JP2021518340A - O−糖タンパク質−2−アセトアミド−2−デオキシ−3−d−グリコピラノシダーゼ阻害剤 - Google Patents
O−糖タンパク質−2−アセトアミド−2−デオキシ−3−d−グリコピラノシダーゼ阻害剤 Download PDFInfo
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- JP2021518340A JP2021518340A JP2020548963A JP2020548963A JP2021518340A JP 2021518340 A JP2021518340 A JP 2021518340A JP 2020548963 A JP2020548963 A JP 2020548963A JP 2020548963 A JP2020548963 A JP 2020548963A JP 2021518340 A JP2021518340 A JP 2021518340A
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- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- alkyl
- methyl
- halo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Description
本願は、2018年7月17日に出願した米国特許仮出願第62/699,443号、2018年6月27日に出願した米国特許仮出願第62/690,536号及び2018年3月14日に出願した米国特許仮出願第62/642,932号に基づく優先権を主張するものであり、これらの仮出願はそれぞれ、参照により、その全体が本明細書に援用される。
Arは、任意に置換された5〜10員のヘテロアリール、任意に置換されたフェニル、または任意に置換された5〜6員の非芳香族複素環に縮合した任意に置換されたフェニルであり、
Y1及びY2はそれぞれ、CRcまたはNであり、Y1またはY2のうちの少なくとも1つは、Nであり、
Zは、CR2R2、C(=O)、(CR2R2)2、CH2C(=O)またはC(=O)CH2であり、
Ra、Rb及びRcはそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキルもしくはC1−C4アルコキシであるか、またはRa及びRbは、その介在する炭素原子と一体となって、C3−C6シクロアルキルを形成し、
mは、0または1であり、
nは、0または1〜7の整数であり、
nが0以外であるときには、R1はそれぞれ独立して、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C1−C4アルコキシまたはC1−C4ハロアルコキシであり、
R2はそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C3−C10シクロアルキルまたはC3−C10ハロシクロアルキルであるか、
あるいは、2つのR2は、それらと結合している炭素原子と一体となって、C3−C10シクロアルキルを形成し、
R3は、−HまたはC1−C4アルキルであり、
R4は、−H、C1−C4アルキル、C1−C4ハロアルキルまたはC3−C6シクロアルキルであるか、
あるいは、R3及びR4は、その介在する原子と一体となって、任意に置換された5〜7員のヘテロシクリルを形成する。
式中、
Ar上の置換基C1−C4アルキル基が任意に、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx、−C(=O)Ry、C3−C6シクロアルキル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)、単環式ヘテロアリール(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)で置換されており、
Ar上の置換基C3−C6シクロアルキル、フェニル及び単環式ヘテロアリール基が任意にかつ独立して、C1−C4アルキル、C1−C4ハロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Ry、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx及び−C(=O)Rxで置換されており、
各Rx及び各Ryが独立して、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、RxまたはRyによって表されるC1−C4アルキルまたはC3−C8シクロアルキルが任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
Rzが、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、Rzによって表されるC1−C4アルキルまたはC3−C8シクロアルキル基が任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
iが、0、1または2である。
R5が、C1−C4アルキル基であるときには、そのC1−C4アルキル基は任意にかつ独立して、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx、−C(=O)Ry、C3−C6シクロアルキル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)、単環式ヘテロアリール(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)で置換されており、
R5が、C3−C6シクロアルキル、フェニルまたは単環式ヘテロアリールであるときには、そのシクロアルキル、フェニルまたは単環式ヘテロアリールは任意にかつ独立して、C1−C4アルキル、C1−C4ハロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Ry、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx及び−C(=O)Rxで置換されており、
各Rx及び各Ryは独立して、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、RxまたはRyによって表されるC1−C4アルキルまたはC3−C8シクロアルキルは任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
Rzは、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、Rzによって表されるC1−C4アルキルまたはC3−C8シクロアルキル基は任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
iは、0、1または2であり、
qは、0、1、2または3であり、
残りの可変基は、第1の実施形態で定義したとおりである。
標題化合物をスキーム1と同様にして、tert−ブチル3−((4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)メチレン)ピペリジン−1−カルボキシレート3−ブロモピリジン及びN−[5−(クロロメチル)チアゾール−2−イル]アセトアミドから調製した。LCMS (ESI): [M+H] 331. 1HNMR: (500 MHz, CDCl3) δ 11.79 (br s, 1H), 8.54 (dd, J=1.8, 4.9 Hz, 1H), 7.59 (dt, J=1.8, 7.6 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J=7.9 Hz, 1H), 7.13 − 7.09 (m, 1H), 3.75 − 3.56 (m, 2H), 2.89 − 2.76 (m, 2H), 2.76 − 2.63 (m, 2H), 2.32 (s, 3H), 2.12 (m, 1H), 2.08 − 2.01 (m, 1H), 1.90 (br t, J=10.4 Hz, 1H), 1.78 − 1.62 (m, 2H), 1.60 − 1.47 (m, 1H), 1.12 − 0.96 (m, 1H).
標題化合物をスキーム1と同様にして、tert−ブチル3−((4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)メチレン)ピペリジン−1−カルボキシレート、2−ブロモ−6−メチルピリジン及びN−[5−(クロロメチル)チアゾール−2−イル]アセトアミドから調製した。LCMS (ESI): [M+H] 345. 1HNMR: (500 MHz, CDCl3) δ 12.11 (br s, 1H), 7.46 (t, J =7.6 Hz, 1H), 7.17 (s, 1H), 6.95 (d, J =7.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 3.64 (q, J=14.0 Hz, 2H), 2.79 (br d, J=8.5 Hz, 2H), 2.71 − 2.61 (m, 2H), 2.52 (s, 3H), 2.31 (s, 3H), 2.16 − 2.06 (m, 1H), 2.02 (br t, J=10.1 Hz, 1H), 1.86 (br t, J=10.4 Hz, 1H), 1.71 − 1.62 (m, 2H), 1.59 − 1.46 (m, 1H), 1.07 − 0.95 (m, 1H).
標題化合物をスキーム1と同様にして、tert−ブチル3−((4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)メチレン)ピペリジン−1−カルボキシレート、4−ブロモピリジン及びN−[5−(クロロメチル)チアゾール−2−イル]アセトアミドから調製した。LCMS (ESI): [M+H] 331. 1HNMR: (500 MHz, メタノール−d4) δ 8.38 (br d, J=5.5 Hz, 2H), 7.23−7.29 (m, 2H), 7.20 (s, 1H), 3.66 (s, 2H), 2.69−2.87 (m, 2H), 2.49−2.68 (m, 2H), 2.21 (s, 3H), 2.00−2.12 (m, 2H), 1.93 (td, J=7.0, 3.1 Hz, 1H), 1.76−1.87 (m, 1H), 1.64−1.76 (m, 2H), 1.46−1.62 (m, 1H), 1.03 (br d, J=9.8 Hz, 1H).
ピーク1:0.137g、LCMS: [M+H] 336. 1HNMR: (500 MHz, CDCl3) δ 12.07 (br s, 1 H), 8.48 − 8.59 (m, 2 H), 7.22 (s, 1 H), 3.79 (s, 2 H), 3.05 (d, J=7.32 Hz, 2 H), 2.74 − 2.88 (m, 2 H), 2.67 − 2.74 (m, 1 H), 2.58 − 2.64 (m, 1 H), 2.35 (dd, J=8.39, 6.56 Hz, 1 H), 2.32 (s, 3 H), 1.98 − 2.07 (m, 1 H), 1.61 (ddt, J=12.63, 8.16, 6.16, 6.16 Hz, 1 H).
ピーク2:0.124g、LCMS: [M+H] 336. 1HNMR: (500 MHz, CDCl3) δ 11.56 (br s, 1 H), 8.53 (s, 2 H), 7.22 (s, 1 H), 3.79 (s, 2 H), 3.05 (d, J=7.17 Hz, 2 H), 2.75 − 2.87 (m, 2 H), 2.68 − 2.74 (m, 1 H), 2.60 (td, J=8.58, 6.03 Hz, 1 H), 2.32 − 2.37 (m, 1 H), 2.32 (s, 3 H), 1.99 − 2.08 (m, 1 H), 1.57 − 1.65 (m, 1 H).
オキシメチル]チアゾール−2−イル]−N−メチル−アセトアミド(335.2mg、1.12mmol)をテトラヒドロフラン(6.4mL)に溶解した。これに、フッ化テトラブチルアンモニウム(テトラヒドロフラン中に1M、2.23mL、2.23mmol)を0℃で滴加した。30分後、その混合物を酢酸エチルで希釈し、飽和塩化アンモニウム水溶液で洗浄し、ブラインで洗浄し、硫酸マグネシウムで乾燥し、濾過し、真空で濃縮した。塩化メチレン中の0→10%メタノールを溶離液として用いたシリカゲルクロマトグラフィーによって、残渣を精製して、標題化合物を得た(159.8mg、収率76.6%)。LCMS: [M+H] 186.9. 1H NMR: (400 MHz, メタノール−d4) δ 7.35 (s, 1H), 4.71 (d, J=0.75 Hz, 2H), 3.68 (s, 3H), 2.41 (s, 3H).
上記の工程から得た3−((4−フルオロ−1H−ピラゾール−1−イル)メチル)ピペリジン塩酸塩の粗混合物をMeCN(4.00mL)に溶解した。その混合物に、トリエチルアミン(0.46g、4.56mmol、0.63mL)及びN−[5−(クロロメチル)チアゾール−2−イル]アセトアミド(0.145mg、0.760mmol)を加えた。その混合物を16時間、室温で撹拌した。その反応混合物を濾過し、真空で濃縮した。残渣を分取HPLC{(カラム:Waters Sunfire OBD(50×100mm、5μm)、条件:0.1%TFA中の95%水/5%ACNで20分(流速:80mL/分))}によって精製して、標題化合物を得た。LCMS (ESI): [M+H] 338. 1HNMR: (500 MHz, メタノール−d4) δ 7.58 (d, J=4.6 Hz, 1H), 7.32−7.34 (m, 1H), 7.21 (s, 1H), 3.96 (d, J=7.3 Hz, 2H), 3.68 (s, 2H), 2.78 (br d, J=11.0 Hz, 1H), 2.64 (br d, J=9.8 Hz, 1H), 2.12−2.21 (m, 5H), 1.90 (br t, J=10.4 Hz, 1H), 1.69−1.77 (m, 1H), 1.52−1.64 (m, 2H), 1.01−1.10 (m, 1H).
EtOAc(20mL)中のtert−ブチル(2S)−2−メチル−4−((5−メチル−1,2,4−オキサジアゾール−3−イル)メチル)ピロリジン−1−カルボキシレート(0.65g、2.3mmol)の溶液に、EtOAc(10mL)中の18MのHClを滴加した。4時間、室温で撹拌した後、形成された沈殿物を濾過によって回収し、EtOAc(20mL)で洗浄し、高真空で乾燥し、標題化合物を得た(0.305g、収率61%)。LC−MS (ESI) m/z [M+H]+ 182. 1H NMR (400 MHz, d2o) δ 1.25 (dd, J = 6.6, 3.2 Hz, 1.5H), 1.29* (dd, J = 6.4, 3.1 Hz, 1.5H), 1.35 (m, 0.5H), 1.85 (m, 1H), 2.28* (m, 0.5H), 2.47 (s, 3H), 2.80 (m, 3H), 2.94 (m, 1H), 3.45 (m, 1H), 3.61 (m, 0.5H), 3.76* (m, 0.5H)
ピーク1:LCMS (ESI): [M+H] 354. 1HNMR: (400 MHz, メタノール−d4) δ 3.91 (dd, J=1.13, 14.43 Hz, 1H), 3.52 (d, J=14.31 Hz, 1H), 2.83 (dd, J=3.26, 9.54 Hz, 1H), 2.70−2.78 (m, 2H), 2.54 (s, 3H), 2.43−2.59 (m, 3H), 2.18 (s, 3H), 2.09−2.24 (m, 1H), 1.19−1.27 (m, 1H), 1.17 (d, J=6.27 Hz, 3H)
ピーク2:LCMS (ESI): [M+H] 354. 1HNMR: (400 MHz, メタノール−d4) δ 3.86−3.96 (m, 1H), 3.54 (d, J=14.56 Hz, 1H), 3.11−3.21 (m, 1H), 2.67−2.73 (m, 2H), 2.54−2.66 (m, 2H), 2.53 (s, 3H), 2.18 (s, 3H), 2.12 (t, J=9.16 Hz, 1H), 1.59−1.82 (m, 2H), 1.15 (d, J=6.27 Hz, 3H).
N−(5−(((2S,4R)−2−メチル−4−((5−メチル−1,2,4−オキサジアゾール−3−イル)メチル)ピロリジン−1−イル)メチル)チアゾール−2−イル)アセトアミド(初期画分):LCMS (ESI): [M+H] 336. 1HNMR: (400 MHz, メタノール−d4) δ 7.23 (s, 1H), 4.07 (dd, J=0.88, 14.18 Hz, 1H), 3.47−3.57 (m, 1H), 2.72−2.84 (m, 3H), 2.41−2.61 (m, 3H), 2.53 (s, 3H), 2.10−2.24 (m, 1H), 2.19 (s, 3H), 1.20−1.32 (m, 1H), 1.17 (d, J=6.02 Hz, 3H).
N−(5−(((2S,4S)−2−メチル−4−((5−メチル−1,2,4−オキサジアゾール−3−イル)メチル)ピロリジン−1−イル)メチル)チアゾール−2−イル)アセトアミド(後期画分):LCMS (ESI): [M+H] 336. 1HNMR: (400 MHz, メタノール−d4) δ 7.24 (s, 1H), 4.07 (dd, J=0.88, 14.18 Hz, 1H), 3.56 (d, J=14.31 Hz, 1H), 3.13 (dd, J=7.03, 9.29 Hz, 1H), 2.53−2.72 (m, 4H), 2.53 (s, 3H), 2.19 (s, 3H), 2.08 (t, J=9.29 Hz, 1H), 1.63−1.83 (m, 2H), 1.15 (d, J=6.02 Hz, 3H).
N−(4−フルオロ−5−(((2S,5S)−2−メチル−5−((5−メチル−1,2,4−オキサジアゾール−3−イル)メチル)ピペリジン−1−イル)メチル)チアゾール−2−イル)アセトアミド(初期画分):LCMS (ESI): [M+H] 368. 1HNMR: (400 MHz, メタノール−d4) δ 3.59−3.81 (m, 2H), 2.68−2.76 (m, 3H), 2.43−2.60 (m, 2H), 2.53 (s, 3H), 2.18 (s, 3H), 2.04−2.13 (m, 1H), 1.60−1.75 (m, 1H), 1.49−1.58 (m, 2H), 1.35−1.47 (m, 1H), 1.11 (d, J=6.27 Hz, 3H).
N−(4−フルオロ−5−(((2S,5R)−2−メチル−5−((5−メチル−1,2,4−オキサジアゾール−3−イル)メチル)ピペリジン−1−イル)メチル)チアゾール−2−イル)アセトアミド(後期画分):LCMS (ESI): [M+H] 368. 1HNMR: (400 MHz, メタノール−d4) δ 3.73−3.96 (m, 2H), 2.90−2.95 (m, 1H), 2.51−2.60 (m, 2H), 2.54 (s, 3H), 2.23−2.34 (m, 1H), 2.19 (s, 3H), 1.96−2.07 (m, 2H), 1.64−1.80 (m, 2H), 1.26−1.42 (m, 1H), 1.20 (d, J=6.27 Hz, 3H), 0.95−1.14 (m, 1H).
OGA酵素の阻害に関する生化学アッセイ
組み換え完全長ヒトOGA酵素は、Origeneから購入した。4−MUGlCNAc基質は、Sigmaから購入した。他の試薬はすべて、SigmaまたはFisherから購入した。アッセイ緩衝液は、pH6.4のマッキルベイン緩衝液系(0.1Mのクエン酸と混合した0.2MのNa2HPO4)及び0.01%BSAからなる。反応物は、1nMのOGA、100μMの4−MUGlcNAc(Km)、及び最終体積10μlの化合物からなる。反応物を90分、室温でインキュベートし、3Mのグリシン40μl(pH10)でクエンチし、Perkin Elmer Envisionというプレートリーダー(Ex:355nm/Em:460nm)で読み取った。20μMから開始して4倍希釈を行う10点用量応答で、化合物を試験した。データは、可変勾配による4パラメーターフィットを用いたGraphPad Prismを用いてフィッティングした。
下記の表1には、本発明の化合物のうちのいくつかの活性データが示されている。
Claims (67)
- 下記の構造式によって表される化合物、
Arが、任意に置換された5〜10員のヘテロアリール、任意に置換されたフェニル、または任意に置換された5〜6員の非芳香族複素環に縮合した任意に置換されたフェニルであり、
Y1及びY2がそれぞれ、CRcまたはNであり、Y1またはY2のうちの少なくとも1つが、Nであり、
Zが、CR2R2、C(=O)、(CR2R2)2、CH2C(=O)またはC(=O)CH2であり、
Ra、Rb及びRcがそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキルもしくはC1−C4アルコキシであるか、またはRa及びRbが、その介在する炭素原子と一体となって、C3−C6シクロアルキルを形成し、
mが、0または1であり、
nが、0または1〜7の整数であり、
nが0以外のときには、R1がそれぞれ独立して、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C1−C4アルコキシまたはC1−C4ハロアルコキシであり、
R2がそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C3−C10シクロアルキルまたはC3−C10ハロシクロアルキルであるか、
あるいは、2つのR2が、それらと結合している炭素原子と一体となって、C3−C10シクロアルキルを形成し、
R3が、−HまたはC1−C4アルキルであり、
R4が、−H、C1−C4アルキル、C1−C4ハロアルキルまたはC3−C6シクロアルキルであるか、
あるいは、R3及びR4が、その介在する原子と一体となって、任意に置換された5〜7員のヘテロシクリルを形成する、前記化合物またはその薬学的に許容される塩。 - 下記の構造式によって表される、請求項1に記載の化合物、
Arが、任意に置換された5〜10員のヘテロアリール、任意に置換されたフェニル、または任意に置換された5〜6員の非芳香族複素環に縮合した任意に置換されたフェニルであり、
Y1及びY2がそれぞれ、CRcまたはNであり、Y1またはY2のうちの少なくとも1つが、Nであり、
Zが、CR2R2、C(=O)、(CR2R2)2、CH2C(=O)またはC(=O)CH2であり、
Ra、Rb及びRcがそれぞれ独立して、−H、ハロ、C1−C4アルキルもしくはC1−C4ハロアルキルであるか、またはRa及びRbが、その介在する炭素原子と一体となって、C3−C6シクロアルキルを形成し、
mが、0または1であり、
nが、0または1〜7の整数であり、
nが0以外のときには、R1がそれぞれ独立して、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C1−C4アルコキシまたはC1−C4ハロアルコキシであり、
R2がそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C3−C10シクロアルキルまたはC3−C10ハロシクロアルキルであるか、
あるいは、2つのR2が、それらと結合している炭素原子と一体となって、C3−C10シクロアルキルを形成し、
R3が、−HまたはC1−C4アルキルであり、
R4が、−H、C1−C4アルキル、C1−C4ハロアルキルまたはC3−C6シクロアルキルであるか、
あるいは、R3及びR4が、その介在する原子と一体となって、任意に置換された5〜7員のヘテロシクリルを形成する、前記化合物またはその薬学的に許容される塩。 - 式中、Arが、任意に置換されたピラゾリル、任意に置換されたイミダゾリル、任意に置換されたチアゾリル、任意に置換されたフェニル、任意に置換されたピリジニル、任意に置換されたピリミジニル、任意に置換されたピラジニル、任意に置換されたイミダゾ[1,2−a]ピリジニル、任意に置換されたチエノ[2,3−d]ピリミジニル、または任意に置換されたチエノ[3,2−d]ピリミジニルである、請求項1〜22のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、Arが、任意に置換されたオキサジアゾリル、任意に置換された1,2,3−トリアゾール−1−イル、任意に置換されたトリアゾロ[4,3−a]ピリジン−3−イル、または任意に置換された1H−ベンゾ[d]イミダゾール−1−イルである、請求項1〜22のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、
Arが任意に、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORy、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx、−C(=O)Rx、フェニル及び単環式ヘテロアリールから選択した1つ以上の基で置換されており、
Ar上の置換基の前記C1−C4アルキル基が任意に、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx、−C(=O)Ry、C3−C6シクロアルキル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)、単環式ヘテロアリール(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)で置換されており、
Ar上の置換基の前記C3−C6シクロアルキル、フェニル及び単環式ヘテロアリール基が任意にかつ独立して、C1−C4アルキル、C1−C4ハロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Ry、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx及び−C(=O)Rxで置換されており、
各Rx及び各Ryが独立して、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、RxまたはRyによって表される前記C1−C4アルキルまたはC3−C8シクロアルキルが任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
Rzが、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、Rzによって表される前記C1−C4アルキルまたはC3−C8シクロアルキル基が任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
iが、0、1または2である、請求項1〜28のいずれか1項に記載の化合物またはその薬学的に許容される塩。 - 式中、Arが任意に、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−CN、−ORz、−NRxRy、−C(=O)NRxRy、−C(=S)NRxRy、−O(C=O)NRxRy、−O(C=S)NRxRy、−C(=O)ORx、−NRxC(=O)Ryフェニル、−C(=O)Rx及び任意に置換された単環式ヘテロアリールから選択した1つ以上の基で置換されている、請求項1〜29のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、Arが任意に、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−ORz、−C(=O)Rx、ならびにC1−C4アルキル、C1−C4ハロアルキル及びハロで任意に置換された単環式ヘテロアリールから選択した1つ以上の基で置換されている、請求項1〜30のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、Arが任意に、−CH3、−CH2CH3、ハロメチル、シクロペンチル、シクロブチル、ハロ、−ORz、−C(=O)Rx、ならびにS及びNから選択した1つまたは2つのヘテロ原子を含むとともに、C1−C4アルキルで任意に置換された5または6員の単環式ヘテロアリールから選択した1つ以上の基で置換されており、Rxが、−HまたはC1−C4アルキルであり、Rzが、任意に置換されたC1−C4アルキルである、請求項1〜31のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、Arが任意に、−CH3、−CH2CH3、−CHF2、−CF3、シクロペンチル、シクロブチル、−F、−Cl、−Br、−OCH3、−C(=O)CH3及びチアゾリルから選択した1つ以上の基で置換されている、請求項1〜23のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 下記の構造式によって表される、請求項1に記載の化合物、
Y1及びY2がそれぞれ、CRcまたはNであり、Y1またはY2のうちの少なくとも1つが、Nであり、
Zが、CR2R2、C(=O)、(CR2R2)2、CH2C(=O)またはC(=O)CH2であり、
Ra、Rb及びRcがそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキルもしくはC1−C4アルコキシであるか、またはRa及びRbが、その介在する炭素原子と一体となって、C3−C6シクロアルキルを形成し、
mが、0または1であり、
nが、0または1〜7の整数であり、
nが0以外のときには、R1がそれぞれ独立して、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C1−C4アルコキシまたはC1−C4ハロアルコキシであり、
R2がそれぞれ独立して、−H、ハロ、C1−C4アルキル、C1−C4ハロアルキル、C3−C10シクロアルキルまたはC3−C10ハロシクロアルキルであるか、
あるいは、2つのR2が、それらと結合している炭素原子と一体となって、C3−C10シクロアルキルを形成し、
R3が、−HまたはC1−C4アルキルであり、
R4が、−H、C1−C4アルキル、C1−C4ハロアルキルまたはC3−C6シクロアルキルであるか、
あるいは、R3及びR4が、その介在する原子と一体となって、任意に置換された5〜7員のヘテロシクリルを形成し、
R5がそれぞれ、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORy、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx、−C(=O)Rx、フェニル及び単環式ヘテロアリールから選択されており、
R5が、C1−C4アルキル基であるときには、前記C1−C4アルキル基が任意にかつ独立して、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Rx、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx及び−C(=O)Ry、C3−C6シクロアルキル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)、単環式ヘテロアリール(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)、ならびにフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)で置換されており、
R5が、C3−C6シクロアルキル、フェニルまたは単環式ヘテロアリールであるときには、前記シクロアルキル、フェニルまたは単環式ヘテロアリールが任意にかつ独立して、C1−C4アルキル、C1−C4ハロアルキル、ハロ、−CN、−NO2、−ORz、−NRxRy、−S(O)iRx、−NRxS(O)iRy、−S(O)iNRxRy、−C(=O)ORx、−OC(=O)ORx、−C(=S)ORx、−O(C=S)Ry、−C(=O)NRxRy、−NRxC(=O)Ry、−C(=S)NRxRy、−NRxC(=S)Ry、−NRx(C=O)ORy、−O(C=O)NRxRy、−NRx(C=S)ORy、−O(C=S)NRxRy、−NRx(C=O)NRxRy、−NRx(C=S)NRxRy、−C(=S)Rx及び−C(=O)Rxで置換されており、
各Rx及び各Ryが独立して、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、RxまたはRyによって表される前記C1−C4アルキルまたはC3−C8シクロアルキルが任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシまたはハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
Rzが、−H、C1−C4アルキルまたはC3−C8シクロアルキルであり、Rzによって表される前記C1−C4アルキルまたはC3−C8シクロアルキル基が任意に、ハロ、ヒドロキシル、C3−C6シクロアルキル及びフェニル(−CH3、ハロメチル、ハロ、メトキシ及びハロメトキシから選択した1つ以上の基で任意に置換されている)から選択した1つ以上の置換基で置換されており、
iが、0、1または2であり、
qが、0、1、2または3である、前記化合物またはその薬学的に許容される塩。 - 式中、R3が、−Hである、請求項1〜50のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R4が、−CH3である、請求項1〜51のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R5が、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−CN、−ORz、−NRxRy、−C(=O)NRxRy、−C(=S)NRxRy、−O(C=O)NRxRy、−O(C=S)NRxRy、−C(=O)ORx、−NRxC(=O)Ryフェニル、−C(=O)Rx及び任意に置換された単環式ヘテロアリールから選択されている、請求項1〜52のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R5が、C1−C4アルキル、C1−C4ハロアルキル、C3−C6シクロアルキル、ハロ、−ORz、−C(=O)Rx、ならびにC1−C4アルキル、C1−C4ハロアルキル及びハロで任意に置換された単環式ヘテロアリールから選択されている、請求項1〜53のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R5が、−CH3、−CH2CH3、ハロメチル、シクロペンチル、シクロブチル、ハロ、−ORz、−C(=O)Rx、ならびにS及びNから選択した1つまたは2つのヘテロ原子を含むとともに、C1−C4アルキルで任意に置換された5または6員の単環式ヘテロアリールから選択されており、Rxが、−HまたはC1−C4アルキルであり、Rzが、任意に置換されたC1−C4アルキルである、請求項1〜54のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R5が、−CH3、−CH2CH3、−CHF2、−CF3、シクロペンチル、シクロブチル、−F、−Br、Cl、−OCH3、−C(=O)CH3及びチアゾリルから選択されている、請求項1〜55のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、R5が、−F、−Br及びClから選択されている、請求項1〜56のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、Ra及びRbのうちの1つが、−Hであり、もう一方が、−CH3、−CF3及び−OCH3から選択されている、請求項1〜57のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、nが、0または1である、請求項1〜58のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 式中、nが0である、請求項1〜59のいずれか1項に記載の化合物またはその薬学的に許容される塩。
- 請求項1〜60のいずれか1項に記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体または希釈剤とを含む医薬組成物。
- 神経変性疾患、タウオパチー、糖尿病、がん及びストレスから選択される疾患または状態である対象の治療方法であって、請求項1〜60のいずれか1項に記載の化合物を有効量、または請求項61に記載の医薬組成物を有効量、前記対象に投与することを含む、前記方法。
- 前記疾患または状態が、急性虚血性脳卒中(AIS)、アルツハイマー病、認知症、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒性認知症、Bluit病、大脳皮質基底核変性症(CBP)、闘拳家認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、てんかん、家族性英国型認知症、家族性デンマーク型認知症、17番染色体に連鎖する前頭側頭型認知症パーキンソニズム(FTDP−17)、ゲルストマン−ストロイスラー−シャインカー病、グアドループ型パーキンソニズム、ハラーフォルデン−シュパッツ病(脳の鉄沈着を伴う神経変性疾患(1型))、虚血性脳卒中、軽度認知障害(MCI)、多系統萎縮症、筋緊張性ジストロフィ、ニーマンピック病(C型)、淡蒼球橋黒質変性症、グアムのパーキンソニズム認知症複合、ピック病(PiD)、脳炎後のパーキンソン病(PEP)、プリオン病(クロイツフェルト−ヤコブ病(GJD)、変異型クロイツフェルト−ヤコブ病(vCJD)を含む)、致死性家族性不眠症、クールー病、進行性核上麻痺、進行性核上麻痺(PSP)、スティール−リチャードソン−オルスゼフスキー症候群、亜急性硬化性全脳炎、神経原線維型老年認知症、ハンチントン病及びパーキンソン病から選択される、請求項62に記載の方法。
- 前記疾患または状態が、急性虚血性脳卒中(AIS)、アルツハイマー病、認知症、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒性認知症、てんかん、虚血性脳卒中、軽度認知障害(MCI)、ハンチントン病及びパーキンソン病から選択される、請求項62及び63のいずれか1項に記載の方法。
- 前記疾患または状態が、アルツハイマー病である、請求項62〜64のいずれか1項に記載の方法。
- O−GlcNAcaseを阻害する必要がある対象のO−GlcNAcaseの阻害方法であって、請求項1〜60のいずれか1項に記載の化合物を有効量、または請求項61に記載の医薬組成物を有効量、前記対象に投与することを含む、前記方法。
- 脳内のタウの過剰リン酸化によって特徴付けられる疾患または状態の治療方法であって、請求項1〜60のいずれか1項に記載の化合物を有効量、または請求項61に記載の医薬組成物を有効量、対象に投与することを含む、前記方法。
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