 H)。[M+H]C18H23FN6O2における計算値375;実測値375。
H), 1.20 - 1.32 (m, 2 H), 2.23 (s, 3 H), 4.38 (s, 2 H), 4.59 - 4.72 (m, 2 H), 6.94 - 6.99 (m, 1 H), 7.02 - 7.08 (m, 1 H), 7.15 - 7.23 (m, 1 H), 7.27 - 7.34 (m,
1 H), 8.35 (s, 1 H), 8.78 (d, J=1.26 Hz, 1 H)。[M+H]C18H21FN4O2Sにおける計算値377;実測値377。
(br s, 1 H), 7.01 (d, J=7.58 Hz, 1 H), 7.38 (br s, 1 H), 7.49 (dd, J=5.05, 3.03
Hz, 1 H), 8.04 (dd, J=5.05, 1.26 Hz, 1 H), 8.36 (s, 1 H), 8.94 (dd, J=3.03, 1.01 Hz, 1 H)。[M+H]C17H19FN4O2Sにおける計算値363;実測値363。
H), 1.52 - 1.85 (m, 3 H), 2.45 (s, 3 H), 4.38 (s, 2 H), 4.56 - 4.74 (m, 1 H), 6.80 (dd, J=3.66, 1.14 Hz, 1 H), 6.93 - 7.10 (m, 2 H), 7.30 (br s, 1 H), 8.32 (s,
1 H), 8.78 (d, J=3.79 Hz, 1 H)。[M+H]C18H21FN4O2Sにおける計算値377;実測値377。
る計算値713;実測値713。
における計算値363;実測値363。
ジン−6−イルアミノ)−4−メチルペンタンアミド(150mg、0.323mmol)、トリブチル(フラン−2−イル)スタンナン(138mg、0.387mmol)、及びテトラキス(トリフェニルホスフィン)パラジウム(0)(373mg、0.323mmol)の溶液を、102℃まで一晩加熱した。溶媒を除去した後、残渣をMeOH/DCM(10mL)に希釈し、分取HPLCにより水(0.05%TFA)及びACN(45〜60%勾配、0.035%TFA)で溶出して精製した。回収した画分を回転蒸発で除去して乾固し、表題化合物を得た(93.1mg、58%)。[M+H]C26H29FN4O5における計算値498;実測値498。
る計算値347;実測値347。
ル(5.16mg、0.015mmol)の溶液を、マイクロ波照射下で160℃まで45分間加熱した。UPLCにより、50%の変換が示された。次いで、反応混合物をマイクロ波照射下で160℃で45分間加熱した。さらに5−シアノチオフェン−2−イルボロン酸(113mg、0.736mmol)を添加し、マイクロ波照射下で160℃で60分間加熱した。溶媒を除去した後、得られた粗物質をMeOH/DMF(6.0mL)中で再構成し、分取HPLCにより水(0.05%TFA)及びACN(40〜80%勾配、0.035%TFA)で溶出して精製した。回収した画分を回転蒸発で除去して乾固し、表題化合物を得た。[M+H]C27H28FN5O4Sにおける計算値538;実測値538。
1.67 - 1.88 (m, 2 H), 4.45 (s, 2 H), 4.50 - 4.57 (m, 1 H), 6.96 - 7.06 (m, 1 H), 7.32 - 7.54 (m, 2 H), 7.86 - 8.02 (m, 1 H), 8.61 (s, 1 H), 9.00 - 9.15 (m, 1 H)。[M+H]C18H18FN5O2Sにおける計算値388;実測値388。
H), 4.42 (s, 2 H), 4.52 - 4.66 (m, 1 H), 6.95 (br s, 1 H), 7.18 (d, J=8.59 Hz, 1 H), 7.34 (br s, 1 H), 8.46 (s, 1 H), 9.11 (s, 1 H), 9.46 (s, 1 H)。[M+H]C16H18FN5O2Sにおける計算値364;実測値364。
(m, 6 H), 1.56 - 1.64 (m, 1 H), 1.67 - 1.86 (m, 2 H), 4.45 (s, 2 H), 4.49 - 4.62 (m, 1 H), 7.00 (s, 1 H), 7.33 (d, J=8.30 Hz, 1 H), 7.44 (s, 1 H), 8.53 - 8.65 (m, 2 H), 8.91 (d, J=1.46 Hz, 1 H)。[M+H]C16H18FN5O2Sにおける計算値364;実測値364。
2mg、0.829mmol)及びPdCl2(PPh3)2(44.7mg、0.064mmol)をジオキサン(5mL)に溶解させた。Na2CO3水溶液(2M、0.5mL)を添加し、キャップを密閉した。反応混合物を85℃で4時間加熱し、次いで水(5mL)で希釈し、EtOAc(2×30mL)で抽出した。有機相をNa2SO4で乾燥させ、溶媒を蒸発させた。得られた残渣をTFA(4mL)で処理し、80℃で1.5時間加熱し、保護基を除去した。次に、TFAを蒸発させ、生成物をDMSO(8mL)に溶解させ、分取HPLCにより精製した。純画分を合わせ、濃縮し、凍結乾燥し、表題化合物のTFA塩を白色固体として得た(52.3mg、24%)。1H NMR (400 MHz, DMSO-d6)δppm 1.40 - 1.95 (m, 8 H), 3.64 (br s, 1 H), 3.92 (s, 2 H), 4.28 - 4.49 (m, 3 H), 6.76 (d, J=5.31 Hz, 1 H), 7.42 (d, J=2.27 Hz, 1 H), 7.72 (d, J=2.27 Hz, 1 H), 7.98 (br s, 3 H), 8.39 (s, 1 H)。[M+H]C17H21FN6Oにおける計算値345;実測
値345。
ミノシクロヘキシルアミノ)−4−ブロモ−7−フルオロ−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン(38mg、0.111mmol)、2−メチルチアゾール−5−カルボン酸(15.85mg、0.111mmol)、酢酸銀(I)(18.48mg、0.111mmol)、及び塩化銅(II)(14.89mg、0.111mmol)の溶液を、135℃まで一晩加熱した。反応混合物をセライトのパッドを通して濾過し、溶媒を真空下で除去した。得られた粗物質をMeOH/DMF(10.0mL)中で再構成し、分取HPLCにより水(0.05%TFA)及びACN(50〜90%勾配、0.035%TFA)で溶出して精製した。回収した画分を合わせ、溶媒を回転蒸発で除去して乾固し、表題化合物をTFA塩(2.3mg、6%)として得た。1H NMR (500 MHz, CDCl3)δppm 1.37 - 1.85 (m, 8 H) 2.93 (s, 2 H) 2.97 - 3.08 (m, 3 H) 4.22 - 4.42 (m, 2 H) 6.52 (s, 1 H) 7.53 (d, J=4.39 Hz, 1 H) 7.72 (br s, 1 H) 8.08 (br s, 1 H) 8.27 (s, 1 H)[M+H]C17H20FN5OSにおける計算値362;実測値362。
L)で洗浄し、Na2SO4で乾燥させ、濾過した。有機相を回転蒸発で除去して乾固し、表題化合物を得た(51mg、11%)。[M+H]C26H32ClFN4O6における計算値552;実
測値552。
(500 MHz, DMSO-d6)δppm 1.78 (d, J=13.18 Hz, 1 H), 2.03 - 2.18 (m, 1 H), 2.46 (s, 3 H), 3.17 (d, J=4.88 Hz, 1 H), 3.55 - 3.65 (m, 1 H), 3.75 (d, J=13.18 Hz, 1 H), 3.85 (br s, 1 H), 3.96 - 4.06 (m, 2 H), 4.41 (d, J=7.81 Hz, 2 H), 6.84 (d, J=2.44 Hz, 1 H), 7.22 (d, J=4.88 Hz, 1 H), 7.92 (br s, 2 H), 8.47 (s, 1 H), 8.83 (d, J=3.42 Hz, 1 H)。[M+H]C17H19FN4O2Sにおける計算値363;実測値363。
J=14.4 Hz, 1 H), 4.52 (q, J=6.8 Hz, 1 H), 5.07 (d, J=14.4 Hz, 1 H), 6.43-6.45 (m, 2 H), 7.28 (d, J=9.2 Hz, 1 H)。[M+H]C17H15Cl2FN2O3における計算値386;実測値385。
H), 1.60-1.84 (m, 5 H), 3.68 (br s, 1 H), 3.89 (s, 2 H), 4.44 (br s, 1 H), 4.71
(q, J=6.65 Hz, 1 H), 6.52 (br s, 1 H), 6.73 (d, J=6.53 Hz, 1 H), 7.72 (br s, 2 H), 8.24 - 8.32 (m, 1 H), 8.46 (s, 1 H), 8.82 (s, 1 H)。[M+H]C18H23FN6Oにおける
計算値359;実測値359。
)の混合物を油浴中で100℃まで20時間加熱した。次いで、溶液を濃縮し、得られた油を水(50mL)に溶解させ、油浴中で50℃まで1時間加熱し、次いで室温まで放冷した。次いで、溶液を50℃まで15分間加熱し、室温まで放冷し、再び50℃まで15分間加熱し、室温まで放冷した。得られた沈殿物を濾過し、水ですすぎ、表題化合物を薄桃色がかった白色固体(1.90g、86%、位置異性体との4:1の混合物)として得た。これをさらに精製することなく次の工程に用いた。1H NMR (400 MHz, DMSO-d6)δppm
1.36 (s, 9 H), 1.50 (s, 3 H), 1.59-1.61 (m, 1 H), 1.97-1.99 (m, 1 H), 1.97-1.99
(m, 1 H), 3.46-3.49 (m, 2 H), 3.80-3.83 (m, 3 H), 4.31-4.33 (m, 1 H), 4.73 (s, 1 H), 6.59 (d, J=7.30 Hz, 1 H), 7.43 (d, J=7.30 Hz, 1 H)。[M+H]C22H30ClFN4O6における計算値501;実測値501。
δppm 1.35 (s, 9 H), 1.52 (s, 9 H), 1.55-1.56 (m, 1 H), 2.46-2.47 (m, 1 H), 3.57-3.59 (m, 2 H), 3.81-3.84 (m, 3 H), 4.61-4.62 (m, 1 H), 4.78 (s, 2 H), 6.61 (d, J=6.35 Hz, 1 H), 7.15 (d, J=6.83 Hz, 1 H), 7.97 (s, 1 H), 8.54 (s, 1 H), 9.24 (s, 1 H)。[M+H]C26H33F3N6O6における計算値583;実測値583。
した。溶液を濃縮し、分取HPLCにより水(10mM NH4HCO3)及びACN/水(80/20v/v、10〜50%勾配、10mM NH4HCO3)で溶出して精製し、表題化合物を白色固体として得た(79mg、96%)。1H NMR (400 MHz, DMSO-d6)δppm 1.75-1.77 (m, 1 H), 2.09-2.12 (m, 1 H), 3.60-3.63 (m, 1 H), 3.76-3.77 (m,
1 H), 3.88-3.98 (m, 3 H), 4.44 (d, J=6.35 Hz, 2 H), 4.54-4.55 (m, 1 H), 7.17 (d, J=5.86 Hz, 1 H), 7.89 (br s, 1 H), 8.54 (s, 1 H), 8.58 (s, 1 H), 9.43 (s, 1 H
)。[M+H]C16H17F3N6O2における計算値383;実測値383。
(500 MHz, DMSO-d6)δppm 0.80 - 0.99 (m, 6 H), 1.51 - 1.84 (m, 3 H), 4.40 (s, 2 H), 4.59 - 4.76 (m, 1 H), 6.99 (br s, 1 H), 7.06 - 7.17 (m, 2 H), 7.34 (br s, 1 H), 7.61 (d, J=4.88 Hz, 1 H), 8.40 (s, 1 H), 8.93 - 9.05 (m, 1 H)。[M+H]C17H19FN4O2Sにおける計算値363;実測値363。
1 H), 1.97-1.99 (m, 1 H), 3.46-3.49 (m, 2 H), 3.80-3.83 (m, 3 H), 4.31-4.33 (m,
1 H), 4.73 (s, 1 H), 6.59 (d, J=7.30 Hz, 1 H), 7.43 (d, J=7.30 Hz, 1 H)。[M+H]C22H30ClFN4O6における計算値501;実測値501。
0mL)中で再構成し、分取HPLCで精製した。回収した画分を合わせ、回転蒸発で除去して乾固し、表題化合物を得た(16mg、85%)。1H NMR (500 MHz, DMSO-d6)δppm 1.79 (d, J=9.76 Hz, 1 H), 2.12 (qd, J=12.94, 5.13 Hz, 1 H), 3.56 - 3.68 (m, 1
H), 3.75 (d, J=11.72 Hz, 1 H), 3.89 (br s, 1 H), 4.02 (d, J=11.72 Hz, 2 H), 4.28 - 4.37 (m, 1 H), 4.38 - 4.49 (m, 2 H), 7.10 - 7.20 (m, 1 H), 7.28 (d, J=4.88 Hz, 1 H), 7.59 - 7.70 (m, 1 H), 7.93 (br s, 2 H), 8.52 (s, 1 H), 9.02 (dd, J=3.91, 0.98 Hz, 1 H)。[M+H]C16H17FN4O2Sにおける計算値349;実測値349。
合物から蒸発させた。生成物をDMSO(8mL)中で再構成し、次いで、分取HPLCにより水(0.05%TFA)及びACN(15〜45%勾配、0.035%TFA)で溶出して精製した。純画分を合わせ、最小体積まで蒸発させた。NaHCO3飽和水溶液(10mL)を添加し、混合物をEtOAc(3×25mL)で抽出した。有機層を合わせ、硫酸ナトリウムで乾燥させ、蒸発させ、表題化合物を薄黄色固体(83mg、44%)として得た。1H NMR (400 MHz, DMSO-d6)δppm 1.16 - 1.80 (m, 8 H), 3.18 (br s, 1
H), 3.86 - 4.11 (m, 1 H), 4.39 (s, 2 H), 6.60 (d, J=6.57 Hz, 1 H), 7.13 (dd, J=5.05, 3.79 Hz, 1 H), 7.60 (dd, J=5.18, 1.14 Hz, 1 H), 8.39 (s, 1 H), 9.00 (dd, J=3.79, 1.01 Hz, 1 H)。[M+H]C17H19FN4OSにおける計算値347;実測値347。
2 H), 7.54 (d, J=5.56 Hz, 1 H), 7.85 (br s, 2 H), 8.67 - 8.80 (m, 2 H)。[M+H]C16H16F4N6O2における計算値401;実測値401。
δppm 1.20-1.65 (m., 8 H), 3.65 - 3.79 (m, 5 H), 4.15 (s, 2 H), 6.40 (d, 1 H), 6.51 (d, 1 H), 6.73 (m, 1 H), 6.97 (d, 1 H), 7.26 (d, 1 H), 8.68 (br s, 1 H)。[M+H]C17H21FN6Oにおける計算値345;実測値345。
0.86 - 0.94 (m, 9 H), 1.05 - 1.21 (m, 6 H), 1.26 - 1.38 (m, 6 H), 1.44 - 1.65 (m, 6 H), 2.56 (s, 3 H), 6.97 - 7.04 (m, 1 H)。
イルアミノ)−7−フルオロ−4−(3−メチルイソチアゾール−5−イル)−1H−ピロロ[3,4−c]ピリジン−3(2H)−オン
における計算値564;実測値564。
で乾燥させ、濾過し、有機相を回転蒸発で除去して乾固した。残渣をTHF/ヘキサンから再結晶化し、表題化合物のTFA塩を得た。[M+H]C16H18FN5O2Sにおける計算値364;実測値364。
H)。
H), 3.78 (br s, 1 H), 3.82 - 3.88 (m, 1 H), 3.93 - 4.02 (m, 2 H), 4.39 (d, J=5.3 Hz, 2 H), 4.45 - 4.54 (m, 1 H), 4.82 (d, J=5.8 Hz, 2H), 5.15 (dd, J=17.2, 1.5 Hz, 1H), 5.22 (dd, J=10.2, 1.4 Hz, 1 H), 6.04 (dddd, J=16.8, 10.6, 5.8, 5.7 Hz, 1 H), 7.09 (d, J=5.3 Hz, 1 H), 7.93 (d, J=4.3 Hz, 3 H), 8.32 (s, 1 H), 8.40 (s, 1 H), 8.85 - 9.03 (m, 1 H)。[M+H]C18H21FN6O2における計算値373;実測値373。
Claims (20)
- 式1の化合物、
又はその薬剤的に許容できる塩、式中:
Gは、Nを示し;
L1及びL2は、各々独立して、NH及び結合から選択され;
R1及びR2は、各々独立して、水素、ハロ、C1−3アルキル、及びC1−3ハロアルキルから選択されるか、又は、R1及びR2は、それらが結合する原子と共にC3−6シクロアルキルを形成し;
R3は、独立して、ハロ、オキソ、NO2、CN、R6、及びR7から選択される1〜5つの置換基で、各々、随意に置換される、C2−6アルキル、C3−8シクロアルキル、C2−5ヘテロシクリル、及びC1−9ヘテロアリールから選択され;
R4は、独立して、ハロ、オキソ、CN、R6、及びR7から選択される1〜5つの置換基で、各々、随意に置換される、C3−8シクロアルキル、C2−5ヘテロシクリル、C6−14アリール、及びC1−9ヘテロアリールから選択される;
各R6は、独立して、OR8、N(R8)R9、NR8C(O)R9、C(O)R8、C(O)OR8、C(O)N(R8)R9、C(O)N(R8)OR9、C(O)N(R8)S(O)2R9、N(R8)S(O)2R9、S(O)nR8、及びS(O)2N(R8)R9から選択され;
各R7は、独立して、ハロ、オキソ、NO2、CN、C1−6アルキル、C1−6ハロアルキル、及びR10から選択される1〜5つの置換基で、各々、随意に置換される、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル(CH2)m、C6−14アリール−(CH2)m、C2−5ヘテロシクリル(CH2)m、及びC1−9ヘテロアリール−(CH2)m−から選択され;
各R8及びR9は、独立して、水素から、又は独立して、ハロ、オキソ、NO2、CN、C1−6アルキル、C1−6ハロアルキル、及びR10から選択される1〜5つの置換基で、各々、随意に置換される、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル(CH2)m、C6−14アリール−(CH2)m、C2−5ヘテロシクリル(CH2)m、及びC1−9ヘテロアリール−(CH2)m−から選択され;
各R10は、独立して、OR11、N(R11)R12、N(R11)C(O)R12、C(O)R11、C(O)OR11、C(O)N(R11)R12、C(O)N(R11)OR12、C(O)N(R11)S(O)2R12、NR11S(O)2R12、S(O)nR11、及びS(O)2N(R11)R12から選択され;
各R11及びR12は、独立して、水素及びC1−6アルキルから選択され;
各nは、独立して、0、1及び2から選択され;ならびに
各mは、独立して、0、1、2、3、及び4から選択され;
式中、前述したヘテロアリール部分の各々は、独立して、N、O、及びSから選択される1〜4つのヘテロ原子を有し、ならびに前述したヘテロシクリル部分の各々は、飽和又は部分的に不飽和であり、及び独立して、N、O、及びSから選択される1また2つのヘテロ原子を有する。 - L1がNHである、請求項1に記載の化合物又は薬剤的に許容できる塩。
- L2が結合である、請求項1又は2に記載の化合物又は薬剤的に許容できる塩。
- R1及びR2が両方とも水素である、請求項1〜3のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- R3が、独立して、ハロ、オキソ、NO2、CN、R6、及びR7から選択される1〜4つの置換基で、各々、随意に置換される、2−アミノ−シクロヘキサ−1−イルである、請求項1〜4のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- R3が、独立して、ハロ、オキソ、NO2、CN、R6、及びR7から選択される、1〜4つの置換基で、随意に置換される、3−アミノテトラヒドロ−2H−ピラン−4−イルである、請求項1〜4のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- R4が、独立して、ハロ、オキソ、CN、R6、及びR7から選択される、1〜5つの置換基で、随意に置換される、C1−9ヘテロアリールである、請求項1〜6のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- R4が、独立して、ハロ、CN、R6、及びR7から選択される、1〜4つの置換基で、随意に置換される、単環C2−4ヘテロアリールである、請求項7に記載の化合物又は薬剤的に許容できる塩。
- R4が、独立して、ハロ、CN、R6、及びR7から選択される、1〜3つの置換基で、各々、随意に置換される、ピロリル、フラニル、チオフォンイル、ピラゾリル、イミダゾリル、イソオキサゾリル、オキサゾリル、イソチオクロメン、及びチアゾリルから選択される、請求項8に記載の化合物又は薬剤的に許容できる塩。
- R4が、独立して、ハロ、CN、R6、及びR7から選択される、1〜3つの置換基で、随意に置換される、ピラゾール−4−イルである、請求項9に記載の化合物又は薬剤的に許容できる塩。
- R4が、メチル、エチル、シクロプロピル又はC1−2ハロアルキルで置換される、請求項7〜10のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- 以下の化合物から選択される、請求項1に記載の化合物。
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−フルオロフェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−クロロフェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
4−(1H−インダゾール−6−イルアミノ)−2−((1R,2S)−2−アミノシクロヘキシルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(3−(トリフルオロメチル)フェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
シス−2−(2−アミノシクロヘキシルアミノ)−4−(3−(トリフルオロメチル)フェニルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(1−メチル−1H−ピラゾール−4−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(4−エチルピペラジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
シス−2−(2−ヒドロキシシクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノピペリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−メチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−イソブチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−フェニル−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(ベンゾ[b]チオフェン−3−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−エチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−ベンジル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(イミダゾ[1,2−a]ピリジン−3−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−プロピル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−(2−メトキシエチル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(2−(アミノメチル)ピペリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−(ジメチルアミノ)シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−(メチルアミノ)シクロヘキシルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2’−((1R,2S)−2−アミノシクロヘキシルアミノ)−4’−(m−トリルアミノ)スピロ[シクロプロパン−1,7’−ピロロ[3,4−d]ピリミジン]−5’(6’H)−オン;
2−(2−アミノエチルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(2−アミノ−2−メチルプロピルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(5−オキソ−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−2−イルアミノ)アセトアミド;
2−(ピロリジン−2−イルメチルアミノ)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノピロリジン−1−イル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1,5−ジメチル−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1H−インドール−2−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1H−ピラゾール−5−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−(3−アミノプロピル)−4−(m−トリルアミノ)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
2−((1R,2S)−2−アミノシクロヘキシルアミノ)−4−(1−(4−フルオロフェニル)−1H−ピラゾール−4−イル)−6,7−ジヒドロ−5H−ピロロ[3,4−d]ピリミジン−5−オン;
前述した化合物のいずれかの立体異性体;及び
前述した化合物のいずれか又は立体異性体の薬剤的に許容できる塩。 - 請求項1〜12のいずれか一項に記載の化合物又は薬剤的に許容できる塩;及び
薬剤的に許容できる賦形剤を含む医薬組成物。 - 薬剤として使用するための、請求項1〜12のいずれか一項に記載の化合物又は薬剤的に許容できる塩。
- アレルギー性鼻炎、アレルギー性喘息、アトピー性皮膚炎、関節リウマチ、多発性硬化症、全身エリテマトーデス、乾癬、免疫性血小板減少性紫斑病、炎症性腸疾患、慢性閉塞性肺疾患、血栓症、血液悪性疾患及び上皮性癌から選択される疾患又は病態の治療のための薬剤として使用するための、請求項14に記載の化合物又は薬剤的に許容できる塩。
- 血液悪性疾患及び上皮性癌から選択される疾患又は病態の治療のための薬剤として使用するための、請求項15に記載の化合物又は薬剤的に許容できる塩。
- 前記血液悪性疾患が、急性脊髄性白血病、B細胞慢性リンパ性白血病、B細胞リンパ腫、及びT細胞リンパ腫から選択される、請求項16に記載の化合物又は薬剤的に許容できる塩。
- 前記上皮性癌が、肺癌、膵癌、及び結腸癌から選択される、請求項16に記載の化合物又は薬剤的に許容できる塩。
- アレルギー性鼻炎、アレルギー性喘息、アトピー性皮膚炎、関節リウマチ、多 発性硬化症、全身エリテマトーデス、乾癬、免疫性血小板減少性紫斑病、炎症性腸疾患、慢性閉塞性肺疾患、血栓症、血液悪性疾患及び上皮性癌から選択される疾患又は病態の治療のための薬剤の製造のための請求項1〜12のいずれか一項に記載の化合物又は薬剤的に許容できる塩の使用。
- 請求項1〜12のいずれか一項に記載の化合物又は薬剤的に許容できる塩及び少なくとも1つのさらなる薬理活性薬剤の有効量の組み合わせ。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2018009017A (ja) * | 2009-12-23 | 2018-01-18 | 武田薬品工業株式会社 | Syk阻害剤としての縮合複素芳香族ピロリジノン |
JP2019056000A (ja) * | 2009-12-23 | 2019-04-11 | 武田薬品工業株式会社 | Syk阻害剤としての縮合複素芳香族ピロリジノン |
JP2020164537A (ja) * | 2009-12-23 | 2020-10-08 | 武田薬品工業株式会社 | Syk阻害剤としての縮合複素芳香族ピロリジノン |
JP2022110135A (ja) * | 2009-12-23 | 2022-07-28 | 武田薬品工業株式会社 | Syk阻害剤としての縮合複素芳香族ピロリジノン |
JP7061106B2 (ja) | 2016-07-15 | 2022-04-27 | メトラー-トレド ゲーエムベーハー | 光源に対する反射器の不適切な位置整合を補償するための光学装置 |
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