JP2021501582A - 化合物及び幹細胞及び/又は前駆細胞の増殖におけるその使用 - Google Patents
化合物及び幹細胞及び/又は前駆細胞の増殖におけるその使用 Download PDFInfo
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Classifications
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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- C07D333/66—Nitrogen atoms not forming part of a nitro radical
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
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Abstract
Description
本出願は、2017年11月3日に出願された米国仮特許出願第62/581,149号の利益を主張するものであり、参照によりその全体が本明細書に組み込まれる。
Xは、O又はSであり;
V1は、N又はCHであり;
V2は、N又はCHであり;
Wは、N又はCであり;
ここで、上記V1、V2、及びWのうちの1つまでがNであり;
R1は、ハロ、アルキル、フルオロアルキル、シクロアルキル、アルキニル、アルケニル、シアノ、又はCOORaであり、ここでRaはアルキルであり;
R2は、H若しくはアルキルであるか、又はWがNである場合は、R2は存在せず;
又は、R1及びR2は、芳香族環原子と共に結合して炭素環を形成し;
R3は、任意に置換されていてもよいフェニル、任意に置換されていてもよい5員又は6員ヘテロアリール、又は任意に置換されていてもよい縮合二環式ヘテロアリールである。)
本明細書で使用される略語又は記号は、以下を含む。AcOH:酢酸、dba:ジベンジリデンアセトン、DMF:N,N−ジメチルホルムアミド、DIPEA:ジイソプロピルアミン、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、EtOAc:酢酸エチル、EtOH:エタノール、MeOH:メタノール、Hex:ヘキサン、MS:質量分析、NMR:核磁気共鳴、THF:テトラヒドロフラン。
本発明の他の特徴は、実施例として本発明の原理を説明する以下の非限定的な実施例から明らかになるであろう。当業者によく知られているように、反応は、反応成分を空気及び湿気から保護する必要がある場合、不活性雰囲気(窒素又はアルゴン)中で行う。温度は摂氏(℃)で示す。以下の実施例で使用される反応物は、本明細書に記載されるように得てもよく、又は本明細書に記載されない場合、それ自体が市販(表ではA0として記載)であるか、又は当該技術分野で既知の方法により市販材料から調製してもよい。フラッシュクロマトグラフィーは、Teledyne isco Rf装置を用いてシリカ(SiO2)で行う。質量スペクトル分析は、エレクトロスプレイ質量分析を用いて記録する。NMRは、500MHz Bruker装置又は400MHz Varian装置で記録する。分取HPLCは、次のいずれかの条件でAgilent装置を用いて実行する:
カラム:Phenomenex−Kinetex C18、21×100mm、5μm
移動相:溶媒A:5%MeOH、95%水+0.1%ギ酸、溶媒B:95%MeOH、5%水+0.1%ギ酸
流量:20mL/分、室温
収集波長=220及び254nm
条件A
移動相:0〜3分:アイソクラティック30%溶媒B、その後、100%溶媒Bまで12分勾配、最終5分:100%溶媒B
条件B
移動相:0〜2分:アイソクラティック30%溶媒B、その後、100%溶媒Bまで8分勾配、最終2分:100%溶媒B
EtOH(4.16mL、71.3mmol)を、NaH(60重量%、2.85g、71.3mmol)のエーテル(51mL)の氷冷懸濁液にゆっくりと加える。追加のEtOH(8.5mL)を加える。次に、1.1(5.0g、59.4mmol)とギ酸エチル(5.02mL、62.4mmol)との混合物を滴下する(55分)。追加のエーテル(10mL)を加え、混合物を室温で一晩撹拌する。エーテル(50mL)を加え、混合物を濾過する。固体をエーテル(25mL)で洗浄し、次いで減圧下で乾燥して、ナトリウム塩1.2を得る。1.2;1H NMR (500 MHz, DMSO-d6) ppm 1.56 (quin, J=7.90 Hz, 2 H), 1.87 (t, J=7.72 Hz, 2 H), 2.24 (td, J=7.30, 0.95 Hz, 2 H), 8.50, 8.87 (2s, 1 H).
2−シアノアセトアミド(4.58g、54.4mmol)の水溶液(27.5mL)を1.2(7.30g、54.4mmol)に加え、続いてピペリジン−1−イウム酢酸(1.38g、9.53mmol)の水溶液(1.4mL)(ピペリジン(0.81g、0.94mL)を水(1.4mL)中のAcOH(0.57g、0.54mL)に加えることにより調製)を加える。混合物を2時間加熱還流し、室温まで温める(一晩)。AcOHを加えてpHを5に調整する。得られた懸濁液を氷浴で冷却し、濾過する。固体を水で洗浄し、風乾してピリドン1.3を得る。1.3; m/z = 161.1 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.03 (quin, J=7.57 Hz, 2 H), 2.64 (t, J=7.41 Hz, 2 H), 2.80 (t, J=7.72 Hz, 2 H), 8.00 (s, 1 H), 12.62 (br. s., 1 H).
ピリドン1.3(1.0g、6.24mmol)を、POCl3(1.75mL、18.7mmol)中のPCl5(0.390g、1.87mmol)の懸濁液に室温で加える。混合物を2.5時間加熱還流する。冷却した混合物を氷と水の混合物(75mL)に注ぐ。混合物を、固体Na2CO3(pH7−8)を加えて塩基性化する。混合物をEtOAc(2×)で抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜40%EtOAc:Hex)で精製して、2−クロロピリジン1.4を得る。1.4; MS: m/z = 179.3/181.1 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.11 (quin, J=7.65 Hz, 2 H), 2.93 (t, J=7.57 Hz, 2 H), 3.00 (t, J=7.72 Hz, 2 H), 8.26 (s, 1 H).
CH2Cl2(10.6mL)中の酸2,1(0.6g、2.66mmol)、(COCl)2(0.466mL、5.32mmol)の懸濁液に、DMF(10.30μL、0.133mmol)を室温で加える。混合物を室温で6時間撹拌してから減圧下で濃縮して塩化アシル2.2を得る。
塩化アシル2.2(649mg、2.66mmol)のジオキサン(1.5mL)溶液を氷冷NH4OH溶液(1.60mL、23.9mmol)に添加する。混合物を0℃で45分間撹拌する。混合物を水(50mL)で希釈し、EtOAcを加える(100mL)。相が分離する。有機層を水(2×)、ブライン(25mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮して、アミド2.3を得る。2.3; MS: m/z = 225.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 7.95 (br. s., 1 H), 8.17 (br. s., 1 H), 8.39 (dd, J=2.52, 0.63 Hz, 1 H), 8.91 (dd, J=2.52, 0.63 Hz, 1 H).
(CF3CO)2O(0.308mL、2.18mmol)をCH2Cl2(14mL)中のアミド2.3(445mg、1.98mmol)の氷冷溶液/懸濁液にすばやく加える。混合物を0℃で2時間撹拌する。飽和NaHCO3溶液(15mL)及びCH2Cl2を加え、混合物を室温で5分間撹拌する。相が分離する。有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜20%EtOAc:Hex)で精製して、クロロピリジン2.4を得る。2.4; 1H NMR (500 MHz, DMSO-d6) ppm 9.09 (dd, J=2.52, 0.63 Hz, 1 H), 9.16 (dd, J=2.52, 0.63 Hz, 1 H).
(COCl)2(1.28mL、14.6mmol)を室温でCH2Cl2(29mL)中の酸3.1(1.00g、7.29mmol)の懸濁液に加える。混合物を室温で2時間撹拌する。反応混合物を減圧下で濃縮して、塩化アシル3.2を得る。化合物は次の反応でそのまま使用する。
ジオキサン(10mL)とTHF(10mL)の混合物中の塩化アシル3.2(1.13g、7.29mmol)の氷冷懸濁液に冷NH4OH溶液(4.86mL、72.9mmol)をすばやく加える。混合物を0℃で45分間撹拌する。粗混合物を水で希釈し、EtOAc(3×)で抽出する。水層を固体NaClで飽和させ、EtOAc(2×)で再抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮して、アミド3.3を得る。3.3; MS: m/z = 137.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.34 (d, J=0.63 Hz, 3 H), 7.53 (br. s., 1 H), 7.98 - 8.04 (m, 1 H), 8.08 (br. s., 1 H), 8.54 (dd, J=2.21, 0.63 Hz, 1 H), 8.82 (d, J=1.58 Hz, 1 H).
AcOH(4.9mL)中のアミド3.3(538mg、3.95mmol)の冷溶液にH2O2(0.90mL、7.90mmol)を加える。混合物を室温で30分間撹拌してから80℃で4時間加熱する。混合物を氷浴で冷却し、KI−デンプン紙で測定して過酸化物の痕跡がなくなるまで20%Na2SO3溶液を加える。次に、15N NH4OHを加えて、混合物を塩基性化する。得られた懸濁液を室温まで温め、濾過し、固体を水で洗浄する。固体を空気中で乾燥させて、3.4を得る。3.4; MS: m/z = 153.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.29 (d, J=0.63 Hz, 2 H), 7.54 - 7.62 (m, 1 H), 7.72 (br. s., 1 H), 8.15 (br. s., 1 H), 8.24 - 8.29 (m, 1 H), 8.43 (s, 1 H).
ピリジン1−オキシド3.4(306mg、2.01mmol)を冷POCl3(約5℃)(1.87mL、20.11mmol)に加える。得られた懸濁液を60℃で4時間及び100℃で2.5時間加熱する。冷却した反応混合物を氷と水の混合物(50mL)に注ぎ、激しく撹拌する。約7のpHとするために固体Na2CO3を加える。混合物をEtOAcで抽出する。有機層を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜30%EtOAc:Hex)で精製して、最初に6−クロロ異性体3.6、次に2−クロロ異性体3.5を得る。3.6: MS: m/z = 153.1 (MH+); 1H NMR (500 MHz, CDCl3) ppm 2.46 (d, J=0.63 Hz, 3 H), 7.82 (dq, J=2.21, 0.90 Hz, 1 H), 8.54 (dd, J=2.21, 0.63 Hz, 1 H); 3.5: MS: m/z = 153.3/155.2 (MH+); 1H NMR (500 MHz, CDCl3) ppm 2.40 (t, J=0.60 Hz, 3 H), 7.82 (dq, J=2.20, 0.60 Hz, 1 H), 8.43 (dq, J=2.52, 0.90 Hz, 1 H).
4.1(1.0g、5.60mmol;M.Graffner−Nordberg,J.Med.Chem.2001,44,2391)のDMF溶液(11.2mL)を、70℃に維持された亜硝酸イソアミル(1.13mL、8.40mmol)のDMF溶液(4.7mL)に10分かけて加える。1.5時間後、温度を85°Cに上げて18時間維持する。追加量の亜硝酸イソアミル(3.5mL、25.99mmol)を加え、混合物を85℃で4時間撹拌する。混合物を室温に冷却し、水(200mL)に注ぐ。混合物をEtOAc(3×)で抽出する。合わせた有機層を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(0〜50%EtOAc:Hex)で精製して、4.2を得る。4.2; 1H NMR (500 MHz, CDCl3) ppm 8.28 (d, J=2.21 Hz, 1 H), 8.87 (d, J=2.21 Hz, 1 H).
(COCl)2(0.49mL、5.61mmol)及びDMF(8.7μL、0.112mmol)を5.1(506mg、2.24mmol;Schlosser et al.Tetrahedron 2004,60,11869)のCH2Cl2(11.2mL)の懸濁液に室温で加える。混合物を室温で3.5時間撹拌し、次に減圧下で濃縮して、5.2を得る。5.2; 1H NMR (500 MHz, CDCl3) ppm 8.15 (s, 1 H), 8.90 (s, 1 H).
5.2(547mg、2.24mmol)のジオキサン溶液(1.5mL)を、NH4OH(15M)(1.49mL、22.43mmol)のジオキサン氷冷溶液(1.0mL)に滴下する。混合物を0℃で1時間撹拌する。反応混合物を水(125mL)に注ぎ、混合物をEtOAc(2×)で抽出する。合わせた有機層を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮して5.3を得る。5.3; MS: m/z: 分子ピークは観察されなかった。; 1H NMR (500 MHz, CDCl3) ppm 6.11 (br. s., 1 H), 6.42 (br. s., 1 H), 8.09 (s, 1 H), 8.80 (s, 1 H).
Et3N(0.654mL、4.69mmol)及びCH2Cl2(12mL)中の(CF3CO)2O(0.33mL、2.34mmol)を、5.3(405mg、1.80mmol)の氷冷懸濁液/溶液に滴下する。反応混合物を0℃で1.75時間撹拌する。飽和NaHCO3溶液(5mL)を加え、混合物を5分間激しく撹拌する。混合物をCH2Cl2(60mL)及び飽和NaHCO3溶液(20mL)で希釈する。相が分離する。有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(0〜50%EtOAc:Hex)で精製して、5.4を得る。5.4; MS: m/z =分子ピークは観察されなかった。; 1H NMR (500 MHz, CDCl3) ppm 7.94 (s, 1 H), 8.93 (s, 1 H).
(COCl)2(1.91mL、21.8mmol)及びDMF(0.012mL、0.156mmol)をCH2Cl2(18mL)中の6.1(1.35g,3.11mmol;Schlosser et al.Tetrahedron 2004,60,11869)の溶液に室温で加える。混合物を室温で3時間撹拌し、次いで減圧下で濃縮する。残留物を、安定した重量になるまで高真空ポンプで保持し、6.2を得る。6.2; (500 MHz, CDCl3) ppm 7.85 (d, J=8.2 Hz, 1 H), 8.08 (dq, J=8.2, 0.06 Hz, 1 H).
6.2(759mg、3.11mmol)のジオキサン溶液(3.1mL)溶液を、NH4OH(15M)の氷冷溶液(2.1mL、31.1mmol)に滴下する。混合物を0℃で1時間撹拌する。混合物を水(125mL)に注ぎ、EtOAc(2×)で抽出する。合わせた有機層を水、ブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜50%EtOAc:Hex)で精製して、6.3を得る。6.3; MS: m/z = 225.1/227.3 (MH+); 1H NMR (500 MHz, CDCl3) ppm 5.68 (br. s., 1 H), 7.55 (br. s., 1 H), 7.77 (d, J=8.51 Hz, 1 H), 8.05 (dd, J=8.51, 0.63 Hz, 1 H).
(CF3CO)2O(0.23mL、1.63mmol)を、CH2Cl2(8.3mL)中の6.3(281mg、1.251mmol)及びEt3N(0.45mL、3.25mmol)の氷冷溶液/懸濁液に滴下する。混合物を0℃で2時間撹拌する。飽和NaHCO3溶液及びCH2Cl2を加え、混合物を室温で5分間撹拌する。相が分離する。有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜20%EtOAc:Hex)で精製して、6.4を得る。6.4; 1H NMR (400 MHz, CDCl3) ppm 7.87 (d, J=8.61 Hz, 1 H), 8.10 (d, J=8.61 Hz, 1 H).
7.1(302mg、1.57mmol;V.J.Colandrea,国際出願第2005/058848号)、SOCl2(6.9mL、94mmol)及びDMF(0.68mL、8.79mmol)の混合物を一晩(14時間)加熱還流する。冷却した混合物を減圧下で濃縮する。残留物をEtOAc(70mL)に入れ、溶液を飽和NaHCO溶液及びブラインの1:1混合物で洗浄し(3×)、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(0〜20%EtOAc:Hex)で精製して、7.2を得る。7.2; 1H NMR (400 MHz, CDCl3) ppm 1.44 (t, J=7.04 Hz, 3 H), 4.47 (q, J=7.04 Hz, 2 H), 8.58 (d, J=2.35 Hz, 1 H), 9.16 (d, J=2.35 Hz, 1 H).
DMF(10.5mL)中の8.1(1.70g、10.51mmol)、Zn(CN)2(0.74g、6.30mmol)、及びZn(0.031g、0.47mmol)の混合物を脱気する(B.Van Wagenen,米国出願第2003/55085号)。PdCl2(dppf)−CH2Cl2付加物(0.189g、0.231mmol)を加え、溶液を再度脱気し、次いで125℃で5時間加熱する。粗混合物をEtOAc(150mL)で希釈し、混合物を珪藻土を通じて濾過する(ケーキをEtOAc(25mL)で洗浄する)。濾液を水と飽和NaHCO3溶液の混合物(3/1)で2回、及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜100%EtOAc:Hex)で精製して、8.2を得る。8.2; MS: m/z = 153.1/155.1 (MH+); 1H NMR (400 MHz, CDCl3) ppm 2.60 (s, 3 H), 7.34 (d, J=8.22 Hz, 1 H), 7.73 (d, J=8.61 Hz, 1 H).
2−メルカプト酢酸9.1(0.679mL、9.77mmol)と4−フルオロアニリン9.2(0.926mL、9.77mmol)の混合物を130℃で5時間加熱する。冷却した混合物をEtOAcに入れ、溶液を0.5N HCl溶液、水、及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(15〜40%EtOAc:Hex)で精製して、チオール9.3を得る。9.3; MS: m/z = 186.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 2.95 (t, J=5.90 Hz, 1 H), 3.28 (d, J=5.87 Hz, 2 H), 7.15 (t, J=9.00 Hz, 2 H), 7.59 (dd, J=9.39, 5.48 Hz, 2 H), 10.13 (s, 1 H).
CH2Cl2(21.6mL)中の酸10.1(1.45g、10.81mmol)と(COCl)2(1.892mL、21.62mmol)の氷冷溶液にDMF(0.042mL、0.54mmol)を加える。混合物を室温で一晩(16時間)撹拌する。反応混合物を減圧下で濃縮して、中間体10.2を得る。10.2; 1H NMR (500 MHz, CDCl3) ppm 2.44 (s, 3 H), 4.18 (s, 2 H).
DIPEA(0.717mL、4.10mmol)を、CH2Cl2(19mL)中の10.2(569mg、3.73mmol)及び10.3(369mg、3.92mmol)の氷冷溶液に滴下する。混合物を0℃で1時間及び室温で1時間撹拌する。混合物をCH2Cl2で希釈し、溶液を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(20〜50%EtOAc:Hex)で精製して中間体10.4を得る。10.4; MS: m/z = 211.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 2.37 (s, 3 H), 3.90 (s, 2 H), 7.11 (dd, J=7.43, 5.09 Hz, 1 H), 7.78 (ddd, J=8.20, 7.40, 1.96 Hz, 1 H), 8.00 (d, J=8.22 Hz, 1 H), 8.32 (ddd, J=4.70, 2.00, 1.00 Hz, 1 H), 10.71 (s, 1 H).
10.2(0.848g、5.56mmol)のCH2Cl2溶液(2.8mL)を、CH2Cl2(8.4mL)及びピリジン(0.450mL、5.56mmol)中の11.1(0.381g、2.78mmol)の氷冷懸濁液に滴下する。混合物を0℃で1.5時間撹拌する。水(5mL)を加え、混合物をCH2Cl2で希釈する。混合物を1N HCl溶液、水、飽和NaHCO3溶液、ブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(20〜50%EtOAc:Hex)で精製して、11.2を得る。11.2; 1H NMR (500 MHz, CDCl3) ppm 2.39 (s, 3 H), 2.46 (s, 3 H), 2.92 (t, J=7.09 Hz, 2 H), 3.66 (s, 2 H), 3.68 (s, 2 H), 4.32 (t, J=6.94 Hz, 2 H), 7.18 (d, J=8.51 Hz, 2 H), 7.44 (d, J=8.51 Hz, 2 H), 8.08 (br. s., 1 H).
K2CO3(400mg、2.89mmol)を、MeOH(9.6mL)中の11.2(356mg、0.964mmol)の脱気した溶液に室温で加える。混合物を室温で一晩(20時間)撹拌する。混合物を減圧下で濃縮する。水(10mL)を加え、混合物を1N HCl溶液(pH<2)で酸性化する。混合物をEtOAc(2×)で抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(40〜100%EtOAc:Hex)で精製して11.3を得る。11.3; MS: m/z 212.1 (MH+); 1H NMR (500 MHz, CDCl3) ppm 1.39 (br. s., 1 H), 2.03 (t, J=9.30 Hz, 1 H), 2.86 (t, J=6.46 Hz, 2 H), 3.41 (d, J=9.14 Hz, 2 H), 3.82 - 3.90 (m, 2 H), 7.23 (d, J=8.20 Hz, 2 H), 7.50 (d, J=8.51 Hz, 2 H), 8.46 (br. s., 1 H).
EtOH(1.7mL)中のクロロピリジン1.4(30mg、0.168mmol)、チオール9.3(34.2mg、0.185mmol)、及びK2CO3(58.0mg、0.420mmol)の混合物を、4.5時間加熱還流する。冷却した混合物をEtOAcで希釈し、得られた溶液を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。MeOHとCHCl3の混合物中で残留物を再結晶化し、化合物1002を得る。1002; MS: m/z = 328.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 2.14 (quin, J=7.53 Hz, 2 H), 3.00 (t, J=7.43 Hz, 2 H), 3.02 (t, J=7.60 Hz, 2 H), 7.15 (t, J=9.00 Hz, 2 H), 7.29 (br. s, 2 H), 7.69 (dd, J=9.00, 5.09 Hz, 2 H), 8.28 (s, 1 H), 9.42 (s, 1 H).
EtOH(2.3mL)中のクロロピリジン13.1(50mg、0.23mmol)、チオール13.2(42mg、0.25mmol)、及びK2CO3(79.5mg、0.575mmol)の混合物を5時間加熱還流する。冷却した混合物を水(15mL)で希釈する。得られた懸濁液を15分間撹拌し、次いで濾過し、固体を数滴のMeOH及びヘキサンで洗浄して化合物1003を生成する。1003; MS: m/z = 347.9/349.7 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 7.09 (t, J=7.41 Hz, 1 H), 7.33 (t, J=7.88 Hz, 2 H), 7.37 (s, 1 H), 7.69 (d, J=7.57 Hz, 1 H), 8.78 (d, J=2.21 Hz, 1 H), 8.84 (d, J=2.21 Hz, 1 H), 9.54 (s, 1 H).
3.5(40mg、0.262mmol)、チオール13.2(48.2mg、0.288mmol)、及びK2CO3(91mg、0.655mmol)のEtOH懸濁液(2.6mL)を5.5時間加熱還流する。冷却した混合物をEtOAcで希釈し、水及びブライン(15mL)で洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(30−50%EtOAc:Hex)で精製して化合物1009を得る。1009; MS: m/z = 284.3 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.43 (s, 3 H), 7.07 (tt, J=7.37, 1.14 Hz, 1 H), 7.24 - 7.37 (m, 4 H), 7.69 (dd, J=8.67, 1.10 Hz, 2 H), 8.32 (dd, J=2.05, 0.79 Hz, 1 H), 8.54 (dd, J=2.21, 0.63 Hz, 1 H), 9.40 (s, 1 H).
EtOH(1.4mL)中の5.4(30mg、0.145mmol)、チオール15.1(41.1mg、0.167mmol)、及びK2CO3(50.2mg、0.363mmol)の混合物を室温で10分間撹拌し、次いで3時間加熱還流する。冷却した混合物をEtOAc(60mL)で希釈し、溶液を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜50%EtOAc:Hex)で精製し、次いで分取HPLC(方法A)により更に精製して、化合物1049を得る。1049; MS: m/z = 415.9/417.9 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 7.48 (br. s., 2 H), 7.53 (d, J=8.61 Hz, 2 H), 7.70 (d, J=8.61 Hz, 2 H), 8.73 (s, 1 H), 9.39 (s, 1 H), 9.92 (s, 1 H).
DMF(0.65mL)中の16.1(22mg、0.163mmol)、チオール13.2(28.6mg、0.171mmol)、及びK2C03(56.2mg、0.407mmol)の混合物を室温で7分間撹拌する。混合物をEtOAc(50mL)で希釈し、溶液を水及びブラインで洗浄し、次いで乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜20%EtOAc:Hex)で精製して、化合物1118を得る。1118; MS: m/z = 283.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 2.44 (s, 3 H), 7.06 (tt, J=7.40, 1.17 Hz, 1 H), 7.19 (s, 2 H), 7.31 (dd, J=8.61, 7.43 Hz, 1 H), 7.35 (dd, J=8.22, 1.17 Hz, 1 H), 7.69 (dd, J=8.80, 0.98 Hz, 2 H), 7.76 (d, J=8.22 Hz, 1 H), 7.91 (s, 1 H), 9.29 (s, 1 H).
ジオキサン(1.15mL)及び水(0.287mL)中の化合物1037(50mg、0.120mmol)、ボロン酸17.1(44.3mg、0.360mmol)、及びK2CO3(49.8mg、0.360mmol)の脱気(真空からアルゴン、3×)した部分溶液に、PdCl2(dppf)−CH2Cl2付加物(4.91mg、6.01μmol)を室温で加える。混合物を再び脱気し、85℃で21時間加熱する。冷却した混合物をEtOAc(150mL)に入れ、水(30mL)を加える。分離した水層をCH2Cl2(3×)で抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。固体をCHCl3とMeOHの1:1混合物中で再結晶して、化合物1055を得る。1055; MS: m/z = 415.0 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 7.39 - 7.47 (m, 2 H), 7.50 (dd, J=8.02, 5.28 Hz, 1 H), 7.57 (s, 2 H), 7.78 (dt, J=7.04, 2.15 Hz, 1 H), 7.99 - 8.12 (m, 2 H), 8.58 (dd, J=4.70, 1.57 Hz, 1 H), 8.87 (d, J=1.96 Hz, 1 H), 9.04 (d, J=5.87 Hz, 1 H), 9.72 (s, 1 H).
THF(0.72mL)及びDMF(0.72mL)中の化合物1012(50mg、0.143mmol)、Pd(Ph3P)4(16.5mg、0.014mmol)、及びCuI(2.73mg、0.014mmol)の混合物へDIPEA(0.41mL、2.86mmol)とエチニルトリメチルシラン(101μL、0.716mmol)を順次加える。混合物にN2を流し、110℃で2.5時間加熱する。冷却した混合物を水(15mL)で希釈し、EtOAc(3×)で抽出する。水層を濾過し、EtOAcで抽出する。合わせた有機層を乾燥させ(Na2SO4)、濾過し、濃縮する。残留物をフラッシュクロマトグラフィー(0〜100%EtOAc:Hex)で精製して18.1を得る。18.1; MS: m/z = 367.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 0.22 - 0.32 (m, 9 H), 7.55 (s, 2 H), 7.77 (br. s., 2 H), 8.71 - 8.77 (m, 2 H), 9.84 (s, 1 H).
18.1(50mg、0.136mmol)のMeOH溶液(2mL)にK2CO3(37.7mg、0.273mmol)を添加する。混合物を室温で1時間撹拌し、次いで減圧下で濃縮する。CH2Cl2(50mL)中の10%MeOHに溶解した残渣を水で希釈する。得られた懸濁液を濾過し、固体を空気中で乾燥させて、化合物1020を得る。1020; MS: m/z = 295.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 4.50 (s, 1 H), 7.57 (s, 2 H), 7.76 (br. s., 1 H), 8.44 (br. s., 1 H), 8.69 - 8.80 (m, 1 H), 9.84 (br. s., 1 H).
MeOH(5mL)中の1020(20mg、0.068mmol)及びPd−C 10% Degussa Type,50%wetの懸濁液を水素雰囲気下で45分間撹拌する。混合物を0.45μmのフィルターユニットで濾過し、MeOH(1mL)で洗浄し、濃縮して化合物1021を得る。1021; MS: m/z = 299.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 1.28 (t, J=7.57 Hz, 3 H), 2.76 (q, J=7.57 Hz, 2 H), 7.52 (s, 2 H), 7.75 - 7.77 (m, 2 H), 8.41 - 8.44 (m, 3 H), 8.59 (d, J=1.89 Hz, 1 H), 9.74 (s, 1 H).
DME−水(2:1、3mL)中の1003(25.7mg、0.074mmol)、プロパ−1−エン−2−イルボロン酸(7.8μL、0.081mmol)、及びK3PO4(47.0mg、0.221mmol)の混合物を、密閉可能なバイアル中でN2流により5分間パージする。この混合物にPd(Ph3P)4(8.53mg、7.38μmol)を加え、バイアルを密封し、混合物をマイクロ波照射下で90℃で4時間加熱する。冷却した混合物をEtOAc及び水で希釈する。水相をEtOAc(3×)で抽出し、合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物を分取HPLC(方法B)により精製し、1090を得る。1090; MS: m/z = 310.0 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 2.22 (s, 3 H), 5.27 (s, 1 H), 5.65 (s, 1 H), 7.03 - 7.12 (m, 1 H), 7.33 (t, J=7.83 Hz, 2 H), 7.42 (s, 1 H), 7.70 (d, J=7.43 Hz, 2 H), 8.66 (d, J=2.35 Hz, 1 H), 8.87 (d, J=2.35 Hz, 1 H), 9.44 (s, 1 H).
MeOH(25mL)中の化合物1090(57.3mg、0.185mmol)及びPd−C 10% Degussa Type,50%wet(20mg)の懸濁液を水素雰囲気下で18時間撹拌する。混合物を珪藻土のパッドで濾過し、MeOHで洗浄し、減圧下で濃縮する。残留物を分取HPLC(方法B)により精製し、化合物1103を得る。1103; MS: m/z = 312.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 1.31 (d, J=6.65 Hz, 6 H), 3.09 (dt, J=13.89, 6.75 Hz, 1 H), 7.03 - 7.11 (m, 1 H), 7.28 - 7.40 (m, 4 H), 7.70 (d, J=7.83 Hz, 2 H), 8.44 (d, J=1.96 Hz, 1 H), 8.60 (d, J=1.96 Hz, 1 H), 9.40 (s, 1 H).
トルエン/水(5/1)(3.3mL)中の化合物1003(56.9mg、0.163mmol)、アリルトリブチルスタンナン(60.2μL、0.196mmol)、及びK2C03(45.2mg、0.327mmol)の懸濁液を、密閉可能なバイアル中でN2流により10分間パージする。この混合物にPd(Ph3)4(4.72mg、4.09μmol)を加え、バイアルを密封し、混合物を105℃で23時間加熱する。混合物をEtOAc及び水で希釈し、EtOAcで2回抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。反応が完了していないため、残留物を同じ反応条件(15時間加熱)に再度晒す。粗材料を分取HPLC(方法B)で精製し、次いでシリカゲル(3%Et3Nを含むHex/EtOAc(50/50))のパッドを通して濾過する。濾液を減圧下で濃縮して、化合物1111を得る。1111; MS: m/z = 310.0 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 3.53 (d, J=6.65 Hz, 2 H), 5.10 - 5.19 (m, 2 H), 5.97 - 6.11 (m, 1 H), 7.04 - 7.11 (m, 1 H), 7.35 (d, J=6.65 Hz, 2 H), 7.31 (d, J=8.22 Hz, 2 H), 7.65 - 7.73 (m, 2 H), 8.34 (d, J=1.96 Hz, 1 H), 8.54 (d, J=1.96 Hz, 1 H), 9.42 (s, 1 H).
トルエン/水(10/1)(1.57mL)中の化合物1003(29.8mg、0.086mmol)、トリエチルボラン(34.2μL、0.034mmol)、K3PO4(36.3mg、0.171mmol)、及びジ((3S、5S、7S)−アダマンタン−1−イル)(ブチル)ホスフィン(1.53mg、4.28μm)の懸濁液を、密閉可能なバイアル中でN2流により5分間パージする。この混合物にPd2(dba)3(0.980mg、1.070μmol)を加え、バイアルを密封し、混合物を105℃で17時間加熱する。冷却した混合物をEtOAc及び水で希釈し、EtOAcで2回抽出する。合わせた有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物を分取HPLC(方法B)で精製し、化合物1112を得る。1112; MS: m/z = 298.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 1.28 (t, J=7.43 Hz, 3 H), 2.76 (q, J=7.70 Hz, 2 H), 7.07 (t, J=7.24 Hz, 1 H), 7.29 - 7.36 (m, 4 H), 7.69 (d, J=8.22 Hz, 2 H), 8.38 (s, 1 H), 8.57 (s, 1 H), 9.40 (s, 1 H).
MeOH(6mL)中の化合物1111(30mg、0.097mmol)及びPd−C 10% Degussa Type,50%wet(10.3mg)の懸濁液を水素雰囲気下で18時間撹拌する。混合物を濾過し(0.45μmフィルターユニット)、減圧下で濃縮する。残留物を分取HPLC(方法B)で精製し、化合物1134を得る。1134; MS: m/z = 312.1 (MH+); 1H NMR (400 MHz, DMSO-d6) ppm 0.94 (t, J=7.43 Hz, 3 H), 1.69 (dq, J=15.06, 7.24 Hz, 2 H), 2.67 - 2.74 (m, 2 H), 7.05 - 7.10 (m, 1 H), 7.28 - 7.37 (m, 4 H), 7.67 - 7.73 (m, 2 H) 8.36 (d, J=1.96 Hz, 1 H), 8.54 (d, J=1.96 Hz, 1 H), 9.40 (s, 1 H).
EtOH(1.7mL)中の1.4(75mg、0,420mmol)、25.1(66.6mg、0.441mmol;J.M.Hung et al.,Eur.J.Med.Chem.2014,86,420)及びNa2CO3(46.7mg、0.441mmol)の混合物を18時間加熱還流する。冷却した混合物をEtOAcと水の間で分配する。有機層をブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(10〜30%EtOAc:Hex)で精製して、25.2を得る。25.2; MS: m/z = 294.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.06 (quin, J=7.65 Hz, 2 H), 2.85 (td, J=7.49, 3.63 Hz, 4 H), 5.06 (s, 2 H), 7.06 (t, J=7.41 Hz, 1 H), 7.31 (t, J=8.20 Hz, 2 H), 7.56 (dd, J=8.67, 1.10 Hz, 2 H), 8.09 (s, 1 H), 10.16 (s, 1 H).
t−BuOK(45.4mg、0.405mmol)を室温でTHF(3.2mL)中の25.2(95mg、0.324mmol)の溶液に加える。混合物を2時間加熱還流する。混合物をCH2Cl2に入れ、溶液を水及びブラインで洗浄し、乾燥させ(Na2SO4)、濾過し、減圧下で濃縮する。残留物をフラッシュクロマトグラフィー(2〜15%EtOAc:CH2Cl2)で精製し、化合物1153を生成する。1153; MS: m/z = 294.2 (MH+); 1H NMR (500 MHz, DMSO-d6) ppm 2.14 (quin, J=7.57 Hz, 2 H), 2.98 (t, J=7.25 Hz, 2 H), 2.99 (t, J=7.57 Hz, 2 H), 6.33 (s, 2 H), 7.04 (tt, J=7.57, 0.95 Hz, 1 H), 7.30 (dd, J=8.51, 7.57 Hz, 2 H), 7.82 (dd, J=7.57, 1.26 Hz, 2 H), 8.12 (s, 1 H), 9.84 (s, 1 H).
化合物1001; MS: m/z = 310.3; 1H NMR (500 MHz, DMSO-d6) ppm 2.14 (quin, J=7.49 Hz, 2 H), 2.90 - 3.06 (m, 4 H), 7.06 (tt, J=7.57, 0.95 Hz, 1 H), 7.29 (s, 1 H), 7.31 (dd, J=8.51, 7.57 Hz, 2 H), 7.69 (dd, J=8.51, 1.30 Hz, 2 H), 8.28 (s, 1 H), 9.35 (s, 1 H).
化合物1049; 実施例15に記載
実施例1
CD34+活性評価
RosetteSep(商標)CD34 preenrichment cocktailを用いて、ヒトCD34+臍帯血(CB)細胞を新鮮(フレッシュ)ユニットから単離し、続いて、EasySepキット(商標)(StemCell Technologies)を用いてCD34陽性選択を行った。次に、100ng/mLの幹細胞因子(SCF、Shenandoah)、100ng/mLのFMS様チロシンキナーゼ3リガンド(FLT3L、Shenandoah)、50ng/mLのトロンボポエチン(TPO、Shenandoah)、2mMのGlutaMAX(商標)(Invitrogen)、10μg/mLの低密度リポタンパク質(LDL、StemCell Technologies)、10μg/mLのシプロフロキサシン及び35nMのUM0128171を添加したStemSpan ACF(StemCell Technologies)からなるHSC増殖培地で37℃で6日間培養することにより、細胞を大量に予備増殖させた。培養を毎日モニターし、必要に応じて新鮮培地を補充した。予備増殖後、細胞を採取し、等分し、使用するまで凍結した。
AhRを介した遺伝子転写の阻害
HEK細胞株にAhR応答性ホタルルシフェラーゼレポーター遺伝子X4−4.27をトランスフェクションし、生成された安定したトランスフェクタントをpBAsi−hU6 Pur DNA(ピューロマイシン耐性遺伝子を有するプラスミド;TaKaRa、滋賀、日本)と共にphRL−CMV(Renillaルシフェラーゼ発現ベクター;Promega)で再びトランスフェクションし、ハイグロマイシンB及びピューロマイシン(2mg/mL)の両方の存在下で維持した。得られたクローンの1つをHEK−XRE11.1と名付け、レポーター遺伝子アッセイで使用した。
実施例3
インビトロでの細胞組成の評価
3つの臍帯血ユニットからのヒトCD34+臍帯血(CB)細胞を前述のように単離し、使用するまで凍結した。1つ目の実験では、解凍時に2つのユニットをプールし、CB CD34+細胞を35nMのUM0128171(UM171という)、1μΜの化合物1001、その両方の組み合わせ、又はDMSOを補充したHSC増殖培地で7日間培養した。培養を毎日モニターし、必要に応じて新鮮培地を補充した。2つ目の実験では、1つのユニットを解凍し、CB CD34+細胞を、0.5μΜの化合物1001(単独又は35nM UM171と組み合わせて)、0.5μΜの化合物1114(単独又は35nM UM171と組み合わせて)、0.5μMのSR1(単独又は35nMのUM171と組み合わせて)、DMSO、又は35nM UM171を補充したHSC増殖培地で7日間培養した。
(対象亜集団の細胞パーセンテージ×生細胞総数)/100
インビボでの生着及び骨髄系対リンパ系の寄与の評価
MSG(NOD.Cg−Prkdcscid I12rgtmlvVjl/SzJ、The Jackson Laboratory、ME、米国)マウスを、the Institute for Research in Immunology and Cancerにて無菌換気ラック内で特定の無菌条件下で飼育及び収容した。全ての動物研究が、カナダ動物管理協会(the Canadian Council on Animal Care)のガイドラインに従って、Comite de Deontologie et Experimentation Animaie de l’Universite de Montrealにより認可された。
Claims (26)
- 出発細胞集団と、式Iの化合物又はその薬学的に許容される塩とを接触させることを含む、幹細胞及び/又は前駆細胞を増殖する方法。
Xは、O又はSであり;
V1は、N又はCHであり;
V2は、N又はCHであり;
Wは、N又はCであり;
ここで、前記V1、V2、及びWのうちの1つまでがNであり;
R1は、ハロ、アルキル、フルオロアルキル、シクロアルキル、アルキニル、アルケニル、シアノ、又はCOORaであり、ここでRaはアルキルであり;
R2は、H若しくはアルキルであるか、又はWがNである場合は、R2は存在せず;
又は、R1及びR2は、芳香族環原子と共に結合して炭素環を形成し;
R3は、任意に置換されていてもよいフェニル、任意に置換されていてもよい5員又は6員ヘテロアリール、又は任意に置換されていてもよい縮合二環式ヘテロアリールである。) - 前記化合物は式Iaの化合物である、請求項1に記載の方法。
- 前記化合物は式Ibの化合物である、請求項1に記載の方法。
- 前記化合物は式Icの化合物である、請求項1に記載の方法。
- 前記化合物は式Idの化合物である、請求項1に記載の方法。
- 前記化合物は式Ieの化合物である、請求項1に記載の方法。
- R1は、ハロ、C1−6アルキル、C1−6フルオロアルキル、C3−6シクロアルキル、C2−3アルキニル、C2−3アルケニル、シアノ、又はCOORaであり、ここでRaはC1−6アルキルである、請求項1〜6のいずれか一項に記載の方法。
- R2はHである、請求項1〜7のいずれか一項に記載の方法。
- R3は、3位、4位、及び5位のいずれかで任意に一置換若しくは二置換されていてもよいフェニルである、請求項1〜8のいずれか一項に記載の方法。
- R3は、任意に一置換されていてもよい5員又は6員ヘテロアリールである、請求項1〜8のいずれか一項に記載の方法。
- i)前記出発細胞集団を、幹細胞及び/又は前駆細胞を増殖するための第1の化合物と接触させ、前記細胞を第1の期間増殖すること、任意で前記第1の化合物を実質的に除去すること、前記式Iの化合物又はその薬学的に許容される塩を加えること、及び前記細胞を更に第2の期間増殖すること、又はii)前記出発細胞集団を、幹細胞及び/又は前駆細胞を増殖するための化合物及び前記式Iの化合物と接触させることを含む、請求項1〜10のいずれか一項に記載の方法。
- 請求項1〜11のいずれか一項に記載の方法により増殖した幹細胞集団及び/又は前駆細胞集団。
- 請求項12に記載の細胞集団を投与すること、又は請求項1〜10のいずれか一項に記載の化合物を投与することを含む、造血障害/悪性腫瘍、自己免疫疾患、及び/又は遺伝性免疫不全疾患を治療する方法。
- 式Iの化合物又はその薬学的に許容される塩であり、
但し、前記化合物は下記の表1−1及び表1−2の化合物以外である、化合物又はその薬学的に許容される塩。
Xは、O又はSであり;
V1は、N又はCHであり;
V2は、N又はCHであり;
Wは、N又はCであり;
ここで、前記V1、V2、及びWのうちの1つまでがNであり;
R1は、ハロ、アルキル、フルオロアルキル、シクロアルキル、アルキニル、アルケニル、シアノ、又はCOORaであり、ここでRaはアルキルであり;
R2は、H若しくはアルキルであるか、又はWがNである場合は、R2は存在せず;
又は、R1及びR2は、芳香族環原子と共に結合して炭素環を形成し;
R3は、任意に置換されていてもよいフェニル、任意に置換されていてもよい5員又は6員ヘテロアリール、又は任意に置換されていてもよい縮合二環式ヘテロアリールである。)
- 前記化合物は式Iaの化合物である、請求項14に記載の化合物。
- 前記化合物は式Ibの化合物である、請求項14に記載の化合物。
- 前記化合物は式Icの化合物である、請求項14に記載の化合物。
- 前記化合物は式Idの化合物である、請求項14に記載の化合物。
- 前記化合物は式Ieの化合物である、請求項14に記載の化合物。
- R1は、ハロ、C1−6アルキル、C1−6フルオロアルキル、C3−6シクロアルキル、C2−3アルキニル、C2−3アルケニル、シアノ、又はCOORaであり、ここでRaはC1−6アルキルである、請求項14〜19のいずれか一項に記載の化合物。
- R2はHである、請求項14〜20のいずれか一項に記載の化合物。
- R3は、3位、4位、及び5位のいずれかで任意に一置換若しくは二置換されていてもよいフェニルである、請求項14〜21のいずれか一項に記載の化合物。
- R3は、任意に一置換されていてもよい5員又は6員ヘテロアリールである、請求項14〜21のいずれか一項に記載の化合物。
- 前記化合物は、本明細書に記載のTable 1及びTable 2から選択される、請求項14に記載の化合物。
- 請求項1〜24のいずれか一項に記載の化合物又はその薬学的に許容される塩、及び任意で薬学的に許容される担体を含む、医薬組成物。
- 請求項12に記載の幹細胞及び/若しくは前駆細胞、又は請求項1〜13のいずれか一項に記載の方法により増殖した幹細胞及び/若しくは前駆細胞、並びに任意で薬学的に許容される担体を含む、医薬組成物。
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CN111417640A (zh) | 2020-07-14 |
JP7499698B2 (ja) | 2024-06-14 |
US20230338429A1 (en) | 2023-10-26 |
KR20200084873A (ko) | 2020-07-13 |
IL274291B1 (en) | 2023-06-01 |
BR112020008330A2 (pt) | 2020-10-06 |
MX2020004414A (es) | 2020-10-19 |
AU2023241382A1 (en) | 2023-10-26 |
IL274291A (en) | 2020-06-30 |
US11696928B2 (en) | 2023-07-11 |
EP3704126A1 (en) | 2020-09-09 |
US20200323923A1 (en) | 2020-10-15 |
AU2018361971A1 (en) | 2020-06-04 |
WO2019087129A1 (en) | 2019-05-09 |
SG11202003807RA (en) | 2020-05-28 |
EP3704126A4 (en) | 2020-12-09 |
CA3080695A1 (en) | 2019-05-09 |
CN111417640B (zh) | 2024-04-05 |
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