CN117659016A - 细胞周期蛋白调节剂 - Google Patents
细胞周期蛋白调节剂 Download PDFInfo
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- CN117659016A CN117659016A CN202211037727.8A CN202211037727A CN117659016A CN 117659016 A CN117659016 A CN 117659016A CN 202211037727 A CN202211037727 A CN 202211037727A CN 117659016 A CN117659016 A CN 117659016A
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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- 238000010798 ubiquitination Methods 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Abstract
本发明提供了一种细胞周期蛋白调节剂。具体地,本发明提供了一种如式(I)所示的化合物或其药学上可接受的盐。
Description
技术领域
本发明属于药物化学领域,具体涉及一种细胞周期蛋白调节剂。
背景技术
不像大多数传统药物直接抑制分子标靶的作用,分子胶降解剂(molecular gluedegrader)则是通过泛素-蛋白酶体系统(ubiquitin-proteasome system)破坏标靶蛋白来达成杀死癌细胞的目的。比如,多发性骨髓瘤药物来那度胺(lenalidomide)就是一种分子胶降解剂,通过招募E3泛素连接酶(ubiquitin ligase)来标记细胞中的目标蛋白,并随后降解它。与传统意义上的小分子抑制剂不同,分子胶水以催化剂的方式驱动靶标泛素化并诱导降解,是能够使传统药理学方法难以治疗的靶点失活的新策略。分子胶水也巧妙地避开了传统抑制剂的局限性,使得一部分靶点从“无成药性”变为“有成药性”。
细胞周期是细胞生命活动的基本过程,它控制着细胞从静止期转向生长增殖期。细细胞周期蛋白依赖激酶(CDKs)和细胞周期蛋白(Cyclins)是整个细胞周期调控机制中的核心分子。在正常细胞中,细胞周期蛋白的活性受到其细胞周期特异性转录和蛋白质降解的严格控制,以及一些CDK抑制蛋白的影响。细胞周期蛋白除了促进细胞分裂外,还肩负调节各种细胞功能的责任。这种机制由细胞周期蛋白及其催化搭档细胞周期蛋白依赖激酶(CDKs)共同运行。但这些影响因素在人类癌症中经常失控,导致细胞周期蛋白的异常激活。细胞周期机制活动异常基本上在所有类型的肿瘤中都存在,这也是肿瘤发生的驱动力。靶向某个特定细胞周期蛋白可能成为一种有效的抗癌策略。
迄今为止,已上市的CDK抑制剂很少,且均为CDK4/6抑制剂。而选择性靶向其他CDK家族的抑制剂,很难做到满足要求的特异性,几乎都为多靶点抑制剂,临床上表现出不可接收的毒性,从而阻止了其临床应用。另外,激酶抑制剂虽能导致激酶亚基的去除,但同时保持细胞周期蛋白的完整性,可能触发代偿机制。而激酶的降解可能导致比其抑制作用更持久的效果。
虽然分子胶降解剂非常理想,临床效果好也很受欢迎,但迄今为止发现的分子胶降解剂仍寥寥可数,且多为偶然发现。CR8作为被新发现的细胞周期素K(CyclinK)降解剂,其首先是一个多激酶抑制剂,能抑制CDK家族中多个周期蛋白的活性,从而带来的毒性限制了其临床应用。除了选择性欠佳,其降解CyclinK的活性也很一般,限制了其催化量的使用。
综上所述,本领域迫切需要开发一类具有更高活性和/或更低毒性的细胞周期蛋白调节剂如细胞周期蛋白降解剂。
发明内容
本发明的目的就是提供具有更高活性的细胞周期蛋白降解剂,或者新型细胞周期蛋白调节剂。
在本发明的第一方面中,提供了一种如式(I)所示的化合物或其药学上可接受的盐,
其中,
R1各自独立地为H或C1-4烷基;
下标n1为1、2或3;
环Ar1选自下组:C6-10芳环、5至10元杂芳环、5至10元桥环;
环Cr1选自下组:H、C3-10碳环基、3至10元杂环基、C6-10芳基、和5至10元杂芳基;
Ra和Rb各自独立地选自下组:H、Re或R;或者Ra和Rb与环Ar1和环Cr1共同形成其中,
X7各自独立地选自下组:-O-、-S-、-N(Rc)-、-C(Rc)2-、-C(Rc)2-C(Rc)2-;
下标n5和n6各自独立地为0、1、2或3;
Re各自独立地选自下组:羟基、C1-6烷基、-O-C1-6烷基、-O-C1-6亚烷基-Rf;
其中,Rf选自下组:-CN、-OH、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2;
下标n3和n4各自独立地为0、1、2、3或4;
R2选自下组:H、CN、任选取代的C1-6烷基、任选取代的C2-6烯基、任选取代的C2-6炔基、任选取代的C3-8环烷基、任选取代的3至8元杂环基;
X1、X2和X6各自独立地为N或C(Rc);
X3、X4和X5各自独立地为N或C;
M1选自下组:无、X8、(M4)s;其中,
X8为N(Rc)或C(Rc)2;
M4各自独立地选自下组:O、S、C(O)O、C(O)、N(Rc)和C1-4亚烷基;
s为1、2或3;
M2为无或如式A所示的环;
式A中,X9是与M1连接的位置,X10是与M3连接的位置;X9为N或C(Rm),X10选自下组:O、S、N或C(Rm);X11和X12各自独立地选自下组:-C(Rm)2-、-N(Rm)-;下标m1和m2各自独立地为0、1、2或3,并且m1+m2≥2;
其中,Rm各自独立地为Rc或Rm1;其中,
Rm1各自独立地选自下组:羟基、任选取代的C1-6烷基、任选取代的C1-6羟基烷基、任选取代的C1-6卤代烷基;或者,两个Rm1共同形成单键、任选取代的C1-4亚烷基或任选取代的1至4元杂亚烷基;
M3选自下组:无、R3、-NH-R3;其中,
R3选自下组:H、任选取代的C1-6烷基、任选取代的C1-6-羟烷基、任选取代的C1-6-卤代烷基;
Rc各自独立地为H或C1-4烷基;
除非特别定义,所述任选取代是指未取代的或基团中一个或多个(如1、2、3或4个)氢被取代基R所取代,并且R选自下组:D、卤素、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、C2-6烯基、C2-6炔基、-CN、-OR'、-NO2、-NR'R"、-SR'、OC(O)R'、-C(O)R'、-CO2R'、-CONR'、-OC(O)NR'R"、-NR"C(O)R'、-NR"-C(O)NR'R"、-NR"C(O)2R'、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、NR"S(O)2R'、任选被一个或多个R'"所取代的C3-10环烷基、任选被一个或多个R'"所取代的4至10元杂环烷基、任选被一个或多个R'"所取代的C6-10芳基、任选被一个或多个R'"所取代的5至10元杂芳基、任选被一个或多个R'"所取代的-C1-4亚烷基-C3-10环烷基、任选被一个或多个R'"所取代的-C1-4亚烷基-4至10元杂环烷基、任选被一个或多个R'"所取代的-C1-4亚烷基-C6-10芳基、任选被一个或多个R'"所取代的-C1-4亚烷基-5至10元杂芳基;
各个R'各自独立地为H、D、任选被一个或多个R'"所取代的选自下组的基团:C1-6烷基、C3-10环烷基、4至10元杂环烷基、C6-10芳基、5至10元杂芳基、-C1-4亚烷基-C3-10环烷基、-C1-4亚烷基-4至10元杂环烷基、-C1-4亚烷基-C6-10芳基-C1-4亚烷基-5至10元杂芳基;
各个R"选自下组:H、D、C1-4烷基、C1-4卤代烷基、和C3-4环烷基;
各个R"'独立地选自下组:D、卤素、羟基、硝基、CN、C1-6烷基、C1-6卤代烷基。
在另一优选例中,所述化合物不为如下所示的CR8:
在另一优选例中,R1为H。在另一优选例中,n1=1。在另一优选例中,R1为H,且n1=1。
在另一优选例中,环Ar1选自下组:C6-10芳环、5至10元杂芳环。
在另一优选例中,环Ar1选自下组:苯环、5至10元杂芳环。
在另一优选例中,环Ar1选自下组:
其中,*代表与环Cr1连接的位置;Xa、Xb、Xc和Xd各自独立地为CH和N;Xg选自下组:NH、O、S;Xh、Xi和Xj各自独立为-CH2-或-CH2-CH2-。
在另一优选例中,为/>
在另一优选例中,环Ar1中,为/>
在另一优选例中,环Ar1选自下组:
其中,*代表与环Cr1连接的位置;Xa、Xb、Xc和Xd各自独立地为CH和N;Xg选自下组:NH、O、S。
在另一优选例中,环Ar1为
其中,*代表与环Cr1连接的位置。
在另一优选例中,为/>其中*代表与环Cr1连接的位置
在另一优选例中,环Cr1中,所述碳环为饱和的或含1或2个双键的不饱和的碳环。
在另一优选例中,环Cr1中,所述C3-10碳环为C4-10碳环;较佳地,为C4-6碳环。
在另一优选例中,环Cr1中,所述3至10元杂环基为饱和的3至10元杂环基。
在另一优选例中,环Cr1中,所述3至10元杂环基为4至10元杂环基;较佳地,为4至6元杂环基。
在另一优选例中,环Cr1选自下组:
其中,Xd和Xe各自独立地为N或CH;Xf为NH、S、O;Xg为N或CH。
在另一优选例中,为/>
在另一优选例中,环Cr1为环Ar2;并且环Ar2选自下组:C6-10芳基、和5至10元杂芳基。
在另一优选例中,环Ar2选自下组:
其中,Xd和Xe各自独立地为-N-或-CH-;Xf为-NH-、-S-、-O-;Xg为N或CH。
在另一优选例中,环Ar2为在另一优选例中,环Ar2为苯基。
在另一优选例中,当M2为无时,环Ar2不为含氮杂芳基(其中,所述含氮杂芳基为环上具有1或2个氮杂原子且不含其他杂原子的杂芳基,如吡啶基、吡唑基、咪唑基和吡嗪基)。
在另一优选例中,当M2为无时,环Ar2不为
在另一优选例中,n3为0(即环Ar1是未取代的);或者,n3为1、2、3或4(即环Ar1被1、2、3或4个Ra所取代),且Ra各自独立地选自下组:D、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,n3为0。在另一优选例中,n3为1,且Ra为Re。
在另一优选例中,n4为0(即环Cr1是未取代的);或者,n4为1、2、3或4(即环Cr1被1、2、3或4个Rb所取代),且Rb各自独立地选自下组:D、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,n4为0。在另一优选例中,n4为1,且Rb为Re。
在另一优选例中,n3为0(即环Ar1是未取代的);或者,n3为1、2、3或4(即环Ar1被1、2、3或4个Ra所取代),且Ra各自独立地选自下组:D、卤素、C1-6烷基、C1-6卤代烷基。
在另一优选例中,当M2为无时,不为/>
在另一优选例中,为/>
在另一优选例中,X1为N,X2为CRc,X3为C,X4为C,X5为N且X6为CRc。在另一优选例中,X1为CRc,X2为CRc,X3为CRc,X4为N,X5为C且X6为CRc。在另一优选例中,X1为N,X2为CRc,X3为CRc,X4为N,X5为C且X6为CRc。在另一优选例中,X1为CRc,X2为CRc,X3为CRc,X4为N,X5为N且X6为CRc。在另一优选例中,X1为CRc,X2为CRc,X3为N,X4为CRc,X5为C且X6为CRc。在另一优选例中,X1为CRc,X2为N,X3为N,X4为CRc,X5为C且X6为CRc。在另一优选例中,X1为N,X2为CRc,X3为N,X4为CRc,X5为C且X6为CRc。
在另一优选例中,Rc均为H。
在另一优选例中,X1为N,X2为CH,X3为C,X4为C,X5为N且X6为CH。在另一优选例中,X1为CH,X2为CH,X3为CH,X4为N,X5为C且X6为CH。在另一优选例中,X1为N,X2为CH,X3为CH,X4为N,X5为C且X6为CH。在另一优选例中,X1为CH,X2为CH,X3为CH,X4为N,X5为N且X6为CH。在另一优选例中,X1为CH,X2为CH,X3为N,X4为CH,X5为C且X6为CH。在另一优选例中,X1为CH,X2为N,X3为N,X4为CH,X5为C且X6为CH。在另一优选例中,X1为N,X2为CH,X3为N,X4为CH,X5为C且X6为CH。
在另一优选例中,
选自下组:
在另一优选例中,
为/>
在另一优选例中,R2为任选取代的C1-6烷基。在另一优选例中,R2为C1-6烷基。在另一优选例中,R2为选自下组:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。
在另一优选例中,式A中,当两个Rm1位于同一碳原子上时,两个Rm1共同形成任选取代的C2-4亚烷基或任选取代的2至4元亚杂烷基(即如式A所示的环为螺环)。
在另一优选例中,式A中,当两个Rm1位于位于相邻两个环原子上时,两个Rm1共同形成任选取代的C1-4亚烷基或任选取代的1至4元亚杂烷基(即如式A所示的环为并环)。
在另一优选例中,式A中,当两个Rm1位于至少间隔一个环原子的两个环原子上时,两个Rm1共同形成单键、任选取代的C1-3亚烷基或任选取代的1至3元亚杂烷基(即如式A所示的环为并环)。
在另一优选例中,两个Rm1共同形成C1-4亚烷基。
在另一优选例中,2≤m1+m2≤4(即如式A所示的环为4至6元环)。
在另一优选例中,X10为O或S时,M3为无;X10为N或C(Rm)时,M3为R3--或-NH-R3。
在另一优选例中,M1为无或X8。
在另一优选例中,M1为无,M3为-NH-R3,且M2为无。
在另一优选例中,R3任选取代的C1-6-羟烷基。
在另一优选例中,为/>
在另一优选例中,M1为无,M3为无或R3,且M2为如式A所示的环。
在另一优选例中,m1和m2各自独立地为1或2。在另一优选例中,m1和m2均为2。
在另一优选例中,X9为N。
在另一优选例中,R3为H。
在另一优选例中,X10为N,M3为R3,且R3为H或C1-6烷基。在另一优选例中,X10为N,M3为R3,且R3为H。
在另一优选例中,X11和X12各自独立地为-C(Rm)2-。
在另一优选例中,X11和X12中至多只有两个Rm为Rm1,其余Rm为Rc(较佳地,其余Rm为H)。
在另一优选例中,M1为无,M3为无或R3,且M2为式A环;并且,式A中,X9为N或C(Rm),X10选自下组:O、S、N或C(Rm);X11和X12各自独立为-C(Rm)2-;下标m1和m2各自独立地为1或2(较佳地下标m1和m2均为2)。
在另一优选例中,M1为无,M3为R3,且M2为式A环;并且,式A中,X9为N或C(Rm),X10为N;X11和X12各自独立地为C(Rm)2-;下标m1和m2各自独立地为1或2(较佳地下标m1和m2均为2)。
在另一优选例中,M1为无,M3为R3,且R3为H,且M2为式A环;并且,式A中,X9为N,X10为N;X11和X12各自独立地为-C(Rm)2-;下标m1和m2各自独立地为1或2(较佳地下标m1和m2均为2)。
在另一优选例中,为/>
在另一优选例中,为/>其中,m3为0、1或2。
在另一优选例中,选自下组:
在另一优选例中,所述的化合物如式I-1所示
其中,各基团如前定义。
在另一优选例中,M1为X8或(M4)s,M3为无或R3,且M2为如式A所示的环;其中,M4各自独立地选自下组:O和C1-4亚烷基;s为1、2或3;且至多一个M4为O。
在另一优选例中,M1为X8,M3为无或R3,且M2为如式A所示的环。
在另一优选例中,X8为N(Rc)。
在另一优选例中,R3为H。
在另一优选例中,m1和m2各自独立地为1、2或3。在另一优选例中,m1和m2各自独立地为1、2或3并且m1+m2≤4。
在另一优选例中,X10为N或C(Rc),M3为R3,且R3为H或C1-6烷基。在另一优选例中,X10为N或CH,M3为R3,且R3为H。
在另一优选例中,X10为N,M3为R3,且R3为H或C1-6烷基。在另一优选例中,X10为N,M3为R3,且R3为H。
在另一优选例中,X11和X12中只有1个Rm为Rm1,其余Rm为Rc(较佳地,其余Rm为H)。
在另一优选例中,M1为X8,M3为R3,且M2为如式A所示的环;并且,式A中,X9为N或C(Rm),X10为N或C(Rm);X11和X12各自独立地选自下组:-C(Rm)2-、-N(Rm)-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为X8,M3为R3,且M2为如式A所示的环;并且,式A中,X9为N或C(Rm),X10为N;X11和X12各自独立地为-C(Rm)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为X8,X8为N(Rc);M3为R3,且R3为H,且M2为式A环;式A中,X9为C(Rm),X10为N;X11和X12各自独立地为-C(Rm)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,为/>
在另一优选例中,为/>其中,下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,选自下组:
在另一优选例中,所述的化合物如式I-2所示
其中,各基团如前定义。
在另一优选例中,M1为无,M3为-NH-R3,且M2为如式A所示的环。
在另一优选例中,m1和m2各自独立地为1、2或3。在另一优选例中,m1和m2各自独立地为1、2或3并且m1+m2≤4。
在另一优选例中,R3为H。
在另一优选例中,X9为N。
在另一优选例中,X10为C(Rm)。在另一优选例中,X10为C(Rc)。在另一优选例中,X10为CH。
在另一优选例中,X11和X12各自独立地为-C(Rm)2-。在另一优选例中,X11和X12各自独立地为-C(Rc)2-。在另一优选例中,X11和X12各自独立地为-CH2-。
在另一优选例中,M1为无,M3为-NH-R3,且M2为如式A所示的环;并且,式A中,X9为N或C(Rm),X10为C(Rm);X11和X12各自独立为-C(Rm)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为无,M3为-NH-R3,且M2为如式A所示的环;并且,式A中,X9为N,X10为C(Rm);X11和X12各自独立为-C(Rm)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为无,M3为-NH-R3,且M2为如式A所示的环;并且,式A中,X9为N,X10为C(Rc);X11和X12各自独立为-C(Rc)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,为/>
在另一优选例中,为/>其中,下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,选自下组:
在另一优选例中,所述的化合物如式I-3所示
其中,各基团如前定义。
在另一优选例中,M1为X8,M3为-NH-R3,且M2为如式A所示的环。
在另一优选例中,X8为N(Rc)。
在另一优选例中,R3为H。
在另一优选例中,m1和m2各自独立地为1、2或3。在另一优选例中,m1和m2各自独立地为1、2或3并且m1+m2≤4。
在另一优选例中,X9为C(Rm);较佳地,X9为C(Rc);较佳地,X9为CH。
在另一优选例中,X10为C(Rm);较佳地,X10为C(Rc);较佳地,X10为CH。
在另一优选例中,X11和X12各自独立地为-C(Rm)2-。在另一优选例中,X11和X12各自独立地为-C(Rc)2-。在另一优选例中,X11和X12各自独立地为-CH2-。
在另一优选例中,M1为X8,M3为-NH-R3,且M2为如式A所示的环;并且,X8为N(Rc)或C(Rc)2;式A中,X9为C(Rc),X10为C(Rc);X11和X12各自独立为-C(Rc)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为X8,M3为-NH-R3,且M2为如式A所示的环;并且,X8为N(Rc);式A中,X9为C(Rc),X10为C(Rc);X11和X12各自独立为-C(Rc)2-;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,M1为X8,M3为-NH-R3,且M2为如式A所示的环;并且,X8为NH;式A中,X9为CH,X10为CH;X11和X12各自独立为-CH2-;;下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,为/>
在另一优选例中,为/>其中,下标m1和m2各自独立地为1、2或3(较佳地,m1和m2各自独立地为1、2或3并且m1+m2≤4)。
在另一优选例中,选自下组:
在另一优选例中,所述的化合物如式I-4所示
其中,各基团如前定义。
在另一优选例中,化合物所述化合物为式I-1化合物,其中,为m3为0、1或2。
在另一优选例中,R1、R2、R3、X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、M1、M2、M3、M4、下标n1、下标n3、下标n4、下标n5、下标n6、下标m1、下标m2、下标m3、下标s、Ar1、Ar2、Cr1、Ra、Rb、Rc、Re、Rf、Rm、Rm1、R、R'、R"和R'"各自独立地为实施例化合物或表A1、A2、A3和表A4中具体化合物中对应基团。
在另一优选例中,所述的化合物为选自表A1、A2、A3和表A4的化合物。
在本发明的第二方面中,提供了一种药物组合物,所述的药物组合物包括:
(i)如第一方面所述的化合物或其药学上可接受的盐;以及
(ii)药学上可以接受的载体。
在本发明的第三方面中,提供了一种如第一方面所述的如式(I)所示的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
在本发明的第四方面中,提供了一种治疗癌症的方法,包括步骤:向有需要的对象施用安全有效量的如第一方面所述的如式(I)所示的化合物或其药学上可接受的盐。
在本发明的第五方面中,提供了一种降解细胞周期素K(Cyclin K)的方法,包括步骤:用如第一方面所述的如式(I)所示的化合物处理对象,从而使细胞周期素K(Cyclin K)降解。
在另一优选例中,所述的对象是细胞。
在另一优选例中,所述的对象是HepG2细胞。
在另一优选例中,所述的方法是体外非治疗性的。
在本发明的第六方面中,提供了一种偶联物或其药学上可接受的盐,所述偶联物是由如第一方面所述的如式(I)所示的化合物与多肽元件或靶向配体形成的偶联物。
在另一优选例中,所述偶联物如式II所示
MD-ML-MP (II)
其中,
MD是衍生自如第一方面所述的如式(I)所示的化合物的部分;
ML为无或用于连接MD和MP的连接部分;
MP为衍生自多肽元件或靶向配体的部分。
在另一优选例中,所述靶向配体是指能够结合细胞外受体的小分子。
在另一优选例中,多肽元件包括(但不限于):多肽、抗体、抗体片段、融合蛋白,或其组合。
在另一优选例中,MP选自下组:多肽、抗体、抗体片段、融合蛋白,或能够结合细胞外受体的小分子配体部分。
在另一优选例中,所述抗体包括(但不限于):纳米抗体(nanobody)、小分子抗体(minibody)、抗体片段(如scFv,Fab)、双抗(Dibody)、单克隆抗体(mAb),或其组合。
在另一优选例中,所述多肽(如靶向多肽)的靶标包括但不局限于:EGFR、FGFR、SSTR1-14、GnRH、TRPV1-6、RGD、iRGD、EphA2,或其组合。
在另一优选例中,所述的小分子配体可结合的靶标包括(但不限于):FR、HSP90、PSMA、ASGPR,其组合。
在另一优选例中,所述抗体可与选自下组的抗原或受体结合(例如,与选自下组的一种(即单功能抗体)或两种(即双功能抗体)或更多种(即多功能抗体)抗原和/或受体结合):DLL3、EDAR、CLL1、BMPR1B、E16、STEAP1、0772P、MPF、5T4,NaPi2b、Sema5b、PSCA hlg、ETBR、MSG783、STEAP2、TrpM4、CRIPTO、CD21、CD22、CD79b、CD19、CD37、CD38、CD138、FcRH2、B7-H4、HER2、NCA、MDP、IL20Rα、短小蛋白聚(Brevican)、EphB2R、ASLG659、PSCA、GEDA、BAFF-R、CD79a、CXCR5、HLA-DOB、P2X5、CD72、LY64、FcRH1、IRTA2、TENB2、PMEL17、TMEFF1、GDNF-Ra1、Ly6E、TMEM46、Ly6G6D、LGR5、RET、LY6K、GPR19、GPR54、ASPHD1、酪氨酸酶(Tyrosinase)、TMEM118、GPR172A、MUC1、CD70、CD71、MUC16、methothelin、FOLR1、TroP1-2、gpNMB、EGFR、ENPP3、PSMA、CA6、GPC-3、PTK7、CD44、CD56、TIM-1、钙粘素-6(Cadherin-6)、ASG-15ME、ASG-22ME、CanAg、AXL、CEACAM5、EphA4、cMet、FGFR2、FGFR3、CD123、Her3、LAMP1、LRRC15、TDGF1、CD66、CD25、BCMA、GCC、Noch3、cMet、EGFR和CD33,或者诸如CD70、Trop2、PD-L1、CD47、CLDN-18.2的受体。
在另一优选例中,所述靶向配体还可与可以被特异性小分子靶向的受体结合,如叶酸,HSP90、葡萄糖转运蛋白-1(glucose transporter 1)(G LUT1)、氨肽酶(aminopeptidase N)(APN)、低密度脂蛋白受体相关蛋白1(low-density lipoproteinreceptor-related protein1)(LRP1),前列腺特异性肽(prostate-specific membraneantigen)(PSMA),整合素αvβ3、铃蟾素(bombesin receptor)、生长抑素受体(somatostatinreceptor)(SSTR)、肿瘤乏氧微环境,以及碳酸酐酶IX(CAIX)等受体。
在本发明的第七方面中,提供了一种药物组合物,所述的药物组合物包括:
(i)如第六方面所述的偶联物或其药学上可接受的盐;以及
(ii)药学上可以接受的载体。
在本发明的第八方面中,提供了一种如第六方面所述的偶联物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
在本发明的第九方面中,提供了一种治疗癌症的方法,包括步骤:向有需要的对象施用安全有效量如第六方面所述的偶联物或其药学上可接受的盐。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1显示了化合物CR-8、UB-018、UB-022、UB-027的免疫组织化学染色(IHC)结果。
图2显示了HEK293细胞中CR-8以及本发明化合物对细胞周期素K降解效果。
具体实施方式
发明人在广泛而深入地研究之后,意外地发现一类具有新颖结构的化合物(如本文中式(I)、式(I-1)、式(I-2)、式(I-3)或式(I-4)所示的化合物,尤其是当Cr1环上不存在N原子时),通过修饰母核其他位置的官能团,也具有优异的诱导细胞周期素K(Cyclin K)降解的效果。基于此,本发明人完成了本发明。
术语
除非另有说明,各结构式中以虚线表示的键代表与其他部分连接的位置。
如本文所用,除非另有定义,术语“烷基”本身或作为另一取代基的一部分是指具有指定碳原子数的直链或支链烃基(即,C1-6表示1-6个碳)。较佳地,烷基具体1~4个碳即C1-4烷基。烷基的例子包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。术语“烯基”指具有一个或多个双键的不饱和烷基。较佳地,烯基具体2~4个碳即C2-4烯基。类似地,术语“炔基”指具有一个或多个三键的不饱和烷基。较佳地,炔基具体2~4个碳即C2-4炔基。此类不饱和烷基的例子包括但不限于:乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基、3-丁炔基和更高级的同系物和异构体。
除非另有说明,术语“杂烷基”本身或与其它术语组合是指的如前所定义的烷基中一个或多个(如1或2个)碳原子被诸如人选自O、N、Si和S的杂原子所替换所形成的稳定的直链或支链基团,且其中氮和硫原子可选地被氧化,氮杂原子可任选地被季铵化。杂原子O、N和S可以位于杂烷基的任何内部位置。杂原子Si可以位于杂烷基的任何位置,包括烷基连接到分子其余部分的位置。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团,例如-CH2-。优选地,在本申请中,具有1、2、3或4个碳原子(即C1-4亚烷基)。
术语“杂亚烷基”本身或作为另一取代基的一部分是指由杂烷基衍生的二价基团。
如本文所用,术语“碳环基”或“碳环”是指具有指定环原子数(例如,C3-10碳环(基)、C4-10碳环(基)、C4-6碳环(基))并且完全饱和的或在环顶之间具有一个或二个双键的烃环(基)。该术语也包括双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。术语“杂环基”或“杂环”是指含有1至5个选自N、O和S的杂原子的碳环(基),其中氮和硫原子任选被氧化,且氮原子任选被季铵化。杂环(基)可以是单环、双环或多环体系,优选单环。杂环(基)的非限制性例子包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑烷酮、乙内酰脲、二氧戊环、苯邻二甲酰亚胺、哌啶、1,4-二恶烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环(基)可以经环碳或杂原子连接于分子的其余部分。
术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基)并且完全饱和的烃环。环烷基可以是一价或二价的。
术语“烷氧基”以其常规意义使用,指代分别经氧原子、氨基或硫原子连接于分子的其余部分的那些烷基。
除非另有表述,术语“卤代”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴、或碘原子。此外,诸如“卤代烷基”等术语表示包括单卤代烷基或多卤代烷基。例如,术语“C1-4卤代烷基”表示包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
除非另有表述,术语“芳基”表示多不饱和的(通常芳香性)的烃基,其可以是单环或稠合在一起或共价连接的多环(最多三环)。术语"杂芳基"是指含有1至5个选自N、O、和S的杂原子的芳基(或环),其中氮和硫原子任选被氧化,氮原子任选被季铵化。杂芳基可通过杂原子连接于分子的其余部分。芳基的非限制性例子包括苯基、萘基和联苯基,而杂芳基的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基(benzotriazinyl)、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异恶唑基、异苯并呋喃基(isobenzofuryl)、异吲哚基、中氮茚基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、恶唑基、异恶唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等等。以上芳基和杂芳基环系统各自的取代基选自下述可接受的取代基的组。
在一些实施例中,上述术语(如“烷基”,“芳基”和“杂芳基”)将包括指定基团的取代和未取代形式。下面提供了每种类型基团的优选取代基。为简洁起见,术语芳基和杂芳基将指代如下文所提供的取代或未取代的形式,而术语“烷基”和相关的脂肪族基团是指未取代的形式,除非指明被取代。
烷基(包括通常称为亚烷基,烯基,炔基和环烷基的那些基团)的取代基可以是选自下组的各种基团:-卤素、-OR'、-NR'R"、-SR'、-SiR'R"R"‘、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R"‘、-NR"C(O)2R'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NR'S(O)2R"、-CN和-NO2,数量从零到(2M'+1),其中M'是这种基团中的碳原子总数。R'、R"和R"‘各自独立地表示氢,未取代的C1-8烷基,未取代的杂烷基,未取代的芳基,被1-3个卤素取代的芳基,未取代的C1-8烷基,C1-8烷氧基或C1-8硫代烷氧基,或未取代的芳基-C1-4烷基。当R'和R"连接到相同的氮原子时,它们可以与氮原子结合形成3-,4-,5-,6-或7-元环。例如,-NR'R"是指包括1-吡咯烷基和4-吗啉基。术语“酰基”,单独或作为另一基团的一部分使用,是指其中在最接近该基团的连接点的碳上两个取代基的被取代基=O取代(例如-C(O)CH3,-C(O)CH2CH2OR'等)。
类似地,芳基和杂芳基的取代基是多种的,并且通常选自:-卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"C(O)2R'、-NR'-C(O)NR"R"'、-NH-C(NH2)=NH、-NR'C(NH2)=NH、-NH-C(NH2)=NR'、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、-NR'S(O)2R"、-N3、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数量从零到芳香环体系上的开放化合价的总数;其中R'、R"和R"'独立地选自氢,C1-8烷基,C3-6环烷基,C2-8烯基,C2-8炔基,未取代的芳基和杂芳基,(未取代的芳基)-C1-4烷基和未取代的芳氧基-C1-4烷基。其它合适的取代基包括通过1-4个碳原子的亚烷基链连接到环原子上的每一个上述芳基取代基。
如本文所用,术语“杂原子”意在包括氧(O)、氮(N)、硫(S)和硅(Si)。
对于本文提供的化合物,从取代基(通常为R基团)到芳香环(例如苯,吡啶等)的中心的键将被理解为是指在芳香环的任何可用顶点提供连接的键。在一些实施例中,该描述也包括稠合在芳环上的环上的连接。例如,绘制到吲哚苯部分的中心的键将表示与吲哚的六元或五元环部分的任何可用顶点连接的键。
如本文所用,“衍生自……的部分”是指将活性物质(例如,诸如抗体等的多肽元件或靶向配体)通过一定手段(例如使其上活性基团反应,或引入活性基团进行反应)从而使活性物质与其他部分形成连接基团后余下的活性物质的部分或片段,该部分或片段保留了所述活性物质的功能(如靶向期望受体的能力)。具体的“衍生”形成的连接基团包括但不限于:-NH-、-CONH-、-CO-、-S-S-等等。
术语"药学上可接受的盐"意在包括活性化合物与相对无毒的酸或碱制备的盐,其取决于本文所述化合物上具体的取代基。当本发明化合物含有相对酸性的官能团时,可通过将中性形式的此类化合物与充足量的所需碱(无溶剂的或在合适的惰性溶剂中的)接触来获得碱加成盐。衍生自药学上可接受的无机碱的盐的例子包括铝、铵、钙、铜、铁,亚铁、锂、镁、锰,亚锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,包括取代的胺、环状胺、自然产生的胺等等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、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(glucamine)、葡萄糖胺(glucosamine)、组氨酸、海巴明、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等等。当本发明化合物含有相对碱性的官能团时,可通过将中性形式的此类化合物与充足量的所需酸(无溶剂的或在合适的惰性溶剂中的)接触来获得酸加成盐。药学上可接受的酸加成盐的例子包括衍生自无机酸的那些,例如盐酸、氢溴酸、硝酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷酸、硫酸、单氢硫酸、氢碘酸、或亚磷酸等等;以及衍生自相对无毒的有机酸的盐,例如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、扁桃酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸,酒石酸、甲磺酸等等。还包括氨基酸的盐,例如精氨酸盐等等,和有机酸的盐,例如葡萄糖醛酸(glucuronic acid)或半乳糖醛酸(galactunoric acid)等。本发明的某些具体化合物同时含有碱性和酸性官能团,从而能将化合物转换成碱加成盐或酸加成盐。
通过将盐与碱或酸接触并以常规方式分离母体化合物,可以再生该化合物的中性形式。化合物的母体形式与各种盐形式在某些物理性能(例如在极性溶剂中的溶解度)上不同,但除此之外,就本发明的目的而言,那些盐与母体形式化合物是等价的。
除盐形式外,本发明提供前药形式的化合物。本文所述的化合物的前药是在生理条件下很容易经历化学变化以提供本发明化合物的那些化合物。另外,前药可以在离体环境中通过化学或生物化学方法转变为本发明化合物。例如,当置于含合适的酶或化学试剂的经皮贴片贮器中时,前药可缓慢转变为本发明的化合物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水化形式。溶剂化形式通常与非溶剂化形式等价,应包括在本发明范围内。本发明的某些化合物可以多晶型或无定形形式存在。通常,就本发明所考虑的应用而言,所有物理形式是等价的,应包括在本发明范围内。
本发明的某些化合物拥有不对称碳原子(光学中心)或双键;消旋体、非对映体、几何异构体、区域异构体和单独的异构体(例如,分离的对映体)均应包括在本发明范围内。当本文提供的化合物具有确定的立体化学(表示为R或S,或具有虚线或楔形键指明)时,被本领域技术人员将理解那些化合物为基本上不含其他异构体(例如至少80%,90%,95%,98%,99%和至多100%不含其他异构体)。
本发明化合物还可在构成此类化合物的一个或多个同位素原子处含有非天然比例的原子同位素。某同位素的非天然比例可以定义为从所讨论原子的天然发现的量到100%该原子的量。例如,化合物可以掺入放射性同位素,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,例如氘(2H)或碳-13(13C)。除了本申请所述的那些用途,此类同位素变体可提供额外的用途。例如,本发明化合物的同位素变体可以有额外的用途,包括但不限于作为诊断的和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药代动力学和药效学特征,从而有助于增加治疗期间的安全性、耐受性或疗效。无论是否有放射性,本发明化合物的所有同位素变体均应包括在本发明范围内。
分子胶降解剂
目前研究发现,细胞周期蛋白依赖型激酶(cyclin-dependent kinases,CDK)抑制剂CR8也是分子胶降解剂,CR8通过诱导CDK12/cyclin K与CUL4/DDB1直接形成复合物,使cyclin K发生泛素化并通过蛋白酶体系统降解,进而能更有效的杀死癌细胞。
进一步通过对蛋白-小分子-蛋白复合物CUL4-RBX1-DDB1-CR8-CDK12-cyclin的结构进行解析,发现CDK12扮演了类似于CRBN底物受体的角色,CDK12表面与CR8的2-吡啶部分的存在和正确的取向,使CR8的功能获得性增加,导致cyclin K的降解。即CR8-苯基吡啶赋予了它分子胶水的活性,诱导的cyclin K降解,增加了CR8的毒性。
通过对CR8结构进行改性,作者发现CR8分子胶水的活性很大程度上依赖于暴露在激酶表面的2-吡啶部分。他们得出结论,这个化学基团使得CR8像分子胶降解剂一样发挥功能。因此,对抑制剂的暴露在蛋白表面的部分进行化学修饰,可以将它们变成针对特定蛋白标靶的分子胶降解剂。
然而,发明人在研究中发现具有本发明、式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-4)所示结构,尤其是式(I-1)所示结构的化合物在存在或不存在吡啶取代基(或其他含氮杂芳环类取代基)或者是否是吡啶取代基(或其他含氮杂芳环类取代基)的情况下依然具有优异的诱导细胞周期蛋白如细胞周期素K降解的效果,并基于此,发明人提供了一系列新颖的细胞周期蛋白调节剂(更具体地分子胶降解剂)。
在一个实施方案中,提供了一种如式(I)所示的化合物或其药学上可接受的盐,
其中,各基团如第一方面中定义。
在一个优选的实施方案中,提供了如式(I-1)、式(I-2)、式(I-3)或式(I-4)所示的化合物或其药学上可接受的盐;
其中,各基团如前定义。
在本发明的一个方面提供了如下任一所示的分子胶降解剂
其中,n2为2-4(即n2所在环为4至6元环),环Ar1还可任选地被n3个Ra取代基取代(未示出)和环Cr1还任选地被n4个Rb取代基取代(未示出);R1、R2、R3、X1、X2、X3、X4、X5、X6、X8、X9、下标n1、n3、n4、Ar1、Cr1、Ra和Rb如本文中其他部分定义。
在本发明的另一个方面提供了如下任一所示的分子胶降解剂
其中,n2为2-4(即n2所在环为4至6元环);环Ar1还可任选地被n3个Ra取代基取代(未示出)和环Ar2还任选地被n4个Rb取代基取代(未示出);;R1、R2、R3、X1、X2、X3、X4、X5、X6、X8、X9、下标n1、n3、n4、Ar1、Cr1、Ra和Rb如本文中其他部分定义。
活性成分
如本文所用,术语“本发明化合物”指如式(I)所示的化合物。该术语还包括及式I化合物的各种晶型形式、或药学上可接受的盐。
在本文中,活性成分也可以是式(I)所示的化合物与抗体或多肽的形成的偶联物。
药物组合物和施用方法
由于本发明化合物具有优异的对诱导诱导细胞周期素K(Cyclin K)降解的活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物,或者由本发明化合物与抗体或多肽形成的偶联物可用于治疗、预防与细胞周期素K(Cyclin K)有关或细胞周期素K(Cyclin K)参与的的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:癌症等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。
“药学上可以接受的载体”指的是:一种或多种兼容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“兼容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
多肽元件
如本文所用,术语“多肽元件”包括肽段(如3-20aa的短肽)或蛋白。此外,该术语还包括完整的蛋白或其片段。优选的多肽元件包括抗体(如完整抗体、单链抗体、纳米抗体、抗体片段),尤其是针对肿瘤细胞标志物(如位于肿瘤细胞表面的肿瘤标志物,如细胞表面的受体)或针对炎性因子(如与自身免疫疾病相关的炎性因子)的抗体。
如本文所用,术语“抗体”或“免疫球蛋白”是有相同结构特征的约150000道尔顿的异四聚糖蛋白,其由两个相同的轻链(L)和两个相同的重链(H)组成。每条轻链通过一个共价二硫键与重链相连,而不同免疫球蛋白同种型的重链间的二硫键数目不同。每条重链和轻链也有规则间隔的链内二硫键。每条重链的一端有可变区(VH),其后是多个恒定区。每条轻链的一端有可变区(VL),另一端有恒定区;轻链的恒定区与重链的第一个恒定区相对,轻链的可变区与重链的可变区相对。特殊的氨基酸残基在轻链和重链的可变区之间形成界面。
如本文所用,术语“单域抗体”、“纳米抗体”具有相同的含义,指克隆抗体重链的可变区,构建仅由一个重链可变区组成的单域抗体,它是具有完整功能的最小的抗原结合片段。通常先获得天然缺失轻链和重链恒定区1(CH1)的抗体后,再克隆抗体重链的可变区,构建仅由一个重链可变区组成的单域抗体。
如本文所用,术语“可变”表示抗体中可变区的某些部分在序列上有所不同,它形成了各种特定抗体对其特定抗原的结合和特异性。然而,可变性并不均匀地分布在整个抗体可变区中。它集中于轻链和重链可变区中称为互补决定区(CDR)或超变区中的三个片段中。可变区中较保守的部分称为构架区(FR)。天然重链和轻链的可变区中各自包含四个FR区,它们大致上呈β-折叠构型,由形成连接环的三个CDR相连,在某些情况下可形成部分折叠结构。每条链中的CDR通过FR区紧密地靠在一起并与另一链的CDR一起形成了抗体的抗原结合部位。恒定区不直接参与抗体与抗原的结合,但是它们表现出不同的效应功能,例如参与抗体的依赖于抗体的细胞毒性。
脊椎动物抗体(免疫球蛋白)的“轻链”可根据其恒定区的氨基酸序列归为明显不同的两类(称为κ和λ)中的一类。根据其重链恒定区的氨基酸序列,免疫球蛋白可以分为不同的种类。主要有5类免疫球蛋白:IgA,IgD,IgE,IgG和IgM,其中一些还可进一步分成亚类(同种型),如IgG1,IgG2,IgG3,IgG4,IgA和IgA2。对应于不同类免疫球蛋白的重链恒定区分别称为α、δ、ε、γ、和μ。不同类免疫球蛋白的亚单位结构和三维构型是本领域人员所熟知的。
一般,抗体的抗原结合特性可由位于重链和轻链可变区的3个特定的区域来描述,称为可变区域(CDR),将该段间隔成4个框架区域(FR),4个FR的氨基酸序列相对比较保守,不直接参与结合反应。这些CDR形成环状结构,通过其间的FR形成的β折叠在空间结构上相互靠近,重链上的CDR和相应轻链上的CDR构成了抗体的抗原结合位点。可以通过比较同类型的抗体的氨基酸序列来确定是哪些氨基酸构成了FR或CDR区域。
本发明中,多肽元件不仅可包括完整的抗体,还包括具有免疫活性的抗体的片段(如如Fab或(Fab’)2片段;抗体重链;或抗体轻链)或抗体与其他序列形成的融合蛋白。因此,本发明还包括所述抗体的片段、衍生物和类似物。
靶向配体
靶向配体(或靶蛋白部分或靶蛋白配体或配体)是能够结合目标靶蛋白的小分子。
在本申请的一些实施方案中,靶向配体可以是(或源自)靶标分子。
本申请的一些实施方案涉及靶标分子,代表性的靶标分子其包括但不限于:叶酸、Hsp90抑制剂、激酶抑制剂、MDM2抑制剂、靶向含人BET溴结构域的蛋白的化合物、靶向胞质信号蛋白FKBP12的化合物、HDAC抑制剂、人赖氨酸甲基转移酶抑制剂、血管生成抑制剂、免疫抑制化合物、靶向芳基烃受体(AHR)和靶向肿瘤厌氧微环境的化合物。
在某些实施方案中,靶向配体是能够结合激酶、BET含溴结构域的蛋白、胞质信号蛋白(例如FKBP12)、核蛋白、组蛋白脱乙酰酶、赖氨酸甲基转移酶、调节血管生成的蛋白、调节免疫应答的蛋白、芳烃受体(AHR)、雌激素受体、雄激素受体、糖皮质激素受体或转录因子(例如,SMARCA4、SMARCA2、TRIM24)。
在某些实施方案中,靶向配体能够结合的激酶包括但不限于:酪氨酸激酶(例如,AATK、ABL、ABL2、ALK、AXL、BLK、BMX、BTK、CSF1R、CSK、DDR1、DDR2、EGFR、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB6、ERBB2、ERBB3、ERBB4、FER、FES、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1、FLT3、FLT4、FRK、FYN、GSG2、HCK、HRAS、HSP90、IGF1R、ILK、INSR、INSRR、IRAK4、ITK、JAK1、JAK2、JAK3、KDR、KIT、KRAS、KSP、KSR1、LCK、LMTK2、LMTK3、LTK、LYN、MATK、MERTK、MET、MLTK、MST1R、MUSK、NPR1、NRAS、NTRK1、NTRK2、NTRK3、PDGFRA、PDGFRB、PLK4、PTK2、PTK2B、PTK6、PTK7、RET、ROR1、ROR2、ROS1、RYK、SGK493、SRC、SRMS、STYK1、SYK、TEC、TEK、TEX14、TIE1、TNK1、TNK2、TNNI3K、TXK、TYK2、TYRO3、YES1或ZAP70)、丝氨酸/苏氨酸激酶(例如酪蛋白激酶2、蛋白激酶A、蛋白激酶B、蛋白激酶C、Raf激酶、CaM激酶、AKT1、AKT2、AKT3、ALK1、ALK2、ALK3、ALK4、AuroraA、AuroraB、AuroraC、CHK1、CHK2、CLK1、CLK2、CLK3、DAPK1、DAPK2、DAPK3、DMPK、ERK1、ERK2、ERK5、GCK、GSK3、HIPK、KHS1、LKB1、LOK、MAPKAPK2、MAPKAPK、MEK、MNK1、MSSK1、MST1、MST2、MST4、NDR、NEK2、NEK3、NEK6、NEK7、NEK9、NEK11、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PIM1、PIM2、PLK1、RIP2、RIP5、RSK1、RSK2、SGK2、SGK3、SIK1、STK33、TAO1、TAO2、TGF-β、TLK2、TSSK1、TSSK2、ΜLK1或ΜLK2)、周期素依赖性蛋白激酶(例如Cdk1-Cdk11)和富含亮氨酸的重复激酶(例如LRRK2)。
本发明的主要优点包括
(a)本发明的化合物具有优异的诱导胞周期素K(Cyclin K)降解的效果。
(b)深入研究发现,本发明的化合物还具有诱导其他细胞周期蛋白降解的功能,从而进一步增加了其细胞毒性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
A.制备实施例
通用合成方法
本发明的化合物可通过对本领域技术人员显而易见的任何方法制备、分离或获得。本发明的化合物也可以根据下面提供的示例性制备方案(如实施例中的方法)制备。示例性制备方案中未提供的反应条件、步骤和反应物对于本领域技术人员来说是显而易见的和是已知的。如本文所用,在这些过程中、方案和实施例中使用的符号和惯例,无论特定缩写是否被具体定义,都具有本领域技术人员所熟知的含义。具体地,但不限于,以下缩写可在实施例中和整个说明书中使用:g(克);mg(毫克);mL(毫升);μL(微升);毫米(毫摩尔);μM(微摩尔);MHz(赫兹);MHz(兆赫兹);mmol(毫摩尔);hr或hrs(小时);min(分钟);MS(质谱);ESI(电喷雾离子化);TLC(薄层色谱);HPLC(高效液相色谱);THF(四氢呋喃);CDCl3(氘代氯仿);AcOH(乙酸);DCM(二氯甲烷);DMSO(二甲基亚砜);EtOAc(乙酸乙酯);MeOH(甲醇);;和BOC(叔丁氧羰基)等。
除非另有说明,实施例中使用的原料可通过该市售获得或者以本领域技术人员已知的方式或实施例中记载的类似方法合成。
实施例1:化合物UB-001的合成
步骤1:UB-001c
将UB-001a(2000mg,13.6mol),UB-001b(2.32g,13.6mmol),pdCl2dppf(300mg),Na2CO3(2.8g)加入二氧六环(32mL)和水(8mL)中。反应体系在80℃搅拌16小时,反应完成后冷却至室温。将混合物加入水中,用乙酸乙酯萃取,盐水(30mL),硫酸钠干燥,过滤,浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=5%),得到黄色固体UB-001c(1.8g,收率55.5%)。LCMS[M+H]+=239.2
步骤2:UB-001d
LAH(4.2ml,1M in THF)滴加到UB-001c(500mg,2.1mmol)的无水THF(10mL)中。反应体系在20℃搅拌16小时,反应完成后用Na2SO4*10H2O淬灭。将混合物加入水中,用乙酸乙酯萃取,盐水(30mL),硫酸钠干燥,过滤,浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=2-20%),得到黄色固体UB-001d(200mg,收率44.5%)。LCMS[M+H]+=215.3
步骤3:UB-001f
把混合物UB-001d(100mg,0.47mmol),UB-001e(0.1g,0.47mmol)溶于正丁醇(2mL)120℃反应3小时。反应液浓缩,粗品用柱层析分离(PE/EA=30-70%)得到白色固体UB-001f(120mg,收率65.1%)。LCMS[M+H]+=394.2
步骤4:UB-001
把混合物UB-001f(30mg,0.08mmol),吗啡啉(33.12mg,0.38mmol),HCl(cat.)溶于正丁醇(2mL)180℃反应5小时。反应液浓缩,粗品用柱层析分离(DCM/MeOH=0-10%)得到白色固体UB-001(10mg,29.1%收率)。1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),8.03–7.95(m,2H),7.89–7.73(m,3H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.6Hz,1H),5.43(t,J=5.9Hz,1H),4.65(s,1H),4.61(d,J=5.8Hz,2H),4.02(q,J=7.2Hz,2H),3.61(s,8H),1.35(t,J=7.2Hz,3H).LCMS[M+H]+=446.6
实施例2:化合物UB-002的合成
步骤1:UB-002
把混合物UB-001f(30mg,0.08mmol),1-Boc-哌嗪(14mg,0.08mmol),HCl(cat.)溶于正丁醇(2mL),180℃反应3小时。反应液浓缩,粗品用柱层析分离(DCM/MeOH=0-10%)得到黄色固体(5mg,14.8%收率)。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99(d,J=8.0Hz,2H),7.88–7.81(m,2H),7.76(d,J=7.8Hz,1H),7.46(d,J=8.0Hz,2H),7.41(d,J=7.6Hz,1H),5.45(s,1H),4.67–4.58(m,3H),4.03(q,J=7.2Hz,2H),3.80(t,J=5.2Hz,4H),2.96(t,J=5.1Hz,4H),1.36(t,J=7.2Hz,3H),1.24(d,J=3.5Hz,1H).LCMS[M+H]+=445.6
实施例3:化合物UB-003的合成
步骤1:UB-003
把混合物UB-001f(30mg,0.08mmol),1-甲基-哌嗪(76mg,0.8mmol),HCl(cat.)溶于正丁醇(2mL),180℃反应3小时。反应液浓缩,粗品用制备板分离(DCM/MeOH=10%)得到黄色固体UB-003(5.9mg,16.9%收率)。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),8.01–7.96(m,2H),7.87–7.79(m,2H),7.75(d,J=7.8Hz,1H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.5Hz,1H),5.45(t,J=5.9Hz,1H),4.62(t,J=8.0Hz,3H),4.02(q,J=7.2Hz,2H),3.70(s,4H),2.49–2.39(m,4H),2.24(s,3H),1.35(t,J=7.2Hz,3H).LCMS[M+H]+=459.3.
实施例4:化合物UB-004的合成
步骤1:UB-004c
把混合物UB-004a(100mg,0.47mmol),UB-004b(101mg,0.47mmol)DIPEA(95mg)溶于正丁醇(2mL)120℃反应3小时。反应液浓缩,粗品用柱层析分离(PE/EA=30-70%)得到白色固体UB-004c(120mg,收率60.4%)。LCMS[M+H]+=364.2
步骤2:UB-004
把混合物UB-004e(30mg,0.08mmol),哌嗪-1-羧酸叔丁酯(70.8mg,0.38mmol),HCl(cat.)溶于正丁醇(2mL)180℃反应5小时。反应液浓缩,粗品用柱层析分离(DCM/MeOH=0-10%)得到黄色固体UB-004(10mg,收率27.0%)。1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.65–7.54(m,4H),7.48–7.40(m,4H),7.37–7.30(m,1H),4.63(s,2H),4.01(q,J=7.2Hz,2H),3.68–3.54(m,4H),2.75–2.63(m,4H),1.35(t,J=7.2Hz,3H).LCMS[M+H]+=414.4
实施例5:化合物UB-005的合成
步骤1:UB-005a
LAH(4.2ml,1M in THF)滴加到UB-005a(500mg,2.1mmol)的无水THF(10mL)中。反应体系在20℃搅拌16小时,反应完成后用Na2SO4*10H2O淬灭。将混合物加入水中,用乙酸乙酯萃取,盐水(30mL),硫酸钠干燥,过滤,浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=2-20%),得到黄色固体UB-005b(200mg,收率44.5%)。LCMS[M+H]+=214.2
步骤2:UB-005d
把混合物UB-005b(100mg,0.47mmol),UB-005c(101mg,0.47mmol),DIPEA(95mg)溶于正丁醇(2mL)120℃反应3小时。反应液浓缩,粗品用柱层析分离(PE/EA=30-70%)得到白色固体UB-005d(120mg,65.1%收率)。LCMS[M+H]+=394.3
步骤3:UB-005
把混合物UB-005e(30mg,0.08mmol),哌嗪-1-羧酸叔丁酯(70.8mg,0.38mmol),HCl(cat.)溶于正丁醇(2mL)180℃反应5小时。反应液浓缩,粗品用柱层析分离(DCM/MeOH=0-10%)得到黄色固体UB-005(10mg,29.5%收率)。1H NMR(400MHz,DMSO-d6)δ7.99(d,J=8.3Hz,3H),7.87–7.73(m,3H),7.45(d,J=8.1Hz,2H),7.40(d,J=7.6Hz,1H),5.41(s,1H),4.61(d,J=4.2Hz,4H),4.01(q,J=7.2Hz,2H),3.63(t,J=5.1Hz,4H),2.74(d,J=10.2Hz,4H),1.35(t,J=7.2Hz,3H).LCMS[M+H]+=444.6
实施例6:化合物UB-006的合成
步骤1:UB-006
把混合物UB-006a(50mg,0.14mmol),UB-006b(59.7mg,0.69mmol)溶于正丁醇(2mL)180℃反应16小时。反应液浓缩,粗品用柱层析分离(DCM/MeOH=0-10%)得到黄色固体UB-006(16mg,26.3%收率)。1H NMR(400MHz,DMSO-d6)δ8.67–8.60(m,1H),8.04–7.97(m,2H),7.93–7.82(m,2H),7.72(s,1H),7.45(d,J=8.0Hz,2H),7.35–7.28(m,1H),6.08(d,J=7.6Hz,1H),4.65(s,2H),4.48(d,J=4.5Hz,1H),3.97(q,J=7.2Hz,2H),3.61(s,1H),1.79(d,J=11.3Hz,4H),1.33(t,J=7.2Hz,3H),1.28–1.14(m,5H).LCMS[M+H]+=444.9
实施例7:化合物UB-007的合成方法
步骤1:UB-007b
将化合物UB-007a(35.8g,0.2mol)加入到三口反应瓶中,用四氢呋喃(360mL)溶解,在氩气保护下,分五批次加入四氢铝锂(17.6g,0.44mol)。反应液在16℃下反应2小时,反应液用饱和硫酸钠溶液(20g)淬灭,固体抽滤,滤饼用四氢呋喃(100mL)洗涤。滤液旋干得到产物(UB-007b,37g,100%收率)性状黄色固体.LCMS[M+1]+=184.3
步骤2:UB-007d
将化合物UB-007b(18.4g,0.1mol),UB-007c(18.9g,0.1mol),三乙胺(40.4g,0.4mol)溶解于叔丁醇(200mL)中在110℃下反应14小时。反应液降温到20℃,有大量固体析出来,抽滤,滤饼用乙醇/水(100mL/10mL)洗涤,真空干燥得到目标化合物(UB-007d,20.7g,80%收率)性状黄色固体。LCMS[M+1]+=336.8
步骤3:UB-007f
将化合物UB-007d(27g,0.08mol),K2CO3(55.2g,0.4mol)溶解于二甲亚砜(270mL)中,室温搅拌5分钟。化合物UB-007e(59.3g,0.48mol)滴加到反应液中。滴毕,反应液在30℃下反应14小时。反应液加水(1000ml)淬灭反应,用乙酸乙酯(200mL*3)萃取。有几层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=5/1)得到化合物(UB-007f,27g,90%收率)性状淡黄色固体。LCMS[M+1]+=378.9。1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.62(dd,J=8.0,2.0Hz,4H),7.48(t,J=8.1Hz,4H),7.39(t,J=7.3Hz,1H),6.58(s,1H),5.04–4.80(m,3H),1.60(d,J=6.8Hz,6H).
步骤4:UB-007
将化合物UB-007f(110mg,0.29mmol),化合物UB-007g(446mg,1.45mmol)溶解于(2mL)二甲亚砜中,在145℃下反应14小时。反应液降温到20℃,用乙酸乙酯(20mL)萃取三次。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=1/2)得到化合物(UB-007,39mg,31.2%收率),淡黄色固体。LCMS[M+1]+=431.6.1H NMR(400MHz,CDCl3)δ7.66–7.58(m,4H),7.57(s,1H),7.53–7.44(m,4H),7.38(t,J=7.3Hz,1H),6.77(s,1H),5.00(d,J=6.0Hz,1H),4.83(s,2H),4.61(dt,J=13.5,6.8Hz,1H),4.01–3.91(m,1H),3.85(dd,J=10.7,2.3Hz,1H),3.67(dd,J=10.5,7.6Hz,1H),1.73–1.57(m,2H),1.53(d,J=6.7Hz,6H),1.05(t,J=7.4Hz,3H).
实施例8:化合物UB-008的合成方法
步骤1:UB-008(LS22002-016)
将化合物UB-007f(185.15mg,0.49mmol),哌啶(200mg,2.35mmol)溶解于(2mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加入水(50ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=1/2)得到化合物(UB-007,31mg,14.8%收率)性状淡黄色固体。LCMS[M+1]+=427.5
实施例9:化合物UB-009的合成
步骤1:UB-009
将化合物UB-007f(200mg,0.53mmol),吗啡啉(416mg,5.3mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(50ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=1/2)得到化合物(UB-009,38.5mg,17%收率)性状淡黄色固体。LCMS[M+1]+=429.6.1HNMR(400MHz,CDCl3)δ7.68(s,1H),7.59(dd,J=15.8,7.8Hz,4H),7.51–7.43(m,4H),7.38(t,J=7.3Hz,1H),6.64(s,1H),4.85(s,2H),4.75–4.60(m,1H),3.80(d,J=3.4Hz,8H),1.56(d,J=6.7Hz,6H).
实施例10:化合物UB-010的合成
步骤1:UB-010
将化合物UB-007f(200mg,0.53mmol),哌嗪(461mg,5.3mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-010,85mg,37.5%收率)性状淡黄色固体。LCMS[M+1]+=428.6。1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.57(dd,J=12.3,7.9Hz,4H),7.45(dd,J=12.5,7.7Hz,4H),7.36(s,1H),4.79(s,2H),4.66(dt,J=12.9,6.3Hz,2H),4.11(s,4H),3.22(s,4H),1.55(d,J=6.7Hz,6H).
实施例11:化合物UB-011的合成
步骤1:UB-011
将化合物UB-007f(110mg,0.29mmol),N-甲基哌嗪(290mg,2.9mmol)溶解于(2mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-011,53.9mg,42%收率)性状淡黄色固体。LCMS[M+1]+=442.7。1HNMR(400MHz,CDCl3)δ7.59(dd,J=12.8,7.9Hz,5H),7.50–7.44(m,4H),7.37(t,J=7.3Hz,1H),6.43(s,1H),4.85(s,2H),4.73–4.63(m,1H),4.00(s,4H),2.67(s,4H),2.49(s,3H),1.56(d,J=6.8Hz,6H).
实施例12:化合物UB-012的合成
步骤1:UB-012b
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-012a(500mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,得到化合物(UB-012b,200mg,90.1%收率)性状淡黄色固体。LCMS[M+1]+=542.6
步骤2:UB-012
将化合物UB-012b(200mg,0.45mmol)溶解于(3mL)甲醇中,搅拌下加入1N盐酸甲醇气(3mL),在25℃下反应18小时。将反应液旋干,碳酸钠饱和溶液调节pH至9,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-012,131mg,66%收率)性状淡黄色固体。LCMS[M+1]+=442.7.1HNMR(500MHz,DMSO-d6)δ8.17(s,2H),7.81(s,1H),7.61(dd,J=15.5,7.7Hz,4H),7.44(t,J=7.8Hz,4H),7.34(t,J=7.3Hz,1H),6.17(s,1H),4.63(s,2H),4.57–4.44(m,1H),3.61(d,J=7.2Hz,1H),2.91(t,J=11.1Hz,1H),1.95(t,J=15.9Hz,4H),1.45(t,J=12.4Hz,7H),1.32–1.07(m,2H).
实施例13:化合物UB-013的合成
步骤1:UB-013b(LS22002-011-1)
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-012a(500mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,得到化合物(UB-013b,200mg,90.1%收率)性状淡黄色固体。LCMS[M+1]+=542.6
步骤2:UB-013(LS22002-011-2)
将化合物UB-013b(200mg,0.45mmol)溶解于(3mL)甲醇中,搅拌下加入1N盐酸甲醇气(3mL),在25℃下反应18小时。将反应液旋干,碳酸钠饱和溶液调节pH至9,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-013,77mg,38%收率)性状淡黄色固体。LCMS[M+1]+=442.71H NMR(500MHz,DMSO-d6)δ8.09(s,1H),7.89(s,1H),7.61(dd,J=18.2,7.8Hz,4H),7.50(d,J=7.7Hz,2H),7.44(t,J=7.7Hz,2H),7.34(t,J=7.3Hz,1H),4.75–4.56(m,3H),4.30(d,J=12.9Hz,1H),3.54–3.21(m,2H),3.09(dd,J=13.9,6.2Hz,2H),3.00(t,J=10.9Hz,1H),2.51(s,1H),2.01(d,J=10.0Hz,1H),1.73(dd,J=9.2,4.0Hz,1H),1.63–1.52(m,1H),1.47(t,J=10.0Hz,7H).
实施例14:化合物UB-014的合成
步骤1:UB-014b
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-014a(500mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,得到化合物(UB-014b,200mg,90.1%收率)性状淡黄色固体,粗品直接用于下一步。LCMS[M+1]+=542.6
步骤2:UB-014
将化合物UB-014b(200mg,0.45mmol)溶解于(3mL)甲醇中,搅拌下加入1N盐酸甲醇气(3mL),在25℃下反应18小时。将反应液旋干,碳酸钠饱和溶液调节pH至9,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-014,35mg,17.6%收率)性状淡黄色固体。LCMS[M+1]+=442.5.1HNMR(400MHz,DMSO-d6)δ8.05(s,1H),7.90(s,1H),7.63(dd,J=14.2,8.0Hz,4H),7.48(dd,J=16.7,8.5Hz,4H),7.37(t,J=7.3Hz,1H),4.80–4.47(m,4H),4.31(d,J=12.9Hz,1H),3.03(d,J=7.5Hz,4H),2.02–1.92(m,1H),1.79–1.69(m,1H),1.51(d,J=6.8Hz,9H).
实施例15:化合物UB-015的合成
步骤1:UB-015b
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-015a(500mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,得到化合物(UB-015b,200mg,90.1%收率)性状淡黄色固体,粗品直接用于下一步。LCMS[M+1]+=542.5
步骤2:UB-015
将化合物UB-015b(200mg,0.45mmol)溶解于(3mL)甲醇中,搅拌下加入1N盐酸甲醇气(3mL),在25℃下反应18小时。将反应液旋干,碳酸钾饱和溶液调节pH至9,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-015,45mg,22.6%收率)性状淡黄色固体。LCMS[M+1]+=442.5
实施例16:化合物UB-016的合成
步骤1:UB-016c
N6-([1,1'-联苯]-4-基甲基)-9-异丙基-N2-(哌啶-4-基)-9H-嘌呤-2,6-二胺
向反应瓶中加入UB-016a(200mg,0.53mmol),UB-016b(318.4mg,1.59mmol),Pd2(dba)3(49mg,0.054mmol),Xphos(126mg,0.265mmol)and Cs2CO3(518mg,1.59mmol),和1,4-dioxane(10mL).将反应混合物置换氩气三次,然后升温至100℃搅拌过夜。将反应混合物用水(30mL)稀释,然后用乙酸乙酯(30mL*3)萃取,分离有机相,用盐水(50mL)洗涤并用无水硫酸钠干燥,然后浓缩并通过色谱法(二氯甲烷:二氯甲烷/甲醇10/1=40:60)纯化得到产物得到黄色固体化合物(UB-016c,369.6mg,粗品)LCMS[M+1]+=542.3.
步骤2:UB-016
N6-([1,1'-联苯]-4-基甲基)-9-异丙基-N2-(哌啶-4-基)-9H-嘌呤-2,6-二胺
在室温下向100mL底部烧瓶中加入UB-016c(369.6mg,0.68mmol)、盐酸的1,4-二氧六环溶液(4mL)和二氯甲烷(8.0mL)。然后将溶液在室温搅拌2小时。过滤反应混合物,滤饼用二氯甲烷(5mL)洗涤,用碳酸氢钠饱和水溶液中和,并用二氯甲烷(3*50mL)萃取。将合并的有机相用盐水洗涤,用无水硫酸钠干燥并减压浓缩,然后加入甲醇和水,并冷冻干燥,得到黄色固体产物(UB-016,85.6mg,产率:28.4%)LCMS[M+1]+=442.2.1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.59(dd,J=17.4,7.8Hz,4H),7.47–7.40(m,4H),7.33(t,J=7.3Hz,1H),6.17(d,J=7.2Hz,1H),4.64(s,2H),4.52(dt,J=13.2,6.5Hz,1H),3.72(s,1H),2.95(d,J=11.3Hz,2H),2.56(d,J=11.2Hz,1H),1.86(s,2H),1.78(s,2H),1.46(d,J=6.7Hz,6H),1.32(dd,J=16.4,8.8Hz,2H),1.24(d,J=6.1Hz,1H).
实施例17:化合物UB-017的合成
步骤1:UB-017
将化合物UB-007f(188.5mg,0.5mmol),4-氨基哌啶(250mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应18小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=1/2)得到化合物(UB-017,147mg,66%收率)性状淡黄色固体。LCMS[M+1]+=442.7。1HNMR(500MHz,DMSO-d6)δ8.09(s,1H),7.87(s,1H),7.78(s,2H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.48–7.42(m,4H),7.34(t,J=7.4Hz,1H),4.68–4.54(m,4H),3.26–3.16(m,1H),2.86(t,J=11.7Hz,2H),2.54(s,1H),1.88(d,J=10.5Hz,2H),1.47(d,J=6.8Hz,6H),1.37(dd,J=19.5,10.2Hz,2H).
实施例18:化合物UB-018的合成
步骤1:UB-018
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-018a(285.5mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应14小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(石油醚/乙酸乙酯=1/2)得到化合物(UB-018,85mg,37%收率)性状淡黄色固体。LCMS[M+1]+=456.31H NMR(500MHz,DMSO-d6)δ8.08(s,1H),7.89(s,2H),7.62(d,J=7.3Hz,2H),7.59(d,J=8.2Hz,2H),7.48(d,J=7.9Hz,2H),7.44(t,J=7.7Hz,2H),7.34(t,J=7.3Hz,1H),4.79–4.49(m,4H),4.27(d,J=13.1Hz,1H),3.15–2.97(m,3H),2.54(s,1H),2.05–1.94(m,1H),1.73(dd,J=8.9,4.4Hz,1H),1.54(d,J=8.7Hz,1H),1.48(d,J=6.8Hz,8H).
实施例19:化合物UB-019的合成
步骤1:UB-019b
将化合物UB-007f(188.5mg,0.5mmol),化合物UB-019a(535.5mg,2.5mmol)溶解于(3mL)二甲亚砜中,在145℃下反应14小时。反应液降温到20℃,加水(20ml)淬灭反应,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,得到化合物(UB-019b,200mg,85.1%收率)性状淡黄色固体,粗品直接用于下一步。LCMS[M+1]+=556.6
步骤2:UB-019
将化合物UB-019b(200mg,0.45mmol)溶解于(3mL)甲醇中,搅拌下加入1N盐酸甲醇气(3mL),在25℃下反应14小时。将反应液旋干,碳酸钠饱和溶液调节pH至9,用乙酸乙酯(20mL*3)萃取。有机层用盐水洗,无水硫酸钠干燥,旋干,柱层析分离纯化(二氯甲烷/甲醇=13/1)得到化合物(UB-019,26mg,11.4%收率)性状淡黄色固体。LCMS[M+1]+=556.6
实施例20:化合物UB-020的合成
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步骤1:UB-020c
叔丁基(R)-4-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-3-甲基哌嗪-1-羧酸酯
在Ar下向UB-007f(200mg,0.530mmol)和UB-020b(424mg,0.120mmol)的无水二氧六环溶液中(10mL)加入Pd2(dba)3(48mg,0.054mmol)、Cs2CO3(518mg,1.59mmol))和XPhos(126mg,0.265mmol)。将混合物在100℃下搅拌3小时。将反应液浓缩并通过快速色谱法纯化,用PE/EA=0-50%洗脱,得到白色固体化合物(UB-020c,110mg,产率38.3%)。LCMS[M+1]+=542.4
步骤2:UB-020
(R)-N-([1,1'-联苯]-4-基甲基)-9-异丙基-2-(2-甲基哌嗪-1-基)-9H-嘌呤-6-胺
向反应瓶中加入UB-020c(110mg,0.203mmol)和8mL DCM溶液,加入HCl的二氧六环溶液(3mL)。将混合物在室温下搅拌1小时。将反应混合物用NaHCO3(5mL)淬灭并用DCM(10mL*3)萃取,分离有机相,用盐水(10mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱法纯化,用DCM:10%MeOH/DCM=0-100%洗脱,得到白色固体化合物(UB-020,42.5mg,产率47.5%)LCMS[M+1]+=442.31H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.84(s,1H),7.64–7.59(m,2H),7.58(d,J=8.2Hz,2H),7.47–7.40(m,4H),7.33(t,J=7.3Hz,1H),4.70(dd,J=15.0,11.6Hz,2H),4.56(dt,J=13.4,6.7Hz,2H),4.38–4.29(m,1H),3.00–2.83(m,2H),2.79(s,2H),1.47(dd,J=6.7,1.0Hz,6H),1.08(d,J=6.5Hz,3H).
实施例21:化合物UB-021的合成
步骤1:UB-021c
(S)-4-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-3-甲基哌嗪-1-羧酸叔丁酯
将化合物UB-021b(637mg,3.18mmol),化合物UB-007f(200mg,0.53mmol),碳酸铯(519mg,1.59mmol),Pd2(dba)3(73mg,0.08mmol)和Xphos(142mg,0.30mmol)溶解于(6mL)超干-二氧六环中,在100℃下反应过夜。反应完成后,反应液降温到室温,将反应液浓缩并且通过硅胶柱纯化(EA/PE=40%),得到化合物(UB-021c,280mg,97%产率)性状黄色固体。LCMS[M+1]+=542.3.
步骤2:UB-021
(S)-N-([1,1'-联苯]-4-基甲基)-9-异丙基-2-(2-甲基哌嗪-1-基)-9H-嘌呤-6-胺
将化合物UB-021c(280mg,0.52mmol)溶于二氯甲烷(6mL),加入盐酸-1,4-二氧六环(6mmol,1.5mL)。反应在40℃下搅拌4小时。反应完成后,向反应液中加入碳酸氢钠饱和溶液调节PH至8~9,并且用DCM萃取(40mL*3)。合并有机相并用饱和食盐水洗,用无水硫酸钠干燥。将萃取液浓缩并通过硅胶柱纯化(DCM/MeOH=30%)并且冻干,得到想要的化合物UB-021(40mg,24%产率)性状白色固体。LCMS[M+1]+=442.3.1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.88(s,1H),7.60(dd,J=13.8,8.0Hz,4H),7.47–7.42(m,4H),7.34(t,J=7.3Hz,1H),4.87(s,1H),4.56(ddd,J=33.3,26.3,16.3Hz,4H),3.15(d,J=12.0Hz,1H),3.09–2.90(m,3H),2.74(t,J=22.8Hz,1H),1.47(d,J=6.7Hz,6H),1.24(d,J=6.0Hz,1H),1.12(d,J=6.5Hz,3H).
实施例22:化合物UB-022的合成
步骤1:UB-022h
向三口烧瓶中依次加入化合物UB-007f(270mg,0.72mmol),UB-022g(416mg,2.34mmol),Cs2CO3(624mg,2.15mmol),Pd2(dba)3(90mg,0.10mmol)和XPhos(234mg,0.49mmol)。将混合物用氩气置换三次,然后加入无水1,4-二氧六环(16mL),将混何物于100℃下搅拌19小时。将混何物冷却至室温,减压浓缩后通过硅胶色谱柱纯化(DCM:10%MeOHin DCM=0-78%),得到产物UB-022h(65mg,产率:16%)。LCMS[M+1]+=558.3
步骤2:UB-022
向化合物UB-022h(65mg,0.12mmol)在CH2Cl2(3mL)中的混合物加入HCl/二氧六环(4N,1.5mL)。将反应混合物在25℃下搅拌17小时。将反应混合物浓缩,用饱和Na2CO3水溶液调节至pH=8-9。用CH2Cl2(20mL*3)萃取后,将合并的有机层用盐水洗涤,用无水Na2SO4干燥,然后将混合物减压浓缩,通过反相柱纯化得到产物UB-022(15.7mg,产率:29%),为白色固体。LCMS[M+1]+=458.3.1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.48–7.40(m,4H),7.33(t,J=7.3Hz,1H),4.67–4.51(m,4H),4.43(d,J=12.9Hz,1H),3.79(t,J=9.3Hz,1H),3.42(dd,J=9.8,4.7Hz,2H),3.23(d,J=12.3Hz,2H),3.00–2.87(m,2H),2.68(dd,J=12.3,4.0Hz,1H),2.64–2.54(m,1H),1.46(d,J=6.2Hz,6H).
实施例23:化合物UB-023的合成
步骤1:UB-023c
叔丁基(R)-4-(6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-3-(羟甲基)哌嗪-1-羧酸盐
在Ar下向反应瓶中加入UB-007f(300mg,0.8mmol)、UB-023b(520mg,2.4mmol)和无水二氧六环溶液(18mL),加入Pd2(dba)3(80mg,0.08mmol)、Cs2CO3(800mg,2.4mmol))和XPhos(200mg,0.4mmol)。将混合物在100℃下搅拌3小时。将反应浓缩并通过快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=0-40%洗脱,得到黄色油状化合物(UB-023c,200mg,产率44.8%)。LCMS[M+1]+=558.3
步骤2:UB-023
(R)-(1-(6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-2-基)甲醇
在反应瓶中加入UB-023c(200mg,0.359mmol)、8mL DCM溶液和HCl的二氧六环溶液(2mL)。将混合物在室温下搅拌1小时。将反应混合物用NaHCO3(4mL)淬灭并用DCM(20mL*3)萃取,分离有机相,用盐水(20mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱纯化,用DCM/(DCM:MeOH=10:1)=0-100%洗脱,得到浅黄色固体状化合物(UB-023,25.5mg,产率15.5%)LCMS[M+1]+=458.3。1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.87(s,1H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.48–7.41(m,4H),7.34(t,J=7.3Hz,1H),4.70(s,1H),4.67–4.58(m,2H),4.54(dd,J=13.3,5.7Hz,2H),3.78(t,J=9.2Hz,1H),3.49(dd,J=10.1,4.8Hz,1H),3.37(s,1H),3.07(dd,J=24.9,12.1Hz,2H),2.84(dd,J=12.3,3.7Hz,1H),2.71(dd,J=23.4,11.4Hz,1H),1.50–1.44(m,6H).
实施例24:化合物UB-024的合成
步骤1:UB-024i
在室温下向K2CO3(8.39g,60.17mmol)在MeCN(100mL)中的搅拌悬浮液中加入化合物UB-024g(4.00g,20.24mmol)。将所得混合物搅拌15分钟,然后加入苄基溴(2.6mL,21.89mmol)。将反应混合物在回流温度下搅拌14小时。将反应混合物浓缩并通过硅胶色谱法纯化(40g,45mL/min;DCM:10%MeOH的DCM溶液=0-6-30%),得到产物UB-024(3.95g,产率:77%),为白色固体。LCMS[M+1]+=252.1
步骤2:UB-024k
向搅拌的化合物UB-024i(3.95g,15.73mmol)在DCM(80mL)中的冷却溶液中加入Et3N(3.3mL,23.74mmol),然后缓慢加入溴乙酰溴(3.81g,18.88mmol)。将反应混合物升至室温搅拌过夜。将混合物减压浓缩并通过硅胶色谱法纯化(PE:EA=0-15-30%),得到产物UB-024k(4.62g,产率:79%),为无色液体。LCMS[M+1]+=372.1&374.1
步骤3:UB-024l
将化合物UB-024k(4.62g,12.43mmol)溶解在CH3OH(20mL)中,然后加入NH3在CH3OH中的溶液(7N,1.5mL)并将混合物在室温下搅拌17h。然后减压除去溶剂并用硅胶柱色谱法纯化(25g,45mL/min;CH2Cl2/10%CH3OH in CH2Cl2=0-30%),得到产物UB-024l(2.18g,产率:64%),为白色固体。LCMS[M+1]+=277.1
步骤4:UB-024m
向在冰浴中冷却至0℃的UB-024l(2.18g,7.92mmol)在无水四氢呋喃(30mL)中的搅拌溶液中,缓慢加入LiAlH4在THF中的溶液(48mL,48mmol)。将所得悬浮液在0℃下保持10分钟,然后回流1.5小时。然后将反应冷却下来并将水和硫酸钠直接加入混合物中直到气体释放完成。然后将混合物通过硅藻土过滤,滤饼用MeOH洗涤,除去溶剂,得到产物UB-024m(1.70g,75%产率),为浅橙色油。LCMS[M+1]+=221.2
步骤5:UB-024n
在室温下,向化合物UB-024m(1.74g,7.90mmol)在(40mL)的溶液中加入碳酸氢钠(1.99g,23.69mmol)的水(20mL)溶液。向上述混合物中缓慢加入二碳酸二叔丁酯(2.59g,11.87mmol),并将混合物在室温下搅拌17小时。将混合物减压浓缩并通过硅胶色谱法纯化(25g,45mL/min;DCM:10%MeOH的DCM溶液=0-10%),得到产物UB-024n(1.78g,产率:71%),为浅黄色液体。LCMS[M+1]+=321.2
步骤6:UB-024o
在室温下将Pd/C加入到化合物UB-024n(1.78g,5.56mmol)在EtOH(40mL)的溶液中。将混合物脱气并用H2重新填充三次。然后将混合物在室温下搅拌24小时。混合物通过硅藻土垫过滤,并用MeOH洗涤,滤液浓缩得到产物UB-024o(1.28g,产率100%)。LCMS[M+1]+=231.2
步骤7:UB-024p
向三颈圆底烧瓶中加入化合物UB-007f(170mg,0.45mmol)、UB-024o(225mg,0.98mmol)、Cs2CO3(440mg,1.35mmol)、Pd2(dba)3(43mg,0.05mmol)和XPhos(112毫克,0.23毫摩尔)。将混合物脱气并用氩气重新填充3次。并且通过注射器将干燥的二恶烷(14mL)添加到混合物中。然后将混合物在100℃下搅拌4小时。将反应混合物浓缩并通过硅胶色谱法纯化(DCM:10%MeOH in DCM=0-24%),得到产物UB-024p(158mg,产率:61%),为黄色固体。LCMS[M+1]+=572.3
步骤8:UB-024
向化合物UB-024p(158mg,0.28mmol)在CH2Cl2(6mL)中的混合物加入HCl/二氧六环(4N,1.5mL)。将反应混合物在25℃搅拌17小时。将反应混合物浓缩,用Na2CO3水溶液调节至pH=8-9。然后将混合物减压浓缩并通过硅胶色谱法纯化(DCM:10%MeOH in DCM=0-33%),得到产物UB-024(41mg,产率:32%),为白色固体。LCMS[M+1]+=472.31H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.83(s,1H),7.62(dd,J=5.2,3.3Hz,2H),7.58(d,J=8.3Hz,2H),7.44(dd,J=8.0,6.8Hz,4H),7.37–7.29(m,1H),4.65(s,3H),4.53(m,1H),4.44(d,J=11.2Hz,1H),3.36(t,J=6.9Hz,2H),2.91–2.77(m,3H),2.69–2.60(m,1H),1.84(d,J=6.6Hz,2H),1.46(dd,J=6.7,3.4Hz,6H).
实施例25:化合物UB-025的合成
步骤1:UB-025c
二甲基苄基-L-天冬氨酸
在室温下向反应瓶中加入K2CO3(6.29g,45.54mmol)和20mL MeCN,在搅拌的悬浮液中加入UB-025a(3.0g,15.18mmol)。将反应液搅拌15分钟。加入UB-025b(2.726g,15.94mmol)。将反应混合物在回流温度下搅拌16小时。蒸发溶剂并用DCM(3×50mL)萃取残余物并Na2SO4干燥。减压蒸发溶剂。将残余物通过柱色谱DCM:(DCM:MeOH=10:1)=0-10%纯化,得到无色油状化合物(UB-025c,3.0g,产率78.7%)。LCMS[M+1]+=252.1
步骤2:UB-025e
N-苄基-N-(2-溴乙酰基)-L-天冬氨酸二甲酯
在反应瓶中加入UB-025c(3.0g,12mmol)、无水DCM(15mL)溶液和Et3N(1.82g,18mmol)。将混合物冷却至0℃并缓慢加入UB-025d(1.89g,14.3mmol)的5mL无水DCM的溶液。将反应在室温搅1小时。棕色溶液用1M HCl溶液洗涤两次,用饱和NaHCO3溶液洗涤两次,用盐水洗涤一次。有机相用Na2SO4干燥,然后浓缩并用快速色谱法纯化PE/EA=0-20%,得到淡黄色油状化合物(UB-025e,3.1g,产率69.6%)。LCMS[M+1]+=372.0;374.0
步骤3:UB-025f
S)-2-(1-苄基-3,6-二氧代哌嗪-2-基)乙酸甲酯
在反应瓶中加入UB-025e(3.1g,8.36mmol)和CH3OH(10mL)中,搅拌均匀,然后加入6mL 7M的NH3/CH3OH溶液并将混合物在室温下搅拌7小时。然后除去溶剂并用快速色谱法(DCM/MeOH=0-30%)纯化残余物,得到白色固体状的化合物(UB-025f,1.6g,产率69.3%)。LCMS[M+1]+=277.1
步骤4:UB-025g
(S)-2-(1-苄基哌嗪-2-基)乙烷-1-醇
在冰浴下向反应瓶中加入UB-025f(500mg,1.81mmol)和10mL无水THF溶液,然后缓慢滴加LiAlH4/THF(10.9mL,1mmol/mL)溶液。将所得悬浮液在0℃下搅拌10分钟,然后回流90分钟。用Na2SO4和H2O淬灭反应混合物。混合物通过硅藻土过滤,然后浓缩,得到黄色油状化合物(UB-025g,400mg,产率100%),直接用于下一步反应。LCMS[M+1]+=221.2
步骤5:UB-025h
(S)-4-苄基-3-(2-羟乙基)哌嗪-1-羧酸叔丁酯
在室温将NaHCO3(1570mg,18.7mmol)和水(10mL)加入到溶有UB-025g(380mg,1.7mmol)的1,4-二氧六环(10mL)溶液中。加入(Boc)2O(524mg,2.4mmol)并将混合物在室温下搅拌1小时。反应完成后加入水(20mL)和EA(20mL)并分离各层。用EA(20mL)再次萃取水层。合并的有机物用水(30mL)和饱和氯化钠水溶液(20mL)洗涤,用硫酸钠干燥,过滤,真空浓缩。将所得油状物通过硅胶快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=10-30%洗脱,得到黄色油状化合物(UB-025h,500mg,产率91.9%)。LCMS[M+1]+=321.3
步骤6:UB-025i
(S)-3-(2-羟乙基)哌嗪-1-羧酸叔丁酯
将Pd/C(50mg,10%wt)加入到用氮气吹扫的容器中。加入EtOH(5mL),然后加入UB-025h(500mg)的EtOH(5mL)溶液。将容器密封,用氮气吹扫,用氢气吹扫,并在氢气加压下室温反应过夜。将反应混合物过滤并真空浓缩,得到黄色油状化合物(1246i,200mg,产率58.2%)。LCMS[M+1]+=231.2
步骤7:UB-025k
叔丁基(S)-4-(6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-3-(2-羟乙基)哌嗪-1-羧酸盐
在Ar下向反应瓶中加入UB-025i(156mg,0.413mmol)、UB-007f(190mg,0.825mmol)、Pd2(dba)3(38mg,0.041mmol)、Cs2CO3(404mg,1.24mmol)、XPhos(100mg,0.21mmol)和无水二氧六环(10mL)溶液。将混合物在100℃下搅拌3小时。将反应浓缩并通过快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=0-40%洗脱,得到黄色固体状化合物(UB-025k,90mg,产率38%)。LCMS[M+1]+=572.3
步骤8:UB-025 047
(S)-2-(1-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-2-基)乙-1-醇
在反应瓶中加入UB-025k(90mg,0.16mmol)和6mL DCM溶液,搅拌均匀,加入TFA(1mL)。将混合物在室温下搅拌1小时。将反应混合物用NaHCO3淬灭并用DCM(10mL*3)萃取,分离有机相,用盐水(10mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=0-100%得到白色固体状化合物(UB-025,25mg,产率33.8%)。LCMS[M+1]+=472.2。1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.84(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.47–7.41(m,4H),7.34(d,J=7.4Hz,1H),4.66(d,J=30.1Hz,3H),4.54(dd,J=13.5,6.8Hz,1H),4.50–4.44(m,1H),3.37(t,J=6.7Hz,3H),2.91(t,J=10.9Hz,3H),2.75–2.64(m,1H),1.93–1.80(m,2H),1.46(dd,J=6.7,3.2Hz,6H).
实施例26:化合物UB-026的合成
步骤1:UB-026h
将化合物UB-007f(80mg,0.11mmol)、UB-026g(210mg,1.05mmol)溶解于N-甲基吡咯烷酮(2mL)中,加入N,N-二异丙基乙按(216mg,1.68mmol),然后在微波中180℃下反应3小时。将反应混合物冷却至室温并加入水(10mL),沉淀出固体,过滤沉淀物,用水(20mL)洗涤,固体用二氯甲烷溶解,然后浓缩,残留物用硅胶纯化凝胶柱层析(石油醚/乙酸乙酯=2/1)得到所需产物(UB-026h,84mg,产率74%),性状黄色液体。LCMS[M+1]+=542.
步骤2:UB-026
将化合物UB-026h(84mg,0.15mmol)溶于二氯甲烷(4mL)和盐酸/二氧六环在二恶烷(1mL)中,然后在40℃下搅拌1小时。将反应混合物浓缩,用饱和碳酸氢钠水溶液调节至pH=8-9。用二氯甲烷(20mL*3)萃取后,将合并的有机层用食盐水洗涤,经无水硫酸钠干燥,过滤,浓缩,并将残留的水溶液冻干,得到所需产物(UB-026,20.2mg,产率30%),性状白色固体。LCMS[M+1]+=442.1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.84(s,1H),7.65–7.54(m,4H),7.44(dt,J=7.8,3.6Hz,4H),7.38–7.29(m,1H),4.57(td,J=13.5,13.0,6.2Hz,3H),4.44(dd,J=12.7,3.0Hz,2H),2.86(d,J=11.1Hz,1H),2.68(td,J=12.0,2.7Hz,1H),2.57(td,J=11.4,4.7Hz,3H),2.31(dd,J=12.5,10.3Hz,1H),1.46(d,J=6.7Hz,6H),0.98(d,J=6.2Hz,3H).
实施例27:化合物UB-027的合成
步骤1:UB-027c
(R)-4-(6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-2-甲基哌嗪-1-羧酸叔丁酯
将化合物UB-027b(2650mg,13.26mmol),化合物UB-007f(1000mg,2.65mmol)溶解于(7mL)NMP中,在微波180℃下反应3小时。反应液降温到室温,加水至溶液析出固体,过滤。将滤渣溶解并且通过硅胶柱纯化(DCM/MeOH=10%),得到化合物(UB-027c,712mg,50%收率和470mg的产物掉Boc)性状黄色油。LCMS[M+1]+=542.3.
步骤2:UB-027
(R)-N-([1,1'-联苯]-4-基甲基)-9-异丙基-2-(3-甲基哌嗪-1-基)-9H-嘌呤-6-胺
将化合物UB-027c(712mg,1.32mmol)溶于二氯甲烷(16mL),加入盐酸-1,4-二氧六环(16mmol,4mL)。反应在40℃下搅拌4小时。反应完成后,向反应液中加入碳酸氢钠饱和溶液调节PH至8~9,并且用DCM萃取(40mL*3)。合并有机相并用饱和食盐水洗,用无水硫酸钠干燥。将萃取液浓缩并且冻干,得到想要的化合物UB-027(525.9mg,45%产率)性状白色固体。LCMS[M+1]+=442.31H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.84(s,1H),7.64–7.55(m,4H),7.47–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.56(dt,J=13.4,6.7Hz,3H),4.44(d,J=12.3Hz,2H),2.85(d,J=11.3Hz,1H),2.67(t,J=12.0Hz,1H),2.61–2.53(m,2H),2.30(dd,J=12.3,10.4Hz,1H),1.46(d,J=6.7Hz,6H),0.97(d,J=6.2Hz,3H).
实施例28:化合物UB-028的合成
步骤1:UB-028c
(R)-叔丁基4-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)-2-(羟甲基)哌嗪-1-羧酸盐
将化合物UB-028b(287mg,1.33mmol),化合物UB-007f(100mg,0.27mmol)溶解于(3mL)NMP中,在微波180℃下反应3小时。反应液降温到室温,加水至溶液析出固体,过滤。将滤渣溶解并且通过硅胶柱纯化(DCM/MeOH=30%),得到化合物(UB-028c,42mg,59%收率)性状黄色油。LCMS[M+1]+=558.3.
步骤2:UB-028
(R)-(4-(6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-2-基)甲醇
将化合物UB-028c(42mg,0.07mmol)溶于二氯甲烷(2mL),加入盐酸-1,4-二氧六环(2mmol,0.5mL)。反应在40℃下搅拌4小时。反应完成后,向反应液中加入碳酸氢钠饱和溶液调节PH至8~9,并且用DCM萃取(40mL*3)。合并有机相并用饱和食盐水洗,用无水硫酸钠干燥。将萃取液浓缩并且冻干,得到想要的化合物UB-028(17.5mg,54%产率)性状白色固体。LCMS[M+1]+=458.2.1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.87(s,1H),7.60(dd,J=16.3,7.7Hz,4H),7.48–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.87(s,1H),4.69–4.42(m,5H),3.42(d,J=3.4Hz,2H),3.01(d,J=11.4Hz,1H),2.85(t,J=11.2Hz,1H),2.79–2.54(m,3H),1.47(d,J=6.7Hz,6H).
实施例29:化合物UB-029的合成
步骤1:UB-029b
(S)-哌嗪-2-基甲醇
向反应瓶中加入UB-029a(250mg,1.16mmol)和8mL DCM中的溶液,搅拌均匀,加入TFA(2mL)。将混合物在室温下搅拌1小时。将反应混合物浓缩,得到白色固体状化合物(UB-029b,400mg,产率100%)直接用于下一步反应。LCMS[M+1]+=117.1
步骤2:UB-029
(S)-(4-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-2-基)甲醇
在微波管中加入UB-029b(153mg,1.323mmol)、UB-007f(100mg,0.265mmol)、DIPEA(274mg,2.12mmol)和NMP(4mL)溶液。将混合物在微波条件下180℃搅拌3小时。将反应混合物倒入H2O中。过滤收集所得沉淀,滤液用EA萃取3次,合并有机相,过滤通过硅胶柱色谱纯化[洗脱液:DCM/(10%MeOH/DCM)=0-100%],得到白色固体状化合物(UB-029,62mg,产率51%)。LCMS[M+1]+=458.3。1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.85(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.49–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.68(t,J=5.1Hz,1H),4.61(d,J=6.3Hz,1H),4.56(dd,J=13.4,6.8Hz,2H),4.45(d,J=12.6Hz,1H),3.38–3.34(m,2H),2.93(d,J=11.5Hz,1H),2.76(t,J=12.0Hz,1H),2.60(t,J=9.8Hz,2H),2.48–2.39(m,1H),1.46(d,J=6.7Hz,6H).
实施例30:化合物UB-030的合成
步骤1:UB-030b
(S)-2-(哌嗪-2-基)乙烷-1-醇
向反应瓶中加入UB-030a(460mg,2mmol)和8mL DCM溶液,搅拌均匀,加入TFA(2mL)。将混合物在室温下搅拌1小时。将反应混合物浓缩,得到白色固体状化合物(UB-030b,300mg,产率100%)。直接用于下一步反应。LCMS[M+1]+=131.2
步骤2:UB-030
(S)-2-(4-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-2-基)乙-1-醇
在微波管中加入UB-030b(138mg,1.058mmol)、UB-007f(80mg,0.0.212mmol)、DIPEA(220mg,1.7mmol)和NMP(4mL)溶液。将混合物在微波条件下180℃搅拌3小时。将反应混合物倒入H2O中。过滤收集所得沉淀,滤液用EA萃取3次,合并有机相,过滤通过硅胶柱色谱纯化[洗脱液:DCM/(10%MeOH/DCM)=0-100%],得到白色固体状化合物(UB-030,59mg,产率59.0%)。LCMS[M+1]+=472.3。1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.84(s,1H),7.64–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.44(t,J=8.1Hz,4H),7.33(t,J=7.3Hz,1H),4.57(td,J=13.3,6.5Hz,3H),4.48(d,J=10.8Hz,1H),4.42(d,J=12.8Hz,1H),3.53(td,J=6.4,2.2Hz,2H),2.90(d,J=11.8Hz,1H),2.76(d,J=11.5Hz,1H),2.62(dd,J=16.8,10.5Hz,2H),2.45(d,J=10.3Hz,1H),1.54–1.48(m,2H),1.46(d,J=6.8Hz,6H).
实施例31:化合物UB-031的合成
步骤1:UB-031h
向化合物UB-031h(313mg,1.36mmol)在CH2Cl2(3mL)中的混合物加入HCl/二氧六环(4N,3.5mL)。将反应混合物在25℃下搅拌17小时。将反应混合物浓缩,用饱和Na2CO3水溶液调节至pH=8-9。用CH2Cl2(20mL*3)萃取后,将合并的有机层用盐水洗涤,用无水Na2SO4干燥,然后将混合物减压浓缩,得到产物UB-031h(177mg,产率:100%),为白色固体。LCMS[M+1]+=131.2步骤2:UB-031
向微波管中分别加入化合物UB-007f(70mg,0.19mmol),化合物UB-031h(177mg,0.47mmol),DIPEA(192mg,1.48mmol)和N-甲基吡咯烷酮(3mL),将混何用微波在180℃下加热6小时。将混何物冷却至室温,减压浓缩后通过硅胶柱层析法纯化(4g,40mL/min;DCM:10%MeOH in DCM=0-33%),得到产物粗(48mg,产率:55%),为棕黄色液体。粗产物进一步通过制备液相色谱(Prep.HPLC,流动相:HCl/水/乙腈)纯化,得到产物UB-031(31.5mg,产率:36%),为黄色固体。LCMS[M+1]+=472.3。1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.91(s,1H),7.64–7.56(m,5H),7.47–7.41(m,5H),7.33(dd,J=10.4,4.3Hz,2H),4.65–4.45(m,6H),3.56(dd,J=11.3,5.8Hz,2H),3.18(d,J=12.1Hz,1H),3.09(d,J=11.0Hz,3H),2.87(s,3H),1.67(td,J=14.5,7.0Hz,3H),1.47(d,J=6.8Hz,8H).
实施例32:化合物UB-032的合成
步骤1:UB-032
N-([1,1'-联苯]-4-基甲基)-9-环丁基-2-(哌嗪-1-基)-9H-嘌呤-6-胺
在10mL的微波管中加入UB-007f(60mg,0.16mmol),UB-032b(148mg,0.80mmol),DIPEA(164mg,1.27mmol),NMP(3mL),所得混合物微波在180℃下反应3小时,反应结束后加入30mL的水,固体析出过滤,滤饼经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~30/70)分离得到白色固体化合物UB-032(30mg,产率42%)。LCMS[M+H]+=456.3.1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(s,1H),7.65–7.60(m,2H),7.57(d,J=8.2Hz,2H),7.48–7.40(m,4H),7.34(d,J=7.3Hz,1H),4.56(dt,J=13.4,6.7Hz,3H),3.76(dd,J=12.7,3.0Hz,2H),3.41(dd,J=12.8,6.2Hz,3H),3.15(s,2H),1.46(dd,J=6.7,4.7Hz,6H),1.01(d,J=6.3Hz,6H).
实施例33:化合物UB-033的合成
步骤1:UB-033h
向三口烧瓶中依次加入化合物UB-007f(270mg,0.72mmol),UB-033g(416mg,2.34mmol),Cs2CO3(624mg,2.15mmol),Pd2(dba)3(90mg,0.10mmol)和XPhos(234mg,0.49mmol)。将混合物用氩气置换三次,然后加入无水1,4-二氧六环(16mL),将混何物于100℃下搅拌19小时。将混何物冷却至室温,减压浓缩后通过硅胶色谱柱纯化(DCM:10%MeOHin DCM=0-78%),得到产物UB-033h(109mg,产率:27%)。LCMS[M+1]+=558.3
步骤2:UB-033
向化合物UB-033h(109mg,0.20mmol)在CH2Cl2(3mL)中的混合物加入HCl/二氧六环(4N,1.5mL)。将反应混合物在25℃下搅拌17小时。将反应混合物浓缩,用饱和Na2CO3水溶液调节至pH=8-9。用CH2Cl2(20mL*3)萃取后,减压浓缩后通过硅胶色谱柱纯化(DCM:10%MeOHin DCM=0-100%),得到产物UB-033(59.3mg,产率:60%),为浅黄色固体。LCMS[M+1]+=458.3。1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.82(s,1H),7.65–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.48–7.41(m,4H),7.33(t,J=7.3Hz,1H),4.62(s,2H),4.55(m,3H),4.37(d,J=12.5Hz,1H),3.80(t,J=9.4Hz,1H),3.42–3.35(m,2H),3.16(d,J=12.0Hz,1H),2.86(t,J=12.8Hz,2H),2.58(dd,J=12.1,3.8Hz,1H),1.46(dd,J=6.7,0.9Hz,6H).
实施例34:化合物UB-034的合成
步骤1:UB-034c
叔丁基(R)-3-(((6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氧基)甲基)哌嗪-1-羧酸盐
在Ar下向反应瓶中加入UB-007f(300mg,0.8mmol)、UB-034b(520mg,2.4mmol)和无水二氧六环溶液(18mL),加入Pd2(dba)3(80mg,0.08mmol)、Cs2CO3(800mg,2.4mmol))和XPhos(200mg,0.4mmol)。将混合物在100℃下搅拌3小时。将反应浓缩并通过快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=0-40%洗脱,得到黄色油状化合物(UB-034c,200mg,产率44.8%)。LCMS[M+1]+=558.3
步骤2:UB-034
(R)-N-([1,1'-联苯]-4-基甲基)-9-异丙基-2-(哌嗪-2-基甲氧基)-9H-嘌呤-6-胺
在反应瓶中加入UB-034c(200mg,0.359mmol)、8mL DCM溶液和HCl的二氧六环溶液(2mL)。将混合物在室温下搅拌1小时。将反应混合物用NaHCO3(4mL)淬灭并用DCM(20mL*3)萃取,分离有机相,用盐水(20mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱纯化,用DCM/(DCM:MeOH=10:1)=0-100%洗脱,得到浅黄色固体状化合物(UB-034,80.5mg,产率49%)。LCMS[M+1]+=458.3。1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.05(s,1H),7.61(dd,J=11.1,7.8Hz,4H),7.43(dd,J=11.9,5.2Hz,4H),7.35(d,J=7.3Hz,1H),4.80–4.50(m,3H),4.06(d,J=5.6Hz,2H),2.86(d,J=9.2Hz,2H),2.77(d,J=10.6Hz,1H),2.70(d,J=11.1Hz,1H),2.61–2.55(m,1H),2.32(d,J=10.7Hz,1H),1.49(d,J=6.7Hz,6H).
实施例35:化合物UB-035的合成
步骤1:UB-035c
叔丁基4-(9-异丙基-6-((2-丙氧基-[1,1'-联苯]-4-基)甲基)氨基)-9H-嘌呤-2-基)哌嗪-1-羧酸盐
在100ml圆底烧瓶中加入UB-007f(80mg,0.147mmol),UB-035b(54mg,0.439mmol),碳酸铯(142mg,0.436mmol),DMF(5mL),所得混合物常温下反应1小时,反应结束后加入20mL的水,用乙酸乙酯萃取三次,有机溶剂用无水硫酸钠干燥,旋干得到黄色固体化合物UB-035c(70mg,产率81%)。LCMS[M+H]+=586.2
步骤2:UB-035
9-异丙基-2-(哌嗪-1-基)-N-(2-丙氧基-[1,1'-联苯]-4-基)甲基)-9H-嘌呤-6-胺
在50mL圆底烧瓶中加入UB-035c(70mg,0.11mmol),二氯甲烷(3mL)和盐酸二氧六环(2mL,8mmol),所得混合物在室温反应2个小时,反应用饱和碳酸氢钠溶液淬灭至pH为中性,用二氯甲烷萃取,有机相减压浓缩,残留物经制备得到白色固体化合物UB-035(14mg,产率25%)。LCMS[M+1]+=428.3。1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.80(s,1H),7.66–7.55(m,4H),7.51–7.40(m,4H),7.33(t,J=7.3Hz,1H),4.65(s,1H),4.56(dt,J=13.4,6.7Hz,1H),3.66(t,J=5.4Hz,1H),3.59(dd,J=11.5,5.7Hz,2H),3.53–3.44(m,2H),3.27–3.18(m,2H),2.06(td,J=13.1,6.8Hz,1H),1.90(s,2H),1.73(dd,J=12.4,6.4Hz,1H),1.47(d,J=6.8Hz,6H).
实施例36:化合物UB-036的合成
步骤1:UB-036c
(R)-(1-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)吡咯烷-3-基)氨基甲酸叔丁酯
将化合物UB-036b(198mg,1.06mmol),化合物UB-007f(80mg,0.21mmol)溶解于(2mL)NMP中,在微波180℃下反应3小时。反应液降温到室温,加水至溶液析出固体,过滤。将滤渣溶解并且通过硅胶柱纯化(DCM/MeOH=10%),得到化合物(UB-036c,25mg,57%产率)性状黄色油。LCMS[M+1]+=528.3.
步骤2:UB-036
(R)-N-([1,1'-联苯]-4-基甲基)-2-(3-氨基吡咯烷-1-基)-9-异丙基-9H-嘌呤-6-胺
将化合物UB-036c(25mg,0.05mmol)溶于二氯甲烷(2mL),加入盐酸-1,4-二氧六环(2mmol,0.5mL)。反应在40℃下搅拌4小时。反应完成后,向反应液中加入碳酸氢钠饱和溶液调节PH至8~9,并且用DCM萃取(40mL*3)。合并有机相并用饱和食盐水洗,用无水硫酸钠干燥。将萃取液浓缩并且冻干,得到想要的化合物UB-036(3.5mg,10%产率)性状白色固体。LCMS[M+1]+=428.2。1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.79(d,J=5.9Hz,1H),7.64–7.56(m,4H),7.45(dd,J=14.6,7.5Hz,4H),7.33(t,J=7.3Hz,1H),4.78–4.50(m,3H),3.53(dddd,J=17.9,15.8,14.0,10.9Hz,4H),3.13(dd,J=10.8,5.0Hz,1H),1.99(dt,J=12.3,6.7Hz,1H),1.63(td,J=13.1,6.6Hz,1H),1.47(d,J=6.8Hz,6H).
实施例37:化合物UB-037的合成
步骤1:UB-037c
(S)-3-((6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)吡咯烷-1-羧酸叔丁酯
向反应瓶中加入UB-007f(100mg,0.265mmol),UB-037b(160mg,0.8mmol),Pd2(dba)3(146.6mg,0.16mmol),Cs2CO3(172.7mg,0.53mmol),X-phos(380.8mg,0.8mmol)和1,4-dioxane(10mL).将反应混合物置换氩气三次,然后升温至100℃搅拌过夜。将反应混合物用水(30mL)稀释,然后用乙酸乙酯(30mL*3)萃取,分离有机相,用盐水(50mL)洗涤并用无水硫酸钠干燥,然后浓缩并通过色谱法(二氯甲烷:二氯甲烷/甲醇10/1=75:25)纯化得到产物得到黄色固体化合物(UB-037c,120mg,产率35.58%).LCMS[M+1]+=528.2
步骤2:UB-037
N6-([1,1'-联苯]-4-基甲基)-9-异丙基-N2-(吡咯烷-3-基)-9H-嘌呤-2,6-二胺
在室温下向100mL底部烧瓶中加入UB-037c(121.2mg,0.23mmol)、盐酸的1,4-二氧六环溶液(4mL)和二氯甲烷(8.0mL)。然后将溶液在室温搅拌2小时。过滤反应混合物,滤饼用二氯甲烷(5mL)洗涤,用碳酸氢钠饱和水溶液中和,并用二氯甲烷(3*50mL)萃取。将合并的有机相用盐水洗涤,用无水硫酸钠干燥并减压浓缩,然后加入甲醇和水,并冷冻干燥,得到黄色固体产物(UB-037,54.7mg,产率:56.3%)。LCMS[M+1]+=428.2.1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.60(dd,J=15.0,7.9Hz,4H),7.44(t,J=7.6Hz,4H),7.33(t,J=7.3Hz,1H),6.28(d,J=6.6Hz,1H),4.67(s,1H),4.53(dt,J=13.6,6.7Hz,1H),4.20(d,J=6.2Hz,1H),2.90(dd,J=11.4,6.6Hz,1H),2.87–2.81(m,1H),2.73–2.64(m,1H),2.57(dd,J=11.0,4.2Hz,1H),1.91(dd,J=12.8,6.3Hz,1H),1.63–1.50(m,1H),1.47(d,J=6.7Hz,6H).
实施例38:化合物UB-038的合成
步骤1:UB-038c
(R)-叔丁基-3-(6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)吡咯烷-1-羧酸盐
在100mL的圆底烧瓶中依次加入化合物UB-038a(400mg,1.06mmol),UB-038b(1.18g,6.36mmol),Pd2(dba)3(97mg,0.106mmol),XPhos(252mg,0.53mmol),Cs2CO3(1.03g,3.18mmol),1,4-二氧六环(10mL),所得混合物用氩气置换三次后加热至100℃反应24h,反应结束后,减压浓缩,残留物经柱层析(洗脱剂:DCM:PE:EA=100/0~80/20)分离得到淡黄色固体化合物UB-038c(200mg,产率36%)。LCMS[M+H]+=528.3.
步骤2:UB-038
(R)-N6-([1,1'-联苯]-4-基甲基)-9-异丙基-N2-(吡咯烷-3-基)-9H-嘌呤-2,6-二胺
在50mL圆底烧瓶中加入UB-038c(80mg,0.15mmol),二氯甲烷(3mL)和三氟乙酸(128mg,1.13mmol),所得混合物在室温反应2个小时,反应用饱和碳酸氢钠溶液淬灭至pH为中性,用二氯甲烷萃取,有机相减压浓缩,残留物经柱层析(洗脱剂:DCM/(10%MeOH inDCM)=100/0~90/10)分离得到白色固体化合物UB-038(42mg,产率87%)。LCMS[M+1]+=428.3。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.07(s,1H),7.91(s,1H),7.69–7.55(m,2H),7.48–7.39(m,2H),7.34(t,J=7.3Hz,1H),6.73(s,1H),4.67(s,1H),4.56(dt,J=13.5,6.8Hz,1H),4.39(d,J=4.8Hz,1H),3.40–3.27(m,2H),3.28–3.16(m,1H),3.12(s,1H),2.12(dd,J=13.4,7.0Hz,1H),1.97(d,J=5.7Hz,1H),1.48(d,J=6.8Hz,6H).
实施例39:化合物UB-039的合成
步骤1:UB-039c
叔丁基((1R,3S)-3-((6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)环戊基)氨基甲酸酯
向反应瓶中加入UB-007f(100mg,0.265mmol),UB-039b(160mg,0.8mmol),Pd2(dba)3(146.6mg,0.16mmol),Cs2CO3(172.7mg,0.53mmol),X-phos(380.8mg,0.8mmol)和1,4-dioxane(10mL).将反应混合物置换氩气三次,然后升温至100℃搅拌过夜。反应完成将反应液旋干拌样,通过硅胶柱纯化DCM/MeOH=0-25%(10%MeOH)得到黄色固体化合物UB-039c(40mg,产率28%).LCMS[M+1]+=542.3.
步骤2:UB-039
N6-([1,1'-联苯]-4-基甲基)-N2-((1S,3R)-3-氨基环戊基)-9-异丙基-9H-嘌呤-2,6-二胺
将UB-039c(50mg,0.09mmol)溶于3mL THF中,再加入HCl/二氧六环(1mL)。反应液再室温下搅拌过夜。反应液通过过硅胶色谱法纯化得到白色固体化合物UB-039(3.3mg,产率8%)。LCMS[M+1]+=442.3.1H NMR(400MHz,DMSO-d6)1HNMR(400MHz,)δ7.88(s,1H),7.82(s,1H),7.61(dd,J=13.6,7.8Hz,4H),7.44(dd,J=11.9,5.3Hz,4H),7.34(t,J=7.3Hz,1H),6.44(d,J=7.1Hz,1H),4.66(s,2H),4.53(dt,J=13.4,6.8Hz,1H),4.18(d,J=7.0Hz,1H),2.43–2.30(m,1H),2.00(dd,J=14.8,7.0Hz,1H),1.89(s,2H),1.65(d,J=4.8Hz,2H),1.47(d,J=6.7Hz,6H),1.36–1.28(m,2H),1.25(s,2H),1.22–1.22(m,1H).
实施例40:合成化合物UB-040的一般方法
步骤1:UB-040c
叔丁基((1S,3S)-3-((6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)环戊基)氨基甲酸酯
向反应瓶中加入UB-007f(50mg,0.13mmol),UB-040b(96.1mg,0.48mmol),Pd2(dba)3(18.3mg,0.02mmol),Xphos(38.2mg,0.08mmol)and Cs2CO3(156.4mg,0.48mmol),和1,4-dioxane(10mL).将反应混合物置换氩气三次,然后升温至100℃搅拌过夜。然后将反应混合物在100℃搅拌24小时。将反应混合物用水(30mL)稀释,然后用乙酸乙酯(30mL*3)萃取,分离有机相,用盐水(50mL)洗涤并用无水硫酸钠干燥,然后浓缩并通过色谱法(二氯甲烷:二氯甲烷/甲醇10/1=75:25)纯化得到产物得到黄色固体化合物(UB-040c,38mg,收率:21.9%).LCMS[M+1]+=542.3.
步骤2:UB-040
N6-([1,1'-联苯]-4-基甲基)-N2-((1S,3S)-3-氨基环戊基)-9-异丙基-9H-嘌呤-2,6-二胺
在室温下向100mL底部烧瓶中加入UB-040c(37.9mg,0.07mmol)、盐酸的1,4-二氧六环溶液(2mL)和二氯甲烷(4.0mL)。然后将溶液在室温搅拌2小时。过滤反应混合物,滤饼用二氯甲烷(5mL)洗涤,用碳酸氢钠饱和水溶液中和,并用二氯甲烷(3*50mL)萃取。将合并的有机相用盐水洗涤,用无水硫酸钠干燥并减压浓缩,然后加入甲醇和水,并冷冻干燥,得到黄色固体产物(UB-040,13.9mg,产率:44.8%)。LCMS[M+1]+=428.2.1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.64–7.61(m,2H),7.58(d,J=8.2Hz,2H),7.47–7.40(m,5H),7.33(t,J=7.3Hz,1H),6.19(d,J=7.0Hz,1H),4.67(s,2H),4.53(dt,J=13.3,6.6Hz,1H),4.31(dd,J=14.1,7.1Hz,1H),2.07–2.00(m,1H),1.90–1.82(m,1H),1.68(dd,J=13.1,6.6Hz,1H),1.64–1.56(m,1H),1.47(d,J=6.7Hz,6H),1.43–1.34(m,2H),1.25–1.14(m,2H).
实施例41:合成化合物UB-041的一般方法
步骤1:UB-041c
叔丁基2-((1s,3s)-3-((6-(([1,1'-联苯基]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)
将化合物UB-041b(158mg,0.85mmol),化合物UB-007f(80mg,0.21mmol),碳酸铯(207mg,0.64mmol),Pd2(dba)3(25mg,0.02mmol)和Xphos(51mg,0.11mmol)溶解于(5mL)超干-二氧六环中,在100℃下反应过夜。反应完成后,反应液降温到室温,将反应液浓缩并且通过硅胶柱纯化(EA/PE=50%),得到化合物(UB-041c,30mg,5%产率)性状黄色固体。LCMS[M+1]+=528.3.
步骤2:UB-041
(1s,3s)-3-((6-(([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)氨基)环丁-1-氯化铵.
将化合物UB-041c(30mg,0.06mmol)溶于二氯甲烷(2mL),加入盐酸-1,4-二氧六环(2mmol,0.5mL)。反应在40℃下搅拌4小时。反应完成后,向反应液中加入碳酸氢钠饱和溶液调节PH至8~9,并且用DCM萃取(40mL*3)。合并有机相并用饱和食盐水洗,用无水硫酸钠干燥。将萃取液浓缩并且冻干,得到想要的化合物UB-041(14.9mg,55%产率)性状白色固体。LCMS[M+1]+=428.3。1H NMR(400MHz,DMSO-d6)δ9.60(d,J=117.0Hz,1H),8.73(s,1H),8.31(s,3H),7.64(d,J=7.7Hz,4H),7.55–7.44(m,4H),7.36(t,J=7.3Hz,1H),5.30(d,J=16.8Hz,1H),4.86–4.62(m,3H),4.13(s,1H),2.67(s,2H),2.13(d,J=7.7Hz,2H),1.53(d,J=6.3Hz,6H),1.23(s,1H).
实施例42:合成化合物UB-042的一般方法
步骤1:UB-042c
2-羟基-[1,1'-联苯]-4-腈
在100mL的圆底烧瓶中依次加入化合物UB-042a(1.55g,7.57mmol),UB-042b(1.85g,15.14mmol),Pd(dppf)Cl2(550mg,0.757mmol),K2CO3(3.13g,22.71mmol),1,4-二氧六环(45mL)和水(10mL),所得混合物用氩气置换三次后加热至100℃反应过夜,反应结束后,减压浓缩,残留物经柱层析(洗脱剂:DCM:PE:EA=100/0~30/70)分离得到淡黄色固体化合物UB-042c(1.1g,产率78%)。LCMS[M+H]+=196.1.
步骤2:UB-042d
4-(氨甲基)-[1,1'-联苯]-2-醇
在100mL圆底烧瓶中加入UB-042c(1.1g,5.64mmol),雷尼镍(110mg),胺甲醇(10mL),所得混合物用氢气置换三次常温下反应1小时,反应结束后用硅藻土过滤,滤液减压浓缩,残留物经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~50/50)分离得到白色固体化合物UB-042d(840mg,产率63%)。LCMS[M+H]+=200.1.
步骤3:UB-042f
4-((2-氯-9-异丙基-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-醇
在100mL圆底烧瓶中加入UB-042d(840mg,4.22mmol),UB-042e(1.02g,4.43mmol),三乙胺(1.28g,12.66mmol),异丙醇(15mL),所得混合物用在110℃下反应3小时,反应结束后冷却到室温,固体析出过滤,滤饼用乙醇和水10:1洗涤,得到白色固体化合物UB-042f(1.3g,产率78%)。LCMS[M+H]+=394.1.
步骤4:UB-042h
叔丁基4-(6-((2-羟基-[1,1'-联苯]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
在20mL的微波管中加入UB-042f(1.0g,2.54mmol),UB-042g(2.36g,12.72mmol),DIPEA(2.62g,20.35mmol),NMP(8mL),所得混合物微波在180℃下反应3小时,反应结束后加入30mL的水,固体析出过滤,滤饼经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~30/70)分离,得到白色固体化合物UB-042h(900mg,产率65%)。LCMS[M+H]+=544.3
步骤5:UB-042
4-(9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-醇
在50mL圆底烧瓶中加入UB-042h(60mg,0.11mmol),二氯甲烷(3mL)和盐酸二氧六环(2mL,8mmol),所得混合物在室温反应4个小时,反应用饱和碳酸氢钠溶液淬灭至pH为中性,用二氯甲烷萃取,有机相减压浓缩,残留物经制备得到白色固体化合物UB-042(14mg,产率29%)。LCMS[M+1]+=444.1。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.85(s,2H),8.16(d,J=14.5Hz,1H),7.93(s,1H),7.56–7.44(m,2H),7.36(t,J=7.6Hz,2H),7.26(t,J=7.3Hz,1H),7.16(d,J=7.8Hz,1H),6.94(s,1H),6.87(d,J=7.9Hz,1H),4.73–4.32(m,3H),3.87(d,J=4.8Hz,4H),3.08(s,4H),1.48(d,J=6.8Hz,6H).
实施例43:化合物UB-043的一般合成方法
步骤1:UB-043c
叔丁基4-(6-(((2-(2-羟基乙氧基)-[1,1'-联苯基]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
向微波管中加入化合物UB-043a(100mg,0.18mmol),化合物UB-043b(112.6mg,0.90mmol),K2CO3(124.2mg,0.90mmol)和5mL N-甲基吡咯烷酮,反应液在微波管中加热至150℃反应4小时。将反应液倒入水中,过滤得滤饼,滤液用乙酸乙酯萃取2次,合并有机相和滤饼,除去溶剂后,浓缩物通过快速色谱法纯化((甲醇:二氯甲烷(1:10)/二氯甲烷=0-70%)得到白色固体化合物UB-043c(73.0mg,产率66.7%)。LCMS[M+1]+=588.3.
步骤2:UB-043
2-((4-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-基)氧基)乙醇
将化合物UB-043c(73.0mg,0.12mmol)溶于4mL的二氯甲烷中,加入盐酸二氧六环溶液(1mL),室温搅拌3小时。反应液用碳酸氢钠溶液中和,用二氯甲烷萃取,收集有机相,干燥,除去溶剂后,浓缩物通过快速色谱法纯化((甲醇:二氯甲烷(1:10)/二氯甲烷=0-100%)得到白色固体化合物UB-043(29.7mg,产率49.0%)。LCMS[M+1]+=488.3。1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.85(s,1H),7.56–7.48(m,2H),7.36(t,J=7.5Hz,2H),7.31–7.24(m,1H),7.24–7.15(m,2H),7.02(d,J=7.7Hz,1H),4.76(s,1H),4.57(dt,J=13.5,6.7Hz,3H),3.98(t,J=5.2Hz,2H),3.62(dd,J=12.8,8.1Hz,6H),2.71(dd,J=8.3,3.4Hz,4H),1.46(d,J=6.8Hz,6H).
实施例44:化合物UB-044的合成
步骤1:UB-044c
(S)-叔丁基(1-(6-([1,1'-联苯]-4-基甲基)氨基)-9-异丙基-9H-嘌呤-2-基)吡咯烷-3-基)氨基甲酸酯
在10mL的微波管中加入UB-044a(80mg,0.212mmol),UB-044b(197mg,1.06mmol),DIPEA(218mg,1.69mmol),NMP(3mL),所得混合物微波在180℃下反应3小时,反应结束后加入30mL的水,固体析出过滤,滤饼经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~30/70)分离,得到白色固体化合物UB-044c(60mg,产率54%)。LCMS[M+H]+=528.3
步骤2:UB-044
(S)-N-([1,1'-联苯]-4-基甲基)-2-(3-氨基吡咯烷-1-基)-9-异丙基-9H-嘌呤-6-胺
在50mL圆底烧瓶中加入UB-044c(60mg,0.11mmol),二氯甲烷(3mL)和盐酸二氧六环(2mL,8mmol),所得混合物在室温反应4个小时,反应用饱和碳酸氢钠溶液淬灭至pH为中性,用二氯甲烷萃取,有机相减压浓缩,残留物经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~90/10)分离得到白色固体化合物UB-044(14mg,产率29%)。LCMS[M+1]+=486.2。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.04(s,1H),7.87(s,1H),7.46(d,J=7.2Hz,2H),7.37(t,J=7.6Hz,2H),7.28(t,J=7.3Hz,1H),7.20(d,J=7.7Hz,1H),7.15(s,1H),7.01(d,J=7.0Hz,1H),4.57(dd,J=13.5,6.8Hz,3H),3.89(t,J=6.4Hz,2H),3.70(s,5H),2.83(s,4H),1.64(dd,J=13.9,6.7Hz,2H),1.47(d,J=6.8Hz,6H),0.89(t,J=7.4Hz,3H).
实施例45:化合物UB-045的合成
步骤1:UB-045c
叔丁基4-(6-(((2-(4-((叔丁基二甲基甲硅烷基)氧基)丁氧基)-[1,1'-联苯]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
向100mL的反应瓶中加入化合物UB-045a(80mg,0.147mmol),碳酸铯(96mg,0.294mmol)和5mL N,N-二甲基甲酰胺,反应液搅拌至微黄色,然后加入化合物UB-045b(80mg,0.294mmol),反应液加热至80℃反应18小时。冷却至室温,除去溶剂后,浓缩物通过快速色谱法纯化(乙酸乙酯/石油醚=0-50%)得到白色固体化合物1225c(110.0mg,产率97%)。LCMS[M+1]+=616.4.
步骤2:UB-045
4-((4-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-基)氧基)丁-1-醇
将化合物UB-045c(110.0mg,0.179mmol)溶于4mL的二氯甲烷中,加入盐酸二氧六环溶液(1mL),室温搅拌3小时。反应液用碳酸氢钠溶液中和,用二氯甲烷萃取,收集有机相,干燥,除去溶剂后,浓缩物通过快速色谱法纯化((甲醇:二氯甲烷(1:10)/二氯甲烷=0-100%)得到白色固体化合物UB-045(41.7mg,产率48.1%)。LCMS[M+1]+=516.3。1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.91(s,1H),7.48–7.42(m,2H),7.36(dd,J=15.2,7.4Hz,2H),7.28(t,J=7.3Hz,1H),7.19(dd,J=14.0,7.2Hz,2H),7.01(d,J=7.0Hz,1H),4.58(dd,J=13.5,6.7Hz,3H),3.94(t,J=6.5Hz,2H),3.82(d,J=3.8Hz,4H),3.39(d,J=6.4Hz,2H),3.00(s,4H),1.66(dd,J=14.6,6.7Hz,2H),1.48(t,J=6.8Hz,8H).
实施例46:化合物UB-046的一般合成方法
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步骤1:UB-046c
2'-羟基-[1,1'-联苯]-4-腈
向UB-046a(3.0g,16.5mmol)和UB-046b(3.4g,24.7mmol)在1,4-二氧六环(60mL)和H2O(20mL)中的溶液中加入(dppf)PdCl2(600mg,0.82mmol)、K2CO3(6.8g,49.4mmol)在N2下。将混合物回流搅拌4小时,混合物逐渐变浑浊。将反应混合物浓缩并通过硅胶柱色谱法纯化残余物[洗脱液:PE/EA=0-40%],得到黄色固体状的化合物(UB-046c,3.26g,产率100%)。LCMS[M+1]+=177.1
步骤2:UB-046d
4'-(氨基甲基)-[1,1'-联苯]-2-醇
在H2下加入UB-046c(2.8g,14.36mmol)、Raney Ni(280mg)、NH3的甲醇溶液(15mL)。将混合物在室温搅拌过夜。将混合物通过硅藻土过滤,将滤液浓缩并通过硅胶柱色谱法纯化[洗脱液:DCM/10%MeOH/DCM=0-50%],得到白色固体状的化合物(UB-046d,1.4g,产率49%)。LCMS[M+1]+=200.1
步骤3:UB-046f
4'-(((2-氯-9-异丙基-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-醇
向反应瓶中加入UB-046d(1090mg,5.48mmol)、UB-046e(1290mg,5.58mmol)、Et3N(1660mg,16.44mmol)和异丙醇(20mL)。将混合物在80℃下搅拌4小时。将混合物浓缩并通过硅胶柱色谱法纯化[洗脱液:DCM/10%MeOH/DCM=0-50%],得到黄色固体状的化合物(1218f,1.8g,产率83.4%)。LCMS[M+1]+=394.2
步骤4:UB-046h
4-(6-(((2'-羟基-[1,1'-联苯]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸叔丁酯
在微波管中加入UB-046f(1500mg,3.807mmol)、UB-046g(3.54g,19.03mmol)、DIPEA(3.93g,30.4mmol)和NMP(6mL)。将混合物在微波条件下180℃搅拌3小时。将反应混合物倒入H2O中。过滤收集所得沉淀,滤液用EA萃取3次,合并有机相,将滤液浓缩并通过硅胶柱色谱纯化[洗脱液:DCM/10%MeOH/DCM=0-20%],得到白色固体状的化合物(UB-046h,1.11g,产率53.2%)。LCMS[M+1]+=544.3
步骤5:UB-046
4'-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-醇
向UB-046h(50mg,0.09mmol)的3mL DCM溶液中加入HCl在二恶烷(1mL)中的溶液。将混合物在室温搅拌2小时。将反应混合物用NaHCO3淬灭并用DCM(10mL*3)萃取,分离有机相,用盐水(10mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱纯化[洗脱液:DCM/10%MeOH/DCM=0-100%]得到白色固体状的化合物(UB-046,13.5mg,产率33.9%)。LCMS[M+1]+=444.3。1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.96(s,1H),7.84(s,1H),7.44(d,J=8.2Hz,2H),7.37(d,J=8.1Hz,2H),7.20(dd,J=7.6,1.6Hz,1H),7.15–7.09(m,1H),6.91(d,J=8.0Hz,1H),6.84(t,J=7.4Hz,1H),4.69–4.47(m,3H),3.61(d,J=5.0Hz,4H),2.71(d,J=4.5Hz,4H),1.46(d,J=6.7Hz,6H).
实施例47:化合物UB-047的合成
步骤1:UB-047c
叔丁基4-(6-(((2'-(2-羟基乙氧基)-[1,1'-联苯基]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
在微波管中加入UB-047a(80mg,0.147mmol)、UB-047b(92mg,0.737mmol)、K2CO3(102mg,0.737mmol)在NMP(3mL)中的溶液。将混合物在微波条件下150℃搅拌4小时。将反应混合物倒入H2O中。过滤收集所得沉淀,滤液用EA萃取3次,合并有机相,将滤液浓缩并通过硅胶柱色谱纯化[洗脱液:DCM:10%MeOH/DCM=0-70%],得到白色固体状的化合物(UB-047c,60mg,产率69.5%)。LCMS[M+1]+=588.3
步骤2:UB-047
2-((4'-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-基)氧)乙烷-1-醇
在反应瓶中加入UB-047c(60mg,0.102mmol)和3mL DCM溶液,加入HCl的二氧六环溶液(2mL)。将混合物在室温搅2小时。将反应混合物用NaHCO3淬灭并用DCM(10mL*3)萃取,分离有机相,用盐水(10mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱纯化,用DCM:10%MeOH/DCM=0-100%]得到浅黄色固体状的化合物(UB-047,39mg,产率78.5%)。LCMS[M+1]+=488.1。1H NMR(400MHz,DMSO-d6)δ8.04(d,J=19.2Hz,1H),7.86(s,1H),7.48(d,J=8.2Hz,2H),7.37(d,J=8.2Hz,2H),7.29(dd,J=13.3,4.8Hz,2H),7.09(d,J=8.0Hz,1H),6.99(t,J=7.0Hz,1H),4.58(td,J=13.8,7.1Hz,3H),4.01(t,J=5.1Hz,2H),3.68–3.62(m,6H),2.81–2.72(m,4H),1.47(d,J=6.8Hz,6H).
实施例48:化合物UB-048的合成
步骤1:UB-048h
将化合物UB-048f(80mg,0.15mmol)和Cs2CO3(384mg,1.18mmol)在DMF(3mL)中的混合物在室温下搅拌5分钟,然后将化合物UB-048g(264mg,1.18mmol)加入混合物中并在60℃下搅拌2.5小时。将混何物冷却至室温,减压浓缩后通过硅胶色谱柱纯化[二氯甲烷(二氯甲烷:甲醇=10:1)=0-21%],得到产物UB-048h(64mg,产率:63%),为白色固体。LCMS[M+1]+=687.2。
步骤2:UB-048
向化合物UB-048h(64mg,0.09mmol)在CH2Cl2(3mL)中的混合物加入HCl/二氧六环(4N,1.5mL)。将反应混合物在25℃下搅拌17小时。将反应混合物浓缩,用饱和Na2CO3水溶液调节至pH=8-9。用CH2Cl2(20mL*3)萃取后,将合并的有机层用盐水洗涤,用无水Na2SO4干燥,然后将混合物减压浓缩,得到产物UB-048(29.3mg,产率:65%),为白色固体。LCMS[M+1]+=487.3。1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.86–7.81(s,1H),7.44(d,J=8.2Hz,2H),7.38(d,J=8.2Hz,2H),7.27(dt,J=7.7,4.5Hz,2H),7.08(d,J=7.9Hz,1H),7.00(t,J=7.1Hz,1H),4.57(td,J=13.6,6.8Hz,3H),3.93(t,J=5.6Hz,2H),3.70(d,J=24.2Hz,1H),3.65–3.55(m,4H),2.81(t,J=5.6Hz,2H),2.70(s,4H),1.46(d,J=6.8Hz,6H).
实施例49:化合物UB-049的合成
步骤1:UB-049h
将化合物UB-049f(100mg,0.18mmol)和Cs2CO3(180mg,0.55mmol)在DMF(3mL)中的混合物在室温下搅拌5分钟,然后将化合物UB-049g(86mg,0.70mmol)加入混合物中并在室温下搅拌1小时。将H2O(20mL)添加到反应混合物中,然后将水层用二氯甲烷(30mL×4)萃取。合并有机层,用无水Na2SO4干燥,然后将混合物减压浓缩,得到粗产物UB-049h(89mg,产率:83%),为淡黄色液体,其不经纯化直接用于下一步反应。LCMS[M+1]+=586.4
步骤2:UB-049
向化合物UB-049h(89mg,0.15mmol)在CH2Cl2(3mL)中的混合物加入HCl/二氧六环(4N,1.5mL)。将反应混合物在25℃下搅拌17小时。将反应混合物浓缩,用饱和Na2CO3水溶液调节至pH=8-9。用CH2Cl2(20mL*3)萃取后,将合并的有机层用盐水洗涤,用无水Na2SO4干燥,然后将混合物减压浓缩,得到产物UB-049(54mg,产率:70%),为白色固体。LCMS[M+1]+=486.3。1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.84(s,2H),7.42(d,J=8.2Hz,3H),7.37(d,J=8.2Hz,3H),7.32–7.23(m,3H),7.06(d,J=8.1Hz,1H),6.98(t,J=7.3Hz,2H),4.68–4.50(m,4H),3.92(t,J=6.3Hz,3H),3.65–3.54(m,6H),2.70(s,6H),1.65(dd,J=13.8,6.6Hz,3H),1.46(d,J=6.8Hz,9H),0.91(t,J=7.4Hz,5H).
实施例50:化合物UB-050的一般合成方法
步骤1:UB-050b
(4-溴丁氧基)(叔丁基)二甲基硅烷
在冰浴下向反应瓶中加入UB-050a(500mg,3.268mmol)和DCM(10mL)溶液,加入咪唑(666mg,9.8mmol),搅拌10分钟。缓慢加入TBSCl(738mg,4.9mmol)并搅拌3小时。浓缩DCM,用30mL EA稀释,用10%NaHCO3溶液和盐水(30x 2mL)洗涤。有机溶剂经Na2SO4干燥并真空蒸发,得到无色油状化合物(UB-050b,620mg,产率71%),直接用于下一步反应。
步骤2:UB-050e
叔丁基4-(6-(((2'-(4-((叔丁基二甲基甲硅烷基)氧基)丁氧基)-[1,1'-联苯]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
向反应瓶中加入UB-050c(80mg,0.147mmol)和Cs2CO3(96mg,0.294mmol)及DMF溶液(5mL)。真空换氮三次。在室温下搅拌,反应液变成黄色。然后加入UB-050d(80mg,0.294mmol)并将反应液在80℃下加热18小时。然后将反应液冷却至室温,过滤。浓缩溶剂,得到的残余物通过硅胶柱色谱法纯化[洗脱液:PE/EA=0-50%],得到浅黄色固体化合物(UB-050e,110mg,产率97%)。LCMS[M+1]+=616.4
步骤3:UB-050
4-((4'-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-基)氧)丁烷-1-醇
向反应瓶中加入UB-050e(100mg,0.162mmol)和8mL DCM溶液,加入HCl的二氧六环溶液(3mL)。将混合物在室温搅拌过夜。将反应混合物用NaHCO3(5mL)淬灭并用DCM(10mL*3)萃取,分离有机相,用盐水(10mL*3)洗涤并用Na2SO4干燥,然后浓缩并通过快速色谱法纯化,用DCM:10%MeOH/DCM=0-100%,得到白色固体化合物(UB-050,14mg,产率16.7%)。LCMS[M+1]+=516.3。1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.84(s,1H),7.42(d,J=8.3Hz,2H),7.37(d,J=8.3Hz,2H),7.31–7.22(m,2H),7.07(d,J=7.8Hz,1H),7.02–6.95(m,1H),4.73–4.50(m,3H),3.97(t,J=6.6Hz,2H),3.65–3.57(m,4H),3.40(t,J=6.4Hz,2H),2.77–2.66(m,4H),1.68(s,2H),1.48(dd,J=14.1,7.5Hz,8H).
实施例51:化合物UB-051的合成
步骤1:UB-051c
叔丁基4-(6-(((2'-(3-氰基丙氧基)-[1,1'-联苯]-4-基)甲基)氨基)-9-异丙基-9H-嘌呤-2-基)哌嗪-1-羧酸盐
在N2下,向反应瓶中加入UB-051a(100mg,0.185mmol)、Cs2CO3(120mg,0.925mmol)和DMF溶液(5mL)。在室温下搅拌,反应液变成黄色。然后加入UB-051b(55mg,0.925mmol)并将反应液在80℃加热3小时。然后将反应液冷却至室温,然后过滤。蒸发掉溶剂,得到的残余物通过硅胶柱色谱法纯化[洗脱液:PE/EA=0-80%],得到无色油状物化合物(UB-051c,100mg,产率88.6%)。LCMS[M+1]+=611.3
步骤2:UB-051
4-((4'-(((9-异丙基-2-(哌嗪-1-基)-9H-嘌呤-6-基)氨基)甲基)-[1,1'-联苯]-2-基)氧)丁腈
向反应瓶中加入UB-051c(100mg,0.16mmol)、6mL DCM溶液和三氟乙酸(2mL)。将混合物在室温下搅拌1小时。将反应混合物用NaHCO3(4mL)淬灭并用DCM(20mL*3)萃取,分离有机相,用盐水(20mL*3)洗涤并用Na2SO 4干燥,然后浓缩并通过快速色谱法纯化,用DCM/(DCM:MeOH=10:1)=0-100%洗脱,得到白色固体状化合物(UB-051,11.4mg,产率14%)。LCMS[M+1]+=511.2。1H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.85(s,1H),7.44–7.37(m,4H),7.34–7.24(m,2H),7.10(d,J=8.2Hz,1H),7.02(t,J=7.5Hz,1H),4.78–4.43(m,3H),4.03(t,J=6.0Hz,2H),3.62(s,4H),2.73(s,4H),2.53(d,J=5.2Hz,2H),1.95(p,J=6.6Hz,2H),1.47(d,J=6.8Hz,6H).
实施例52:化合物UB-052的合成
步骤1:UB-052c
N-([1,1'-联苯]-4-基甲基)-2-氯-9-环丁基-9H-嘌呤-6-胺
在100mL的圆底烧瓶中依次加入化合物UB-052a(100mg,0.298mmol),UB-052b(60mg,0.446mmol),(dppf)PdCl2(22mg,0.029mmol),Cs2CO3(386mg,1.19mmol),DMF(5mL),所得混合物用氩气置换三次后加热至100℃反应5h,反应结束后,减压浓缩,残留物经柱层析(洗脱剂:DCM:PE:EA=100/0~80/20)分离得到淡黄色固体化合物UB-052c(80mg,产率46%)。LCMS[M+1]+=390.1.
步骤2:UB-052
N-([1,1'-联苯]-4-基甲基)-9-环丁基-2-(哌嗪-1-基)-9H-嘌呤-6-胺
在10mL的微波管中加入UB-052c(60mg,0.15mmol),UB-052d(66mg,0.77mmol),DIPEA(158mg,1.23mmol),NMP(3mL),所得混合物微波在180℃下反应3小时,反应结束后加入30mL的水,固体析出过滤,滤饼经柱层析(洗脱剂:DCM/(10%MeOH in DCM)=100/0~30/70)分离得到白色固体化合物UB-052(30mg,产率45%)。LCMS[M+H]+=440.2.1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.94(s,1H),7.66–7.60(m,2H),7.58(d,J=8.2Hz,2H),7.49–7.39(m,4H),7.33(t,J=7.3Hz,1H),4.92–4.75(m,1H),4.63(s,2H),3.72–3.49(m,5H),2.71(dd,J=14.2,9.6Hz,4H),2.59(ddd,J=19.3,9.7,2.5Hz,2H),2.42–2.27(m,2H),1.92–1.73(m,2H).
实施例53:合成化合物UB-053的一般方法
步骤1:UB-053c
2,6-二氯-9-苯基-9H-嘌呤叔丁基
向UB-053a(519.40mg,2.65mmol)的二氯甲烷(20mL)溶液中加入UB-053b(645.01mg,5.29mmol)、Cu(OAc)2(960.82mg,5.29mmol)、TEA(804.46mg,7.95mmol),将混合物在室温搅拌1小时。将反应混合物浓缩并通过色谱法(二氯甲烷)纯化,得到白色固体(UB-053c,63.1mg,产率:7.5%)LCMS[M+1]+=265.0;267.0.
步骤2:UB-053e
N-([1,1'-联苯]-4-基甲基)-2-氯-9-苯基-9氢-嘌呤-6-胺
向UB-053c(43.55mg,0.24mmol)的叔丁醇(4mL)溶液中加入UB-053d(63.07mg,0.24mmol),TEA(96.33mg,0.95mmol),混合物在110℃下搅拌过夜。反应结束后过滤,并用乙醇:水(10:1)(20mL)洗涤滤饼,并将滤饼抽干得到白色固体(UB-053e,67.6mg,产率:69%).LCMS[M+1]+=412.1.
步骤3:UB-053
N-([1,1'-联苯]-4-基甲基)-9-苯基-2-(哌嗪-1-基)-9H-嘌呤-6-胺
向微波管中加入UB-053e(41.2mg,0.10mmol),UB-053f(41.3mg,0.48mmol),DIPEA(98.2mg,0.76mmol)和NMP(3mL)并在180℃下微波反应3h.将反应混合物用水(200mL)稀释并用二氯甲烷(3×70mL)萃取。合并的有机相用盐水洗涤,用无水硫酸钠干燥并减压浓缩。粗产物经硅胶色谱纯化(二氯甲烷:二氯甲烷/甲醇:10/1=10:90)得到白色固体(UB-053,34.0mg,产率:51.15%).LCMS[M+1]+=462.2.1H NMR(400MHz,DMSO-d6)δ9.07(s,2H),8.50(s,1H),8.43(s,1H),7.88(d,J=7.8Hz,2H),7.65–7.60(m,4H),7.57(t,J=7.9Hz,2H),7.50–7.39(m,5H),7.35(t,J=7.3Hz,1H),4.69(s,2H),3.89(d,J=4.7Hz,4H),3.08(s,4H).
实施例54:化合物UB-054的合成
步骤1:UB-054c
2,6-二氯-9-(3-氟苯基)-9H-嘌呤
将化合物UB-054b(740mg,5.29mmol),化合物UB-054a(500mg,2.64mmol),溶解于(10mL)二氯甲烷中,再加入醋酸铜(961mg,5.29mmol)和三乙胺(804mg,7.96mmol)。在室温下反应3小时。反应完成后,将反应液浓缩并且通过硅胶柱纯化(二氯甲烷),得到化合物(UB-054c,200mg,26%产率)性状黄色固体。LCMS[M+1]+=283.0&284.9.
步骤2:UB-054e
N-([1,1'-联苯]-4-基甲基)-2-氯-9-(3-氟苯基)-9H-嘌呤-6-胺
将化合物UB-054c(200mg,0.71mmol),UB-054d(120mg,0.68mmol)和三乙胺(206mg,2.04mmol)溶于异丙醇(3mL)。反应在80℃下搅拌2小时。反应完成后,将反应液冷却至室温。将反应液过滤得到想要的化合物UB-054e(75mg,53%产率)性状白色固体。LCMS[M+1]+=430.1。
步骤3:UB-054
N-([1,1'-联苯基]-4-基甲基)-9-(3-氟苯基)-2-(哌嗪-1-基)-9H-嘌呤-6-胺
将化合物UB-054f(40mg,0.47mmol),UB-054e(40mg,0.09mmol)和DIPEA(96mg,0.74mmol)溶解于NMP(3mL)。反应在微波180℃下搅拌3小时。反应完成后,将反应液冷却至室温。加水至反应液固体析出并过滤。溶解滤渣并通过硅胶柱纯化(DCM/MeOH=30%),并冻干得到想要的化合物UB-0450(16mg,20%产率)性状白色固体。LCMS[M+1]+=480.2。1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.25(s,1H),7.92(dt,J=10.8,2.2Hz,1H),7.88–7.83(m,1H),7.65–7.56(m,5H),7.48–7.41(m,4H),7.34(t,J=7.3Hz,1H),7.22(td,J=8.5,2.2Hz,1H),4.67(s,2H),3.70–3.57(m,4H),2.81–2.66(m,4H),1.29(d,J=49.5Hz,3H).
实施例55:化合物UB-055的合成
步骤1:UB-055c
2,6-二氯-9-(1-甲基-1H-吡唑-4-基)-9H-嘌呤
将化合物UB-055b(666mg,5.29mmol),化合物UB-055a(500mg,2.64mmol),溶解于(10mL)二氯甲烷中,再加入醋酸铜(961mg,5.29mmol)和三乙胺(804mg,7.96mmol)。在室温下反应3小时。反应完成后,将反应液浓缩并且通过硅胶柱纯化(二氯甲烷),得到化合物(UB-055c,120mg,16.9%产率)性状黄色固体。LCMS[M+1]+=269.1.
步骤2:UB-055e
N-([1,1'-联苯]-4-基甲基)-2-氯-9-(1-甲基-1H-吡唑-4-基)-9H-嘌呤-6-胺
将化合物UB-055c(120mg,0.45mmol),UB-055d(80mg,0.43mmol)和三乙胺(130mg,1.29mmol)溶于异丙醇(2mL)。反应在80℃下搅拌2小时。反应完成后,将反应液冷却至室温。将反应液过滤得到想要的化合物UB-055e(95mg,53%产率)性状白色固体。LCMS[M+1]+=416.2。
步骤3:UB-055
N-([1,1'-联苯]-4-基甲基)-9-(1-甲基-1H-吡唑-4-基)-2-(哌嗪-1-基)-9H-嘌呤-6-胺
将化合物UB-055f(99mg,1.15mmol),UB-055e(95mg,0.23mmol)和DIPEA(238mg,1.84mmol)溶解于NMP(3mL)。反应在微波180℃下搅拌3小时。反应完成后,将反应液冷却至室温。加水至反应液固体析出并过滤。溶解滤渣并通过硅胶柱纯化(DCM/MeOH=60%)并且冻干,得到想要的化合物UB-055(64mg,59%产率)性状白色固体。LCMS[M+1]+=466.2。1HNMR(400MHz,DMSO-d6)δ8.29(s,1H),8.29(s,1H),8.28–8.12(m,2H),8.15(d,J=4.4Hz,1H),7.98(s,1H),7.98(s,1H),7.68–7.55(m,4H),7.66–7.58(m,4H),7.48–7.42(m,4H),7.52–7.39(m,4H),7.34(t,J=7.3Hz,1H),7.34(t,J=7.3Hz,1H),4.66(s,2H),4.66(s,2H),3.92(s,3H),3.92(s,3H),3.69–3.61(m,4H),3.75–3.58(m,4H),2.74(s,4H),2.74(s,4H).
实施例59-63:化合物UB-056到UB-063的合成
UB-059,UB-060的合成方法,类似UB-032的合成。
UB-061的合成方法,类似UB-041的合成。
UB-062、UB-063的合成方法,类似UB-043的合成。
表A1
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表A2
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表A3
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表A4
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B.测试实施例
测试实施例1:细胞增殖实验
试剂:RPMI-1640培养基、McCoy's5A培养基、IMDM培养基、MEM培养基、L-15培养基、胎牛血清、青-链双抗、胰蛋白酶等、2-mercaptoethanol、NEAA、pyruvate等。
测试用细胞进行常规培养,细胞铺板前至少传2代以上。
将25uL 1000个HT-29、N87、SKOV3、Colo-205和MDA-MB-231细胞接种于黑色壁透明底384孔板中,加入25uL不同浓度化合物,在37℃、5%CO2条件下培养过夜,
将25uL 1500个H82和H69细胞接种于黑色壁透明底384孔板中,加入25uL不同浓度化合物在37℃、5%CO2条件下培养细胞72小时。室温平衡384孔板,每孔加入25μL Cell试剂,在水平振荡摇床上振荡混匀2分钟使细胞裂解,室温孵育10分钟稳定发光信号,然后使用Envision检测化学发光信号。
所有细胞都进行相对应受试样品的IC50测定。
使用Alarm blue法检测各孔荧光强度,并计算IC50。
IC50由以下公式计算:
Y=Max+(Min-Max)/[1+(X/IC50)×Slope]
其中Min、Max和Slope分别表示最小值、最大值和斜率。
结果如表1所示,本发明的化合物在多个肿瘤细胞系上进行了细胞抑制实验,结果显示,大多数化合物在多个肿瘤细胞中都表现出很强的细胞杀伤作用,具有作为抗肿瘤药物开发的潜力。
表1
测试实施例2:免疫组织化学染色(Immunohistochemistry,IHC)
培养的细胞中,加入适量的化合物。在37℃组织培养箱中,孵育2小时。
培养的细胞用PBS洗涤两次后,加入100μL 10%中性缓冲福尔马林,固定20分钟。
PBS洗洗涤3次之后,用CCNK抗体和通用二步法检测试剂盒(小鼠/兔增强聚合物法检测系统,PV-9000,Zsbio Inc,Beijing)进行免疫组织化学染色。
具体地,加入试剂盒中的内源性过氧化物酶阻断剂100μL,室温孵育10分钟;PBS缓冲液冲洗3分钟×3次。
加入100μL CCNK抗体1:5000稀释液,37℃孵育60分钟;PBS缓冲液冲洗3分钟×3次。
加入100μL反应增强液,37℃孵育20分钟;PBS缓冲液冲洗3分钟×3次。
加入100μL增强酶标羊抗小鼠/兔IgG聚合物,37℃孵育20分钟;PBS缓冲液冲洗3分钟×3次。
置于75%乙醇中,浸泡3分钟×2次;置于95%乙醇中,浸泡3分钟×2次;去除多余的液体后,置于无水乙醇中,浸泡3分钟×3次;去除多余的液体后,风干,封片后显微镜观察、拍照。
结果如图1和表2所示,可以看出本发明的化合物能够快速有效的降解Cyclin K蛋白,且大多化合物降解Cyclin K的活性显著优于CR8。
测试实施例3:蛋白质印迹
用500uL 0.01mg/mL聚-D-赖氨酸氢溴酸盐包被透明12孔板,37℃放置1h,去除包被液,用1mL PBS清洗2遍,接种40万个HEK293细胞于12孔板中。细胞用化合物处理24h,去除培养基,用PBS清洗后,加入RIPA buffer裂解细胞;细胞裂解液加入Loading buffer后取适量体积缓慢加到胶板对应的孔中,跑SDS-PAGE胶(4%-12%)。跑胶结束后转到PVDF膜上,用5%脱脂奶粉室温封闭1小时。将膜放到用5%脱脂奶粉稀释的抗-细胞周期素K(Cyclin K)一抗中,4度慢摇过夜。一抗孵育结束后,用TBST摇床洗膜3次;加入与一抗对应的用5%脱脂奶粉稀释的抗兔HRP二抗,室温慢摇1小时。二抗孵育结束后,再次用TBST摇床洗膜3次。将PVDF膜平放到暗盒中,用ECL显影液均匀浸润条带,置于ChemDoc XRS+凝胶成像仪中拍照。使用ImageJ软件定量分析蛋白条带强度。
结果如图2和表2所示,可见本发明的化合物能够快速有效的降解Cyclin K蛋白,且大多化合物降解Cyclin K的活性显著优于CR8。
表2
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在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如式(I)所示的化合物或其药学上可接受的盐,
其中,
R1各自独立地为H或C1-4烷基;
下标n1为1、2或3;
环Ar1选自下组:C6-10芳环、5至10元杂芳环、5至10元桥环;
环Cr1选自下组:H、C3-10碳环基、3至10元杂环基、C6-10芳基、和5至10元杂芳基;
Ra和Rb各自独立地选自下组:H、Re或R;或者Ra和Rb与环Ar1和环Cr1共同形成其中,
X7各自独立地选自下组:-O-、-S-、-N(Rc)-、-C(Rc)2-、-C(Rc)2-C(Rc)2-;
下标n5和n6各自独立地为0、1、2或3;
Re各自独立地选自下组:羟基、C1-6烷基、-O-C1-6烷基、-O-C1-6亚烷基-Rf;
其中,Rf选自下组:-CN、-OH、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2;
下标n3和n4各自独立地为0、1、2、3或4;
R2选自下组:H、CN、任选取代的C1-6烷基、任选取代的C2-6烯基、任选取代的C2-6炔基、任选取代的C3-8环烷基、任选取代的3至8元杂环基;
X1、X2和X6各自独立地为N或C(Rc);
X3、X4和X5各自独立地为N或C;
M1选自下组:无、X8、(M4)s;其中,
X8为N(Rc)或C(Rc)2;
M4各自独立地选自下组:O、S、C(O)O、C(O)、N(Rc)和C1-4亚烷基;
s为1、2或3;
M2为无或如式A所示的环;
式A中,X9是与M1连接的位置,X10是与M3连接的位置;X9为N或C(Rm),X10选自下组:O、S、N或C(Rm);X11和X12各自独立地选自下组:-C(Rm)2-、-N(Rm)-;下标m1和m2各自独立地为0、1、2或3,并且m1+m2≥2;
其中,Rm各自独立地为Rc或Rm1;其中,
Rm1各自独立地选自下组:羟基、任选取代的C1-6烷基、任选取代的C1-6羟基烷基、任选取代的C1-6卤代烷基;或者,两个Rm1共同形成单键、任选取代的C1-4亚烷基或任选取代的1至4元杂亚烷基;
M3选自下组:无、R3、-NH-R3;其中,
R3选自下组:H、任选取代的C1-6烷基、任选取代的C1-6-羟烷基、任选取代的C1-6-卤代烷基;
Rc各自独立地为H或C1-4烷基;
除非特别定义,所述任选取代是指未取代的或基团中一个或多个(如1、2、3或4个)氢被取代基R所取代,并且R选自下组:D、卤素、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、C2-6烯基、C2-6炔基、-CN、-OR'、-NO2、-NR'R"、-SR'、OC(O)R'、-C(O)R'、-CO2R'、-CONR'、-OC(O)NR'R"、-NR"C(O)R'、-NR"-C(O)NR'R"、-NR"C(O)2R'、-S(O)R'、-S(O)2R'、-S(O)2NR'R"、NR"S(O)2R'、任选被一个或多个R'"所取代的C3-10环烷基、任选被一个或多个R'"所取代的4至10元杂环烷基、任选被一个或多个R'"所取代的C6-10芳基、任选被一个或多个R'"所取代的5至10元杂芳基、任选被一个或多个R'"所取代的-C1-4亚烷基-C3-10环烷基、任选被一个或多个R'"所取代的-C1-4亚烷基-4至10元杂环烷基、任选被一个或多个R'"所取代的-C1-4亚烷基-C6-10芳基、任选被一个或多个R'"所取代的-C1-4亚烷基-5至10元杂芳基;
各个R'各自独立地为H、D、任选被一个或多个R'"所取代的选自下组的基团:C1-6烷基、C3-10环烷基、4至10元杂环烷基、C6-10芳基、5至10元杂芳基、-C1-4亚烷基-C3-10环烷基、-C1-4亚烷基-4至10元杂环烷基、-C1-4亚烷基-C6-10芳基-C1-4亚烷基-5至10元杂芳基;
各个R"选自下组:H、D、C1-4烷基、C1-4卤代烷基、和C3-4环烷基;
各个R"'独立地选自下组:D、卤素、羟基、硝基、CN、C1-6烷基、C1-6卤代烷基。
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
环Ar1选自下组:
其中,*代表与环Cr1连接的位置;Xa、Xb、Xc和Xd各自独立地为CH和N;Xg选自下组:NH、O、S;Xh、Xi和Xj各自独立为-CH2-或-CH2-CH2-;
和/或,环Cr1选自下组:
其中,Xd和Xe各自独立地为N或CH;Xf为NH、S、O;Xg为N或CH。
3.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
选自下组:
4.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,
所述的化合物如式I-1所示
或者,所述的化合物如式I-2所示
或者,所述的化合物如式I-3所示
或者,所述的化合物如式I-4所示
5.如权利要求4所述的化合物或其药学上可接受的盐,其特征在于,
所述化合物为式I-1化合物,
其中,
为/>
m3为0、1或2。
6.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述的化合物为选自表A1、A2、A3和表A4的化合物。
7.一种药物组合物,其特征在于,所述的药物组合物包括:
(i)如权利要求1所述的化合物或其药学上可接受的盐;以及
(ii)药学上可以接受的载体。
8.一种如权利要求1所述的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
9.一种偶联物或其药学上可接受的盐,其特征在于,所述偶联物是由如权利要求1所述的化合物与多肽元件或靶向配体形成的偶联物。
10.一种如权利要求9所述的偶联物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
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