CN115867534A - 非溶酶体葡糖神经酰胺酶抑制剂及其用途 - Google Patents
非溶酶体葡糖神经酰胺酶抑制剂及其用途 Download PDFInfo
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- CN115867534A CN115867534A CN202180046369.4A CN202180046369A CN115867534A CN 115867534 A CN115867534 A CN 115867534A CN 202180046369 A CN202180046369 A CN 202180046369A CN 115867534 A CN115867534 A CN 115867534A
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- methyl
- hydroxymethyl
- piperidine
- triol
- piperidin
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Classifications
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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Abstract
本发明提供了用于抑制葡糖神经酰胺酶的化合物、所述化合物的前药、和包含所述化合物或所述化合物的前药的药物组合物。
Description
技术领域
本发明部分涉及抑制葡糖神经酰胺酶的化合物及其用途。
背景技术
葡糖神经酰胺酶是一组催化鞘糖脂葡糖神经酰胺(GlcCer,又称葡糖脑苷脂)的β-葡萄糖苷键水解裂解产生D-葡萄糖和神经酰胺的酶。在人体中,有三种不同具有葡糖神经酰胺酶活性的酶:溶酶体β-葡糖脑苷脂酶(GCase或GBA1,EC 3.2.1.45),非溶酶体葡糖神经酰胺酶(GBA2,EC 3.2.1.45)和胞质β-葡糖脑苷脂酶(GBA3,EC 3.2.1.21)。GCase是由基因GBA编码的溶酶体酶;GBA中的纯合子功能丧失突变引起溶酶体贮积症戈谢病,其特征在于葡糖神经酰胺在溶酶体内的病理性积累。1GBA2是一种位于内质网(ER)和高尔基体膜细胞质侧的膜相关蛋白,并且在中枢神经系统(CNS)中以高水平表达。2,3GBA3是主要在肝脏中表达的胞质酶。3,4
葡糖神经酰胺酶在调节其底物分子葡糖神经酰胺的细胞水平中起重要作用,葡糖神经酰胺是一类广泛的细胞膜脂质,鞘糖脂(GSLs)的最简单成员和生物合成前体。3,5GSL代谢和平衡的失调涉及广泛的疾病,包括:神经障碍阿尔茨海默病(AD)、6帕金森病(PD)7、7多发性硬化(MS)、8亨廷顿氏病(HD)、9肌萎缩性侧索硬化(ALS)、10和神经元蜡样脂褐质沉积症(巴顿病);11溶酶体贮积病C型尼曼-匹克病(NPC)、12IV型粘脂贮积症(MLIV)、13和桑德霍夫病;14和肝病非酒精性脂肪肝病(NAFLD)15和非酒精性脂肪性肝炎(NASH)。15已被证明小分子GBA2抑制剂在NPC啮齿动物模型中可以延长寿命并改善运动协调。16,17类似地,有证据表明,抑制GBA2可延长MLIV13和桑德霍夫病14啮齿动物模型的寿命并延迟运动缺陷。在具有突触核蛋白病的鼠模型中,已经显示小分子GBA2抑制剂减少脑中α-突触核蛋白聚集体的积累。14此外,用小分子GBA2抑制剂治疗减少了神经元蜡样脂褐质沉积症(巴顿病)的小鼠模型中的神经炎症和神经变性。18在啮齿动物戈谢病模型中,GBA2活性的降低也被证明可以挽救临床表型。19此外,研究表明GBA2参与调节炎症反应,2并且GBA2活性的降低减少了囊性纤维化(CF)细胞模型中的炎症。20葡糖基神经酰胺水平的增加在肝脏疾病啮齿动物模型中也表现出有益效果,包括非酒精性脂肪性肝炎(NASH)、21肝炎、22肝细胞癌(HCC)、23自身免疫性胆管炎、24和和药物诱导的肝损伤(DILI)。25
GBA2的酶活性可以通过亚氨基糖(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,Miglustat)和(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)药理学阻断;然而,这些化合物对GBA2没有选择性,因为它们还表现出对其他酶(包括Gcase、葡糖神经酰胺合酶(GCS,EC2.4.1.80)和肠α-葡糖苷酶)的抑制活性。26
国际专利申请PCT/GB 2003/003099,2003年7月17日提交,2004年1月22日以WO2004/007453公开;PCT/GB 2004/002450,2004年6月9日提交,2004年12月23日以WO 2004/111001公开;PCT/GB 2004/002451,2004年6月9日提交,2004年12月23日以WO 2004/111002公开;PCT/GB 2005/000071,2005年1月11日提交,2005年7月28日以WO 2005/068426公开;PCT/NL2015/050188,2015年3月23日提交,2015年10月1日以WO 2015/147639公开;PCT/IB2020/054355,2020年5月7日提交,2020年11月19日以WO 2020/229968公开,涉及GBA2的小分子抑制剂。
发明内容
本发明部分地提供了用于抑制非溶酶体葡糖神经酰胺酶(GBA2)的化合物、所述化合物的前药、所述化合物和前药的用途、包括所述化合物或所述化合物的前药的药物组合物、以及治疗由GBA 2活性水平、和/或葡糖神经酰胺水平、和/或鞘糖脂代谢或平衡失调调节的疾病和病症的方法。在一些实施方案中,本发明提供了通过向有需要的患者施用有效量的一种或多种本发明所述的化合物或化合物的前药来预防和/或治疗神经疾病的组合物和方法,包括阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病和肌萎缩性侧索硬化(ALS)、或溶酶体贮积病,包括戈谢病、C型尼曼-匹克病、IV型粘脂贮积症和桑德霍夫病,或肝病,包括非酒精性脂肪性肝炎(NASH)。
在一个方面,本发明提供式(I)化合物或其药学上可接受的盐:
其中,R1可以是H且R2可以是CH2OH;或R1可以是CH2OH且R2可以是H;和
R3可以是(CH2)nR4,其中n可以是1或2,并且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基,螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基,(金刚烷基)甲基、(吡啶-2-基)甲基,(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基,(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻唑-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基,4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被下列之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是 其中,R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;和
条件是R1是CH2OH且R2是H时,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
在替代实施方案中,本发明提供式(Ia)所示的化合物或其药学上可接受的盐:
其中,R3可以是(CH2)nR4,其中n可以是1或2,并且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺旋[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基,(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基,1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻唑-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被下列之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可能是 其中,R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基。
在替代实施方案中,本发明提供式(Ib)所示的化合物或其药学上可接受的盐:
其中,R3可以是(CH2)nR4,其中n可以是1或2,并且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基,1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻唑-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3;或
R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被下列之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是 其中,R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
在替代实施方案中,本发明提供式(Ic)所示的化合物或其药学上可接受的盐:
其中,R6和R7可以独立地选自一组包含:H、F、Cl、C1-6烷基、OCH3、苯基、环丙基、乙烯基、甲氧基甲基、2-氟丙-2-基、CHF2、CF2CH3、和/或CF3,条件是R6和R7中至少有一个不是H。在一些实施方案中,R6可以是H,且R7可以是CF3、2-氟丙-2-基、CHF2、CF2CH3、异丙基、或叔丁基。在一些实施方案中,R6可以是CF3、2-氟丙-2-基、CHF2、CF2CH3、异丙基、或叔丁基,且R7可以是H。
在替代实施方案中,本发明提供式(Id)所示的化合物或其药学上可接受的盐:
其中,R6和R7可以独立选自一组包含:H、F、Cl、C1-6烷基、OCH3、苯基、环丙基、乙烯基、甲氧基甲基、2-氟丙-2-基、CHF2、CF2CH3、和/或CF3,条件是R6和R7中至少有一个不是H。
在替代实施方案中,本发明提供式(Ie)所示的化合物或其药学上可接受的盐:
其中,R8、R9和R10可以独立选自一组包含:吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基,3,5-二甲基-1H-吡唑-4-基、H、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3,条件是R8、R9和R10中至少有一个不是H。在一些实施方案中,R8、R9和R10可以独立选自一组包含:H、F、Cl、四氢-2H-吡喃-4-基、4-吗啉基、吡咯烷-1-基、和哌啶-1-基,条件是R8、R9和R10中至少有一个不是H。
在替代实施方案中,本发明提供式(If)所示的化合物或其药学上可接受的盐:
其中,R8、R9和R10可以独立选自一组包含:H、F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、和/或CF3,条件是所述化合物不是(2R,3R,4R,5S)-2-(羟甲基)-1-(4-苯丁基)哌啶-3,4,5-三醇、(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(2-丙氧基苯基)丙基)哌啶-3,4,5-三醇、(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(3-丙氧基苯基)丙基)哌啶-3,4,5-三醇、或(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(4-丙氧基苯基)丙基)哌啶-3,4,5-三醇。
在替代实施方案中,本发明提供式(Ig)所示的化合物或其药学上可接受的盐:
其中,R8、R9和R10可以独立选自一组包含:H、F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、和/或CF3。在一些实施方案中,R8、R9和R10独立选自一组包含:H、F和CF3。
在替代实施方案中,本发明提供式(Ih)所示的化合物或其药学上可接受的盐:
其中,R11可以选自一组包含:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目。
在替代实施方案中,本发明提供式(Ii)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施方案中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Ij)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施方案中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Ik)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施方案中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Il)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施方案中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Im)所示的化合物或其药学上可接受的盐:
其中,R6和R7可以独立选自一组包含:H、F、Cl、C1-6烷基、OCH3、苯基、环丙基、乙烯基、甲氧基甲基、2-氟丙-2-基、CHF2、CF2CH3、和/或CF3。在一些实施方案中,R6可以是H,且R7可以是CF3、2-氟丙-2-基、CHF2、CF2CH3、异丙基、或叔丁基。在一些实施方案中,R6可以是CF3、2-氟丙-2-基、CHF2、CF2CH3、异丙基、或叔丁基,且R7可以是H。
在替代实施方案中,本发明提供式(In)所示的化合物或其药学上可接受的盐:
其中,R6和R7可以独立选自一组包含:H、F、Cl、C1-6烷基、OCH3、苯基、环丙基、乙烯基、甲氧基甲基、2-氟丙-2-基、CHF2、CF2CH3、和/或CF3。
在替代实施方案中,本发明提供式(Io)所示的化合物或其药学上可接受的盐:
其中,R8、R9和R10可以独立选自一组包含:吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、H、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3,条件是该化合物不是(2S,3R,4R,5S)-2-(羟甲基)-1-苯乙基哌啶-3,4,5-三醇、(2S,3R,4R,5S)-2-(羟甲基)-1-((R)-2-苯丙基)哌啶-3,4,5-三醇、或(2S,3R,4R,5S)-2-(羟甲基)-1-((S)-2-苯丙基)哌啶-3,4,5-三醇。在一些实施方案中,R8、R9和R10可以独立选自一组包含:H、F、Cl、四氢-2H-吡喃-4-基、4-吗啉基、吡咯烷-1-基、和哌啶-1-基,条件是R8、R9和R10中至少有一个不是H。
在替代实施方案中,本发明提供式(Ip)所示的化合物或其药学上可接受的盐:
其中,R8、R9和R10可以独立选自一组包含:H、F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、和/或CF3,条件是R8、R9和R10中至少有一个不是H。
在替代实施方案中,本发明提供式(Iq)所示的化合物或其药学上可接受的盐:
其中R8、R9和R10可以独立选自一组包含:H、F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、和/或CF3。在一些实施例中,R8、R9和R10可以独立选自一组包含:H、F和CF3。
在替代实施方案中,本发明提供式(Ir)所示的化合物或其药学上可接受的复合物:
其中,R11可以选自一组包含:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目。
在替代实施方案中,本发明提供式(Is)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:从苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施例中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供公式(It)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施方案中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Iu)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施例中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,本发明提供式(Iv)所示的化合物或其药学上可接受的盐:
其中,R12可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、或苯基羰基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。在一些实施例中,R12可以选自一组包含:2-(三氟甲基)苯基、2-(三氟甲基)吡啶-3-基、3-(三氟甲基)吡啶-2-基、4-(三氟甲基)吡啶-2-基、5-(三氟甲基)吡啶-3-基、6-(三氟甲基)吡啶-2-基、4-(三氟甲基)嘧啶-5-基、和4-(三氟甲基)噻唑-2-基。
在替代实施方案中,所述化合物可以是前药;所述化合物可以抑制非溶酶体葡糖神经酰胺酶(GBA2);所述化合物可以抑制GBA2(例如,哺乳动物GBA2);所述化合物可以抑制野生型GBA2;或者所述化合物可以抑制突变GBA2。
在替代实施方案中,根据式(I)、式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)、式(If)、式(Ig)、式(Ih)、式(Ii)、式(Ij)、式(Ik)、式(Il)、式(Im)、式(In)、式(Io)、式(Ip)、式(Iq)、式(Ir)、式(Is)、式(It)、式(Iu)、或式(Iv)所示的化合物可以表现出增强的选择性和/或渗透性。
在替代实施方案中,根据式(Ic)、式(Ie)、式(Ig)、式(Im)、式(Io)、或式(Iq)所示的化合物可以表现出增强的选择性和/或渗透性。
在替代实施方案中,根据式(Ic)、式(Ie)、式(Ig)、式(Im)、式(Io)、或式(Iq)所示的化合物可表现出增强的选择性。
在替代实施方案中,根据式(Ic)、式(Ie)、式(Ig)、式(Im)、式(Io)、或式(Iq)所示的化合物在体内给药时可以达到更高的脑浓度。
在替代方面,本发明提供了药物组合物,其包括根据本发明的化合物或其药学上可接受的盐以及药学上可接受的载体。
在替代方面,本发明提供了在需要的受试者中抑制GBA2的方法,或在需要的受试者中治疗神经系统疾病、或溶酶体贮积病、或肝脏疾病的方法,所述方法通过向受试者施用有效量的如本发明所述的式(I)的化合物,包括式(Ia)-(Iv)中的任何一种或多种,或其药学上可接受的盐。神经疾病可以是,但不限于阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、肌萎缩性侧索硬化(ALS)、伴有认知损伤的肌萎缩性侧索硬化(ALSci)、成瘾、焦虑、嗜银颗粒性痴呆、共济失调-毛细血管扩张症(A-T)、注意力缺陷/多动障碍(ADHD)、自闭症谱系障碍(ASD)、贝克肌营养不良(BMD)、双相障碍(BD)、布卢特病、小脑性共济失调、腓骨肌萎缩症(CMT)、慢性疲劳综合征、皮质基底节变性(CBD)、拳击手痴呆、路易体痴呆(DLB)、德热里纳-索塔斯病、弥漫性神经原纤维缠结伴钙化症、唐氏综合征、杜兴肌营养不良(DMD)、癫痫、特发性震颤(ET)、家族性英国型痴呆(familial British dementia)、家族性丹麦型痴呆(familial Danish dementia)、纤维肌痛、连锁于17号染色体伴帕金森病的额颞叶痴呆(FTDP-17)、弗里德赖希共济失调、格斯特曼-施特劳斯钠病(Gerstmann-Straussler-Scheinker disease)、青光眼、瓜地洛帕帕金森综合征(Guadeloupean parkinsonism)、格林-巴利综合征、哈勒沃登-施帕茨病(神经变性伴脑铁积聚1型)、失眠、兰伯特-伊顿肌无力综合征(LEMS)、重度抑郁症(MDD)、偏头痛、轻度认知障碍(MCI)、多发性脑梗死性痴呆、多系统萎缩(MSA)、重症肌无力、肌强直性营养不良(包括DM1和DM2型)、神经元蜡样脂褐质沉积症(包括1、2、3、4、5、6、7、8、9和10型)、神经病(包括周围神经病变、自主神经病变、神经炎、和糖尿病神经病变)、眼咽型肌营养不良、疼痛、苍白球脑桥黑质变性、关岛型帕金森综合征-痴呆复合征、皮克氏病(PiD)、脑炎后帕金森综合征(PEP)、原发性侧索硬化(PLS)、朊病毒病(包括克雅氏病(CJD)、变异型克雅氏病(vCJD)、致命性家族性失眠、和库鲁病)、进行性皮质下神经胶质增生、进行性核上性麻痹(PSP)、理查森综合征(Richardson’s syndrome)、精神分裂症、癫痫发作、脊髓损伤、脊髓性肌萎缩(SMA)、脊髓小脑性共济失调(包括1、2、3、4、5、6、7、8、10、11、12、13、14、16、17、18、19、20、21、22、23、25、26、27、28和29型)、中风、亚急性硬化性全脑炎、缠结性痴呆、迟发性运动障碍、抽动秽语综合征(TS)、血管性痴呆、或威尔逊病。
溶酶体贮积病可以是,但不限于戈谢病(包括I、II和III型)、尼曼-匹克病(包括A、B和C型)、粘脂贮积症(包括I、II、III、IV、VI和VII型)、脑腱性黄瘤症、法布里病、法伯病、GM1神经节苷脂贮积病、克拉伯病、异染性脑白质营养不良(MLD)、多发性硫酸酯酶缺乏症、庞贝病、桑德霍夫病、或泰萨二氏病。
肝病可以是非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、阿拉杰里综合征(Alagille syndrome)、酒精相关性肝病、α-1抗胰蛋白酶缺乏症、自身免疫性肝炎、自身免疫性胆管炎、良性肝肿瘤、胆道闭锁、肝硬化、克里格勒-纳贾尔综合征、药物诱导的肝损伤(DILI)、半乳糖血症、吉尔伯特综合征、血色素沉着症、肝性脑病、肝细胞癌(HCC)、妊娠肝内胆汁淤积症(ICP)、溶酶体酸性脂肪酶缺乏症(LAL-D)、肝囊肿、肝癌、新生儿黄疸、原发性胆汁性胆管炎(PBC)、原发性硬化性胆管炎(PSC)、瑞氏综合征、I型糖原贮积病、或病毒性肝炎(包括A、B、C、D和E型)。
在替代实施方案例中,本发明提供了在有需要的受试者中治疗神经系统疾病的方法,所述方法通过向受试者施用有效量的如本发明所述的式(Ic)、式(Ie)、式(Ig)、式(Im)、式(Io)、或式(Iq)中的任何一种或多种化合物,或其药物上可接受的盐。
在替代实施方案中,所述施用可以降低受试者中GBA2的酶活性水平。在替代实施方案中,所述施用可以调节受试者中葡糖神经酰胺和/或鞘糖脂的水平。在替代实施方案中,所述施用可以提高受试者中葡糖神经酰胺的水平。在替代实施方案中,所述施用可以提高受试者中神经节苷脂GM1的水平。在替代实施方案中,所述施用可调节受试者中神经酰胺和/或鞘氨醇和/或鞘氨醇-1-磷酸(S1P)的水平。受试者可以是人。
在替代方面,本发明提供了有效量的如本发明所述的式(I)化合物,包括式(Ia)-(Iv)中的任何一种或多种,或其药学上可接受的盐,在制备药物中的用途。所述药物可以用于抑制GBA2,用于治疗由GBA2调节的病症,或用于治疗神经疾病或溶酶体贮积病或肝病。
本发明内容不一定描述本发明的所有特征。
具体实施方式
详细说明
本发明部分地提供了用于抑制非溶酶体葡糖神经酰胺酶(GBA2)的化合物及其用途。
"非溶酶体葡糖神经酰胺酶"或"GBA 2"是指具有葡糖神经酰胺酶活性的位于ER和高尔基体膜的细胞质侧的非溶酶体膜相关酶(EC 3.2.1.45),其催化糖脂葡糖神经酰胺的β-葡萄糖苷键的水解断裂。GBA2的替代名称包括:NLGase、葡糖神经酰胺酶β2、β-葡糖脑苷脂酶2、β-葡萄糖苷酶2、葡糖神经酰胺酶2、胆汁酸β-葡萄糖苷酶、“葡萄糖苷酶、β-(胆汁酸)2”、KIAA1605、DKFZp762K054、SPG46、和AD035。在一些实施方案中,GBA2可以是哺乳动物GBA2,例如大鼠、小鼠或人GBA2。GBA2可以是野生型GBA2或突变型GBA2。在一些实施方案中,GBA2可以是野生型哺乳动物GBA2,例如大鼠、小鼠或人野生型GBA2。在一些实施方案中,GBA2可以是突变型哺乳动物GBA2,例如大鼠、小鼠或人突变型GBA2。在一些实施方案中,GBA2可以具有如以下登录号中任一个所示的序列:Q9HCG7、Q69ZF3、D3DRP2、Q5TCV6、Q96A51、Q96LY1、Q96SJ2、Q9H2L8、Q5M868、或O16581。在替代实施方案中,GBA2可以具有如以下登录号中的任一个所示的替代剪接同种型序列:Q9HCG7-1,Q9HCG7-2,Q9HCG7-3。在替代实施方案中,GBA2可以由以下登录号中的任一个中所示的序列编码:NP_065995.1、NP_001317589.1、NP_766280.2、NP_001013109.2、NM_020944、NM_172692、NM_001330660、XM_011517973、XP_005251583.1、XP_006716872.1、XP_011516275.1、XP_016870426.1、XP_016870427.1、XP_016870428.1、XP_016870429.1、XP_016870430.1、XP_016870431.1、XP_016870432.1、XP_016870433.1、XP_016870434.1、或XP_016870435.1。
在替代实施方案中,人GBA2可以具有以下列出的序列:
在替代实施方案中,人GBA2可以具有编码SEQ ID NO:1所示序列的核酸分子的核酸序列。
在一些实施方案中,根据本发明的一种或多种化合物可以抑制GBA2的活性,例如,抑制从葡糖神经酰胺裂解葡萄糖的能力或抑制从合适的底物分子,例如,4-甲基伞形酮-β-D吡喃葡糖苷裂解葡萄糖的能力。“抑制(inhibit)”、“抑制(inhibition)”或“抑制(inhibiting)”意指与参考样品或化合物相比,或与野生型GBA2相比,GBA2的活性降低约10%至约90%之间的任何值,或约30%至约60%之间的任何值,或超过约100%,或降低约1倍、2倍、5倍、10倍或更多。应当理解,抑制不需要完全抑制。在一些实施方案中,抑制可以是暂时的,例如持续5分钟-60分钟、1小时-5小时、1小时-12小时、1小时-24小时、24小时-48小时、1天-2天、1天-5天、1天-7天、1天-14天、1天-28天、或任何这些范围内的任何特定时间,例如5分钟、10分钟、15分钟、20分钟、25分钟、30分钟、60分钟、1.5小时、2小时、2.5小时、3小时、4小时、5小时、6小时、7小时、8小时、9小时、10小时、11小时、12小时、13小时、14小时、15小时、16小时、17小时、18小时、19小时、20小时、21小时、22小时、23小时、24小时、1.5天、2天、2.5天、3天、3.5天、4天、4.5天、5天、6天、7天、8天、9天、10天、11天、12天、13天、或14天。在一些实施方案中,抑制可以是局部的。例如,根据本发明的一种或多种化合物可以抑制特定细胞区室内的GBA2,例如内质网(ER)或高尔基体(Golgi);或者根据本发明的一种或多种化合物可以抑制特定组织类型(例如脑或肝)内的GBA2。
在一些实施方案中,根据本发明的一种或多种化合物可以特异性结合GBA2。在替代实施方案中,根据本发明的一种或多种化合物可以特异性结合GBA2的活性位点。在一些实施方案中,根据本发明的特异性结合GBA2的活性位点的一种或多种化合物也可以抑制GBA2的活性。在替代实施方案中,根据本发明的一种或多种化合物可以特异性结合人非溶酶体葡糖神经酰胺酶(GBA2)而不是人溶酶体葡糖神经酰胺酶(GCase)和/或人细胞溶质葡糖神经酰胺酶(GBA3)。在替代实施方案中,根据本发明的一种或多种化合物可以特异性结合人非溶酶体葡糖神经酰胺酶(GBA2)而不是人葡糖神经酰胺合酶(GCS)。在替代实施方案中,根据本发明的一种或多种化合物可以特异性结合人非溶酶体葡糖神经酰胺酶(GBA2)而不是肠α-葡萄糖苷酶,其中肠α-葡萄糖苷酶可以是蔗糖酶-异麦芽糖酶或麦芽糖酶-葡糖淀粉酶。“特异性结合”是指化合物结合样品中的GBA2但基本上不结合其他分子,例如乳糖酶、蔗糖酶、麦芽糖酶、异麦芽糖酶、蔗糖酶-异麦芽糖酶、葡糖淀粉酶、麦芽糖酶-葡糖淀粉酶、葡糖神经酰胺合酶、α-葡萄糖苷酶II、ERα-葡萄糖苷酶、肠α-葡萄糖苷酶、糖原磷酸化酶、酸性α-葡萄糖苷酶、β-己糖胺酶、乙酰氨基葡萄糖酶(O-GlcNAcase)、GCase或GBA3。“基本上不结合”意指结合特异性在约5倍至约100,000倍、或约10倍至约100,000倍的范围内、或在约100倍至约100,000倍的范围内、或在约1000倍至约100,000倍的范围内、或至少约5倍、10倍、20倍、50倍、100倍、200倍、500倍、1000倍、1500倍、2000倍、2500倍、3000倍、3500倍、4000倍、4500倍、5000倍、6000倍、7000倍、10,000倍、25,000倍、50,000倍、75,000倍,或在所述范围内或附近的任何值,其中“结合特异性”是指各结合常数的比率,即Ki(其他分子)/Ki(GBA2),或各自IC50的比率,即IC50(其他分子)/IC50(GBA2)。表现出增强的结合特异性的化合物的实例包括,但不限于实施例4、8、12、13、14、15、16、20、21、22、23、24、25、27、28、29、31、32、311、312、313、或314的化合物。在一些实施方案中,与合适的参考化合物,例如,(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,miglustat)或(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)相比,根据本发明的一种或多种化合物可表现出增强的结合特异性或增强的选择性。在一些实施方案中,“增强的结合特异性”或“增强的选择性”是指与合适的参考化合物相比,测量的结合特异性(如上所定义)增加约10%至约100%之间的任何值,或约10%至约100%之间的任何整数值,例如,约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或超过100%、或增加约1倍至约100,000倍、或约5倍至约100,000倍、或约10倍至约100,000倍、或在约100倍至约100,000倍的范围内、或在约1000倍至约100,000倍的范围内、或至少约1倍、2倍、3倍、4倍、5倍、10倍、20倍、30倍、40倍、50倍、100倍、150倍、200倍、250倍、300倍、350倍、400倍、450倍、500倍、1000倍、1500倍、2000倍、2500倍、3000倍、3500倍、4000倍、4500倍、5000倍、6000倍、7000倍、10,000倍、25,000倍、50,000倍、75,000倍、100,000倍,或所述范围内或附近的任何值,或更多。
在替代实施方案中,根据本发明的一种或多种化合物可以特异性结合人非溶酶体葡糖神经酰胺酶(GBA 2)而不是大鼠肠α-葡萄糖苷酶,其中大鼠肠α-葡萄糖苷酶可以是蔗糖酶-异麦芽糖酶或麦芽糖酶-葡糖淀粉酶。在一些实施方案中,与合适的参考化合物例如,(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,miglustat)或(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)相比,根据本发明的一种或多种化合物可以基本上不抑制大鼠肠α-葡萄糖苷酶。在一些实施方案中,“基本上不抑制”意指在下文描述的用于抑制大鼠肠葡萄糖苷酶的试验中小于约30%的抑制百分比。在一些实施方案中,“基本上不抑制”意指在下文描述的用于抑制大鼠肠葡萄糖苷酶的试验中小于约20%的抑制百分比。在一些实施方案中,“基本上不抑制”意指在下文描述的用于抑制大鼠肠葡萄糖苷酶的试验中小于约10%的抑制百分比。
在一些实施方案中,本发明的一种或多种化合物可以抑制GBA2从葡糖神经酰胺裂解为葡萄糖。在一些实施方案中,本发明的一种或多种化合物可以抑制α-突触核蛋白的聚集和/或抑制路易体的形成。“抑制(inhibit)”、“抑制(inhibition)”或“抑制(inhibiting)”意指与参考样品或化合物、或与野生型GBA2相比,减少约10%至约90%之间的任何值、或约30%至约60%之间的任何值、或超过约100%、或减少约1倍、2倍、5倍、10倍或更多倍。应当理解,抑制不需要完全抑制。在一些实施方案中,抑制可以是暂时的。
在一些实施方案中,本发明的一种或多种化合物可以减少CNS中的炎症。在一些实施方案中,本发明的一种或多种化合物可以减少α-突触核蛋白聚集和/或路易体形成。“减少(decreasing)”或“减少(decrease)”意指与参考样品或化合物相比,减少约5%与约90%之间的任何值,或约30%与约60%之间的任何值,或超过约100%,或减少约1倍、2倍、5倍、10倍、15倍、25倍、50倍、100倍或更多。
在一些实施方案中,本发明的一种或多种化合物可提高葡糖神经酰胺水平。在一些实施方案中,本发明的一种或多种化合物可升高鞘糖脂水平。在一些实施方案中,本发明的一种或多种化合物可升高GM1神经节苷脂水平。“升高(elevating)”或“增强(enhancing)”或“增加(increasing)”意指与参考样品相比,增加约5%与约90%之间的任何值,或约30%与约60%之间的任何值,或超过约100%,或增加约1倍、2倍、5倍、10倍、15倍、25倍、50倍、100倍或更多。在一些实施方案中,根据本发明的一种或多种化合物可以提高脑内葡糖神经酰胺水平和/或鞘糖脂水平和/或GM1神经节苷脂水平。
在一些实施方案中,本发明的一种或多种化合物可以在体内提高GCase活性水平和/或GCase蛋白水平,并且可以有效地治疗需要或响应于GCase活性增强的病症。在一些实施方案中,本发明的一种或多种化合物可以在体内特异性地通过与GBA2的相互作用来提高GCase活性水平和/或GCase蛋白水平,并且可以有效地治疗需要或响应于GCase活性增强的病症。“升高(elevating)”或“增强(enhancing)”或“增加(increasing)”是指与参考样品或化合物相比,或与野生型或突变型GCase相比,增加约5%至约100%之间的任何值,例如约5%、10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或超过100%,或增加约1倍、2倍、5倍、10倍、15倍、25倍、50倍、100倍或更多。
在一些实施方案中,根据本发明的一种或多种化合物可以表现出增强的渗透性。可以使用多种标准实验技术评估渗透性,包括但不限于原位灌注、离体组织扩散、体外细胞单层(例如Caco-2细胞、MDCK细胞、LLC-PK1细胞)和人工细胞膜(例如PAMPA试验);用于测量有效渗透率(Peff)或表观渗透率(Papp)的合适技术例如由Volpe在AAPSJournal,2010,12(4),670-678中综述。在一些实施方案中,当在用于测定Peff或Papp的这些试验的一种或多种中测试时,根据本发明的化合物中的一种或多种可显示出增强的渗透性。在一些实施方案中,表现出增强的渗透性的化合物可表现出更大的口服吸收。在一些实施方案中,表现出增强的渗透性的化合物在体内施用时可表现出更大的脑外显率。在一些实施方案中,当在体内施用时,表现出增强的渗透性的化合物可以实现更高的脑浓度。在一些实施方案中,表现出增强的渗透性的化合物在体内施用时可表现出更高的脑/血浆浓度比。在一些实施方案中,“增强的渗透性(enhancedpermeability)”意指与合适的参考化合物诸如例如(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,miglustat)或(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)相比,测量的Peff或Papp增加约10%至约100%之间的任何值,或约10%至约100%之间的任何整数值,例如约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或超过100%,或增加约1倍、2倍、3倍或更多。在一些实施例中,“增强的渗透性(enhancedpermeability)”意指在使用体外细胞单层测量Papp的合适试验中的可测量的Papp值(即大于零的值)。在一些实施方案中,“增强的渗透性(enhancedpermeability)”意指在使用体外细胞单层测量Papp的合适试验中的Papp值大于2x 10-6cm/s。在替代实施方案中,“增强的渗透率(enhanced permeability)”意指在使用体外细胞单层测量Papp的合适测定法中的Papp值在2x10-6cm/s至40x 10-6cm/s范围内。在一些实施方案中,“更高的脑浓度(higherbrain concentration)”是指当所述化合物在体内施用时,与合适的参考化合物诸如,例如(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,miglustat)或(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)相比,测量的脑浓度增加约10%至约100%之间的任何值,或约10%至约100%之间的任何整数值,例如约10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或超过100%,或增加约1倍、2倍、3倍、4倍、5倍、10倍、20倍、30倍、40倍、或50倍、或更多。
“参考化合物”或“对照”可以是文献中描述的碳水化合物模拟亚氨基糖,其是GBA2抑制剂。作为GBA2抑制剂的参考化合物或对照的实例包括但不限于(2R,3R,4R,5S)-1-丁基-2-(羟甲基)哌啶-3,4,5-三醇(NB-DNJ,miglustat)、(2R,3R,4R,5S)-1-(5-((3R,5R,7R)-金刚烷-1-基甲氧基)戊基)-2-(羟甲基)哌啶-3,4,5-三醇(AMP-DNM,Genz-529648)。26
在一些实施方案中,本发明提供一般由式(I)描述的化合物,包括式(Ia)-(Iv)中的任何一种或多种,及其盐、前药和其对映异构体形式:
如式(I)所示:R1可以是H且R2可以是CH2OH;R1可以是CH2OH且R2可以是H;和
R3可以是(CH2)nR4,其中n是1或2,且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基,(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基,(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基,1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻唑-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基,3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基团上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3可以是 其中R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是当R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基或4-苯丁基;而且
条件是当R1是CH2OH且R2是H时,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
在一些实施例中,如式(I)所示,R1可以是H,且R2可以是CH2OH。在一些实施例中,R1可以是CH2OH,且R2可以是H。
在一些实施例中,如式(I)所示,R3可以是(CH2)nR4,其中n是1或2,且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基,1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或者R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或者R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3的一个或多个取代基取代一个至最大数量;或者R3可以是其中R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3的中的一个或多个取代基取代一个至最大数目,条件是当R1是H且R2是CH2OH,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;条件是当R1是CH2OH且R2是H,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
在一些实施例中,R3可以是(CH2)nR4,其中n是1或2,且R4可以是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基,(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基,(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基,1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目,条件是当R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基或4-苯丁基;条件是当R1是CH2OH且R2是H,则R3不是3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
在一些实施例中,R3可以是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉基、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目,条件是R3不是苯乙基。
在一些实施例中,R3可以是(1-甲酰基哌啶-4-基)甲基,在甲酰基团上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一种或多种取代基取代一个至最大数目。
在一些实施例中,R3可以是 其中,R5可以选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目。
在一些实施例中,R1可以是H;R2可以是CH2OH;R3可以是(CH2)nR4,其中n可以是1,且R4可以是环己基或1-苯基哌啶-4-基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目,条件是R3不是环己基甲基。
在一些实施例中,R1可以是CH2OH;R2可以是H;R3可以是(CH2)nR4,其中n可以是1,且R4可以是环己基或1-苯基哌啶-4-基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目。
在一些实施例中,R1可以是H;R2可以是CH2OH;和R3可以是(4,4-二甲基环己基)甲基、(4,4-二氟环己基)甲基、(4,4-二氯环己基)甲基、(4-乙基环己基)甲基、((1s,4S)-4-乙烯基环己基)甲基、((1s,4S)-4-异丙基环己基)甲基、(1r,4R)-4-异丙基环己基)甲基、(4-(叔丁基)环己基)甲基、((1s,4S)-4-(叔丁基)环己基)甲基、((1r,4R)-4-(叔丁基)环己基)甲基、((1s,4S)-4-(三氟甲基)环己基)甲基、((1r,4R)-4-(三氟甲基)环己基)甲基、((1s,4S)-4-(2-氟丙-2-基)环己基)甲基、((1r,4R)-4-(2-氟丙-2-基)环己基)甲基、((反式)-3-(三氟甲基)环己基)甲基、((顺式)-3-(三氟甲基)环己基)甲基、((1s,4S)-4-甲氧基环己基)甲基、((1r,4R)-4-甲氧基环己基)甲基、(4-(甲氧基甲基)环己基)甲基、((1s,4S)-4-环丙基环己基)甲基、((1r,4R)-4-环丙基环己基)甲基、(4-苯基环己基)甲基、(螺[2.5]辛-6-基)甲基、(螺[3.5]壬-7-基)甲基、(螺[4.5]癸-8-基)甲基、2-(4,4-二氟环己基)乙基、2-((1s,4S)-4-(三氟甲基)环己基)乙基、2-((1r,4R)-4-(三氟甲基)环己基)乙基、2-(金刚烷-1-基)乙基、2-甲基苯乙基、2-甲氧基苯乙基,2-氟苯乙基、2-氯苯乙基、2,3-二氟苯乙基,2,4-二氟苯乙基、2,5-二氟苯乙基、3,4-二氟苯乙基、2-氟-4-甲氧基苯乙基、3-氯-2-氟苯乙基、4-氯-2-氟苯乙基、5-氯-2-氟苯乙基、2,6-二氟苯乙基、3-氯-2,6-二氟苯乙基、2,6-二氟-4-(丙-1-烯-2-基)苯乙基、2,6-二氟-4-异丙基苯乙基、2,6-二氟-3-异丙基苯乙基、4-环丙基-2,6-二氟苯乙基、2,6-二氟-4-(三氟甲基)苯乙基、2-6-二氟-4-(吡咯烷-1-基)苯乙基、2,6-二氟-4-(哌啶-1-基)苯乙基、2,6-二氟-4-吗啉基苯乙基、4-丁氧基-2,6-二氟苯乙基、4-(环丙基甲氧基)-2,6-二氟苯乙基、4-((四氢呋喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-4-基)氧基)苯乙基、4-苯氧基苯乙基、4-((四氢呋喃-3-基)甲氧基)苯乙基、(R)-2-苯丙基、(S)-2-苯丙基、2-([1,1'-联苯基]-4-基]乙基、2-(3,5-二氟-[1,1'-联苯基]-4-基)乙基、2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基]乙基、2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基、2-(噻吩-2-基)乙基、2-(噻吩-3-基)乙基、2-(吡啶-2-基)乙基、3-(2-氟苯基)丙基、3-(4-氟苯基)丙基、3-(噻吩-2-基)丙基、3-(噻吩-3-基)丙基、(1-苯基哌啶-4-基)甲基、(1-(2-氟苯基)哌啶-4基)甲基,(1-(3-氟苯基)哌啶-4-基)甲基、(1-(4-氟苯基)哌啶4-基)甲基、(1-(4-(三氟甲基)苯基)哌啶-4-基)甲基、(4-甲基-1-苯基哌啶-4-基)甲基、(4-氟-1-苯基哌啶-4-基)甲基、2-(1-苯基哌啶-4基)乙基、(1-(2,2,2-三氟乙基)哌啶-4--基)甲基、(1-异丁酰基哌啶-4-基)甲基、(1-新戊酰基哌啶-4-基)甲基、(1-丁酰基哌啶-4-基)甲基、(1-(3-甲基丁酰基)哌啶-4-基)甲基、(1-(3,3-二甲基丁酰基)哌啶-4-基)甲基、(1-(2-环戊基乙酰基)哌啶-4-基)甲基、(1-(环丙烷羰基)哌啶-4-基)甲基、(1-(环丁烷羰基)哌啶-4-基)甲基、(1-环戊烷羰基)哌啶-4-基)甲基、(1-(环己烷羰基(哌啶)-4-基)甲基、(1-((1s,4s)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-((1r,4r)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-(4-甲氧基环己烷羰基)哌啶-4-基)甲基、(1-(4-(三氟甲基)环己烷羰基)哌啶-4-基)甲基、(1-苯甲酰基哌啶-4基)甲基、(1-(3-(三氟甲基)苯甲酰基)哌啶-4-基)甲基、(1-(2-苯乙酰基)哌啶-4-基)甲基、(1-(噻吩-3-羰基)吡啶-4-基)甲基、((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基、(1,2,3,4-四氢萘-2-基)甲基、(2,3-二氢-1H-茚-2-基)甲基、2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基、(1-(吡啶-3-基)哌啶-4-基)甲基、(1-(环己基甲酰胺基)哌啶-4-基)甲基、(1-(环己基甲硫酰胺基)哌啶-4-基)甲基、(1-((1S,2R)-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基、((R)-1-苯基吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、(R)-1-(2-氟苯基)吡咯烷-3-基)甲基、(R)-1-(3-氟苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基、(R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、(R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基、(S)-(1-(4-(三氟甲基)苯甲酰基)吡咯烷-3-基)甲基)、((R)-1-(邻甲苯基)哌啶-3-基)甲基、((R)-1-(2-氟苯基)哌啶-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、3-氟苯乙基、4-氟苯乙基、3,4-二氯苯乙基、3-(三氟甲基)苯乙基、4-(三氟甲基)苯乙基、((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基、4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基、((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基、((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、或((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基。
在一些实施例中,R1可以是CH2OH;R2可以是H;和R3可以是环己基甲基、(4,4-二甲基环己基)甲基、(4,4-二氟环己基)甲基、(4,4-二氯环己基)甲基、(4-乙基环己基)甲基、((1s,4S)-4-乙烯基环己基)甲基、((1s,4S)-4-异丙基环己基)甲基、(1r,4R)-4-异丙基环己基)甲基、(4-(叔丁基)环己基)甲基、((1s,4S)-4-(叔丁基)环己基)甲基、((1r,4R)-4-叔丁基)环己基)甲基、((1s,4S)-4-(三氟甲基)环己基)甲基、((1r,4R)-4-(三氟甲基)环己基)甲基、((1s,4S)-4-(2-氟丙-2-基)环己基)甲基,((1r,4R)-4-(2-氟丙-2-基)环己基)甲基、((反式)-3-(三氟甲基)环己基)甲基、((顺式)-3-(三氟甲基)环己基)甲基、((1s,4S)-4-甲氧基环己基)甲基、((1r,4R)-4-甲氧基环己基)甲基,(4-(甲氧甲基)环己基)甲基、((1s,4S)-4-环丙基环己基)甲基、((1r,4R)-4-环丙基环己基)甲基、(4-苯基环己基)甲基、(螺[2.5]辛-6-基)甲基、(螺[3.5]壬-7-基)甲基、(螺[4.5]癸-8-基)甲基、2-环己基乙基、2-(4,4-二氟环己基)乙基、2-((1s,4S)-4-(三氟甲基)环己基)乙基、2-((1r,4R)-4-(三氟甲基)环己基)乙基、2-(金刚烷-1-基)乙基、3-环己基丙基、2-甲基苯乙基、2-甲氧基苯乙基、2-氟苯乙基、2-氯苯乙基、2,3-二氟苯乙基、2,4-二氟苯乙基、2,5-二氟苯乙基、3,4-二氟苯乙基、2-氟-4-甲氧基苯乙基、3-氯-2-氟苯乙基、4-氯-2-氟苯乙基、5-氯-2-氯苯乙基、2,6-二氟苯乙基、3-氯-2,6-二氟苯乙基、2,6-二氟-4-(丙-1-烯-2-基)苯乙基、2,6-二氟-4-异丙基苯乙基、2,6-二氟-3-异丙基苯乙基、4-环丙基-2,6-二氟苯乙基、2,6-二氟-4-(三氟甲基)苯乙基、2-6-二氟-4-(吡咯烷-1-基)苯乙基、2,6-二氟-4-(哌啶-1-基)苯乙基、2,6-二氟-4-吗啉基苯乙基、4-丁氧基-2,6-二氟苯乙基、4-(环丙基甲氧基)-2,6-二氟苯乙基、4-((四氢呋喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-4-基)氧基)苯乙基、4-苯氧基苯乙基、4-((四氢呋喃-3-基)甲氧基)苯乙基、2-([1,1'-联苯基]-4-基]乙基、2-(3,5-二氟-[1,1'-联苯基]-4-基)乙基、2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基、2-(噻吩-2-基)乙基、2-(噻吩-3-基)乙基、2-(吡啶-2-基)乙基、3-(2-氟苯基)丙基、3-(4-氟苯基)丙基、3-(噻吩-2-基)丙基、3-(噻吩-3-基)丙基、(1-苯基哌啶-4-基)甲基、(1-(2-氟苯基)哌啶-4基)甲基、(1-(3-氟苯基)哌啶-4-基)甲基、(1-(4-氟苯)哌啶4-基)甲基、(1-(4-(三氟甲基)苯基)哌啶-4-基)甲基、(4-甲基-1-苯基哌啶-4-基)甲基、(4-氟-1-苯基哌啶-4-基)甲基、2-(1-苯基哌啶-4基)乙基、(1-(2,2,2-三氟乙基)哌啶-4-基)甲基、(1-异丁酰基哌啶-4-基)甲基、(1-新戊酰基哌啶-4-基)甲基、(1-丁酰基哌啶-4-基)甲基、(1-(3-甲基丁酰基)哌啶-4-基)甲基、(1-(3,3-二甲基丁酰基)哌啶-4-基)甲基、(1-(2-环戊基乙酰基)哌啶-4-基)甲基、(1-(环丙烷羰基)哌啶-4-基)甲基,(1-(环丁烷羰基)哌啶-4-基)甲基、(1-环戊烷羰基)哌啶-4-基)甲基、(1-(环己烷羰基)哌啶-4-基)甲基、(1-((1s,4s)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-((1r,4r)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-(4-甲氧基环己烷羰基)哌啶-4-基)甲基、(1-(4-(三氟甲基)环己烷羰基)哌啶-4-基)甲基、(1-苯甲酰基哌啶-4基)甲基,(1-(3-(三氟甲基)苯甲酰基)哌啶-4-基)甲基、(1-(2-苯乙酰基)哌啶-4-基)甲基、(1-(噻吩-3-羰基)吡啶-4-基)甲基、((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基、(1,2,3,4-四氢萘-2-基)甲基、(2,3-二氢-1H-茚-2-基)甲基、2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基、(1-(吡啶-3-基)哌啶-4-基)甲基、(1-环己基甲酰胺基)哌啶-4-基)甲基、(1-(环己基甲硫酰胺基)哌啶-4-基)甲基、(1-((1S,2R)-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基、((R)-1-苯基吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、(R)-1-(2-氟苯基)吡咯烷-3-基)甲基、(R)-1-(3-氟苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基、(R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基、(S)-(1-(4-(三氟甲基)苯甲酰基)吡咯烷-3-基)甲基)、((R)-1-(邻甲苯基)哌啶-3-基)甲基、((R)-1-(2-氟苯基)哌啶-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、3-氟苯乙基、4-氟苯乙基、3,4-二氯苯乙基、3-(三氟甲基)苯乙基、4-(三氟甲基)苯乙基、((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基、4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基、((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基、((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、4-丁氧基苯乙基、((1s,4R)-4-(二氟甲基)环己基)甲基、((1r,4S)-4-(二氟甲基)环己基)甲基、((1s,4R)-4-(1,1-二氟乙基)环己基)甲基、或((1r,4S)-4-(1,1-二氟乙基)环己基)甲基。
在一些实施例中,R1可以是H;R2可以是CH2OH;和R3可以是2-氟苯乙基、3-氟苯乙基、4-氟苯乙基、2,6-二氟苯乙基,3-(三氟甲基)苯乙基、4-(三氟乙基)苯乙基、(R)-2-苯丙基、(S)-2-苯丙基、2-(吡啶-2-基)乙基、2-(噻吩-2-基)乙基、或2-(噻吩-3-基)乙基。
在一些实施例中,R1可以是CH2OH;R2可以是OH;和R3可以是环己基甲基、((1r,4R)-4-(三氟甲基)环己基)甲基、((1s,4S)-4-(2-氟丙-2-基)环己基)甲基)、(2,3-二氢-1H-茚-2-基)甲基、2-环己基乙基、3-环己基丙基、2-氟苯乙基、3-氯-2-氟苯乙基、2-([1,1'-联苯基]-4-基)乙基、2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基、4-丁氧基苯乙基、4-丁氧基-2,6-二氟苯乙基、(1-(4-氟苯基)哌啶-4-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R-)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3基)甲基)、(R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、(1s,4R)-4-(二氟甲基)环己基)甲基、((1r,4S)-4-(二氟甲基)环己基)甲基、(1s,4R)-4-(1,1-二氟乙基)环己基)甲基、或((1r,4S)-4-(1,1-二氟乙基)环己基)甲基。
在本发明的具体实施方案中,根据式(I)的化合物包括表1中所述的化合物。
表1
如本领域技术人员所理解的,上述式(I)也可以替换表示如下:
在本发明的替代实施方案中,表2中的一种或多种化合物特别排除在式(I)或式(Ia)-(Iv)的任一种或多种中所述化合物之外。
表2
如本发明所用,单数形式“一个(a)”和“一个(an)”和“该(the)”包括复数指示物,除非上下文另有明确规定。例如,“化合物”是指一种或多种这样的化合物,而“酶”包括特定的酶以及本领域技术人员已知的其他家族成员等同物。
在整个本发明中,预期术语“化合物(compound)”或“化合物(compunds)”是指本发明讨论的化合物并且包括所述化合物的前体和衍生物,包括酰基保护的衍生物,以及所述化合物、前体和衍生物的药学上可接受的盐。本发明还包括所述化合物的前药、包含所述化合物和药学上可接受的载体的药物组合物、以及包含所述化合物的前药和药学上可接受的载体的药物组合物。
本发明的化合物可以含有一个或多个除式(I)中指定的那些以外的另外的不对称中心,包括式(Ia)-(Iv)中的任何一种或多种,并且因此可以作为单一对映异构体、非对映异构体混合物和单独的非对映异构体存在。取决于分子上各种取代基的性质,可以存在这样的另外的不对称中心。每个这样的另外的不对称中心将独立地产生两种光学异构体,并且意在将混合物中的所有此类可能的光学异构体和非对映异构体以及作为纯化或部分纯化的化合物包括在本发明的范围内。本说明书中描述的未指定另外的不对称中心的特定立体化学的化合物的任何式、结构或名称,意在涵盖如上所述的任何和所有现有异构体及其任何比例的混合物。当指定另外的不对称中心的立体化学时,本发明意在涵盖呈纯形式或作为与其它异构体任何比例混合物的一部分的特定异构体。
“烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,不含不饱和键并且包括,例如,1-10个碳原子,如1、2、3、4、5、6、7、8、9、或10个碳原子,并且其通过单键与分子的其余部分连接。在替代实施方案中,烷基可以含有1至8个碳原子,例如1、2、3、4、5、6、7或8个碳原子。在替代实施方案中,烷基可以含有1至6个碳原子,例如1、2、3、4、5、或6个碳原子。在替代实施方案中,烷基可以含有1至5个碳原子,例如1、2、3、4、或5个碳原子。除非在说明书中另有具体说明,否则烷基可以任选地被如本发明所述的一个或多个取代基取代。除非本发明另有具体说明,否则应当理解,取代可以发生在烷基的任何碳上。
“环烷基”是指仅由碳和氢原子组成的稳定的单价单环、双环或三环烃基,其具有例如3-15个碳原子,并且其是饱和的并且通过单键与分子的其余部分连接。在替代实施方案中,环烷基可以含有3至6个碳原子,例如3、4、5、或6个碳原子。除非本文另有具体说明,否则术语“环烷基”意指包括如本发明所述的任选地被取代的环烷基。
“烷氧基”是指式-ORa的基团,其中每个Ra独立地为本发明所述的C1-10烷基或C1-6烷基或C1-5烷基。烷氧基可以如本发明所述任选地被取代。
“任选的”或“任选地”是指随后描述的情况的事件可能发生或可能不发生,并且该描述包括事件或情况发生一次或多次和不发生的例子。例如,“任选取代的烷基”是指烷基可以被取代或可以不被取代,并且该描述包括取代的烷基和不取代的烷基,并且烷基可以被取代一次或多次。任选地取代的烷基的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基等。合适的任选的取代基的实例包括但不限于H、F、Cl、CH3、OH、OCH3、CF3、CHF2、CH2F、和CN。
治疗适应症
本发明部分地提供了治疗由GBA2酶或GBA2活性水平直接或间接调节的病症的方法,例如,通过抑制GBA2酶或通过降低GBA2酶活性水平而受益的病症。此类病症可包括但不限于神经疾病,诸如阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病和肌萎缩性侧索硬化(ALS),以及溶酶体贮积病,诸如戈谢病、C型尼曼-匹克病、IV型粘脂贮积症和桑德霍夫病,以及肝病,诸如非酒精性脂肪性肝炎(NASH)。因此,本发明的一种或多种化合物可用于治疗处于发展风险中或已经诊断患有各种神经疾病或其他疾病的受试者。如本文所用的术语“治疗”可包括治疗、预防和/或改善。
在替换实施方案中,本发明的一种或多种化合物还可用于治疗与GBA2的缺乏或过度表达或葡糖神经酰胺的积累或消耗有关的疾病或病症,或对糖苷酶抑制剂疗法或糖苷酶抑制疗法有反应的任何疾病或病症。此类疾病和病症可包括,但不限于神经疾病,诸如阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、和肌萎缩性侧索硬化(ALS),以及溶酶体贮积病,诸如戈谢病、C型尼曼-匹克病、IV型粘脂贮积症、和桑德霍夫病,以及肝病,诸如非酒精性脂肪性肝炎(NASH)。此类疾病和病症还可包括与酶葡糖神经酰胺合酶的积累或缺乏、或鞘糖脂代谢和/或平衡的失调相关的疾病或病症。还包括保护或治疗表达GBA2的靶细胞的方法,其失调可导致疾病或病理。
在替代实施方案中,本发明提供了降低动物受试者如兽(veterinary)和人受试者中GBA2酶活性水平的方法。GBA2活性水平的这种降低可用于预防或治疗神经或神经变性疾病(例如阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、和肌萎缩性侧索硬化(ALS));提供神经保护作用;防止对多巴胺能神经元的损伤;和预防或治疗溶酶体贮积病(例如戈谢病、C型尼曼-匹克病、IV型粘脂贮积症、和桑德霍夫病);以及预防或治疗肝病(例如非酒精性脂肪性肝炎(NASH))。
在替代实施方案中,本发明提供了在动物受试者,例如兽和人受试者中抑制GBA2酶的方法。
在替代实施方案中,本发明提供了在动物受试者如兽和人受试者中减轻CNS炎症的方法。感兴趣的疾病状态可以包括神经变性疾病,例如阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、和肌萎缩性侧索硬化(ALS),其中神经炎症涉及疾病发病机制。在一些实施方案中,根据本发明的化合物可用于通过降低GBA2酶活性水平来预防、治疗或改善神经炎症,从而提供治疗益处。
在替代实施方案中,本发明提供了在动物受试者如兽和人受试者中抑制α-突触核蛋白聚集、或抑制路易体形成的方法。感兴趣的疾病状态可包括帕金森病(PD)和相关的神经变性突触核蛋白病,其中α-突触核蛋白的异常聚集与疾病发病机理有关。在一些实施方案中,根据本发明的化合物可用于通过降低GBA2酶活性水平来阻断α-突触核蛋白的聚集,从而提供治疗益处。
可用本发明化合物治疗的神经疾病可以包括,但不限于:阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、肌萎缩性侧索硬化(ALS)、伴有认知损伤的肌萎缩性侧索硬化(ALSci)、成瘾、焦虑、嗜银颗粒性痴呆、共济失调-毛细血管扩张症(A-T)、注意力缺陷/多动障碍(ADHD)、自闭症谱系障碍(ASD)、贝克肌营养不良(BMD)、双相障碍(BD)、布卢特病、小脑性共济失调、腓骨肌萎缩症(CMT)、慢性疲劳综合征、皮质基底节变性(CBD)、拳击手痴呆、路易体痴呆(DLB)、德热里纳-索塔斯病、弥漫性神经原纤维缠结伴钙化症、唐氏综合征、杜兴肌营养不良(DMD)、癫痫、特发性震颤(ET)、家族性英国型痴呆、家族性丹麦型痴呆、纤维肌痛、连锁于17号染色体伴帕金森病的额颞叶痴呆(FTDP-17)、弗里德赖希共济失调、格斯特曼-施特劳斯钠病、青光眼、瓜地洛帕帕金森综合征、格林-巴利综合征、哈勒沃登-施帕茨病(神经变性伴脑铁积聚1型)、失眠、兰伯特-伊顿肌无力综合征(LEMS)、重度抑郁症(MDD)、偏头痛、轻度认知障碍(MCI)、多发性脑梗死性痴呆、多系统萎缩(MSA)、重症肌无力、肌强直性营养不良(包括DM1和DM2型)、神经元蜡样脂褐质沉积症(包括1、2、3、4、5、6、7、8、9和10型)、神经病(包括周围神经病变、自主神经病变、神经炎、和糖尿病神经病变)、眼咽型肌营养不良、疼痛、苍白球脑桥黑质变性、关岛型帕金森综合征-痴呆复合征、皮克氏病(PiD)、脑炎后帕金森综合征(PEP)、原发性侧索硬化(PLS)、朊病毒病(包括克雅氏病(CJD)、变异型克雅氏病(vCJD)、致命性家族性失眠、和库鲁病)、进行性皮质下神经胶质增生、进行性核上性麻痹(PSP)、理查森综合征、精神分裂症、癫痫发作、脊髓损伤、脊髓性肌萎缩(SMA)、脊髓小脑性共济失调(包括1、2、3、4、5、6、7、8、10、11、12、13、14、16、17、18、19、20、21、22、23、25、26、27、28和29型)、中风、亚急性硬化性全脑炎、缠结性痴呆、迟发性运动障碍、抽动秽语综合征(TS)、血管性痴呆、和威尔逊病。
可用本发明的化合物治疗的溶酶体贮积病可包括,但不限于:戈谢病(包括I、II、和III型)、尼曼-匹克病(包括A、B、和C型)、粘脂贮积症(包括I、II、III、IV、VI、和VII型)、脑腱性黄瘤症、法布里病、法伯病、GM1神经节苷脂贮积病、克拉伯病、异染性脑白质营养不良(MLD)、多发性硫酸酯酶缺乏症、庞贝病、桑德霍夫病、或泰萨二氏病。
可用本发明化合物治疗的肝病可包括,但不限于:非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、阿拉杰里综合征(Alagille syndrome)、酒精相关性肝病、α-1抗胰蛋白酶缺乏症、自身免疫性肝炎、自身免疫性胆管炎、良性肝肿瘤、胆道闭锁、肝硬化、克里格勒-纳贾尔综合征、药物诱导的肝损伤(DILI)、半乳糖血症、吉尔伯特综合征、血色素沉着症、肝性脑病、肝细胞癌(HCC)、妊娠肝内胆汁淤积症(ICP)、溶酶体酸性脂肪酶缺乏症(LAL-D)、肝囊肿、肝癌、新生儿黄疸、原发性胆汁性胆管炎(PBC)、原发性硬化性胆管炎(PSC)、瑞氏综合征、I型糖原贮积病、或病毒性肝炎(包括A、B、C、D和E型)。
在一些实施方案中,根据本发明的化合物可用于治疗其中涉及GBA2酶活性水平调节的疾病,或本发明所述的任何病症。
可以使用一种或多种根据本发明的化合物治疗的其它病症是与GBA2酶活性水平相关的触发、影响或以任何其它方式的那些病症。预期本发明的一种或多种化合物可用于治疗此类病症并且特别,但不限于帕金森病、神经元蜡样脂褐质沉积症(巴顿病)、戈谢病、C型尼曼-匹克病、IV型粘脂贮积症、和桑德霍夫病。
药物和兽药组合物、剂量和给药
包括根据本发明的化合物或根据本发明使用的药物组合物被认为在本发明的范围内。在一些实施方案中,提供了药物组合物,其包含有效量的式(I)化合物,包括式(Ia)-(Iv)中的任何一种或多种。
式(I)化合物,包括式(Ia)-(Iv)中的任何一种或多种,及其药学上可接受的盐、对映异构体、溶剂化物或衍生物可能是有用的,因为它们可能在动物包括人中具有药理学活性。在一些实施方案中,当施用于受试者例如人时,根据本发明的一种或多种化合物在血浆中可以是稳定的。
通常,根据本发明的化合物可以施用于有需要的受试者,或者通过使细胞或样品,例如,与包含治疗有效量的根据式(I)的化合物包括式(Ia)-(Iv)中的任何一种或多种的药物组合物接触。
在一些实施方案中,根据本发明、或根据本发明使用的化合物可以与任何其它活性剂或药物组合物组合提供,其中此类组合疗法可用于抑制GBA2活性水平,例如,以治疗神经疾病、或溶酶体贮积病、或肝病、或本发明所述的任何病症。在一些实施方案中,根据本发明、或根据本发明使用的化合物,可以与一种或多种可用于预防或治疗帕金森病的药剂组合提供。此类药剂的实例可包括,但不限于:
·左旋多巴(L-DOPA);
·多巴胺拮抗剂,如溴隐亭培高利特普拉克索罗匹尼罗 吡贝地尔 卡麦角林阿朴吗啡 罗替戈汀(AY-27,110)、(DAR-0100)、表隐亭(β-二氢麦角隐亭),N-正丙基去甲阿朴吗啡(NPA),喹高利特(EMD-49,980)、(PNU-95,666)、帕多芦诺、阿普林多等;
·腺苷A2A受体拮抗剂,例如伊曲茶碱(KW-6002)、普拉登南(preladenant)、非帕美唑(fipamezole)(JP-1730)、SCH-420814、BIIA-014、LuAA4707等;
·代谢型谷氨酸受体5(mgluR5)调节剂,如地派谷兰(dipraglurant)等;
·烟碱乙酰胆碱受体(nAChR)激动剂,如烟碱,ABT-418、WAY-317、538(SEN-12333)、EVP-6124、MEM 3454、奈非西坦等;
·乙酰胆碱酯酶抑制剂(AChEIs),如(多奈哌齐)、(利凡斯的明)、(Razadyne加兰他敏)、(他克林)、石杉碱甲、苯丝氨酸、Debio-9902SR(ZT-1SR)、扎那哌齐(TAK0147)、更斯的明、NP7557等;
·非典型抗精神病药,如氯氮平等;或
应当理解,根据本发明、或根据本发明使用的化合物与可用于治疗帕金森病的药剂的组合不限于本发明所述的实例,而是可以包括与可用于治疗帕金森病的任何药剂的组合。根据本发明、或根据本发明使用的化合物与可用于治疗帕金森病的其他药剂的组合可以单独或联合施用。一种药剂的施用可以在其他药剂的施用之前、同时或之后。
在一些实施方案中,根据本发明、或用于根据本发明使用的化合物可以与一种或多种用于预防或治疗戈谢病的药剂组合提供。这些试剂的实例可以包括,但不限于:
·抗癫痫药,如(卡马西平)、(乙琥胺)、(非氨酯)、(替加宾)、(左乙拉西坦)、(拉莫三嗪)、(普瑞巴林)、(加巴喷丁)、(苯妥英)、(托吡酯)、(奥卡西平)、(丙戊酸盐、丙戊酸)、(唑尼沙胺)、(地西泮)、(劳拉西泮)(氯硝西泮)、(吡仑帕奈)、Oxtellar(奥卡西平)等;或
·基因治疗。
应当理解,根据本发明、或根据本发明使用的化合物与可用于治疗戈谢病的药剂的组合不限于本发明所述的实例,而是可以包括与可用于治疗戈谢病的任何药剂的组合。根据本发明、或根据本发明使用的化合物与可用于治疗戈谢病的其他药剂的组合可以单独或联合施用。一种药剂的施用可以在其他药剂的施用之前、同时或之后。
在替代实施方案中,根据本发明的化合物可以作为“前药”或作为受保护形式提供,其在施用于受试者后释放化合物。例如,化合物可以携带保护基团,所述保护基团在体液中例如在血流中通过水解而分裂,从而释放活性化合物或者在体液中被氧化或还原以释放化合物。相应地,“前药”意指可以在生理条件下或通过溶剂分解转化为本发明的生物活性化合物的化合物。因此,术语“前药”是指药学上可接受的本发明化合物的代谢前体。当施用于有需要的受试者时,前药可以是无活性的,但可以在体内转化为本发明的活性化合物。前药通常在体内快速转化以产生本发明的母体化合物,例如,通过在血液中水解。前药化合物经常在受试者中提供可溶性、组织相容性或延迟释放的优点。
术语“前药”还意指包括任何共价结合的载体,所述载体在将这种前药施用于受试者时在体内释放本发明的活性化合物。本发明化合物的前药可以通过修饰存在于本发明化合物中的官能团来制备,采用在常规操作中或在体内裂解成本发明的母体化合物的修饰方法。前药包括其中羟基、氨基或巯基与任何基团连接的本发明化合物,当将本发明化合物的前药施用于哺乳动物受试者时,所述化合物分别裂解形成游离羟基、游离氨基或游离巯基。前药的实例包括,但不限于本发明的一种或多种化合物中的醇官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物和胺官能团的乙酰胺、甲酰胺和苯甲酰胺衍生物等。
前药的讨论可以在下述文献中找到,“Smith andWilliams’Introduction to thePrinciples of Drug Design,”H.J.Smith,Wright,Second Edition,London(1988);Bundgard,H.,Design of Prodrugs(1985),pp.7-9,21-24(Elsevier,Amsterdam);ThePractice ofMedicinal Chemistry,Camille G.Wermuth et al.,Ch 31,(AcademicPress,1996);A Textbook of Drug Design and Development,P.Krogsgaard-Larson andH.Bundgaard,eds.Ch 5,pgs 113191(Harwood Academic Publishers,1991);Higuchi,T.,et al.,"Pro-drugs as Novel Delivery Systems,"A.C.S.Symposium Series,Vol.14;或在Bioreversible Carriers in Drug Design,ed.Edward B.Roche,AmericanPharmaceutical Association and Pergamon Press,1987。
本发明的一种或多种化合物的合适的前药形式可以包括这样的实施方案,其中如式(I)所示的一个或多个OH基团,包括式(Ia)-(Iv)中的任何一种或多种,可以被保护为OC(O)R,其中R可以任选被C1-6烷基取代。在这些情况下,酯基可以在体内(例如在体液中)水解,释放OH基团并释放活性化合物。本发明优选的前药实施方案可包括式(I)化合物,包括式(Ia)-(Iv)中的任何一种或多种,其中一个或多个OH基团可用乙酸酯保护,例如OC(O)CH3。
根据本发明、或根据本发明使用的化合物,可以单独提供或在脂质体、纳米颗粒、佐剂或任何药学上可接受的载体、稀释剂或赋形剂的存在下与其它化合物组合提供,以适于施用于受试者(例如哺乳动物,例如人、牛、绵羊等)的形式。如果需要,用根据本发明的化合物的治疗可以与用于本发明所述的治疗适应症的更传统和现有的疗法组合。根据本发明的化合物可以长期或间歇地提供。“长期(chronic)”施用是指以与急性模式相反的连续模式施用化合物,以便在延长的时间段内维持初始治疗效果(活性)。“间歇性”施用不是不间断地连续进行的治疗,而是本质上是循环的。这些术语如本发明所用的“施用(administration)”、“可施用(administrable)”或“施用(administering)”应理解为意指向需要治疗的受试者提供本发明的化合物。
“药学上可接受的载体、稀释剂或赋形剂”可包括,但不限于,任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂,其已被例如美国食品和药物管理局或其它政府机构批准可用于人或家畜。
本发明的化合物可以以药学上可接受的盐的形式给药。在这种情况下,根据本发明的药物组合物可以包含这种化合物的盐,优选生理学上可接受的盐,其是本领域已知的。在一些实施方案中,如本发明所用的术语“药学上可接受的盐”是指包含以其盐形式使用的包括式(Ia)-(Iv)中的任何一种或多种的式I化合物的活性成分,特别是其中与活性成分的游离形式或其他先前公开的盐形式相比,盐形式赋予活性成分改善的药代动力学性质。
“药学上可接受的盐”可包括酸加成盐和碱加成盐。“药学上可接受的酸加成盐”是指保留不是生物学上或其他不期望的游离碱的生物有效性和性质的那些盐,并且可以与无机酸(例如盐酸、氢溴酸、硫酸、硝酸、磷酸等)和有机酸(例如乙酸、三氟乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等)形成。
“药学上可接受的碱加成盐”是指可以保留不是生物学上或其他不期望的游离酸的生物有效性和性质的那些盐。这些盐可以通过向游离酸中加入无机碱或有机碱来制备。衍生自无机碱的盐可包括,但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐可以是铵、钠、钾、钙和镁盐。衍生自有机碱的盐可包括,但不限于伯胺、仲胺和叔胺,取代的胺包括天然存在的取代的胺、环胺和碱性离子交换树脂,例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机碱可以是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。
因此,术语“药学上可接受的盐”包括所有可接受的盐,包括但不限于乙酸盐、乳糖醛酸盐、苯磺酸盐、月桂酸盐、苯甲酸盐、苹果酸盐、碳酸氢盐、马来酸盐、硫酸氢盐、扁桃酸盐、酒石酸氢盐、甲磺酸盐、硼酸盐、甲基溴化物、溴化物、甲基亚硝酸盐、乙二胺四乙酸钙、甲基硫酸盐、樟脑磺酸盐、粘酸盐、碳酸盐、萘磺酸盐、氯化物、硝酸盐、克拉维酸盐、N-甲基葡糖胺、柠檬酸盐、铵盐、二盐酸盐、油酸盐、乙二胺四乙酸盐、草酸盐、乙二磺酸盐、双羟萘酸盐(pamoate)(双羟萘酸盐(embonate))、依托酸盐、棕榈酸盐、乙磺酸盐、泛酸盐、富马酸盐、磷酸盐/二磷酸盐、葡庚糖酸盐、聚半乳糖醛酸盐、葡糖酸盐、水杨酸盐、谷氨酰胺、硬脂酸盐、甘氨酰苯磺酸盐、硫酸盐、己基间苯二甲酸盐、次乙酸盐、羟基胺、琥珀酸盐、氢溴酸盐、鞣酸盐、盐酸盐、酒石酸盐、羟基萘甲酸盐、氯茶碱盐、碘化物、甲苯磺酸盐、异硫酸盐、三硫代盐酸盐、乳酸盐、泛酸盐、戊酸盐等。
本发明化合物的药学上可接受的盐可以用作改变溶解度或水解特性的剂量,或者可以用于缓释或前药制剂中。此外,本发明化合物的药学上可接受的盐可包括由阳离子(例如钠、钾、铝、钙、锂、镁、锌)和由碱(例如氨、乙二胺、N-甲基-谷氨酰胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟甲基)甲胺和四甲基氢氧化铵)形成的盐。
药物制剂通常可以包括一种或多种制剂给药方式(mode of administration)可接受的载体,所述给药方式可以是注射、吸入、局部给药、灌洗或适合于所选治疗的其他模式。合适的载体可以是本领域已知的用于此类给药方式的那些。
合适的药物组合物可以通过本领域已知的方法配制,并且它们的给药方式和剂量由技术人员确定。对于肠胃外给药,可以将化合物溶解于无菌水或盐水或用于非水溶性化合物的给药的药学上可接受的载体中,例如用于维生素K的那些。对于肠内给药,化合物可以片剂、胶囊或溶解在液体形式中给药。片剂或胶囊可以是肠溶包衣的,或在缓释制剂中。许多合适的制剂是已知的,包括包封待释放的化合物的聚合物或蛋白质微粒、软膏、凝胶、水凝胶或溶液,其可以局部(topically)或局部(locally)施用化合物。可以使用缓释贴剂或植入物以提供在延长的时间段内的释放。本领域技术人员已知的许多技术描述于Remington:The Science&Practice ofPharmacy by Alfonso Gennaro,20th ed.,Williams&Wilkins,(2000)。用于肠胃外施用的制剂可以,例如,含有赋形剂、聚亚烷基二醇如聚乙二醇、植物来源的油或氢化萘。生物相容的、生物可降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用于控制化合物的释放。用于调节化合物的其他潜在有用的肠胃外递送系统可包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入输注系统和脂质体。用于吸入的制剂可以含有赋形剂,例如乳糖,或者可以是含有例如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水溶液,或者可以是用于以滴鼻剂形式或作为凝胶施用的油性溶液。
根据本发明的化合物或药物组合物可以通过口服或非口服给药,例如肌内、腹膜内、静脉内、脑池内注射或输注、皮下注射、透皮或透粘膜途径。在一些实施方案中,根据本发明或本发明使用的化合物或药物组合物可以通过医疗装置或器具如植入物、移植物、假体、支架等方式给药。可以设计植入物,其旨在包含和释放这些化合物或组合物。一个实例是由适于在一段时间内释放化合物的聚合物材料制成的植入物。化合物可以单独施用或作为与药学上可接受的载体的混合物给药,例如固体制剂如片剂、胶囊、颗粒、粉末等;液体制剂如糖浆、注射剂等;注射剂、滴剂、栓剂、阴道栓剂。在一些实施方案中,根据本发明或本发明使用的化合物或药物组合物可以通过吸入喷雾、鼻、阴道、直肠、舌下或局部途径给药,并且可以单独或一起配制为合适的剂量单位制剂,其含有适合于每种给药途径的常规无毒药学上可接受的载体、佐剂和媒介物。
本发明的化合物可用于治疗动物,包括小鼠、大鼠、马、牛、绵羊、狗、猫和猴。然而,本发明的化合物也可用于其他生物体,例如鸟类物种(例如鸡)。本发明的一种或多种化合物也可有效用于人类。术语“受试者”或在本文中可替代地认为“患者”旨在指已经成为治疗、观察或实验对象的动物,优选哺乳动物,最优选人。然而,本发明的一种或多种化合物、方法和药物组合物可用于治疗动物。相应地,如本发明所用,“受试者”可以是人、非人灵长类动物、大鼠、小鼠、牛、马、猪、绵羊、山羊、狗、猫等。受试者可能疑似患有可能需要抑制GBA2活性的病症或处于患有可能需要抑制GBA2活性的病症的风险中。
根据本发明的化合物的“有效量”可以包括治疗有效量或预防有效量。“治疗有效量”是指在必要的剂量和时间段内实现所需治疗结果的有效量,所述治疗结果例如抑制GBA2、降低GBA2酶活性水平、抑制α-突触核蛋白聚集或本发明所述的任何病症。化合物的治疗有效量可以根据诸如个体的疾病状态、年龄、性别和体重以及化合物在个体中引发期望反应的能力等因素而变化。可以调整剂量方案以提供最佳治疗反应。治疗有效量也可以是治疗有益效果超过化合物的任何毒性或有害作用的量。“预防有效量”可以指在必要的剂量和时间段内实现所需预防结果的有效量,所述预防结果例如抑制GBA2、降低GBA2酶活性水平、抑制α-突触核蛋白聚集或本发明所述的任何病症。通常,预防剂量可以在疾病之前或在疾病的早期阶段用于受试者,使得预防有效量可以小于治疗有效量。化合物的治疗或预防有效量的合适范围可以是0.1nM-0.1M、0.1nM-0.05M、0.05nM-15μM或0.01nM-10μM的任何整数。
在可选择的实施方案中,在可能需要抑制GBA 2活性的病症的治疗或预防中,合适的剂量水平通常可以是约0.01-500mg/kg受试者体重/天,并且可以以单剂量或多剂量施用。在一些实施方案中,剂量水平可以是每天约0.1至约250mg/kg/天。应当理解,任何特定患者的具体剂量水平和给药频率可以变化,并且可以取决于多种因素,包括所用特定化合物的活性、该化合物的代谢稳定性和作用时间、年龄、体重、一般健康状况、性别、饮食、给药方式和时间、排泄速率、药物组合、特定病症的严重程度和正在接受治疗的患者。
应注意,剂量值可随待缓解病症的严重程度而变化。对于任何特定受试者,可以根据个体需要和管理或监督组合物给药的人的专业判断随时间调整特定剂量方案。本发明所述的剂量范围仅是示例性的,并不限制可由医疗从业者选择的剂量范围。组合物中活性化合物的量可以根据诸如受试者的疾病状态、年龄、性别和体重等因素而变化。可以调整剂量方案以提供最佳治疗反应。例如,可以施用单次推注,可以随时间施用几个分开的剂量,或者可以根据治疗情况的紧急程度按比例减少或增加剂量。以剂量单位形式配制肠胃外组合物可能是有利的,以便于施用和剂量的均匀性。通常,本发明的化合物应当在不引起实质性毒性的情况下使用,并且如本发明所述,一种或多种化合物可以表现出用于治疗用途的合适的安全性特征。本发明化合物的毒性可以使用标准技术确定,例如通过在细胞培养物或实验动物中测试并确定治疗指数,即LD50(对群体的50%致死的剂量)与LD100(对群体的100%致死的剂量)之间的比率。然而,在一些情况下,例如在严重的疾病状况下,可能需要施用大量过量的组合物。
在通式(I)的化合物中,包括通式(Ia)-(Iv)中的任何一种或多种,原子可以表现出它们的天然同位素丰度,或者一个或多个原子可以人工富集具有相同原子序数但原子质量或质量数不同于自然界中主要发现的原子质量或质量数的特定同位素。本发明旨在包括通式(I)所示的化合物的所有合适的同位素变体,包括式(Ia)-(Ik)中的任何一个或多个。例如,氢(H)的不同同位素形式包括氕(1H),氘(2H)和氚(3H)。氕是自然界中发现的主要氢同位素。富集氘可以提供某些治疗优势,例如增加体内半衰期或减少剂量需求,或者可以提供可用作表征生物样品的标准品的化合物。通式(I)内的同位素-富集的化合物,包括式(Ia)-(Iv)中的任何一种或多种,可以通过本领域技术人员熟知的常规技术或通过与本发明方案和实施例中描述的那些类似的过程,使用适当的同位素富集的试剂和/或中间体来制备。
其他用途
在替代实施方案中,本发明的一种或多种化合物可用于研究GBA2在细胞和生物体水平的生理作用。在一些实施方案中,一种或多种化合物可用于开发动物模型用于研究可能与GBA2的缺陷、GBA2的过表达、葡糖神经酰胺的积累、葡糖神经酰胺的消耗、鞘糖脂的积累、鞘糖脂的消耗有关的疾病或病症,以及用于研究可能与GBA2的缺陷或过表达、或葡糖神经酰胺的积累或消耗、或鞘糖脂的积累或消耗有关的疾病和病症的治疗。此类疾病和病症可包括,但不限于神经疾病,包括阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、肌萎缩性侧索硬化(ALS)和神经元蜡样脂褐质沉积症(巴顿病);溶酶体贮积病,包括戈谢病、C型尼曼-匹克病、IV型粘脂贮积症和桑德霍夫病;或肝病,包括非酒精性脂肪性肝炎(NASH)。
化合物在治疗与溶酶体贮积病(例如戈谢病、C型尼曼-皮克病、IV型粘脂贮积症或桑德霍夫病)相关的病理学治疗中的有效性可以使用标准技术来证实,例如通过在已建立的细胞和/或转基因动物疾病模型中测试化合物预防、治疗或改善疾病症状的能力。13,14,16,17,27
本文描述了本发明的各种替代实施方案和实施例。这些实施方案和实施例是说明性的,并且不应被解释为限制本发明的范围。
实施例
以下示例旨在说明本发明的实施例,不旨在以限制性方式进行解释。
缩写
DCM=二氯甲烷
DIPEA=二异丙基乙胺
DMA=二甲基乙酰胺
DMF=N,N-二甲基甲酰胺
EtOH=乙醇
HOAc=乙酸
MeOH=甲醇
RT=室温
TFA=2,2,2-三氟乙酸
实施例1
(2R,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(100mg,0.19mmol)和1-(2-溴乙基)-2-氟苯(194mg,0.95mmol)的DMF(5mL)溶液中加入K2CO3(210mg,1.52mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中,并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2-氟苯乙基)哌啶,为白色固体(63mg,51%)。ESI MS m/z 646.32[M+H]+。
向上述物质(63mg,0.098mmol)的EtOH(10mL)溶液中加入Pd(OH)2/C(20wt.%,8.6mg,0.012mmol)和6N HCl(0.1mL)。将混合物用氢气(1atm)处理18h。通过硅藻土过滤除去催化剂,并且在减压下蒸发溶剂。将残余物溶于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2R,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(21mg,75%)。1HNMR(400MHz,CD3OD)δ7.29(td,J=7.6,1.8Hz,1H),7.23(tdd,J=7.4,5.2,1.8Hz,1H),7.10(td,J=7.5,1.2Hz,1H),7.05(ddd,J=9.7,8.2,1.2Hz,1H),3.96(dd,J=11.9,2.5Hz,1H),3.88(dd,J=11.9,3.1Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.37(t,J=12Hz,1H),3.18(t,J=9.0Hz,1H),3.09(dd,J=11.1,4.9Hz,1H),3.05-2.81(m,4H),2.43(t,J=
10.8Hz,1H),2.30(dt,J=9.5,2.9Hz,1H);ESI MS m/z 286.14[M+H]+。
实施例2
(2R,3R,4R,5S)-1-(3-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(100mg,0.19mmol)和1-(2-溴乙基)-3-氟苯(194mg,0.95mmol)的DMF(5mL)溶液中加入K2CO3(210mg,1.52mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(3-氟苯乙基)哌啶,为白色固体(71mg,58%)。ESI MS m/z 646.32[M+H]+。
向上述物质(71mg,0.11mmol)的EtOH(10mL)溶液中加入Pd(OH)2/C(20wt.%,8.6mg,0.012mmol)和6N HCl(0.1mL)。将混合物用氢气(1atm)处理18h。通过硅藻土过滤除去催化剂并在减压下蒸发溶剂。将残余物溶于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2R,3R,4R,5S)-1-(3-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(22mg,70%)。1H NMR(400MHz,CD3OD)δ7.29(td,J=7.9,6.1Hz,1H),7.05(dt,J=7.6,1.2Hz,1H),7.00(dt,J=10.1,2.1Hz,1H),6.95-6.87(m,1H),3.96(dd,J=12.0,2.5Hz,1H),3.86(dd,J=12.0,3.2Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.34(t,J=12Hz,1H),3.18(t,J=9.0Hz,1H),3.09(dd,J=11.2,4.9Hz,1H),3.05-2.74(m,4H),2.38(t,J=10.8Hz,1H),2.29(dt,J=9.5,2.9Hz,1H);ESIMS m/z 286.14[M+H]+.
实施例3
(2R,3R,4R,5S)-1-(4-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(100mg,0.19mmol)和1-(2-溴乙基)-4-氟苯(194mg,0.95mmol)的DMF(5mL)溶液中加入K2CO3(210mg,1.52mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中,并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(4-氟苯乙基)哌啶,为白色固体(70mg,57%)。ESI MS m/z 646.32[M+H]+。
向上述物质(70mg,0.11mmol)的EtOH(10mL)溶液中加入Pd(OH)2/C(20wt.%,8.6mg,0.012mmol)和6N HCl(0.1mL)。将混合物用氢气(1atm)处理18h。通过硅藻土过滤除去催化剂,在减压下蒸发溶剂。将残余物溶于1M NH3的MeOH(10mL)中,并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2R,3R,4R,5S)-1-(4-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(16mg,51%)。1H NMR(400MHz,CD3OD)δ7.29-7.19(m,2H),7.05-6.97(m,2H),3.95(dd,J=11.9,2.5Hz,1H),3.85(dd,J=11.9,3.1Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.34(t,J=12Hz,1H),3.17(t,J=9.0Hz,1H),3.09(dd,J=11.1,4.9Hz,1H),3.05-2.72(m,4H),2.37(t,J=10.8Hz,1H),2.28(dt,J=9.5,2.9Hz,1H);ESI MS m/z 286.14[M+H]+。
实施例4
(2R,3R,4R,5S)-1-(2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
将密封管中的(2R,3R,4R,5S)-3,4,5三(苄氧基)-2-((苄氧基)甲基)哌啶(0.30g,0.57mmol)、2-(2-溴乙基)-1,3-二氟苯(0.40g,1.8mmol)和DIPEA(0.35g,2.7mmol)的无水DMF(5mL)混合物在85℃下搅拌16h。将反应混合物冷却至室温并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(3×20mL)萃取后,将合并的萃取物用盐水(2×30mL)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:6至1:3)纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2,6-二氟苯乙基)哌啶,为淡黄色油状物(0.10g,26%)。ESI MS m/z 664.364[M+H]+。
在-78℃和N2下,向上述物质(0.10g,0.15mmol)的无水DCM(3mL)溶液中加入BCl3(在DCM中的浓度为1.0M,1.5mL,1.5mmol),并将混合物在0℃下搅拌3h。将反应混合物冷却至-78℃,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和并在硅胶上通过快速色谱法(1M NH3在1:4的MeOH/DCM中)纯化,得到(2R,3R,4R,5S)-1-(2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.040g,87%)。1H NMR(500MHz,DMSO-d6)δ7.33-7.24(m,1H),7.10-7.00(m,2H),4.72-.67(m,3H),4.15(dd,J=6.1,4.2Hz,1H),3.76-3.71(m,1H),3.54-3.48(m,1H),3.26-3.18(m,1H),3.05-2.99(m,1H),2.96-2.82(m,3H),2.80-2.68(m,3H),2.20(t,J=10.6Hz,1H),2.06(dt,J=9.3,2.9Hz,1H);ESI MS m/z 304.129[M+H]+。
实施例5
(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(三氟甲基)苯乙基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(100mg,0.19mmol)和1-(2-溴乙基)-3-(三氟甲基)苯(240mg,0.95mmol)的DMF(5mL)溶液中加入K2CO3(210mg,1.52mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中,并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶快速色谱法纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(3-(三氟甲基)苯乙基)哌啶,为白色固体(70mg,53%)。ESI MS m/z 696.33[M+H]+。
在-78℃,N2下,向上述物质(70mg,0.10mmol)的无水DCM(5mL)搅拌溶液中加入BCl3(在DCM中的浓度为1M,1.0mL,1.0mmol)。将混合物在0℃下搅拌2h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(三氟甲基)苯乙基)哌啶-3,4,5-三醇,为白色固体(21mg,63%)。1H NMR(400MHz,CD3OD)δ7.59-7.44(m,4H),3.97(dd,J=11.9,2.5Hz,1H),3.86(dd,J=11.9,3.1Hz,1H),3.52(ddd,J=10.4,9.0,4.9Hz,1H),3.34(t,J=12Hz,1H),3.19(t,J=9.0Hz,1H),3.13(dd,J=11.1,4.9Hz,1H),3.09-2.84(m,4H),2.42(t,J=10.8Hz,1H),2.34(dt,J=9.5,2.9Hz,1H);ESI MS m/z 336.14[M+H]+。
实施例6
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-(三氟甲基)苯乙基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-(苄氧基)甲基)哌啶(100mg,0.19mmol)和1-(2-溴乙基)-4-(三氟甲基)苯(193mg,0.76mmol)的DMF(8mL)溶液中加入DIPEA(0.35mL,1.9mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶快速色谱法纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(4-(三氟甲基)苯乙基)哌啶,为白色固体(76mg,61%)。
在-78℃、Ar下,向上述物质(70mg,0.1mmol)的无水DCM(2mL)溶液中加入BCl3(1.0mL,在DCM中的浓度为1M,1.0mmol)。将混合物在-78℃下搅拌2h并在0℃下搅拌2h;加入MeOH(20mL)。将混合物在0℃下再搅拌2h,并在旋转蒸发仪下蒸发至干。将残余物在硅胶上通过快速色谱法使用10%MeOH和2%NH3的DCM溶液纯化,得到苯基(2R,3R,4R,5S)-2-(羟甲基)-1-(4-(三氟甲基)苯乙基)哌啶-3,4,5-三醇,为白色泡沫(26mg,70%)。1H NMR(400MHz,CD3OD)δ7.58(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H),3.97(dd,J=12.0,2.5Hz,1H),3.85(dd,J=12.0,3.3Hz,1H),3.51(ddd,J=10.4,9.0,4.9Hz,1H),3.36-3.33(m,1H),3.18(t,J=9.0Hz,1H),3.10-2.71(m,5H),2.38(t,J=10.8Hz,1H),2.30(dt,J=9.5,2.9Hz,1H);ESI MS m/z 336.1[M+H]+。
实施例7和8
(2R,3R,4R,5S)-2-(羟甲基)-1-((R)-2-苯丙基)哌啶-3,4,5-三醇和(2R,3R,4R,5S)-2-(羟甲基)-1-((S)-2-苯丙基)哌啶-3,4,5-三醇
在Ar下,向2-苯丙醛(78mg,0.57mmol)、(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(200mg,0.38mmol)和HOAc(三滴)的无水MeOH(10mL)溶液中加入NaBH3CN(38mg,95%,0.57mmol)。将混合物在室温下搅拌18h,加入饱和NaHCO3水溶液(30mL),用EtOAc(3×30mL)萃取混合物。将合并的有机萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,将残余物在硅胶上通过快速色谱法使用30%EtOAc的己烷纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2-苯丙基)哌啶(两种异构体的比例为1:3)(207mg,85%)。
在-78℃,Ar下,向上述物质(155mg,0.24mmol,两种异构体的比例为1:3)的无水DCM(2mL)溶液中加入BCl3(3.0mL,在DCM中的浓度为1M,3.0mmol)。混合物在-78℃下搅拌2h并在0℃下搅拌2h;加入MeOH(20mL)。将混合物在0℃下再搅拌2h,并在旋转蒸发仪下蒸发至干。将残余物在硅胶上通过快速色谱法使用10%MeOH和2%NH3的DCM溶液纯化,得到苯基(2R,3R,4R,5S)-2-(羟甲基)-1-((R)-2-苯丙基)哌啶-3,4,5-三醇,为白色泡沫(14.5mg,87%);1HNMR(400MHz,CD3OD)δ7.32-7.22(m,4H),7.19(t,J=7.1Hz,1H),3.94-3.61(m,2H),3.48(td,J=9.8,4.7Hz,1H),3.36-3.32(m,1H),3.27-2.86(m,4H),2.49(t,J=8.7Hz,1H),2.10(q,J=10.2,9.5Hz,2H),1.29(d,J=5.6Hz,3H);ESI MS m/z 282.2[M+H]+。还分离出(2R,3R,4R,5S)-2-(羟甲基)-1-((S)-2-苯丙基)哌啶-3,4,5-三醇,为白色泡沫(34mg,67%);1H NMR(400MHz,CD3OD)δ7.68-6.63(m,5H),3.82(d,J=11.7Hz,1H),3.68(dd,J=11.9,3.0Hz,1H),3.37-3.28(m,1H),3.27-2.94(m,5H),2.66-2.43(m,1H),2.24-2.11(m,1H),2.03(t,J=10.9Hz,1H),1.24(d,J=6.2Hz,3H);ESI MS m/z 282.2[M+H]+。每种化合物都作为一种非对映体进行分离,苯丙基的立体化学随机分配。
实施例9
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(吡啶-2-基)乙基)哌啶-3,4,5-三醇
向密封管中的(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(300mg,0.57mmol)和2-(2-溴乙基)吡啶(900mg,4.86mmol)的DMF(15mL)溶液中加入K2CO3(1000mg,7.24mmol)。将混合物在80℃下搅拌18h,并冷却至室温。将反应混合物倒入冰水(30mL)中并用EtOAc(3×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到2-(2-((2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)乙基)吡啶,为白色固体(340mg,95%)。ESI MS m/z 629.34[M+H]+。
在-78℃,N2下,向上述物质(183mg,0.29mmol)的无水DCM(5mL)的搅拌溶液中加入BCl3(在DCM中的浓度为1M,2.1mL,2.1mmol)。将混合物在0℃下搅拌2h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶解于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(吡啶-2-基)乙基)哌啶-3,4,5-三醇,为白色固体(63mg,81%)。1H NMR(400MHz,CD3OD)δ8.51-8.45(m,1H),7.81(td,J=7.7,1.8Hz,1H),7.41(d,J=7.8Hz,1H),7.35-7.24(m,1H),4.07-3.92(m,2H),3.59(ddd,J=10.5,8.9,4.8Hz,1H),3.54-3.40(m,2H),3.32-3.19(m,3H),3.13(t,J=7.6Hz,2H),2.71-2.57(m,2H);ESIMS m/z 269.15[M+H]+。
实施例10
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-2-基)乙基)哌啶-3,4,5-三醇
在Ar下,向2-(噻吩-2-基)乙醛(80mg,0.63mmol)、(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(221mg,0.42mmol)和HOAc(三滴)的无水MeOH(10mL)溶液中加入NaBH3CN(50mg,95%,0.62mmol)。将混合物在室温下搅拌18h,加入饱和NaHCO3水溶液(30mL),并用EtOAc(3×30mL)萃取混合物。将合并的有机萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法使用30%EtOAc的己烷纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2-(噻吩-2-基)乙基)哌啶(175mg,66%)。
在-78℃,Ar下,向上述物质(175mg,0.27mmol)的无水DCM(2mL)溶液中加入BCl3(3.0mL,DCM中的浓度为1M,3.0mmol)。将混合物在-78℃下搅拌2h并在0℃下搅拌2h,然后加入MeOH(20mL)。将混合物在0℃下再搅拌2h,并在旋转蒸发仪下蒸发至干。将残余物在硅胶上通过快速色谱法使用10%MeOH和2%NH3的DCM溶液纯化,得到苯基(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-2-基)乙基)哌啶-3,4,5-三醇,为白色泡沫(63mg,85%)。1H NMR(400MHz,CD3OD)δ7.24(dd,J=5.1,1.3Hz,1H),7.05-6.67(m,2H),3.95(d,J=2.7Hz,2H),3.60(ddd,J=10.6,9.1,4.9Hz,1H),3.46(t,J=9.4Hz,1H),3.31-3.01(m,6H),2.88-2.44(m,2H);ESI MS m/z 274.1[M+H]+。
实施例11
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-3-基)乙基)哌啶-3,4,5-三醇
在Ar下,向2-(噻吩-3-基)乙醛(85mg,0.67mmol)、(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(221mg,0.42mmol)和HOAc(三滴)的无水MeOH(10mL)的溶液中加入NaBH3CN(50mg,95%,0.63mmol)。将混合物在室温下搅拌18h,加入饱和NaHCO3水溶液(30mL),并用EtOAc(3×30mL)萃取混合物。将合并的有机萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法使用30%EtOAc的己烷纯化,得到(2R,3R,4R,5S)-3,4,5-三(苄氧基)-2-(苄氧基)甲基)-1-(2-(噻吩-3-基)乙基)哌啶(181mg,68%)。
在-78℃,Ar下,向上述物质(181mg,0.28mmol)的无水DCM(2mL)溶液中加入BCl3(6.0mL,在DCM中的浓度为1M,6.0mmol)。将混合物在-78℃下搅拌2h并在0℃下搅拌2h,加入MeOH(20mL)。将混合物在0℃下再搅拌2小时,并在旋转蒸发仪下蒸发至干。将残余物在硅胶上通过快速色谱法使用10%MeOH和2%NH3的DCM溶液纯化,得到苯基(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-3-基)乙基)哌啶-3,4,5-三醇,为白色泡沫(23mg,29%)。1H NMR(400MHz,CD3OD)δ7.34(dd,J=5.0,2.9Hz,1H),7.11(d,J=2.9Hz,1H),7.02(d,J=4.8Hz,1H),3.92(qd,J=12.2,2.8Hz,2H),3.55(td,J=9.9,4.8Hz,1H),3.39(t,J=9.5Hz,1H),3.22(t,J=9.1Hz,1H),3.15-3.05(m,2H),3.01-2.94(m,1H),2.90-2.85(m,2H),2.42(t,J=10.9Hz,1H),2.37-2.29(m,1H);ESI MS m/z274.3[M+H]+。
实施例12
(2S,3R,4R,5S)-1-(环己基甲基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将密封管中的(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol)、(溴甲基)环己烷(0.18g,1.0mmol)和DIPEA(0.20g,1.6mmol)的无水DMF(5mL)混合物在85℃下搅拌16h。将反应混合物在室温下冷却并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(2×30mL)萃取后,将合并的萃取物用盐水(2×20mL)洗涤,并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(环己基甲基)哌啶,为淡黄色油状物(0.17g,71%)。
在-78℃和Ar下,向上述物质(0.17g,0.27mmol)的无水DCM(8mL)溶液中加入BCl3(在DCM中的浓度为1.0M,2.0mL,2.0mmol),并将混合物在0℃下搅拌3h。反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3在1:5的MeOH/DCM中)纯化,得到(2S,3R,4R,5S)-1-(环己基甲基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.059g,83%)。1H NMR(400MHz,DMSO-d6)δ4.73(d,J=4.6Hz,1H),4.64(d,J=4.2Hz,1H),4.60(d,J=5.1Hz,1H),4.06(t,J=5.0Hz,1H),3.65-3.56(m,2H),3.44-3.38(m,1H),3.30-3.20(m,1H),3.11-3.02(m,1H),2.81-2.72(m,1H),2.58-2.30(m,4H),1.75-1.55(m,5H),1.46-1.33(m,1H),1.24-1.05(m,3H),0.85-0.70(m,2H);ESI MS m/z 260.187[M+H]+。
实施例13
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-(苄氧基)甲基)哌啶(400mg,0.76mmol)和(1r,4r)-4-(三氟甲基)环己烷甲醛(274mg,1.52mmol)的无水DCM(10mL)搅拌溶液中加入HOAc(0.2mL),并将混合物搅拌30分钟。加入NaBH(OAc)3(340mg,1.60mmol),并将所得混合物在室温下搅拌18h。用NaHCO3溶液在0℃下淬灭反应。将混合物用EtOAc(3×20mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1r,4S)-4-(三氟甲基)环己基)-甲基)哌啶,为油状物(375mg,72%)。ESIMS m/z 688.35[M+H]+。
在-78℃,N2下,向上述物质(240mg,0.35mmol)的无水DCM(5mL)搅拌溶液中加入BCl3溶液(在DCM中的浓度为1M,1.75mL,1.75mmol)。将混合物在0℃下搅拌4h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶解于1MNH3的MeOH(10mL)中,并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2S,3R,4R,5S)-2-(羟甲基-1-(((1r,4S)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇,为白色固体(78mg,68%)。1H NMR(400MHz,CD3OD)δ3.88-3.77(m,2H),3.69(dd,J=9.3,5.5Hz,1H),3.55-3.46(m,1H),3.39-3.34(m,1H),2.99(q,J=5.5Hz,1H),2.72(ddd,J=12.6,5.4,1.0Hz,1H),2.64-2.46(m,3H),2.15-2.02(m,1H),2.02-1.89(m,4H),1.56-1.44(m,1H),1.40-1.24(m,2H),1.04-0.85(m,2H);ESI MS m/z 328.17[M+H]+。
实施例14
(2S,3R,4R,5S)-1-(((1s,4S)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.25g,0.50mmol)、顺-4-(2-氟丙-2-基)环己烷甲醛(0.12g,0.70mmol)和NaBH(OAc)3(0.21g,1.0mmol)的DCM(15mL)混合物在室温下搅拌3天。将反应混合物用饱和NaHCO3水溶液(10mL)稀释,并用DCM(3×15mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:7至1:5)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1s,4R)-4-(2-氟丙-2-基)环己基)甲基)哌啶,为淡黄色油状物(0.31g,91%)。
在氢气下在一个大气压下将上述物质(0.31g,0.45mmol)、Pd(OH)2/C(20%Pd质量百分数,0.10g,0.19mmol)和6滴浓HCl的MeOH(20mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物在0℃下溶解于无水吡啶(3mL)中,向其中加入Ac2O(0.5mL)。将混合物在室温下搅拌16h,并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(2×20mL)萃取后,将合并的提取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:4至1:3)纯化,得到澄清的油状物。将澄清的油状物在室温下用1M NH3的MeOH(5mL)处理16h。在减压下浓缩后,将残余物在硅胶上通过快速色谱法(0.5M NH3 MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(((1s,4R)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇(0.057g,39%,三步),为白色固体。1HNMR(400MHz,CD3OD)δ3.86-3.78(m,2H),3.69(dd,J=9.3,5.5Hz,1H),3.55-3.43(m,1H),3.35(t,J=8.9Hz,1H),3.04-2.96(m,1H),2.84-2.68(m,2H),2.68-2.52(m,2H),1.91-1.68(m,3H),1.66-1.38(m,5H),1.27(d,J=21.8Hz,6H),1.26-1.10(m,2H);ESI MS m/z320.233[M+H]+。
实施例15
(2S,3R,4R,5S)-1-((2,3-二氢-1H-茚-2-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(130mg,0.23mmol)和2,3-二氢-1H-茚-2-甲醛(40mg,0.27mmol)的无水DCM(5mL)搅拌溶液中加入HOAc(0.1mL)并搅拌30分钟。加入NaBH(OAc)3(73mg,0.35mmol),并将所得混合物在室温下搅拌18h。在0℃下用NaHCO3溶液淬灭反应。将混合物用EtOAc(3×20mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((2,3-二氢-1H-茚-2-基)甲基)哌啶,为油状物(90mg,60%)。ESI MS m/z 654.35[M+H]+。
在-78℃和N2下向上述物质(90mg,0.14mmol)的无水DCM(5mL)搅拌溶液加入BCl3溶液(在DCM中的浓度为1M,0.69mL,0.69mmol)。将混合物在0℃下搅拌4h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶解于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下去除溶剂。将残余物通过硅胶色谱法纯化,得到(2S,3R,4R,5S)-1-((2,3-二氢-1H-茚-2-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(23mg,56%)1H NMR(400MHz,CD3OD)δ7.20-7.14(m,2H),7.11-7.06(m,2H),3.91-3.80(m,2H),3.76-3.70(m,1H),3.59-3.51(m,1H),3.42-3.34(m,1H),3.10-2.97(m,3H),2.85-2.60(m,7H);ESI MS m/z 294.17[M+H]+。
实施例16
(2S,3R,4R,5S)-1-(2-环己基乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将密封管中的(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol)、(2-溴乙基)环己烷(0.19g,1.0mmol)和DIPEA(0.20g,1.6mmol)的无水DMF(5mL)混合物在85℃下搅拌16h。将反应混合物在室温下冷却并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(2×30mL)萃取后,将合并的萃取物用盐水(2×20mL)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:12至1:7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2-环己基乙基)哌啶,为淡黄色油状物(0.17g,71%)。
在-78℃和Ar下,向上述物质(0.17g,0.27mmol)的无水DCM(8mL)溶液中加入BCl3(在DCM中的浓度为1.0M,2.0mL,2.0mmol),并将混合物在0℃下搅拌3h。将反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3在1:5的MeOH/DCM中)纯化,得到(2S,3R,4R,5S)-1-(2-环己基乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.054g,74%)。1H NMR(400MHz,DMSO-d6)δ4.71(d,J=4.8Hz,1H),4.65(d,J=4.2Hz,1H),4.61(d,J=5.1Hz,1H),4.09(s,br.,1H),3.67-3.55(m,2H),3.47-3.36(m,1H),3.31-3.21(m,1H),3.12-3.06(m,1H),2.85-2.76(m,1H),2.72-2.62(m,1H),2.61-2.43(m,2H),2.42-2.32(m,1H),1.75-1.54(m,5H),1.35-1.04(m,6H),0.93-0.80(m,2H);ESI MS m/z 274.202[M+H]+。
实施例17
(2S,3R,4R,5S)-1-(3-环己基丙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将密封管中的(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol)、(3-溴丙基)环己烷(0.21g,1.0mmol)和DIPEA(0.20g,1.6mmol)的无水DMF(5mL)混合物在85℃下搅拌16h。将反应混合物在室温下冷却并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(2×30mL)萃取后,将合并的萃取物用盐水(2×20mL)洗涤,并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:12至1:7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(3-环己基丙基)哌啶,为淡黄色油状物(0.25g,100%)。
在-78℃和Ar下,向上述物质(0.25g,0.38mmol)的无水DCM(8mL)溶液中加入BCl3(在DCM中的浓度为1.0M,3.0mL,3.0mmol),并将混合物在0℃下搅拌3h。将反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3在1:5的MeOH/DCM中)纯化,得到(2S,3R,4R,5S)-1-(3-环己基丙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.095g,87%)。1H NMR(400MHz,DMSO-d6)δ4.81-4.61(m,3H),4.09(s,br.,1H),3.69-3.56(m,2H),3.48-3.36(m,1H),3.32-3.23(m,1H),3.15-3.04(m,1H),2.90-2.77(m,1H),2.63-2.32(m,4H),1.70-1.54(m,5H),1.44-1.32(m,2H),1.25-1.08(m,6H),0.91-0.78(m,2H);ESI MS m/z 288.218[M+H]+。
实施例18
(2S,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(7.50g,14.3mmol)(J.Am.Chem.Soc.2017,139,14192-14197),1-(2-溴乙基)-2-氟苯(4.14g,20.4mmol)(Tetrahedron Asymmetry,2001,12,4,585-596),四丁基碘化铵(Bu4NI)(0.450g,1.22mmol)和K2CO3(4.14g,30.0mmol)的无水DMF(40mL)溶液在100℃下搅拌16h。将反应混合物在室温下冷却并用水(300mL)稀释。用Et2O(2×100mL)萃取后,将合并的萃取物用盐水(3×100mm L)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:10至1:5)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(2-氟苯乙基)哌啶,为淡黄色油状物(3.60g,39%);ESI MS m/z646.327[M+H]+。
在-78℃和N2下,向上述物质(3.60g,5.57mmol)的无水DCM(40mL)溶液中加入BCl3(在DCM中的浓度为1.0M,33mL,33mmol),并将混合物在0℃下搅拌3h。将反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和并在硅胶上通过快速色谱法(1M NH3的MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(1.48g,93%)。1HNMR(400MHz,CD3OD)δ7.26(td,J=7.5,1.8Hz,1H),7.22-7.16(m,1H),7.07(td,J=7.5,1.2Hz,1H),7.04-6.99(m,1H),3.94-3.75(m,2H),3.67(dd,J=8.8,5.2Hz,1H),3.53(ddd,J=9.5,8.0,4.9Hz,1H),3.38(t,J=8.5Hz,1H),3.12-2.97(m,2H),2.95-2.77(m,4H),2.63(dd,J=12.4,9.5Hz,1H);ESI MS m/z 286.139[M+H]+。
实施例19
(2S,3R,4R,5S)-1-(3-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.35g,0.67mmol),2-(3-氯-2-氟苯基)乙醛(0.14g,0.81mmol)和NaBH(OAc)3(0.20g,0.94mmol)的DCM(10mL)混合物在室温下搅拌16h。将反应混合物用饱和NaHCO3水溶液(10mL)稀释。并用DCM(3×15mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:9至1:6)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(3-氯-2-氟苯乙基)哌啶,为淡黄色油状物(0.43g,94%)。
在-78℃和Ar下,向上述物质(0.43g,0.63mmol)的无水DCM(10mL)溶液中加入BCl3(在DCM中的浓度为1.0M,4.0mL,4.0mmol),并将混合物在0℃下搅拌3h。将反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3在1:5的MeOH/DCM中)纯化,得到(2S,3R,4R,5S)-1-(3-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.15g,74%)。1HNMR(400MHz,DMSO-d6)δ7.42-7.36(m,1H),7.31-7.25(m,1H),7.16-7.10(m,1H),4.71(d,J=4.9Hz,1H),4.67(d,J=4.1Hz,1H),4.65(d,J=5.2Hz,1H),4.17(t,J=5.0Hz,1H),3.72-3.56(m,2H),3.40-3.30(m,1H),3.30-3.20(m,1H),3.12-3.04(m,1H),2.98-2.92(m,1H),2.87-2.81(m,1H),2.80-2.67(m,4H),2.44(dd,J=11.9,9.4Hz,1H);ESI MS m/z 320.109[M+H]+。
实施例20
(2S,3R,4R,5S)-1-(2-([1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将密封管中的(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol),4-(2-溴乙基)-1,1'-联苯(0.25g,0.96mmol)和DIPEA(0.20g,1.6mmol)的无水DMF(5mL)混合物在85℃下搅拌16h。将反应混合物在室温下冷却并用饱和NaHCO3水溶液(20mL)稀释。用EtOAc(2×30mL)萃取后,将合并的萃取物用盐水(2×20mL)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-1-(2-([1,1'-联苯基]-4-基)乙基)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶,为淡黄色油状物(0.18g,67%)。
在-78℃和Ar下,向上述物质(0.18g,0.26mmol)的无水DCM(8mL)溶液中加入BCl3(在DCM中的浓度为1.0M,2.0mL,2.0mmol),并将混合物在0℃下搅拌3h。将反应混合物在-78℃下冷却,用MeOH淬灭,然后浓缩至干燥。残余物用1M NH3的MeOH中和并在硅胶上通过快速色谱法(0.5M NH3在1:5的MeOH/DCM中)纯化,得到(2S,3R,4R,5S)-1-(2-([1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(0.031g,35%)。1H NMR(400MHz,DMSO-d6)δ7.69-7.61(m,2H),7.60-7.52(m,2H),7.50-7.40(m,2H),7.37-7.27(m,3H),4.48-4.60(m,3H),4.19(s,br.,1H),3.73-3.59(m,2H),3.47-3.39(m,1H),.3.35-3.23(m,1H),3.16-3.05(m,1H),3.04-2.89(m,2H),2.85-2.67(m,4H),2.53-2.44(m,1H);ESI MS m/z 344.185[M+H]+。
实施例21
(2S,3R,4R,5S)-1-(2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol)、2-(4-(3,6-二氢-2H-吡喃-4-基)-2,6-二氟苯基)乙醛(0.12g,0.50mmol)和NaBH(OAc)3(0.15g,0.71mmol)的DCM(10mL)混合物在室温下搅拌16h。将反应混合物用饱和NaHCO3水溶液(10mL)稀释,并用DCM(3×15mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:6至1:4)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(4-(3,6-二氢-2H-吡喃-4-基)-2,6-二氟苯乙基)哌啶,为淡黄色油状物(0.27g,75%)。
在氢气下在一个大气压下将上述物质(0.27g,0.36mmol)、Pd(OH)2/C(20%Pd质量百分数,0.070g,0.13mmol)和5滴浓HCl的MeOH(20mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇(0.12g,86%),为白色固体。1H NMR(400MHz,DMSO-d6)δ6.98-6.92(m,2H),4.71(d,J=4.8Hz,1H),4.69-4.62(m,2H),4.14(t,J=4.9Hz,1H),3.97-3.82(m,2H),3.72-3.51(m,2H),3.39(td,J=11.5,2.8Hz,2H),3.40-3.30(m,1H),3.30-3.20(m,1H),3.12-3.03(m,1H),2.98-2.56(m,7H),2.42(t,J=10.6Hz,1H),1.81-1.42(m,4H);ESI MS m/z 388.193[M+H]+。
实施例22
(2S,3R,4R,5S)-1-(4-丁氧基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,将(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.20g,0.38mmol)、2-(4-丁氧基苯基)乙醛(0.12g,0.62mmol)和NaBH(OAc)3(0.15g,0.71mmol)的DCM(10mL)混合物在室温下搅拌3天。将反应混合物用饱和NaHCO3水溶液(10mL)稀释,并用DCM(3×15mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:9至1:6)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(4-丁氧基苯乙基)哌啶,为淡黄色油状物(0.23g,86%)。
在氢气下在一个大气压下向上述物质(0.23g,0.33mmol)、Pd(OH)2/C(20%Pd质量百分数,0.10g,0.19mmol)和5滴浓HCl的MeOH(20mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3
MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(4-丁氧基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇(0.051g,46%),为白色固体。1H NMR(400MHz,DMSO-d6)δ7.16-7.01(m,2H),6.90-6.73(m,2H),4.87-4.51(m,3H),4.14(s,br.1H),3.91(t,J=6.5Hz,2H),3.70-3.57(m,2H),3.45-3.35(m,1H),3.34-3.24(m,1H),3.14-3.06(m,1H),2.93-2.83(m,2H),2.73-2.55(m,4H),2.50-2.39(m,1H),1.71-1.62(m,2H),1.49-1.33(m,2H),0.92(t,J=7.4Hz,3H);ESI MS m/z 340.212[M+H]+。
实施例23
(2S,3R,4R,5S)-1-(4-丁氧基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇
在N2下,将(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(1.20g,2.29mmol)、2-(4-丁氧基-2,6-二氟苯基)乙醛(0.68g,3.0mmol)和NaBH(OAc)3(0.85g,4.0mmol)的DCM(30mL)混合物在室温下搅拌3天。将反应混合物用饱和NaHCO3水溶液(30mL)稀释,并用DCM(3×20mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(4-丁氧基-2,6-二氟苯乙基)哌啶,为淡黄色油状物(1.3g,77%)。ESI MS m/z 736.3689[M+H]+。
在氢气下在一个大气压下将上述物质(1.30g,1.76mmol)、Pd(OH)2/C(20%Pd质量百分数,0.25g,0.47mmol)和浓HCl(0.5mL)的MeOH(80mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和,随后在硅胶上通过快速柱色谱法(0.5M NH3MeOH/DCM,1:4)纯化,得到(2S,3R,4R,5S)-1-(4-丁氧基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇(0.58g,88%),为白色固体。1H NMR(400MHz,CD3OD)δ6.53-6.47(m,2H),3.94(t,J=6.4Hz,2H),3.88-3.75(m,2H),3.63(dd,J=8.9,5.3Hz,1H),3.50(ddd,J=9.5,8.1,5.0Hz,1H),3.36(t,J=8.5Hz,1H),3.06-2.90(m,2H),2.88(dd,J=12.4,5.0Hz,1H),2.83-2.74(m,3H),2.61(dd,J=12.4,9.5Hz,1H),1.80-1.68(m,2H),1.54-1.44(m,2H),0.98(t,J=7.4Hz,3H);ESI MS m/z376.1604[M+H]+。
实施例24
(2S,3R,4R,5S)-1-((1-(4-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(600mg,1.06mmol)和4-甲酰基哌啶-1-羧酸叔丁酯(272mg,1.28mmol)的无水DCM(10mL)搅拌溶液中加入HOAc(0.2mL),并将混合物搅拌30分钟。加入NaBH(OAc)3(337mg,1.59mmol),并将所得混合物在室温下搅拌18h。在0℃下用NaHCO3溶液淬灭反应。将混合物用EtOAc(3×20mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到4-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-羧酸叔丁酯,为油状物(740mg,97%)。ESI MS m/z721.42[M+H]+。
将TFA(3mL)冷却至0℃,并加入上述物质(740mg,1.03mmol)的DCM(6mL)中。将混合物在0℃下搅拌10分钟,然后在室温下搅拌2h。在真空下除去TFA和DCM。将残余物溶解于EtOAc(50mL)中并用NaHCO3溶液(2×20mL)洗涤,然后用水洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,将粗品(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(哌啶-4-基甲基)哌啶直接用于下一步,无需进一步纯化(624mg,98%)。ESI MS m/z621.37[M+H]+。
向上述物质(228mg,0.37mmol)和4-溴氟苯(128mg,0.74mmol)的甲苯(10mL)搅拌溶液中加入Pd2(dba)3(34mg,0.037mmol)和RuPhos(35mg,0.074mmol),然后在氩气下加入Cs2CO3(361mg,1.11mmol)。将混合物在100℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×30mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((1-(4-氟苯基)哌啶-4-基)甲基)哌啶,为油状物(208mg,79%)。ESI MS m/z 715.39[M+H]+。
在N2,-78℃下向上述物质(110mg,0.15mmol)的无水DCM(5mL)搅拌溶液中加入BCl3溶液(在DCM中的浓度为1M,0.75mL,0.75mmol)。将混合物在0℃下搅拌4h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶解于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下去除溶剂。将残余物通过硅胶色谱法纯化,得到(2S,3R,4R,5S)-1-((1-(4-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇,为白色固体(25mg,47%)。1H NMR(400MHz,CD3OD)δ7.04-6.93(m,4H),3.91-3.80(m,2H),3.74-3.69(m,1H),3.60-3.49(m,3H),3.41-3.34(m,1H),3.06-2.99(m,1H),2.80-2.56(m,6H),1.97-1.84(m,2H),1.72-1.58(m,1H),1.41-1.26(m,2H);ESI MS m/z 355.20[M+H]+。
实施例25
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.78g,1.5mmol)的DCM(20mL)溶液中加入(S)-3-甲酰基吡咯烷-1-羧酸叔丁酯(0.45g,2.25mmol)和HOAc(0.5mL)。在室温下搅拌10分钟后,加入NaBH(OAc)3(0.5g,2.5mmol),并在室温下将混合物搅拌过夜。将反应混合物浓缩,然后用DCM(25mL)稀释。将有机物用饱和NaHCO3水溶液、盐水洗涤,用无水Na2SO4干燥并浓缩。将残余物在硅胶上通过快速色谱法(EtOAc/己烷,3:7)纯化,得到(R)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-羧酸叔丁酯,为油状物(1.0g,94%)。1H NMR(400MHz,CDCl3)δ7.40-7.27(m,20H),4.88(d,J=11.0Hz,1H),4.82(d,J=11.1Hz,1H),4.74(d,J=11.4Hz,1H),4.71-4.62(m,3H),4.54(d,J=12.1Hz,1H),4.50(d,J=12.4Hz,1H),3.73(dd,J=10.2,2.5Hz,1H),3.67(td,J=6.8,5.8,3.6Hz,1H),3.59-3.42(m,3H),3.39-3.25(m,3H),3.04-2.89(m,1H),2.87-2.79(m,1H),2.76-2.63(m,1H),2.61-2.52(m,2H),2.37-2.25(m,1H),1.88-1.80(bs,1H),1.60-1.54(m,2H),1.50(s,9H);ESI MS m/z 707.404[M+H]+。
将上述物质(1.0g,1.45mmol)在0℃下溶于3:7TFA:DCM(16mL)溶液中并搅拌30分钟。将反应混合物加热2h至室温,然后浓缩至干燥。用EtOAc(30mL)稀释并将有机物用饱和NaHCO3(2×50mL)洗涤,用无水Na2SO4干燥,并浓缩,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((S)-吡咯烷-3-基甲基)哌啶,为油状物(0.8g,90%)。1HNMR(400MHz,CDCl3)δ7.40-7.26(m,20H),4.88(d,J=10.9Hz,1H),4.83(d,J=10.9H z,1H),4.76-4.62(m,4H),4.56-4.49(m,3H),3.85(dd,J=10.1,7.1Hz,1H),3.73(dd,J=10.2,2.6Hz,1H),3.70-3.63(m,1H),3.59-3.47(m,2H),3.34(td,J=6.6,6.2,2.7Hz,1H),3.06-2.91(m,3H),2.90-2.83(m,1H),2.80-2.44(m,4H),2.31(tt,J=13.9,6.1Hz,1H),1.84(dtd,J=13.2,8.0,5.6Hz,1H),1.42(dq,J=13.8,7.2Hz,1H);ESI MS m/z 607.350[M+H]+。
向上述物质(0.19g,0.31mmol)和2-氯-3-(三氟甲基)吡啶(0.11g,0.62mmol)的无水DMF(5mL)溶液中加入K2CO3(0.12g,0.93mmol)并将反应混合物在120℃下加热过夜。将反应混合物在EtOAc(50mL)和水之间分配;分离有机物,并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,2:8)纯化,得到3-(三氟甲基)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-基)吡啶,为油状物(0.1g,43%)。1HNMR(400MHz,CDCl3)δ8.32(dd,J=4.7,1.7Hz,1H),7.81(dd,J=7.8,1.8Hz,1H),7.41-7.27(m,20H),6.66(dd,J=7.8,4.7Hz,1H),4.89(d,J=10.9Hz,1H),4.84(d,J=10.9Hz,1H),4.75(d,J=11.5Hz,1H),4.70(s,2H),4.68-4.62(m,1H),4.58-4.49(m,2H),3.88(dd,J=10.2,7.1Hz,1H),3.74(dd,J=10.4,2.8Hz,1H),3.72-3.49(m,6H),3.40-3.31(m,2H),2.88(dt,J=11.9,5.8Hz,1H),2.78(dd,J=12.8,8.4Hz,1H),2.67(dd,J=12.7,6.6Hz,1H),2.64-2.53(m,1H),2.40(dq,J=14.6,7.3Hz,1H),1.97(dq,J=11.7,5.8Hz,1H),1.63(dq,J=12.3,8.0Hz,1H);ESI MS m/z752.362[M+H]+。
在-78℃,Ar下,向上述物质(0.1g,0.13mmol)的DCM(8mL)溶液中加入BCl3(在DCM中的浓度为1.0M,0.8mL,0.8mmol),并将混合物搅拌3h,同时浴温达到0℃。然后将混合物在-78℃下冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇(0.031g,60.9%),为白色固体。1H NMR(400MHz,CD3OD)δ8.25(dd,J=4.8,1.8Hz,1H),7.87(dd,J=7.8,1.8Hz,1H),6.73(dd,J=7.8,4.7Hz,1H),3.91-3.82(m,2H),3.71(dd,J=9.3,5.5Hz,1H),3.68-3.61(m,3H),3.53(ddd,J=10.0,8.5,5.2Hz,1H),3.44-3.35(m,2H),3.06(p,J=6.1,5.7Hz,1H),2.90-2.73(m,3H),2.68-2.60(m,1H),2.53(h,J=7.6Hz,1H),2.10(dq,J=11.9,6.1Hz,1H),1.71(dq,J=12.1,7.9Hz,1H);ESI MS m/z 392.176[M+H]+。
实施例26
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇
在Ar下向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((S)-吡咯烷-3-基甲基)哌啶(0.14g,0.23mmol)和2-溴-4-(三氟甲基)噻唑(0.1g,0.46mmol)的DMA(5mL)搅拌溶液加入Cs2CO3(0.22g,0.69mmol)。将混合物在80℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,将残余物在硅胶上通过快速色谱法纯化,得到4-(三氟甲基)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-基)噻唑,为油状物(0.11g,63%)。1HNMR(400MHz,CDCl3)δ7.39-7.27(m,20H),6.90(d,J=1.2Hz,1H),4.89(d,J=10.9Hz,1H),4.83(d,J=10.9Hz,1H),4.75(d,J=11.5Hz,1H),4.70-4.68(m,2H),4.64(d,J=11.5Hz,1H),4.57-4.48(m,2H),3.87(dd,J=10.2,7.3Hz,1H),3.77-3.64(m,2H),3.60-3.42(m,5H),3.34-3.27(m,1H),3.16(dd,J=10.1,6.5Hz,1H),2.84(dd,J=12.2,5.4Hz,1H),2.76-2.46(m,4H),2.09-1.98(m,1H),1.72(dq,J=12.7,7.5Hz,1H);ESI MS m/z 758.321[M+H]+。
在-78℃下,Ar下,向上述物质(0.11g,0.15mmol)的DCM(5ml)溶液中加入BCl3(在DCM中的浓度为1.0M,0.75ml,0.75mmol),并将混合物搅拌3h,同时浴温达到0℃。然后将混合物在-78℃下冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-)4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇(0.04g,67%),为白色固体。1HNMR(400MHz,CD3OD)δ7.14(s,1H),3.90-3.82(m,2H),3.71(dd,J=9.3,5.5Hz,1H),3.65-3.44(m,4H),3.37(dd,J=8.9,6.7Hz,1H),3.28(dd,J=10.1,6.4Hz,1H),3.06(q,J=5.7Hz,1H),2.88-2.80(m,2H),2.76(dd,J=12.7,8.5Hz,1H),2.71-2.61(m,2H),2.20(dtd,J=12.2,6.9,4.9Hz,1H),1.86(dq,J=12.4,7.6Hz,1H);ESI MS m/z 398.132[M+H]+。
实施例27
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-)(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((R)-吡咯烷-3-基甲基)哌啶(210mg,0.35mmol)和2-氯-3-(三氟甲基)吡啶(127mg,0.70mmol)的DMF(5mL)搅拌溶液中加入DIPEA(0.24mL,1.39mmol)。将混合物在100℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×30mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到3-(三氟甲基)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-基)吡啶,为油状物(100mg,38%)。ESI MS m/z 752.36[M+H]+。
在N2,-78℃下,向上述物质(95mg,0.13mmol)的无水DCM(5mL)搅拌溶液中加入BCl3溶液(在DCM中的浓度为1M,0.63mL,0.63mmol)。将混合物在0℃下搅拌4h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下去除溶剂。将残余物通过硅胶色谱法纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇,为白色固体(30mg,59%)。1HNMR(400MHz,CD3OD)δ8.26(dd,J=4.9,1.8Hz,1H),7.87(dd,J=7.8,1.9Hz,1H),6.73(dd,J=7.8,4.7Hz,1H),3.90-3.82(m,2H),3.76-3.59(m,4H),3.58-3.49(m,1H),3.44-3.34(m,2H),3.11-3.03(m,1H),2.90(dd,J=12.8,6.8Hz,1H),2.83-2.76(m,1H),2.73-2.61(m,2H),2.60-2.48(m,1H),2.15-2.04(m,1H),1.80-1.67(m,1H);ESI MS m/z 392.17[M+H]+。
实施例28
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(1.42g,2.71mmol)和(R)-3-甲酰基吡咯烷-1-羧酸叔丁酯(0.60g,3.01mmol)的无水DCM(20mL)搅拌溶液中加入HOAc(0.2mL),并将混合物搅拌30分钟,然后加入NaBH(OAc)3(745mg,3.51mmol),将所得混合物在室温下搅拌18h。在0℃下用NaHCO3溶液淬灭反应。将混合物用EtOAc(3×20mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到(S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-羧酸叔丁酯,为油状物(1.51g,79%)。ESI MS m/z 707.41[M+H]+。
将TFA(7mL)冷却至0℃并加入上述物质(1.51g,2.13mmol)的DCM(20mL)中。将混合物在0℃下搅拌10分钟,然后在室温下搅拌2h。在真空下除去TFA和DCM。将残余物溶解于EtOAc(80mL)中并用NaHCO3溶液(2×20mL)洗涤,然后用水洗涤,分离,用Na2SO4干燥。过滤后,在减压下蒸发溶剂。将残余物在硅胶上通过快速色谱法纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((R)-吡咯烷-3-基甲基)哌啶,为油状物(886mg,68%)。ESI MS m/z 607.35[M+H]+。
向上述物质(210mg,0.35mmol)和2-溴-4-(三氟甲基)噻唑(162mg,0.70mmol)的DMA(5mL)搅拌溶液中加入Cs2CO3(457mg,2.40mmol)。将混合物在80℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×30mL)萃取。将合并的有机层用水(2×10mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到4-(三氟甲基)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)吡咯烷-1-基)噻唑,为油状物(161mg,61%)。ESI MS m/z 758.32[M+H]+。
在N2,-78℃下向上述物质(150mg,0.35mmol)的无水DCM(5mL)搅拌溶液中加入BCl3溶液(在DCM中的浓度为1M,1.0mL,1.0mmol)。将混合物在0℃下搅拌4h,然后用无水MeOH(1mL)淬灭。将混合物在室温下搅拌10分钟。在真空下除去溶剂,将残余物溶解于1M NH3的MeOH(10mL)中并再搅拌10分钟,然后在真空下除去溶剂。将残余物通过硅胶色谱法纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇,为白色固体(50mg,63%)。1HNMR(400MHz,CD3OD)δ7.15-7.13(m,1H),3.90-3.82(m,2H),3.74-3.67(m,1H),3.65-3.43(m,4H),3.40-3.34(m,1H),3.31-3.23(m,1H),3.09-3.02(m,1H),2.94-2.60(m,5H),2.25-2.14(m,1H),1.94-1.80(m,1H);ESI MS m/z 398.13[M+H]+。
实施例29
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-)(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.8g,1.5mmol)的DCM(30mL)溶液中加入(S)-3-甲酰基哌啶-1-羧酸叔丁酯(0.42g,2.0mmol)和HOAc(0.5mL)。在室温下搅拌10分钟后,加入NaBH(OAc)3(0.48g,2.26mmol),并在室温下将混合物搅拌过夜。将反应混合物浓缩,然后用DCM(25mL)稀释。将有机物用饱和NaHCO3水溶液、盐水洗涤,用无水Na2SO4干燥并浓缩。将残余物在硅胶上通过快速色谱法(EtOAc/己烷,3:7)纯化,得到(R)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-2-羧酸叔丁酯,为油状物(1.0g,94%)。1HNMR(400MHz,CDCl3)δ7.38-7.27(m,20H),4.88(d,J=11.1Hz,1H),4.82(d,J=11.1Hz,1H),4.75(d,J=11.5Hz,1H),4.71-4.63(m,3H),4.57-4.49(m,2H),3.99-3.87(m,2H),3.85(dd,J=10.1,6.9Hz,1H),3.75-3.68(m,2H),3.63-3.48(m,2H),3.31-3.25(m,1H),2.89-2.77(m,2H),2.66-2.51(m,3H),2.44(dd,J=13.0,5.6Hz,1H),1.73-1.57(m,3H),1.46(s,9H),1.45-1.33(m,1H),1.07(q,J=10.1Hz,1H);ESIMS m/z721.421[M+H]+。
在0℃下将上述物质(1.0g,1.4mmol)溶于3:7TFA:DCM(16mL)溶液中并搅拌30分钟。将反应混合物加热2小时至室温,然后浓缩至干燥。用EtOAc(30mL)稀释并将有机物用饱和NaHCO3水溶液(2×50mL)洗涤,用无水Na2SO4干燥并浓缩,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((S)-哌啶-3-基甲基)哌啶,为油状物(0.8g,92%)。1HNMR(400MHz,CDCl3)δ7.85(bs,1H),7.39-7.27(m,20H),4.85(d,J=11.0Hz,1H),4.81(d,J=10.9Hz,1H),4.72-4.61(m,4H),4.56-4.45(m,2H),3.85(dd,J=10.3,7.6Hz,1H),3.70(dd,J=10.3,2.6Hz,1H),3.63(dd,J=9.2,5.7Hz,1H),3.57-3.46(m,2H),3.42(dd,J=12.7,3.7Hz,1H),3.34-3.21(m,2H),2.92(dd,J=11.9,5.3Hz,1H),2.72(ddt,J=16.3,11.7,5.2Hz,1H),2.65-2.49(m,3H),2.41(dd,J=13.1,10.6Hz,1H),2.05-1.93(m,1H),1.83-1.69(m,3H),1.11-0.96(m,1H);ESI MS m/z 621.362[M+H]+。
向上述物质(0.155g,0.25mmol)和2-氯-3-(三氟甲基)吡啶(0.09g,0.5mmol)的无水DMF(6mL)溶液中加入K2CO3(0.1g,0.75mmol)并将反应混合物在120℃下加热过夜。将反应混合物在EtOAc(50mL)和水之间分配,将有机物分离,并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,2∶8)纯化,得到3-(三氟甲基)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-基)吡啶,为油状物(0.1g,52.2%)。1HNMR(400MHz,CDCl3)δ8.42(dd,J=4.8,1.8Hz,1H),7.85(dd,J=7.8,2.0Hz,1H),7.37-7.27(m,20H),6.95(dd,J=7.8,4.7Hz,1H),4.85(d,J=10.9Hz,1H),4.81(d,J=10.9Hz,1H),4.73(d,J=11.4Hz,1H),4.69-4.59(m,3H),4.56-4.47(m,2H),3.85(dd,J=10.1,6.8Hz,1H),3.77-3.63(m,3H),3.62-3.45(m,3H),3.25(td,J=6.4,2.5Hz,1H),3.02-2.87(m,2H),2.65-2.54(m,2H),2.54-2.45(m,2H),1.90(q,J=5.3Hz,1H),1.84-1.58(m,3H),1.14-1.01(m,1H);ESI MS m/z 766.378[M+H]+。
在-78℃,Ar下,向上述物质(0.1g,0.13mmol)的DCM(6ml)溶液中加入BCl3(在DCM中的浓度为1.0M,0.65ml,0.65mmol),并将混合物搅拌3h,同时浴温达到0℃。然后将混合物在-78℃下冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-)3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇(0.033g,62%),为白色固体。1HNMR(400MHz,CD3OD)δ8.43(dd,J=4.9,1.8Hz,1H),7.98(dd,J=7.8,1.9Hz,1H),7.13-7.07(m,1H),3.89-3.82(m,2H),3.74-3.69(m,1H),3.66(dd,J=9.4,5.6Hz,1H),3.53-3.46(m,2H),3.37(d,J=1.9Hz,1H),2.99-2.92(m,2H),2.80(dd,J=12.2,5.4Hz,1H),2.68(dd,J=13.2,5.3Hz,1H),2.63-2.50(m,3H),1.93(dt,J=9.6,4.8Hz,1H),1.88-1.76(m,2H),1.76-1.63(m,1H),1.21-1.10(m,1H);ESI MS m/z 406.189[M+H]+。
实施例30
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇
在Ar下,向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((S)-哌啶-3-基甲基)哌啶(0.16g,0.25mmol)和2-溴-4-(三氟甲基)噻唑(0.11g,0.50mmol)的DMA(5mL)搅拌溶液中加入Cs2CO3(0.24g,0.75mmol)。将混合物在80℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到4-(三氟甲基)-2-((R)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-基)噻唑,为油状物(0.11g,59.5%)。1H NMR(400MHz,CDCl3)δ7.41-7.27(m,20H),6.89(d,J=1.2Hz,1H),4.89(d,J=10.8Hz,1H),4.84(d,J=10.8Hz,1H),4.75(d,J=11.5Hz,1H),4.72-4.63(m,3H),4.58-4.50(m,2H),3.96(dt,J=13.2,4.2Hz,1H),3.87(dd,J=10.2,7.2Hz,1H),3.81-3.69(m,3H),3.66-3.59(m,1H),3.54(q,J=9.9,9.1Hz,1H),3.31-3.24(m,1H),3.23-3.12(m,1H),2.89-2.74(m,2H),2.68-2.52(m,3H),1.81-1.71(m,3H),1.61(qd,J=10.6,10.0,4.6Hz,1H),1.18(q,J=10.7Hz,1H);ESI MS m/z 772.331[M+H]+。
在-78℃,Ar下,向上述物质(0.11g,0.14mmol)的DCM(8ml)溶液中加入BCl3(在DCM中的浓度为1.0M,1.1ml,1.1mmol),并将混合物搅拌3h,同时浴温达到0℃。然后将混合物在-78℃下冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和,并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇(0.049g,85%),为白色固体。1HNMR(400MHz,CD3OD)δ7.17(s,1H),3.94-3.85(m,4H),3.74(dd,J=9.4,5.6Hz,1H),3.54(ddd,J=10.2,8.6,5.2Hz,1H),3.36(d,J=9.0Hz,1H),3.20(ddd,J=13.4,10.6,3.4Hz,1H),3.02(p,J=6.1Hz,1H),2.95(dd,J=13.0,9.3Hz,1H),2.79(dd,J=12.4,5.2Hz,1H),2.74-2.55(m,3H),1.94-1.75(m,3H),1.70-1.58(m,1H),1.30-1.22(m,1H);ESI MS m/z412.144[M+H]+。
实施例31
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇
向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.91g,1.7mmol)的DCM(30mL)溶液中加入(R)-3-甲酰基哌啶-1-羧酸叔丁酯(0.54g,2.5mmol)和HOAc(0.5mL)。在室温下搅拌10分钟后,加入NaBH(OAc)3(0.6g,2.9mmol),并在室温下将混合物搅拌过夜。将反应混合物浓缩,然后用DCM(25mL)稀释。将有机物用饱和NaHCO3水溶液、盐水洗涤,用无水Na2SO4干燥并浓缩。将残余物在硅胶上通过快速色谱法(EtOAc/己烷,3:7)纯化,得到(S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-羧酸叔丁酯,为油状物(1.0g,81%)。1HNMR(400MHz,CDCl3)δ7.38-7.27(m,20H),4.88(d,J=11.0Hz,1H),4.83(d,J=11.0Hz,1H),4.77-4.67(m,3H),4.65(d,J=11.5Hz,1H),4.57-4.47(m,2H),3.99-3.89(m,2H),3.85(dd,J=10.1,6.9Hz,1H),3.73(dd,J=11.1,3.6Hz,2H),3.70(d,J=8.7Hz,1H),3.60-3.48(m,2H),3.37(tt,J=6.4,2.3Hz,1H),2.90-2.73(m,2H),2.65-2.52(m,2H),2.52-2.35(m,1H),1.80-1.72(bs,1H),1.68-1.58(m,2H),1.48(s,9H),1.45-1.34(m,1H),1.02(q,J=11.2Hz,1H);ESI MS m/z 721.417[M+H]+。
在0℃下将上述物质(1.0g,1.4mmol)溶于3:7TFA:DCM(16mL)溶液中并搅拌30分钟。将反应混合物加热2h至室温,然后浓缩至干燥。将有机物用EtOAc(30mL)稀释并用饱和NaHCO3(2×50mL)洗涤,用无水Na2SO4干燥,并浓缩,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((R)-哌啶-3-基甲基)哌啶,为油状物(0.85g,93%)。1HNMR(400MHz,CDCl3)δ7.89(bs,1H),7.38-7.26(m,20H),4.86-4.75(m,2H),4.69(d,J=6.8Hz,1H),4.68-4.59(m,3H),4.51(d,J=12.1Hz,1H),4.46(d,J=12.1Hz,1H),3.83(dd,J=10.3,7.3Hz,1H),3.72-3.66(m,1H),3.62(dd,J=9.1,5.6Hz,1H),3.55-3.41(m,2H),3.34-3.26(m,3H),2.80-2.50(m,4H),2.48-2.34(m,2H),2.07-1.99(m,1H),1.86-1.65(m,3H),0.99(q,J=11.0Hz,1H);ESI MS m/z 621.368[M+H]+。
向上述物质(0.18g,0.29mmol)和2-氯-3-(三氟甲基)吡啶(0.10g,0.58mmol)的无水DMF(6mL)溶液中加入K2CO3(0.12g,0.87mmol)并将反应混合物在120℃下加热过夜。将反应混合物在EtOAc(50mL)和水之间分配,分离有机物,并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,2∶8)纯化,得到3-(三氟甲基)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-基)吡啶,为油状物(0.1g,46.8%)。1HNMR(400MHz,CDCl3)δ8.41(dd,J=4.8,1.8Hz,1H),7.84(dd,J=7.8,1.9Hz,1H),7.38-7.27(m,20H),6.94(dd,J=7.8,4.7Hz,1H),4.86(d,J=10.9Hz,1H),4.80(d,J=10.9Hz,1H),4.74-4.60(m,4H),4.54(d,J=12.1Hz,1H),4.48(d,J=12.2Hz,1H),3.85(dd,J=10.2,6.7Hz,1H),3.73(dd,J=10.2,2.4Hz,1H),3.68(dd,J=9.3,5.8Hz,1H),3.65-3.60(m,1H),3.58-3.43(m,4H),2.95-2.86(m,1H),2.81-2.73(m,2H),2.63-2.46(m,2H),2.33(dd,J=12.7,8.6Hz,1H),1.97(bs,1H),1.81-1.56(m,3H),1.10-0.97(m,1H);ESI MS m/z 766.37[M+H]+。
在-78℃,Ar下,向上述物质(0.1g,0.13mmol)的DCM(6ml)溶液中加入BCl3(在DCM中的浓度为1.0M,1.0ml,1.0mmol),并将混合物搅拌3h,同时浴温达到0℃。然后在-78℃下将混合物冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇,为白色固体(0.03g,62%)。1HNMR(400MHz,CD3OD)δ8.44(dd,J=5.0,1.8Hz,1H),7.98(dd,J=7.8,1.9Hz,1H),7.14-7.07(m,1H),3.92-3.80(m,2H),3.70(dd,J=9.3,5.1Hz,1H),3.64(dt,J=12.6,2.2Hz,1H),3.57-3.43(m,2H),3.38(t,J=8.7Hz,1H),3.13-3.06(m,1H),2.96(t,J=11.5Hz,1H),2.82(dd,J=13.0,5.4Hz,1H).2.78-2.43(m,4H),2.08-1.98(m,1H),1.94-1.84(m,1H),1.83-1.76(m,1H),1.76-1.63(m,1H),1.23-1.12(m,1H);ESI MS m/z 406.194[M+H]+。
实施例32
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇
在Ar下向(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-((R)-哌啶-3-基甲基)哌啶(0.15g,0.24mmol)和2-溴-4-(三氟甲基)噻唑(0.11g,0.48mmol)的DMA(5mL)搅拌溶液中加入Cs2CO3(0.23g,0.72mmol)。将混合物在80℃下搅拌18h,然后在0℃下加入水。将混合物用EtOAc(2×20mL)萃取。将合并的有机层用水(2×20mL)洗涤,分离,并用Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法纯化,得到4-(三氟甲基)-2-((S)-3-(((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲基)哌啶-1-基)噻唑,为油状物(0.12g,64.7%)。1H NMR(400MHz,CDCl3)δ7.43-7.27(m,20H),6.90(s,1H),4.90(d,J=10.9Hz,1H),4.84(d,J=10.9Hz,1H),4.78-4.64(m,4H),4.55(d,J=12.2Hz,1H),4.51(d,J=12.1Hz,1H),3.96-3.80(m,3H),3.78-3.71(m,2H),3.61(ddd,J=10.2,8.7,5.6Hz,1H),3.51(t,J=9.2Hz,1H),3.44-3.38(m,1H),3.14(ddd,J=13.7,11.1,3.1Hz,1H),2.82-2.74(m,3H),2.65(dd,J=11.9,10.3Hz,1H),2.40(dd,J=12.8,8.3Hz,1H),1.93-1.82(m,1H),1.83-1.69(m,2H),1.66-1.54(m,1H),1.14(ddd,J=18.1,10.2,5.8Hz,1H);ESI MS m/z 772.329[M+H]+。
在-78℃,Ar下,向上述物质(0.12g,0.15mmol)的DCM(8ml)溶液中加入BCl3(在DCM中的浓度为1.0M,1.3mL,1.3mmol),并将混合物搅拌3h,同时浴温达到0℃。然后将混合物在-78℃下冷却,并小心加入MeOH(3mL)。在室温下搅拌30分钟后,将混合物在减压下浓缩。将所得残余物用1M NH3的MeOH溶液(2×5mL)中和,并在减压下再次浓缩。将残余物在硅胶上通过快速色谱法(MeOH/DCM,1:9)纯化,得到(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇(0.056g,90%),为白色固体。1HNMR(400MHz,CD3OD)δ7.18(s,1H),3.97-3.89(m,2H),3.88-3.85(m,2H),3.72(dd,J=9.1,5.3Hz,1H),3.56(ddd,J=9.3,8.2,5.5Hz,1H),3.37(t,J=8.7Hz,1H),3.16(ddd,J=12.9,11.0,3.3Hz,1H),3.05(q,J=5.7Hz,1H),2.89(dd,J=13.0,9.8Hz,1H),2.82-2.75(m,1H),2.74-2.64(m,2H),2.56(dd,J=13.0,8.4Hz,1H),1.99-1.85(m,2H),1.80(dt,J=13.3,3.9Hz,1H),1.70-1.58(m,1H),1.30-1.21(m,1H);ESI MS m/z 412.154[M+H]+。
实施例311
(2S,3R,4R,5S)-1-(((1s,4R)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,向在0℃下冷却的环己烷-1,4-二基二甲醇(2.00g,13.9mmol)的无水DCM(60mL)溶液中加入DIPEA(2.06g,16.0mmol)和苯甲酰氯(1.97g,14.0mmol)。将混合物在室温下搅拌16h,然后用饱和NaHCO3水溶液(50mL)稀释。用DCM(3×30mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:3至1:2)纯化,得到(4-(羟甲基)环己基)苯甲酸甲酯,为淡黄色油状物(1.51g,43%)。
将上述物质(0.950g,3.83mmol)和DMP(2.12g,5.0mmol)的DCM(30mL)混合物在室温下搅拌1h,形成白色悬浮液。加入己烷(40mL),并将悬浮液通过硅藻土滤饼过滤。收集滤液并在真空下浓缩,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:4)纯化,得到(4-甲酰基环己基)苯甲酸甲酯,为无色油状物(0.50g,53%)。
在Ar下,向在-78℃下冷却的上述物质(0.50g,2.0mmol)的无水DCM(10mL)溶液中加入DAST(0.80g,5.0mmol),并将混合物在-78℃下搅拌30分钟,然后在室温下搅拌5h。将混合物在-78℃下冷却并用饱和NaHCO3水溶液(20mL)淬灭。收集有机层,并用DCM(3×20mL)萃取水层。将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:10)纯化,得到(4-(二氟甲基)环己基)苯甲酸甲酯,为无色油状物(0.40g,75%)。
将上述物质(0.40g,1.5mmol)和K2CO3(0.45g,0.33mmol)的MeOH(25mL)混合物搅拌16h。在真空下除去溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:2)纯化,得到(4-(二氟甲基)环己基)甲醇,为澄清液体(0.21g,86%)。
向在0℃下冷却的上述物质(0.21g,1.3mmol)的丙酮(25mL)中溶液中加入在0℃下预冷却的CrO3(0.60g,6.0mmol)的2.0M H2SO4(6mL)水溶液。将混合物在0℃下搅拌1h,并在室温下搅拌16h。然后加入异丙醇(5mL),并将混合物再搅拌1h。在真空下浓缩后,将混合物用水(50mL)稀释并用DCM(3×20mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶1至3∶1)纯化,得到4-(二氟甲基)环己烷羧酸,为白色固体(0.22g,96%)。1H NMR表明该固体含有顺式和反式异构体的混合物,其比例为顺式∶反式=0.32:0.68。
将4-(二氟甲基)环己烷羧酸(0.050g,0.28mmol)、(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.147g,0.281mmol)(Lahav et al.JAm Chem Soc 2017,139,14192-14197)、HATU(0.20g,0.53mmol)和DIPEA(0.11g,0.85mmol)的DMF(5mL)混合物在室温下搅拌16h。将混合物用饱和NaHCO3水溶液(20mL)稀释并用EtOAc(3×15mL)萃取。将合并的萃取物用盐水(2×20mL)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:5至1:3)纯化和分离,得到((1r,4S)-4-(二氟甲基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.13g,68%)和((1s,4R)-4-(二氟甲基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.055g,29%),两者均为白色固体。ESI MS m/z 684.352[M+H]+。
在Ar下,向在0℃下冷却的((1r,4R)-4-(二氟甲基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.14g,0.20mmol)的无水Et2O(10mL)溶液中加入LAH(0.050g,1.3mmol),并将混合物在0℃下搅拌4h。然后用水淬灭反应并用饱和NaHCO3水溶液(20mL)稀释。用Et2O(3×30mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1s,4R)-4-(二氟甲基)环己基)甲基)哌啶,为无色油状物(0.10g,73%)。ESI MS m/z 670.372[M+H]+。
在氢气(1atm.)下将上述物质(0.10g,0.15mmol)、Pd(OH)2/C(20%Pd质量百分数,0.050g,0.094mmol)和2滴浓HCl的MeOH(15mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3 MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(((1s,4R)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇(0.033g,72%),为白色固体。1HNMR(500MHz,CD3OD)δ5.75(td,J=57.1,5.3Hz,1H),3.90-3.79(m,2H),3.70(dd,J=9.3,5.5Hz,1H),3.55-3.48(m,1H),3.39-3.33(m,1H),3.04-2.99(m,1H),2.78-2.70(m,2H),2.65-2.57(m,2H),1.90-1.76(m,2H),1.64-1.46(m,8H);ESI MS m/z 310.184[M+H]+。
实施例312
(2S,3R,4R,5S)-1-(((1r,4S)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,向在0℃下冷却的((1r,4S)-4-(二氟甲基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.25g,0.37mmol)的无水THF(10mL)溶液中加入LAH(0.050g,1.3mmol),并将混合物在0℃下搅拌4小时。然后用水淬灭反应并用饱和NaHCO3水溶液(20mL)稀释。用Et2O(3×30mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1r,4S)-4-(二氟甲基)环己基)甲基)哌啶(0.075g,30%),为无色油状物。ESI MS m/z 670.377[M+H]+。
在氢气(1atm.)下将上述物质(0.075g,0.11mmol)、Pd(OH)2/C(20%Pd质量百分数,0.050g,0.094mmol)和2滴浓HCl的MeOH(20mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和,并在硅胶上通过快速色谱法(0.5M NH3 MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(((1r,4S)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇(0.021g,60%),为白色固体。1HNMR(400MHz,CD3OD)δ5.71(td,J=57.1,4.5Hz,1H),3.89-3.77(m,2H),3.70(dd,J=9.2,5.4Hz,1H),3.56-3.48(m,1H),3.40-3.33(m,1H),3.03-2.96(m,1H),2.73(dd,J=12.4,5.4Hz,1H),2.65-2.46(m,3H),2.00-1.81(m,4H),1.80-1.62(m,1H),1.55-1.41(m,1H),1.26-1.10(m,2H),1.00-0.82(m,2H);ESI MS m/z 310.183[M+H]+。
实施例313
(2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
向顺式/反式-4-(羟甲基)环己烷羧酸(3.20g,20.2mmol)的无水MeOH(50mL)溶液中滴加SOCl2(4.8g,40mmol),并将混合物在室温下搅拌4h。然后在真空下除去溶剂,并将残余物用饱和NaHCO3水溶液(40mL)稀释。用DCM(3×40mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,得到澄清液体。将液体溶解于无水DMF(30mL)中并在0℃下冷却,然后加入咪唑(2.72g,40.0mmol)和TBDMSCl(4.52g,30.0mmol)。在室温下搅拌16h后,将混合物用盐水(100mL)稀释并用EtOAc(3×40mL)萃取。将合并的萃取物用盐水(2×100mL)洗涤并用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:9)纯化,得到无色油状物。在Ar下,将油状物溶解于无水THF(50mL)中,并将溶液在0℃下冷却。分批加入LAH(1.00g,26.3mmol),并将混合物在0℃下搅拌1h。加入湿七水硫酸钠(50g)以淬灭反应,并将悬浮液搅拌30分钟。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶4至1∶2)纯化,得到顺式和反式-(4-(((叔丁基二甲基硅基)氧基)甲基)环己基)甲醇的混合物,为无色油状物(4.6克,88%,3步)。
在Ar下,向在-78℃下冷却的DMSO(1.95g,25.0mmol)的无水DCM(80mL)溶液中加入草酰氯溶液(1.93g,15.0mmol)。加入后,将混合物在-78℃下搅拌1h,并加入上述物质(2.58g,10.0mmol)的无水DCM(20mL)溶液。将混合物在-78℃下搅拌1h后,加入Et3N(5.4mL,40mmol),并将混合物在-78℃下搅拌30分钟,然后在室温下搅拌30分钟。然后将混合物用饱和NaHCO3水溶液(50mL)稀释并收集有机层。水层用DCM(50mL)萃取并将合并的有机萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上用快速色谱法(EtOAc/己烷,1:9)纯化,得到4-(((叔丁基二甲基硅基)氧基)甲基)-环己烷甲醛,为无色油状物(2.30g,90%)。
在Ar下,向在0℃下冷却的上述物质(2.30g,9.00mmol)的无水THF(40mL)溶液中加入MeMgCl(在THF中的浓度为3.0M,4.0mL,12mmol),并将混合物在室温下搅拌16h。将混合物用冰水淬灭,用饱和NH4Cl水溶液(30mL)稀释,并用EtOAc(2×50mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:4)纯化,得到1-(4-(((叔丁基二甲基硅基)氧基)甲基)环己基)乙醇,为无色油状物(2.40g,98%)。
将上述物质(2.40g,8.80mmol)和DMP(5.60g,13.2mmol)的DCM(50mL)混合物在室温下搅拌3h,形成白色悬浮液。加入己烷(50mL),将悬浮液通过硅藻土滤饼过滤。收集滤液并在真空下浓缩,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:15至1:6)纯化,得到1-(4-(((叔丁基二甲基硅基)氧基)甲基)环己基)乙酮,为无色油状物(2.11g,89%)。
在Ar下,向在0℃下冷却的上述物质(2.11g,7.8mmol)的无水THF(30mL)溶液中加入TBAF(在THF中的浓度为1.0M,10.0mL,10.0mmol),并将混合物在室温下搅拌3h。用饱和NaHCO3水溶液(40mL)稀释后,将混合物用EtOAc(2×30mL)萃取,并将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,2∶3至1∶1)纯化,得到1-(4-(羟甲基)环己基)乙酮,为澄清液体(1.10g,92%)。
在Ar下,向在0℃下冷却的上述物质(1.10g,7.20mmol)的无水DCM(25mL)溶液中加入DMAP(0.25g,2.0mmol)、DIPEA(1.93g,15.0mmol)和苯甲酰氯(1.40g,10.0mmol)。将混合物在室温下搅拌16h,并用饱和NaHCO3水溶液(30mL)稀释。用DCM(3×30mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:6至1:3)纯化,得到(4-乙酰基环己基)苯甲酸甲酯,为淡黄色油状物(1.85g,99%)。
在Ar下,向上述物质(1.70g,6.53mmol)的无水DCM(15mL)溶液中加入DAST(5.74g,35.9mmol),将混合物在室温下搅拌1小时,然后加热回流4天。混合物在-78℃下冷却,并用饱和NaHCO3水溶液(50mL)淬灭。用DCM(2×50mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:11至1:9)纯化,得到(4-(1,1-二氟乙基)环己基)苯甲酸甲酯,为淡黄色油状物(1.45g,79%)。
将上述物质(1.45g,5.13mmol)和K2CO3(1.5g,11mmol)的MeOH(40mL)混合物搅拌16h。在真空下除去溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:4至1:2)纯化,得到(4-(1,1-二氟乙基)环己基)甲醇,为澄清液体(0.85g,93%)。
向在0℃下冷却的上述物质(0.85g,4.8mmol)的丙酮(40mL)溶液中加入在0℃下预冷却的CrO3(1.5g,15mmol)的2.0M H2SO4水溶液(10mL)。将混合物在0℃下搅拌1h,并在室温下搅拌16h。然后加入异丙醇(5mL),并将混合物再搅拌1h。在真空下浓缩后,将混合物用水(50mL)稀释并用DCM(3×30mL)萃取。将合并的萃取物用无水Na2SO4干燥。过滤后,在真空下蒸发溶剂,得到4-(1,1-二氟乙基)环己烷羧酸,为白色固体(0.90g,98%)。1H NMR表明该固体含有顺式和反式异构体的混合物,其比例为顺式∶反式=0.35:0.65。
将4-(1,1-二氟乙基)环己烷羧酸(0.192g,1.00mmol)和(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶(0.340g,0.649mmol)、HATU(0.46g,1.2mmol)和DIPEA(0.19g,1.5mmol)的DMF(10mL)混合物在室温下搅拌16h。将混合物用饱和NaHCO3水溶液(20mL)稀释并用EtOAc(3×20mL)萃取。将合并的萃取物用盐水(2×20mL)洗涤并用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1:6至1:4)纯化和分离,得到((1r,4S)-4-(1,1-二氟乙基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.28g,62%)和((1s,4R)-4-(1,1-二氟乙基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.13g,29%),两者均为白色固体。
在Ar下,向在0℃下冷却的((1s,4R)-4-(1,1-二氟乙基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.13g,0.19mmol)的无水Et2O(15mL)溶液中加入LAH(0.050g,1.3mmol),并将混合物在0℃下搅拌4小时。然后用水淬灭反应并用饱和NaHCO3水溶液(20mL)稀释。用Et2O(3×20mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1s,4R)-4-(1,1-二氟乙基)环己基)甲基)哌啶,为无色油状物(0.099g,76%)。ESI MSm/z 684.385[M+H]+。
在氢气(1atm.)下向上述物质(0.099g,0.14mmol)、Pd(OH)2/C(20%Pd质量百分数,0.050g,0.094mmol)和2滴浓HCl的MeOH(20mL)混合物搅拌过夜。将混合物通过硅藻土滤饼过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和并在硅胶上通过快速色谱法(0.5MNH3 MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇(0.034g,72%),为白色固体。1H NMR(400MHz,DMSO-d6)4.74(d,J=4.6Hz,1H),4.65(d,J=4.2Hz,1H),4.61(d,J=5.1Hz,1H),4.10(t,J=5.3Hz,1H),3.69-3.58(m,2H),3.47-3.38(m,1H),3.31-3.22(m,1H),3.14-3.04(m,1H),2.86-2.75(m,1H),2.65(dd,J=13.0,8.3Hz,1H),2.58-2.38(m,3H),1.85-1.47(m,9H),1.47-1.32(m,2H),1.30-1.18(m,2H);ESI MS m/z 324.199[M+H]+。
实施例314
(2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇
在Ar下,向在0℃下冷却的((1r,4S)-4-(1,1-二氟乙基)环己基)((2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)哌啶-1-基)甲酮(0.27g,0.39mmol)的无水Et2O(20mL)溶液中加入LAH(0.080g,2.1mmol),并将混合物在0℃下搅拌4h。然后用水淬灭反应并用饱和NaHCO3水溶液(20mL)稀释。用Et2O(3×30mL)萃取后,将合并的萃取物用无水Na2SO4干燥。过滤后,在减压下蒸发溶剂,并将残余物在硅胶上通过快速色谱法(EtOAc/己烷,1∶12至1∶7)纯化,得到(2S,3R,4R,5S)-3,4,5-三(苄氧基)-2-((苄氧基)甲基)-1-(((1r,4S)-4-(1,1-二氟乙基)环己基)甲基)哌啶,为无色油状物(0.23g,86%)。ESI MS m/z 684.381[M+H]+。
在氢气(1atm.)下将上述物质(0.23g,0.34mmol)、Pd(OH)2/C(20%Pd质量百分数,0.080g,0.15mmol)和3滴浓HCl的MeOH(25mL)混合物搅拌过夜。将混合物通过硅藻土过滤,并收集滤液并浓缩至干燥。将残余物用1M NH3的MeOH中和并在硅胶上通过快速色谱法(0.5M NH3 MeOH/DCM,1:5)纯化,得到(2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)-哌啶-3,4,5-三醇(0.092g,85%),为白色固体。1H NMR(400MHz,DMSO-d6)δ4.74(d,J=4.6Hz,1H),4.64(d,J=4.2Hz,1H),4.60(d,J=5.0Hz,1H),4.09(t,J=5.1Hz,1H),3.67-3.58(m,2H).3.42(dt,J=9.6,5.1Hz,1H),3.29-3.20(m,1H),3.12-3.03(m,1H),2.82-2.74(m,1H),2.57-2.33(m,4H),1.90-1.64(m,5H),1.54(t,J=19.4Hz,3H),1.45-1.30(m,1H),1.19-1.04(m,2H),0.89-0.74(m,2H);ESI MS m/z 324.198[M+H]+。
如表1所示,实施例33-310根据与本发明描述的方案和实施例类似的程序合成。
生物活性
用于测定细胞裂解液中抑制GBA2的IC50值的试验
稳定表达GBA2的HEK 293T细胞产生方式如下。PCR扩增人GBA2(GBA2核苷酸登录号BC011363)使用以下引物:正义5'-CGC AAA TGG GCG GTA GGC GTG---3'和反义5'-TAG TCAGCC ATG GGG CGG AGA---3')克隆到ABM Inc.的pLenti-GIII-CMV中。通过测序验证构建体的正确性。含有带GBA2的pLenti-GIII-CMV质粒的慢病毒颗粒通过使用HEK293T细胞的第三代病毒包装混合物(ABM cat#LV053-G074)制备,并作为病毒颗粒悬浮液提供。病毒悬浮液用于感染HEK293T细胞。稳定表达人GBA2的细胞群通过连续数周使用嘌呤霉素进行选择,通过活性测定和蛋白质印迹来测定。
配制在DMSO中的各种浓度的待测化合物,然后用100mM柠檬酸、200mM磷酸氢二钠和1%v/v C10E6组成的pH 5.5的缓冲液稀释。将稳定的HEK293T-过表达的GBA2细胞系的细胞匀浆(0.25mg/mL)与GCase抑制剂(20μM(6R,7R,8S)-8-乙基-4-氮杂螺[2.5]辛-6,7-二醇)一起在冰上预孵育10分钟。反应液由20μL相同缓冲液的750μM 4-甲基伞形酮-β-D吡喃葡萄糖苷的5%DMSO、用(6R,7R,8S)-8-乙基-4-氮杂螺[2.5]辛-6,7-二醇预处理的20μLGBA2-细胞匀浆和20μL相同缓冲液的各种浓度的待测化合物的10%DMSO组成。反应中的最终浓度为0.083mg/mLGBA2-细胞匀浆、250μM 4-甲基伞形酮-β-D吡喃葡萄糖苷、和各种浓度的抑制剂。将抑制剂和GBA2-细胞匀浆在37℃下一起预孵育5分钟。加入底物启动反应并使其在37℃下反应20分钟以评估GBA2活性。通过加入等体积(60μL)的0.5M NaOH、0.3M甘氨酸,pH 10.5终止反应。在365nm的激发波长和450nm的发射波长下用Biotek Synergy H4酶标仪测量荧光。孵育时不添加酶或不添加抑制剂分别用于确定无酶活性和最大酶活性。通过使用GraphPad Prism将数据拟合成log[抑制剂浓度]对响应的拟合曲线来测定IC50值。IC50值计算为抑制GBA2活性50%所需的抑制剂浓度。
所测试的本发明的化合物显示GBA2抑制的IC50值在0.1nM-50μM的范围内。
上述GBA2抑制试验的代表性数据如表3所示,其中符号“***”表示IC50<100nM;符号“**”表示100nM<IC50<1μM;符号“*”表示1μM<IC50<25μM。
表3
本发明描述了关于一个或多个实施例。然而,不背离本发明权利要求中限定的范围下,显而易见本领域技术人员可以进行许多变化和修改。
因此,尽管这里公开了本发明的各种实施例,但是根据本领域技术人员的公知常识,可以在本发明的范围内进行许多调整和修改。这样的修改包括用已知的等同物替换本发明的任何方面以便以基本上相同的方式实现相同的结果。应当理解,具体实施方案可以以任何方式和任何数量组合以产生另外的实施方案,并且除非上下文另有说明,否则实施方案的任何排列和组合应被认为是由本申请的描述公开的。数值范围包括限定该范围的数字。本发明中数值范围的叙述仅旨在用作单独提及落入该范围内的每个单独值的速记方法。除非本发明另有说明,否则将每个单独的值并入本说明书中,如同其在本发明中单独引用一样。除非本发明另有说明或与上下文明显矛盾,否则在描述本发明的上下文中使用的术语“一(a)”和“一个(an)”和“该(the)”以及类似的引用应被解释为涵盖单数和复数。在说明书中,词语“包含(comprising)”用作开放式术语,基本上等同于短语“包括但不限于”,并且词语“包含(comprises)”具有相应的含义。然而,应当理解,在本发明中使用词语“包含(comprising)”或“包含(comprises)”、或具有相同词根的变体的情况下,还考虑了排除了未指定的任何元素、步骤或成分的“由......组成(consisting)”或“由......组成(consists)”的变体或修饰,或者限制了指定的材料或所述步骤以及那些不会实质上影响所要求保护的发明的基本和新颖特征的“基本上由......组成(consisting essentiallyof)”或“基本上由......组成(consists essentially of)”的变体或修饰。本发明对参考文献的引用不应被解释为承认这些参考文献是本发明的现有技术。所有出版物通过引用并入此,如同每个单独的出版物被具体和单独地指出通过引用并入此并且如同在本发明中完全阐述一样。本发明包括基本上如上文所述并参考实施例的所有实施方案和变化。
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SEQUENCE LISTING
<110> 阿勒克图治疗公司
<120> 非溶酶体葡糖神经酰胺酶抑制剂及其用途
<130> 10103-032WO1
<140> 尚未分配
<141> 2021-05-06
<150> 63/021,432
<151> 2020-05-07
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 926
<212> PRT
<213> Homo sapiens
<400> 1
Met Gly Thr Gln Asp Pro Gly Asn Met Gly Thr Gly Val Pro Ala Ser
1 5 10 15
Glu Gln Ile Ser Cys Ala Lys Glu Asp Pro Gln Val Tyr Cys Pro Glu
20 25 30
Glu Thr Gly Gly Thr Lys Asp Val Gln Val Thr Asp Cys Lys Ser Pro
35 40 45
Glu Asp Ser Arg Pro Pro Lys Glu Thr Asp Cys Cys Asn Pro Glu Asp
50 55 60
Ser Gly Gln Leu Met Val Ser Tyr Glu Gly Lys Ala Met Gly Tyr Gln
65 70 75 80
Val Pro Pro Phe Gly Trp Arg Ile Cys Leu Ala His Glu Phe Thr Glu
85 90 95
Lys Arg Lys Pro Phe Gln Ala Asn Asn Val Ser Leu Ser Asn Met Ile
100 105 110
Lys His Ile Gly Met Gly Leu Arg Tyr Leu Gln Trp Trp Tyr Arg Lys
115 120 125
Thr His Val Glu Lys Lys Thr Pro Phe Ile Asp Met Ile Asn Ser Val
130 135 140
Pro Leu Arg Gln Ile Tyr Gly Cys Pro Leu Gly Gly Ile Gly Gly Gly
145 150 155 160
Thr Ile Thr Arg Gly Trp Arg Gly Gln Phe Cys Arg Trp Gln Leu Asn
165 170 175
Pro Gly Met Tyr Gln His Arg Thr Val Ile Ala Asp Gln Phe Thr Val
180 185 190
Cys Leu Arg Arg Glu Gly Gln Thr Val Tyr Gln Gln Val Leu Ser Leu
195 200 205
Glu Arg Pro Ser Val Leu Arg Ser Trp Asn Trp Gly Leu Cys Gly Tyr
210 215 220
Phe Ala Phe Tyr His Ala Leu Tyr Pro Arg Ala Trp Thr Val Tyr Gln
225 230 235 240
Leu Pro Gly Gln Asn Val Thr Leu Thr Cys Arg Gln Ile Thr Pro Ile
245 250 255
Leu Pro His Asp Tyr Gln Asp Ser Ser Leu Pro Val Gly Val Phe Val
260 265 270
Trp Asp Val Glu Asn Glu Gly Asp Glu Ala Leu Asp Val Ser Ile Met
275 280 285
Phe Ser Met Arg Asn Gly Leu Gly Gly Gly Asp Asp Ala Pro Gly Gly
290 295 300
Leu Trp Asn Glu Pro Phe Cys Leu Glu Arg Ser Gly Glu Thr Val Arg
305 310 315 320
Gly Leu Leu Leu His His Pro Thr Leu Pro Asn Pro Tyr Thr Met Ala
325 330 335
Val Ala Ala Arg Val Thr Ala Ala Thr Thr Val Thr His Ile Thr Ala
340 345 350
Phe Asp Pro Asp Ser Thr Gly Gln Gln Val Trp Gln Asp Leu Leu Gln
355 360 365
Asp Gly Gln Leu Asp Ser Pro Thr Gly Gln Ser Thr Pro Thr Gln Lys
370 375 380
Gly Val Gly Ile Ala Gly Ala Val Cys Val Ser Ser Lys Leu Arg Pro
385 390 395 400
Arg Gly Gln Cys Arg Leu Glu Phe Ser Leu Ala Trp Asp Met Pro Arg
405 410 415
Ile Met Phe Ala Lys Gly Gln Val His Tyr Arg Arg Tyr Thr Arg Phe
420 425 430
Phe Gly Gln Asp Gly Asp Ala Ala Pro Ala Leu Ser His Tyr Ala Leu
435 440 445
Cys Arg Tyr Ala Glu Trp Glu Glu Arg Ile Ser Ala Trp Gln Ser Pro
450 455 460
Val Leu Asp Asp Arg Ser Leu Pro Ala Trp Tyr Lys Ser Ala Leu Phe
465 470 475 480
Asn Glu Leu Tyr Phe Leu Ala Asp Gly Gly Thr Val Trp Leu Glu Val
485 490 495
Leu Glu Asp Ser Leu Pro Glu Glu Leu Gly Arg Asn Met Cys His Leu
500 505 510
Arg Pro Thr Leu Arg Asp Tyr Gly Arg Phe Gly Tyr Leu Glu Gly Gln
515 520 525
Glu Tyr Arg Met Tyr Asn Thr Tyr Asp Val His Phe Tyr Ala Ser Phe
530 535 540
Ala Leu Ile Met Leu Trp Pro Lys Leu Glu Leu Ser Leu Gln Tyr Asp
545 550 555 560
Met Ala Leu Ala Thr Leu Arg Glu Asp Leu Thr Arg Arg Arg Tyr Leu
565 570 575
Met Ser Gly Val Met Ala Pro Val Lys Arg Arg Asn Val Ile Pro His
580 585 590
Asp Ile Gly Asp Pro Asp Asp Glu Pro Trp Leu Arg Val Asn Ala Tyr
595 600 605
Leu Ile His Asp Thr Ala Asp Trp Lys Asp Leu Asn Leu Lys Phe Val
610 615 620
Leu Gln Val Tyr Arg Asp Tyr Tyr Leu Thr Gly Asp Gln Asn Phe Leu
625 630 635 640
Lys Asp Met Trp Pro Val Cys Leu Ala Val Met Glu Ser Glu Met Lys
645 650 655
Phe Asp Lys Asp His Asp Gly Leu Ile Glu Asn Gly Gly Tyr Ala Asp
660 665 670
Gln Thr Tyr Asp Gly Trp Val Thr Thr Gly Pro Ser Ala Tyr Cys Gly
675 680 685
Gly Leu Trp Leu Ala Ala Val Ala Val Met Val Gln Met Ala Ala Leu
690 695 700
Cys Gly Ala Gln Asp Ile Gln Asp Lys Phe Ser Ser Ile Leu Ser Arg
705 710 715 720
Gly Gln Glu Ala Tyr Glu Arg Leu Leu Trp Asn Gly Arg Tyr Tyr Asn
725 730 735
Tyr Asp Ser Ser Ser Arg Pro Gln Ser Arg Ser Val Met Ser Asp Gln
740 745 750
Cys Ala Gly Gln Trp Phe Leu Lys Ala Cys Gly Leu Gly Glu Gly Asp
755 760 765
Thr Glu Val Phe Pro Thr Gln His Val Val Arg Ala Leu Gln Thr Ile
770 775 780
Phe Glu Leu Asn Val Gln Ala Phe Ala Gly Gly Ala Met Gly Ala Val
785 790 795 800
Asn Gly Met Gln Pro His Gly Val Pro Asp Lys Ser Ser Val Gln Ser
805 810 815
Asp Glu Val Trp Val Gly Val Val Tyr Gly Leu Ala Ala Thr Met Ile
820 825 830
Gln Glu Gly Leu Thr Trp Glu Gly Phe Gln Thr Ala Glu Gly Cys Tyr
835 840 845
Arg Thr Val Trp Glu Arg Leu Gly Leu Ala Phe Gln Thr Pro Glu Ala
850 855 860
Tyr Cys Gln Gln Arg Val Phe Arg Ser Leu Ala Tyr Met Arg Pro Leu
865 870 875 880
Ser Ile Trp Ala Met Gln Leu Ala Leu Gln Gln Gln Gln His Lys Lys
885 890 895
Ala Ser Trp Pro Lys Val Lys Gln Gly Thr Gly Leu Arg Thr Gly Pro
900 905 910
Met Phe Gly Pro Lys Glu Ala Met Ala Asn Leu Ser Pro Glu
915 920 925
Claims (25)
1.式(I)化合物或其药学上可接受的盐,其特征在于,
其中,
R1是H且R2是CH2OH;或R1是CH2OH且R2是H;和
R3是(CH2)nR4,其中n是1或2,并且R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、[1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基,3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被下列之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是其中,R5选自由以下组成的组:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是当R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;和
条件是当R1是CH2OH且R2是H时,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
2.根据权利要求1所述的化合物,其特征在于,
R1是H;
R2是CH2OH;和
R3是(4,4-二甲基环己基)甲基、(4,4-二氟环己基)甲基、(4,4-二氯环己基)甲基、(4-乙基环己基)甲基、((1s,4S)-4-乙烯基环己基)甲基,((1s,4S)-4-异丙基环己基)甲基、((1r,4R)-4-异丙基环己基)甲基,4-(叔丁基)环己基)甲基、((1s,4S)-4-(叔丁基)环己基)甲基、((1r,4R)-4-(叔丁基)环己基)甲基、((1s,4S)-4-(三氟甲基)环己基)甲基、((1r,4R)-4-(三氟甲基)环己基)甲基、((1s,4S)-4-(2-氟丙-2-基)环己基)甲基、((1r,4R)-4-(2-氟丙-2-基)环己基)甲基、((反式)-3-(三氟甲基)环己基)甲基、((顺式)-3-(三氟甲基)环己基)甲基、((1s,4S)-4-甲氧基环己基)甲基、((1r,4R)-4-甲氧基环己基)甲基、(4-甲氧基甲基)环己基)甲基、((1s,4S)-4-环丙基环己基)甲基、((1r,4R)-4-环丙基环己基)甲基、(4-苯基环己基)甲基、(螺[2.5]辛-6-基)甲基、(螺[3.5]壬-7-基)甲基、(螺[4.5]癸-8-基)甲基、2-(4,4-二氟环己基)乙基、2-((1s,4S)-4-(三氟甲基)环己基)乙基、2-((1r,4R)-4-(三氟甲基)环己基)乙基、2-(金刚烷-1-基)乙基、2-甲基苯乙基、2-甲氧基苯乙基,2-氟苯乙基、2-氯苯乙基、2,3-二氟苯乙基、2,4-二氟苯乙基、2,5-二氟苯乙基、3,4-二氟苯乙基、2-氟-4-甲氧基苯乙基、3-氯-2-氟苯乙基、4-氯-2-氟苯乙基、5-氯-2-氟苯乙基、2,6-二氟苯乙基、3-氯-2,6-二氟苯乙基、2,6-二氟-4-(丙-1-烯-2-基)苯乙基、2,6-二氟-4-异丙基苯乙基、2,6-二氟-3-异丙基苯乙基、4-环丙基-2,6-二氟苯乙基、2,6-二氟-4-(三氟甲基)苯乙基、2,6-二氟-4-(吡咯烷-1-基)苯乙基、2,6-二氟-4-(哌啶-1基)苯乙基、2,6-二氟-4-吗啉代苯乙基、4-丁氧基-2,6-二氟苯乙基、4-(环丙基甲氧基)-2,6-二氟苯乙基、4-(四氢呋喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-3-基)氧基)苯乙基、4-(四氢-2H-吡喃-4-基)氧基)苯乙基、4-苯氧基苯乙基、4-((四氢呋喃-3-基)甲氧基)苯乙基、(R)-2-苯丙基、(S)-2-苯丙基、2-([1,1'-联苯基]-4基)乙基、2-(3,5-二氟-[1,1'-联苯基]-4-基)乙基、2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基、2-(噻吩-2-基)乙基、2-(噻吩-3-基)乙基、2-(吡啶-2-基)乙基、3-(2-氟苯基)丙基、3-(4-氟苯基)丙基、3-(噻吩-2-基)丙基、3-(噻吩-3-基)丙基、(1-苯基哌啶-4-基)甲基、(1-(2-氟苯基)哌啶-4-基)甲基、(1-(3-氟苯基)哌啶-4-基)甲基、(1-(4-氟苯基)哌啶-4-基)甲基、(1-(4-(三氟甲基)苯基)哌啶-4-基)甲基、(4-甲基-1-苯基哌啶-4-基)甲基、(4-氟-1-苯基哌啶-4-基)甲基、2-(1-苯基哌啶-4-基)乙基、(1-(2,2,2-三氟乙基)哌啶-4-基)甲基、(1-异丁酰基哌啶-4-基)甲基、(1-特戊酰基哌啶-4-基)甲基、(1-丁酰基哌啶-4-基)甲基、(1-(3-甲基丁酰基)哌啶-4-基)甲基、(1-(3,3-二甲基丁酰基))哌啶-4-基)甲基、(1-(2-环戊基乙酰基)哌啶-4-基)甲基、(1-(环丙烷羰基)哌啶-4-基)甲基、(1-(环丁烷羰基)哌啶-4-基)甲基、(1-(环戊烷羰基)哌啶-4-基)甲基、(1-(环己烷羰基)哌啶-4-基)甲基、(1-((1s,4s)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-((1r,4r)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-(4-甲氧基环己烷羰基)哌啶-4-基)甲基、(1-(4-(三氟甲基))环己烷羰基)哌啶-4-基)甲基、(1-苯甲酰基哌啶-4-基)甲基、(1-(3-(三氟甲基)苯甲酰基)哌啶-4-基)甲基、(1-(2-苯乙酰基)哌啶-4-基)甲基、(1-(噻吩-3-羰基))哌啶-4-基)甲基、((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基、(1,2,3,4-四氢萘-2-基)甲基、(2,3-二氢-1H-茚-2-基)甲基、2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基、(1-(吡啶-3-基))哌啶-4-基)甲基、(1-(环己基甲酰胺基)哌啶-4-基)甲基、(1-(环己基甲硫酰胺基)哌啶-4-基)甲基、(1-((1S,2R)-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基、((R)-1-苯基吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、(R)-1-(2-氟苯基)吡咯烷-3-基)甲基,(R)-1-(3-氟苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基、(S)-(1-(4-(三氟甲基)苯甲酰基)吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)哌啶-3-基)甲基、((R)-1-(2-氟苯基)哌啶-3-基)甲基,((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、3-氟苯乙基、4-氟苯乙基、3,4-二氯苯乙基、3-(三氟甲基)苯乙基、4-(三氟甲基)苯乙基、((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基、4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基、((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基、((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基,((S)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、或((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基。
3.根据权利要求1所述的化合物,其特征在于,
R1是CH2OH;
R2是H;和
R3是环己基甲基、(4,4-二甲基环己基)甲基、(4,4-二氟环己基)甲基、(4,4-二氯环己基)甲基、(4-乙基环己基)甲基、((1s,4S)-4-乙烯基环己基)甲基、((1s,4S)-4-异丙基环己基)甲基、((1r,4R)-4-异丙基环己基)甲基、4-(叔丁基)环己基)甲基、((1s,4S)-4-(叔丁基)环己基)甲基、((1r,4R)-4-(叔丁基)环己基)甲基,((1s,4S)-4-(三氟甲基)环己基)甲基、((1r,4R)-4-(三氟甲基)环己基)甲基、((1s,4S)-4-(2-氟丙-2-基)环己基)甲基、((1r,4R)-4-(2-氟丙-2-基)环己基)甲基、((反式)-3-(三氟甲基)环己基)甲基、((顺式)-3-(三氟甲基)环己基)甲基、((1s,4S)-4-甲氧基环己基)甲基、((1r,4R)-4-甲氧基环己基)甲基、(4-(甲氧基甲基)环己基)甲基、((1s,4S)-4-环丙基环己基)甲基、((1r,4R)-4-环丙基环己基)甲基、(4-苯基环己基)甲基、(螺[2.5]辛-6-基)甲基、(螺[3.5]壬-7-基)甲基、(螺[4.5]癸-8-基)甲基、2-环己基乙基、2-(4,4-二氟环己基)乙基、2-((1s,4S)-4-(三氟甲基)环己基)乙基、2-((1r,4R)-4-(三氟甲基)环己基)乙基、2-(金刚烷-1-基)乙基、3-环己基丙基、2-甲基苯乙基、2-甲氧基苯乙基、2-氟苯乙基、2-氯苯乙基、2,3-二氟苯乙基、2,4-二氟苯乙基、2,5-二氟苯乙基、3,4-二氟苯乙基、2-氟-4-甲氧基苯乙基、3-氯-2-氟苯乙基、4-氯-2-氟苯乙基、5-氯-2-氟苯乙基、2,6-二氟苯乙基、3-氯-2,6-二氟苯乙基、2,6-二氟-4-(丙-1-烯-2-基)苯乙基、2,6-二氟-4-异丙基苯乙基、2,6-二氟-3-异丙基苯乙基、4-环丙基-2,6-二氟苯乙基、2,6-二氟-4-(三氟甲基)苯乙基、2,6-二氟-4-(吡咯烷-1-基)苯乙基、2,6-二氟-4-(哌啶-1-基)苯乙基、2,6-二氟-4-吗啉代苯乙基、4-丁氧基-2,6-二氟苯乙基、4-(环丙基甲氧基)-2,6-二氟苯乙基、4-((四氢呋喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-3-基)氧基)苯乙基、4-((四氢-2H-吡喃-4-基)氧基)苯乙基、4-苯氧基苯乙基、4-((四氢呋喃-3-基)甲氧基)苯乙基、2-([1,1′-联苯基]-4-基)乙基、2-(3,5-二氟-[1,1′-联苯基]-4-基)乙基、2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基、2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基、2-(噻吩-2-基)乙基、2-(噻吩-3-基)乙基、2-(吡啶-2-基)乙基、3-(2-氟苯基)丙基、3-(4-氟苯基)丙基、3-(噻吩-2-基)丙基、3-(噻吩-3-基)-丙基、(1-苯基哌啶-4-基)甲基、(1-(2-氟苯基)哌啶-4-基)甲基、(1-(3-氟苯基)哌啶-4-基)甲基、(1-(4-氟苯基)哌啶-4-基)甲基、(1-(4-(三氟甲基)苯基)哌啶-4-基)甲基、(4-甲基-1-苯基哌啶-4-基)甲基、(4-氟-1-苯基哌啶-4-基)甲基、2-(1-苯基哌啶-4-基)乙基、(1-(2,2,2-三氟乙基)哌啶-4-基)甲基、(1-异丁酰基哌啶-4-基)甲基、(1-特戊酰基哌啶-4-基)甲基、(1-丁酰基哌啶-4-基)甲基、(1-(3-甲基丁酰基)哌啶-4-基)甲基、(1-(3,3-二甲基丁酰基)哌啶-4-基)甲基、(1-(2-环戊基乙酰基)哌啶-4-基)甲基、(1-(环丙烷羰基)哌啶-4-基)甲基、(1-(环丁烷羰基)哌啶-4-基)甲基、(1-(环戊烷羰基)哌啶-4-基)甲基、(1-(环己烷羰基)哌啶-4-基)甲基、(1-((1s,4s)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-((1r,4r)-4-(叔丁基)环己烷羰基)哌啶-4-基)甲基、(1-(4-甲氧基环己烷羰基)哌啶-4-基)甲基、(1-(4-(三氟甲基)环己烷羰基)哌啶-4-基)甲基、(1-苯甲酰基哌啶-4-基)甲基、(1-(3-(三氟甲基)苯甲酰基)哌啶-4-基)甲基、(1-(2-苯基乙酰基)哌啶-4-基)甲基、(1-(噻吩-3-羰基)哌啶-4-基)甲基、((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基、(1,2,3,4-四氢萘-2-基)甲基、(2,3-二氢-1H-茚-2-基)甲基、2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基、(1-(吡啶-3-基)哌啶-4-基)甲基、(1-(环己基甲酰胺基)哌啶-4-基)甲基、(1-(环己基甲硫酰胺基)哌啶-4-基)甲基、(1-((1S,2R))-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基、((R)-1-苯基吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基、(R)-1-(2-氟苯基)吡咯烷-3-基)甲基、(R)-1-(3-氟苯基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基、(S)-(1-(4-(三氟甲基)苯甲酰基)吡咯烷-3-基)甲基、((R)-1-(邻甲苯基)哌啶-3-基)甲基、((R)-1-(2-氟苯基)哌啶-3-基)甲基、((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、3-氟苯乙基、4-氟苯乙基、3,4-二氯苯乙基、3-(三氟甲基)苯乙基、4-(三氟甲基)苯乙基、((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基、4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基、((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基、((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基、((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基、((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基、((S)-1-(3-三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基、((S)-1-(4-三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基、((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基、((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基、((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基、4-丁氧基苯乙基、((1s,4R)-4-(二氟甲基)环己基)甲基、((1r,4S)-4-(二氟甲基)环己基)甲基、((1s,4R)-4-(1,1-二氟乙基)环己基)甲基、或((1r,4S)-4-(1,1-二氟乙基)环己基)甲基。
4.根据权利要求1所述的化合物,其特征在于,所述化合物为:
(2R,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(三氟甲基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-(三氟甲基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((R)-2-苯丙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((S)-2-苯丙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(吡啶-2-基)乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-2-基)乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-3-基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(环己基甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1s,4S)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((2,3-二氢-1H-茚-2-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-环己基乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-环己基丙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-([1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-丁氧基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-丁氧基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((1-(4-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((4,4-二甲基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((4,4-二氟环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((4,4-二氯环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((4-乙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基-1-(((1s,4S))-4-乙烯基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1s,4S))-4-异丙基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-异丙基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1s,4S))-4-(叔丁基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1r,4R)-4-(叔丁基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1s,4S)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1s,4S)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1r,4R)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1s,4S)-4-甲氧基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-甲氧基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((4-(甲氧基甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1s,4S)-4-环丙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((1r,4R)-4-环丙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((4-苯基环己基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(螺[2.5]辛-6-基甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(螺[3.5]壬-7-基甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(螺[4.5]癸-8-基甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1,2,3,4-四氢萘-2-基))甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((2,3-二氢-1H-茚-2-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(4,4-二氟环己基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-((1s,4S)-4-(三氟甲基)环己基)乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-((1r,4R)-4-(三氟甲基)环己基)乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-((3R,5R,7R)-金刚烷-1-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-甲基苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-甲氧基苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-氯苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,3-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,4-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,5-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3,4-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-氟-4-甲氧基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(5-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3,4-二氯苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3-氯-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-(丙-1-烯-2-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-异丙基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-3-异丙基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-环丙基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-(四氢-2H-吡喃-4-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-(三氟甲基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-(吡咯烷-1-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-(哌啶-1-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2,6-二氟-4-吗啉代苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-丁氧基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-(环丙基甲氧基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢呋喃-3-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢-2H-吡喃-3-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢-2H-吡喃-4-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-苯氧基苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢呋喃-3-基)甲氧基)苯乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-([1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(3,5-二氟-[1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3-(2-氟苯基)丙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(3-(4-氟苯基)丙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(噻吩-2-基))丙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(3-(噻吩-3-基)丙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1-苯基哌啶-4-基)甲基)哌啶-3,4,5-三醇;(2R,3R,4R,5S)-1-((1-(2-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((1-(3-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((1-(4-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1-(4-(三氟甲基)苯基)哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((4-甲基-1-苯基哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-((4-氟-1-苯基哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(2-(1-苯基哌啶-4-基)乙基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1-(吡啶-3-基)哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)哌啶-3,4,5-三醇;
2-甲基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丙-1-酮;
2,2-二甲基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丙-1-酮;
1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丁-1-酮;
3-甲基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丁-1-酮;
3,3-二甲基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丁-1-酮;
2-环戊基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)乙酮;
环丙基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环丁基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环戊基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环己基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
((1s,4S)-4-(叔丁基)环己基)(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
((1r,4R)-4-(叔丁基)环己基)(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(4-甲氧基环己基)(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(4-(三氟甲基)环己基)(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
苯基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(3-(三氟甲基)苯基)(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
2-苯基-1-(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)乙酮;
噻吩-3-基(4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
N-环己基-4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-甲酰胺;
N-环己基-4-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-甲硫酰胺;
(2R,3R,4R,5S)-2-(羟甲基)-1-((1-((1S,2R)-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-苯基吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(邻甲苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(2-氟苯基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(3-氟苯基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(4-(三氟甲基)苯基)((R)-3-(((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)吡咯烷-1-基)甲酮;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(邻甲苯基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(2-氟苯基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(3-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2R,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((4,4-二甲基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((4,4-二氟环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((4,4-二氯环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((4-乙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基-1-(((1s,4S)-4-乙烯基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1s,4S)-4-异丙基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-异丙基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1s,4S)-4-(叔丁基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1r,4R)-4-(叔丁基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1s,4S)-4-(三氟甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1r,4R)-4-(2-氟丙-2-基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基-1-(((1s,4S)-4-甲氧基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((1r,4R)-4-甲氧基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((4-(甲氧甲基)环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1s,4S)-4-环丙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1r,4R)-4-环丙基环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((4-苯基环己基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(螺[2.5]辛-6-基甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(螺[3.5]壬-7-基甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(螺[4.5]癸-8-基甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1,2,3,4-四氢萘-2-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(4,4-二氟环己基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-((1s,4S)-4-(三氟甲基)环己基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-((1r,4R)-4-(三氟甲基)环己基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-((3R,5R,7R)-金刚烷-1-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-甲基苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(3-(三氟甲基)苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-(三氟甲基)苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-甲氧基苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-氯苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,3-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,4-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,5-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3,4-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-氟-4-甲氧基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(5-氯-2-氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3,4-二氯苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-氯-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-(丙-1-烯-2-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-异丙基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-3-异丙基苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-环丙基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-(三氟甲基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-(吡咯烷-1-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-(哌啶-1-基)苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2,6-二氟-4-吗啉代苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-丁氧基-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-(环丙基甲氧基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢呋喃-3-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢-2H-吡喃-3-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢-2H-吡喃-4-基)氧基)苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-苯氧基苯乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(4-((四氢呋喃-3-基)甲氧基)苯基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(3,5-二氟-[1,1'-联苯基]-4-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-(3,5-二甲基异噁唑-4-基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(4-(3,5-二甲基-1H-吡唑-4-基)-2,6-二氟苯乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(6-氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(2-(2,3-二氢苯并[b][1,4]二噁英-6-基)乙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((R)-2-苯丙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((S)-2-苯丙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-(吡啶-2-基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-2-基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-(噻吩-3-基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-(2-氟苯基)丙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(3-(4-氟苯基)丙基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(3-(噻吩-2-基)丙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(3-(噻吩-3-基)丙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1-苯基哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((1-(2-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((1-(3-氟苯基)哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1-(4-(三氟甲基)苯基)哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((4-甲基-1-苯基哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-((4-氟-1-苯基哌啶-4-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(2-(1-苯基哌啶-4-基)乙基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1-(吡啶-3-基))哌啶-4-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)哌啶-3,4,5-三醇;
2-甲基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丙-1-酮;
2,2-二甲基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丙-1-酮;
1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丁-1-酮;
3-甲基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)丁-1-酮;
3,3-二甲基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-l-基)甲基)哌啶-1-基)丁-1-酮;
2-环戊基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)乙酮;
环丙基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环丁基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环戊基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
环己基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
((1s,4S)-4-(叔丁基)环己基)(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
((1r,4R)-4-(叔丁基)环己基)(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(4-甲氧基环己基)(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(4-(三氟甲基)环己基)(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
苯基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
(3-(三氟甲基)苯基)(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
2-苯基-1-(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)乙酮;
噻吩-3-基(4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-基)甲酮;
N-环己基-4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-甲酰胺;
N-环己基-4-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)哌啶-1-甲硫酰胺;
(2S,3R,4R,5S)-2-(羟甲基)-1-((1-((1S,2R)-2-(三氟甲基)环己基)氮杂环丁烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-苯基吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(邻甲苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(2-氟苯基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(3-氟苯基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲氧基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(6-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-2-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-甲基吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(5-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(噻吩-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-4-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(苯并[d]噁唑-2-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-2-基)吡咯烷-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(4-(三氟甲基)苯基)((R)-3-(((2S,3R,4R,5S)-3,4,5-三羟基-2-(羟甲基)哌啶-1-基)甲基)吡咯烷-1-基)甲酮;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(2-(三氟甲基)苯基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)吡啶-3-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)嘧啶-5-基)吡咯烷-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(邻甲苯基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(2-氟苯基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(2-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((R)-1-(5-异丙基噻唑-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-2-基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((R)-1-(苯并[d]噻唑-4-基)哌啶-3-基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(4-(三氟甲基)吡啶-3-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-2-(羟甲基)-1-(((S)-1-(6-(三氟甲基)吡啶-2-基)哌啶-3-基)甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1s,4R)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1r,4S)-4-(二氟甲基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1s,4R)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
(2S,3R,4R,5S)-1-(((1r,4S)-4-(1,1-二氟乙基)环己基)甲基)-2-(羟甲基)哌啶-3,4,5-三醇;
或任何前述化合物的药学上可接受的盐。
5.根据权利要求1所述的化合物,其特征在于,所述化合物是前药。
6.根据权利要求1至5中任一项所述的化合物,其特征在于,所述化合物抑制非溶酶体葡糖神经酰胺酶(GBA2)。
7.根据权利要求1至6中任一项所述的化合物,其特征在于,所述化合物特异性结合GBA2。
8.根据权利要求1至7中任一项所述的化合物,其特征在于,所述化合物降低GBA2的酶活性水平。
9.根据权利要求6至8中任一项所述的化合物,其特征在于,所述GBA2是哺乳动物GBA2。
10.一种药物组合物,其特征在于,包含根据权利要求1至9中任一项所述的化合物或其与药学上可接受的载体结合的药学上可接受的盐。
11.一种在有需要的受试者中抑制GBA2的方法,其特征在于,所述方法包括向所述受试者施用有效量的式(I)的化合物或其药学上可接受的盐:
其中,
R1是H且R2是CH2OH;或R1是CH2OH且R2是H;和
R3是(CH2)nR4,其中n是1或2,R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基,3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是其中R5选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基碳基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R1是H且R2是CH2OH,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;和
条件是R1是CH2OH且R2是H时,R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
12.一种在有需要的受试者中降低GBA2酶活性的方法,其特征在于,所述方法包括向所述受试者施用有效量的式(I)的化合物或其药学上可接受的盐:
其中,
R1是H且R2是CH2OH;或者R1是CH2OH且R2是H;和
R3是(CH2)nR4,其中n是1或2,和R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基,1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基取代,各自任选地被F、C1-6烷基、OCH3、和/或CF3的取代基中的一个或多个取代基取代一个至最大数目;或
R3是其中R5选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基碳基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目;
条件是R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基,3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯基丁基;以及
条件是R1是CH2OH且R2是H时,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
13.一种在有需要的受试者中治疗由GBA2调节的病症的方法,其特征在于,所述方法包括向所述受试者施用有效量的式(I)的化合物或其药学上可接受的盐:
其中,
R1是H且R2是CH2OH;或者R1是CH2OH且R2是H;和
R3为(CH2)nR4,其中n是1或2,R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4基、1-(环己基甲硫酰胺基)哌啶-4基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃4基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最多最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-烷基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是其中R5选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基碳基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R1是H且R2是CH2OH时,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;以及
条件是R1是CH2OH且R2是H时,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
14.一种在有需要的受试者中治疗选自神经系统疾病、溶酶体贮积病和肝脏疾病的病症的方法,其特征在于,所述方法包括向所述受试者给予有效量的式(I)的化合物或其药学上可接受的盐:
其中,
R1是H且R2是CH2OH;或者R1是CH2OH且R2是H;和
R3是(CH2)nR4,其中n是1或2,R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基,(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基,1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是苯乙基,被吡咯烷-1-基、哌啶-1-基,4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被以下之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是其中R5选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目,
条件是R1是H且R2是CH2OH,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;和
条件是R1是CH2OH且R2是H,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基。
15.根据权利要求13或14所述的方法,其特征在于,所述病症是阿尔茨海默病、帕金森病、多发性硬化、亨廷顿氏病、肌萎缩性侧索硬化(ALS)、伴有认知损伤的肌萎缩性侧索硬化(ALSci)、成瘾、焦虑、嗜银颗粒性痴呆、共济失调-毛细血管扩张症(A-T)、注意力缺陷/多动障碍(ADHD)、自闭症谱系障碍(ASD)、贝克肌营养不良(BMD)、双相障碍(BD)、布卢特病、小脑性共济失调、腓骨肌萎缩症(CMT)、慢性疲劳综合征、皮质基底节变性(CBD)、拳击手痴呆、路易体痴呆(DLB)、德热里纳-索塔斯病、弥漫性神经原纤维缠结伴钙化症、唐氏综合征、杜兴肌营养不良(DMD)、癫痫、特发性震颤(ET)、家族性英国型痴呆、家族性丹麦型痴呆、纤维肌痛、连锁于17号染色体伴帕金森病的额颞叶痴呆(FTDP-17)、弗里德赖希共济失调、格斯特曼-施特劳斯钠病、青光眼、瓜地洛帕帕金森综合征、格林-巴利综合征、哈勒沃登-施帕茨病(神经变性伴脑铁积聚1型)、失眠、兰伯特-伊顿肌无力综合征(LEMS)、重度抑郁症(MDD)、偏头痛、轻度认知障碍(MCI)、多发性脑梗死性痴呆、多系统萎缩(MSA)、重症肌无力、肌强直性营养不良(包括DM1和DM2型)、神经元蜡样脂褐质沉积症(包括1、2、3、4、5、6、7、8、9和10型)、神经病(包括周围神经病变、自主神经病变、神经炎、和糖尿病神经病变)、眼咽型肌营养不良、疼痛、苍白球脑桥黑质变性、关岛型帕金森综合征-痴呆复合征、皮克氏病(PiD)、脑炎后帕金森综合征(PEP)、原发性侧索硬化(PLS)、朊病毒病(包括克雅氏病(CJD)、变异型克雅氏病(vCJD)、致命性家族性失眠、和库鲁病)、进行性皮质下神经胶质增生、进行性核上性麻痹(PSP)、理查森综合征、精神分裂症、癫痫发作、脊髓损伤、脊髓性肌萎缩(SMA)、脊髓小脑性共济失调(包括1、2、3、4、5、6、7、8、10、11、12、13、14、16、17、18、19、20、21、22、23、25、26、27、28和29型)、中风、亚急性硬化性全脑炎、缠结性痴呆、迟发性运动障碍、抽动秽语综合征(TS)、血管性痴呆、威尔逊病、戈谢病(包括I、II和III型)、尼曼-匹克病(包括A、B和C型)、粘脂贮积症(包括I、II、III、IV、VI和VII型)、脑腱性黄瘤症、法布里病、法伯病、GM1神经节苷脂贮积病、克拉伯病、异染性脑白质营养不良(MLD)、多发性硫酸酯酶缺乏症、庞贝病、桑德霍夫病、泰萨二氏病、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、阿拉杰里综合征(Alagillesyndrome)、酒精相关性肝病、α-1抗胰蛋白酶缺乏症、自身免疫性肝炎、自身免疫性胆管炎、良性肝肿瘤、胆道闭锁、肝硬化、克里格勒-纳贾尔综合征、药物诱导的肝损伤(DILI)、半乳糖血症、吉尔伯特综合征、血色素沉着症、肝性脑病、肝细胞癌(HCC)、妊娠肝内胆汁淤积症(ICP)、溶酶体酸性脂肪酶缺乏症(LAL-D)、肝囊肿、肝癌、新生儿黄疸、原发性胆汁性胆管炎(PBC)、原发性硬化性胆管炎(PSC)、瑞氏综合征、I型糖原贮积病、或病毒性肝炎(包括A、B、C、D和E型)。
16.根据权利要求13或14所述的方法,其特征在于,所述病症是帕金森病。
17.根据权利要求13或14所述的方法,其特征在于,所述病症是阿尔茨海默病、亨廷顿病、肌萎缩性侧索硬化(ALS)、或多发性硬化。
18.根据权利要求13或14所述的方法,其特征在于,所述病症是C型尼曼匹克病。
19.根据权利要求13或14所述的方法,其特征在于,所述病症是戈谢病、IV型粘脂贮积症、神经元蜡样脂褐质沉积症或桑德霍夫病。
20.根据权利要求13或14所述的方法,其特征在于,所述病症是非酒精性脂肪性肝炎(NASH)。
21.根据权利要求11至20中任一项所述的方法,其特征在于,所述化合物是表1中所述的化合物中的一种或多种。
22.根据权利要求11至21中任一项所述的方法,其特征在于,所述施用降低所述受试者中GBA2酶活性的水平。
23.根据权利要求11至22中任一项所述的方法,其特征在于,所述受试者是人。
24.有效量的式(I)化合物或其药学上可接受的盐的用途,其特征在于,
其中,
R1是H且R2是CH2OH;或者R1是CH2OH且R2是H;和
R3是(CH2)nR4,其中n是1或2,R4是环己基、环己基甲基、苯乙基、4-苯基环己基、螺[2.5]辛-6-基、螺[3.5]壬-7-基、螺[4.5]癸-8-基、(5S,8s)-3,3-二甲基-2-氧杂螺[4.5]癸-8-基、1,2,3,4-四氢萘-2-基、2,3-二氢-1H-茚-2-基、(金刚烷基)甲基、(吡啶-2-基)甲基、(苯并[d][1,3]间二氧杂环戊烯-5-基)甲基、(2,3-二氢苯并[b][1,4]二噁英-6-基)甲基、([1,1'-联苯基]-4-基)甲基、1-(2,2,2-三氟乙基)哌啶-4-基、1-(吡啶-3-基)哌啶-4-基、1-(环己基甲酰胺基)哌啶-4-基、1-(环己基甲硫酰胺基)哌啶-4-基、1-苯基哌啶-4-基、1-环己基氮杂环丁烷-3-基、2-(噻吩-2-基)甲基、或2-(噻吩-3-基)甲基,各自任选地被F、Cl、C1-6烷基、环丙基、乙烯基、2-氟丙-2-基、甲氧基甲基、C1-5烷氧基、CHF2、CF2CH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3为苯乙基,被吡咯烷-1-基、哌啶-1-基、4-吗啉代、环丙基甲氧基、(四氢呋喃-3-基)氧基、(四氢-2H-吡喃-3-基)氧基、(四氢-2H-吡喃-4-基)氧基、苯氧基、(四氢呋喃-3-基)甲氧基、四氢-2H-吡喃-4-基、3,5-二甲基异噁唑-4-基、3,5-二甲基-1H-吡唑-4-基、F、Cl、C1-6烷基、环丙基、丙烯-2-基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是(1-甲酰基哌啶-4-基)甲基,在甲酰基上被下列之一取代:C1-6烷基、C3-7环烷基、苯基、噻吩-3-基、苯甲基、或环戊基甲基,各自任选地被F、C1-6烷基、OCH3、和/或CF3中的一个或多个取代基取代一个至最大数目;或
R3是其中R5选自一组包含:苯基、吡啶-2-基、吡啶-3-基、嘧啶-5-基、噻吩-3-基、苯并[d]噻唑-4-基、苯并[d]噻唑-2-基、苯基羰基、噻唑-2-基、苯并[d]噁唑-2-基、和苯并[d]噻唑-2-基,各自任选地被F、Cl、C1-6烷基、C1-6烷氧基、OCF3、和/或CF3中的一个或多个取代基取代一个至最大数目;
条件是R1是H且R2是CH2OH,则R3不是环己基甲基、2-环己基乙基、3-环己基丙基、苯乙基、3-苯丙基、3-(2-丙氧基苯基)丙基、3-(3-丙氧基苯基)丙基、3-(4-丙氧基苯基)丙基、或4-苯丁基;和
条件R1是CH2OH且R2是H,则R3不是苯乙基、3-苯丙基、(R)-2-苯丙基、或(S)-2-苯丙基,在药物制备中的用途。
25.根据权利要求24所述的用途,其特征在于,所述药物用于抑制GBA2、用于降低GBA2酶活性水平、用于治疗由GBA2调节的病症、用于治疗神经疾病、用于治疗溶酶体贮积病、或用于治疗肝病。
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