CN104321060A - α-氨基硼酸衍生物,选择性免疫蛋白酶体抑制剂 - Google Patents
α-氨基硼酸衍生物,选择性免疫蛋白酶体抑制剂 Download PDFInfo
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- CN104321060A CN104321060A CN201280063440.0A CN201280063440A CN104321060A CN 104321060 A CN104321060 A CN 104321060A CN 201280063440 A CN201280063440 A CN 201280063440A CN 104321060 A CN104321060 A CN 104321060A
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Classifications
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Abstract
本发明提供作为LMP7抑制剂用于治疗自身免疫性疾病和炎性疾病的式(I)化合物。在式(I)中,Rb和Rc彼此独立地选自H和C1-C6烷基;其中Rb和Rc可连接形成含氧原子的5或6元环,所述氧原子与Rb和Rc连接;Q表示Ar、Het或环烷基;R1和R2彼此独立地选自H、ORa、Hal、C1-C6烷基,其中1-5个H原子可以独立地被OH或Hal替代;Y表示CR3R4,优选为CH2或C(CH3)2;R3,R4彼此独立地表示H或C1-C6烷基;L表示L1或L2或烷基;n为选自0-3的整数;L1是Q1-CO-M-,其中Q1是Ar或Het,优选为苯基、萘基或吡啶,任选地被1-5个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;L2是Q2-M-,其中Q2是含有1个氮原子和1-3个独立地选自O、S、N或CO的另外的基团的稠合双环系统,和其中至少一个环是芳族的,由此稠合双环系统任选地被1-5个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;Q2是含有1-3个选自N、O、S和CO的杂原子的不饱和或芳族5元环系统,且任选地被苯环或吡啶环取代,其中苯环和吡啶环任选地被1-4个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;M是具有1-5个碳原子的线性或分支亚烷基,其中1-2个H原子可被ORa或苯基替代,所述苯基任选地被1-5个独立地选自Hal、ORa、及任选地被1-5个独立地选自OH和Hal的基团取代的C1-C6烷基的基团取代;或M表示具有3-7个碳原子的亚环烷基;或者M表示噻唑烷基;Ra是H或C1-C6烷基,其中1-5个H原子可以独立地被OH或Hal替代;Ar表示6元芳族碳环,其任选地与另一个具有5-8个碳原子的饱和、不饱和或芳族碳环稠合;Het表示含有1-3个独立地选自N、N+O-、O、S、SO和SO2的杂原子的5或6元饱和、不饱和或芳族杂环,且任选地与另一个具有5-8个原子和任选地含1-3个选自N、O和S的杂原子的饱和、不饱和或芳族环稠合;Hal表示Cl、Br、I或F;优选Cl或F。
Description
本发明提供α-氨基硼酸衍生物,及其在治疗炎性疾病和自身免疫性疾病、神经退行性疾病、及增殖性疾病中的用途。具体地说,本发明的化合物是选择性免疫蛋白酶体抑制剂。
所述蛋白酶体(也称为巨蛋白因子(macropain)、多催化性蛋白酶和20S蛋白酶)是一种高分子量、多亚单位蛋白酶,其已经在从古细菌(archaebacterium)到人的每一种检测的物种中被鉴别出。该酶具有约650,000的天然分子量,并且如电子显微镜所显示的,具有独特的圆柱形形态(Rivett, (1989) Arch. Biochem. Biophys. 268:1-8;和Orlowski, (1990) Biochemistry 29:10289-10297)。该蛋白酶体亚单位的分子量在20,000-35,000 (3-5)的范围,并且彼此是同源的,但不与任何其它已知的蛋白酶同源。
20S蛋白酶体是包含28个分类为α-和β-型的亚单位的700 kDa圆柱形多催化性蛋白酶复合物,所述亚单位以4个堆积的七聚体环排列。在酵母和其它真核细胞中,7个不同的α亚单位形成外环且7个不同的β亚单位构成内环。α亚单位用作19S (PA700)和1 IS (PA28)调节复合物的结合位点,以及用作由两个β亚单位环形成的内部蛋白水解室的物理屏障。因此,在体内,认为该蛋白酶体作为26S颗粒(“26S蛋白酶体”)存在。体内试验已表明,蛋白酶体的20S形式的抑制可能容易地与26S蛋白酶体的抑制相关。
在颗粒形成期间,β亚单位的氨基端前导序列(prosequences)的裂解暴露氨基端苏氨酸残基,所述苏氨酸残基起催化性亲核物质的作用。因此,负责蛋白酶体的催化活性的亚单位具有氨基端亲核残基,并且这些亚单位属于N-末端亲核物质(Ntn) ATTY REF:26500-0023WO1水解酶的种类(这里亲核的N-末端残基为例如Cys、Ser、Thy,和其它亲核部分)。这个种类包括,例如,青霉素G酰基转移酶(PGA)、青霉素V酰基转移酶(PVA)、谷氨酸PRPP氨基转移酶(GAT),和细菌糖基天冬酰胺酶。除了遍在表达的β亚单位外,高级脊椎动物还具有三种干扰素-γ-可诱导的β亚单位(LMP7、LMP2和MECLI),其分别替代它们的正常负体,β5、β1和β2。当所有三种IFN-γ-可诱导的β亚单位存在时,该蛋白酶体被称为“免疫蛋白酶体”。因此,真核细胞可具有不同比例的两种形式的蛋白酶体。
尽管使用不同的肽底物,对真核细胞20S蛋白酶体已定义了三种主要的蛋白水解活性:胰凝乳蛋白酶样活性(CT-L),其在大的疏水残基后裂解;胰蛋白酶样活性(T-L),其在碱性残基后裂解;和肽基谷氨酰肽水解活性(PGPH),其在酸性残基后裂解。两种另外的较少特征性的活性也被认为属于蛋白酶体:BrAAP活性,其在支链氨基酸后裂解;和SNAAP活性,其在小的中性氨基酸后裂解。尽管两种形式的蛋白酶体具有所有5种酶促活性,但基于特异性底物描述了这些形式之间的活性程度的差异。对于两种形式的蛋白酶体,主要的蛋白酶体蛋白水解活性似乎归因于20S核心内的不同催化位点。
在真核细胞中,蛋白降解主要地通过泛素途径介导,其中靶向破坏的蛋白连接于76个氨基酸多肽泛素。一旦选定靶标,则遍在蛋白用作26S蛋白酶体的底物,该蛋白酶体通过其三种主要蛋白水解活性的作用将蛋白裂解为短肽。虽然具有细胞内蛋白更新的一般功能,但蛋白酶体介导的降解在许多过程中也起着重要的作用,如主要的组织相容性复合体(MHC) I型呈递、细胞凋亡和细胞生存力、抗原加工、NF-κΒ激活,和促炎信号的转导。
蛋白酶体活性在涉及蛋白分解的肌肉萎缩症(muscle wasting diseases)中是高的,例如肌肉营养失调、癌症和AIDS。证据也表示蛋白酶体在I型MHC分子的抗原加工中的可能的作用(Goldberg, et al. (1992) Nature 357:375-379)。
蛋白酶体涉及神经退行性疾病和紊乱例如肌萎缩性侧索硬化(ALS),(J Biol Chem 2003, Allen S et al., Exp Neurol 2005, Puttaparthi k et al.),干燥综合征(Sjogren syndrome) (Arthritis & Rheumatism, 2006, Egerer T et al.),系统性红斑狼疮和狼疮性肾炎(SLE/LN),(Arthritis & rheuma 2011, lchikawa et al., J Immunol, 2010, Lang VR et al., Nat Med, 2008, Neubert K et al),肾小球性肾炎(J Am Soc nephrol 2011, Bontscho et al.),类风湿性关节炎(Clin Exp Rheumatol, 2009, Van der Heiden JW et al.),炎性肠道疾病(IBD),溃疡性结肠炎,克罗恩氏病,( Gut 2010, Schmidt N et al., J Immunol 2010, Basler M et al., Clin Exp Immunol, 2009, Inoue S et al.)、多发性硬化(Eur J Immunol 2008, Fissolo N et al., J Mol Med 2003, Elliott PJ et al., J Neuroimmunol 2001, Hosseini et al., J Autoimmun 2000, Vanderlugt CL et al.),肌萎缩性侧索硬化(ALS),(Exp Neurol 2005, Puttaparthi k et al., J Biol Chem 2003, Allen S et al.),骨关节炎(Pain 2011, Ahmed s et al., Biomed Mater Eng 2008, Etienne S et al.),动脉硬化症(J Cardiovasc Pharmacol 2010, Feng B et al.,银屑病(Genes & Immunity, 2007, Kramer U et al.),重症肌无力(J Immunol, 2011, Gomez AM et al.),皮肤纤维化(Thorax 2011, Mutlu GM et al., Inflammation 2011, Koca SS et al., Faseb J 2006, Fineschi S et al.),肾纤维化(Nephrology 2011 Sakairi T et al.),心纤维化(Biochem Pharmacol 2011, Ma y et al.,) 肝纤维化(Am J Physiol gastrointest Liver肝Physiol 2006, Anan A et al.),肺纤维化(Faseb J 2006, Fineschi S et al et al.),免疫球蛋白A肾病(IGa肾病),(Kidney Int, 2009, Coppo R et al.),血管炎(J Am Soc nephrol 2011, Bontscho et al.),移植排斥(Nephrol Dial transplant 2011, Waiser J et al.),血液恶性肿瘤(Br J Haematol 2011, singh AV et al., Curr Cancer Drug Target 2011, Chen D et al.)和哮喘。
然而,应该注意到,可市售获得的蛋白酶体抑制剂抑制蛋白酶体的组成性和免疫性两种形式。甚至硼替佐米(Bortezomib),其为FDA批准的用于治疗复发的多发性骨髓瘤患者的蛋白酶体抑制剂,也不区分这两种形式(Altun et al, Cancer Res 65:7896, 2005)。
此外,硼替佐米的使用与治疗紧急出现的疼痛性外周神经病(PN)相关,这种硼替佐米诱导的神经退行性病变在体外经由不依赖蛋白酶体的机制发生并且硼替佐米在体外和体内抑制几种非蛋白酶体靶标(Clin. Cancer Res, 17(9), 5月1日 , 2011 )。
除了常规的蛋白酶体抑制剂,一种新的途径可以特异性地靶向血液学特异性免疫蛋白酶体,由此增加整体效果并减少负面的脱靶效应。已经表明免疫蛋白酶体-特异性抑制剂可对来自血液源的细胞显示增强的效果(Curr Cancer Drug Targets, 11 (3), 3月, 2011 )。
因此存在对提供新的蛋白酶体抑制剂的需求,所述抑制剂对一种特异性形式的蛋白酶体有选择性。
在另一方面,本发明涉及包含至少一种依据式(I)和相关式的化合物的药物制剂。
这样的药物制剂也可包含另外的活性剂。所述另外的活性剂可选自免疫抑制剂、抗炎药或干扰素。
在另一方面,本发明涉及制备依据式(I)和相关式的化合物的方法。
本发明还涉及由以下单独的包构成的药物套装或药剂盒:
(a) 有效量的依据式(I)或相关式的化合物和/或其药学可用衍生物、互变异构体、盐、溶剂合物和立体异构体,包括其所有比例的混合物,
和
(b) 有效量的另一药物活性成分。
本发明涵盖或者单独的式(I)和相关式的化合物或者与一种或多种其代谢物组合的式(I)和相关式的化合物。
详述
本发明的化合物为免疫蛋白酶体亚单位LMP7的抑制剂。优选地,它们显示对LMP7超过Beta5的选择性。
本发明提供式(I)化合物:
其中
Rb和Rc彼此独立地选自H和C1-C6烷基;其中Rb和Rc可连接形成含氧原子的5或6元环,所述氧原子与Rb和Rc连接;
Q表示Ar、Het或环烷基;
R1、R2彼此独立地选自H、ORa (优选甲氧基)、Hal、其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基;
Y表示CR3R4,优选为CH2或C(CH3)2;
R3,R4彼此独立地表示H或C1-C6烷基,例如甲基;
L表示L1或L2或烷基,优选甲基;
n为选自0、2或3的整数并且优选地为1;
L1是,其中
Q1是Ar或Het,优选为苯基、萘基或吡啶,任选地被1-5个独立地选自ORa、Hal、苯基\及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;
L2是,其中
Q2是含有1个氮原子和1-3个独立地选自O、S、N或CO的另外的基团的稠合双环系统,和其中至少一个环是芳族的,由此稠合双环系统任选地被1-5个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;
或
Q2是含有1-3个选自N、O、S或CO的杂原子的不饱和或芳族5元环系统,且任选地被苯环或吡啶环取代,其中苯环或吡啶环任选地被1-4个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;
M是具有1-5个碳原子的线性或分支亚烷基,其中1-2个H原子可被ORa、或任选地被1-5个独立地选自Hal、ORa及任选地被1-5个独立地选自OH和Hal的基团取代的C1-C6烷基的基团取代的苯基替代;或
M表示具有3-7个碳原子的亚环烷基;或
M表示噻唑烷基;
Ra是H或其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基;
Ar表示6元芳族碳环,其任选地与另一个具有5-8个碳原子的饱和、不饱和或芳族碳环稠合;
Het表示含有1-3个独立地选自N、N+O-、O、S、SO和SO2的杂原子的5或6元饱和、不饱和或芳族杂环,且任选地与另一个具有5-8个原子和任选地含1-3个独立地选自N、O和S的杂原子的饱和、不饱和或芳族环稠合;
Hal表示Cl、Br、I或F;优选Cl或F,
及其对映体、非对映体和混合物,及其药学上可接受的盐;
在L含有1或数个手性中心的情况下,式(I)涵盖任何分离的对映体和非对映体,及其所有比例的混合物。
在一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中L表示L1,从而M为具有3-7个碳原子的亚环烷基。优选地,M选自5-或6-元亚环烷基。这样的亚环烷基的实例如下:
。
在另一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中L表示L1,从而M为具有1-5个碳原子的线性或分支亚烷基,其中1或2个H原子可被ORa或苯基替代,所述苯基任选地被1-5个独立地选自Hal、ORa及C1-C6烷基的基团取代,所述C1-C6烷基任选地被1-5个独立地选自OH和Hal的基团取代。
在另一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中L是L2,从而M表示具有1-5个碳原子的线性或分支亚烷基,其中1或2个H原子可被ORa苯基替代,所述苯基任选地被1-5个独立地选自Hal、ORa及C1-C6烷基的基团取代,所述C1-C6烷基任选地被1-5个独立地选自OH和Hal的基团取代。
优选L2中的M为具有1-5个碳原子的未取代的线性亚烷基。
在另一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中L是L1。L1优选选自以下基团:
在另一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中L是L2。L2优选选自以下基团:
在另一个具体的实施方案中,本发明提供式(I)和相关式的化合物,其中所述基团选自以下基团:
Ar可以是未取代的或优选由以下基团一取代、二取代或三取代:Hal、烷基、OR3、N(R3)2、NO2、CN、COOR3、CF3、OCF3、CON(R3)2、NR3CO烷基、NR3CON(R3)2、NR3SO2烷基、COR3、SO2N(R3)2、SO烷基或SO2烷基、苯基、吡啶基、嘧啶基、O-苯基、O-吡啶基、O-嘧啶基、-[C(R3)2]n-COOR3和/或-O[C(R3)2]n-CON(R3)2。
Ar表示,例如,萘基、苯基、邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基、邻-、间-或对-丙基苯基、邻-、间-或对-异丙基苯基、邻-、间-或对-叔丁基苯基、邻-、间-或对-羟基苯基、邻-、间-或对-硝基苯基、邻-、间-或对-氨基苯基、邻-、间-或对-(N-甲基氨基)苯基、邻-、间-或对-(N-甲基氨基羰基)苯基、邻-、间-或对-乙酰氨基-苯基、邻-、间-或对-甲氧基苯基、邻-、间-或对-乙氧基苯基、邻-、间-或对-乙氧基羰基-苯基、邻-、间-或对-(N,N-二甲基氨基)苯基、邻-、间-或对-(N,N-二甲基-氨基羰基)苯基、邻-、间-或对-(N-乙基氨基)苯基、邻-、间-或对-(N,N-二乙基氨基)-苯基、邻-、间-或对-氟代苯基、邻-、间-或对-溴代苯基、邻-、间-或对-氯代苯基、邻-、间-或对-(甲基磺酰氨基)苯基、邻-、间-或对-(甲基磺酰基)苯基、邻、间或对氨基-硫烷基-苯基、邻-、间-或对-苯氧基苯基,更优选2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二甲基苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氟苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氯苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二溴苯基,2,4-或2,5-二硝基苯基,2,5-或3,4-二甲氧基苯基,3-硝基-4-氯代苯基,3-氨基-4-氯代-,2-氨基-3-氯代-,2-氨基-4-氯代-,2-氨基-5-氯代-或2-氨基-6-氯代-苯基,2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨基苯基,2,3-二氨基苯基,2,3,4-,2,3,5-,2,3,6-,2,4,6-或3,4,5-三氯苯基,2,4,6-三甲氧基-苯基,2-羟基-3,5-二氯苯基,对-碘代苯基,3,6-二氯-4-氨基苯基,4-氟-3-氯代苯基,2-氟-4-溴代苯基,2,5-二氟-4-溴代苯基,3-溴代-6-甲氧基苯基,3-氯代-6-甲氧基苯基,3-氯代-4-乙酰氨基苯基,3-氟-4-甲氧基苯基,3-氨基-6-甲基苯基,3-氯代-4-乙酰氨基苯基或2,5-二甲基-4-氯代苯基。
Ar特别优选地表示,例如,未取代的或由以下基团一取代或二取代的苯基,优选为一取代的苯基:F、OCH3、CH3、CF3、苯基和/或吡啶基,例如,2'-甲氧基-苯基-、2'-三氟甲基-苯基- (携带至少一个2'取代基的芳基)、2'-氯代-苯基、2',6'-二甲基-苯基-或2'-烷基-苯基-,优选2'-甲基-苯基。
Het为例如,2-或3-呋喃基、苯并呋喃基、2-或3-噻吩基、苯并噻吩基、1-, 2-或3-吡咯基、1-, 2-, 4-或5-咪唑基、1-, 3-, 4-或5-吡唑基、2-, 4-或5-噁唑基、3-, 4-或5-异噁唑基、2-, 4-或5-噻唑基、3-, 4-或5-异噻唑基、2-, 3-或4-吡啶基、2-, 4-, 5-或6-嘧啶基,此外优选1,2,3-三唑-1-, -4-或-5-基、1,2,4-三唑-1-, -3-或-5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-哒嗪基、吡嗪基、1-, 2-, 3-, 4-, 5-, 6-或7-吲哚基、吲唑基、4-或5-异吲哚基、1-, 2-, 4-或5-苯并咪唑基、1-, 3-, 4-, 5-, 6-或7-苯并吡唑基、2-, 4-, 5-, 6-或7-苯并噁唑基、3-, 4-, 5-, 6-或7-苯并异噁唑基、2-, 4-, 5-, 6-或7-苯并噻唑基、2-, 4-, 5-, 6-或7-苯并异噻唑基、4-, 5-, 6-或7-苯并-2,1,3-噁二唑基、2-, 3-, 4-, 5-, 6-, 7-或8-喹啉基、1-, 3-, 4-, 5-, 6-, 7-或8-异喹啉基、3-, 4-, 5-, 6-, 7-或8-肉啉基、2-, 4-, 5-, 6-, 7-或8-喹唑啉基、5-或6-喹喔啉基、2-, 3-, 5-, 6-, 7-或8-2H-苯并-1,4-噁嗪基,此外优选1,3-苯并间二氧杂环戊烯-5-基、1,4-苯并二氧杂环己烷-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并噁二唑-5-基。
Het中的杂环基也可以部分地或完全地被氢化。
因此Het也可表示,例如,2,3-二氢-2-, -3-, -4-或-5-呋喃基、2,5-二氢-2-, -3-, -4-或-5-呋喃基、四氢-2-或-3-呋喃基、1,3-二氧杂环戊烷-4-基、四氢-2-或-3-噻吩基、2,3-二氢-1-, -2-, -3-, -4-或-5-吡咯基、2,5-二氢-1-, -2-, -3-, -4-或-5-吡咯基、1-, 2-或3-吡咯烷基、四氢-1-, -2-或-4-咪唑基、2,3-二氢-1-, -2-, -3-, -4-或-5-吡唑基、四氢-1-, -3-或-4-吡唑基、1,4-二氢-1-, -2-, -3-或-4-吡啶基、1,2,3,4-四氢-1-, -2-, -3-, -4-, -5-或-6-吡啶基、1-, 2-, 3-或4-哌啶基、2-, 3-或4-吗啉基、四氢-2-, -3-或-4-吡喃基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷-2-, -4-或-5-基、六氢-1-, -3-或-4-哒嗪基、六氢-1-, -2-, -4-或-5-嘧啶基、1-, 2-或3-哌嗪基、1,2,3,4-四氢-1-, -2-, -3-, -4-, -5-, -6-, -7-或-8-喹啉基、1,2,3,4-四氢-1-, -2-, -3-, -4-, -5-, -6-, -7-或-8-异喹啉基、2-, 3-, 5-, 6-, 7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,此外优选2,3-亚甲基二氧基苯基、3,4-亚甲基二氧基苯基、2,3-亚乙基二氧基苯基、3,4-亚乙基二氧基苯基、3,4-(二氟-亚甲基二氧基)苯基、2,3-二氢苯并呋喃-5-或-6-基、2,3-(2-氧代亚甲基二氧基)-苯基或还表示3,4-二氢-2H-1,5-苯并二氧杂环庚烯-6-或-7-基,此外优选2,3-二氢苯并呋喃基或2,3-二氢-2-氧代呋喃基。
Het可以是未取代的或由以下基团一取代、二取代或三取代:Hal、烷基、-[C(R3)2]n-Ar、-[C(R3)2]n-环烷基、OR3、CF3、OCF3、N(R3)2、NR3CON(R3)2、NO2、CN、-[C(R3)2]n-COOR3、-[C(R3)2]n-CON(R3)2、NR3CO烷基、NR3SO2烷基、COR3、SO2N(R3)2、SO烷基、O-苯基、O-吡啶基、O-嘧啶基、苯基、吡啶基和/或SO2烷基。
烷基为未分支(线性)或分支的,并具有1、2、3、4、5、6、7、8、9、10、11或12个碳原子。烷基优选地表示甲基,此外表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还表示戊基、1-, 2-或3-甲基丁基、1,1-, 1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-, 2-, 3-或4-甲基戊基、1,1-, 1,2-, 1,3-, 2,2-, 2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外优选表示,例如,三氟甲基。
烷基非常特别优选地表示具有1, 2, 3, 4, 5或6个碳原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基、1,1,1-三氟乙基。在一个优选的实施方案中,烷基为全氟代的。
环烷基优选地表示环丙基、环丁基、环戊基、环己基或环庚基。环烷基可优选地被烷基、OH、O-烷基、Hal取代。
在另一个具体的实施方案中,本发明的化合物选自以下基团:
下文缩写指以下所用的缩写:
AcOH (乙酸)、BINAP (2,2'-双(二苯基膦基)-1,1-联二萘)、dba (二亚苄基丙酮)、tBu (叔丁基)、tBuOK (叔丁醇钾)、CDI (1,1'-羰基二咪唑)、DBU (1,8-氮杂双环[5.4.0]十一碳-7-烯)、DCC (二环己基碳二亚胺)、DCM (二氯甲烷)、DIAD (偶氮二羧酸二异丁酯)、DIC (二异丙基碳二亚胺(diisopropilcarbodiimide))、DIEA (二异丙基乙胺)、DMA (二甲基乙酰胺)、DMAP (4-二甲基氨基吡啶)、DMSO (二甲基亚砜)、DMF (N,N-二甲基甲酰胺)、EDC.HCl (1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐)、EtOAc (乙酸乙酯)、EtOH (乙醇)、g (克)、cHex (环己烷)、HATU (二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-铵六氟磷酸盐)、HOBt (N-羟基苯并三唑)、HPLC (高效液相层析)、hr (小时)、MHz (兆赫)、MeOH (甲醇)、min (分钟)、mL (毫升)、mmol (毫摩尔)、mM (毫摩尔浓度)、mp (熔点)、MS (质谱法)、MW (微波)、NMM (N-甲基吗啉)、NMR (核磁共振)、NBS (N-溴代琥珀酰亚胺)、PBS (磷酸盐缓冲盐水)、PMB (对-甲氧基苄基)、PyBOP (苯并三唑-1-基-氧基三吡咯烷基六氟磷酸盐)、RT (室温)、TBAF (氟化四丁基铵)、TBTU (N,N,N',N'-四甲基-O-(苯并三唑-1-基)脲四氟硼酸盐)、T3P (丙烷膦酸酐)、TEA (三乙胺)、TFA (三氟乙酸)、THF (四氢呋喃)、PetEther (石油醚)、TBME (叔丁基甲基醚)、TLC (薄层层析)、TMS (三甲基甲硅烷基)、TMSI (三甲基甲硅烷基碘化物)、UV (紫外线)。
一般地,式(I)化合物,其中R1、n、Rb、Rc、L和Q如上所定义,可从如在流程1中概述的式(II)化合物获得。
第一步包括式(II)化合物(其中L如上所定义)与式(III)化合物(其中R1、n、Ra、Rb、Rc和Q如上所定义)的反应。采用本领域技术人员熟知的用于由羧酸与标准偶联剂(例如但不限于HATU、TBTU、聚合物担载的1-烷基-2-氯代吡啶盐(聚合物担载的Mukaiyama试剂)、1-甲基-2-氯代吡啶碘化物(Mukaiyama试剂)、碳二亚胺(例如DCC、DIC、EDC)和HOBt, PyBOP?和本领域技术人员熟知的其它的此类试剂,优选TBTU)制备酰胺的条件和方法,在碱(例如TEA、DIEA、NMM、聚合物担载的吗啉(优选DIEA))存在或不存在下,在合适的溶剂例如DCM、THF或DMF中,在-10℃至50℃之间的温度下,优选在0℃,进行该反应数小时,例如1小时-24小时。作为选择,通过本领域技术人员熟知的方法,例如但不限于用SOCl2、POCl3、PCl5、(COCl)2在催化量的DMF存在或不存在下,在合适的溶剂例如甲苯、DCM、THF存在或不存在下,在从20℃上升至100℃的温度下,优选地在50℃,处理数小时,例如1小时-24小时,可将式(II)化合物转化为羧酸衍生物例如酰基卤化物或酐。采用本领域技术人员熟知的用于由羧酸衍生物(例如酰氯)与烷基胺制备酰胺的条件和方法,在碱例如TEA、DIEA、NMM的存在下,在合适的溶剂例如DCM、THF或DMF中,在从20℃上升至100℃的温度下,优选地在50℃,进行数小时,例如1小时-24小时,可实现羧酸衍生物向式(I)化合物的转化。
流程1
式(Ia)化合物,其中R1、n、L和Q如上所定义,其中Rb和Rc是H,可由式(Ib)化合物起始制备,其中R1、n、L和Q如上所定义,其中Rb和Rc是C1-C6烷基;从而采用本领域技术人员熟知的用于水解硼酸酯的方法,例如但不限于用HCl、HBr、HI、TFA在过量的小分子量硼酸(例如但不限于i-BuB(OH)2)存在或不存在下处理,Rb和Rc可连接形成含氧原子的5或6元环,所述氧原子与Rb和Rc键合(流程2)。
流程2
式(III)化合物可如在流程3中概述的制备。
流程3
式(IV)化合物(其中R1、n、Rb、Rc和Q如上所定义,附带条件是Rb、Rc不表示H)的转化得到式(V)化合物(其中R1、n、Rb、Rc和Q如上所定义,附带条件是Rb、Rc不表示H)可通过用DCM在强碱例如nBuLi、tBuLi、MeLi、LDA、LiHMDS(优选nBuLi)的存在下,在合适的溶剂例如THF或二氧杂环己烷(优选THF)中,在从-100℃上至室温的温度下处理数小时,例如1小时-24小时来实现。当适当地选择Rb和Rc时,反应可产生对映体富集的产物。例如,当Rb和Rc一起表示(1S, 2S, 3R, 5S)-(+)-蒎烷二醇时,优先形成具有(S)构型的产物(Matteson, D. S.;Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, 5241-5242)。
式(V)化合物(其中R1、n、Rb、Rc、L和Q如上所定义,附带条件是Rb, Rc不表示H)得到式(VII)化合物(其中R1、n、Rb、Rc和Q如上所定义,附带条件是Rb、Rc不表示H)的转化可通过与式(VI)化合物在合适的溶剂例如THF或二氧杂环己烷,优选在THF中,在从-100℃上升至室温的温度下反应数小时,例如1小时-24小时来实现。反应通常伴随构型反转而进行,从而如果式(V)化合物具有(S)构型,则将获得具有(R)构型的式(VII)化合物(Matteson, D. S.;Sadhu, K. M. J. Am. Chem. Soc. 1981, 103, 5241-5242)。
最后,式(VII)化合物向式(II)化合物的转化可通过用合适的酸,例如HCl或TFA,优选TFA,在合适的溶剂例如DCM、二二乙醚、二异丙基醚或THF,优选二二乙醚中,在-30℃至30℃之间的温度下,优选地在-10℃处理数小时,例如1小时-48小时来实现。
作为选择,式(IIIa)化合物,其中R1、n、Rb、Rc和Q如上所定义和Ra表示H,可如在流程4中概述的制备。
流程4
式(VIII)化合物(其中R1和Q如上所定义)可通过与式(IX)化合物(其中Rb和Rc如上所定义)在合适的催化剂(例如但不限于(1,3-二环己基咪唑-2-亚基)叔丁醇铜(I) ((ICy)CuOtBu)的存在下,在合适的溶剂例如苯、甲苯、二氧杂环己烷、THF中,在室温和80℃之间的温度下反应数小时,例如1小时-48小时,转化为式(X)化合物,其中R1、n、Rb、Rc和Q如上所定义。
可采用酸像HCl或TFA,优选HCl,在合适的溶剂例如DCM、二二乙醚、二异丙基醚、THF、二氧杂环己烷或甲醇,优选二氧杂环己烷和甲醇的混合物中,在-10℃至40℃之间的温度下,优选在室温进行数小时,例如1小时-48小时,使式(X)化合物去保护,得到式(IIIa)化合物。
如果上述组的通用合成方法不适用于获得依据式(I)的化合物和/或用于合成式(I)化合物的必需中间体,则应采用本领域技术人员已知的合适的制备方法。
一般来说,任何单独的式(I)化合物的合成途径将取决于各个分子的特定取代基和取决于必需的中间体的现成的可获得性;以及本领域普通技术人员认识到的此类因素。对于所有的保护和去保护方法,参见Philip J. Kocienski, 于"Protecting Groups(保护基团)", Georg Thieme Verlag Stuttgart, New York, 1994和,Theodora W. Greene和Peter G. M. Wuts 于"Protective Groups in Organic Synthesis(有机合成中的保护基团)", Wiley Interscience, 第3版1999。
本发明的化合物可通过从适宜溶剂蒸发的结晶,与溶剂分子缔合地分离。式(I)化合物的药学上可接受的酸加成盐,其包括碱性中心,可以常规的方式制备。例如,游离碱的溶液可用合适的酸(纯的或者在合适的溶液中)处理,并且通过过滤或通过在真空下蒸发反应溶剂分离得到的盐。药学上可接受的碱加成盐可以类似的方式,通过用合适的碱处理包含酸性中心的式(I)化合物的溶液而获得。两种类型的盐可采用离子交换树脂技术形成或互换。
取决于所用的条件,反应时间通常在数分钟和14天之间,且反应温度在约-30℃和140℃之间,通常在-10℃和90℃之间,特别是在约0℃和约70℃之间。
此外,式(I)化合物可通过用溶剂分解剂或氢解剂处理,由其功能性衍生物之一释出式(I)化合物而获得。
用于溶剂分解或氢解的优选的起始原料为符合式(I)的那些原料,但包含相应的受保护的氨基和/或羟基而非一个或多个游离的氨基和/或羟基,优选携带氨基-保护基团而非结合于N原子的H原子的那些原料,特别是携带R'-N基团(其中R'表示氨基-保护基团)而不是HN基团的那些原料,和/或携带羟基-保护基团而不是羟基的H原子的那些原料,例如符合式(I)的那些原料,但携带-COOR"基团,其中R"表示羟基保护基团,而不是-COOH基团。
多个相同的或不同的受保护氨基和/或羟基存在于起始原料的分子中也是可能的。如果存在的保护基团彼此不同,则在许多情况下可选择性地使它们解离。
术语"氨基-保护基团"在通用术语中为已知的并涉及适用于保护(封闭)氨基免受化学反应的基团,但在所需的化学反应已在分子别处进行后可容易地将其除去。典型的此类基团特别是,未取代或取代的酰基、芳基、芳烷氧基甲基或芳烷基。因为氨基-保护基团在所需反应(或反应序列)后除去,它们的类型和大小不是特别至关重要的;然而,优选具有1-20,特别是1-8个碳原子的那些保护基团。术语"酰基"在广义上应与本方法联系起来理解。其包括衍生自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基,且特别是烷氧基-羰基、芳基氧基羰基和尤其是芳烷氧基羰基。此类酰基的实例是烷酰基,例如乙酰基、丙酰基和丁酰基;芳烷酰基,例如苯基乙酰基;芳酰基,例如苯甲酰基和甲苯基;芳基氧基烷酰基,例如POA;烷氧基羰基、例如甲氧基-羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC (叔丁氧基-羰基)和2-碘代乙氧基羰基;芳烷氧基羰基,例如CBZ ("苄氧羰基(carbo-benz-oxy)")、4-甲氧基苄基氧基羰基和FMOC;和芳基-磺酰基、例如Mtr。优选的氨基-保护基团是BOC和Mtr,此外还有CBZ、Fmoc、苄基和乙酰基。
术语"羟基-保护基团"同样在通用术语中是已知的并涉及适用于保护羟基免受化学反应,但在所需的化学反应已在分子别处进行后可容易地除去的基团。典型的此类基团为上述未取代或取代的芳基、芳烷基或酰基,进一步为烷基。羟基-保护基团的性质和大小不是至关重要的,因为它们在所需化学反应或反应序列后同样被除去;优选具有1-20,特别是1-10个碳原子的基团。羟基-保护基团的实例尤其是苄基、4-甲氧基苄基、对-硝基-苯甲酰基、对-甲苯磺酰基、叔丁基和乙酰基,其中苄基和叔丁基是特别优选的。
采用术语"化合物的溶剂合物"指惰性溶剂分子加合到由于它们的相互吸引力而形成的化合物中。溶剂合物是例如单水合物或二水合物或醇合物。
式(I)化合物从它们的官能衍生物中释出-取决于所用的保护基团-例如采用强酸,有利地采用TFA或高氯酸,但也采用其它强无机酸,例如盐酸或硫酸,强有机羧酸,例如三氯乙酸,或磺酸,例如苯磺酸或对-甲苯磺酸。存在另外的惰性溶剂是可能的,但不总是必要的。合适的惰性溶剂优选地为有机的,例如羧酸,例如乙酸;醚,例如THF或二氧杂环己烷;酰胺,例如DMF;卤代烃,例如DCM;此外还有醇,例如甲醇、乙醇或异丙醇,和水。此外,上述溶剂的混合物也是合适的。TFA优选地以过量所用,而不加入更多的溶剂,且高氯酸优选地以乙酸和70%高氯酸的比例9:1的混合物的形式使用。用于分解的反应温度有利地在约0和约50℃之间,优选地在15和30℃之间(RT)。
BOC、OBut和Mtr基团可,例如,优选地采用在DCM中的TFA或采用在二氧杂环己烷中约3-5N HCl在15-30℃下分解,且FMOC基团可采用二甲胺、二乙胺或哌啶在DMF中的约5-50%溶液在15-30℃下解离。
可氢解除去的保护基团(例如CBZ、苄基或从其噁二唑衍生物中释出脒基)可例如通过在催化剂(例如贵金属催化剂,例如钯,有利地在载体例如碳上)的存在下,用氢处理而解离。本文的合适的溶剂为上文指出的那些溶剂,特别是,例如醇,例如甲醇或乙醇,或酰胺,例如DMF。氢解通常在约0和100℃之间的温度下和在约1和200巴之间的压力下进行,优选地在20-30℃和1-10巴下进行。CBZ基团的氢解,例如,在5-10% Pd/C上在甲醇中,或采用甲酸铵(代替氢)在Pd/C上在甲醇/DMF中,在20-30℃下很好地进行。
合适的惰性溶剂的实例为烃,例如己烷、石油醚、苯、甲苯或二甲苯;氯代烃,例如三氯乙烯、1,2-二氯乙烷、四氯甲烷、三氟-甲基苯、氯仿或DCM;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如二乙醚、二异丙基醚、四氢呋喃(THF)或二氧杂环己烷;二醇醚,例如乙二醇单甲基或单乙基醚或乙二醇二甲基醚(二甘醇二甲醚);酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基-甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲基亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如EtOAc,或所述溶剂的混合物。
酯可例如,采用LiOH、NaOH或KOH在水、水/THF、水/THF/乙醇或水/二氧杂环己烷中,在0和100℃之间的温度下皂化。此外,可例如采用乙酸、TFA或HCL水解酯。
此外,游离的氨基可以常规的方式,采用酰氯或酐酰化,或采用未取代或取代的烷基卤烷基化,或与CH3-C(=NH)-OEt,有利地在惰性溶剂例如DCM或THF中和/或在碱例如三乙胺或吡啶的存在下,在-60℃和+30℃之间的温度下反应。
贯穿本说明书,术语离去基团优选地表示Cl、Br、I或反应性修饰的OH基团,例如,活性酯、咪唑(imidazolide)或具有1至6个碳原子的烷基磺酰基氧基(优选甲基磺酰基氧基或三氟甲基磺酰基氧基)或具有6至10个碳原子的芳基磺酰基氧基(优选苯基-或对甲苯基磺酰基氧基)。
用于在典型的酰化反应中激活羧基的这种类型的基团在文献(例如在标准著作,例如Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry(有机化学的方法)], Georg-Thieme-Verlag, Stuttgart)中描述。
活性酯有利地原位形成,例如通过加入HOBt或N羟基琥珀酰亚胺来进行。
采用术语"药学可用衍生物"指例如式I化合物的盐和所谓的前药化合物。
采用术语"前药衍生物"指已用例如烷基或酰基、糖或寡肽修饰和在生物体中快速地裂解以形成活性化合物的式I化合物。
这些也包括如例如在Int. J. Pharm. 115, 61-67 (1995)中描述的依据本发明化合物的可生物降解的聚合物衍生物。
药学可用盐和其它形式
所述式(I)化合物可以其最终的非盐形式使用。另一方面,本发明也涉及这些化合物以其药学上可接受的盐形式的使用,其可通过本领域已知的程序衍生自各种有机和无机酸和碱。式I化合物的药学上可接受的盐形式大部分通过常规的方法制备。如果式I化合物含有酸性中心,例如羧基,则其合适的盐之一可通过化合物与合适的碱反应来形成,得到相应的碱-加成盐。这样的碱为例如碱金属氢氧化物,包括氢氧化钾和氢氧化钠;碱土金属氢氧化物,例如氢氧化镁和氢氧化钙;和各种有机碱,例如哌啶、二乙醇胺和N-甲基-葡糖胺(甲葡胺)、苄星、胆碱、二乙醇胺、乙二胺、苯乙苄胺、二乙胺、哌嗪、赖氨酸、L-精氨酸、氨、三乙胺、甜菜碱、乙醇胺、吗啉和氨丁三醇。在某些包含碱性中心的式I化合物的情况下,酸-加成盐可通过用药学上可接受的有机和无机酸处理这些化合物来形成,所述有机和无机酸例如卤化氢,例如氯化氢或溴化氢,其它矿物酸及其相应的盐,例如硫酸盐、硝酸盐或磷酸盐等,和烷基-和单芳基-磺酸盐,例如甲烷磺酸盐、乙烷磺酸盐、甲苯磺酸盐和苯-磺酸盐,和其它有机酸及其相应的盐,例如碳酸盐、乙酸盐、三氟-乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I化合物的药学上可接受的酸-加成盐包括以下:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯-磺酸盐(besylate)、硫酸氢盐、亚硫酸氢盐、溴化物、樟脑酸盐(camphorate)、樟脑-磺酸盐、癸酸盐、辛酸盐、氯化物、氯代苯甲酸盐、柠檬酸盐、环己基氨基磺酸盐、肉桂酸盐、二葡糖酸盐、二氢-磷酸盐、二硝基苯甲酸盐、十二烷基-硫酸盐、乙烷磺酸盐、甲酸盐、羟乙酸盐、富马酸盐、半乳糖二酸盐(galacterate) (来自粘酸)、半乳糖醛酸盐、葡糖庚酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半-琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基-乙烷-磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、单-氢-磷酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这并不表示限制。两种类型的盐可优选地采用离子-交换树脂技术形成或互换。
此外,式I化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(lll)、锰(II)、钾、钠和锌盐,但这不意味着表示限制。上述盐中优选铵;碱金属盐钠和钾,和碱土金属盐钙和镁。衍生自药学上可接受的有机非毒性碱的式I化合物的盐包括以下的盐:伯胺、仲胺和叔胺,取代的胺,也包括天然存在的取代的胺,环胺,和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、Ν,Ν'-二苄基-乙二胺(苄星)、二环己基胺、二乙醇-胺、二乙基-胺、2-二乙基-氨基-乙醇、2-二甲基-氨基-乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基-哌啶、葡糖胺、氨基葡糖、组氨酸、海巴明、异丙基-胺、利多卡因、赖氨酸、甲葡胺(N-甲基-D-葡糖胺)、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇-胺、三乙胺、三甲胺、三丙基-胺和三(羟基-甲基)-甲基胺(氨丁三醇),但这不旨在表示限制。
包含碱性含N2基团的本发明式I化合物可采用以下试剂季铵化,所述试剂为例如(C1-C4)-烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基硫酸盐;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、十四烷基和十八烷基的氯化物、溴化物和碘化物;和芳基-(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。水溶性和油溶性式I化合物两者都可采用这样的盐制备。
优选的上述药学盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙磺酸盐、扁桃酸盐、甲葡胺、硝酸盐、油酸盐、膦酸盐、三甲基乙酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这不旨在表示限制。
碱性式(I)化合物的酸-加成盐通过以常规的方式使游离碱形式与足量的所需酸接触,导致盐形成来制备。游离碱可通过使盐形式与碱接触并以常规的方式分离游离碱来再生。游离碱形式在某些方面(关于某些物理性质,例如在极性溶剂中的溶解性)与其相应的盐形式不同;然而,为了本发明的目的,盐在其他方面对应于其各自的游离碱形式。
如所提及的,式I化合物的药学上可接受的碱-加成盐用金属或胺,例如碱金属和碱土金属或有机胺形成。优选的金属是钠、钾、镁和钙。优选的有机胺是Ν,Ν'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇-胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
酸性式I化合物的碱-加成盐通过使游离酸形式与足量的所需碱接触,以常规的方式引起盐形成来制备。游离酸可通过使盐形式与酸接触并以常规的方式分离游离酸来再生。游离酸形式在某些方面(关于某些物理性质,例如在极性溶剂中的溶解性)与其相应的盐形式不同;然而,为了本发明的目的,盐在其他方面对应于其各自的游离酸形式。
如果式(I)化合物含有超过一个的能够形成这种类药学上可接受的盐的基团,则式I也涵盖复盐。典型的复盐形式包括,例如,二酒石酸盐、二乙酸盐、二富马酸盐、二甲葡胺、二-磷酸盐、二钠和三盐酸盐,但这不旨在表示限制。
根据以上所述,可以发现,采用本文中的术语"药学上可接受的盐"指包含形式为其盐的一种的式I化合物的活性成分,特别是如果与游离形式的活性成分或较早使用的活性成分的任何其它盐形式比较,这种盐形式赋予活性成分改进的药代动力学性质。活性成分的药学上可接受的盐形式也可第一次为这种活性成分提供其较早时不具有的所需药代动力学性质,并可甚至具有对这种活性成分在其体内治疗效果方面的药效学的正面影响。
由于其分子结构,式(I)化合物可以是手性的并可相应地以各种对映异构形式存在。因此它们可以外消旋的或以光学活性形式存在。
由于依据本发明的化合物的外消旋体或立体异构体的药学活性可以不同,因此使用对映体可能是合乎需要的。在这些情况下,通过本领域技术人员已知的化学或物理手段或甚至在合成使用的相同手段,可将终产物或甚至中间体分离为对映体化合物。
在外消旋胺的情况下,通过与光学活性拆分剂反应从混合物形成非对映体。合适的拆分剂的实例为光学活性酸,例如以下的(R)和(S)形式:酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、合适的N-受保护的氨基酸(例如N-苯甲酰基脯氨酸或N-苯磺酰基脯氨酸),或各种光学活性樟脑磺酸。借助于光学活性拆分剂(例如二硝基苯甲酰基苯基甘氨酸、纤维素三乙酸盐或其它碳水化合物的衍生物或固定在二氧化硅胶体上的手性衍生的甲基丙烯酸酯聚合物)的层析对映体拆分也是有利的。为了此目的,合适的洗脱剂为水性或醇性溶剂混合物,例如,己烷/异丙醇/乙腈,例如比例为82:15:3。
本发明还涉及式I及相关式的化合物的用途,其与至少一种其它药物活性成分组合,所述药物活性成分优选用于治疗多发性硬化的药物例如克拉屈滨,或另一种辅助剂,例如干扰素,例如聚乙二醇化或非聚乙二醇化干扰素,优选干扰素β;和/或与改善血管功能的化合物组合或与免疫调节剂组合,所述免疫调节剂例如芬戈莫德;环孢菌素、雷帕霉素或子囊霉素,或它们的免疫抑制类似物,例如环孢菌素A、环孢菌素G、FK-506、ABT-281、ASM981、雷帕霉素、40-O-(2-羟基)乙基-雷帕霉素等;皮质类固醇;环磷酰胺;硫唑嘌呤;氨甲喋呤;来氟米特;咪唑立宾;麦考酚酸(mycophenolic add);麦考酚酸吗乙酯;15-脱氧精胍菌素;戊酸二氟可龙;二氟泼尼酯;倍他米松二丙酸盐;安西奈德;安吖啶;天冬酰胺酶;硫唑嘌呤;巴利昔单抗;倍可松二丙酸盐;倍他米松;倍他米松乙酸盐;倍他米松二丙酸盐;倍他米松磷酸钠;倍他米松戊酸盐;布地奈德;卡托普利;氮芥盐酸盐;克拉屈滨;氯倍他索丙酸盐;可的松乙酸盐;可的伐唑;环磷酰胺;阿糖胞苷;达克珠单抗;放线菌素;地奈德;去羟米松;地塞米松;地塞米松乙酸盐;地塞米松异烟酸盐;地塞米松间磺基苯甲酸钠;地塞米松磷酸盐;地塞米松叔丁基乙酸盐;乙酸二氯松;多柔比星盐酸盐;表柔比星盐酸盐;氟氯奈德;氟氢可的松乙酸盐;氟氢缩松;氟米松三甲基乙酸盐;氟尼缩松;氟西奈德;醋酸氟轻松;氟可龙;氟可龙己酸盐;氟可龙三甲基乙酸盐;氟米松;氟泼尼定乙酸盐;氟替卡松丙酸盐;吉西他滨盐酸盐;哈西奈德;氢化可的松、氢化可的松乙酸盐、氢化可的松丁酸盐、氢化可的松半琥珀酸盐;美法仑;甲泼尼松;巯嘌呤;甲泼尼龙;甲泼尼龙乙酸盐;甲泼尼龙半琥珀酸盐;米索前列醇;莫罗单抗-cd3;麦考酚酸吗乙酯;帕拉米松乙酸盐;泼那唑啉;泼尼松龙;泼尼松龙乙酸盐;泼尼松龙己酸盐;泼尼松龙间磺基苯甲酸钠;泼尼松龙磷酸钠;强的松;泼尼立定;利福平;利福平钠;他克莫司;特立氟胺;沙利度胺;塞替派;替可的松匹伐酯;曲安西龙;曲安奈德半琥珀酸盐;苯曲安奈德;双醋曲安西龙;己曲安奈德;免疫抑制单克隆抗体,例如,对白细胞受体的单克隆抗体,例如,MHC、CD2、CD3、CD4、CD7、CD25、CD28、B7、CD40、CD45或CD58或它们的配体;或其它免疫调节化合物,例如CTLA41g,或其它附着分子抑制剂,例如mAbs或低分子量抑制剂包括选择蛋白拮抗剂和VLA-4拮抗剂。优选的组合物带有环孢菌素A、FK506、雷帕霉素或40-(2-羟基)乙基-雷帕霉素和芬戈莫德。这些另外的药物,例如干扰素β,可例如通过皮下、肌肉内或口腔途径同时或顺序给药。
这些组合物可用作人类和兽医的药物。
药物制剂可按剂量单位形式给予,其在每剂量单位中包含预定量的活性成分。这样的单位可包含,例如,0.5 mg-1 g,优选地1 mg-700 mg,特别优选地5 mg-100 mg的依据本发明的化合物,取决于治疗的病情、给药方法和患者的年龄、体重和状况,或药物制剂可按剂量单位形式给予,其在每剂量单位中包含预定量的活性成分。优选的剂量单位制剂为包含如上指定的日剂量或部分剂量、或其相应的分数的活性成分的那些制剂。此外,这种类型的药物制剂可采用制药领域通常已知的方法制备。
药物制剂可适合于经由任何所需的合适方法给药,例如通过口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或经皮)、阴道或胃肠外(包括皮下、肌肉内、静脉内或皮内)方法。这样的制剂可采用制药领域已知的所有方法,通过例如使活性成分与赋形剂或辅助剂组合来制备。
适合于口服给予的药物制剂可作为分开的单位给予,例如,胶囊或片剂;散剂或颗粒;在水性或非-水性液体中的溶液或混悬液;可食用泡沫或泡沫食物;或水包油液体乳剂或油包水液体乳剂。
因此,例如,在以片剂或胶囊的形式口服给药的情况下,活性成分组分可与口服的、非毒性和药学上可接受的惰性赋形剂,例如,乙醇、甘油、水等组合。散剂通过将化合物粉碎为合适的细微尺寸并使其与按类似的方式粉碎的药用赋形剂混合来制备,所述赋形剂为例如,可食用碳水化合物,例如,淀粉或甘露醇。同样可存在调味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并填充到成形的明胶壳中生产。助流剂和润滑剂,例如高度分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇,可在填充操作之前加入到粉末混合物中。崩解剂或增溶剂,例如,琼脂、碳酸钙或碳酸钠,同样可以加入以改善胶囊被摄取后药物的可用性。
此外,如果需要或必需,合适的粘合剂、润滑剂和崩解剂以及染料同样可掺入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖,例如,葡萄糖或β-乳糖、由玉米制得的甜味剂,天然和合成橡胶,例如,阿拉伯胶(aracia)、黄蓍胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等,不限于此。片剂通过例如制备粉末混合物,制粒或干燥-压制混合物,加入润滑剂和崩解剂并压制全部混合物以得到片剂来配制。粉末混合物通过使以下混合来制备:按适当的方式粉碎的化合物与稀释剂或如上所述的碱,并任选带有粘合剂例如羧甲基纤维素、藻酸盐、明胶或聚乙烯-吡咯烷酮,分解阻滞剂例如石蜡,吸收加速剂例如季胺盐,和/或吸收剂例如膨润土、高岭土或磷酸二钙。粉末混合物可通过用粘合剂(例如,糖浆、淀粉糊、acadia mucilage、胶或纤维素或聚合物材料的溶液)使其湿润并加压过筛来制粒。作为制粒的备选,可使粉末混合物通过压片机,得到非均匀形状的块,将块破碎以形成颗粒。颗粒可通过加入硬脂酸、硬脂酸盐、滑石或矿物油进行润滑,以防止粘附在片剂铸造模具上。然后压制经润滑的混合物得到片剂。活性成分也可与自由流动的惰性赋形剂组合然后直接压制得到片剂而无需进行制粒或干燥-压制步骤。可存在由虫胶密封层、糖或聚合物材料层和蜡的光泽层构成的透明的或不透明的保护层。可将染料加入到这些包衣中,以便能够在不同的剂量单位之间进行区分。
口服液体,例如溶液、糖浆和酏剂,可按剂量单位形式制备,以使给出的量包含预先规定量的化合物。糖浆可通过使化合物溶于含有合适的调味剂的水溶液中制备,而酏剂采用非毒性的醇性媒介物制备。混悬液可通过将化合物分散于非毒性媒介物中来配制。同样可加入增溶剂和乳化剂,例如,乙氧基化的异硬脂醇和聚氧乙烯山梨醇醚、防腐剂、香料添加剂,例如,薄荷油或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要,口服给药的剂量单位制剂可包封在微囊中。制剂也可以这样一种方式制备,即例如,通过将微粒材料包衣或包埋在聚合物、蜡等中,使释放延长或延迟。
式(I)化合物及其盐、溶剂合物和生理学上的功能衍生物和其它活性成分也可以脂质体传递系统,例如小单层囊泡、大单层囊泡和多层囊泡的形式给予。脂质体可由各种磷脂,例如,胆固醇、十八烷基胺或卵磷脂形成。
式(I)化合物及其盐、溶剂合物和生理学上的功能衍生物和其它活性成分也可采用单克隆抗体传递,所述单克隆抗体作为化合物分子与其偶合的单独的载体。化合物也可偶合至作为靶向的药物载体的可溶性聚合物。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基-甲基丙烯酰氨基苯酚、聚羟乙基天冬氨酸苯酚或聚氧乙烯聚赖氨酸,被棕榈酰基取代。此外,化合物可偶合至一类可生物降解的聚合物,所述聚合物适合于实现药物的控制释放,所述聚合物例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚-原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和交联或两性的水凝胶嵌段共聚物。
适合于透皮给药的药物制剂可作为长效的、与接受者的表皮密切接触的独立膏药来给予。因此,例如活性成分可从膏药经离子电渗疗法递送,如在药物研究(Pharmaceutical Research), 3(6), 318 (1986)中的通用术语所描述的。
适合于局部给予的药用化合物可作为软膏剂、霜剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气溶胶或涂油剂配制。
为治疗眼睛或其它外部组织,例如嘴和皮肤,优选将制剂作为局部软膏剂或霜剂施用。在给出软膏剂的制剂的情况下,活性成分可与石蜡或者与水混溶的霜剂基质一起使用。作为选择,活性成分可用水包油霜剂基质或油包水基质配制以得到霜剂。
适合于局部施用于眼睛的药物制剂包括滴眼剂,其中活性成分被溶解于或悬浮于合适的载体,特别是水性溶剂中。
适合于在口中局部施用的药物制剂包括糖锭剂、锭剂和漱口水。
适合于直肠给药的药物制剂可以栓剂或灌肠剂的形式给予。
适合于鼻腔给药的药物制剂,其中载体物质为包含具有例如在20-500微米范围内粒径的粗制粉末的固体,其以采用吸入的方式给予,即经由鼻道从保持在贴近鼻的包含粉末的容器快速吸入。作为含有作为载体物质的液体的鼻腔喷雾剂或滴鼻剂给药的合适制剂包括在水或油中的活性成分溶液。
适合于经吸入给药的药物制剂包含细颗粒尘或雾,其可通过各种类型的加压分药器,用气溶胶、气雾器或吹药器生成。
适合于阴道给药的药物制剂可作为阴道栓、棉条、霜剂、凝胶剂、泡沫或喷雾制剂给予。
适合于胃肠外给药的药物制剂包括水性和非水性无菌注射液,其含有抗氧化剂、缓冲剂、细菌抑制剂和溶质,藉此使制剂与待治疗的接受者的血液等渗;和水性和非水性无菌混悬液,其可包含悬浮介质和增稠剂。制剂可以单剂量或多剂量容器给予,例如密封的安瓿和小瓶,并以冷冻-干燥(冻干)的状态贮存,以便仅在必需使用之前即刻加入无菌载体液体,例如用于注射目的的水。
按照处方制备的注射液和混悬液可由无菌粉剂、颗粒和片剂制备。
不言而喻,除了上面具体提及的组成,制剂也可包含本领域关于特定类型的制剂常用的试剂;因此,例如适合于口服给药的制剂可包含调味剂。
式I化合物和其它活性成分的治疗有效量取决于许多因素,包括,例如,动物的年龄和体重,需要治疗的准确病情,及其严重性,制剂的性质和给药方法,并且由治疗医生和兽医最终决定。然而,有效量的化合物通常在 每日从0.1至100 mg/kg接受者(哺乳动物)体重范围内和特别典型地每日在从1-10 mg/kg体重范围内。因此,对于体重70 kg的成年哺乳动物,每日实际量通常在70和700 mg之间,其中该量可作为每日单独的剂量给予或通常地以每日一系列部分剂量(例如,2、3、4、5或6次)给予,以使总日剂量为相同的。盐或溶剂合物或其生理学上的功能衍生物的有效量可按化合物本身的有效量的分数来确定。
本发明还涉及治疗罹患鞘氨醇1-磷酸酯相关疾病的患者的方法,包括给予所述患者有效量的式(I)化合物。本发明优选地涉及一种方法,其中鞘氨醇1-磷酸酯-1相关疾病为与过度活性免疫应答相关的自身免疫性紊乱或病症。
本发明还涉及治疗罹患免疫调节异常的患者的方法,包括以有效治疗所述免疫调节异常的量的式(I)化合物给予所述患者。本发明优选地涉及一种方法,其中免疫调节异常为自身免疫或慢性炎性疾病。
实验:
在以下描述的实施例中提供的HPLC数据如下获得。
条件A:柱Waters Xbridge? C8 50 mm x 4.6 mm,流速2 mL/min;8分钟梯度,从在H2O中0.1 % TFA至在CH3CN中0.07 % TFA。
条件B:柱:XTERRA RP18 (250 x 4.6 mm, 5 □m),流速1 mL/min;20分钟梯度,从95% (10mM K2HPO4在H2O中) / 5% CH3CN至100% CH3CN。柱温55℃
手性HPLC:柱CHIRALPAK AD-H (250X4.6) mm, 5μm,流速1 mL/min;流动相:在己烷中的0.1 %TFA:异丙醇(80:20)。
UV检测(maxplot)用于所有条件。
在以下描述的实施例中提供的MS数据如下获得:质谱:LC/MS Waters ZMD (ESI)或Waters Acquity SQD (ESI)
在以下描述的实施例中提供的NMR数据如下获得:1H-NMR:Bruker DPX 400 MHz。采用d6-DMSO,加入数滴D2O,获得最终化合物的所有NMR。光谱在样品制备15-120分钟后记录。
本发明的化合物已根据来自Advanced Chemistry Development Inc., ACD/Labs (7.00 Release). 产品版本:7.10, build:15 Sep 2003的程序"ACD/Name Batch"中使用的的标准来命名。
中间体1:[(1R)-1-氨基-2-(3-噻吩基)乙基]硼酸酸(+)-蒎烷二醇酯三氟乙酸盐
步骤1:3-(溴代甲基)噻吩
将3-噻吩甲醇(5.00 g, 43.7mmol)的二乙醚(40 mL)冷却(0℃)溶液用三溴化磷(1.35 mL, 14.4 mmol)处理并于0℃搅拌反应混合物30 min。然后将反应混合物倾入到冰中并用二乙醚提取。有机层经硫酸钠干燥并浓缩得到标题化合物(5.23 g, 67%),其无须进一步纯化而使用。
1H NMR (400MHz, CDCI3) δ 7.32-7.30 (m, 2H), 7.14 (d, J= 4.6 Hz, 2H), 4.54 (s, 1H)。
步骤2:4,4,5,5-四甲基-2-(3-噻吩基甲基)-1,3,2-二氧硼杂环戊烷
将3-(溴代甲基)噻吩(5.23 g, 29.7 mmol)在脱气的1,4-二氧杂环己烷(90 ml)中的溶液用双(频哪醇合)二硼(9.0 g, 36 mmol)、碳酸钾(12.3 g, 89.1 mmol)和四(三苯基膦)钯(1.72 g, 1.48 mmol)处理并将反应混合物于100℃加热12 h。使该混合物冷却至室温并通过C盐床过滤。浓缩滤液,粗品经二氧化硅柱层析纯化,用在石油醚中的5-10%乙酸乙酯洗脱,得到标题化合物(3.55 g, 55%),为黄色油状物。
1H NMR (400 MHz, CDCI3) δ 7.22-7.20 (m, 1H), 6.96-6.93 (m, 2H), 2.28 (s, 2H), 1.24 (s, 12H).
步骤3:(3-噻吩基甲基)硼酸(+)-蒎烷二醇酯
将4,4,5,5-四甲基-2-(3-噻吩基甲基)-1,3,2-二氧硼杂环戊烷(3.55 g, 15.8 mmol)的二乙醚(40 ml)溶液用(1S, 2S, 3R, 5S)-(+)-蒎烷二醇(3.1 g, 18 mmol)处理。将反应混合物于室温下搅拌2天。反应物质用水(2 x 15 ml)、盐水洗涤,经无水硫酸钠干燥并浓缩得到粗产物,其经硅胶柱层析纯化,用在石油醚中的5%乙酸乙酯洗脱,得到标题化合物(4.0 g, 90%)
1H NMR (400 MHz, CDCI3) δ 7.23 (dd, J= 7.8, 3.2 Hz, 1H), 6.97-6.95 (m, 2H), 4.31 (dd, J= 8.8, 2.0 Hz, 1H), 2.36-2.30 (m, 3H), 2.2-2.18 (m, 1H), 2.07 (t, J= 5.2Hz, 1H), 1.92-1.90 (m, 1H), 1.87-1.84 (m, 1H) 1.40 (s, 3H), 1.32 (s, 3H), 1.10 (d, J= 10.9 Hz, 1H), 0.84 (s, 3H).
步骤4:[(1S)-1-氯代-2-(3-噻吩基)乙基]硼酸酸(+)-蒎烷二醇酯
经10分钟向二氯甲烷(1.42 ml, 21.7 mmol)和四氢呋喃(10 ml)的冷却(-100℃)溶液加入正丁基锂(2.5 M在THF中;3.18 ml;7.96mmol)。搅拌20分钟后,经10分钟加入(3-噻吩基甲基)硼酸(+)-蒎烷二醇酯(2.00 g, 7.24 mmol)的THF (9 ml)溶液,保持温度在-100℃。然后于-100℃经30分钟加入氯化锌(0.5M在THF中;13 mL, 6.5 mmol)溶液。使该混合物达到室温并搅拌18h和浓缩。向生成的油状物中加入二乙醚和饱和的氯化铵(各50 ml)并剧烈搅拌。水层用二乙醚提取3次,合并的有机层经无水硫酸钠干燥并真空浓缩,得到标题化合物(2.1 g, 89%),其无须进一步纯化而原样用于随后的步骤。
1H NMR (400 MHz, CDCI3) δ 7.26 (dd, J= 8.3 Hz, 1H), 7.11 (m, 1H), 7.03 (dd, J= 6.1, 1.1 Hz, 1H), 4.36 (dd, J= 10.7, 2 Hz, 1H), 3.75 (m, 1H), 3.21 (m, 1H), 2.34 (m, 1H), 2.19 (m, 1H), 2.07 (t, J= 5.2, Hz, 2H), 1.91-1.84 (m, 2H), 1.35 (s, 3H), 1.28 (s, 3H), 1.05 (d, J= 11 Hz, 1H), 0.84 (s, 3H).
步骤5:[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-噻吩基)乙基]硼酸
向[(1S)-1-氯代-2-(3-噻吩基)乙基]硼酸酸(+)-蒎烷二醇酯(2.30 g, 7.09 mmol)的10 ml无水THF冷却(-78℃)溶液中加入双(三甲基甲硅烷基)氨化锂(1 M在THF中, 10.6 ml, 10.6 mmol)。使该混合物达到室温,搅拌18 h并浓缩至干。向生成的残留物中加入己烷,然后滤除沉淀的固体。浓缩滤液得到标题化合物(1.72 g, 53%),其无须进一步纯化而原样用于随后的步骤。
1H NMR (400 MHz, CDCI3) δ 7.19-7.17 (m, 1H), 7.01-6.99 (m, 2H), 4.29-4.27 (m, 1H), 3.07-3.05 (m, 1H), 2.79 (m, 1H), 2.68 (m, 1H), 2.3 (m, 1H), 2.15 (m, 1H), 2.02 (t, J= 5.2 Hz, 1H), 1.87-1.86 (m, 1H), 1.79 (m, 1H), 1.36 (s, 3H), 1.25 (s, 3H), 0.94 (m, 1H), 0.85 (s, 3H), 0.08 (s, 18H).
步骤6:[(1R)-1-氨基-2-(3-噻吩基)乙基]硼酸酸(+)-蒎烷二醇酯三氟乙酸盐
向[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-噻吩基)乙基]硼酸(1.72 g, 3.82 mmol)在二乙醚(25 ml)中的冷却(0℃)溶液中滴加入三氟乙酸(0.88 ml, 11.48 mmol)。于室温下搅拌反应3 h。用冰-甲醇将反应混合物冷却至-10℃并过滤形成的白色固体,用乙醚洗涤并干燥, 得到标题化合物。
1H NMR (400 MHz, CDCI3) δ 7.8 (bs, 3H), 7.33-7.27 (m, 1H), 7.23 (m, 1H), 7.01-6.99 (dd, J= 5.0 hz, 1.2 Hz, 1H), 4.35-4.32 (m, 1H), 3.18-3.10 (m, 3H), 2.28-2.15 (m, 3H), 1.99 (m, 1H), 1.90 (m, 1H), 1.85 (t, J= 5.2 Hz, 1 H ), 1.80 (m, 1H), 1.34 (s, 3H), 1.29 (s, 3H), 1.04-1.02 (m, 1H), 0.81 (s, 3H).
中间体2:[(1R)-1-氨基-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐
步骤1:(3-乙基苯基)甲醇
将3-溴代苄基醇(5.00 g, 26.7mmol)在脱气的四氢呋喃(50 ml)中的溶液置于耐压瓶中并用碳酸铯(26.0 g, 80.2 mmol)、与DCM (40 mg, 0.54 mmol)复合的1,1 '-双(二苯基膦基)二茂铁二氯化钯(1:1 )处理。加入三乙基硼烷(1.0 M在THF中, 80 ml, 80 mmol)并将反应混合物于70℃加热5 h。将耐压瓶中的内容物冷却至0℃并经NaOH水溶液(10%)和H2O2水溶液(30%)猝灭。将反应混合物于室温下搅拌30分钟,用稀释含水HCl酸化并用二乙醚提取。将有机层干燥(Na2SO4)并浓缩。经硅胶快速层析纯化粗品,用在石油醚中的5-10%乙酸乙酯洗脱,得到所需的产物(3.5 g, 90%),为淡黄色液体。
1H NMR (400MHz, CDCI3) δ 7.31-7.27 (m, 1H), 7.22-7.14 (m, 3H), 4.68 (s, 2H) 2.70-2.64 (m, 2H), 1.27-1.24 (t, J=7.6, 3H).
步骤2:1-(溴代甲基)-3-乙基苯
将(3-乙基苯基)甲醇(3.50 g, 25.7 mmol)在二乙醚(40 ml)中的冷(0℃)溶液用三溴化磷(0.8 ml, 8.5 mmol)处理并将反应混合物于0℃搅拌30 min。然后将反应混合物倾入到冰中并用乙醚提取。有机层经硫酸钠干燥并浓缩。粗品(3.1 g, 60%)无须进一步纯化而原样用于随后的步骤。
1H NMR (400MHz, CDCI3) δ 7.29-7.15 (m, 3H), 7.15-7.14 (m, 1H), 4.50 (s, 2H) 2.69-2.63 (m, 2H), 1.27-1.23 (t, J= 7.6, 3H).
步骤3:2-(3-乙基苄基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷
将1-(溴代甲基)-3-乙基苯(1.7g, 8.59 mmol)在脱气的1, 4-二氧杂环己烷(40 ml)中的溶液用双(频哪醇合)二硼(2.61 g, 10.3mmol)、碳酸钾(3.56 g, 25.8mmol)、四(三苯基膦)钯(0) (0.497 g, 0.429 mmol)处理并将混合物于100℃加热12h。使烧瓶中的内容物冷却至室温并通过C盐床过滤。浓缩滤液,粗品经硅胶柱层析纯化,用在石油醚中的5-10%乙酸乙酯洗脱,得到标题化合物(1.4 g, 66%),为黄色油状物。
1H NMR (400MHz, CDCI3) δ 7.18-7.14 (m, 3H), 7.03-6.96 (m, 3H), 2.64-2.58 (m, 2H), 2.28 (s, 2H), 1.24-1.21 (m, 15H).
步骤4:(3-乙基苄基)硼酸(+)-蒎烷二醇酯
将2-(3-乙基苄基)-4 ,4,5, 5-四甲基-1,3,2-二氧硼杂环戊烷(1.4 g, 5.68 mmol)的二乙醚(30 ml)溶液用(1S, 2S, 3R, 5S)-(+)-蒎烷二醇(1.45 g, 8.53 mmol)处理。将反应混合物于室温下搅拌12 h,然后混合物用水洗涤两次,然后用盐水洗涤,经无水硫酸钠干燥,然后浓缩。粗产物经硅胶柱层析纯化,用在石油醚中的5%乙酸乙酯洗脱, 得到标题化合物(1.43 g, 84%)。
1H NMR (400 MHz, CDCI3) δ 7.19-7.15 (m, 1H), 7.04-7.01 (m, 2H), 6.98-6.96 (m, 1H), 4.29-4.27 (m, 1H), 2.64-2.58 (m, 2H), 2.34-2.28 (m, 3H), 2.20-2.19 (m, 1H), 2.07-2.04 (m, 1H), 1.89-1.81 (m, 2H), 1.29 (s, 3H), 1.25-1.21 (m, 3H), 1.1-1.08 (m, 1H), 0.84 (s, 3H). GCMS:m/z:298
步骤5:[(1S)-1-氯代-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯
经10分钟向二氯甲烷(0.89 ml, 13.7 mmol)和无水四氢呋喃(6 ml)的冷却(-100℃)混合物中加入正丁基锂(2.5 M在己烷中, 2.0 ml, (3.7 mmol)。于-100℃搅拌20分钟后,经10分钟加入(3-乙基苄基)硼酸(+)-蒎烷二醇酯(1.36 g, 4.56 mmol)的无水THF (4 ml)溶液。然后于-100℃经30分钟加入氯化锌(0.5 M在THF中, 8.2 ml, 4.1 mmol)溶液。使该混合物达到室温并搅拌18 h和浓缩。向生成的油状物中加入二乙醚和饱和的氯化铵(各25 ml)并剧烈搅拌。水层用二乙醚提取3次,合并的有机层经无水硫酸钠干燥并真空浓缩。残留物(1.5 g, 94%)原样用于下一步骤。
GCMS:m/z:346
步骤6:[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯
向[(1S)-1-氯代-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯(1.5 g, 4.32 mmol)在15 ml无水四氢呋喃中的冷却(-78℃)溶液中加入双(三甲基甲硅烷基)氨化锂(1 M在THF中, 6.5 ml, 6.5 mmol)。使该混合物达到室温,搅拌18 h并浓缩至干。向生成的残留物中加入己烷,然后滤除沉淀的固体。浓缩滤液得到所需的粗产物(1.2 g, 58%),其无须进一步纯化而原样用于随后的步骤。
步骤7:[(1R)-1-氨基-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐
将[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯(1.20 g, 2.54 mmol)在二乙醚(20 ml)中的冷却(0℃)溶液用三氟乙酸(0.87 ml, 7.6 mmol)逐滴处理。将反应混合物在低于30℃的温度下减压蒸发。使粗品溶于甲苯并蒸发,并将此顺序重复4次。获得的白色固体(1.0 g, 89%)无须进一步纯化而用于随后的步骤。
1H NMR (400 MHz, DMSO-d6):δ 7.22-7.26 (m, 1H), 7.09-7.11 (m, 3H), 4.31-4.33 (m, 1H), 3.00-3.19 (m, 3H), 2.59-2.65 (m, 2H), 2.18-2.23 (m, 2H), 1.90-1.98 (m, 1H), 1.80-1.89 (m, 1H), 1.33 (s, 3H), 1.20-1.26 (m, 6H), 1.06 (m, 1H), 0.80 (s, 3H)
中间体3:[(1R)-1-氨基-2-(3-三氟甲基苯基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐
步骤1:2-(3-三氟甲基苄基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷
将溴化3-(三氟甲基)苄基(5.00 g, 20.9 mmol)在脱气的1,4-二氧杂环己烷(100 ml)中的溶液用双(频哪醇合)二硼(6.4 g, 25 mmol)、碳酸钾(20.9 g, 62.7 mmol)、四(三苯基膦)钯(0) (1.2 g, 1.0 mmol)处理并将混合物于100℃加热12 h。使烧瓶中的内容物冷却至室温并通过C盐床过滤。浓缩滤液,粗品经硅胶柱层析纯化,用石油醚中的2%乙酸乙酯洗脱,得到标题化合物(5.1 g, 85%),为无色液体。
1H NMR (400 MHz, CDCI3):δ 7.45 (s, 1H), 7.33-7.40 (m, 3H), 2.36 (s, 2H), 1.25 (s, 12H). GCMS:m/z=286
步骤2:(3-三氟甲基苄基)硼酸(+)-蒎烷二醇酯
将2-(3-三氟甲基苄基)-4,4, 5, 5-四甲基-1,3,2-二氧硼杂环戊烷(5.10 g, 17.8 mmol)的二乙醚(50 ml)溶液用(1S, 2S, 3R, 5S)-(+)-蒎烷二醇(4.55 g, 26.7 mmol)处理。将反应混合物于室温下搅拌12 h,然后混合物用水洗涤两次,然后用盐水洗涤并经硫酸钠干燥,然后浓缩。粗产物经硅胶柱层析纯化,用石油醚中的2%乙酸乙酯洗脱,得到标题化合物(6.0 g, 99%),为无色液体。
1H NMR (400 MHz, CDCI3):δ 7.40 (s, 1H), 7.35-7.38 (m, 3H), 4.29 (dd, J= 2.0, 8.8 Hz, 1H), 2.40 (s, 2H), 2.31-2.36 (m, 1H), 2.17-2.21 (m, 1H), 2.05 (t, J= 5.8 Hz, 1H), 1.90-1.92 (m, 1H), 1.80-1.85 (m, 1H), 1.39 (s, 3H), 1.29 (s, 3H), 1.02-1.05 (m, 1H), 0.84 (s, 3H). GCMS:m/z=338
步骤3:(1S)-1-氯代-2-(3-三氟甲基苄基)-乙基硼酸(+)-蒎烷二醇酯
经15分钟向二氯甲烷(1.70 mL, 26.6 mmol)和无水四氢呋喃(17 ml)的冷却(-100℃)混合物中加入正丁基锂(1.6 M, 6.1 mL, 9.75 mmol)。于-100℃搅拌20分钟后,经15 分钟加入(3-三氟甲基苄基)硼酸(+)-蒎烷二醇酯(3.0 g, 8.87 mmol)在无水THF (12 ml)中的溶液。然后于-100℃经30分钟加入氯化锌(0.5 M在THF中, 16.0 mL, 8.0 mmol)溶液。使该混合物达到室温并搅拌18 h和浓缩。向生成的油状物中加入二乙醚和饱和的氯化铵(各25 ml)并剧烈搅拌。水层用二乙醚提取3次,合并的有机层经无水硫酸钠干燥并真空浓缩。将黄色液体(3.4 g, 99%)原样用于随后的步骤。
1H NMR (400 MHz, CDCI3):δ 7.27-7.54 (m, 4H), 4.36 (dd, J= 1.6, 8.9 Hz, 1H), 3.63-3.69 (m, 1H), 3.24-3.26 (m, 1H), 3.17-3.19 (m, 1H), 2.32-2.40 (m, 1H), 2.17-2.19 (m, 1H), 2.05-2.08 (m, 1H), 1.84-1.91 (m, 2H), 1.36 (s, 3H), 1.28 (s, 3H), 0.99-1.02 (m, 1H), 0.84 (s, 3H). GCMS:m/z=386
步骤4:[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-三氟甲基苯基)乙基]硼酸(+)-蒎烷二醇酯
向[(1S)-1-氯代-2-(3-三氟甲基苯基)乙基]硼酸(+)-蒎烷二醇酯(3.4 g, 8.8 mmol)在25 ml无水四氢呋喃中的冷却(-78℃)溶液中加入双(三甲基甲硅烷基)氨化锂(1 M在THF中, 15 ml, 15 mmol)。使该混合物达到室温,搅拌18 h并浓缩至干。向生成的残留物中加入己烷,然后滤除沉淀的固体。浓缩滤液得到作为粗产物的标题化合物,其无须进一步纯化而原样用于随后的步骤。
1H NMR (400 MHz, CDCI3):δ 7.27-7.53 (m, 4H), 4.22-4.25 (m, 1H), 3.06-3.07 (m, 1H), 2.91-2.93 (m, 1H), 2.22-2.32 (m, 3H), 2.02-2.03 (m, 1H), 1.87-1.88 (m, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 0.94-0.96 (m, 1H), 0.83 (s, 3H), 0.17 (s, 12H), 0.06 (s, 6H)
步骤5:[(1R)-1-氨基-2-(3-三氟甲基苯基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐
于0℃,将[(1R)-1-[双(三甲基甲硅烷基)氨基]-2-(3-三氟甲基苯基)乙基]硼酸(+)-蒎烷二醇酯(1.5 g, 2.93 mmol)在二乙醚(15 ml)中的冷却(0℃)溶液用三氟乙酸(0.67 ml, 8.8 mmol)逐滴处理。于室温下搅拌反应3 h。将反应混合物在低于30℃的温度下减压蒸发。使粗品溶于甲苯并蒸发,并将此顺序重复4次。获得的粗产物(1.7 g)无须进一步纯化而用于随后的步骤。
1H NMR (400 MHz, CDCI3):δ 7.27-7.54 (m, 4H), 4.33-4.35 (m, 1H), 3.10-3.39 (m, 2H), 2.15-2.35 (m, 2H), 2.01-2.08 (m, 2H), 1.89-1.95 (m, 2H), 1.37 (s, 3H), 1.27 (s, 3H), 0.94-0.97 (m, 1H), 0.83 (s, 3H)
中间体4:4-联苯-3-基-4-氧代-丁酸
步骤1:4-联苯-3-基-4-氧代-丁酸乙基酯
将4-(3-溴代-苯基)-4-氧代-丁酸乙基酯(500 mg, 1.75mmol)、苯基硼酸(340 mg, 2.62 mmol)和氟化铯(1.06g, 7 mmol)在二氧杂环己烷:水(2:1, 20 ml)中的混合物用氮气脱气15 min,然后用双(三苯基膦)二氯化钯(II) (11 mg, 0.175 mmol)处理并将反应混合物在微波反应器中于90℃辐照1 h。然后用乙酸乙酯稀释反应混合物,通过C盐过滤,并在减压下蒸发溶剂。经硅胶快速层析纯化粗品,采用乙酸乙酯和石油醚作为洗脱剂,得到标题化合物(0.40 g, 83%)。
MS(ESI+):283.0, HPLC (方法A):Rt. 5.2 min, HPLC纯度95.3%
步骤2:4-联苯-3-基-4-氧代-丁酸
将4-联苯-3-基-4-氧代-丁酸乙基酯(400 mg, 1.41 mmol)在四氢呋喃:水(4:1, 10 mL)中的溶液用LiOH.H2O (170 mg, 4.23 mmol)处理并将反应混合物于室温下搅拌过夜。在减压下浓缩反应混合物,残留物用水稀释并用乙酸乙酯提取三次。水层用HCl (1.5N)水溶液酸化并用二氯甲烷提取。有机层经硫酸钠干燥并浓缩,得到标题化合物(0.3 g, 83%).
1H NMR (400 MHz, DMSO-d6):δ 8.20 (s, 1H), 7.92-7.98 (m, 2H), 7.72-7.74 (m, 2H), 7.60-7.64 (m, 1H), 7.50-7.51 (m, 2H), 7.40-7.41 (m, 1H), 3.32-3.35 (m, 2H), 2.59-2.61 (m, 2H). MS(ESI+):255.0, HPLC Rt. 4.0 min, HPLC纯度99.7 %.
中间体5:6-苯基-吡啶-2-甲醛
将6-溴代吡啶-2-甲醛(500 mg, 2.68 mmol)、苯基硼酸(870 mg, 6.7mmol)和氟化铯(610 mg, 4.0 mmol)的混合物溶于二氧杂环己烷:水(2:1 ) 7.5 mL中并用氮气脱气15 min。然后加入双(三苯基膦)二氯化钯(II) (94 mg, 0.13 mmol)并将反应混合物在微波反应器中于 90℃辐照2 h。然后用乙酸乙酯稀释反应混合物,通过C盐过滤并蒸发。经硅胶快速层析纯化粗品,采用乙酸乙酯和石油醚作为洗脱剂。
MS(ESI+):184.0, HPLC (方法A) Rt. 3.3 min, HPLC纯度95.1 %
中间体6:4-氧代-4-(6-苯基-吡啶-2-基)-丁酸
步骤1:4-氧代-4-(6-苯基-吡啶-2-基)-丁酸甲基酯
将6-苯基-吡啶-2-甲醛(中间体5;800 mg, 4.37 mmol)的甲醇溶液用丙烯酸甲酯(0.54 mL, 5.2mmol)、3-乙基-5-(2-羟基乙基)-4-甲基-1,3-噻唑溴化物(220 mg, 0.87 mmol)和三乙胺(1.8 mL, 13mmol)处理。然后将反应混合物于70℃回流1 h。使反应混合物冷却至RT,用在水中的饱和NH4Cl溶液猝灭并用乙酸乙酯提取。分离有机层,用NaHCO3、盐水洗涤,经Na2SO4干燥并浓缩。粗品经硅胶柱层析纯化,采用乙酸乙酯和石油醚作为洗脱剂(0.80 g;68%)。
MS(ESI+):270.0
步骤2:4-氧代-4-(6-苯基-吡啶-2-基)-丁酸
将4-氧代-4-(6-苯基-吡啶-2-基)-丁酸甲基酯(600 mg, 2.2 mmol)在四氢呋喃:水(4:1, 10ml)中的溶液用LiOH.H2O (280 mg, 6.68 mmol)处理并将反应混合物于室温下搅拌过夜。除去溶剂,残留物用水稀释并用二氯甲烷洗涤。然后用HCl水溶液(1.5 N)中和水层并用二氯甲烷提取。有机层经硫酸钠干燥并浓缩。通过制备型HPLC进一步纯化获得的固体。
1H NMR (400 MHz, DMSO-d6):δ 8.20-8.26 (m, 3H), 8.00-8.10 (m, 1H), 7.88-7.90 (m, 1H), 7.47-7.57 (m, 3H), 3.50-3.53 (m, 2H), 2.62-2.65 (m, 2H). HPLC (方法A) Rt. 3.9 min, HPLC纯度99.5 %
中间体7:3-(N-羟基甲脒基)-丙酸甲基酯
将3-氰基丙酸甲基酯(2.00 g, 17.7 mmol)、羟胺盐酸盐(1.80 g, 26.5mmol)和三乙胺(5 mL, 35 mmol)在乙醇中的混合物于85℃回流2h。蒸发反应混合物并与甲苯共沸三次并无须进一步纯化而直接用于随后的步骤(2.5 g, 96%)。
中间体8:3-(5-苯基-[1,2,4]噁二唑-3-基)-丙酸
步骤1:3-(5-苯基-[1,2,4]噁二唑-3-基)-丙酸甲基酯
于室温下,将苯甲酸(2.00 g, 16.4 mmol)和1.1 '-羰基二咪唑(3.8 g, 18 mmol)在二甲基甲酰胺(25 mL)中搅拌2h。然后加入3-(N-羟基甲脒基)-丙酸甲基酯(中间体7;2.5 g, 18 mmol)并将反应混合物于室温下搅拌过夜。然后将反应混合物于100℃加热2h。用乙酸乙酯稀释反应混合物并用盐水洗涤。有机层经硫酸钠干燥并浓缩。粗品经硅胶柱层析纯化,采用二氯甲烷和甲醇作为洗脱剂。
1H NMR (400 MHz, DMSO-d6):δ 8.06-8.09 (m, 2H), 7.67-7.72 (m, 1H), 7.60-7.64 (m, 2H), 3.61 (s, 3H), 3.03-3.06 (m, 2H), 2.80-2.84 (m, 2H). MS(ESI+):233.0, HPLC (方法A) Rt 3.9 min, HPLC纯度95.5 %
步骤2:3-(5-苯基-[1,2,4]噁二唑-3-基)-丙酸
将3-(5-苯基-[1,2,4]噁二唑-3-基)-丙酸甲基酯(800 mg, 3.44 mmol)在四氢呋喃:水(4:1 )中的溶液用LiOH.H2O (400 mg, 10.3 mmol)处理并将反应混合物于室温下搅拌过夜。在减压下除去溶剂,残留物用水稀释,用二氯甲烷洗涤。然后用HCl水溶液(1.5 N)中和水层并用二氯甲烷提取。有机层经硫酸钠干燥并浓缩。产物无须进一步纯化而用于随后的步骤。
1H NMR (400 MHz, DMSO-d6):δ 8.07-8.10 (m, 2H), 7.60-7.72 (m, 3H), 2.98-3.01 (m, 2H), 2.71-2.74 (m, 2H). MS(ESI+):219.0, HPLC (方法A) Rt 3.1 min, HPLC纯度99.6 %
中间体9:3-叠氮基-丙酸
将β-丙氨酸(15.0 g, 168 mmol)的无水甲醇溶液用碳酸钾(46.3 g, 336 mmol)、CuSO4.5H2O (0.83 g, 3.36 mmol)和咪唑磺酰基叠氮化物(35.0 g, 202 mmol)处理并将反应混合物于室温下搅拌16 小时。在低于30℃的温度下,在减压下蒸发反应混合物。残留物用水稀释;将pH调节至6并用乙酸乙酯提取。将含水相的pH最终调节至3并用乙酸乙酯提取水层;分离有机层,经Na2SO4干燥并浓缩,得到粗品3-叠氮基-丙酸。
中间体10:3-(4-苯基-[1,2,3]三唑-1-基)-丙酸
将苯基乙炔(1.61 g, 15.8 mmol)和3-叠氮基-丙酸(2.0 g, 17.4 mmol)在t-BuOH:H2O (2:1, 45 ml)中的溶液用抗坏血酸钠(469 mg, 2.37 mmol)和CuSO4.5H2O (196 mg, 0.79 mmol)处理并将反应混合物于室温下搅拌12h。将乙酸乙酯加入到反应混合物并用水提取。然后用水接着用盐水洗涤有机层。浓缩合并的有机层,在真空下干燥,得到为白色固体的标题化合物(1.6 g, 46%)。
1H NMR (400 MHz, DMSO-d6):δ 12.58 (s, 1H), 8.55 (s, 1H), 7.82 (d, J= 7.4 Hz, 2H), 7.44 (t, J= 7.4 Hz, 2H), 7.32 (t, J= 7.4 Hz, 1H), 4.60 (s, 2H), 3.01 (s, 2H). MS(ESI+):218.0. HPLC (方法A) RT 2.7 min, HPLC纯度99.7 %.
中间体11:3-(1-苯基-1H-[1,2,3]三唑-4-基)-丙酸
根据对中间体10描述的方案制备该中间体。
1H NMR (400 MHz, DMSO-d6):δ 12.25 (s, 1H), 8.57 (s, 1H), 7.87-7.85 (m, 2H), 7.60-7.56 (m, 2H), 7.46 (t, J= 7.4 Hz, 1H), 2.93 (t, J= 7.4 Hz, 2H), 2.66 (t, J= 7.4 Hz, 2H). MS(ESI+):218.2. HPLC (方法A) RT 2.7 min, HPLC纯度99.8 %.
中间体11:(1-氧代异喹啉-2(1H)-基)乙酸
步骤1:异喹啉-N-氧化物
将异喹啉(20.0 g, 155 mmol)的二氯甲烷(400 mL)溶液用间-氯过苯甲酸(40.0 g, 232 mmol)处理并将反应混合物于室温下搅拌过夜。过滤反应混合物,蒸发滤液并无须进一步纯化而用于后面的步骤(20.0 g, 89%)。
MS (ESI+):M=146.3
步骤2:1-氯代异喹啉
将磷酰氯(200 ml)在冰冷条件下滴加到异喹啉-N-氧化物(20.0 g)中。然后将反应混合物加热至回流,于105℃过夜。在减压下蒸发磷酰氯,然后残留物用冰骤冷并用二氯甲烷提取。分离有机层,经硫酸钠干燥并浓缩。粗品经硅胶柱层析纯化,采用乙酸乙酯和石油醚作为洗脱剂(21.0 g;85%)。
1H NMR (400 MHz, DMSO-d6):δ 8.25-8.31 (m, 2H), 8.08 (d, J= 8.0 Hz, 1H), 7.88-7.91 (m, 2H), 7.80-7.84 (m, 1H). MS (ESI+):164.0, HPLC (方法A) Rt 8.29min;HPLC纯度96.0 %
步骤3:异喹啉-1(2H)-酮
将1-氯代异喹啉(8.1 g)在冰醋酸(170 mL)中的溶液用乙酸铵(25 g)处理。然后将反应混合物于100℃加热3h。使反应混合物冷却至室温并在减压下蒸发溶剂。残留物用冰骤冷,过滤形成的固体并在过滤器上干燥(5.8 g, 80%)。
1H NMR (400 MHz, DMSO-d6):δ 11.24 (s, 1H), 8.18 (d, J= 8.4 Hz, 1H), 7.63-7.71 (m, 2H), 7.45-7.49 (m, 1H), 7.15-7.18 (m, 1H), 6.55 (d, J= 7.2 Hz, 1H). MS (ESI+):146.0, HPLC (方法A) Rt 2.23min;HPLC纯度98.2 %
步骤4:(1-氧代异喹啉-2(1H)-基)乙酸叔丁酯
将异喹啉-1(2H)-酮3 (1.0 g, 6.9 mmol)和乙酸叔丁酯(2.0 mL, 13.8 mmol)在二甲基甲酰胺(15 mL)中的冷(0℃)溶液用氢化钠(60%在矿物油中, 660 mg, 17.2 mmol)处理。10分钟后,将反应混合物用冰骤冷,过滤形成的固体并干燥(1.2 g;60%)。
1H NMR 400 MHz, CDCI3:δ 8.42-8.44 (m, 1H), 7.63-7.67 (m, 1H), 7.47-7.53 (m, 2H), 7.01 (d, J= 8.0 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H), 4.64 (s, 2H), 1.49 (s, 9H). MS (ESI+):204.3, HPLC (方法A) Rt 4.08min;HPLC纯度98.4 %
步骤5:(1-氧代异喹啉-2(1H)-基)乙酸
将(1-氧代异喹啉-2(1H)-基)乙酸叔丁酯(1.2 g, 4.6mmol)在二氯甲烷(20 mL)中的冷溶液用三氟乙酸(10 mL)逐滴处理。然后将反应混合物于室温下搅拌3h。蒸发溶剂并使该残留物与甲苯共沸。用乙醚研磨形成的固体,得到标题化合物。
1 H NMR (400 MHz, DMSO-d6):δ 10.76 (s, 1H), 8.18-8.20 (m, 1H), 7.64-7.73 (m, 2H), 7.42-7.52 (m, 2H), 6.62 (d, J= 8.0 Hz, 1H), 4.67 (s, 2H). MS (ESI+):204.3, HPLC (方法A) Rt 2.34 min;HPLC纯度99.3 %
中间体12和13:(+)-2-(3-氯代苯基)-4-氧代-4-苯基丁酸和(-)-2-(3-氯代苯基)-4-氧代-4-苯基丁酸
外消旋的2-(3-氯代苯基)-4-氧代-4-苯基丁酸通过手性制备型HPLC在CHIRALPAK IA (250x20) mm, 5μm上分离, 流动相己烷:异丙基醇(65:35), 流速:10 ml/min。
两种产物在13.7 min (中间体12)和在18.6 min (中间体13)洗脱。两种产物采用以下HPLC方法分析:
柱:CHIRALPAK AD-H (250x4.6) mm, 5μm
流动相:0.1 %TFA在己烷:异丙基醇(80:20)中
流速:1.0ml/min
中间体12:Rt-10.8 min (纯度100 %);αD +101.9°;乙醇, c= 1.0 g/100 mL
中间体13:Rt-14.9 min (纯度99.2 %)
手性中心绝对指定作为(R)或者(S)是任意的。
中间体14和15:(+)-2-(4-氯代苯基)-4-氧代-4-苯基丁酸和(-)-2-(4-氯代苯基)-4-氧代-4-苯基丁酸
外消旋的2-(4-氯代苯基)-4-氧代-4-苯基丁酸通过手性制备型HPLC在CHIRALPAK IA (250x20) mm, 5μm上分离, 流动相己烷:异丙基醇(60:40), 流速:10 ml/min。
两种产物在14.2 min (中间体14)和在21.4 min (中间体15)洗脱。两种产物采用以下HPLC方法分析:
柱:CHIRALPAK AD-H (250x4.6) mm, 5μm
流动相:0.1 %TFA在己烷:异丙基醇(80:20)中
流速:1.0ml/min
中间体14:Rt-15.4 min (纯度99.3 %). αD +103.4°;乙醇, c= 0.57 g/100 mL
中间体15:Rt-22.2 min (纯度99.3 %). αD -111.5°;乙醇, c= 0.57 g/100 mL
手性中心绝对指定作为(R)或者(S)是任意的。
中间体16和17:(+)-2-苄基-4-(4-甲氧基苯基)-4-氧代-丁酸和(-)-2-苄基-4-(4-甲氧基苯基)-4-氧代-丁酸
外消旋的2-苄基-4-(4-甲氧基苯基)-4-氧代-丁酸通过手性制备型HPLC在CHIRALCEL OJ-H (250x20) mm, 5μm上分离, 流动相己烷:异丙基醇(75:25), 流速:10 ml/min.
两种产物在15.5 min (中间体16)和在20.2 min (中间体17)洗脱。两种产物采用以下HPLC方法分析:
柱:CHIRALCEL OJ (250x4.6) mm, 5μm
流动相:0.1 %TFA在己烷:异丙基醇(90:10)中
流速:1.0ml/min
中间体16:Rt-22.3 min (纯度98.7 %). αD +21.1 °;乙醇, c= 1.0 g/100 mL
中间体17:Rt-33.6 min (纯度97.7 %). αD -21.0°;乙醇, c= 1.0 g/100 mL)
手性中心绝对指定作为(R)或者(S)是任意的。
中间体18:(1R)-2-(苯并呋喃-3-基)-1-(3a,5,5-三甲基六氢-4,6-亚甲基苯并[d][1,3,2]二氧硼杂环戊烷-2-基)乙胺三氟乙酸盐
步骤1:苯并呋喃-3-基甲醇
将1-苯并呋喃-3-甲醛(5g, 34.2 mmol)的甲醇(50 ml)溶液用冰冷却并分部分加入硼氢化钠(1.9g, 51.3 mmol)。将反应混合物于室温下搅拌1 h。浓缩反应混合物,使残留物在饱和氯化铵和二氯甲烷之间分配。分离有机层,经硫酸钠干燥并浓缩。粗品(5.0 g, 98%)无须进一步纯化而原样用于随后的步骤。
1H NMR (400 MHz, CDCI3):δ 7.68-7.70 (m, 1H), 7.62 (s, 1H), 7.50-7.52 (m, 1H), 7.26-7.36 (m, 2H), 4.86 (s, 2H).
步骤2:3-(溴代甲基)苯并呋喃
将苯并呋喃-3-基甲醇(5.0 g, 33.7 mmol)在二乙醚(50 ml)的冷(0℃)溶液用三溴化磷(1.1 ml, 11.2 mmol)处理并将反应混合物于0℃搅拌30 min。然后将反应混合物倾入到冰中并用乙醚提取。有机层经硫酸钠干燥并浓缩。粗品(7.1 g, 100%)无须进一步纯化而原样用于随后的步骤。
1H NMR (400MHz, CDCI3):δ 7.71-7.74 (m, 2H), 7.53 (s, 1H), 7.31-7.39 (m, 2H), 4.65 (s, 2H).
步骤3:2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷
将3-(溴代甲基)苯并呋喃(7.1 g, 33.8 mmol)在脱气的1, 4-二氧杂环己烷(70 ml)中的溶液用双(频哪醇合)二硼(10.3g, 40.5mmol)、碳酸钾(13.9 g, 101.0mmol)、四(三苯基膦)钯(0) (1.9 g, 1.7 mmol)处理并将混合物于100℃加热12h。使烧瓶中的内容物冷却至室温并通过C盐床过滤。浓缩滤液,粗品经硅胶柱层析纯化,用在石油醚中的2-5%乙酸乙酯洗脱,得到标题化合物(6.1 g, 69%),为黄色油状物。
1H NMR (400 MHz, CDCI3) δ 7.52-7.57 (m, 2H), 7.44-7.46 (m, 1H), 7.21-7.30 (m, 2H), 2.23 (s, 2H), 1.29 (s, 12H).
步骤4:2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
将2-(苯并呋喃-3-基甲基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷(6.1 g, 23.6 mmol)的二乙醚(60 ml)溶液用(1S, 2S, 3R, 5S)-(+)-蒎烷二醇(6.0 g, 35.4 mmol)处理。将反应混合物于室温下搅拌12 h,然后混合物用水洗涤两次,然后用盐水洗涤,经无水硫酸钠干燥,然后浓缩。粗产物经硅胶柱层析纯化,用在石油醚中的5%乙酸乙酯洗脱, 得到标题化合物(6.3 g, 82%)。
1H NMR (400 MHz, CDCI3):δ 7.56-7.58 (m, 1H), 7.53-7.55 (m, 1H), 7.44-7.46 (m, 1H), 7.23-7.28 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1H), 2.32-2.34 (m, 1H), 2.28 (s, 2H), 2.21-2.22 (m, 1H), 2.08 (t, J = 5.88 Hz, 1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1H), 0.85 (s, 3H). GCMS:m/z:310
步骤5:[(1S)-1-氯代-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
经20分钟向二氯甲烷(6.3 ml, 60.9 mmol)和无水四氢呋喃(36 ml)的冷却(-100℃)混合物中加入正丁基锂(1.6 M在己烷中, 14.0 ml, (22.3 mmol)。搅拌20分钟后,经20分钟于-100℃加入2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.3 g, 20.3 mmol)在无水THF (22 ml)中的溶液。然后于-100℃经30分钟加入氯化锌(0.5 M在THF中, 36.5 ml, 18.2 mmol)溶液。使该混合物达到室温并搅拌18 h和浓缩。向生成的油状物中加入二乙醚和饱和的氯化铵(各100 ml)并剧烈搅拌。水层用二乙醚提取3次,合并的有机层经无水硫酸钠干燥并真空浓缩。残留物(7.3 g, 99%)原样用于下一步骤。
1H NMR (400 MHz, DMSO-d6):δ 7.57-7.60 (m, 2H), 7.47-7.49 (m, 1H), 7.25-7.31 (m, 2H), 4.34-4.36 (m, 1H), 3.29-3.31 (m, 1H), 3.22-3.24 (m, 1H), 2.31-2.35 (m, 1H), 2.12-2.14 (m, 1H), 2.06 (t, J = 5.84 Hz, 1H), 1.86-1.90 (m, 2H), 1.42 (s, 3H), 1.04 (d, J = 11.04 Hz, 1H), 0.85 (s, 3H). GCMS:m/z:358.2
步骤6:[(1R)-1-[双(三甲基甲硅烷基)氨基]- 2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯
向[(1S)-1-氯代-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(7.3 g, 20.3 mmol)在40 ml无水四氢呋喃中的冷却(-78℃)溶液中加入双(三甲基甲硅烷基)氨化锂(1 M在THF中, 25.5 ml, 25.5 mmol)。使该混合物达到室温,搅拌18 h并浓缩至干。向生成的残留物中加入己烷,然后滤除沉淀的固体。浓缩滤液得到所需的粗产物(6.7 g, 68%),其无须进一步纯化而用于随后的步骤。
1H NMR (400 MHz, CDCI3):δ 7.59-7.60 (m, 1H), 7.45-7.50 (m, 2H), 7.24-7.28 (m, 2H), 4.31 (dd, J = 1.56, 8.70 Hz, 1H), 3.14-3.18 (m, 1H), 2.90-2.92 (m, 1H), 2.72-2.75 (m, 1H), 2.30-2.34 (m, 1H), 2.14-2.15 (m, 1H), 2.03 (t, J = 5.68 Hz, 1H), 1.80-1.88 (m, 2H), 1.39 (s, 3H), 1.30 (s, 3H), 1.01 (d, J = 10.88 Hz, 1H), 0.84 (s, 3H), 0.09 (s, 18H).
步骤7:[(1R)-1-氨基-2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯三氟乙酸盐
将[(1R)-1-[双(三甲基甲硅烷基)氨基]- 2-(苯并呋喃-3-基甲基)硼酸(+)-蒎烷二醇酯(6.7 g, 13.9 mmol)在二乙醚(30 ml)中的冷却(0℃)溶液用三氟乙酸(3.2 ml, 41.7 mmol)滴加处理。反应混合物在低于30℃温度下在减压下蒸发。使粗品溶于甲苯并蒸发,并将此顺序重复4次。获得的白色固体(2.3 g, 36%),其无须进一步纯化而用于随后的步骤。
1H NMR (400 MHz, DMSO-d6):δ 7.66 (s, 1H), 7.60-7.61 (m, 1H), 7.45-7.47 (m, 1H), 7.20-7.29 (m, 2H), 4.28-4.30 (m, 1H), 3.16-3.27 (m, 3H), 2.13-2.25 (m, 3H), 1.94 (t, J = 5.56 Hz, 1H), 1.81-1.86 (m, 2H), 1.25 (s, 6H), 1.01 (d, J = 8.00 Hz, 1H), 0.75 (s, 3H).
实施例1:[(1R)-1-[(4-氧代-4-苯基丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸
步骤1:[(1R)-1-[(4-氧代-4-苯基丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸(+)-蒎烷二醇酯
将中间体1 (100 mg, 0.24 mmol)在无水二氯甲烷(15 ml)中的冷却(0℃)溶液用二异丙基乙胺(0.12 ml, 0.72 mmol)和3-苯甲酰基丙酸(42 mg, 0.24 mmol)和TBTU (91 mg, 0.29 mmol)处理。将反应混合物于0℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入10 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物经硅胶层析纯化来分离,用石油醚/乙酸乙酯1:1洗脱。
MS (ESI+):466.3, HPLC (方法A):Rt 5.44min 85.0 %
步骤2:[(1R)-1-[(4-氧代-4-苯基丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸
将[(1R)-1-[(4-氧代-4-苯基丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸(+)-蒎烷二醇酯(74 mg, 0.16 mmol)在甲醇/戊烷(1:1, 15 ml)中的冷却(0℃)溶液用2-甲基丙基硼酸(64 mg, 0.636mmol)和HCl水溶液(1.5 N, 0.4 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水的甲醇层。残留物用冰处理,用NaOH水溶液(2N)碱化并用二氯甲烷提取三次。然后用HCl水溶液(1.5 N)酸化水层并用二氯甲烷提取两次。DCM层经硫酸钠干燥、过滤并浓缩,得到固体残留物,其经高效硅胶快速层析纯化,获得为白色固体的标题化合物。
1H NMR (400 MHz, DMSO-d6):δ 8.66 (s, 1H), 7.89-7.94 (m, 2H), 7.58-7.62 (m, 1H), 7.45-7.49 (m, 2H), 7.29-7.31 (m, 1H), 7.04 (s, 1H), 6.92-6.93 (m, 1H), 3.24-3.26 (m, 2H), 2.68-2.72 (m, 2H), 2.55-2.58 (m, 3H). MS (ESI+):314.0 [M+H-H2O], HPLC (方法A):Rt 2.89min;HPLC纯度95.8 %。
以下化合物采用实施例1遵照的相同程序合成:
实施例2:[(1R)-1-({[(1RS,2RS)-2-苯甲酰基环己基]羰基}氨基)-2-(3-噻吩基)乙基]硼酸
该实施例为非对映体的混合物。在环己烷环上的手性中心具有反式构型。从得自Rielke Chemicals的反式-2-苯甲酰基环己烷-1-羧酸起始制备。淡粉红色固体。 1H NMR (400 MHz, DMSO-d6):δ 8.14-8.84 (m, 1H), 7.82-7.91 (m, 2H), 7.25-7.58 (m, 4H), 6.77-6.88 (m, 2H), 3.60-3.63 (m, 1H), 2.63-2.69 (m, 1H), 2.43-2.49 (m, 1H), 2.13-2.28 (m, 1H), 1.86-1.89 (m, 1H), 1.66-1.76 (m, 3H), 1.30-1.40 (m, 2H), 1.18-1.23 (m, 3H), 1.06-1.08 (m, 2H). MS (ESI+):368.0 [M+H-H2O], HPLC (方法A):Rt 3.71 min;HPLC纯度50.6%+45.6%。
实施例3:[(1R)-1-{[2-(RS)-(3-氯代苯基)-4-氧代-4-苯基丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
该实施例为非对映体的混合物。灰白色固体。1 H NMR (400 MHz, DMSO-d6):δ 7.95-7.96 (m, 2H), 7.58-7.60 (m, 1H), 7.48-7.50 (m, 2H), 7.42-7.44 (m, 1H), 7.22-7.34 (m, 4H), 6.88-6.95 (m, 1H), 6.60-6.62 (m, 1H), 4.13 (t, J= 5.1 Hz, 1H), 3.75-3.85 (m, 1H), 3.24-3.28 (m, 2H), 2.64-2.73 (m, 2H). MS (ESI+):424.0 [M+H-H2O], HPLC (方法A):Rt 8.57;8.96min;HPLC纯度28.7%+67.9%。
实施例4:[(1R)-1-{[2-(RS) -(4-氯代苯基)-4-氧代-4-苯基丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
该实施例为非对映体的混合物。白色固体。1 H NMR (400 MHz, DMSO-d6):δ 7.95-7.95 (m, 2H), 7.60-7.62 (m, 1H), 7.48-7.52 (m, 2H), 7.31-7.41 (m, 6H), 6.88-6.97 (m, 1H), 6.63-6.64 (m, 1H), 4.12-4.15 (m, 1H), 3.85-3.95 (m, 1H), 3.25-3.29 (m, 1H), 3.12-3.14 (m, 1H), 2.66-2.75 (m, 2H). MS (ESI+):424.0 [M+H-H2O], HPLC (方法A):Rt 8.56;8.97min;HPLC纯度40.0%+53.4%。
实施例5:[1-({[(1RS,2SR)-2-苯甲酰基环戊基]羰基}氨基)-2-(3-噻吩基)乙基]硼酸
该实施例为非对映体的混合物。在环己烷环上的手性中心具有反式构型。从得自Rielke Chemicals的反式-2-苯甲酰基环戊烷-1-甲酸起始制备。灰白色固体。1 H NMR (400 MHz, DMSO-d6):δ 7.91-7.93 (m, 1H), 7.82-7.84 (m, 1H), 7.59-7.61 (m, 1H), 7.55-7.57 (m, 1H), 7.33 (s, 1H), 7.25-7.26 (m, 1H), 6.87-6.92 (m, 1H), 6.78-6.86 (m, 1H), 4.01-4.02 (m, 1H), 3.00-3.15 (m, 2H), 2.66-2.68 (m, 2H), 2.00-2.03 (m, 1H), 1.85-1.92 (m, 1H), 1.56-1.68 (m, 4H). MS (ESI+):354.3 [M+H-H2O], HPLC (方法A):Rt 3.53min;HPLC纯度92.0 %。
实施例9:[(1R)-1-{[4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
灰白色固体。 1 H NMR (400 MHz, DMSO-d6):δ 8.65 (s, 1H), 7.87-7.92 (m, 2H), 7.30-7.35 (m, 1H), 7.04 (s, 1H), 6.95-6.98 (m, 2H), 6.92-6.93 (m, 1H), 3.81 (s, 3H), 3.18-3.20 (m, 2H), 2.65-2.74 (m, 2H), 2.52-2.55 (m, 3H). MS (ESI+):344.3 [M+H-H2O], HPLC (方法A):Rt 3.00min;HPLC纯度96.2 %。
实施例10:[(1R)-1-[(2-(RS) -甲基-4-氧代-4-苯基丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸
该实施例为非对映体的混合物。在环己烷环上的手性中心具有反式构型。由得自ABCR的2-甲基-4-氧代-4-苯基丁酸起始制备。灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.56-8.61 (m, 1H), 7.87-7.91 (m, 2H), 7.57-7.59 (m, 1H), 7.46-7.51 (m, 2H), 7.26-7.28 (m, 1H), 7.09 (s, 1H), 6.93 (s, 1H), 3.20-3.30 (m, 1H), 3.04-3.09 (m, 1H), 2.93-2.96 (m, 1H), 2.65-2.74 (m, 2H), 2.48-2.50 (m, 1H), 1.02-1.05 (m, 3H). MS (ESI+):328.3 [M+H-H2O], HPLC (方法A):Rt 3.15min;
HPLC纯度87.0%。
实施例12:[(1R)-1-{[4-(2-甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1 H NMR (400 MHz, DMSO-d6):δ 7.51-7.53 (m, 2H), 7.49 (s, 1H), 7.14 (d, J= 8.1 Hz, 1H), 7.07 (s, 1H), 7.00-7.06 (m, 1H), 6.92-6.94 (m, 1H), 3.84 (s, 3H), 3.07-3.13 (m, 3H), 2.80-2.81 (m, 1H), 2.76-2.78 (m, 1H), 2.38 (t, J= 7.0 Hz, 2H).
MS (ESI+):344.0 [M+H-H2O], HPLC (方法A):Rt 3.03;HPLC纯度93.2%。
实施例13:[(1R)-1-{[4-(2,4-二甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。 1 H NMR (400 MHz, DMSO-d6):δ 7.63 (d, J= 8.6 Hz, 1H), 7.34-7.36 (m, 1H), 7.06 (s, 1H), 6.94 (s, 1H), 6.57-6.60 (m, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.04-3.10 (m, 3H), 2.75-2.80 (m, 1H), 2.65-2.71 (m, 1H), 2.34-2.35 (m, 2H).
MS (ESI+):374.0 [M+H-H2O], HPLC (方法A):Rt 3.13;3.41 min;HPLC纯度99.0% 。
实施例6:{(1R)-2-(3-乙基苯基)-1-[(4-氧代-4-苯基丁酰基)氨基]乙基}硼酸
步骤1:{(1R)-2-(3-乙基苯基)-1-[(4-氧代-4-苯基丁酰基)氨基]乙基}硼酸(+)-蒎烷二醇酯
将中间体2 (150 mg, 0.34 mmol)在无水二甲基甲酰胺(10 ml)中的冷(-10℃)溶液用二异丙基乙胺(0.17 ml, 1.0 mmol)、3-苯甲酰基丙酸(60 mg, 0.340mmol)和TBTU (130 mg, 0.41 mmol)处理。将反应混合物于-10℃搅拌3h,然后在减压下浓缩,保持外浴温度低于30℃,然后加入10 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(120 mg, 72%)经硅胶快速层析纯化来分离,用石油醚/乙酸乙酯1:1洗脱。MS (ESI+):488.3, HPLC (方法A):Rt 6.08min;HPLC纯度91.0%。
步骤2:{(1R)-2-(3-乙基苯基)-1-[(4-氧代-4-苯基丁酰基)氨基]乙基}硼酸
将{(1R)-2-(3-乙基苯基)-1-[(4-氧代-4-苯基丁酰基)氨基]乙基}硼酸(+)-蒎烷二醇酯(120 mg, 0.25 mmol)在甲醇/戊烷(1:1, 15ml)中的冷(0℃)溶液用2-甲基丙基硼酸(99 mg, 0.99 mmol)和HCl水溶液(1.5 N, 0.5 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。残留物经高效硅胶快速层析纯化,获得固体,其用戊烷研磨,得到为灰白色固体的标题化合物。
1H NMR (400 MHz, DMSO-d6):δ 7.91-7.92 (m, 2H), 7.70-7.72 (m, 1H), 7.60-7.62 (m, 2H), 7.10-7.14 (m, 1H), 6.94-6.98 (m, 3H), 3.12-3.18 (m, 3H), 2.73-2.76 (m, 1H), 2.64-2.67 (m, 1H), 2.51-2.55 (m, 2H), 2.40-2.43 (m, 2H), 1.13 (t, J= 7.6 Hz, 3H). MS (ESI+):336.0 [M+H-H2O], HPLC (方法A):Rt 3.75min;HPLC纯度96.8%。
以下化合物采用实施例6遵照的相同程序合成:
实施例7:((1R)-2-(3-乙基苯基)-1-{[4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.85-7.90 (m, 2H), 6.91-7.13 (m, 6H), 3.81 (s, 3H), 3.52-3.54 (m, 1H), 3.09-3.18 (m, 2H), 2.65-2.68 (m, 2H), 2.52-2.54 (m, 2H), 2.46-2.48 (m, 1H), 2.37-2.40 (m, 1H), 1.06-1.15 (m, 3H). MS (ESI+):366.3 [M+H-H2O], HPLC (方法A):Rt 3.77min;HPLC纯度96.4%。
实施例8:((1R)-2-(3-乙基苯基)-1-{[4-(2-甲氧基苯基)-4-氧代丁酰基]氨基}乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.49-7.53 (m, 2H), 7.10-7.15 (m, 2H), 6.93-7.02 (m, 4H), 3.84 (s, 3H), 3.05-3.14 (m, 3H), 2.76-2.78 (m, 1H), 2.73-2.74 (m, 1H), 2.48-2.49 (m, 2H), 2.33-2.37 (m, 2H), 1.08-1.14 (m, 3H). MS (ESI+):366.3 [M+H-H2O], HPLC (方法A):Rt 3.81 min;HPLC纯度90.1%。
实施例11:[(1R)-1-{[4-(2,4-二甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.49 (s, 1H), 7.64 (d, J= 8.7 Hz, 1H), 7.04-7.07 (m, 1H), 6.99 (s, 1H), 6.90-6.93 (m, 2H), 6.52-6.58 (m, 2H), 3.79 (s, 6H), 3.10-3.14 (m, 2H), 2.66-2.74 (m, 2H), 2.48-2.49 (m, 1H), 2.48 (m, 4H), 1.10 (t, J= 7.6 Hz, 3H).
MS (ESI+):396.2 [M+H-H2O], HPLC (方法A):Rt 3.85min;HPLC纯度97.7 %。
实施例14:[(1R)-1-{[(2R)-2-(3-氯代苯基)-4-氧代-4-苯基丁酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
白色固体。一种非对映体。大多数从硼酸基团移动的手性位置的构型被任意指定。该实施例由中间体12 (+)-2-(3-氯代苯基)-4-氧代-4-苯基丁酸制备(具有αD +101.9°;乙醇, c= 1.0 g/100 ml). 1H NMR (400 MHz, DMSO-d6):δ 7.95 (d, J= 8.0 Hz, 2H), 7.61- 7.63 (m, 1H), 7.49-7.53 (m, 2H), 7.27-7.41 (m, 4H), 7.04-7.07 (m, 1H), 6.91-6.96 (m, 2H), 6.79-6.81 (m, 1H), 4.07-4.11 (m, 1H), 3.71-3.76 (m, 1H), 3.29-3.34 (m, 1H), 3.05-3.10 (m, 1H), 2.62-2.73 (m, 2H), 2.48-2.49 (m, 1H), 1.08 (t, J= 8.0 Hz, 3H). MS (ESI+):446.0 [M+H- H2O], HPLC (方法A):Rt 5.02min;HPLC纯度85.1 %。
实施例15:[(1R)-1-{[(2R)-2-(4-氯代苯基)-4-氧代-4-苯基丁酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
一种非对映体。大多数从硼酸基团移动的手性位置的构型被任意指定。该实施例由中间体14 (+)-2-(4-氯代苯基)-4-氧代-4-苯基丁酸制备(具有αD +103.4°;乙醇, c= 0.57 g/100 mL). 灰白色固体. 1H NMR (400 MHz, DMSO-d6):δ 8.50 (s, 1H), 7.93-7.95 (m, 2H), 7.60-7.63 (m, 1H), 7.46-7.49 (m, 2H), 7.14-7.19 (m, 3H), 7.00-7.04 (m, 1H), 6.90-6.92 (m, 1H), 6.78-6.80 (m, 2H), 4.15-4.18 (m, 1H), 3.75-3.82 (m, 1H), 3.32-3.34 (m, 1H), 2.59-2.62 (m, 1H), 2.38-2.44 (m, 2H), 2.21-2.26 (m, 1H), 1.07 (t, J= 8.0 Hz, 3H).
MS (ESI+):446.3 [M+H-H2O], HPLC (方法A):Rt 13.54min;HPLC纯度97.1 %, CHIRAL HPLC Rt 5.48 min (98.3%)。
实施例16:[(1R)-1-{[(2R)-2-(4-氯代苯基)-4-氧代-4-苯基丁酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
一种非对映体。大多数从硼酸基团移动的手性位置的构型被任意指定。该实施例由中间体15 (-)-2-(4-氯代苯基)-4-氧代-4-苯基丁酸起始制备(具有αD -11 1.5°;乙醇, c= 0.57 g/100 ml). 淡粉红色固体. 1H NMR (400 MHz, DMSO-d6):δ 8.75 (s, 1H), 7.85-7.87 (m, 2H), 7.55-7.59 (m, 1H), 7.41-7.43 (m, 2H), 7.30-7.39 (m, 2H), 7.21-7.23 (m, 2H), 7.00-7.04 (m, 1H), 6.89-6.91 (m, 1H), 6.83-6.85 (m, 1H), 4.17-4.21 (m, 1H), 3.67-3.74 (m, 1H), 3.39-3.40 (m, 2H), 2.63-2.67 (m, 1H), 2.57-2.59 (m, 1H), 2.45-2.48 (m, 2H), 1.10 (t, J= 7.6 Hz, 3H). MS (ESI+):446.3 [M+H-H2O], HPLC (方法A):Rt 13.58min;HPLC纯度97.1 %, CHIRAL HPLC Rt 8.15 min (98.3%)。
实施例17:[(1R)-1-[(4-联苯-4-基-4-氧代丁酰基)氨基]-2-(3-乙基苯基)乙基]硼酸
步骤1:[(1R)-1-[(4-联苯-4-基-4-氧代丁酰基)氨基]-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯
将中间体2 (300 mg, 0.68 mmol)在无水N,N-二甲基甲酰胺(25 ml)中的冷(-10℃)溶液用N,N-二异丙基乙胺(0.35 ml, 2.0 mmol)、3-(4-苯基苯甲酰基)丙酸(173 mg, 0.68 mmol)和TBTU (262 mg, 0.815mmol)处理。将反应混合物于-10℃搅拌3h,然后用乙酸乙酯稀释并用盐水反复洗涤。分离有机层,经硫酸钠干燥并浓缩。经硅胶快速层析纯化粗品,用乙酸乙酯和石油醚洗脱(淡黄色胶状液体)。
MS (ESI+):564.3;HPLC (方法A):Rt. 6.6 min;HPLC纯度97.7 %;CHIRAL HPLC (方法A):Rt. 4.5 min;HPLC纯度98.5 %
步骤2:[(1R)-1-[(4-联苯-4-基-4-氧代丁酰基)氨基]-2-(3-乙基苯基)乙基]硼酸
将[(1R)-1-[(4-联苯-4-基-4-氧代丁酰基)氨基]-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯(167 mg, 0.296 mmol)在甲醇/戊烷(1:1, 30mL)中的冷(0℃)溶液用2-甲基丙基硼酸(120 mg, 1.18 mmol)和HCl水溶液(1.5 N, 0.8 ml)处理。将反应混合物于室温下搅拌15h,然后在减压下蒸发。经硅胶快速层析纯化粗品,用二氯甲烷和甲醇洗脱,获得为灰白色固体的标题化合物。
1H NMR (400 MHz, DMSO-d6):δ 7.95-7.94 (m, 2H), 7.67-7.73 (m, 4H), 7.41-7.49 (m, 3H), 7.05-7.09 (m, 1H), 6.91-7.09 (m, 3H), 3.27-3.38 (m, 3H), 2.72-2.77 (m, 2H), 2.57-2.62 (m, 2H), 2.46-2.50 (m, 2H), 1.07-1.11 (m, 3H). MS (ESI+):412.0 [M+H-H2O]. HPLC (方法B):Rt 13.1 min;HPLC纯度91.9 %。
以下产物根据对实施例17描述的相同两步方案制备:
实施例18:((1R)-2-(3-乙基苯基)-1-{[4-(2-萘基)-4-氧代丁酰基]氨基}乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.59 (s, 1H), 8.04 (d, J= 8.1 Hz, 1H), 7.89-7.95 (m, 3H), 7.55-7.66 (m, 2H), 6.94-7.05 (m, 3H), 6.87-6.89 (m, 1H), 3.40-3.42 (m, 2H), 2.73-2.76 (m, 2H), 2.64-2.66 (m, 2H), 2.40-2.50 (3H, m), 1.07 (t, J= 7.5 Hz, 3H). MS (ESI+):386.3 [M+H-H2O];HPLC (方法B):Rt 12.7 min, HPLC纯度96.1 %。
实施例19:[(1R)-1-[(4-联苯-3-基-4-氧代丁酰基)氨基]-2-(3-乙基苯基)乙基]硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.13 (s, 1H), 7.88 (d, J= 7.8 Hz, 2H), 7.78 (d, J= 8.6 Hz, 2H), 7.52-7.56 (m, 1H), 7.42-7.48 (m, 2H), 7.36-7.39 (m, 1H), 7.01-7.03 (m, 1H), 6.93-6.98 (m, 2H), 6.87 (d, J= 7.2 Hz, 1H), 3.31-0.00 (m, 2H), 2.70-2.80 (m, 2H), 2.48-2.62 (m, 5H), 1.05-1.09 (m, 3H). MS (ESI+):412.0 [M+H-H2O];HPLC (方法A):Rt. 4.6 min, HPLC纯度96.4 %。
实施例20:[(1R)-1-[(4-联苯-4-基-4-氧代丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.98 (d, J= 8.0 Hz, 2H), 7.68-7.76 (m, 4H), 7.46-7.52 (m, 2H), 7.39-7.41 (m, 1H), 7.30 (m, 1H), 7.05 (s, 1H), 6.94 (d, J= 4.8 Hz, 1H), 3.29-3.31 (m, 2H), 2.70-2.72 (m, 2H), 2.54-2.59 (m, 3H). MS (ESI+):390.0 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度97.8 %。
实施例21:[(1R)-1-{[4-(2-萘基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1 H NMR (400 MHz, DMSO-d6):δ 8.65 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 7.94-8.02 (m, 3H), 7.59-7.67 (m, 2H), 7.36-7.38 (m, 1H), 7.10 (s, 1H), 6.95-6.96 (m, 1H), 3.32-3.35 (m, 2H), 3.14-3.17 (m, 1H), 2.70-2.83 (m, 2H), 2.48-2.50 (m, 2H). MS (ESI+):364.0 [M+H-H2O];HPLC (方法A):Rt. 3.6 min, HPLC纯度95.6 %。
实施例22:[(1R)-1-[(4-联苯-3-基-4-氧代丁酰基)氨基]-2-(3-噻吩基)乙基]硼酸
白色固体。1 H NMR (400 MHz, DMSO-d6):δ 8.12 (s, 1H), 7.89-7.93 (m, 2H), 7.69 (d, J= 7.6 Hz, 2H), 7.59-7.63 (m, 1H), 7.46-7.50 (m, 2H), 7.37-7.40 (m, 1H), 7.32-7.34 (m, 1H), 7.06 (s, 1H), 6.94 (d, J= 4.4 Hz, 1H), 3.24-3.27 (m, 2H), 3.08-3.11 (m, 1H), 2.66-2.81 (m, 2H), 2.45-2.49 (m, 2H). MS (ESI+):390.0 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度96.5 %。
实施例23:[(1R)-1-{[4-氧代-4-(6-苯基吡啶-2-基)丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
灰白色固体。1 H NMR (400 MHz, DMSO-d6):δ 8.17-8.23 (m, 3H), 8.07 (t, J= 7.6 Hz, 1H), 7.89 (d, J= 6.8 Hz, 1H), 7.46-7.56 (m, 3H), 7.35-7.37 (m, 1H), 7.09 (s, 1H), 6.95 (d, J= 5.2 Hz, 1H), 3.47-3.49 (m, 2H), 3.15 (t, J= 6.0 Hz, 1H), 2.63-2.83 (m, 3H). MS (ESI+):413.3 [M+Na-H2O]. HPLC (方法A):Rt. 3.8 min, HPLC纯度94.4 %。
实施例24:[(1R)-1-{[(2R)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基]硼酸
一种非对映体. 大多数从硼酸基团移动的手性位置的构型被任意指定。该实施例由中间体17 (-)-2-苄基-4-(4-甲氧基苯基)-4-氧代-丁酸起始制备(具有αD -21.0°;乙醇, c= 1.0 g/100 ml)。白色固体。
1H NMR (400 MHz, DMSO-d6):δ 7.86 (d, J= 8.8 Hz, 2H), 7.32-7.34 (m, 1H), 7.20-7.26 (m, 4H), 7.14-7.18 (m, 1H), 7.00 (d, J= 8.8 Hz, 2H), 6.95 (s, 1H), 6.87-6.89 (m, 1H), 3.81 (s, 3H), 3.24-3.28 (m, 1H), 3.09-3.13 (m, 2H), 2.85-2.90 (m, 1H), 2.56-2.75 (m, 4H). MS (ESI+):434.2 [M+H-H2O]. HPLC (方法A):Rt. 4.1 min, HPLC纯度95.9 %。
实施例25:[(1R)-1-{[(2S)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}-2-(3-噻吩基)乙基)]硼酸
一种非对映体。大多数从硼酸基团移动的手性位置的构型被任意指定。该实施例由中间体16 (+)-2-苄基-4-(4-甲氧基苯基)-4-氧代-丁酸起始制备(具有αD +21.1 °;乙醇, c= 1.0 g/100 ml). 灰白色固体. 1H NMR (400 MHz, DMSO-d6):δ 7.86 (d, J= 8.8 Hz, 2H), 7.30-7.32 (m, 1H), 7.14-7.26 (m, 5H), 6.99 (d, J= 6.0 Hz, 2H), 6.79-6.83 (m, 2H), 3.80 (s, 3H), 3.16-3.27 (m, 2H), 3.04-3.00 (m, 1H), 2.75-2.83 (m, 2H), 2.48-2.69 (m, 3H). MS (ESI+):434.2 [M+H-H2O]. HPLC (方法A):Rt. 4.2 min, HPLC纯度92.7%。
实施例26:{(1R)-1-{[4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}-2-[3-(三氟甲基)苯基]乙基}硼酸
浅棕色固体。1H NMR (400 MHz, DMSO-d6):δ 7.89 (d, J= 8.9 Hz, 2H), 7.45-7.49 (m, 4H), 7.02 (d, J= 8.9 Hz, 2H), 3.81 (s, 3H), 3.12-3.16 (m, 1H), 3.06-3.08 (m, 2H), 2.85-2.90 (m, 1H), 2.70-2.76 (m, 1H), 2.35-2.39 (m, 2H). MS (ESI+):406.0 [M+H-H2O]. HPLC (方法A):Rt. 3.9 min, HPLC纯度97.3%。
实施例27:{(1R)-1-{[2-(RS)-苄基-4-(4-甲氧基苯基)-4-氧代丁酰基]氨基}-2-[3-(三氟甲基)苯基]乙基}硼酸
非对映体的混合物。黄色固体。1H NMR (400 MHz, DMSO-d6):δ 7.82 (d, J= 8.7 Hz, 1H), 7.37-7.46 (m, 3H), 7.30 (d, J= 7.6 Hz, 1H), 7.13-7.25 (m, 5H), 6.98 (d, J= 8.7 Hz, 2H), 3.81 (s, 3H), 3.37 (s, 1H), 3.21-3.23 (m, 1H), 3.17-3.19 (m, 1H), 3.06-3.10 (m, 1H), 2.97-3.00 (m, 1H), 2.74-2.83 (m, 3H), 2.56-2.67 (m, 2H). MS (ESI+):496.2 [M+H-H2O]. HPLC (方法A):Rt. 4.7 min, HPLC纯度73.9%+14.4%。
以下化合物根据对实施例1描述的相同两步方案制备:
实施例28:((1R)-2-(3-乙基苯基)-1-{[3-(1H-吲唑-1-基)丙酰基]氨基}乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.04 (s, 1H), 7.70-7.75 (m, 1H), 7.56-7.61 (m, 1H), 7.23-7.27 (m, 1H), 7.02-7.10 (m, 2H), 6.90-6.95 (m, 1H), 6.81-6.85 (m, 1H), 6.73-6.75 (m, 1H), 4.61 (t, J= 6.80 Hz, 2H), 2.78-2.81 (m, 1H), 2.65-2.69 (m, 3H), 2.48-2.50 (m, 2H), 2.35-0.00 (m, 1H), 1.08-1.13 (m, 3H). MS (ESI+):348.3 [M+H-H2O]. HPLC (方法B):Rt 11.8 min, HPLC纯度87.9%。
实施例29:[(1R)-1-{[3-(1H-苯并咪唑-1-基)丙酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.88 (s, 1H), 7.52-7.61 (m, 2H), 7.15-7.18 (m, 2H), 6.98-7.02 (m, 1H), 6.90 (m, 1H), 6.88 (s, 1H), 6.72-6.74 (m, 1H), 4.48-4.52 (m, 2H), 2.89-2.90 (m, 2H), 2.74 (m, 1H), 2.59-2.66 (m, 2H), 2.41-2.45 (m, 2H), 2.36-2.38 (m, 1H), 1.07 (m, 3H). MS (ESI+):370.3 [M+Na-H2O]. HPLC (方法A):Rt 2.8 min, HPLC纯度95.9%。
实施例30:((1R)-2-(3-乙基苯基)-1-{[3-(2-氧代-1,3-苯并噻唑-3(2H)-基)丙酰基]氨基}乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.51-7.65 (m, 1H), 7.24-7.34 (m, 2H), 7.14-7.18 (m, 1H), 7.05-7.09 (m, 1H), 6.89-6.93 (m, 1H), 6.82-6.91 (m, 2H), 4.12-4.15 (m, 2H), 2.61-2.71 (m, 5H), 2.50-2.52 (m, 1H), 2.30-2.40 (m, 1H), 1.09-1.11 (m, 3H)
MS (ESI+):381.0 [M+H-H2O]. HPLC (方法A):Rt 3.8 min, HPLC纯度95.7%。
实施例31:[(1R)-1-{[3-(1H-1,2,3-苯并三唑-1-基)丙酰基]氨基}-2-(3-乙基苯基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.61-8.68 (m, 1H), 7.97-8.02 (m, 1H), 7.80-7.84 (m, 1H), 7.41-7.45 (m, 1H), 7.32-7.38 (m, 1H), 7.00-7.04 (m, 1H), 6.90-6.93 (m, 1H), 6.77 (s, 1H), 6.71 (d, J= 7.6 Hz, 1H), 4.90-4.93 (m, 2H), 2.92-2.95 (m, 2H), 2.65-2.67 (m, 2H), 2.50-2.45 (m, 2H), 2.30-2.31 (m, 1H), 1.06-1.10 (m, 3H)
MS (ESI+):349.0 [M+H-H2O]. HPLC (方法A):Rt 3.3 min, HPLC纯度96.4%。
实施例32:[(1R)-1-{[3-(1H-吲唑-1-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.02 (s, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1H), 7.34-7.38 (m, 1H), 7.23-7.25 (m, 1H), 7.09-7.12 (m, 1H), 6.67-6.70 (m, 2H), 4.50-4.56 (m, 2H), 3.03-3.06 (m, 1H), 2.48-2.65 (m, 4H)
MS (ESI+):326.0 [M+H-H2O];HPLC (方法A):Rt. 3.0 min, HPLC纯度95.4%。
实施例33:[(1R)-1-{[3-(1H-苯并咪唑-1-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.09 (m, 1H), 7.56-7.63 (m, 2H), 7.18-7.26 (m, 3H), 6.72 (d, J= 4.4 Hz, 2H), 4.39-4.43 (m, 2H), 3.11-3.14 (m, 1H), 2.59-2.72 (m, 4H). MS (ESI+):348.0 [M+Na-H2O]. HPLC (方法A):Rt. 2.0 min, HPLC纯度96.6%。
实施例34:[(1R)-1-{[3-(2-氧代-1,3-苯并噻唑-3(2H)-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.60-7.62 (m, 1H), 7.30-7.37 (m, 3H), 7.15-7.20 (m, 1H), 6.79-6.84 (m, 2H), 4.08 (t, J= 7.2 Hz, 2H), 3.11-3.15 (m, 1H), 2.61-2.73 (m, 2H), 2.42-2.48 (m, 2H). MS (ESI+):359.0 [M+H-H2O]. HPLC (方法A):Rt. 3.1 min, HPLC纯度98.9%。
实施例35:[(1R)-1-{[3-(1H-1,2,3-苯并三唑-1-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.01 (d, J= 8.0 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.51-7.54 (m, 1H), 7.36-7.40 (m, 1H), 7.26-7.28 (m, 1H), 6.72-6.74 (m, 2H), 4.80-4.90 (m, 2H), 3.11-3.15 (m, 1H), 2.76-2.80 (m, 2H), 2.57-2.71 (m, 2H). MS (ESI+):327.0 [M+H-H2O]. HPLC (方法A):Rt. 2.5 min, HPLC纯度86.4%。
实施例38:{(1R)-1-{[3-(1H-苯并咪唑-1-基)丙酰基]氨基}-2-[3-(三氟甲基)苯基]乙基}硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.07 (s, 1H), 7.63 (d, J= 7.5 Hz, 1H), 7.55 (d, J= 7.5 Hz, 1H), 7.44 (d, J= 7.9 Hz, 1H), 7.40 (s, 1H), 7.17-7.29 (m, 3H), 7.08 (d, J= 7.8 Hz, 1H), 4.38 (t, J= 6.7 Hz, 2H), 3.15-3.19 (m, 1H), 2.77-2.82 (m, 1H), 2.63-2.68 (m, 1H), 2.58 (t, J= 6.8 Hz, 2H). MS (ESI+):410.0 [M+Na-H2O]. HPLC (方法A):Rt. 3.0 min, HPLC纯度95.3%。
以下化合物根据对实施例6描述的相同两步方案制备:
实施例36:((1R)-2-(3-乙基苯基)-1-{[3-(5-苯基-1,2,4-噁二唑-3-基)丙酰基]氨基}乙基)硼酸
浅棕色固体。1H NMR (400 MHz, DMSO-d6):δ 8.06-8.08 (m, 2H), 7.67-7.71 (m, 1H), 7.59-7.63 (m, 2H), 7.07-7.10 (m, 1H), 6.90-6.97 (m, 3H), 3.17-3.20 (m, 1H), 2.93 (t, J= 7.6 Hz, 2H), 2.65-2.79 (m, 2H), 2.48-2.54 (m, 4H), 1.13 (t, J= 7.9 Hz, 3H). MS (ESI+):376.3 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度97.0% 。
实施例37:[(1R)-1-{[3-(5-苯基-1,2,4-噁二唑-3-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1 H NMR (400 MHz, DMSO-d6):δ 8.06-8.09 (m, 2H), 7.67-7.71 (m, 1H), 7.59-7.63 (m, 2H), 7.31-7.33 (m, 1H), 7.03 (s, 1H), 6.89-6.91 (m, 1H), 3.15-3.19 (m, 1H), 2.93-2.97 (m, 2H), 2.68-2.83 (m, 2H), 2.55-2.57 (m, 2H). MS (ESI+):354.0 [M+H-H2O]. HPLC (方法A):Rt. 3.3 min, HPLC纯度97.8%。
实施例39:{(1R)-1-{[3-(5-苯基-1,2,4-噁二唑-3-基)丙酰基]氨基}-2-[3-(三氟甲基)苯基]乙基}硼酸
灰白色固体。1 H NMR (400 MHz, DMSO-d6):δ 8.04 (d, J= 7.2 Hz, 2H), 7.66-7.69 (m, 1H), 7.58-7.62 (m, 2H), 7.40-7.45 (m, 4H), 3.17-3.20 (m, 1H), 2.85-2.91 (m, 3H), 2.70-2.76 (m, 1H), 2.49-2.51 (m, 2H). MS (ESI+):416.2 [M+H-H2O]. HPLC (方法B):Rt. 4.1 min, HPLC纯度96.9%。
实施例40:[(1R)-1-{[3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.37 (s, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.42 (t, J= 8.4 Hz, 2H), 7.30-7.33 (m, 1H), 7.24-7.26 (m, 1H), 6.90 (s, 1H), 6.80 (d, J= 8.4 Hz, 2H), 4.53-4.62 (m, 2H), 3.12-3.16 (m, 1H), 2.63-2.77 (m, 4H). MS (ESI+):353.0 [M+H-H2O]. HPLC (方法A):Rt 3.0 min, HPLC纯度99.7%。
实施例41:[(1R)-1-{[3-(1-苯基-1H-1,2,3-三唑-4-基)丙酰基]氨基}-2-(3-噻吩基)乙基]硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.39 (s, 1H), 7.78-7.80 (m, 2H), 7.54-7.58 (m, 2H), 7.44-7.47 (m, 1H), 7.27-7.29 (m, 1H), 6.91 (s, 1H), 6.85 (d, J= 4.8 Hz, 1H), 2.92-3.11 (m, 1H), 2.88-2.92 (m, 2H), 2.74-2.79 (m, 1H), 2.63-2.69 (m, 1H), 2.46-2.49 (m, 2H). MS (ESI+):353.0 [M+H-H2O]. HPLC (方法A):Rt 2.9 min, HPLC纯度95.1 %。
实施例42:((1R)-2-(3-乙基苯基)-1-{[(1-氧代异喹啉-2(1H)-基)乙酰基]氨基}乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.82 (s, 1H), 8.19 (d, J= 8.0 Hz, 1H), 7.66-7.72 (m, 1H), 7.61-7.63 (m, 1H), 7.46-7.50 (m, 1H), 7.31 (d, J= 8.0 Hz, 1H), 6.98-7.02 (m, 1H), 6.87-6.92 (m, 2H), 6.57 (d, J= 8.0 Hz, 1H), 4.71-4.76 (m, 2H), 2.66-2.70 (m, 2H), 2.49-2.50 (m, 1H), 2.45-2.48 (m, 2H), 1.08 (t, J= 8.0 Hz, 3H). MS (ESI+):361.3 [M+H-H2O]。
以下化合物根据对实施例17描述的相同两步方案制备:
实施例43:(R)-(1-(4-(4-甲氧基苯基)-4-氧代丁酰氨基)-2-(4-(三氟甲氧基)苯基)乙基)硼酸
浅棕色固体。1H NMR (400 MHz, DMSO-d6):δ 7.90 (dd, J = 1.92, 6.96 Hz, 2H), 7.26 (d, J = 8.64 Hz, 2H), 7.18 (d, J = 8.12 Hz, 2H), 7.00-7.03 (m, 2H), 3.80 (s, 3H), 3.08-3.12 (m, 3H), 2.78-2.83 (m, 1H), 2.65-2.70 (m, 1H), 2.39 (t, J = 6.88 Hz, 2H). MS (ESI+):422.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度97.3%。
实施例44:((1R)-1-(2-苄基-4-(4-甲氧基苯基)-4-氧代丁酰氨基)-2-(4-(三氟甲氧基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.82 (d, J = 8.88 Hz, 2H), 7.22-7.26 (m, 2H), 7.14-7.18 (m, 3H), 7.05-7.07 (m, 4H), 6.98 (d, J = 8.92 Hz, 2H), 3.77 (s, 3H), 3.18-3.24 (m, 1H), 2.95-3.04 (m, 2H), 2.73-2.83 (m, 2H), 2.59-2.71 (m, 3H). MS (ESI+):512.2 [M+H-H2O]. HPLC (方法A):Rt. 4.9 min, HPLC纯度73.2%+19.5%。
实施例45:((R)-1-((R)-2-苄基-4-(4-甲氧基苯基)-4-氧代丁酰氨基)-2-(4-甲氧基-3-(三氟甲基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.82 (d, J = 8.92 Hz, 2H), 7.32-7.32 (m, 1H), 7.21-7.26 (m, 3H), 7.13-7.18 (m, 3H), 6.97-6.99 (m, 3H), 3.81-3.83 (m, 3H), 3.74 (s, 3H), 3.14-3.16 (m, 1H), 2.98-3.07 (m, 2H), 2.68-2.84 (m, 3H), 2.53-2.60 (m, 2H). MS (ESI+):526.2 [M+H-H2O]. HPLC (方法A):Rt. 4.7 min, HPLC纯度95.8%。
实施例46:(R)-(2-(4-甲氧基-3-(三氟甲基)苯基)-1-(4-(4-甲氧基苯基)-4-氧代丁酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.88-7.92 (m, 2H), 7.38-7.39 (m, 2H), 7.10 (d, J = 8.84 Hz, 1H), 7.00-7.04 (m, 2H), 3.81 (s, 6H), 3.05-3.13 (m, 3H), 2.75-2.80 (m, 1H), 2.61-2.67 (m, 1H), 2.32-2.40 (m, 2H). MS (ESI+):436.2 [M+H-H2O]. HPLC (方法A):Rt. 3.9 min, HPLC纯度95.7%。
实施例47:(R)-(2-(3-氟-5-甲氧基苯基)-1-(4-(4-甲氧基苯基)-4-氧代丁酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.91 (d, J = 8.84 Hz, 2H), 7.02 (d, J = 8.88 Hz, 2H), 6.55-6.59 (m, 3H), 3.81 (s, 3H), 3.71 (s, 3H), 3.09-3.13 (m, 3H), 2.73-2.78 (m, 1H), 2.60-2.66 (m, 1H), 2.49-2.50 (m, 2H), 2.38-2.40 (m, 1H). MS (ESI+):386.2 [M+H-H2O]. HPLC (方法A):Rt. 3.4 min, HPLC纯度99.3%。
实施例48:(R)-(1-(4-(4-甲氧基苯基)-4-氧代丁酰氨基)-2-(3-(三氟甲氧基)苯基)乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.89-7.92 (m, 2H), 7.34-7.38 (m, 1H), 7.18-7.20 (m, 1H), 7.13-7.14 (m, 2H), 7.00-7.04 (m, 2H), 3.82 (s, 3H), 3.08-3.17 (m, 3H), 2.82-2.87 (m, 1H), 2.70-2.73 (m, 1H), 2.39-2.40 (m, 2H). MS (ESI+):422.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度99.0%。
实施例49:((1R)-1-(2-苄基-4-(4-甲氧基苯基)-4-氧代丁酰氨基)-2-(3-氟-5-甲氧基苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.79-7.80 (m, 2H), 7.11-7.25 (m, 5H), 6.95-6.97 (m, 2H), 6.43-6.49 (m, 2H), 6.35 (d, J = 9.36 Hz, 1H), 3.76 (s, 1H), 3.65 (s, 3H), 3.19-3.25 (m, 1H), 3.00-3.02 (m, 1H), 2.77-2.98 (m, 3H), 2.61-2.66 (m, 2H), 2.44-2.46 (m, 1H). MS (ESI+):476.2 [M+H-H2O]. HPLC (方法A):Rt. 4.4 min, HPLC纯度72.2%+23.0%。
实施例50:(R)-(2-(4-氟-3-(三氟甲基)苯基)-1-(4-(4-甲氧基苯基)-4-氧代丁酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.89 (d, J = 8.00 Hz, 2H), 7.48-7.52 (m, 2H), 7.29-7.34 (m, 1H), 7.01 (d, J = 8.00 Hz, 2H), 3.80 (s, 3H), 3.07-3.12 (m, 3H), 2.81-2.86 (m, 1H), 2.66-2.72 (m, 1H), 2.50-2.51 (m, 2H), 2.35-2.39 (m, 2H). MS (ESI+):424.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度98.6%。
实施例58:(R)-(2-(3-乙基苯基)-1-(3-(1-苯基-1H-1,2,3-三唑-4-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.40 (s, 1H), 7.83-7.83 (m, 2H), 7.54-7.58 (m, 2H), 7.44-7.47 (m, 1H), 7.05-7.09 (m, 1H), 6.87-6.94 (m, 3H), 3.12-3.16 (m, 1H), 2.86-2.90 (m, 2H), 2.73-2.74 (m, 1H), 2.60-2.66 (m, 1H), 2.41-2.51 (m, 4H), 1.11 (t, J = 7.60 Hz, 3H). MS (ESI+):375.2 [M+H-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度96.8%。
实施例61:(R)-(2-(3-氟-5-甲氧基苯基)-1-(3-(5-苯基-1,2,4-噁二唑-3-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.03-8.03 (m, 2H), 7.57-7.68 (m, 3H), 6.47-6.52 (m, 3H), 3.65 (s, 3H), 3.11-3.14 (m, 1H), 2.90-2.94 (m, 2H), 2.71-2.76 (m, 1H), 2.58-2.63 (m, 1H), 2.51-2.53 (m, 2H). MS (ESI+):396.2 [M+H-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度97.1 %。
以下化合物根据对实施例1描述的相同两步方案制备:
实施例51:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(4-(三氟甲氧基)苯基)乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.09 (s, 1H), 7.64 (d, J = 7.56 Hz, 1H), 7.57 (d, J = 7.68 Hz, 1H), 7.19-7.28 (m, 2H), 6.96 (d, J = 8.08 Hz, 2H), 6.85 (d, J = 8.56 Hz, 2H), 4.40 (t, J = 6.32 Hz, 2H), 3.07-3.10 (m, 1H), 2.49-2.70 (m, 4H). MS (ESI+):426.0
[M+Na-H2O]. HPLC (方法A):Rt. 3.2 min, HPLC纯度96.5%。
实施例52:(R)-(2-(3-乙基苯基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.30 (s, 1H), 7.77 (d, J = 7.20 Hz, 2H), 7.41 (t, J = 7.76 Hz, 3H), 7.29-7.33 (m, 1H), 7.00 (t, J = 7.52 Hz, 1H), 6.88 (d, J = 7.88 Hz, 1H), 6.81 (s, 1H), 6.75 (d, J = 7.40 Hz, 1H), 3.07-3.11 (m, 1H), 2.66-2.70 (m, 3H), 2.55-2.57 (m, 1H), 2.39-2.44 (m, 2H), 1.03 (t, J = 7.96 Hz, 3H). MS (ESI+):397.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度96.5%。
实施例53:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(4-甲氧基-3-(三氟甲基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.09 (s, 1H), 7.65 (d, J = 8.24 Hz, 1H), 7.56 (d, J = 7.40 Hz, 1H), 7.19-7.29 (m, 3H), 6.91 (dd, J = 1.92, 8.54 Hz, 1H), 6.81 (d, J = 8.56 Hz, 1H), 4.39 (t, J = 6.76 Hz, 2H), 3.76 (s, 3H), 3.09-3.13 (m, 1H), 2.67-2.70 (m, 1H), 2.54-2.61 (m, 3H). MS (ESI+):440.0 [M+Na-H2O]. HPLC (方法A):Rt. 3.0 min, HPLC纯度94.5%。
实施例54:(R)-(2-(3-乙基苯基)-1-(3-(2-甲基-1H-苯并[d]咪唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.43-7.50 (m, 2H), 7.13-7.17 (m, 2H), 6.89-6.99 (m, 2H), 6.77 (s, 1H), 6.59 (d, J = 7.40 Hz, 1H), 4.28-4.32 (m, 2H), 3.10-3.13 (m, 1H), 2.52-2.62 (m, 4H), 2.40-2.44 (m, 2H), 1.07 (t, J = 7.60 Hz, 3H). ). MS (ESI+):384.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.0 min, HPLC纯度98.7%。
实施例55:(R)-(1-(3-(2 -甲基-1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(噻吩-3-基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 7.44-7.50 (m, 2H), 7.11-7.25 (m, 3H), 6.65-6.68 (m, 2H), 4.28-4.37 (m, 2H), 3.09-3.12 (m, 1H), 2.51-2.68 (m, 7H). MS (ESI+):362.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.0 min, HPLC纯度93.7%。
实施例56:(R)-(2-(4-甲氧基-3-(三氟甲基)苯基)-1-(3-(5-苯基-1,2,4-噁二唑-3-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.06 (d, J = 7.20 Hz, 2H), 7.59-7.70 (m, 3H), 7.31-7.35 (m, 2H), 7.04 (d, J = 8.44 Hz, 1H), 3.76 (s, 3H), 3.14-3.17 (m, 1H), 2.90-2.94 (m, 2H), 2.76-2.81 (m, 1H), 2.63-2.68 (m, 1H), 2.48-249.00 (m, 2H). MS (ESI+):446.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度97.7%。
实施例57:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(3-氟-5-甲氧基苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.07 (s, 1H), 7.54-7.62 (m, 2H), 7.17-7.26 (m, 2H), 6.51-6.54 (m, 1H), 6.50 (s, 1H), 6.37-6.45 (m, 1H), 4.36-4.40 (m, 2H), 3.64 (s, 3H), 3.11-3.14 (m, 1H), 2.53-2.69 (m, 4H). MS (ESI+):390.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.5 min, HPLC纯度98.8%。
实施例59:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(3-(三氟甲氧基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.08 (s, 1H), 7.55-7.57 (m, 1H), 7.61-7.63 (m, 1H), 7.15-7.26 (m, 3H), 7.05-7.07 (m, 1H), 7.00 (s, 1H), 6.81-6.83 (m, 1H), 4.39 (t, J = 6.72 Hz, 2H), 3.15 (t, J = 5.60 Hz, 1H), 2.73-2.78 (m, 1H), 2.57-2.65 (m, 3H). MS (ESI+):426.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.1 min, HPLC纯度99.6%。
实施例60:(R)-(1-(3-(5-苯基-1,2,4-噁二唑-3-基)丙酰氨基)-2-(3-(三氟甲氧基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.04-8.05 (m, 2H), 7.58-7.70 (m, 3H), 7.29-7.33 (m, 1H), 7.08-7.29 (m, 3H), 3.17-3.21 (m, 1H), 2.82-2.93 (m, 3H), 2.67-2.73 (m, 1H), 2.49-2.51 (m, 2H). MS (ESI+):432.0 [M+H-H2O]. HPLC (方法A):Rt. 4.2 min, HPLC纯度98.3%。
实施例62:((R)-1-((R)-2-苄基-3-(1-苯基-1H-1,2,3-三唑-4-基)丙酰氨基)-2-(噻吩-3-基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.39 (s, 1H), 7.76-7.78 (m, 2H), 7.53-7.57 (m, 2H), 7.44-7.46 (m, 1H), 7.23-7.27 (m, 3H), 7.16-7.18 (m, 3H), 6.62-6.67 (m, 2H), 3.07-3.10 (m, 1H), 2.81-2.94 (m, 3H), 2.71-2.75 (m, 1H), 2.56-2.66 (m, 3H). MS (ESI+):443.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度97.7%。
实施例63:((R)-1-((S)-2-苄基-3-(1-苯基-1H-1,2,3-三唑-4-基)丙酰氨基)-2-(噻吩-3-基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.39 (s, 1H), 7.75-7.77 (m, 2H), 7.52-7.56 (m, 2H), 7.44-7.45 (m, 1H), 7.23-7.27 (m, 2H), 7.15-7.19 (m, 4H), 6.61-6.64 (m, 2H), 2.84-2.95 (m, 4H), 2.63-2.70 (m, 3H), 2.52-2.54 (m, 1H). MS (ESI+):443.2 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度99.6%。
实施例64:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(4-氟-3-(三氟甲基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.07 (s, 1H), 7.63 (d, J = 8.00 Hz, 1H), 7.54 (d, J = 8.00 Hz, 1H), 7.39-7.41 (m, 1H), 7.18-7.27 (m, 2H), 7.04-7.10 (m, 2H), 4.38 (t, J = 6.60 Hz, 2H), 3.08-3.12 (m, 1H), 2.71-2.76 (m, 1H), 2.56-2.62 (m, 3H). MS (ESI+):428.0 [M+Na-H2O]. HPLC (方法A):Rt. 3.1 min, HPLC纯度98.8 %。
实施例65:(R)-(2-(3-氟-5-甲氧基苯基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.37 (s, 1H), 7.78 (d, J = 8.00 Hz, 2H), 7.39-7.43 (m, 2H), 7.29-7.32 (m, 1H), 6.46-6.53 (m, 3H), 4.55 (t, J = 6.80 Hz, 2H), 3.66 (s, 3H), 3.13-3.17 (m, 1H), 2.58-2.75 (m, 4H). MS (ESI+):395.3 [M+H-H2O]. HPLC (方法A):Rt. 3.4 min, HPLC纯度98.6%。
实施例66:(R)-(1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)-2-(3-(2,2,2-三氟乙基)苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.40 (s, 1H), 7.77-7.80 (m, 2H), 7.40-7.43 (m, 2H), 7.23-7.33 (m, 2H), 7.01-7.05 (m, 3H), 4.54 (t, J = 6.80 Hz, 2H), 3.15-3.19 (m, 1H), 2.79-2.83 (m, 1H), 2.63-2.69 (m, 3H). MS (ESI+):431.0 [M+H-H2O]. HPLC (方法A):Rt. 4.0 min, HPLC纯度96.2%。
实施例67:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(3-乙氧基苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.07 (s, 1H), 7.62 (d, J = 7.60 Hz, 1H), 7.56 (d, J = 7.60 Hz, 1H), 7.17-7.26 (m, 2H), 6.95 (t, J = 8.00 Hz, 1H), 6.58-6.63 (m, 2H), 6.39 (d, J = 8.00 Hz, 1H), 4.39 (t, J = 6.40 Hz, 2H), 3.85-3.90 (m, 2H), 3.11-3.13 (m, 1H), 2.55-2.64 (m, 4H), 1.24 (t, J = 6.80 Hz, 3H). MS (ESI+):386.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.5 min, HPLC纯度98.5 %。
实施例68:(R)-(2-(3-乙氧基苯基)-1-(3-(5-苯基-1,2,4-噁二唑-3-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.05 (d, J = -8.00 Hz, 2H), 7.65-7.69 (m, 1H), 7.58-7.62 (m, 2H), 7.06 (t, J = 7.60 Hz, 1H), 6.63-6.67 (m, 3H), 3.89-3.94 (m, 2H), 3.14-3.17 (m, 1H), 2.92 (t, J = 7.60 Hz, 2H), 2.71-2.76 (m, 1H), 2.61-2.64 (m, 1H), 2.52-2.59 (m, 2H), 1.26-1.28 (m, 3H). MS (ESI+):392.3 [M+H-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度98.7%。
实施例69:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(4-氟-3-甲氧基苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.07 (s, 1H), 7.62 (d, J = 8.00 Hz, 1H), 7.55 (d, J = 8.00 Hz, 1H), 7.19-7.27 (m, 2H), 6.74-6.81 (m, 2H), 6.27-6.30 (m, 1H), 4.40 (t, J = 6.40 Hz, 2H), 3.66 (s, 3H), 3.05-3.09 (m, 1H), 2.60-2.64 (m, 3H), 2.54-2.58 (m, 1H). MS (ESI+):386.2 [M+H-H2O]. HPLC (方法A):Rt. 2.4 min, HPLC纯度96.6%。
实施例70:(2-(3-乙氧基苯基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.34 (s, 1H), 7.78 (d, J = 8.00 Hz, 2H), 7.42 (t, J = 13.88 Hz, 2H), 7.29-7.33 (m, 1H), 6.99-7.03 (m, 1H), 6.59-6.62 (m, 2H), 6.55 (d, J = 8.00 Hz, 1H), 4.55 (t, J = 7.24 Hz, 2H), 3.85-3.91 (m, 2H), 3.12-3.15 (m, 1H), 2.66-2.71 (m, 3H), 2.58-2.61 (m, 1H), 1.24 (t, J = 7.00 Hz, 3H). MS (ESI+):413.3 [M+Na-H2O]. HPLC (方法A):Rt. 3.4 min, HPLC纯度98.5 %。
实施例71:(R)-(2-(4-氟-3-(三氟甲基)苯基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.35 (s, 1H), 7.76-7.78 (m, 2H), 7.39-7.45 (m, 3H), 7.29-7.32 (m, 2H), 7.15-7.20 (m, 1H), 4.53 (t, J = 8.00 Hz, 2H), 3.11-3.14 (m, 1H), 2.77-2.82 (m, 1H), 2.62-2.69 (m, 3H). MS (ESI+):433.3 [M+H-H2O]. HPLC (方法A):Rt. 3.9 min, HPLC纯度98.1%。
实施例72:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(3-甲氧基-4-甲基苯基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.06 (s, 1H), 7.62 (d, J = 8.00 Hz, 1H), 7.54 (d, J = 8.00 Hz, 1H), 7.19-7.27 (m, 2H), 6.77 (d, J = 8.00 Hz, 1H), 6.54 (s, 1H), 6.26 (d, J = 8.00 Hz, 1H), 4.40 (t, J = 6.40 Hz, 2H), 3.59 (s, 3H), 3.09 (t, J = 7.20 Hz, 1H), 2.58-2.63 (m, 4H), 1.98 (s, 3H). MS (ESI+):386.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.7 min, HPLC纯度97.1 %。
实施例73:(R)-(2-(3-乙基苯基)-1-(3-(4-(2-甲氧基苯基)-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.25 (s, 1H), 8.07-8.09 (m, 1H), 7.28-7.32 (m, 1H), 6.97-7.09 (m, 3H), 6.87 (d, J = 8.00 Hz, 1H), 6.82 (s, 1H), 6.77 (d, J = 8.00 Hz, 1H), 4.56 (t, J = 8.00 Hz, 2H), 3.85 (s, 3H), 3.13-3.17 (m, 1H), 2.59-2.71 (m, 4H), 2.37-2.43 (m, 2H), 1.03 (t, J = 8.00 Hz, 3H). MS (ESI+):427.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.8 min, HPLC纯度97.6%。
实施例74:(R)-(2-(3-乙基苯基)-1-(3-(4-(3-甲氧基苯基)-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.37 (s, 1H), 7.33-7.35 (m, 3H), 6.99-7.03 (m, 1H), 6.84-6.90 (m, 3H), 6.78 (d, J = 8.00 Hz, 1H), 4.55 (t, J = 12.00 Hz, 2H), 3.79 (s, 3H), 3.10-3.14 (m, 1H), 2.65-2.69 (m, 3H), 2.58-2.60 (m, 1H), 2.41-2.46 (m, 2H), 1.06-1.08 (m, 3H). MS (ESI+):427.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度98.0%。
实施例75:(R)-(2-(3-乙基苯基)-1-(3-(4-(4-甲氧基苯基)-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.23 (s, 1H), 7.71 (d, J = 8.00 Hz, 2H), 6.96-7.04 (m, 4H), 6.85-6.91 (m, 1H), 6.79 (d, J = 8.00 Hz, 1H), 4.53 (t, J = 8.00 Hz, 2H), 3.11-3.15 (m, 1H), 2.54-2.73 (m, 4H), 2.42-2.45 (m, 2H), 1.05-1.09 (m, 3H). MS (ESI+):427.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度98.1 %。
实施例76:(R)-(2-(3-乙基苯基)-1-(3-(4-(吡啶-3-基)-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR (400 MHz, DMSO-d6):δ 8.95 (s, 1H), 8.45-8.49 (m, 2H), 8.15-8.17 (m, 1H), 7.46-7.49 (m, 1H), 6.98-7.02 (m, 1H), 6.83-6.88 (m, 2H), 6.77 (d, J = 8.00 Hz, 1H), 4.55-4.59 (m, 2H), 3.11-3.13 (m, 1H), 2.67-2.70 (m, 3H), 2.57-2.59 (m, 1H), 2.39-2.45 (m, 2H), 1.04 (t, J = 8.00 Hz, 3H). MS (ESI+):398.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.4 min, HPLC纯度97.9%。
实施例78:(R)-(1-乙酰氨基-2-(苯并呋喃-3-基)乙基)硼酸
步骤1:(R)-(1-乙酰氨基-2-(苯并呋喃-3-基)乙基)硼酸(+)-蒎烷二醇酯
将中间体18 (700 mg, 1.54 mmol)在无水二氯甲烷(20 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.8 ml, 4.6 mmol)和乙酰氯(0.09 ml, 1.54 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(520 mg, 88 %)经硅胶层析纯化来分离,用在二氯甲烷中的2 %甲醇洗脱。
MS (ESI+):382.3
步骤2:(R)-(1-乙酰氨基-2-(苯并呋喃-3-基)乙基)硼酸
将(R)-(1-乙酰氨基-2-(苯并呋喃-3-基)乙基)硼酸(+)-蒎烷二醇酯(520 mg, 1.35 mmol)在甲醇/戊烷(1:1, 30 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸(545 mg, 5.4 mmol)和HCl水溶液(1.5 N, 1 mL)处理并将反应混合物于室温下搅拌15 h。然后将反应混合物用戊烷提取三次。在低于30℃的温度下浓缩含水甲醇层。残留物用冰处理,用NaOH的水溶液(2N)碱化并用二氯甲烷提取三次(弃去)。然后水层用HCl的水溶液(1.5 N)酸化并用二氯甲烷提取三次。DCM层经硫酸钠干燥,过滤并浓缩,得到固体残留物,其用二乙醚研磨并冻干,获得标题化合物(42 mg, 26 %),为白色固体。
1H NMR:(400 MHz, DMSO-d6):δ 7.64 (s, 1H), 7.58-7.60 (d, J =8.0 Hz, 1H), 7.48-7.50 (d, J = 8.0 Hz, 1H), 7.19-7.28 (m, 2H), 3.09-3.13 (m, 1H), 2.81-2.86 (m, 1H), 2.69-2.75 (m, 1H), 1.77 (s, 3H).
MS (ESI+):230.0 [M+H-H2O], HPLC (方法A):Rt 2.0min;HPLC纯度98.8%。
以下化合物采用实施例78遵照的相同程序合成。
实施例77:(R)-(1-乙酰氨基-2-(3-乙基苯基)乙基)硼酸
淡粉红色固体。1H NMR (400 MHz, DMSO-d6):δ 7.11-7.15 (m, 1H), 6.93-6.98 (m, 3H), 2.98-3.01 (m, 1H), 2.71-2.76 (m, 1H), 2.49-2.54 (m, 3H), 1.77 (s, 3H), 1.10-1.14 (m, 3H). MS (ESI+):218.0 [M+H-H2O]. HPLC (方法A):Rt. 2.4 min, HPLC纯度98.0%。
实施例95:(R)-(1-乙酰氨基-2-(萘-2-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.76-7.78 (m, 3H), 7.61 (s, 1H), 7.38-7.46 (m, 2H), 7.32-7.35 (m, 1H), 3.04-3.08 (m, 1H), 2.90-2.95 (m, 1H), 2.73-2.78 (m, 1H), 1.79 (s, 3H). MS (ESI+):240.3 [M+H-H2O]. HPLC (方法A):Rt. 2.6 min, HPLC纯度92.4%。
实施例108:(R)-(1-乙酰氨基-2-(5-甲氧基苯并呋喃-3-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.60 (s, 1H), 7.38 (d, J = 8.88 Hz, 1H), 7.09- 7.10 (m, 1H), 6.84 (dd, J = 2.56, 8.92 Hz, 1H), 3.76 (s, 3H), 3.08-3.12 (m, 1H), 2.78-2.83 (m, 1H), 2.66-2.72 (m, 1H), 1.79 (s, 3H). MS (ESI+):260.0 [M+H-H2O]. HPLC (方法A):Rt. 2.2 min, HPLC纯度96.5%。
实施例79:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-甲氧基苯基)丙酰氨基)乙基)硼酸
步骤1:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-甲氧基苯基)丙酰氨基)乙基)硼酸频哪醇酯.
将中间体18 (170 mg, 0.37 mmol)在无水N,N-二甲基甲酰胺(20 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.2 ml, 1.1 mmol)和3-(4-甲氧基苯基)丙酸(67 mg, 0.37 mmol)和TBTU (142 mg, 0.44 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(160 mg, 86 %)经硅胶层析纯化来分离,用在石油醚中的40 %乙酸乙酯洗脱。
MS (ESI+):502.2
步骤2:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-甲氧基苯基)丙酰氨基)乙基)硼酸
将(R)-(2-(苯并呋喃-3-基)-1-(3-(4-甲氧基苯基)丙酰氨基)乙基)硼酸频哪醇酯(160 mg, 0.32 mmol)在甲醇/戊烷(1:1, 20 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸(129 mg, 1.3 mmol)和HCl水溶液(1.5 N, 0.5 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。残留物用冰处理,用NaOH的水溶液(2N)碱化并用二氯甲烷提取三次(弃去)。然后水层用HCl的水溶液(1.5 N)酸化并用二氯甲烷提取三次。DCM层经硫酸钠干燥,过滤并浓缩,得到固体残留物,其用二乙醚研磨并冻干获得标题化合物(25 mg, 21 %),为白色固体。
1H NMR:(400 MHz, DMSO-d6):δ 7.57 (d, J = 7.68 Hz, 1H), 7.49 (t, J = 3.92 Hz, 2H), 7.21-7.26 (m, 2H), 7.06 (d, J = 8.44 Hz, 2H), 6.77 (d, J = 8.48 Hz, 2H), 3.67 (s, 3H), 3.15-3.17 (m, 1H), 2.65-2.81 (m, 5H), 2.30 (t, J = 7.32 Hz, 2H). MS (ESI+):350.3 [M+H-H2O]. HPLC (方法A):Rt. 3.5 min, HPLC纯度93.8%。
以下化合物采用实施例79遵照的相同程序合成。
实施例80:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-氟代苯基)丙酰氨基)乙基)硼酸
灰白色固体。1H NMR (400 MHz, DMSO-d6):400 MHz, DMSO-d6:δ 7.57 (d, J = 7.16 Hz, 1H), 7.48 (d, J = 6.88 Hz, 1H), 7.15-7.28 (m, 4H), 6.99-7.04 (m, 2H), 3.18 (t, J = 5.72 Hz, 1H), 2.80-2.81 (m, 1H), 2.71-2.75 (m, 3H), 2.32 (t, J = 7.28 Hz, 2H). MS (ESI+):338.3
[M+H-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度99.0%。
实施例81:(R)-(2-(苯并呋喃-3-基)-1-(3-(2-氟代苯基)丙酰氨基)乙基)硼酸
灰白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.57 (d, J = 7.2 Hz, 1H), 7.50-7.52 (m, 2H), 7.18-7.28 (m, 4H), 7.02-7.12 (m, 2H), 3.18-3.21 (m, 1H), 2.73-2.82 (m, 4H), 2.34 (t, J = 7.36 Hz, 2H). MS (ESI+):338.3 [M+H-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度97.9%。
实施例82:(R)-(2-(苯并呋喃-3-基)-1-(3-(2-甲氧基苯基)丙酰氨基)乙基)硼酸
淡粉红色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.57 (d, J = 7.00 Hz, 1H), 7.48 (d, J = 7.36 Hz, 2H), 7.20-7.28 (m, 2H), 7.12-7.19 (m, 1H), 7.05-7.07 (m, 1H), 6.91 (d, J = 7.80 Hz, 1H), 6.77-6.81 (m, 1H), 3.73 (s, 1H), 3.12-3.15 (m, 1H), 2.79-2.81 (m, 1H), 2.68-2.74 (m, 3H), 2.29 (t, J = 7.20 Hz, 2H). MS (ESI+):350.3 [M+H-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度98.1 %。
实施例84:(R)-(2-(苯并呋喃-3-基)-1-(3-(3-甲氧基苯基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.57 (d, J = 7.08 Hz, 1H), 7.47-7.49 (m, 2H), 7.19-7.28 (m, 2H), 7.14 (t, J = 7.96 Hz, 1H), 6.70-6.73 (m, 3H), 3.68 (s, 3H), 3.16-3.19 (m, 1H), 2.80-2.81 (m, 1H), 2.69-2.74 (m, 3H), 2.34 (t, J = 7.32 Hz, 2H). MS (ESI+):350.3 [M+H-HzO]. HPLC (方法A):Rt. 3.6 min, HPLC纯度99.7%。
实施例85:(R)-(2-(苯并呋喃-3-基)-1-(3-(3-氟代苯基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:( 400 MHz, DMSO-d6):δ 7.56-7.58 (m, 1H), 7.47-7.49 (m, 2H), 7.19-7.28 (m, 3H), 6.93-7.00 (m, 3H), 3.17-3.20 (m, 1H), 2.68-2.85 (m, 4H), 2.36 (t, J = 7.36 Hz, 2H). MS (ESI+):338.3 [M+H-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度98.4%。
实施例86:(R)-(2-(苯并呋喃-3-基)-1-(3-环己基丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.58-7.62 (m, 2H), 7.48 (d, J = 7.92 Hz, 1H), 7.19-7.28 (m, 2H), 3.10-3.13 (m, 1H), 2.80-2.85 (m, 1H), 2.68-2.72 (m, 1H), 2.05 (t, J = 7.92 Hz, 2H), 1.56-1.59 (m, 5H), 1.27-1.32 (m, 2H), 1.04-1.08 (m, 4H), 0.74-0.80 (m, 2H).
MS (ESI+):326.3 [M+H-H2O]. HPLC (方法A):Rt. 4.2 min, HPLC纯度99.2%。
实施例87:(R)-(2-(苯并呋喃-3-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.57 (d, J = 7.84 Hz, 1H), 7.52 (d, J = 7.56 Hz, 1H), 7.46 (d, J = 8.04 Hz, 1H), 7.41 (s, 1H), 7.13-7.34 (m, 5H), 4.05-4.09 (m, 2H), 3.14-3.84 (m, 1H), 2.75-2.80 (m, 1H), 2.64-2.70 (m, 1H), 2.43-2.49 (m, 2H). MS (ESI+):393.0 [M+H-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度98.8%。
实施例88:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(苯并呋喃-3-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.09 (s, 1H), 7.61-7.63 (m, 1H), 7.56 (d, J = 7.44 Hz, 1H), 7.43-7.46 (m, 2H), 7.18-7.27 (m, 4H), 7.09-7.13 (m, 1H), 4.39-4.43 (m, 2H), 3.13-3.17 (m, 1H), 2.72-2.86 (m, 1H), 2.50-2.66 (m, 3H). MS (ESI+):382.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.6 min, HPLC纯度94.3%。
实施例89:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)
丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.34 (s, 1H), 7.76 (d, J = 7.48 Hz, 2H), 7.48 (d, J = 7.28 Hz, 2H), 7.41 (t, J = 7.52 Hz, 3H), 7.31 (t, J = 7.40 Hz, 1H), 7.23 (t, J = 7.52 Hz, 1H), 7.16 (t, J = 7.16 Hz, 1H), 4.55-4.56 (m, 2H), 3.16-3.18 (m, 1H), 2.77-2.86 (m, 1H), 2.66-2.73 (m, 3H). MS (ESI+):409.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.5 min, HPLC纯度94.8%。
实施例90:(R)-(2-(苯并呋喃-3-基)-1-(3-(1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.31 (s, 1H), 7.68 (d, J = 8.92 Hz, 2H), 7.55-7.57 (m, 2H), 7.45 (d, J = 7.96 Hz, 1H), 7.18-7.27 (m, 2H), 7.08 (d, J = 9.00 Hz, 2H), 3.79 (s, 3H), 3.17-3.21 (m, 1H), 2.82-2.90 (m, 3H), 2.67-2.76 (m, 1H), 2.43-2.50 (m, 2H). MS (ESI+):439.3 [M+Na-H2O]. HPLC (方法A):Rt. 3.4 min, HPLC纯度95.0%。
实施例91:(R)-(2-(苯并呋喃-3-基)-1-(2-(N-甲基甲基磺酰氨基)乙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.60-7.60 (m, 2H), 7.48 (d, J = 7.84 Hz, 1H), 7.19-7.28 (m, 2H), 3.68 (d, J = 8.12 Hz, 2H), 3.33-3.36 (m, 1H), 2.87-2.92 (m, 4H), 2.76-2.82 (m, 1H), 2.66 (s, 3H). MS (ESI+):337.0 [M+H-H2O]. HPLC (方法A):Rt. 2.8 min, HPLC纯度97.5%。
实施例94:(R)-(2-(苯并呋喃-3-基)-1-(3-苯基丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.56 (d, J = 7.68 Hz, 1H), 7.46-7.49 (m, 2H), 7.18-7.28 (m, 4H), 7.11-7.15 (m, 3H), 3.13-3.15 (m, 1H), 2.79-2.80 (m, 1H), 2.71-2.75 (m, 3H), 2.34 (t, J = 7.32 Hz, 2H). MS (ESI+):320.2 [M+H-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度97.6%。
实施例96:(R)-(2-(萘-2-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)
丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):400 MHz, DMSO-d6:δ 7.80 (d, J = 8.32 Hz, 1H), 7.71 (d, J = 8.48 Hz, 2H), 7.60 (d, J = 7.76 Hz, 1H), 7.37-7.43 (m, 3H), 7.30-7.34 (m, 1H), 7.25 (d, J = 8.00 Hz, 1H), 7.15-7.18 (m, 2H), 4.04 (t, J = 6.96 Hz, 2H), 3.19-3.23 (m, 1H), 2.82-2.87 (m, 1H), 2.71-2.77 (m, 1H), 2.41 (t, J = 7.00 Hz, 2H). MS (ESI+):403.0 [M+H-H2O]. HPLC (方法A):Rt. 3.9 min, HPLC纯度98.6% 。
实施例97:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(萘-2-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.09 (s, 1H), 7.75-7.77 (m, 1H), 7.59-7.65 (m, 3H), 7.54 (dd, J = 2.04, 6.80 Hz, 1H), 7.36-7.41 (m, 2H), 7.29 (s, 1H), 7.20-7.27 (m, 2H), 7.06 (dd, J = 1.52, 8.40 Hz, 1H), 4.38-4.41 (m, 2H), 3.20 (d, J = 2.32 Hz, 1H), 2.74-2.81 (m, 1H), 2.59-2.61 (m, 1H), 2.49-2.57 (m, 2H). MS (ESI+):392.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.9 min, HPLC纯度96.5%。
实施例98:(R)-(2-(萘-2-基)-1-(3-(1-苯基-1H-1,2,3-三唑-4-基)
丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.37 (s, 1H), 7.78-7.78 (m, 3H), 7.69-7.72 (m, 2H), 7.52-7.57 (m, 3H), 7.46 (d, J = 7.40 Hz, 1H), 7.36-7.41 (m, 2H), 7.25 {dd, J = 1.48, 8.44 Hz, 1H), 3.17-3.20 (m, 1H), 2.87-2.94 (m, 3H), 2.75-2.81 (m, 1H), 2.42-2.50 (m, 2H). MS (ESI+):419.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度96.7%。
实施例99:(R)-(2-(萘-2-基)-1-(3-(1-(吡啶-3-基)-1H-1,2,3-三唑-4-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.90 (s, 1H), 8.58-8.59 (m, 1H), 8.33 (s, 1H), 8.14 (d, J = 8.04 Hz, 1H), 7.57-7.71 (m, 4H), 7.44 (s, 1H), 7.33-7.35 (m, 2H), 7.20 (d, J = 8.24 Hz, 1H), 3.04-3.07 (m, 1H), 2.86-2.94 (m, 3H), 2.65-2.71 (m, 1H), 2.49-2.50 (m, 2H). MS (ESI+):420.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.7 min, HPLC纯度95.9%。
实施例100:(R)-(1-(3-(1-(4-甲氧基苯基)-1H-1,2,3-三唑-4-基)丙酰氨基)-2-(萘-2-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.24 (s, 1H), 7.65-7.78 (m, 5H), 7.51 (s, 1H) 7.38-7.42 (m, 2H), 7.23-7.26 (m, 1H), 7.06-7.08 (m, 2H), 3.77 (s, 3H), 3.15-3.18 (m, 1H), 2.85-2.94 (m, 3H), 2.74-2.80 (m, 1H), 2.42-2.50 (m, 2H). MS (ESI+):449.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.7 min, HPLC纯度90.2%。
实施例102:(R)-(2-(1-甲基-1H-吲唑-5-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.85 (s, 1 Η), 7.61 (d, J = 8.68 Hz, 1H), 7.39 (d, J = 8.64 Hz, 1H), 7.35-7.31 (m, 1H), 7.26 (d, J = 7.56 Hz, 1H), 7.19-7.15 (m, 2H), 7.04 (dd, J = 1.36, 8.66 Hz, 1H), 4.05 (t, J = 7.00 Hz, 2H), 3.92 (s, 3H), 3.15-3.14 (m, 1H), 2.74 (t, J = 5.36 Hz, 1H), 2.66 (t, J = 5.28 Hz, 1H), 2.41 (t, J = 6.92 Hz, 2H). MS (ESI+):429.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.8 min, HPLC纯度98.0%。
实施例103:(R)-(2-(1-甲基-1H-吲唑-5-基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.36 (s, 1H), 7.79 (d, J = 8.40 Hz, 3H), 7.44-7.43 (m, 2H), 7.34-7.33 (m, 2H), 7.27 (s, 1H), 7.05 (dd, J = 1.48, 8.66 Hz, 1H), 4.60-4.58 (m, 2H), 3.88 (s, 3H), 3.15 (t, J = 5.64 Hz, 1H), 2.80 (t, J = 5.36 Hz, 1H), 2.74-2.72 (m, 1H), 2.68 (t, J = 6.52 Hz, 2H). MS (ESI+):423.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.7 min, HPLC纯度95.0%。
实施例104:(R)-(2-(苯并[b]噻吩-3-基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.34 (s, 1H), 7.83-7.86 (m, 1H), 7.76-7.78 (m, 2H), 7.68-7.71 (m, 1H), 7.39-7.43 (m, 2H), 7.28-7.34 (m, 3H), 7.12 (s, 1H), 4.56 (t, J = 6.68 Hz, 2H), 3.22-3.25 (m, 1H), 2.96-3.01 (m, 1H), 2.81-2.87 (m, 1H), 2.69 (t, J = 6.56 Hz, 2H). MS (ESI+):425.2 [M+Na-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度94.8%。
实施例105:(R)-(2-(苯并[b]噻吩-3-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.87-7.89 (m, 1H), 7.72-7.74 (m, 1H), 7.58 (d, J - 7.20 Hz, 1H), 7.26-7.37 (m, 4H), 7.14-7.18 (m, 1H), 7.03 (s, 1H), 4.05-4.08 (m, 2H), 3.20-3.24 (m, 1H), 2.93-2.98 (m, 1H), 2.83-2.86 (m, 1H), 2.41-2.49 (m, 2H).
MS (ESI+):409.0 [M+H-H2O]. HPLC (方法A):Rt. 3.8 min, HPLC纯度86.0%。
实施例106:(R)-(1-(3-(1H-苯并[d]咪唑-1-基)丙酰氨基)-2-(苯并[b]噻吩-3-基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.09 (s, 1H), 7.85-7.87 (m, 1H), 7.67-7.70 (m, 1H), 7.63 (d, J = 7.48 Hz, 1H), 7.55 (d, J = 7.56 Hz, 1H), 7.28-7.30 (m, 2H), 7.19-7.26 (m, 2H), 6.86 (s, 1H), 4.39-4.42 (m, 2H), 3.18-3.21 (m, 1H), 2.92-2.95 (m, 1H), 2.76-2.82 (m, 1H), 2.58-2.61 (m, 2H). MS (ESI+):398.0 [M+Na-H2O]. HPLC (方法A):Rt. 2.7 min, HPLC纯度96.0%。
实施例107:(R)-(2-(苯并[d][1,3]间二氧杂环戊烯-5-基)-1-(3-(4-苯基-1H-1,2,3-三唑-1-基)丙酰氨基)乙基)硼酸
白色固体。1H NMR:(400 MHz, DMSO-d6):δ 8.25 (s, 1H), 7.72-7.74 (m, 2H), 7.38-7.42 (m, 2H), 7.29-7.33 (m, 1H), 6.45-6.48 (m, 2H), 6.25 (d, J = 7.92 Hz, 1H), 5.73 (s, 2H), 4.59-4.61 (m, 2H), 2.74-2.84 (m, 3H), 2.49-2.56 (m, 1H), 2.26-2.32 (m, 1H). MS (ESI+):413.0 [M+Na-H2O]. HPLC (方法A):Rt. 3.1 min, HPLC纯度95.2%。
实施例109:(R)-(2-(5-甲氧基苯并呋喃-3-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)乙基)硼酸
浅棕色固体。1H NMR:(400 MHz, DMSO-d6):δ 7.58 (d, J = 7.16 Hz, 1H), 7.34-7.39 (m, 2H), 7.31 (d, J = 8.16 Hz, 1H), 7.27 (d, J = 7.36 Hz, 1H), 7.13-7.17 (m, 1H), 7.07-7.08 (m, 1H), 6.83 (dd, J = 2.56, 8.88 Hz, 1H), 4.06 (t, J = 7.68 Hz, 2H), 3.74 (s, 3H), 3.17-3.20 (m, 1H), 2.73-2.74 (m, 1H), 2.64-2.68 (m, 1H), 2.42-2.46 (m, 2H). MS (ESI+):423.0 [M+H-H2O]. HPLC (方法A):Rt. 3.6 min, HPLC纯度92.6%。
实施例92:(R)-(2-(苯并呋喃-3-基)-1-(3-(哌嗪-1-基)丙酰氨基)乙基)硼酸盐酸盐
步骤1:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-(叔丁氧基羰基)哌嗪-1-基)丙酰氨基)乙基)硼酸频哪醇酯.
将中间体18 (300 mg, 0.66 mmol)在无水N,N-二甲基甲酰胺(10 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.3 ml, 1.9 mmol)和3-(4-(叔丁氧基羰基)哌嗪-1-基)丙酸(170 mg, 0.66 mmol)和TBTU (254 mg, 0.79 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(350 mg, 87%)经硅胶层析纯化来分离,用在二氯甲烷中的4 %甲醇洗脱。
MS (ESI+):580.4
步骤2:(R)-(2-(苯并呋喃-3-基)-1-(3-(4-(叔丁氧基羰基)哌嗪-1-基)丙酰氨基)乙基)硼酸.
将(R)-(2-(苯并呋喃-3-基)-1-(3-(4-(叔丁氧基羰基)哌嗪-1-基)丙酰氨基)乙基)硼酸频哪醇酯(350 mg, 0.6 mmol)在甲醇/戊烷(1:1, 30 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸(242 mg, 2.4 mmol)和HCl水溶液(1.5 N, 0.7 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。残留物用冰处理,用NaOH的水溶液(2N)碱化并用二氯甲烷提取三次(弃去)。然后水层用HCl的水溶液(1.5 N)酸化并用二氯甲烷提取三次。DCM层经硫酸钠干燥,过滤并浓缩。所需产物(85 mg, 31 %)经硅胶层析纯化来分离,用在二氯甲烷中的30 %甲醇洗脱。
MS (ESI+):450.2 [M+Na-H2O].
步骤3:(R)-(2-(苯并呋喃-3-基)-1-(3-(哌嗪-1-基)丙酰氨基)乙基)硼酸盐酸盐.
将化合物(R)-(2-(苯并呋喃-3-基)-1-(3-(4-(叔丁氧基羰基)哌嗪-1-基)丙酰氨基)乙基)硼酸(0.085g, 0.19 mmol)溶于1,4-二氧杂环己烷(5 mL)并冷却至10℃。向其中加入在二氧杂环己烷(5 mL)中的4 N HCl并于室温下搅拌过夜。将反应混合物在减压下浓缩并用二乙醚洗涤残留物,得到固体。将该固体进一步冻干,获得标题化合物(47 mg, 64 %),为浅棕色固体。
1H NMR:(400 MHz, DMSO-d6):δ 7.66 (s, 1H), 7.62 (d, J = 7.24 Hz, 1H), 7.49 (d, J = 8.12 Hz, 1H), 7.21-7.29 (m, 2H), 3.25-3.37 (m, 11 H), 2.88-2.93 (m, 1H), 2.75-2.81 (m, 1H), 2.55-2.56 (m, 2H). MS (ESI+):350.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.0 min, HPLC纯度93.5%。
实施例83:(R)-(1-(2-(1H-咪唑-5-基)乙酰氨基)-2-(苯并呋喃-3-基)乙基)硼酸盐酸盐
步骤1:(R)-(1-(2-(1H-咪唑-5-基)乙酰氨基)-2-(苯并呋喃-3-基)乙基)硼酸频哪醇酯.
将中间体18 (170 mg, 0.37 mmol)在无水N,N-二甲基甲酰胺(20 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.2 ml, 1.1 mmol)和2-(1H)-咪唑-5-基-乙酸(47 mg, 0.37 mmol)和TBTU (142 mg, 0.44 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(110 mg, 66 %)经硅胶层析纯化来分离,用在二氯甲烷中的7 %甲醇洗脱。
MS (ESI+):448.2
步骤2:(R)-(1-(2-(1H-咪唑-5-基)乙酰氨基)-2-(苯并呋喃-3-基)乙基)硼酸盐酸盐
将(R)-(1-(2-(1H-咪唑-5-基)乙酰氨基)-2-(苯并呋喃-3-基)乙基)硼酸频哪醇酯(110 mg, 0.24 mmol)在甲醇/戊烷(1:1, 20 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸(96 mg, 0.96 mmol)和HCl水溶液(1.5 N, 0.5 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。向该残留物中加入水并用二氯甲烷提取三次。冻干水层获得标题化合物(25 mg, 32 %),为浅棕色半固体。
1H NMR:(400 MHz, DMSO-d6):δ 8.68 (s, 1H), 7.58 (t, J = 7.60 Hz, 2H), 7.47 (d, J = 8.08 Hz, 1H), 7.18-7.28 (m, 3H), 3.52 (s, 2H), 3.26-3.30 (m, 2H), 2.86-2.88 (m, 1H), 2.78-2.80 (m, 1H). MS (ESI+):318.3 [M+Na-H2O]. HPLC (方法A):Rt. 2.1 min, HPLC纯度95.2%。
以下化合物采用实施例83遵照的相同程序合成。
实施例93:(R)-(2-(苯并呋喃-3-基)-1-(3-(吡啶-4-基)丙酰氨基)乙基)硼酸盐酸盐
浅棕色半固体。1H NMR:(400 MHz, DMSO-d6):δ 8.65 (d, J = 6.56 Hz, 2H), 7.83 (d, J = 6.48 Hz, 2H), 7.55-7.58 (m, 2H), 7.48 (d, J = 7.96 Hz, 1H), 7.19-7.28 (m, 2H), 3.20-3.23 (m, 1H), 3.03 (t, J = 7.16 Hz, 2H), 2.81-2.86 (m, 1H), 2.66-2.73 (m, 1H), 2.54-2.51 (m, 2H). MS (ESI+):343.2 [M+Na-H2O]. HPLC (方法A):Rt. 2.0 min, HPLC纯度96.1 %。
实施例101:(R)-(2-(1H-吲哚-3-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)
丙酰氨基)乙基)硼酸
步骤1:叔丁基3-((2R)-2-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)-2-(3a,5,5-三甲基六氢-4,6-亚甲基苯并[d][1,3,2]二氧硼杂环戊烷-2-基)乙基)-1H-吲哚-1-甲酸酯.
将[(1R)-1-氨基-2-(1H-吲哚-3-基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐(500 mg, 0.90 mmol)在无水N,N-二甲基甲酰胺(20 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.5 ml, 2.7 mmol)和[3-(2-氧代-苯并噻唑-3-基)丙酸] (190 mg, 0.9 mmol)和TBTU (346 mg, 1.1 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(280 mg, 48 %)经硅胶层析纯化来分离,用在石油醚中的30 %乙酸乙酯洗脱。
MS (ESI+):644.2
步骤2:N-((1R)-2-(1H-吲哚-3-基)-1-(3a,5,5-三甲基六氢-4,6-亚甲基苯并[d][1,3,2]二氧硼杂环戊烷-2-基)乙基)-3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰胺盐酸盐.
将化合物叔丁基3-((2R)-2-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)-2-(3a,5,5-三甲基六氢-4,6-亚甲基苯并[d][1,3,2]二氧硼杂环戊烷-2-基)乙基)-1H-吲哚-1-甲酸酯(280 mg, 0.43 mmol)溶于二氯甲烷(10 mL)和冷却至10℃。向其中加入在二氧杂环己烷(10 mL)中的4 N HCl 并于室温下搅拌过夜。反应混合物在减压下浓缩并用二乙醚洗涤残留物,获得所需产物(200 mg, 85 %)。
步骤3:(R)-(2-(1H-吲哚-3-基)-1-(3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰氨基)乙基)硼酸
将N-((1R)-2-(1H-吲哚-3-基)-1-(3a,5,5-三甲基六氢-4,6-亚甲基苯并[d][1,3,2]二氧硼杂环戊烷-2-基)乙基)-3-(2-氧代苯并[d]噻唑-3(2H)-基)丙酰胺盐酸盐(200 mg, 0.36 mmol)在甲醇/戊烷(1:1, 20 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸( 145 mg, 1.4 mmol)和HCl水溶液(1.5 N, 0.5 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。残留物用冰处理,用NaOH的水溶液(2N)碱化并用二氯甲烷提取三次(弃去)。然后水层用HCl的水溶液(1.5 N)酸化并用二氯甲烷提取三次。DCM层经硫酸钠干燥,过滤并浓缩,得到固体残留物,其用二乙醚研磨并冻干获得标题化合物(13 mg, 15 %),为灰白色固体。
1H NMR:(400 MHz, DMSO-d6):δ 7.59 (d, J = 7.80 Hz, 1H), 7.42 (d, J = 7.92 Hz, 1H), 7.26-7.34 (m, 3H), 7.17 (t, J = 7.36 Hz, 1H), 7.01 (t, J = 7.60 Hz, 1H), 6.88-6.93 (m, 2H), 4.05-4.09 (m, 2H), 3.17-3.21 (m, 1H), 2.80-2.85 (m, 1H), 2.70-2.75 (m, 1H), 2.41-2.44 (m, 2H). MS (ESI+):392.0 [M+H-H2O]. HPLC (方法A):Rt. 3.2 min, HPLC纯度92.1 %。
实施例110:((1R)-2-(3-乙基苯基)-1-(3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酰氨基)乙基)硼酸
步骤1:乙基-2-(叠氮基甲基)丙烯酸酯
向乙基-2-(溴代甲基)丙烯酸酯(5 g, 26.1 mmol)在DMSO (50 ml)中的溶液中加入叠氮化钠(2.5 g, 38.4 mmol)并将反应混合物于室温下搅拌2h。用水猝灭反应并用乙酸乙酯提取。分离有机层,经无水硫酸钠干燥并浓缩。粗品(5.0 g)无须进一步纯化而用于后面的步骤(发现乙基-2-(叠氮基甲基)丙烯酸酯放置数小时后不稳定)。
步骤2:乙基-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙烯酸酯
向苯基乙炔(3.0 g, 29.4 mmol)和乙基-2-(叠氮基甲基)丙烯酸酯(5.0 g, 32.3 mmol)在t-BuOH:H2O (2:1 ) (50 ml.)中的溶液中加入抗坏血酸钠( 0.87 g, 4.4 mmol)和CuSO4.5H2O (0.36 g, 1.5 mmol)。将反应混合物于室温下搅拌12h。用乙酸乙酯稀释反应混合物并用水、盐水溶液洗涤。分离有机层,经无水硫酸钠干燥并浓缩。获得的固体(3.0 g, 39%)无须进一步纯化而用于后面的步骤。
1H NMR:(400 MHz, DMSO-d6):δ 8.5 (s, 1H), 7.8 (d, J = 8.2 Hz, 2H), 7.4 (t, J = 7.7 Hz, 2H), 7.30-7.34 (m, 1H), 6.4 (s, 1H), 5.8 (s, 1H), 5.3 (s, 2H), 4.2 (q, J = 7.0 Hz, 2H), 1.2 (t, J = 7.0 Hz, 3H)。
步骤3:乙基-3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酸酯
于室温下,向乙基-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙烯酸酯(3.0 g, 11.6 mmol)在乙腈(30 ml.)中的溶液中加入噻唑-2(3H)-酮(1.2 g, 11.6 mmol)和DBU (2.6 g, 17.4 mmol)并将反应混合物于室温下搅拌过夜。将反应混合物在减压下浓缩并将残留物用乙酸乙酯提取并用水、盐水溶液洗涤。分离有机层,经无水硫酸钠干燥并浓缩。粗制化合物经柱层析纯化,采用乙酸乙酯和石油醚作为洗脱剂,得到标题化合物(1.2 g, 28 %)。
MS (ESI+):359.2 [M+H]
步骤4:3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酸
向乙基-3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酸酯(1.2 g, 3.3mmol)在THF:H2O (20 m L)中的溶液中加入氢化锂单水合物(0.41 g, 9.9 mmol)并将反应混合物于室温下搅拌过夜。蒸发反应混合物。向残留物加入水并用二氯甲烷提取三次(弃去)。然后即刻酸化含水层并用二氯甲烷提取。然后经无水硫酸钠干燥有机层并浓缩,得到标题化合物(200 mg, 18 %)。
MS (ESI+):331.0 [M+H]
步骤5:((1R)-2-(3-乙基苯基)-1-(3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酰氨基)乙基)硼酸频哪醇酯.
将[(1R)-1-氨基-2-(3-乙基苯基)乙基]硼酸(+)-蒎烷二醇酯三氟乙酸盐(200 mg, 0.45 mmol)在无水N,N-二甲基甲酰胺(10 ml)中的冷却(-10℃)溶液用二异丙基乙胺(0.2 ml, 1.3 mmol)和3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酸(148 mg, 0.45 mmol)和TBTU (173 mg, 0.54 mmol)处理。将反应混合物于-10℃搅拌3h。在减压下浓缩反应混合物,保持外浴温度低于30℃,然后加入25 ml乙酸乙酯。有机层用盐水洗涤,经硫酸钠干燥并浓缩。所需产物(290 mg, 99 %)经硅胶层析纯化来分离,用在石油醚中的25 %乙酸乙酯洗脱。
MS (ESI+):640.3
步骤6:((1R)-2-(3-乙基苯基)-1-(3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酰氨基)乙基)硼酸
将((1R)-2-(3-乙基苯基)-1-(3-(2-氧代噻唑-3(2H)-基)-2-((4-苯基-1H-1,2,3-三唑-1-基)甲基)丙酰氨基)乙基)硼酸频哪醇酯(290 mg, 0.45 mmol)在甲醇/戊烷(1:1, 20 mL)中的冷却(0℃)溶液用2-甲基丙基硼酸(181 mg, 1.8 mmol)和HCl水溶液 (1.5 N, 0.5 mL)处理并将反应混合物于室温下搅拌15 h。然后用戊烷提取反应混合物三次。在低于30℃的温度下浓缩含水甲醇层。残留物用冰处理,用NaOH的水溶液(2N)碱化并用二氯甲烷提取三次(弃去)。然后水层用HCl的水溶液(1.5 N)酸化并用二氯甲烷提取三次。DCM层经硫酸钠干燥,过滤并浓缩,得到固体残留物,其用二乙醚研磨并冻干获得标题化合物(61 mg, 26 %),为淡粉红色固体。
1H NMR:(400 MHz, DMSO-d6):δ 8.20 (d, J = 8.56 Hz, 1H), 7.79-7.82 (m, 2H), 7.43 (t, J = 7.76 Hz, 2H), 7.33-7.37 (m, 1H), 6.93-7.08 (m, 3H), 6.80-6.86 (m, 1H), 6.71-6.75 (m, 1H), 6.31-6.35 (m, 1H), 4.56-4.62 (m, 1H), 4.37-4.44 (m, 1H), 3.82-3.84 (m, 1H), 3.33-3.34 (m, 1H), 3.20-3.22 (m, 1H), 2.62-2.67 (m, 2H), 2.44-2.49 (m, 2H), 1.05-1.11 (m, 3H).
MS (ESI+):488.3 [M+H-H2O]. HPLC (方法A):Rt. 4.4 min, HPLC纯度91.0%。
实施例111:LMP7活性的测定
LMP7抑制作用的测量在基于荧光强度分析的384孔格式板上进行。
将纯化的人免疫蛋白酶体(0.5 nM)和在DMSO中的系列稀释化合物(浓度范围从10 μΜ至38 pM)或对照品(0.5% DMSO)于37℃在包含50 mM Tris pH 7.4和0.03% SDS的分析缓冲液中培育30分钟。通过加入浓度40μΜ的荧光肽底物Suc-LLVY-AMC (Bachem I-1395)来引发反应。于37℃培育90分钟后,用荧光读出仪(BMG Pherastar读出仪或等同物)于λex =350 nm和λem = 450 nm测量荧光强度。
对于实施例79、80、83、84、85、87、88、89、90、91、93、94、96、97、101和110,LMP7抑制作用的测量在基于荧光强度分析的384孔格式板上进行。
将纯化的人免疫蛋白酶体(0.25 nM)和在DMSO中的系列稀释化合物(浓度范围从10 μΜ至38 pM)或对照品(0.5% DMSO)于37℃在包含50 mM Tris pH 7.4和0.03% SDS的分析缓冲液中培育30分钟。通过加入浓度40μΜ的荧光肽底物Suc-LLVY-AMC (Bachem I-1395)来引发反应。于37℃培育90分钟后,用荧光读出仪(BMG Pherastar读出仪或等同物)于λex =350 nm和λem = 450 nm测量荧光强度。
实施例112:β5活性的测定
β5抑制作用的测量在基于荧光强度分析的384孔格式板上进行。
将纯化的人组成型蛋白酶体(1.0 nM)和在DMSO中的系列稀释化合物(浓度范围从10 μΜ至38 pM)或对照品(0.5% DMSO)于37℃在包含50 mM Tris pH 7.4和0.03% SDS的分析缓冲液中培育30分钟。通过加入浓度40μΜ的荧光肽底物Suc-LLVY-AMC (Bachem I-1395)来引发反应。于37℃培育90分钟后,用荧光读出仪(BMG Pherastar读出仪或等同物)于λex =350 nm和λem = 450 nm测量荧光强度。
所述化合物的生物学活性概述于下表中:
*: IC50 > 5 μΜ, **: 0.5 μΜ < IC50 < 5 μΜ, ***: 0.05 μΜ < IC50 < 0.5 μΜ, ****: IC50 < 0.05 μΜ, +: 选择性< 10, ++: 10 <选择性< 30, +++: 选择性> 30, n.d: 未测定。
Claims (15)
1.一种式(I)化合物
其中
Rb和Rc彼此独立地选自H或C1-C6烷基;其中Rb和Rc可连接形成含氧原子的5或6元环,所述氧原子与Rb和Rc连接;
Q表示Ar、Het或环烷基;
R1和R2彼此独立地选自H、ORa、Hal、其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基;
Y表示CR3R4,优选为CH2或C(CH3)2;
R3,R4彼此独立地表示H或C1-C6烷基;
L表示L1或L2或烷基;
n为选自0-3的整数;
L1是,其中
Q1是Ar或Het,优选为苯基、萘基或吡啶,任选地被1-5个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;
L2是,其中
Q2是含有1个氮原子和1-3个独立地选自O、S、N或CO的另外的基团的稠合双环系统,和其中至少一个环是芳族的,由此稠合的双环系统任选地被1-5个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;或
Q2是含有1-3个选自N、O、S或CO的杂原子的不饱和或芳族5元环系统,且任选地被苯环或吡啶环取代,其中苯环或吡啶环任选地被1-4个独立地选自ORa、Hal、苯基、及其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基的基团取代;
M是具有1-5个碳原子的线性或分支亚烷基,其中1-2个H原子可被ORa或苯基替代,所述苯基任选地被1-5个独立地选自Hal、ORa、及任选地被1-5个独立地选自OH和Hal的基团取代的C1-C6烷基的基团取代;或
M表示具有3-7个碳原子的亚环烷基;或
M表示噻唑烷基;
Ra是H或其中1-5个H原子可以独立地被OH或Hal替代的C1-C6烷基;
Ar表示6元芳族碳环,其任选地与另一个具有5-8个碳原子的饱和、不饱和或芳族碳环稠合;
Het表示含有1-3个独立地选自N、N+O-、O、S、SO和SO2的杂原子的5或6元饱和、不饱和或芳族杂环,且任选地与另一个具有5-8个原子和任选地含1-3个选自N、O和S的杂原子的饱和、不饱和或芳族环稠合;
Hal表示Cl、Br、I或F;优选Cl或F,
及其对映体、非对映体,及其药学上可接受的盐。
2.权利要求1的式(I)化合物,其中L选自以下基团:
或者其中L选自以下的基团:
。
3.权利要求1或2的式(I)化合物,其中基团
选自以下的基团:
。
4.权利要求1的式(I)化合物,其中所述化合物选自以下组:
。
5.一种药用组合物,其包含权利要求1-4中一项或多项的至少一种式(I)化合物和/或其药学可用盐、溶剂合物和立体异构体,包括其所有比例的混合物,和任选的赋形剂和/或辅助剂。
6.一种药用组合物,其包含权利要求1-4中一项或多项的至少一种式(I)化合物和/或其药学可用盐、溶剂合物和立体异构体,包括其所有比例的混合物,和至少一种另外的活性成分。
7.由以下单独的包构成的药物套装(药剂盒):
(a) 有效量的权利要求1-4中一项或多项的式(I)化合物和/或其药学可用盐、溶剂合物和立体异构体,包括其所有比例的混合物,
和
(b) 有效量的其它药物活性成分。
8.权利要求1-4中一项或多项的化合物及其药学可用盐、互变异构体、溶剂合物和立体异构体,包括其所有比例的混合物,用于制备治疗和/或预防与过度活性免疫应答相关的自身免疫紊乱或病症的药物。
9.权利要求1-4中一项或多项的化合物及其药学可用盐、互变异构体、溶剂合物和立体异构体,包括其所有比例的混合物,用于制备治疗和/或预防免疫调节异常的药物。
10.权利要求8或9的化合物,其中所述免疫调节异为选自以下的自身免疫疾病或慢性炎性疾病:系统性红斑狼疮、慢性类风湿性关节炎、炎性肠道疾病、多发性硬化、肌萎缩性侧索硬化(ALS)、动脉硬化症、硬皮病、自身免疫肝炎、干燥综合征、狼疮性肾炎、肾小球性肾炎、类风湿性关节炎、银屑病、重症肌无力、免疫球蛋白A肾病、血管炎、移植排斥和哮喘。
11.权利要求1-4中一项或多项的化合物及其药学可用盐、互变异构体、溶剂合物和立体异构体,包括其所有比例的混合物,用于制备治疗和/或预防LMP7相关疾病的药物。
12.权利要求11的化合物,其中所述LMP7相关疾病选自肌萎缩性侧索硬化、干燥综合征、系统性红斑狼疮、狼疮性肾炎、肾小球性肾炎、类风湿性关节炎、炎性肠道疾病、溃疡性结肠炎、克罗恩氏病、多发性硬化、肌萎缩性侧索硬化、骨关节炎、动脉硬化症、银屑病、重症肌无力、皮肤纤维化、肾纤维化、心纤维化、肝纤维化、肺纤维化、免疫球蛋白A肾病、血管炎、移植排斥、血液恶性肿瘤和哮喘。
13.一种合成权利要求1的式(I)化合物的方法,其包括使式(II)化合物与式(III)化合物反应的步骤,
其中L如权利要求1所定义,
其中R1、R2、Q、Ra、Rb和n如权利要求1所定义。
14.权利要求13的方法,其中式(II)化合物和式(III)化合物之间的反应在选自以下的偶联剂的存在下进行:HATU、TBTU、聚合物担载的1-烷基-2-氯代吡啶盐(聚合物担载的Mukaiyama试剂)、碘化1-甲基-2-氯代吡啶 (Mukaiyama试剂)、碳二亚胺。
15.权利要求1-4的化合物,其用作药物。
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Cited By (8)
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CN107151255A (zh) * | 2016-03-06 | 2017-09-12 | 复旦大学 | 硼酸类化合物及其制备方法和用途 |
CN107556336A (zh) * | 2017-10-16 | 2018-01-09 | 康化(上海)新药研发有限公司 | 一种呋喃‑2‑甲烷基硼酸频哪醇酯的合成方法 |
CN108130370A (zh) * | 2018-01-05 | 2018-06-08 | 武汉大学 | Psmb8及其抑制剂在制备治疗脂肪肝及其相关疾病药物中的应用 |
WO2021143924A1 (zh) * | 2020-01-19 | 2021-07-22 | 首药控股(北京)股份有限公司 | 硼酸衍生物 |
CN114075227A (zh) * | 2020-08-19 | 2022-02-22 | 北京大学 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
WO2022037648A1 (zh) * | 2020-08-19 | 2022-02-24 | 北京大学 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
CN114075227B (zh) * | 2020-08-19 | 2023-07-04 | 北京嵩润医药科技有限责任公司 | 吡唑硼酸类化合物、包含其的药物组合物及它们的用途 |
WO2023061445A1 (zh) * | 2021-10-14 | 2023-04-20 | 首药控股(北京)股份有限公司 | 硼酸衍生物 |
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EP2793900B1 (en) | 2018-08-22 |
CN104321060B (zh) | 2018-08-07 |
CA2860142A1 (en) | 2013-06-27 |
IL233200A0 (en) | 2014-07-31 |
US9688702B2 (en) | 2017-06-27 |
JP6129203B2 (ja) | 2017-05-17 |
AU2012356890B2 (en) | 2017-06-08 |
BR112014015363A2 (pt) | 2017-06-13 |
BR112014015363A8 (pt) | 2017-06-13 |
MX2014007362A (es) | 2014-08-01 |
EA201400735A1 (ru) | 2015-04-30 |
MX352652B (es) | 2017-12-04 |
AU2012356890A1 (en) | 2014-08-07 |
SG10201605152SA (en) | 2016-08-30 |
WO2013092979A1 (en) | 2013-06-27 |
JP2015502387A (ja) | 2015-01-22 |
US20140364396A1 (en) | 2014-12-11 |
SG11201403254QA (en) | 2014-07-30 |
IL233200A (en) | 2017-08-31 |
CA2860142C (en) | 2020-10-27 |
HK1206261A1 (zh) | 2016-01-08 |
EP2793900A1 (en) | 2014-10-29 |
KR20140114391A (ko) | 2014-09-26 |
ES2699267T3 (es) | 2019-02-08 |
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