CN113509557A - 靶向蛋白酶降解平台(ted) - Google Patents
靶向蛋白酶降解平台(ted) Download PDFInfo
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- CN113509557A CN113509557A CN202010276301.2A CN202010276301A CN113509557A CN 113509557 A CN113509557 A CN 113509557A CN 202010276301 A CN202010276301 A CN 202010276301A CN 113509557 A CN113509557 A CN 113509557A
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Abstract
本发明涉及靶向蛋白酶降解平台(TED),具体地,本发明公开了一种式I所示的靶标分子‑连接体‑E3连接酶配体的偶联物,RT‑L1‑RE3(式I),其中,所述RT为靶标分子的一价基团;所述RE3为E3连接酶配体的一价基团;所述L1为连接A和B的连接头;且L1如下式II所示:‑W1‑L2‑W2‑(II)。
Description
技术领域
本发明属于生物医药,具体地,涉及一种靶向蛋白酶降解平台(TED)。
背景技术
现代分子生物学从3个基本层次上调控蛋白的表达水平:首先,在DNA水平,通过基因敲除,从而使目标蛋白的DNA失活;其次,在mRNA水平,通过小分子RNA,与目标蛋白的mRNA结合,从而抑制mRNA的翻译及表达;再次,在蛋白水平,通过对翻译后靶蛋白的修饰,例如甲基化、磷酸化、糖基化等,从而调整靶蛋白的量及活性。
就药物研发的总体发展来看,小分子和大分子两种药物形式都有各自的优势与不足。如小分子药物的发展一直面临如何维持体内药物浓度以及耐药性等关键挑战。有些靶点部位的形状不利于小分子的药物设计而成为“不可成药”的靶点。针对这些靶点目前还未找到有效的调控方式。单抗虽相对于小分子具有高亲和力和高选择性的优势,易于开发成高效、高选择性的药物,但其最大的弊端在于无法透过细胞膜,因此无法作用于胞内靶点。抗体药物偶联体(ADC)利用具有内吞性的抗体提供靶向并作为载体将超级毒素药物送达靶向部位。ADC类药物开发遇到的瓶颈是治疗窗口不够宽,除了抗体本身引起的毒副作用外,超级毒素会因偶联的非均一性而在到达靶位前脱落,引起严重毒副作用。此外,泛素-蛋白酶体***正常生理功能负责清理细胞中变性、变异或者有害的蛋白。
综上所述,本领域迫切需要开发能够更高效、且可重复利用的降解靶蛋白从而治疗相关疾病的化合物。
发明内容
本发明的目的在于提供一种能够更高效、且可重复利用的降解靶蛋白从而治疗相关疾病的化合物。
在本发明的第一方面,提供了一种如式I所示的偶联物或其药学上可接受的盐,其特征在于,
RT-L1-RE3 (I)
其中,
(a)所述RE3为E3连接酶配体部分;
(b)所述RT为靶标分子部分;
(c)所述L1为连接RE3和RT部分的连接头,且L1如式II所示;
-W1-L2-W2- (II)
其中,
W1和W2各自独立地为-(W)s-;
W各自独立地选自下组:无、-C(Rb)2-、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-、NR、取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基、取代或未取代的C6-10芳基、取代或未取代的5至10元杂芳基;
s=0、1、2、3、或4;
L2如式III所示,
-(ML)o- (III)
其中,
ML各自独立地为M、MT或MN;
其中,
o为5~50的整数;
M各自独立地为选自下组的二价基团:-C(Rb)2-、、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-、取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基、取代或未取代的C6-10芳基、取代或未取代的5至10元杂芳基、氨基酸残基;
MN各自独立地为选自下组的二价基团:-N(R’)-、-N(含N(R’)环原子的4至10元杂环烷基)-、含N(R’)环原子的4至10元杂环烷基、被至少一个-N(Rb)R’(较佳地,-NHR’)所取代的-C(Rb)2-、C3-8环烷基、4至10元杂环烷基、C6-10芳基或5至10元杂芳基;
MT各自独立地为选自下组的二价基团:-N(R”)-、-N(含N(R”)环原子的4至10元杂环烷基)-、含N(R”)环原子的4至10元杂环烷基、被至少一个-N(Rb)R”(较佳地,-NHR”)所取代的-C(Rb)2-、C3-8环烷基、4至10元杂环烷基、C6-10芳基或5至10元杂芳基;
R为R’或R”;
R’各自独立地选自下组:H、C1-6烷基、OH、SH、-COO-C1-6烷基、-OC(O)-C1-6烷基、氨基保护基团;
R”为-W3-L3-W4-(RP)q;
W3和W4各自独立地为-(W)s-;且W和s的定义同W1和W2基团中的定义;
L3为二价连接基团;
RP为多肽元件或者靶标分子T;
q为>0(较佳地,m为0.1~10,更佳地,0.2~5);
Ra各自独立地选自下组:H、OH、SH、取代或未取代的C1-6烷基、氨基保护基团、含N(Rc)环原子的4至10元杂环烷基;
Rb各自独立地选自下组:H、卤素、OH、SH、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷基酰基(-C(O)-C1-6烷基)、羧基、-COO-C1-6烷基、-OC(O)-C1-6烷基;或者,位于相同碳上的2个Rb以及与它们相连的碳共同构成取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基;
Rc各自独立地选自下组:H、OH、SH、取代或未取代的C1-6烷基、氨基保护基团;
除非特别说明,所述的取代是指基团中一个或多个(如1、2、或3个)氢被选自下组的取代基所取代:卤素(较佳地,F、Cl、Br或I)、氰基(CN)、氧代(=O)、硫代(=S)、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基酰基(C1-6烷基-C(O)-)、-COO-C1-6烷基、-OC(O)-C1-6烷基、NH2、NH(C1-6烷基)、N(C1-6烷基)2。
在另一优选例中,W不为NR。
在另一优选例中,L2不存在-O-O-。
在另一优选例中,L2中,至少一个ML为MT或MN。
在另一优选例中,L2中,所有ML均为M。
在另一优选例中,L2中,当二个或更多个ML为MT或MN时,L2中包括MT和MN、或L2仅包括MT,或L2仅包括MN。
在另一优选例中,L2中,至少一个ML为MN。
在另一优选例中,L2中,至少一个ML为MT。
在另一优选例中,L2中,1、2或3个ML各自独立地为MT或MN。
在另一优选例中,L2中,1、2或3个ML各自独立地为MN。
在另一优选例中,L2中,1、2或3个ML各自独立地为MT。
在另一优选例中,L2为L5,且L5如式IIIc所示;
-(M)o1-(M’)-(M)o2-(IIIc)
其中,
M’各自独立地为MT或MN;
M、MT和MN如式I中定义;
o1和o2各自独立地为1~50的整数且4≤o1+o2≤49。
在另一优选例中,L2为L6,且L6如式IIIa所示;
-(M)o1-(MN)-(M)o2-(IIIa)
其中,
M、MN如前定义;
o1和o2各自独立地为1~50的整数且4≤o1+o2≤49。
在另一优选例中,o1和o2各自独立地为1、2、3、4、5、6、7或8。
在另一优选例中,所述的偶联物如式IV所示;
RT-W1-L6-W2-RE3(IV)
其中,L6、W1、W2、RT和RE3如式I中定义。
3.如权利要求1所述的偶联物,其特征在于,L2为L7,且L7如式IIIb所示;
-(M)o1-(MT)-(M)o2-(IIIb)
其中,M、MT如前定义;
o1和o2各自独立地为1~50的整数且4≤o1+o2≤49。
在另一优选例中,o1和o2各自独立地为1、2、3、4、5、6、7或8。
在另一优选例中,所述的偶联物如式V所示;
RT-W1-L7-W2-RE3(V);
其中,L7、W1、W2、RT和RE3如式I中定义。
在另一优选例中,所述的偶联物如式1-1、1-2、1-3、2或3所示;
RT-W1-L5-Wb-C≡C-RE3(1-1);
RT-W1-L5-CO-RE3(1-2);
RT-W1-L5-CONH-RE3(1-3);
RT-Wa-Cr1-Wa-Cr2-L5-W2-RE3(2)
RT-Ar1-L5-W2-RE3(3)
其中,
Ar1为-五或六元含氮杂芳基-;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L7连接;
Wa和Wb的定义同W;且W、W1、W2、RT、RE3和L5如前定义。
在另一优选例中,所述的偶联物如式1a-1、1a-2、1a-3、2a或3a所示;
RT-W1-L6-Wb-C≡C-RE3(1a-1);
RT-W1-L6-CO-RE3(1a-2);
RT-W1-L6-CONH-RE3(1a-3);
RT-Wa-Cr1-Wa-Cr2-L6-W2-RE3(2a)
RT-Ar1-L6-W2-RE3(3a)
其中,
Ar1、Cr1、Cr2、Wa、Wb、W1、W2、RT、RE3和L6如前定义。
在另一优选例中,所述的偶联物如式1b-1、1b-2、1b-3、2b或3b所示;
RT-W1-L7-Wb-C≡C-RE3(1b-1);
RT-W1-L7-CO-RE3 (1b-2);
RT-W1-L7-CONH-RE3 (1b-3);
RT-Wa-Cr1-Wa-Cr2-L7-W2-RE3 (2b)
RT-Ar1-L7-W2-RE3 (3b)
其中,
Ar1为五或六元含氮杂芳基;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L7连接;
Wa和Wb的定义同W;且W、W1、W2、RT、RE3和L7如式I中定义。
在另一优选例中,L2为L8,且L8如式IIId所示;
-(M)o3- (IIId)
其中,M如前定义(较佳地,M为CH2),o3为1、2、3、4或5。
在另一优选例中,所述的偶联物如RT-W1-L8-W2-RE3所示;其中,RT、W1、L8、W2、和RE3如前定义。优选地,W1为Wa-Cr1-Cr2(更优选地,为NH-Cr1-Cr2),Cr1和Cr2如前定义。
在另一优选例中,当所述杂芳基(如5至10元杂芳基)为二价基团时,所述杂芳基(如5至10元杂芳基)为其中,V1、V2和V4各自独立地选自:-O-、-S-、-N=、-NH-、-CH=、-CH2-;V3选自下组:-N=、-CH=;较佳地,所述5至10元杂芳基选自下组:
在另一优选例中,M各自独立地选自下组:O、C(Rb)2;较佳地,其中,Rb各自独立地为H或C1-6烷基(如甲基)。
在另一优选例中,W选自下组:无、-C(Rb)2-、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-;或者W为取代或未取代的选自下组的基团:
在另一优选例中,Ra各自独立地为H或C1-6烷基(如甲基)。
在另一优选例中,Rb各自独立地为H或C1-6烷基(如甲基)。
在另一优选例中,Rc各自独立地为H或C1-6烷基(如甲基)。
在另一优选例中,L3为-(Ma)p-;其中,Ma的定义同M,p为1~50的整数。
在另一优选例中,p=1、2、3、4、5、6、7、8、9、10、11、12、13、14或15。
在另一优选例中,Ma各自独立地为选自下组的二价基团:-C(Rb)2-、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-、取代或未取代的-C3-8环烷基-、取代或未取代的-4至10元杂环烷基、取代或未取代的-C6-10芳基、取代或未取代的5至10元杂芳基、氨基酸残基。
在另一优选例中,-W3-L3-W4-RP选自下组:
其中,L4为-(M)q-,其中M的定义同L2中定义;
q为0~50的整数且q小于p(较佳地,q=0-30的整数;更佳地,q=0、1、2、3、4、5、6、7、8、9或10);R20和R21各自独立地选自下组:-H,-Me,-Et,-nPr,iPro,cPro。
在另一优选例中,所述的偶联物不为PCT/CN2019/110225中所公开的那些具体化合物。
在另一优选例中,所述偶联物为选自组1、组2和组3中的偶联物。
在另一优选例中,所述的偶联物为选自组1a、组2a和组3a中的偶联物。
在另一优选例中,所述的偶联物为选自组1、组2和组3中的偶联物;其中,R和R1为R”(即R和R1各自独立地为-W3-L3-W4-(RP)q)。
在另一优选例中,式I所示的偶联物为如式X所示的偶联物
RP-(W4-L3-W3-RTED)t (X)
其中,t=1/q(较佳地,t=1-8;更佳地,t=2-7);
RP如上定义,优选地为RP为多肽元件,更佳地为抗体;
RTED-W4-L3-W3-为式I所示偶联物的失去RP基团后余下的部分。
在另一优选例中,RTED为衍生自表A中的偶联物、组1a、2a和3a中的偶联物或实施例1.5的具体化合物的一价基团(其中,所述的衍生是指表A或实施例1.5所示的具体化合物失去连接基团的主链或连接基团的支链上NH或NH2的氢形成的一价基团)。
在另一优选例中,Ab通过N端或C端的氨基酸,或氨基酸侧链(较佳地,选自下组的氨基酸侧链:Lys、Cys),或被还原打开二硫键而形成的巯基,与式III所示的W4-L3 W3-(较佳地,W4-L3-W3-中的或者-NH2基团)连接。
在另一优选例中,所述的靶标分子为靶标分子A或靶标分子T。
在另一优选例中,所述靶标分子A或T包括:小分子、纳米载体,或其组合。
在另一优选例中,所述靶标分子A和T各自独立地选自下组:叶酸、HSP90、TINFRm、TNFR2、NADPH氧化酶(oxidase)、BclIBax、C5a受体(receptor),HMG-CoA还原酶(reductase)、PDE I-V、角鲨烯环化酶抑制剂(Squalene cyclase inhibitors)、CXCR1、CXCR2、一氧化氮(NO)合成酶(Nitric oxide(NO)synthase)、环加氧酶(cyclo-oxygenase)1-2、5HT受体(5HT receptors)、多巴胺受体(dopamine receptors)、G-蛋白(G-proteins)、Gq、组胺受体(Histamine receptors)、脂肪氧合酶(Lipoxygenases)、类胰蛋白酶丝氨酸蛋白酶(Tryptase serine protease)、胸苷酸合成酶(Thymidylate synthase)、嘌呤核苷酸磷酸化酶(Purine nucleotide phosphorylase)、GAPDH锥虫(GAPDH trypanosomal)、糖原磷酸化酶(Glycogen phosphorylase)、碳酸酐酶(Carbonic anhydrase)、趋化因子受体(Chemokine receptors)、JAW STAT、RXR及其类似物、HIV 1蛋白酶(HIV 1 protease)、HIV1整合酶(HIV 1 integrase)、流感(Influenza)、乙型肝炎逆转录酶(hepatitis B reversetranscriptase)、神经氨酸酶(neuraminidase)、钠通道(Sodium channel)、MDR、蛋白质P1-糖蛋白(protein P1-glycoprotein)、酪氨酸激酶(Tyrosine kinases)、CD23、CD124、TKp56 lck、CD4、CD5、IL-1受体(IL-1receptor)、IL-2受体(IL-2receptor)、TNF-aR,ICAM1,Ca+通道(Ca+channels)、VCAM、VLA-4整合素(VLA-4integrin)、VLA-4整合素(VLA-4integrin)、选择素(Selectins)、CD40/40L、新霉素和受体(Newokinins and receptors)、肌苷一磷酸脱氢酶(Inosine monophosphate dehydrogenase)、p38 MAP激酶(p38 MAPkinase)、白细胞介素-1转化酶(Interleukin-1converting enzyme)、胱天蛋白酶(Caspase)、HCV NS3蛋白酶(HCV NS3 protease)、HCV-NS3 RNA解旋酶(HCV-NS3 RNAhelicase)、甘氨酰胺核糖核苷酸甲酰转移酶(Glycinamide ribonucleotide formyltransferase)、鼻病毒3C蛋白酶(rhinovirus 3C protease)、HSV-I、CMV、ADP聚合酶(ADP1-polymerae)、CDK、VEGF、催产素受体(oxytoxin receptor)、msomal转移蛋白抑制剂(msomaltransfer protein inhibitor)、胆汁酸转移蛋白抑制剂(Bile acid transfer proteininhibitor)、5-a还原酶(5-a reductase)、血管紧张素11(Angiotensin 11),甘氨酸受体(Glycine receptors)、去甲肾上腺素再摄取受体(noradrenaline reuptake receptor)、内皮素受体(Endothelin receptors)、神经肽Y和受体(Neuropeptide Y and receptors)、***受体(Estrogen receptors)、AMP、AMP脱氨酶(AMP deaminase)、ACC、EGFR、法呢基转移酶(Farnesyltransferase)。
在另一优选例中,所述的多肽元件包括:抗体、蛋白,或其组合。
在另一优选例中,所述抗体包括:纳米抗体、小分子抗体(minibody),或其组合。
在另一优选例中,所述多肽元件为抗体;优选地,所述抗体包括纳米抗体(nanobody)和/或小分子抗体(minibody)。
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:DLL3、EDAR、CLL1、BMPR1B、E16、STEAP1、0772P、MPF、5T4,NaPi2b、Sema 5b、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。
在另一优选例中,RT选自表B所示的基团。
在另一优选例中,所述E3连接酶配体部分A1选自:WO2017/176957A1中的A1基团(较佳地,WO2017/176957A1中的A-10、A-11、A-15、A-28、A-48、A-69、A-85、A-93、A-98、A-99或A-101的相应部分)。
在另一优选例中,所述E3连接酶配体部分选自:
各式中,虚线表示与其他部分连接的位置(即与RT-L1连接的位置);
其中,Rx各自独立地选自下组:无、NH、NH-CO、O、S、SO、SO2、SO2(NH2)NH、C1~C4亚烷基、C2~C5亚烯基、C2~C5亚炔基;Ry为C=O,C=S或CH2。
在另一优选例中,所述E3连接酶配体部分选自表C中所示的基团。
在另一优选例中,当RE3为(A1)(较佳地为表B中的A1.2)时,式I偶联物如式1-1所示,RT-W1-L5-Wb-C≡C-RE3(1-1);较佳地,L5中至少一个M为O和/或W1为NH或NH-Cr2,和/或Wb为CH2;更佳地,L5中,7≤o1+o2≤12。
在另一优选例中,当RE3为(A1)(较佳地为表B中的A1.2)时,式I偶联物如RT-Wa-Cr1-Cr2-(M)o3-W2-RE3所示,且Cr1和Cr2均不为无;较佳地,L2为-(M)o3-,且下标o3 o3为1、2、3、4、或5。
在另一优选例中,RT、RE3、RP、L1、L2、L3、L4、L5、L6、L7、W1、W2、W3、W4Wa、Wb、W、ML、M、M’、MT、MN、下标s、下标p、下标q、下标o、下标o1、下标o2、Ra、Rb、Rc、R、R’、R”、Cr1、Cr2、Ar1各自独立地为本文中具体化合物或通式中所对应的基团;较佳地,为组1、组2、组3、组1a、组2a、组3a、表A中所示的具体化合物或通式中所对应的基团。
在本发明的第二方面,提供了一种药物组合物,其中,所述的药物组合物含有如第一方面所述的偶联物和药学上可接受的载体。
在本发明的第三方面,提供了如第一方面所述的偶联物在制备用于治疗或预防与靶标蛋白过量相关的疾病的药物中的的用途。
在本发明的第四方面,提供了一种如第一方面所述的偶联物在治疗或预防与靶标蛋白过量相关的疾病中用途。
在本发明的第五方面,提供了一种减少细胞中靶标蛋白含量的方法,其中,将细胞与如第一方面所述的偶联物相接触,从而减少细胞中靶标蛋白的含量。
在另一优选例中,所述的方法是体外方法。
在另一优选例中,所述的方法是非诊断性和非治疗性的。
在本发明的第六方面,提供了一种TED化合物或其药学上可接受的盐,其中,所述的TED化合物如式VI所示;
RT W1-(ML)o-W2-RE3 (VI)
其中,
ML各自独立地为M或MN
M、MN、RE3、RT、W1、W2和下标o如式I中定义。
在另一优选例中,所述TED化合物如式IV所示。
在另一优选例中,所述TED化合物如如式1a-1、1a-2、1a-3、2a或3a所示。
在另一优选例中,所述TED化合物用于与RP偶联。
在另一优选例中,所述TED化合物通过-W3-L3-W4-与RP偶联。
在另一优选例中,所述TED化合物为选自组1、组2和组3的化合物,且R和R1各自独立地为R’。
在另一优选例中,所述TED化合物为选自表A、组1a、组2a和组3a的化合物。
在本发明的第七方面,提供了一种ACTED化合物或其药学上可接受的盐,其中,所述的ACTED化合物如式VII所示;
RT W1-(ML)o-W2-RE3 (VII)
其中,
ML各自独立地为M或MT
M、MT、RE3、RT、W1、W2和下标o如式I中定义。
在另一优选例中,所述ACTED化合物如式V所示。
在另一优选例中,所述ACTED化合物如式X所示。
在另一优选例中,所述ACTED化合物如如式1b-1、1b-2、1b-3、2b或3b所示。
在另一优选例中,所述TED化合物为选自组1、组2和组3的化合物,且R和R1各自独立地为R”。
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显示了本发明化合物对MV4;11细胞系中BRD4和PLK1的降解情况。
图2显示了本发明化合物对MV4;11细胞系中BRD4和PLK1的降解情况。
图3显示了本发明化合物对TMD-8细胞系中BRD4和PLK1的降解情况。
具体实施方式
本发明人经过广泛而深入的研究,首次开发了一种结构新颖的TED偶联物,本发明偶联物具有式I所示的结构。此外,本发明偶联物非常适合进一步与多肽元件(尤其是抗体、蛋白配体)和/或其他具有靶向性的分子连接,或者进一步与多肽元件和/或其他具有靶向性的分子等进一步连接后或进一步连接了多肽元件和/或其他具有靶向性的分子的偶联物中的多肽元件和/或其他具有靶向性的分子,使得本发明偶联物具有优异的特异性(例如靶向肿瘤细胞的特异性),能够显著提高药物选择性,对致病蛋白实施更精准降解,减少非特异性降解可能引起的周身毒性,并有可能克服药物吸收代谢遇到的困难,铲除产生耐药性的机会。在此基础上发明人完成了本发明。
术语
如本文所用,术语“本发明化合物”、“本发明偶联物”可互换使用,指本发明第一方面中所述的式I化合物或偶联物。
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。术语“环烷基”是指具有指定环原子数(例如,C3-6环烷基)并且完全饱和的或在环顶之间具有不超过一个双键的烃环。
如本文所用,术语“环烷基”是指具有指定环原子数(例如,C3-8环烷基)并且完全饱和的或在环顶之间具有不超过一个双键的烃环。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“杂环烷基”是指含有一至五个选自N、O和S的杂原子的环烷基,其中氮和硫原子任选被氧化,且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。杂环烷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、1,4-二噁烷、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。杂环烷基可以经环碳或杂原子连接于分子的其余部分。对于诸如环烷基烷基和杂环烷基烷基的术语,是指环烷基或杂环烷基通过烷基或亚烷基连接体连接到分子的其余部分。例如,环丁基甲基-是连接到分子其余部分的亚甲基连接基上的环丁基环。
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-CH2CH2CH2CH2-。烷基(或亚烷基)通常具有1-24个碳原子,其中本发明优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”是较短链烷基或亚烷基,通常具有4个或更少的碳原子。类似地,“亚烯基”或“亚炔基”分别指具有双键或三键的不饱和形式的“亚烷基”。
除非另有说明,术语“杂烷基”本身或与其它术语组合是指的稳定的直链或支链或环状烃基或其组合,由指定数目的碳原子和和1至3个选自O,N,Si和S的杂原子组成,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。实施例包括-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3,-Si(CH3)3,-CH2-CH=N-OCH3,和-CH=CH-N(CH3)-CH3。最多两个杂原子可以是连续的,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。类似地,除非另有说明,术语“杂烯基”和“杂炔基”其本身或与另一个术语的组合分别指烯基或炔基,其分别含有指定数目的碳和1至3个选自O,N,Si和S的杂原子,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。
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饱和或不饱和或多不饱和的二价基团,例如-CH2-CH2-S-CH2CH2-和-CH2-S-CH2-CH2-NH-CH2-,-O-CH2-CH=CH-,-CH2-CH=C(H)CH2-O-CH2-和-S-CH2-C≡C-。对于杂亚烷基,杂原子也可以占据链末端中的任一个或两个(例如,亚烷基氧基,亚烷基二氧基,亚烷基氨基,亚烷基二氨基等)。
术语"烷氧基"、"烷氨基"和"烷硫基"(或硫代烷氧基)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。此外,对于二烷基氨基,烷基部分可以相同或不同,也可和与各烷基相连的氮原子组合形成3-7元环。因此,-NRaRb所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
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***基、苯并异噁唑基、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、***基、四唑基、噁唑基、异噁唑基、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***各自的取代基选自下述可接受的取代基的组。
为简洁起见,当术语“芳基”与其它术语(例如芳氧基,芳硫基,芳烷基)组合使用时,包括如上所定义的芳基和杂芳基环。因此,术语“芳烷基”是指包括其中芳基连接到与分子的其余部分连接的烷基的那些基团(例如苄基,苯乙基,吡啶基甲基等)。
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。
芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-的取代基取代,其中T和U独立地为-NH-,-O-,-CH2-或单键,且q是0至2的整数。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-,其中A和B独立地是-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR’-或单键,且r是1至3的整数。由此形成的新环中的一个单键可以任选地被双键取代。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t-的取代基替代,其中s和t独立地为0至3的整数,并且X是-O-、-NR’-、-S-、-S(O)-、-S(O)2-、或-S(O)2NR’-。-NR’-和-S(O)2NR’-中的取代基R’选自氢或未取代的C1-6烷基。
在本发明中,环烷基或杂环烷基为二价基时,所述的环烷基或杂环烷基可失去位于同一环原子(环碳原子上)的两个氢从而与链上的其他链原子连接(形成类似于螺环结构),或者可失去位于不同环原子上的两个氢从而与链上的其他链原子连接(如-亚环戊基-)。
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,术语“氨基酸残基”是指氨基酸的N端-NH2脱去一个H,C端的-COOH脱去-OH所形成的基团。除非另有定义,在本文中,氨基酸包括天然氨基酸或非天然氨基酸,包括D型和/或L型氨基酸。氨基酸的例子包括但不限于Ala(A)、Arg(R)、Asn(N)、Asp(D)、Cys(C)、Gln(Q)、Glu(E)、Gly(G)、His(H)、Ile(I)、Leu(L)、Lys(K)、Met(M)、Phe(F)、Pro(P)、Ser(S)、Thr(T)、Trp(W)、Tyr(Y)、Val(V)。优选地,在本文中,氨基酸为选自下组的氨基酸:L-甘氨酸(L-Gly),L-丙氨酸(L-Ala),β-丙氨酸(β-Ala),L-谷氨酸(L-Glu),L-天冬氨酸(L-Asp),L-组氨酸(L-His),L-精氨酸(L-Arg),L-赖氨酸(L-Lys),L-缬氨酸(L-Val),L-丝氨酸(L-Ser),L-苏氨酸(L-Thr)。
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。
靶向蛋白酶降解平台TED
本发明提供基于本发明偶联物的靶向蛋白酶降解平台(TED),该平台利用了细胞内的“清洁工”—泛素-蛋白酶体***。
典型地,基于本发明TED技术,可利用细胞自身的蛋白质破坏机制来从细胞中去除特定致癌病蛋白,因此是一种靶向治疗的替代方法。
与传统蛋白抑制剂作用原理不同,本发明的TED技术是一个双功能杂合化合物,一边用来结合目标蛋白,另一边用来结合一个E3连接酶,使得目标蛋白可以与E3连接酶结合,把目标蛋白泛素化,从而被蛋白组降解。理论上TED技术只是提供结合活性,不需直接抑制目标蛋白的功能活性,又可以重复利用,因此,具有优异的应用前景。
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、Fab),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(参见Kabat等,NIH Publ.No.91-3242,卷I,647-669页(1991))。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。
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、免疫抑制化合物和靶向芳基烃受体(AHR)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)、***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)。
靶标分子
在本发明的式I所示的偶联物中,通过偶联物中的RT(靶标分子部分)来结合靶标蛋白。
在本发明中,靶标分子可以是靶标分子A、靶标分子T、或其组合。
在本发明中,所述靶标分子可以是所述靶标蛋白的任意一种抑制剂。所述靶标分子可以是所述靶标蛋白的高效抑制剂,也可以活性比较差的抑制剂。具体地,本发明的靶标分子可以是针对本领域任一种靶标蛋白的本领域已知的小分子抑制剂。
在某些实施方案中,本文所用的靶标分子具有可与连接头进行连接的基团(如-O-,-NRa-(其中,Ra为H、或C1-6烷基等取代基,-CO-、-COO-等等),以一价与本发明的连接体分子(如本发明中L1)对接成醚、胺、酰胺等等,从而形成靶标分子部分。
所述靶标蛋白可以是本领域已知的各种靶标蛋白,代表性的例子包括(但并不限于):MDM2、AKT、BCR-ABL、Tau、BET(BRD2,BRD3,BRD4)、ERRα、FKBP12、RIPK2、ERBB3、雄激素受体、MetAP2、TACC3、FRS2α、PI3K、DHFR、GST、Halo Tag、CRABPI,CRABPII、RAR、芳烃受体、***受体。不同的靶标蛋白和一些相应的抑制剂可市售获得或用常规方法制备。例如,对于MDM2,其抑制剂可参见WO 2017176957、WO2017176958A1等文献。
在另一个具体实施方案中,RT选自表B
表B
E3连接酶配体
在本发明中,E3连接酶配体部分(RE3)用于结合E3连接酶。
在一个具体实施方案中,代表性的E3连接酶配体部分具有如式A1或A2所示的结构:
式A中,RX选自:无、C1-C6烷基、C2-C6烯基、C2-C6炔基、O、NH、S、CO或SOn(n为1或2)等;RY为CH2、C=S、CO;而且,所述E3连接酶配体(式I中的RE3)可通过其中的RX基团与本发明的L1进行连接,如-Rx-L1-RT(如-O-L1-RT);
或者,代表性的E3连接酶配体部分具有如式A1b所示的结构:
式A1b中,R’为H或C1-C6烷基(如Me),R为H、或C1-C6烷基(如Me或Et)。
在某些实施方案中,本文所用E3连接酶配体具有可与连接头进行连接的基团(如-O-,-NRa-(其中,Ra为H、或C1-C6烷基等取代基),-CO-、-COO-等等),以一价与本发明的连接体分子(如本发明中L1等)对接成醚、胺、酰胺等等。
在另一个具体实施方案中,本发明所用的RE3(E3连接酶配体部分)选自表C:
表C
连接体分子(如本文中所述的L1)
本发明的连接体分子用于连接靶标分子和E3连接酶配体。例如通过两端的官能团(例如-OH、-SH、-NH2、-NHR、-SOOH或-COOH)与靶标分子或E3连接酶配体连接;其中,R选自:取代或未取代的C1-C10烷基、-(C=O)-R’、(C=O)NH-R’、-NH(C=O)-R’、-SO2-R’、-NHSO2-R’、-SO2NH-R’、-SO-R’、-NHSO-R’、-SONH-R’、-PO3-R’、-NHCOO-R’、-COO-R’或-NH-CO-NH-R’、-NH-CO-O-R’或-X’-L3-Z;其中L3为连接基团,而Z为多肽元件(如配体、抗体或其肽段等)或者靶向分子如具有靶向功能的小分子(如叶酸、HSP90抑制剂等)。
连接体(头)和偶联方法
本发明的连接体(头)L1用于连接靶标分子(部分)P1和E3连接酶配体(部分)A1。
优选地,所述靶标分子(部分)或E3连接酶配体(部分)可以通过-O-、-S-、-NH-、-NR-、-(C=O)-、-(C=O)O-、-SO2-等基团与连接体连接。
在本发明的连接体上,还可进一步含有其它各种官能团,例如-OH、-NHR、-SH等官能团。
典型地,本发明的连接体L1,可以以下通式II表示:
-W1-L2-W2- 式II
式中,W1、L2、W2的定义如本发明第一方面中所述。
在另一优选例中,W1和W2各自独立地为以下一价基团失去1个氢原子形成的二价所形成的二价基团:-OH、-NH2、-SH、-COOH、-SO2H等等。例如,连接体与靶标分子的连接方式可以通过如下所示的连接基团进行连接:
或者,W1和W2各自独立地包括具有刚性的部分(如含四元、五元、或六元脂肪环(饱和碳环)部分、或者五元或、六元芳香性杂环部分等)的二价连接基团,示例性的实例如下以及实施例中所示:
其中,上述各式中的R如上定义;n为1或2或3。
在一个具体实施方案中,W1和W2各自独立地选自下组:
无、-N(Ra)-、-C(Rb)2-、-N(Ra)-C(Rb)2-、-C(=O)-、-C(O)-N(Ra)-、-C(Rb)2-C≡C-、-C≡C-、-C(O)-C≡C-、-CH(OH)-C≡C-、-O-、-S-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基、取代或未取代的C6-10芳基、取代或未取代的5至10元杂芳基。
活性成分
如本文所用,术语“本发明化合物”指式I所示的化合物或偶联物。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。
具体地,本发明提供了一类具有适于进一步与多肽元件(例如,抗体、蛋白配体等)或靶标分子T连接或者连接有多肽元件或靶标分子T的如式I所示的偶联物;
RT-L1-RE3 (I)
其中,RL为E3连接酶配体部分,RT为靶标分子部分,L1为连接A1和P1部分的连接头。
优选地,RL、RT和L1的定义如前所述。
在一个具体实施例中,本发明提供的适于进一步与多肽元件或靶标分子T连接的偶联物如式IV所示;
RT-W1-L6-W2-RE3 (IV)
其中,RT、RE3、W1、W2和L7如前定义。
在一个具体实施例中,本发明提供的连接有多肽元件或靶标分子T的偶联物如式V所示;
RT-W1-L7-W2-RE3 (V);
其中,RT、RE3、W1、W2和L7的定义如前所述。
在一个具体实施方案中,本发明还提供了如RT-W1-L5-Wb-C≡C-RE3(1-1)、RT-W1-L5-CO-RE3(1-2)或RT-W1-L5-CONH-RE3(1-3)所示的偶联物;
其中,Wb的定义同W的定义;W1、RT、RE3和L5的定义如前所述。
在另一优选例中,式1-1中,W1选自下组:NH、O;较佳地,W为NH。
在另一优选例中,式1-1中,Wb选自下组:无、-CH2-、-CH(OH)-、-C(=O)-。
在一个具体实施方案中,本发明提供了如下式所示的偶联物;
其中,W1、RT、RE3和R的定义如前所述;优选地,R为H、C1-6烷基(如Me、Et等);
m=0、1、2、3等(优选地,m不为0);
优选地,W1为W,且W如前定义。更优选地,W1为NH。
在一个具体实施方案中,本发明还提供了如下式所示的偶联物;
各式中,
R、R1、RT和RE3如前定义;
m=0,1,2,3,4等整数。
在另一个具体实施方案中,所述的偶联物选自组1的偶联物:
组1
其中,RT、RE3、R和R1如前定义;优选地,R和R1各自独立地为-W3-L3-W4-(RP)q,其中,W3、L3、W4、RP和m如前定义。
在一个具体实施方案中,本发明还提供了如RT-W1-L6-Wb-C≡C-RE3(1a-1)、RT-W1-L6-CO-RE3(1a-2)或RT-W1-L6-CONH-RE3(Ia-3)所示的偶联物;
其中,Wb的定义同W的定义;W1、RT、RE3和L5的定义如前所述。
在一个具体实施方案中,本发明还提供了如RT-Wa-L6-Wb-C≡C-RE3所示的偶联物;其中,Wa和Wb的定义同W的定义;RT、RE3和L6的定义如前所述。
在另一个优选的实施方案中,Wa选自下组:NH、O;较佳地,W为NH。
在另一个优选的实施方案中,Wb选自下组:无、-CH2-、-CH(OH)-、-C(=O)-。
在另一个具体实施方案中,所述的偶联物选自组1a的偶联物:
组1a
其中,RT和RE3如前定义。
在一个具体实施方案中,
本发明还提供了如RT-Wa-Cr1-Wa-Cr2-L5-W2-RE3(2)所示的偶联物;
其中,
Wa的定义同W的定义;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L5连接;
W、RT、RE3、W2和L5的定义如前所述。
在另一优选例中,W2选自下组:Wb-C≡C、C(=O)、C(=O)NH。
在另一个具体实施方案中,本发明还提供了如RT-Wa-Cr1-Cr2-L5-Wb-C≡C-RE3所示的偶联物;
其中,Wa和Wb的定义同W的定义;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L5连接;
RT、RE3和L5的定义如前所述。
优选地,Wa选自下组:NH、O;较佳地,Wa为NH。
优选地,Wb选自下组:无、-CH2-、-CH(OH)-、-C(=O)-。
优选地,所述的偶联物选自下组:
RT-NH-Cr1-Cr2-L5-CH2-C≡C-RE3;
RT-NH-Cr1-Cr2-L5-C(=O)-C≡C-RE3;
RT-NH-Cr1-Cr2-L5-CH(OH)-C≡C-RE3;
RT-NH-Cr1-Cr2-L5-C≡C-RE3;各式中,RT、RE3、Cr1、Cr2和L5的定义如前所述。
优选地,所述的偶联物选自下组:
RT-NH-Cr1-Cr2-L8-C≡C-RE3;
其中,RT、RE3、Cr1、Cr2和L8的定义如前所述。
在另一优选例中,Cr1选自下组:
在另一优选例中,Cr2选自下组:
在一个具体实施方案中,本发明提供了如下式所示的偶联物;
其中,
X4选自下组:CH2、O、NH、NR;
Y1和Y3各自独立地选自下组:CH、N;
Wa选自下组:NH、O;
m=0、1、2、3等(优选地,m不为0);
n=0、1、2、3等(优选地,n不为0);
RT、RE3和R的定义如前所述;优选地,R为H、C1-6烷基(如Me、Et等)、Ac、CHO、CONH2。
在另一个具体实施方案中,所述的偶联物为选自组2的偶联物:
组2
其中,RT、RE3、R和R1如前定义;优选地,R和R1各自独立地为-W3-L3-W4-(RP)q,其中,W3、L3、W4、RP和m如前定义。
在一个具体实施方案中,本发明还提供了如RT-Wa-Cr1-Wa-Cr2-L6-W2-RE3(I-2a)所示的偶联物;
其中,
Wa的定义同W的定义;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L5连接;
W、RT、RE3、W2和L5的定义如前所述。
在另一优选例中,W2选自下组:Wb-C≡C、C(=O)、C(=O)NH。
在另一个具体实施方案中,本发明还提供了如RT-Wa-Cr1-Cr2-L6-Wb-C≡C-RE3所示的偶联物;其中,Wa、Wb、Cr1、Cr2、RT、RE3和L5的定义如前所述。
优选地,所述的偶联物选自下组:
RT-NH-Cr1-Cr2-L6-CH2-C≡C-RE3;
RT-NH-Cr1-Cr2-L6-C(=O)-C≡C-RE3;
RT-NH-Cr1-Cr2-L6-CH(OH)-C≡C-RE3;
和RT-NH-Cr1-Cr2-L6-C≡C-RE3;
各式中,RT、RE3、Cr1、Cr2和L6的定义如前所述。
在另一个具体实施方案中,所述的偶联物为选自组2a中的偶联物:
组2a
在一个具体实施方案中,本发明提供了如RT-Ar1-L5-W2-RE(3)所示的偶联物;
其中,Ar1为-五或六元含氮杂芳基-;L5、RT、W2和RE3如前定义。
在另一优选例中,W2选自:-CONH-、-CO-、-CONH-、-Wb-C≡C-。
在一个具体实施方案中,本发明提供了如RT-Ar1-L5-CONH-RE3、RT-Ar1-L5-CO-RE3或RT-Ar1-L5-Wb-C≡C-RE3所示的偶联物;
其中,Ar1为-五或六元含氮杂芳基-;L5、RT和RE3如前定义。
在一个具体实施方案中,本发明提供了如下式所示的偶联物;
各式中,
V1、V2和V4各自独立地选自:-O-、-S-、-N=、-NH-、-CH=、-CH2-;
V3选自下组:-N=、-CH=;
R、R1、RT和RE3如前定义;
m=0,1,2,3,4等整数(较佳地,m不为0)。
在一个具体实施方案中,本发明提供了如下式所示的偶联物;
各式中,
R、R1、RT和RE3如前定义;
m=0,1,2,3,4等整数(较佳地,m不为0)。
在另一个具体实施方案中,所述的偶联物选自组3:
组3
其中,RT、RE3、R和R1如前定义;优选地,R和R1各自独立地为-W3-L3-W4-(RP)q,其中,W3、L3、W4、RP和m如前定义。
在一个具体实施方案中,本发明还提供了如RT-Ar1-L6-W2-RE所示的偶联物;
其中,Ar1、L5、RT、W2和RE3如前定义。
在一个具体实施方案中,本发明提供了如RT-Ar1-L6-CONH-RE3、RT-Ar1-L6-CO-RE3或RT-Ar1-L6-Wb-C≡C-RE3所示的偶联物;其中,Ar1、L6、RT和RE3如前定义。
在另一个具体实施方案中,所述的偶联物选自组3a-1~组3a-5;
组3a
其中,RT和RE3如前定义。
ACTED
在本发明中,当靶标分子为抗体,或多肽,或环肽,或者叶酸受体配体,或者HSP90配体,或其他细胞外靶蛋白配体时,也可将本发明的偶联物简称为ACTED或ACTED分子或ACTED化合物。
其中,TED是指如式I所示偶联物或如式VI所示的TED化合物失去N上的基团所形成的一价基团;
RP、L4如前定义。
在一个具体实施例中,本发明的ACTED实例包括但不限于选自下组的化合物或偶联物:
本发明的主要优点包括:
(a)本发明的偶联物TED,对肿瘤细胞上活性高,且具有细胞选择性,安全性好。
(b)本发明的偶联物TED,可以催化量发挥抑制细胞增殖的效果。细胞内能够循环发挥降解靶蛋白的作用,实现减少给药剂量,延长给药周期,达到安全有效的抗肿瘤效果。
(c)本发明的偶联物TED,连接头(L1)部分带有可与药物递送载体(如抗体,多肽,其他小分子配体)链接的活性位点。
下面结合具体实施方案,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。
除非特别说明,实施例中所用的起始原料或化合物均可市售获得或者通过本领域技术人员已知方法制备得到。
实施例1
实施例1.1P1-连接头b-A1的合成报告:
实施例1.1.1化合物UBI-1289合成(NH2-11b-A1)
步骤1:UBI-1289b(V1179-123)的合成:UBI-1289a(7.2g,36.3mmol)冰浴下加入4MHCl/二氧六环(25mL)反应过夜。加入***(25mL)打浆过滤干燥得到白色固体UBI-1289b(4.4g,收率89%)。
步骤2:UBI-1289d(V1179-126)的合成:UBI-1289b(4.2g,31.2mmol)溶于乙腈(150mL)加入K2CO3(13g,93.6mmol)和UBI-1289c(8.8g,31.2mmol)加热至80℃反应过夜。反应液过滤浓缩过柱(二氯甲烷/甲醇=0%~10%)得到黄色油状产物UBI-1289d(5g,收率56%)。LCMS[M+H]+=286.2.
步骤3:UBI-1289e(V1179-127)的合成:UBI-1289d(5g,17.5mmol)冰浴下加入4MHCl/二氧六环(10mL)室温反应1小时。反应浓缩得到白色固体产物UBI-1289e(7.8g)。
步骤4:UBI-1289g(V1179-130):UBI-1289e(7.2g,16.2mmol)溶于乙腈(100mL)加入K2CO3(4.5g,32.4mmol)和UBI-1289f(3g,17.9mmol)反应过周末。反应液过滤,滤液浓缩过柱(二氯甲烷/甲醇=0%~10%)得到黄色油状产物UBI-1289g(1g,23%yield)as ayellow oil.LCMS[M+H]+=272.3
步骤5:UBI-1289h(V1179-131):UBI-1289g(1g,3.7mmol)溶于THF(20mL)加入NaHCO3(621mg,7.4mmol)和Boc2O(800mg,3.7mmol)室温反应3小时。过滤浓缩过柱(二氯甲烷/甲醇=0%~3%)得到黄色油状粗产物UBI-1289h(490mg)。LCMS[M+H]+=372.2
步骤6:UBI-1289i(V1179-138):UBI-1289h(490mg,1.32mmol)溶于乙醇(10mL)加入2M NaOH(1.5mL,3mmol)室温反应过夜。食盐水(15mL)加入用***(20mL*2)萃取.水层用盐酸调至pH~5。再用乙酸乙酯(40mL*3)萃取,有机相合并用无水硫酸钠干燥过滤旋干得到无色油状粗品UBI-1289i(300mg)。LCMS[MS+H]+=344.1
步骤7:UBI-1289j(V2111-001):UBI-1289i(240mg,0.69mmol),A1(181mg,0.69mmol),HATU(524mg,1.38mmol),DIPEA(0.5mL)溶于DMF(3mL)室温反应过夜。反应浓缩过柱(二氯甲烷/甲醇=0%~30%)得到黄色油状产物UBI-1289j(V2111-001,140mg)。LCMS[M+H]+=585.4
步骤8:UBI-1289(V2111-002):UBI-1289j(140mg,0.24mmol)溶于THF(2mL)加入1MMe3P(0.36mL,0.36mmol),室温反应1小时。水(0.5mL)加入再反应1小时。反应液浓缩过反相(乙腈/水=0%~30%)得到黄色固体UBI-1289(40mg,收率30%)。LCMS[M+H]+=559.3
实施例1.2P1-连接头c-A1的合成
实施例1.2.1化合物UBI-1267的合成
步骤1:UBI-1267b(V879-078)
UBI1267a(10g,27.2mmol)和TEA(8.4mL,60.94mmol)溶于THF(250mL)冷却到0℃,然后加入MsCl(2.35mL,33.2mmol),80℃反应48小时。反应液冷却至室温,过滤,滤液加压浓缩得到油状物。然后加入HCl(1M)水溶液,用二氯甲烷萃取(20mL*3),有机相先后用饱和NaHCO3水溶液,水,饱和食盐水洗,无水Na2SO4干燥,浓缩得到粗品固体。该固体加入石油醚/乙酸乙酯(3/1)50mL重结晶。得到白色固体目标物UBI-1267b(4g,收率42%).
1H NMR(400MHz,氯仿-d)δ7.54–7.41(m,5H),7.36–7.09(m,10H),3.76(s,3H),2.26(s,1H),1.91–1.82(m,1H),1.47–1.33(m,1H).
步骤2:UBI-1267c(V907-082)
化合物UBI-1267b(2g,5.8mmol)溶于二氯甲烷(30mL)在0℃条件下加入三乙胺(5mL)。然后室温反应3小时。反应液加水(30mL)并用二氯甲烷(20mL)洗一次。水相用NaHCO3调节至pH>8。该水相在0℃条件下慢慢滴加PNZCl(7.6g,0.04mol)的乙酸乙酯(150mL)溶液。然后室温反应16小时。反应液用乙酸乙酯(20mL)萃取两次。有机相用无水硫酸钠干燥后旋干得到粗品。该粗品通过柱层析分离(石油醚/二氯甲烷=1/2)得到白色固体目标产物UBI-1267c(6.7g,收率61%)。LCMS[M+H]+=101。1H NMR(400MHz,氯仿-d)δ8.37–8.03(m,2H),7.74–7.43(m,2H),5.46–4.94(m,2H),3.76(s,3H),3.16(dd,J=5.3,3.2Hz,1H),2.64(dd,J=3.2,1.3Hz,1H),2.52(dd,J=5.3,1.3Hz,1H).
步骤3:UBI-1267e(V1686-112)
化合物UBI-1267c(3g,10.7mmol),UBI-1267d(30mL)冷却至0℃。然后BF3 Et2O(456mg,3.2mmol)慢慢滴加至反应液中并慢慢升至室温反应2小时。该反应液直接通过反相柱层析(甲醇/水=5%~95%40分钟)得到浅黄色油状目标产物UBI-1267e(3.6g,收率84%)。LCMS[M+H]+=225
1H NMR(400MHz,氯仿-d)δ8.45–8.09(m,2H),7.53(d,J=8.3Hz,2H),5.86(d,J=8.8Hz,1H),5.21(dd,J=13.3,4.3Hz,2H),4.47(d,J=8.6Hz,1H),4.00(dd,J=9.8,3.2Hz,2H),3.85–3.70(m,6H),3.68–3.55(m,5H).
步骤4:UBI-1267g(V1686-124)
化合物UBI-1267f(160mg,0.99mmol)溶于N,N-二甲基甲酰胺(10mL)后加入碳酸铯(646mg,1.98mmol),碘化钾(247mg,1.49mmol)以及UBI-1267e(400mg,0.99mmol),通过微波加热至100℃反应2小时。反应液过滤后滤液浓缩得到粗产物。该粗产物通过反相柱层析(甲醇/水=5%-95%,40分钟,75%收集)得到棕色油状目标产物UBI-1267g(300mg,收率61%)。LCMS[M+H]+=315。1H NMR(400MHz,氯仿-d)δ8.22(dd,J=9.3,2.6Hz,2H),7.67–7.38(m,2H),5.35–5.06(m,2H),4.60–4.34(m,1H),3.77(s,3H),3.69–3.54(m,7H),3.44(m,1H),2.85(d,J=12.9Hz,2H),2.63(s,2H),1.96(d,J=9.0Hz,3H),1.71(m,2H).
步骤5:UBI-1267h(V1686-137)
化合物UBI-1267g(530mg,1.07mmol)溶于甲醇(2mL),四氢呋喃(6mL)以及水(2mL)后加入氢氧化锂(68mg,1.61mmol)并反应过夜。反应液用乙酸乙酯(20mL)洗一次,水相通过3N稀盐酸调节pH=6并浓缩得到100mg白色固体目标产物UBI-1267h(450mg,收率87%)。该粗产物直接用于下一步反应。LCMS[M+H]+=301
步骤6:UBI-1267i(V1686-139)
化合物UBI-1267h(100mg,0.21mmol)以及来那度胺(54mg,0.21mmol)溶于干燥吡啶(3mL)后冰浴冷却至0℃,然后慢慢滴加三氯氧磷(319mg,2.1mmol)超过10分钟(颜色由棕色变为浅黄色)。该反应升至室温反应10分钟(颜色变为黑色)。反应液加水淬灭后直接浓缩得到粗产品。该粗产品通过反相柱层析(甲醇/水=5%-95%,40分钟,60%收集)得到棕色固体目标产物UBI-1267i(70mg,收率47%)。LCMS[M+H]+=542。1H NMR(400MHz,DMSO-d6)δ11.02(t,J=5.6Hz,1H),8.24(d,J=8.4Hz,2H),7.79(s,2H),7.64(d,J=8.2Hz,2H),7.53(d,J=10.3Hz,3H),5.26–5.00(m,3H),4.51(s,1H),4.20(m,5H),3.80–3.48(m,12H),3.17(s,2H),2.92(m,5H),2.12–1.64(m,8H).
步骤7:UBI-1267(V1686-141)
化合物UBI-1267i(70mg,0.10mmol)溶于四氢呋喃(5mL)和水(0.5mL)后加入三苯基膦树脂(100mg,0.15mmol)并加热至75℃反应18小时。反应液过滤后滤液浓缩得到棕色油状目标产物UBI-1267(60mg,收率90%)。LCMS[M+H]+=516
实施例1.2.2化合物UBI-1276的合成(P1-11c-COOH)
步骤1:UBI-1276c(V1899-053)
60%的NaH(857mg,20.4mmol)在冰浴下加入到无水DMF再加入UBI-1276a(2g,8.58mmol)反应15分钟。然后加入UBI-1276b(1.2g,10.7mmol)反应升至室温反应2小时.反应液旋干加入少量***和水打浆,把上层有机相丢弃丢弃,水层用盐酸调至pH~3。再用乙酸乙酯萃取,有机相合并用无水硫酸钠干燥过滤旋干。粗品过柱(二氯甲烷/甲醇=0%~20%)得到黄色油状产物UBI-1276c(1.148g,收率48%).
步骤2:UBI-1276d(V1685-061)
UBI-1276b(500mg,0.49mmol)溶于DCM冷却至-78℃.向反应液中通如臭氧气体,鼓泡20分钟直到反应液变蓝色。N2通入反应液20分钟后冷却至-78℃,然后加入二甲硫醚,缓慢升至室温,搅拌16小时。反应液浓缩得到粗品直接用于下一步反应。LCMS[M-H]+=260.1
步骤3:UBI-1276(V1782-105)
UBI-1276d(115mg,0.44mmol)溶于甲醇(4mL)加入UBI-1284d(120mg,0.22mmol)和NaOAc(18mg,0.22mmol)再反应15分钟.然后加入NaBH3CN(28mg,0.44mmol)加入再反应1小时.反应液旋干粗品过柱(二氯甲烷/甲醇=0%~100%)得到黄色油状产物UBI-1276(170mg,收率34%).LCMS[M+H]+=753.2.
1H NMR(400MHz,DMSO-d6)δ8.44–8.37(m,1H),8.09(d,J=7.7Hz,1H),7.85(s,1H),7.59(s,1H),7.48(dq,J=4.7,1.9Hz,2H),6.37(s,2H),4.36(t,J=8.1Hz,1H),4.23(dd,J=7.6,3.6Hz,1H),3.94(s,3H),3.76(d,J=7.1Hz,2H),3.70(d,J=7.4Hz,2H),3.46(d,J=6.0Hz,2H),3.39(d,J=2.8Hz,2H),3.25(s,3H),2.93(d,J=11.2Hz,2H),2.14–1.97(m,4H),1.89(d,J=3.0Hz,3H),1.81–1.71(m,7H),1.67–1.57(m,5H),1.37(s,9H),0.76(t,J=7.4Hz,3H).
实施例1.2.3化合物UBI-1287的合成(P1-10c-A1)
步骤1:UBI-1287b(V1782-116)
60%NaH(4.88g,122mmoL)冰浴下加入到无水DMF(30mL),UBI-1287a(10g,48.8mmoL)溶于无水DMF(20mL)滴加到上述反应液中。反应半小时,再加入UBI-1276b(5.3mL,61mmoL)反应升至室温反应2小时.反应液旋干加入少量***和水打浆,把上层有机相丢弃丢弃,水层用盐酸调至pH~3。再用乙酸乙酯萃取,有机相合并用无水硫酸钠干燥过滤旋干。粗品过柱(二氯甲烷/甲醇=0%~10%)得到无色油状产物UBI-1287b(10.5g,收率88%)。LCMS[M-H]+=244.3
1H NMR(400MHz,DMSO-d6)δ12.67(s,1H),6.90(d,J=8.3Hz,1H),5.85(ddt,J=17.4,10.5,5.3Hz,1H),5.24(dq,J=17.3,1.8Hz,1H),5.14(dq,J=10.4,1.5Hz,1H),4.14(dt,J=8.4,5.5Hz,1H),3.94(dq,J=5.3,1.7Hz,2H),3.60(dt,J=6.5,3.8Hz,2H),1.38(s,9H).
步骤2:UBI-1287c(V1782-134)
UBI-1287b(245mg,1mmol),A1(260mg,1mmol),HATU(760mg,2mmol),DIPEA(390mg,3mmol)溶于DMF(5mL)室温反应过夜.反应液浓缩过柱(二氯甲烷/甲醇=0%~10%)得到浅黄色固体产物UBI-1287c(400mg,收率82%)。LCMS[M+H]+=487.1
步骤3:UBI-1287d(V1782-141)
UBI-1287c(200mg,0.4mmol)加入到水(3mL)和丙酮(15mL)再将催化量的K2OsO4.2H2O(cat.)和NaIO4(263mg,1.2mmol)加入室温反应2小时.过滤浓缩,加水用乙酸乙酯萃取(20mL*2).有机相合并用无水硫酸钠干燥过滤,过滤液直接用于下一步反应。LCMS[M+H]+=489.3
步骤4:UBI-1287(V1782-142)
UBI-1287d(V1782-141)和UBI-1284d(40mg,0.073mmol)溶于甲醇(5mL)加入NaOAc(6mg,0.073mmol)室温反应15分钟.再加入NaBH3CN(9mg,0.15mmol)室温反应1小时.反应浓缩制备得到白色固体产物UBI-1287(8mg,收率11%)。LCMS[M+H]+=980.2.
实施例1..2.4化合物UBI-1288的合成(P1-12c-A1)
步骤1:UBI-1288b(V1782-140)
UBI-1288a(500mg,1.83mmol),A1(473mg,1.83mmol),HATU(1.39g,3.66mmol),DIPEA(715mg,5.49mmol)溶于DMF(5mL)室温反应过夜.反应液浓缩过柱(二氯甲烷/甲醇=0%~10%)得到白色固体UBI-1288b(320mg,收率34%)。LCMS[M+H]+=515.2
步骤2:UBI-1288c(V1782-143)
UBI-1288b(150mg,0.3mmol)加入到水(2mL)和丙酮(8mL)再加入催化量的K2OsO4.2H2O室温反应2小时。再加入NaIO4(192mg,0.9mmol)室温反应过夜.过滤浓缩,加水用乙酸乙酯萃取(20mL*2).有机相合并用无水硫酸钠干燥过滤,过滤液直接用于下一步反应。LCMS[M+H]+=517.3
步骤3:UBI-1288(V1782-145)
UBI-1288c和UBI-1284d(40mg,0.073mmol)溶于甲醇(5mL)加入NaOAc(6mg,0.073mmol)和催化量HOAc反应20分钟.然后加入NaBH3CN(9mg,0.15mmol)室温反应1小时.反应液制备得到白色固体UBI-1288(25mg,收率33%)。LCMS[M+H]+=1008.2.
1H NMR(400MHz,DMSO-d6)δ11.03(s,1H),9.94(s,1H),9.42(s,1H),8.39(d,J=7.1Hz,1H),8.10(s,1H),7.80(s,1H),7.74(t,J=9.3Hz,1H),7.52(m,4H),7.13(m,1H),5.17(m,1H),4.42–4.21(m,5H),4.13(m,1H),3.93(s,3H),3.72(m,2H),3.28(m,2H),3.23(s,3H),3.13(m,2H),2.91(m,1H),2.61(m,2H),2.46–2.44(m,1H),2.27(m,1H),2.02(m,6H),1.89–1.72(m,7H),1.63(m,5H),1.52(m,2H),1.39(s,9H),0.76(t,J=7.4Hz,3H).
实施例1.3P1-连接头h-A1的合成报告
实施例1.3.1化合物UBI-1268的合成(P1-13h)
步骤1:UBI-1268b(V2037-023)
化合物UBI-1268a(2.1g,7.3mmol)溶于3N稀盐酸(50mL)后室温反应2小时。反应液用二氯甲烷(30mL)萃取,有机相用无水硫酸钠干燥后直接用于下一步反应。LCMS[M+H]+=287
步骤2:UBI-1268d(V2037-024)
化合物UBI-1268c(600mg,2.46mmol)溶于甲醇(30mL)后加入乙酸钠(403mg,4.92mmol)以及UBI-1268b(1.56g,7.38mmol)并在25℃条件下反应1小时后加入氰基硼氢化钠(463mg,7.38mol)。该反应室温过夜。反应液浓缩后用水(20mL)洗一次,乙酸乙酯(30mL)萃取,有机相浓缩后通过柱层析(甲醇/二氯甲烷=0-10%)得到无色油状目标产物UBI-1268d(790mg,收率25%)。LCMS[M+H]+=441。1H NMR(400MHz,氯仿-d)δ4.27(q,J=7.1Hz,2H),4.18(d,J=8.8Hz,2H),3.83(dd,J=12.0,6.9Hz,5H),3.63(t,J=5.0Hz,2H),3.12(d,J=27.2Hz,6H),2.73(t,J=5.0Hz,2H),2.27(m,2H),1.94(d,J=14.0Hz,2H),1.45(s,9H),1.32(t,J=7.1Hz,3H).
步骤3:UBI-1268e(V2037-025)
化合物UBI-1268d(220mg,0.5mmol)溶于甲醇(10mL)加入一滴醋酸以及多聚甲醛(23mg,0.75mmol)并在25℃条件下反应1小时后加入氰基硼氢化钠(94mg,1.5mol)。该反应室温过夜。反应液水(10mL)洗一次,乙酸乙酯(20mL)萃取,有机相浓缩后得到无色油状目标产物UBI-1268e(200mg,收率25%)。该粗产物直接用于下一步反应。LCMS[M+H]+=455
步骤4:UBI-1268f(V2037-027)
化合物UBI-1268e(220mg,0.48mmol)溶于乙醇(1mL),四氢呋喃(3mL)以及水(1mL)后加入氢氧化锂(31mg,0.73mmol)并室温反映过夜。反应液用乙酸乙酯(10mL)洗一次,水相通过3N HCl酸化至pH=6,后冻干得到白色固体目标产物UBI-1268f(250mg,收率100%)(含盐)。该粗产物直接用于下一步反应。LCMS[M+H]+=427。
步骤5:UBI-1268g(V2037-032)
化合物UBI-1268f(200mg,0.47mmol)以及来那度胺(121mg,0.47mmol)溶于干燥吡啶(5mL)并冷却至0℃,然后慢慢滴加三氯氧磷(718mg,4.69mmol)超过10分钟(颜色由棕色转为淡黄色)。然后室温反应10分钟(颜色变为黑色)。反应液加水(5mL)淬灭后浓缩得到粗产物。该粗产物通过反相柱层析(甲醇/水=5%-95%,40分钟,60%收集)得到棕色固体目标产物UBI-1268g(100mg,收率32%)。LCMS[M+H]+=668
步骤6:UBI-1268(V2037-033)
化合物UBI-1268g(30mg,0.04mmol)溶于二氯甲烷(8mL)以及甲醇(2mL)后加入催化量Pd/C。反应液在氢气条件下室温反应4小时。反应液过滤后滤液浓缩得到黄色油状目标产物UBI-1268g(10mg,收率35%)。该粗产物直接用于下一步反应。LCMS[M+H]+=642
实施例1.3.2化合物UBI-1269的合成(P1-13h)
步骤1:UBI-1269c(V2037-041)
化合物1269a(2g,11.4mmol)溶于二氯甲烷(60mL)冷却至0℃后加入三氟乙酸乙酯(1.6g,11.4mmol)。该反应室温过夜。反应液浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1269c(1.5g,收率48%)。LCMS[M+H]+=273。1H NMR(400MHz,氯仿-d)δ8.23(s,1H),3.72–3.53(m,8H),3.52–3.43(m,2H),2.81(t,J=6.6Hz,2H),1.98–1.81(m,4H),1.73(p,J=6.3Hz,2H).
步骤2:UBI-1269e(V2037-043)
化合物UBI-1269c(600mg,2.2mmol)溶于乙腈(15mL)并加入碳酸钾(365mg,2.6mmol)以及UBI-1269d(293mg,2.2mmol),反应液加热至60℃后反应16小时。反应液过滤后滤液浓缩得到粗产物。该粗产物通过柱层析分离(甲醇/二氯甲烷=0-10%)得到无色油状目标产物UBI-1269e(240mg,收率34%)。LCMS[M+H]+=325。1H NMR(400MHz,氯仿-d)δ7.91(s,1H),3.69–3.62(m,2H),3.62–3.55(m,5H),3.54–3.43(m,4H),2.83(dt,J=12.0,6.6Hz,4H),2.46(td,J=6.6,2.7Hz,2H),2.07–1.96(m,1H),1.93–1.72(m,4H).
步骤3:UBI-1269f(V2037-044)
化合物UBI-1269e(250mg,0.77mmol)溶于四氢呋喃(15mL)后加入碳酸氢钠(97mg,1.16mmol)以及(Boc)2O(200mg,0.93mmol)并室温反应1小时。反应液浓缩后通过柱层析分离(甲醇/二氯甲烷=1/20)得到无色油状目标产物UBI-1269f(130mg,收率40%)。LCMS[M+H]+=425
步骤4:UBI-1269g(V2037-047)
化合物UBI-1269f(150mg,2.9mmol)溶于甲醇/四氢呋喃/水(5/5/3mL)后加入氢氧化钠(42mg,1.06mmol)并室温反应1小时。反应液浓缩得到无色油状目标产物UBI-1269g(110mg,收率95%)。该粗产物直接用于下一步反应。LCMS[M+H]+=329
步骤5:UBI-1269(V2037-049)
化合物P1(149mg,0.35mmol)溶于N,N-二甲基甲酰胺(2mL)并加入HATU(266mg,070mmol)以及DIEA(136mg,1.05mmol)。室温反应20分钟后加入UBI-1269g(115mg,0.35mmol),然后室温反应16小时。反应液加水(10mL)并用乙酸乙酯(10mL)萃取一次,有机相浓缩后有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到棕色油状目标产物UBI-1269(150mg,收率58%)。LCMS[M+H]+=736
实施例1.3.3化合物UBI-1270的合成方法(P1-12h)
步骤1:UBI-1270c(V2037-055)
化合物UBI-1270a(3g,17.1mmol)溶于UBI-1270b(10mL)以及50%aq.NaOH(50mL)并加入N(Bu)4HSO4(11.7g,34.3mmol),该反应在40℃条件下反应16小时。该反应水(20mL)洗一次,二氯甲烷(50mL)萃取,有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到无色油状目标产物UBI-1270c(4g,收率83%)。LCMS[M+H]+=282
步骤2:UBI-1270d(V2037-057)
化合物UBI-1270c(5.5g,19.6mmol)用于N,N-二甲基甲酰胺(50mL)并加入叠氮化钠(1.9g,29.4mmol)在80℃条件下反应4小时。反应液加入冰水(30mL)并用二氯甲烷(20mL)萃取两次。有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/20)得到无色油状目标产物UBI-1270d(1.2g,收率21%)。LCMS[M+H]+=289。1H NMR(400MHz,氯仿-d)δ4.91(s,1H),3.72–3.63(m,5H),3.63–3.58(m,2H),3.58–3.51(m,2H),3.40(t,J=5.0Hz,2H),3.23(d,J=5.9Hz,2H),1.88–1.70(m,2H),1.44(d,J=0.8Hz,9H).
步骤3:UBI-1270e(V2037-063)
化合物UBI-1270d(1.2g,4.2mmol)溶于二氯甲烷(15mL)后加入HCl/二氧六环(15mL)并室温反应2小时。反应液浓缩后得到黄色油状目标产物UBI-1270e(1g,收率100%)。LCMS[M+H]+=189
步骤4:UBI-1270g(V2037-065)
化合物UBI-1270e(500mg,2.2mmol)溶于乙腈(40mL)后加入碳酸钾(676mg,4.9mmol),催化量碘化钾以及UBI-1270f(499mg,2.2mmol),反应液在90℃条件下反应16小时。反应液过滤,滤液浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1270g(280mg,收率52%)。LCMS[M+H]+=241。1H NMR(400MHz,氯仿氯仿-d)δ5.48(s,1H),3.85–3.57(m,8H),3.44(dd,J=5.5,4.4Hz,2H),3.04(dt,J=13.3,6.4Hz,4H),2.67(td,J=6.7,2.7Hz,2H),2.11(t,J=2.7Hz,1H),2.02(dq,J=8.8,6.0Hz,2H).
步骤5:UBI-1270h(V2037-067)
化合物UBI-1270g(280mg,1.2mmol)溶于四氢呋喃(10mL)以及水(2mL)后加入(Boc)2O(381mg,1.7mmol)以及碳酸氢钠(196mg,2.3mmol)并室温反应1小时。反应液水(10mL)洗一次,乙酸乙酯(15mL)萃取,有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1270h(270mg,收率68%)。LCMS[M+H]+=341
步骤6:UBI-1270i(V2037-069)
化合物UBI-1270h(270mg,0.08mmol)溶于四氢呋喃(5mL)加入三甲基膦(1.2mL)后在45℃条件下条件下反应1小时。再加入水(1mL)后45℃反应1小时。反应液浓缩后得到无色油状目标产物UBI-1270i(250mg,收率100%)。该粗产物直接用于下一步反应。LCMS[M+H]+=315
步骤7:UBI-1270(V2037-070)
化合物P1(338mg,0.80mmol)溶于N,N-二甲基甲酰胺(6mL)后加入HATU(363mg,0.96mmol)以及DIEA(308mg,2.39mmol)。室温反应20分钟后加入,UBI-1270i(250mg,0.80mmol)。然后反应室温过夜。反应液加水(10mL),并用乙酸乙酯(15mL)萃取,有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到浅黄色油状目标产物UBI-1270(400mg,收率70%)。LCMS[M+H]+=722。1H NMR(400MHz,DMSO-d6)δ8.47–8.30(m,2H),7.85(s,1H),7.60(s,1H),7.49(d,J=8.0Hz,2H),4.41–4.30(m,1H),4.24(dd,J=7.6,3.6Hz,1H),3.93(s,3H),3.59–3.51(m,4H),3.49(dd,J=6.1,3.7Hz,2H),3.42(q,J=5.9Hz,2H),3.36(t,J=6.2Hz,2H),3.24(d,J=4.0Hz,4H),3.21(d,J=5.3Hz,1H),3.20–3.15(m,2H),2.81(s,1H),2.33(s,2H),1.89(d,J=8.5Hz,2H),1.77(ddd,J=14.6,7.8,3.7Hz,4H),1.64(dt,J=14.4,4.7Hz,5H),1.37(s,9H),0.76(t,J=7.5Hz,3H).
实施例1.3.4化合物UBI-1271的合成方法(P1-13h)
步骤1:UBI-1271c(V)
化合物UBI-1271a(10g,64.6mmol)溶于二氧六环(25mL)以及60%氢氧化钾(10mL)后加入UBI-1271b(15g,129.3mmol),并在25℃条件下反应18小时。反应液浓缩后用二氯甲烷(30mL)萃取三次。有机相浓缩后通过柱层析分离(石油醚/乙酸乙酯=0-100%)得到无色油状目标产物UBI-1271c(8g,收率43%)。LCMS[M+H]+=290。1H NMR(400MHz,DMSO-d6)δ6.81–6.58(m,1H),3.56(t,J=6.2Hz,2H),3.35(t,J=6.1Hz,2H),3.04(q,J=6.0Hz,2H),2.41(t,J=6.2Hz,2H),1.38(d,J=11.9Hz,18H).
步骤2:UBI-1271d(V2037-056)
化合物UBI-1271c(8g,28mmol)溶于四氢呋喃(80mL)并冷却至0℃后加入LiAlH4/THF(30.4mL)并室温反应1小时。反应液加水(100mL)淬灭,乙酸乙酯(150mL)萃取,有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1271d(4.6g,收率75%)。LCMS[M+H]+=220。1H NMR(400MHz,氯仿-d)δ4.84(s,1H),3.76(t,J=5.7Hz,2H),3.63(t,J=5.8Hz,2H),3.54–3.42(m,2H),3.31(t,J=5.2Hz,2H),2.12(s,1H),1.83(p,J=5.8Hz,2H),1.45(s,9H).
步骤3:UBI-1271e(V2037-060)
化合物UBI-1271d(1g,4.6mmol)溶于二氯甲烷(10mL)后加入三乙胺(553mg,5.5mmol),然后甲磺酰氯(680mg,5.9mmol)溶于二氯甲烷(10mL)慢慢滴加入反应液。该反应室温反应2小时候加水(10mL)并用二氯甲烷(20mL)萃取,有机相浓缩后得到黄色油状目标产物UBI-1271e(1.2g,收率88%)。该粗产物直接用于下一步反应。LCMS[M+H]+=298
步骤4:UBI-1271g(V2037-061)
化合物UBI-1271f(742mg,4.6mmol)溶于乙腈(15mL)后加入碳酸钾(1.4g,10.0mmol)以及UBI-1271e(1.4g,4.6mmol)并加热至60℃反应16小时。反应液过滤,滤液浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到无色油状目标产物UBI-1271g(1.2g,收率60%)。LCMS[M+H]+=328
1H NMR(400MHz,氯仿-d)δ5.04(s,1H),3.85–3.69(m,2H),3.58(m,2H),3.51(q,J=6.3,5.7Hz,2H),3.30(q,J=5.3Hz,2H),2.92(m,4H),1.93–1.79(m,2H),1.57(m,4H),1.45(s,9H).
步骤5:UBI-1271h(V2037-064)
化合物UBI-1271g(1.6g,4.9mmol)溶于二氯甲烷(15mL)后加入HCl/二氧六环(15mL)并室温反应2小时。反应液浓缩后得到黄色油状目标产物UBI-1271h(1.2g,收率100%)。该粗产物直接用于下一步反应。LCMS[M+H]+=228
步骤6:UBI-1271j(V2037-066)
化合物UBI-1271h(600mg,2.3mmol)溶于乙腈(40mL)后加入碳酸钾(691mg,5.0mmol),催化量碘化钾以及UBI-1271i(510mg,2.3mmol),反应液加热至90℃反应16小时。反应液过滤,滤液浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1271j(230mg,收率36%)。LCMS[M+H]+=280。1H NMR(400MHz,氯仿-d)δ4.05(t,J=5.1Hz,3H),3.81–3.51(m,5H),3.41–2.92(m,8H),2.59(m,2H),2.28–1.91(m,5H).
步骤7:UBI-1271k(V2037-068)
化合物UBI-1271j(120mg,0.43mmol)溶于四氢呋喃(10mL)和水(2mL)后加入(Boc)2O(141mg,0.65mmol)以及碳酸氢钠(72mg,0.86mmol)并室温反应1小时。反应液加水(10mL)后用乙酸乙酯(15mL)萃取,有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1271k(110mg,收率67%)。LCMS[M+H]+=380
步骤8:UBI-1271l(V2037-072)
化合物UBI-1271k(230mg,0.61mmol)溶于四氢呋喃(5mL)后加入三甲基膦(0.73mL)并在45℃条件下加热1小时。然后加水(1mL)再反应1小时。反应液浓缩后得到无色油状目标产物UBI-1271l(210mg,收率100%)。该粗产物直接用于下一步反应。LCMS[M+H]+=354
步骤9:UBI-1271(V2037-073)
化合物P1(253mg,0.59mmol)溶于N,N-二甲基甲酰胺(6mL)后加入HATU(271mg,0.71mmol)以及DIEA(230mg,1.78mmol)并室温反应20分钟后加入UBI-1271l(210mg,0.59mmol)并室温反应16小时。反应液加水(10mL),乙酸乙酯萃取(20mL),有机相浓缩后通过柱层析分离(甲醇/二氯甲烷=1/10)得到浅黄色油状目标产物UBI-1271(360mg,收率80%)。LCMS[M+H]+=761
实施例1.3.5化合物UBI-1272的合成方法(P1-14h)
步骤1:UBI-1272b(V2128-008)
化合物UBI-1272a(5g,28.5mmol)和三乙胺(3.5g,34.2mmol)在干燥二氯甲烷(50ml)中的溶液中缓慢加入甲烷磺酰氯(4.2g,37.1mmol),将反应在0℃下搅拌30分钟后升至室温反应5小时。反应液加水(10mL)并用二氯甲烷(10mL)萃取三次。有机层用盐水洗涤,经无水硫酸钠干燥,浓缩,得到无色油状目标产物UBI-1272b(7.2g,收率100%)。
步骤2:UBI-1272d(V2128-009)
在0℃下,化合物UBI-1272c(12.6g,165.8mmol)的N,N-二甲基甲酰胺(80ml)溶液中加入60%氢化钠(2.2g,55.3mmol。室温30分钟后慢慢加入UBI-1272b(7g,27.6mmol)的N,N-二甲基甲酰胺(20ml)溶液,然后室温反应12小时。在0℃下用饱和氯化铵溶液淬灭反应。将得到的混合物在减压下浓缩。将残余物用盐水稀释并用乙酸乙酯萃取。合并的有机层用盐水洗涤,并用无水硫酸钠干燥,过滤并浓缩。残余物通过硅胶柱色谱纯化,用33%乙酸乙酯的石油醚溶液洗脱,得到浅黄色油状目标产物UBI-1272d(2.6g,收率40%)。
1H NMR(400MHz,DMSO-d6)δ6.75(s,1H),4.36(t,J=5.2Hz,1H),3.52–3.33(m,6H),2.98–2.92(m,2H),1.60(dt,J=17.0,6.6Hz,4H),1.37(s,9H).
步骤3:UBI-1272e(V2037-076)
化合物UBI-1272d(1.5g,6.4mmol)溶于二氯甲烷(20mL)并加入三乙胺(780mg,7.7mmol),甲磺酰氯(958mg,8.4mmol)溶于二氯甲烷(10mL)满满滴加入反应液中并室温反应2小时。反应液加水(10mL),二氯甲烷(15mL)萃取,有机相旋干后得到浅黄色油状目标产物UBI-1272e(2.0g,收率100%)。该粗产物直接用于下一步反应。LCMS[M+H]+=312
步骤4:UBI-1272g(V2037-079)
化合物UBI-1272f(1.0g,6.4mmol)溶于乙腈(50mL)后加入碳酸钾(2.0g,14.2mmol),催化量碘化钾以及UBI-1272e(2.0g,6.4mmol)并加热到90℃反应16小时。反应液过滤,滤液浓缩后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1272g(550mg,收率26%)。LCMS[M+H]+=342。1H NMR(400MHz,氯仿-d)δ4.90(s,1H),3.47(dd,J=11.7,5.8Hz,6H),3.22(q,J=6.3Hz,2H),2.84(m,2H),2.53(m,2H),2.34(m,1H),2.02(m,2H),1.89–1.62(m,6H),1.44(s,9H).
步骤5:UBI-1272h(V2037-080)
化合物UBI-1272g(550mg,1.61mmol)溶于二氯甲烷(5mL)后加入HCl/二氧六环(3mL)并室温反应2小时。反应液旋干后得到黄色油状粗产物UBI-1272h(500mg,收率100%)。该粗产物直接用于下一步反应。LCMS[M+H]+=242
步骤6:UBI-1272j(V2037-081)
化合物UBI-1272h(570mg,2.0mmol)溶于乙腈(40mL)后加入碳酸钾(621mg,4.5mmol),催化量碘化钾以及UBI-1272i(458mg,2.0mmol)后加热到90℃反应16小时。反应液过滤,滤液旋干后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1272j(470mg,收率78%)。LCMS[M+H]+=294
步骤7:UBI-1272k(V2037-082)
化合物UBI-1272j(470mg,1.6mmol)溶于四氢呋喃(10mL)和水(2mL)后加入(Boc)2O(525mg,2.4mmol)以碳酸氢钠(269mg,3.2mmol)并室温反应1小时。反应液加水(10mL),并用乙酸乙酯(20mL)萃取,有机相旋干后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1272k(250mg,收率40%)。LCMS[M+H]+=394。1H NMR(400MHz,氯仿-d)δ3.50–3.22(m,9H),2.79(m,2H),2.42(m,4H),2.28–2.10(m,2H),2.05–1.86(m,3H),1.77(tt,J=14.2,6.7Hz,6H),1.46(s,9H).
步骤8:UBI-1272l(V2037-083)
化合物UBI-1272k(250mg,0.64mmol)溶于四氢呋喃(5mL)后加入三甲基膦(0.95mL)并加热至45℃反应1小时。加水(1mL)后继续45℃反应1小时。反应液旋干后得到无色油状目标产物UBI-1272l(230mg,收率99%)。该粗产物直接用于下一步反应。LCMS[M+H]+=368
步骤9:UBI-1272(V2037-084)
化合物P1(266mg,0.63mmol)溶于N,N-二甲基甲酰胺(6mL)后加入HATU(286mg,0.75mmol)以及DIEA(243mg,1.88mmol)。室温反应20分钟后加入UBI-1272l(230mg,0.63mmol)再室温反应16小时。反应液加水(10mL),乙酸乙酯萃取(20mL),有机相旋干后通过柱层析分离(甲醇/二氯甲烷=1/10)得到黄色油状目标产物UBI-1272(380mg,收率78%)。LCMS[M+H]+=775
实施例1.3.6化合物UBI-1273的合成方法(P1-15h)
步骤1:UBI-1273b(V2037-087)
化合物UBI-1272h(570mg,2.1mmol)溶于乙腈(40mL)后加入碳酸钾(621mg,4.5mmol),催化量碘化钾以及UBI-1273a(333mg,2.1mmol)并升温至90℃反应16小时。反应液过滤,滤液旋干后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1273b(400mg,收率19%)。
LCMS[M+H]+=308
步骤2:UBI-1273c(V2037-089)
化合物UBI-1273b(500mg,1.6mmol)溶于四氢呋喃(10mL)和水(2mL)后加入(Boc)2O(532mg,2.4mmol)以及碳酸氢钠(274mg,3.3mmol)并室温反应1小时。反应液加水(10mL),乙酸乙酯(20mL)萃取,有机相旋干后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1273c(250mg,收率38%)。
LCMS[M+H]+=408
1H NMR(400MHz,氯仿-d)δ3.57–3.36(m,5H),3.27(m,4H),2.80(s,2H),2.45(s,2H),2.19(td,J=7.1,2.7Hz,3H),1.96(t,J=2.7Hz,3H),1.86–1.54(m,8H),1.45(s,9H).
步骤3:UBI-1273d(V2037-091)
化合物UBI-1273c(250mg,0.61mmol)溶于四氢呋喃(5mL)后加入三甲基膦(0.92mL)并加热至45℃反应1小时。再加水(1mL)后继续45℃反应1小时。反应液旋干后得到无色油状目标产物UBI-1273d(230mg,收率100%)。该目标产物直接用于下一步反应。
LCMS[M+H]+=382
步骤4:UBI-1273(V2037-093)
化合物P1(257mg,0.60mmol)溶于N,N-二甲基甲酰胺(6mL)后加入HATU(275mg,0.72mmol)以及DIEA(234mg,1.81mmol)。室温反应20分钟后加入UBI-1273d(230mg,0.60mmol)继续室温反应16小时。反应液加水(10mL),乙酸乙酯(20mL)萃取,有机相旋干后通过柱层析分离(甲醇/二氯甲烷=1/10)得到浅黄色油状目标产物UBI-1273(330mg,收率69%)。
LCMS[M+H]+=790
实施例1.3.7化合物UBI-1275的合成方法(P1-13h)
步骤1:UBI-1275a(V2037-109))
化合物UBI-1272d(600mg,2.6mmol)溶于二氯甲烷(10mL)后加入HCl/二氧六环(5mL)并室温反应2小时。反应液旋干后得到黄色油状目标产物UBI-1275a(500mg,收率100%)。该粗产物直接用于下一步反应。
LCMS[M+H]+=134
步骤2:UBI-1275c(V2037-110)
化合物UBI-1275a(436mg,2.6mmol)溶于乙腈(40mL)后加入碳酸钾(782mg,5.7mmol),催化量碘化钾以及UBI-1275b(577mg,2.6mmol)并升温至90℃反应16小时。反应液过滤,滤液旋干后通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色油状目标产物UBI-1275c(400mg,收率86%)。
LCMS[M+H]+=186
步骤3:UBI-1275d(V2037-111)
化合物UBI-1275c(600mg,3.2mmol)溶于四氢呋喃(10mL)和水(2mL)后加入(Boc)2O(1.1g,4.9mmol)以及碳酸氢钠(545mg,6.5mmol)并室温反应1小时。反应液加水(10mL),乙酸乙酯(20mL)萃取,有机相旋干后通过柱层析分离(甲醇/二氯甲烷=1/10)得到无色油状目标产物UBI-1275d(260mg,收率28%)。
LCMS[M+H]+=286
步骤4:UBI-1275e(V2128-054)
化合物UBI-1275d(245mg,0.86mmol)溶于二氯甲烷(8ml)后加入戴斯马丁试剂(546mg,1.3mmol)并室温反应1小时。反应液过滤后直接用于下一步。
LCMS[M+1]+=284.
步骤5:UBI-1275(V2128-056)
化合物UBI-1275e(220mg,0.78mmol)以及UBI-1275f(280mg,0.54mmol)溶于二氯甲烷/甲醇=10/1(16ml)并加入乙酸钠(106mg,0.78mmol)并继续室温反应1小时,然后向混合物中加入氰基硼氢化钠(49mg,0.78mmol,继续室温反应3小时。反应液加水并用二氯甲烷萃取三次,用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩,得到粗品。粗产物通过柱层析分离(甲醇/二氯甲烷=0-10%)得到黄色固体目标产物UBI-1275(55mg,收率9%)。
LCMS[M+H]+=747。
实施例1.3.8化合物UBI-1274的合成方法(NH2-10h-A1)
步骤1:UBI-1274c(V2127-034)
化合物UBI-1274a(900mg,3.18mmol),DIEA(410mg,3.18mmol)以及UBI-1274b(411mg,4.77mmol)溶于乙腈(30mL)加热至80℃反应18小时。反应液旋干后通过柱层析分离(石油醚/乙酸乙酯=50%~100%20分钟,然后甲醇/二氯甲烷=0%~10%40分钟)得到白色固体目标产物UBI-1274c(1.0g,收率86%)。
步骤2:UBI-1274d(V2037-116)
化合物UBI-1274c(260mg,0.70mmol)溶于甲醇(2mL),四氢呋喃(6mL)以及水(2mL)后加入氢氧化锂(36mg,0.85mmol)并在室温下反应1小时。反应液用乙酸乙酯(15mL)洗一次,水相通过3N HCl酸化至pH=6并浓缩得到白色固体目标产物UBI-1274d(330mg,收率100%)。
LCMS[M+H]+=356
步骤3:UBI-1274e(V2037-113)
化合物UBI-1274d(250mg,0.70mmol)溶于N,N-二甲基甲酰胺(6mL)后加入HATU(321mg,0.85mmol)以及DIEA(273mg,2.11mmol)。室温反应20分钟后,加入来那度胺(182mg,0.70mmol),继续室温反应16小时。反应液加水(10mL),乙酸乙酯(20mL)萃取,有机相旋干后通过制备板分离(甲醇/二氯甲烷=1/10)得到黄色油状目标产物UBI-1274e(18mg,收率4%)。
LCMS[M+H]+=597
步骤4:UBI-1274(V2037-114)
化合物UBI-1274e(20mg,0.03mmol)溶于二氯甲烷(2mL)后加入HCl/二氧六环(0.3mL),并室温反应2小时。反应液旋干得到黄色油状目标产物UBI-1274(15mg,收率100%)。该粗产物直接用于下一步反应。
LCMS[M+H]+=497
实施例1.3.9化合物UBI-1278的合成方法(9h-A1)
步骤1:UBI-1278b(V1661-133)
UBI-1278a(4.197g,20.5mmol)溶解在无水DMF(60mL),降温至0℃,氢化钠(1.64g,41mmol)按加入到上述溶液中。反应混合物在0℃搅拌30分钟。将溴丙炔(80%甲苯溶液,2.2mL,20.5mmol)慢慢滴加入体系(15min),继续在0℃下反应2小时直至反应完全。加水(50mL)淬灭,乙酸乙酯萃取(50mL×3)。合并有机层,无水硫酸钠干燥。反应液浓缩后通过硅胶柱层析分离(石油醚:乙酸乙酯=2:1),得到UBI-1278b(4.86g,98%收率)。LC-MS:[M-56]+=188.2
步骤2:UBI-1278d(V1661-136)
UBI-1278b(1g,6.94mmol)、三乙胺(1.1mL,7.8mmol)溶解在四氢呋喃(20mL)中,冷却至-10℃。滴加UBI-1278c(1.0mL,7.8mmol),于-10℃搅拌1小时。反应体系加热到0℃。将NaBH4(0.78g,20.8mmol)溶于四氢呋喃(10mL)和水(2mL)的混合物滴加入上述体系。0℃搅拌1小时。将混合物倒入20%柠檬酸的水溶液中。用乙酸乙酯(30mL×3)萃取。合并有机相,用饱和食盐水洗涤、干燥(MgSO4)、过滤。浓缩后通过硅胶柱层析分离(石油醚:乙酸乙酯=8:1),得到UBI-1278d(0.9g,100%收率)LC-MS:[M-56]+=174.2
步骤3:UBI-1278e(V2031-017)
在氮气保护下,将UBI-1278d(300mg,1.3mmol)、UBI-1237(480mg,1.3mmol)、PdCl2(PPh3)2(46mg,0.06mmol)、碘化铜(25mg)、三乙胺(400mg)加入无水DMF(10mL)中,反应体系加热至80℃,搅拌2小时。冷却至室温,将混合物加入水中,用二氯甲烷萃取,用水洗,硫酸钠干燥,过滤,反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),得到UBI-1278e(200mg,收率32.4%)。LC-MS:[M+H]+=472.5
步骤4:UBI-1278f(V2031-018)
将戴斯马丁试剂(555mg,1.31mmol)加入UBI-1278e(200mg,0.87mmol)的二氯甲烷(10mL)溶液中,于0℃下搅拌1小时。用饱和硫代硫酸钠溶液淬火,二氯甲烷萃取。用饱和碳酸氢钠溶液、盐水和水洗涤有机相,硫酸钠上干燥。反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%)纯化得到黄色固体UBI-1278f(110mg,收率55.3%)。LC-MS:[M+H]+=580.2
步骤5:UBI-1278h(V2031-027)
将UBI-1278f(40mg,0.24mmol)、UBI-1278g(113mg,0.24mmol)、乙酸(10mg)加入甲醇(2mL),搅拌一小时。然后氰基硼氢化钠(30mg,0.48mmol)添加入,反应体系于60℃搅拌3小时h。反应完成后(5mL)和提取与乙酸乙酯(20mL×3)。合并有机相,无水硫酸钠干燥,反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),纯化得到化合物UBI-1278h(40mg,收率81%)。LC-MS:[M+H]+=580.2
步骤6:UBI-1278(V2031-035)
将PMe3(1mL)加入到UBI-1278h(40mg,0.07mmol)的四氢呋喃(5mL)。体系在45℃搅拌1h,加入水(0.5mL),体系在20℃搅拌16h,减压浓缩得到无色油状目标产物UBI-1278(38mg,100%收率)LCMS:[M+H]+=554.3
实施例1.3.10化合物UBI-1279的合成方法(P1-9h)
步骤1:UBI-1279c(V2031-047)
在氩气保护下,UBI-1279a(500mg,7.14mmol)加入到无水DMF(10mL),氢化钠(571mg,14.3mmol)分批加入到体系。反应混合物搅拌30分钟后,UBI-1279b(2.11g,10.7mmol)加入。加完后反应体系在0℃下搅拌2小时,直到完全转化(TLC分析监测,乙酸乙酯:石油醚=1:10)。用水(20mL)淬灭,减压除去溶剂。用乙酸乙酯(30mL×3)提取,硫酸钠干燥,反应液浓缩后通过硅胶柱层析分离(0%-20%乙酸乙酯:石油醚),得到无色油状物UBI-1279c(0.72g,54.1%的收率)。LCMS:[M+H]+=187.2
1H NMR(400MHz,氯仿-d)δ4.63(t,J=5.1Hz,1H),3.72–3.57(m,6H),3.53(d,J=5.2Hz,2H),2.48(td,J=7.0,2.7Hz,2H),1.97(t,J=2.7Hz,1H),1.22(dd,J=7.1,1.4Hz,6H).
步骤2:UBI-1279d(V2031-062)
将UBI-1279c(0.72g,3.87mmol)加入到1N HCl(20mL)水溶液中。在室温下搅拌2小时。反应完后用二氯甲烷(30mL×2)萃取,硫酸钠干燥,过滤,浓缩得到UBI-1279d(430mg,收率100%)。LCMS:[M+H]+=113.1
步骤3:UBI-1205f(V2031-062)
将UBI-1279d(50mg,0.45mmol)、UBI-1279e(230mg,0.45mmol)、乙酸(50mg)加入到甲醇(5mL),反应体系搅拌一小时。然后氰基硼氢化钠(56mg,0.89mmol)加入,该反应体系在20℃搅拌16小时。反应完全后用水淬火(20mL),乙酸乙酯萃取(30mL×3)。合并有机层,硫酸钠干燥,过滤,反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=0~10%),得到白色固体UBI-1279f(115mg,收率44.6%)。LCMS:[M+H]+=578.3
步骤4:UBI-1279(V2031-063)
将UBI-1279f(100mg,0.48mmol)、二碳酸二叔丁酯(57mg,0.26mmol)、碳酸氢钠(43mg)、水(2mL)加入到四氢呋喃(5mL)中。反应在室温下搅拌3小时,反应完成后反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=0~10%)进行色谱洗脱,得到黄色油状物UBI-1279(50mg,42.6%收率).LCMS:[M+H]+=678.3
实施例1.3.11化合物UBI-1280的合成方法(P1-11h)
步骤1:UBI-1280b(V2031-075)
将UBI-1279d(250mg,2.23mmol)、UBI-1280a(290mg,2.23mmol)、乙酸(50mg)加入到甲醇(5mL),反应体系搅拌1小时。氰基硼氢化钠(281.3mg,4.46mmol)加入体系,20℃搅拌16小时。反应完成后,反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=0~20%),得到黄色油状物UBI-1280b(200mg,收率39.6%)。LCMS:[M+H]+=227.2
步骤2:UBI-1280c(V2031-078)
将UBI-1280b(200mg,0.88mmol)、二碳酸二叔丁酯(290mg,1.33mmol)、碳酸氢钠(223mg)、水(2mL)加入四氢呋喃(5mL)中。反应在室温下搅拌3小时,反应完成后,反应液浓缩后通过硅胶柱层析分离(石油醚/乙酸乙酯=1/1),得到黄色油状物UBI-1280c(200mg,收率69.3%)。LCMS:[M+H]+=327.2
步骤3:UBI-1280d(V2031-080)
室温条件下,将1mL 1M三甲基膦(四氢呋喃溶液)加入UBI-1280c(200mg),5mL四氢呋喃和0.1mL水中。反应体系搅拌过夜,反应完成后。真空拉干,得到UBI-1280d(170mg,收率95.9%),未纯化,直接用于下一步。LCMS:[M+H]+=301.2
步骤4:UBI-1280(V2031-086)
P1(170mg,0.4mmol)、UBI-1280d(150mg,0.5mol)、HATU(285mg,0.75mmol)、二异丙基乙基胺(193.5mg,1.5mol)溶于DMF(10mL)中,室温下搅拌18小时。反应完成后将混合物倒入水中(20mL),然后用乙酸乙酯(20mL×3)提取。将合成的有机层用盐水洗涤,硫酸钠干燥,浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%)纯化,得到黄色固体UBI-1280(100mg,收率35.4%)。LCMS:[M+H]+=708.4
实施例1.3.12化合物UBI-1281的合成方法(P1-12h)
步骤1:UBI-1281b(V2031-076)
将UBI-1281a(2.0g,28.57mmol)、四丁基硫酸氢铵(0.97g,2.86mmol)、双(2-氯乙基)醚(12.2g,85.7mmol)加入50%氢氧化钠水溶液(12mL),该反应体系在40℃下剧烈搅拌16小时。反应完成后(TLC监测),将反应混合物加入80mL水和80mL二氯甲烷的混合物中,用二氯甲烷萃取。合并有机相,硫酸钠干燥。反应液浓缩后通过硅胶柱层析分离(石油醚/乙酸乙酯=1/1),得到无色油状物UBI-1281b(3.5g,收率69.4%)。LCMS:[M+H]+=177.1
1H NMR(400MHz,氯仿-d)δ3.80–3.75(m,2H),3.68–3.62(m,8H),2.49(d,J=2.6Hz,2H),1.98(s,1H).
步骤2:UBI-1281c(V2031-079)
将UBI-1281b(200mg,1.13mmol)、3-叠氮基丙胺(97.7mg,1.13mmol)、碘化钾(188.6mg,1.13mmol)、碳酸钾(313.6mg,2.27mmol)加入乙腈(5mL)中,反应混合物在80℃下搅拌16小时。反应完成后加水(5mL),乙酸乙酯萃取、干燥(硫酸钠)、过滤、浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%)得到无色油状物UBI-1281c(200mg,收率73.5%)。
LCMS:[M+H]+=241.2 1H NMR(400MHz,氯仿-d)δ3.98–3.87(m,2H),3.74–3.67(m,4H),3.64(t,J=6.7Hz,2H),3.57(t,J=6.3Hz,2H),3.28–3.21(m,2H),3.18(t,J=7.3Hz,2H),2.50(td,J=6.7,2.7Hz,2H),2.21–2.11(m,2H),2.06(t,J=2.7Hz,1H).
步骤3:UBI-1281d(V2031-078)
将UBI-1281c(200mg,0.88mmol)、二碳酸二叔丁酯(290mg,1.33mmol)、碳酸氢钠(223mg)、水(2mL)加入四氢呋喃(5mL)中。反应体系在室温下进行3小时,反应完成后,反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),得到黄色油状物UBI-1281d(200mg,收率70.6%)。LCMS:[M+H]+=341.2
步骤4:UBI-1281e(V2031-081)
在室温条件下,将0.88mL 1M三甲基膦(四氢呋喃)加入至UBI-1281d(200mg,0.59mmol)5mL四氢呋喃和0.1mL水中反应体系室温搅拌过夜。反应完成后油泵拉干得到UBI-1281e(150mg,收率81.2%)。LCMS:[M+H]+=314.2
步骤5:UBI-1281(V2031-082)
P1(162mg,0.38mmol)、UBI-1281e(150mg,0.48mol)、HATU(272mg,0.72mmol)、二异丙基乙基胺(185mg,1.43mmol)溶解在DMF(10mL)中,室温下搅过夜。将混合物倒入水中(20mL),然后用乙酸乙酯(20mL×3)萃取。合并有机层,饱和盐水洗涤,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=10%),得到黄色固体UBI-1281(100mg,收率36.4%)。LCMS:[M+H]+=722.4
实施例1.3.13化合物UBI-1282的合成方法(P1-10h)
步骤1:UBI-1282c(V2031-48)
将UBI-1282a(500mg,5.94mmol)溶于无水DMF(10mL)中,钠氢(356.6mg,8.92mmol)分批加入。反应体系搅拌30分钟后,再加入UBI-1282b(1.76g,8.92mmol)。然后反应体系继续0℃下搅拌2小时,直到完全转化(TLC分析监测,乙酸乙酯:石油醚=1:10)。反应完成后加水(20mL)淬灭,用乙酸乙酯(30mL×3)萃取,硫酸钠干燥。合并有机相,硫酸钠干燥过滤液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%)得到UBI-1282c(0.9g,收率75.6%)。
LCMS:[M+H]+=201.2
1H NMR(400MHz,氯仿-d)δ4.62(t,J=5.2Hz,1H),3.70(dq,J=9.4,7.0Hz,2H),3.62–3.53(m,4H),3.49(d,J=5.3Hz,2H),2.29(td,J=7.0,2.6Hz,2H),1.94(t,J=2.7Hz,1H),1.80(tt,J=7.1,6.2Hz,2H),1.22(t,J=7.1Hz,6H).
步骤2:UBI-1282d(V2031-062)
将UBI-1282c(0.8g,4mmol)加入到1N HCl(20mL)中。反应体系在室温下搅拌2小时。反应完成后用二氯甲烷(30mL×2)萃取,硫酸钠干燥,过滤浓缩得到UBI-1282d(350mg,收率69.4%),该粗品直接用于下一步。LCMS:[M+H]+=127.1
步骤3:UBI-1282(V2031-090)
将UBI-1282d(50mg,0.45mmol)、UBI-1282e(113mg,0.22mmol)、乙酸(10mg)加入甲醇(5mL)中,室温搅拌一小时。然后氰基硼氢化钠(56mg,0.89mmol)加入混合搅拌在20摄氏度16小时。反应液浓缩后通过硅胶柱层析分离得到黄色固体UBI-1282(55mg,收率40%)。
LCMS:[M+H]+=618.4
实施例1.3.14化合物UBI-1254的合成方法(P1-14h)
步骤1:UBI-1254c(V2118-034)
UBI-1254a(1.0g,12mmol)溶于DMF(30mL)中,零度下加入NaH(60%,576mg,24mmol),升至室温反应一个小时。UBI-1254b(3g,12mmol)加入反应液中,室温下继续搅拌6个小时反应完毕后,将反应液倒入冰水中,加EA萃取三次。EA层合并,用水洗两次,食盐水洗一次。干燥过滤,绊样过柱纯化(PE/EA)得到无色油状产物UBI-1254c(1g,产率33%)。
1H NMR(400MHz,CDCl3)δ3.64(t,J=6.2Hz,2H),3.45(td,J=6.3,1.2Hz,4H),2.23(td,J=7.1,2.7Hz,2H),1.89(t,J=2.7Hz,1H),1.73(pd,J=6.6,4.8Hz,4H),0.91–0.75(m,9H),0.05-0(m,6H).
步骤2:UBI-1254d(V2118-035)
将UBI-1254b(1g,4mmol)溶于30mL THF中,向其中加入10mL的TBAF in THF(1M),室温下反应过夜(16小时左右)。反应完毕,加入饱和氯化铵溶液淬灭,旋蒸除去THF。并用EA萃取三次,合并有机层,干燥过滤,绊样过柱纯化(PE/EA)得到无色油状产物UBI-1254d(480mg,产率:85%)。LC-MS:[M+H]+=143
步骤3:UBI-1254e(V2118-036)
UBI-1254d(110mg,0.77mmol)溶于DCM(10mL)中,加入TEA(157mg,1.55mmol)零度下慢慢滴加MsCl(106mg,0.92mmol)。滴加完毕后室温反应一个小时,点板监测反应完毕。向溶液中加入饱和NaHCO3溶液,并用DCM(20mL*2)萃取两次。合并有机层,干燥过滤,绊样过柱纯化(PE/EA)得到黄色油状产物UBI-1254e(160mg,产率94%)。LC-MS:[M+H]+=221
步骤4:UBI-1254g(V2118-037)
将UBI-1254e(160mg,0.72mmol),UBI-1254f(450mg,0.82mmol),K2CO3(113mg,0.82)加到ACN(50mL)中,并在80℃下反应16个小时。冷却过滤除去固体。滤液加水,然后用DCM(50mL*3)萃取三次。合并有机层,干燥过滤,绊样纯化(DCM/MeOH)得到黄色固体产物UBI-1254g(160mg,纯度75%)。
LC-MS:[M+H]+=675
步骤5:UBI-1254h(V2118-038)
将UBI-1254g(160mg,0.24mmol)溶于10mLTHF中,并向其中加入Boc2O(110mg,0.5mmol)和饱和NaHCO3(84mg,1mmol in 10mL H2O)溶液,室温反应2个小时。点板监测反应完毕,加水,并用DCM:MeOH=10:1(10mL*3)萃取三次。合并有机层,干燥过滤,绊样纯化(DCM/MeOH)得到黄色固体产物UBI-1254h(120mg),两步收率25%。
LC-MS:[M+H]+=775
实施例1.3.15化合物UBI-1251(P1-15h)的合成
步骤1:UBI-1251b(V2118-044)
将UBI-1254e(250mg,1.14mmol),UBI-1251a(670mg,1.19mmol),K2CO3(164mg,1.19)加入DMF(20mL)中,混合物在80℃下反应16个小时(过夜反应)。冷却,过滤除去多余的固体。滤液加50mL水,然后用DCM(50mL*2)萃取两次。合并有机层,用Na2SO4干燥,过滤,加硅胶绊样,上过柱机纯化(DCM/MeOH)。最终得到黄色固体产物UBI-1251b(140mg,纯度65%),纯度不高,有部分原料和副产物,在下一步纯化除去。
LC-MS:[M+H]+=689
步骤5:UBI-1251b(V2118-045)
UBI-1251a(140mg,0.2mmol)溶解在10mLTHF中,向其中加入Boc2O(87mg,0.4mmol)和NaHCO3溶液(84mg,1mmol in 10mL H2O),室温下搅拌2小时。点板监测反应完全后,用DCM:MeOH=10:1(10mL*3)萃取三次。合并有机层,加入Na2SO4干燥,过滤绊样过柱纯化(DCM/MeOH),最终得到产物UBI-1251b(85mg,两步收率9.5%),为黄色固体。
LC-MS:[M+H]+=789
实施例1.3.16化合物UBI-1252的合成方法(P1-10h)
步骤1:UBI-1252b(V2118-007)
UBI-1252a(20g,149mmol)溶解在DCM(200mL)中,零度下加入TsCl(85g,447mmol),TEA(124mL,894mmol)和DMAP(1.8g,14.9mmol),然后室温下反应8个小时。过滤除去固体,滤液绊样过柱纯化(PE/EA),流动相为PE和EA,最终得到产物UBI-1252b(39g,88.2mmol,产率59%),为黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.90–7.67(m,4H),7.44–7.28(m,4H),4.72–4.47(m,1H),3.94–3.65(m,3H),3.64–3.25(m,3H),2.45(d,J=4.3Hz,6H),1.08–0.92(m,3H).
LCMS[M+H]+=443
步骤2:UBI-1252c(V2118-008)
UBI-1252b(39g,88mmol)溶解到200mLDMF中,轻轻搅拌,向溶液中小心加入NaN3(17g,264mmol),80℃度下反应过夜(16个小时)。TLC监测(PE/EA=10/1,1/1)产物消失,新点生成。过滤除去多余的NaN3,然后加200mL水,并用EA(200mL*2)萃取两次。EA层合并,并用200mL水洗两次,100mL饱和食盐水洗一次,然后用Na2SO4干燥,过滤,旋干得到黄色油状产物UBI-1252c(15g,产率94%)。
LCMS[M+H]+=185
步骤3:UBI-1252d(V2118-009)
0℃下,向溶液Et2O(100mL)/EtOAc(200mL)/THF(50mL)中加入UBI-1252c(15g,82mmol)和1M HCl溶液(123mL,123mmol)并搅拌。PPh3(21.5g,82mmol)溶解于EtOAc(150mL)/Et2O(50mL)中,并慢慢滴加到上面的混合物中,一小时内滴加完毕。室温下反应三个小时。水层用EA(100mL)洗两次,EA弃去。向水层中滴加2M NaOH溶液直到PH到10左右,然后DCM萃取(200mL*2)两次。合并DCM层,加硫酸钠干燥,过滤,旋干,得到黄色油状粗产物UBI-1252d(12g,产率92%)。
LCMS[M+H]+=159
步骤4:UBI-1252f(V2118-010)
UBI-1252d(1g,6.3mmol),UBI-1252e(1.4g,6.3mmol)和K2CO3(2.6g,19mmol)加入到150mL ACN中,60℃反应过夜(16小时左右).冷却过滤除去固体,滤液旋干过柱(DCM/MeOH=0~10%)纯化得到黄色油状产物UBI-1252f(820mg,产率62%)。
LCMS[M+H]+=211
步骤5:UBI-1252g(V2118-011)
UBI-1252f(820mg,3.9mmol)溶解到10mL THF中,加入NaHCO3溶液(983mg,11.7mmol溶于10mL H2O)和Boc2O(1.27g,5.85mmol),20℃下反应两个小时。反应完毕后加EA(20mL*2)萃取两次,合并有机层,干燥过滤,过柱纯化(DCM/MeOH=0~10%)得到黄色油状产物UBI-1252g(850mg,产率70%)。
1H NMR(400MHz,CDCl3)δ3.77–3.00(m,8H),2.43(s,2H),1.96(s,1H),1.52–1.38(m,9H),1.24–1.06(m,6H).
LCMS[M+H]+=311
步骤6:UBI-1252h(V2118-054)
UBI-1252g(200mg,0.64mmol)溶到10mL THF中,加入PMe3(98mg,1.28mmol),室温反应三个小时。点板监测反应完毕,旋干得到产物UBI-1252h(272mg),直接用于下一步。
LCMS[M+H]+=285
步骤7:UBI-1252j(V2118-055)
UBI-1252h(272mg,0.64mmol),UBI-1252i(183,0.64mmol)溶解到20mL DCM中,并向其中加入HATU(243mg,0.64mmol)和DIPEA(248mg,1.92mmol),室温反应一个小时。点板监测反应完毕。旋干绊样过柱(DCM/MeOH=10:1),得到黄色固体产物UBI-1252j 105mg,两步收率23.5%。
LCMS[M+H]+=692.
实施例1.3.17化合物UBI-1253的合成方法(P1-11h)
步骤1:UBI-1253a(V2118-029)
UBI-1253a(1g,5.3mmol)溶到DCM(50mL)中,加入TEA(1.6g,15.9mmol),然后冷却至零度,慢慢滴加MsCl(736mg,6.4mmol)。滴加完毕后,室温反应一个小时。用NaHCO3饱和溶液淬灭,DCM(50mL*2)萃取两次。合并有机层,干燥过滤,过柱纯化(PE/EA)得到黄色油状产物UBI-1253b(1.2g,产率86%)。
LC-MS:[M+H]+=268
步骤2:UBI-1253d(V2118-030)
将UBI-1253b(1.2g,4.5mmol),UBI-1253c(566mg,4.5mmol),K2CO3(1.2g,9mmol)加入到ACN(50mL)中,60℃下反应16个小时。冷却过滤,滤液旋干除去乙腈,然后加水50mL,并用DCM萃取两次。合并有机层,干燥过滤,过柱纯化(DCM/MeOH)得到黄色油状产物UBI-1253d(1.2g,产率89%)。
1H NMR(400MHz,CDCl3)δ5.39(s,1H),3.37(dd,J=47.0,13.8Hz,2H),3.20–3.03(m,2H),2.83–2.63(m,2H),2.34(t,J=6.8Hz,2H),2.15(s,2H),1.99–1.76(m,3H),1.76–1.60(m,2H),1.59–1.48(m,3H),1.45(d,J=8.0Hz,9H).
LC-MS:[M+H]+=298
步骤3:UBI-1253e(V2118-031)
UBI-1253d(1.2g,4mmol)溶于DCM(20mL)中,向其中加入4M HCl in二氧六环(2mL),室温反应一个小时。静置倾倒掉上层清液,固体用Et2O洗两次,倒掉Et2O。剩下的固体油泵拉干即得到黄色固体产物UBI-1253e(HCl盐)(900mg,产率96%)。
LCMS[M+H]+=198
步骤4:UBI-1253g(V2118-032)
100mLACN中加入UBI-1253e(900mg,4.7mmol),UBI-1253f(1g,4.7mmol)和K2CO3(1.3g,9.4mmol),60℃反应过夜(16个小时左右)。冷却过滤,滤液旋干绊样,过柱纯化(DCM:MeOH=0~10%)得到黄色油状产物UBI-1253g(530mg,纯度75%)。纯度不高,其中有部分原料和副产物,在下一步纯化除去。
LCMS[M+H]+=250
步骤5:UBI-1253h(V2118-033)
UBI-1253g(530mg,2mmol)溶解到30mL THF中,加入NaHCO3溶液(504mg,6mmol,in10mL H2O)和Boc2O(872mg,4mmol),室温下反应2个小时。加水并用DCM(50mL*2)萃取两次。合并有机层,干燥过滤,旋干绊样,过柱纯化(DCM/MeOH)得到黄色油状产物UBI-1253h(510mg),两步收率36%。
LCMS[M+H]+=350
步骤6:UBI-1253i(V2118-042)
UBI-1253h(510mg,1.46mmol)溶于20mL THF中并加入PMe3(222mg,2.9mmol),室温反应三个小时,旋干得到产物UBI-1253i(324mg,yield:69%)直接用于下一步反应。
LCMS[M+H]+=324
步骤7:UBI-1253k(V2118-043)
将UBI-1253i(324mg,1mmol),UBI-1253j(292mg,1mmol),HATU(456mg,1.2mmol)陆续加入到DMF(15mL)中,然后加入DIPEA(387mg,3mmol),室温反应2个小时。旋干直接过柱纯化(DCM/MeOH)得到白色固体产物UBI-1253k(70mg,产率9.6%)。
LCMS[M+H]+=731
实施例1.3.18化合物UBI-1277的合成方法(NH2-12h-A1)
步骤1:UBI-1277b(V1782-093)
UBI-1277a(600mg,3.27mmol)溶于甲醇(12mL)冰浴下加入NaBH4(247mg,6.55mmol).反应慢慢升至室温反应2小时.加入饱和NH4Cl(30mL)淬灭然后用乙酸乙酯(20mL*3)萃取,有机相合并用无水硫酸钠干燥过滤旋干得到黄色油状产物(580mg,收率100%).LCMS[M-100]+=86.3
步骤2:UBI-1277c(V1782-096)
UBI-1277b(580mg,2.7mmol),UBI-1237(500mg,1.35mmol),Pd(PPh3)2Cl2(95mg,0.135mmol),CuI(51mg,0.27mmol),TEA(136mg,1.35mmol)溶于无水DMF(12mL)加热至80℃N2保护下反应1.5小时.反应降至室温旋干粗产品过柱(石油醚/乙酸乙酯=0%~100%)得到棕色油状产物UBI-1277c(500mg).LCMS[M+H]+=428.2
步骤3:UBI-1277d(V1782-121)
UBI-1277c(400mg,0.94mmol)溶于DCM(5mL)加入4M HCl/二氧六环(5mL)室温反应过夜。溶剂旋干粗品中加入***打浆,过滤固体干燥得到棕色固体产物UBI-1277d(340mg).LCMS[M+H]+=328.4
步骤4:UBI-1277e(V1782-127)
UBI-1277d(300mg,0.82mmol)溶于甲醇(20mL)加入UBI-1301(600mg,2.47mmol)和NaOAc(130mg,1.64mmol)反应1小时.然后加入NaBH3CN(77mg,1.23mmol)再反应1小时.反应用饱和食盐水淬灭用二氯甲烷萃取有机相干燥之后过滤,过滤液直接用到下一步.LCMS[M+H]+=524.2.
步骤5:UBI-1277f(V1782-130)
UBI-1277e(500mg,crude)溶于THF(5mL)加入Boc2O(1mL).室温反应1小时.反应液旋干过柱(二氯甲烷/甲醇=0%~10%)得到无色油状产物UBI-1277f(100mg)。LCMS[MS+H]+=624.3
步骤6:UBI-1277(V1782-131)
UBI-1277f(100mg,0.16mmol)溶于THF(5mL)加入三苯基膦树脂(200mg)40℃反应48小时.过滤旋干得到黄色固体产物UBI-1277f(40mg,收率42%)。LCMS[M+H]+=598.4.
实施例1.3.19化合物UBI-1290合成方法(P1-10h)
步骤1:UBI-1290a(V2111-014)
UBI-1279d(200mg,0.38mmol)溶于甲醇(3mL)冰浴下加入UBI-1295(72mg,0.57mmol)室温反应1小时。然后加入NaBH3CN(48mg,0.76mmol)反应10分钟。水(5mL)加入用二氯甲烷(15mL)萃取,有机相合并用无水硫酸钠干燥过滤,过滤液直接用于下一步反应。
步骤2:UBI-1290(V2111-015)
UBI-1290a溶于THF(3mL)加入Boc2O(0.5mL)和饱和NaHCO3(0.5mL)室温反应1小时。水(5mL)加入并用DCM(15mL)萃取,有机相有机相合并用无水硫酸钠干燥过滤,粗品过柱(二氯甲烷/甲醇=0%~10%)得到黄色油状UBI-1290(120mg)。LCMS[M+H]+=692.3
化合物UBI-1291合成方法(P1-2h)
步骤1:UBI-1291(V2111-049)
P1(37mg,0.35mmol),UBI-1291a(100mg,0.23mmol),HATU(175mg,0.46mmol),DIPEA(89mg,0.69mmol)溶于DMF(3mL)室温反应3小时。反应液过滤旋干过柱(二氯甲烷/甲醇=0%~10%)得到黄色固体UBI-1291(130mg,收率100%)。LCMS[M+H]+=477.4
1H NMR(400MHz,DMSO-d6)δ8.52(t,J=5.8Hz,1H),8.43(d,J=8.3Hz,1H),7.85(s,1H),7.62(s,1H),7.48(d,J=8.0Hz,2H),4.42–4.31(m,1H),4.24(m,1H),3.94(s,3H),3.62(m,2H),3.41–3.35(m,2H),3.25(s,3H),3.14(m,2H),2.85(m,1H),2.42(m,2H),2.04(m,1H),1.89(m,2H),1.84–1.73(m,4H),1.65–1.59(m,2H),0.76(t,J=7.5Hz,3H).
化合物UBI-1292合成方法(NH2-13h-A1)
步骤1:UBI-1292c(V2111-035)
UBI-1292b(2.7g,16.7mmol),UBI-1292a(37g,83.6mmol),Bu4NHSO4(12.4g,36.6mmol)和60%KOH(30mL)40℃反应过夜。水加入再用DCM(50mL*3)萃取,有机相浓缩旋干,粗品过柱(石油醚/乙酸乙酯=0%~100%)得到无色是油状产物UBI-1292c(2g,收率27%)。LCMS[M-100]+=332.3
步骤2:UBI-1292d(V2111-034)
UBI-1292c(700mg,1.6mmol)溶于无水DMF(10mL)加入NaN3(320mg,4.8mmol)80℃反应5小时。水(10mL)加入用乙酸乙酯(20mL*3)萃取,有机相浓缩旋干过柱(石油醚/乙酸乙酯=0%~100%)得到无色油状产物UBI-1292d(430mg,收率89%)。LCMS[M-100]+=203.2
步骤3:UBI-1292e(V2111-036)
UBI-1292d(430mg,1.42mmol)溶于二氯甲烷(3mL)加入HCl/二氧六环(7mL,28mmol)室温反应2小时。反应液浓缩得到黄色油状产物UBI-1292e(300mg)。LCMS[M+H]+=203.3
步骤4:UBI-1292g(V2111-037)
UBI-1292e(340mg,1.42mmol)溶于乙腈(7mL)加入UBI-1292f(318mg,1.42mmol),K2CO3(390mg,2.84mmol)反应70℃过夜。反应降温过滤滤液直接用于下一步。LCMS[M+H]+=255.4
步骤5:UBI-1292h(V2111-039)
UBI-1292g溶于THF(6mL)加入Boc2O(0.5mL)和NaHCO3(300mg)室温反应1小时。水(5mL)加入用二氯甲烷(15mL)有机相浓缩干燥过滤旋干过柱(石油醚/乙酸乙酯=0%~100%)得到黄色油状产物UBI-1292h(200mg)。LCMS[M-100]+=255.4
步骤6:UBI-1292i(V2111-045)
UBI-1292h(130mg,0.36mmol),UBI-1237(120mg,0.32mmol),Pd(PPh3)2Cl2(60mg,0.085mmol),CuI(40mg,0.21mmol),TEA(3drop)溶于无水DMF(5mL)在N2保护下40℃反应1小时。反应液旋干,过柱(二氯甲烷/甲醇=0%~10%)得到黄色油状产物UBI-1292i(200mgmixture)。
步骤7:UBI-1292(V2111-047)
UBI-1292i(15mg crude)溶于THF(2mL)加入1M Me3P(1mL)室温反应1小时。水(0.5mL)加入再反应1小时。反应液浓缩再过反相(乙腈/水=0%~100%)得到红色固体(V2111-047,20mg)。LCMS[M+H]+=571.5
1H NMR(400MHz,DMSO-d6)δ7.72(d,J=7.6Hz,1H),7.63(d,J=7.5Hz,1H),7.53(t,J=7.5Hz,1H),5.16(m,1H),4.45(m,1H),4.30(m,1H),3.62(m,1H),3.56–3.37(m,10H),2.99–2.90(m,1H),2.69(m,2H),2.60(m,2H),2.44(m,2H),2.02(m,1H),1.90(m,2H),1.43–1.35(m,9H),1.09–0.96(m,6H).
实施例1.3.20化合物UBI-1293合成方法(P1-13h)
步骤1:UBI-1293b(V2111-063)
UBI-1293a(1.5g,6.83mmol),TEA(1.5mL,10.8mmol)溶于无水二氯甲烷(15mL)冰浴下加入MsCl(1.5mL,18.9mmol)室温反应2小时。水(30mL)加入用二氯甲烷(20mL*3)萃取,有机相合并用无水硫酸钠干燥过滤,过滤液旋干得到黄色油状产物UBI-1293b(1.78g,收率87%)直接用于下一步反应。LCMS[M-100]+=198.2
步骤2:UBI-1293c(V2111-063)
UBI-1293b(1.78g,6mmol)溶于乙腈(50mL)加入UBI-1238(1.07g,6.6mmol),K2CO3(1.65g,12mmol)80℃反应过夜。反应液过滤浓缩过柱(乙腈/水=0%~30%)得到黄色油状产物UBI-1293c(400mg,收率20%)。LCMS[M+H]+=328
步骤3:UBI-1293d(V2111-064)
UBI-1293c(0.4g,1.2mmol)加入4M HCl/二氧六环(4mL,20mmol)室温反应2小时。反应液浓缩得到黄色油状产物UBI-1293d(0.3g,收率100%)。LCMS[M+H]+=228
步骤4:UBI-1293e(V2111-069)
UBI-1293d(724mg,2.75mmol)溶于乙腈(70mL)加入UBI-1292f(616mg,2.75mmol),K2CO3(760mg,5.5mmol),KI(228mg,1.37mmol)80℃反应过夜。反应液降温,过滤滤液直接用于下一步反应。LCMS[M+H]+=280.2
步骤5:UBI-1293f(V2111-070)
UBI-1293e溶于THF(6mL)加入Boc2O(2mL,8.25mmol)和NaHCO3(700mg,8.25mmol)室温反应1小时。水(5mL)加入用二氯甲烷(15mL)萃取,有机相合并用无水硫酸钠干燥过滤,过滤液旋干过柱(二氯甲烷/甲醇=0%~100%)得到无色油状产物UBI-1293f(350mgmixture)。LCMS[M+H]+=380.2
步骤6:UBI-1293g(V2111-073)
UBI-1293f(350mg,0.46mmol)溶于THF(2mL)加入1M Me3P(3mL,3mmol)50℃反应1小时。水(0.5mL)加入再50℃反应1小时。反应浓缩直接用于下一步反应。LCMS[M+H]+=354.3
步骤7:UBI-1293(V2111-072)
UBI-1293g(60mg,0.17mmol),P1(50mg,0.11mmol),HATU(130mg,0.34mmol),DIPEA(66mg,0.51mmol)溶于DMF(1mL)室温反应3小时。水加入再用乙酸乙酯(10mL*2)萃取。有机相合并用无水硫酸钠干燥过滤,过滤液旋干爬大板纯化(二氯甲烷/甲醇=0%~10%)得到白色固体产物UBI-1293(25mg,收率20%)。LCMS[M+H]+=761.51H NMR(400MHz,DMSO-d6)δ8.43(d,J=8.3Hz,1H),8.30(s,1H),7.85(s,1H),7.62(s,1H),7.49(d,J=11.2Hz,2H),4.35(m,1H),4.24(m,1H),4.05(d,J=7.1Hz,1H),3.94(s,3H),3.71(m,2H),3.55(m,2H),3.44(m,3H),3.29(m,2H),3.27(m,2H),3.25(s,3H),3.17–3.07(m,2H),2.85(m,1H),2.37(m,2H),2.02(m,3H),1.93–1.71(m,10H),1.65(m,4H),1.40(s,9H),0.77(t,J=7.4Hz,3H).
实施例1.3.21化合物UBI-1294合成方法(P1-14h)
步骤1:UBI-1294b(V2111-077)
UBI-1293d(443mg,1.68mmol)溶于乙腈(70mL)加入UBI-1294a(272mg,1.68mmol),K2CO3(464mg,3.36mmol)80℃反应过夜。反应降温后过滤滤液直接用于下一步反应。LCMS[M+H]+=294.3
步骤2:UBI-1294c(V2111-079)
UBI-1294b溶于THF(6mL)加入Boc2O(2mL,9.17mmol)和饱和NaHCO3(2mL),室温反应过夜。水(5mL)加入用二氯甲烷(15mL)萃取,有机相合并用无水硫酸钠干燥过滤,过滤液旋干过柱纯化(二氯甲烷/甲醇=0%~100%)得到黄色油状产物UBI-1294c(400mgmixture)。LCMS[M+H]+=394.2
步骤3:UBI-1294e(V2111-081)
UBI-1294d(400mg,1mmol)溶于THF(2mL)加入1M Me3P(1.5mL,1.5mmol)50℃反应1小时。水(0.5mL)加入再50℃反应1小时。溶剂浓缩旋干直接用于下一步。LCMS[M+H]+=368
步骤4:UBI-1294(V2111-083)
UBI-1294d(360mg,1mmol),P1(300mg,0.7mmol),HATU(760mg,2mmol),DIPEA(390mg,3mmol)溶于DMF(5mL)室温反应过夜。加水并用乙酸乙酯(10mL*2)萃取,有机相合并浓缩过柱(二氯甲烷/甲醇=0%~10%)得到白色固体产物UBI-1294(230mg,收率30%)。LCMS[M+H]+=775.3
1H NMR(400MHz,DMSO-d6)δ8.42(d,J=8.2Hz,1H),8.29(d,J=7.3Hz,1H),7.84(s,1H),7.63(m,1H),7.53–7.45(m,2H),4.42–4.32(m,1H),4.31–4.23(m,1H),3.95(m,4H),3.70(m,3H),3.55(m,2H),3.45(m,3H),3.25(s,3H),3.20(m,5H),2.81(m,1H),2.16–2.12(m,2H),2.10–1.98(m,4H),1.88(m,2H),1.76(m,8H),1.63(m,5H),1.40(d,J=1.6Hz,9H),0.77(t,J=7.4Hz,3H).
实施例1.3.22化合物UBI-1260(P1-11h)的合成方法:
步骤1:UBI-1260a(V1685-067)
UBI-1143c(40g,247mmol)和K2CO3(68.2g,494mmol)溶于乙腈,加入溴乙醇(21g,494mmol),80度反应16小时。反应完成后,过滤,滤液减压旋蒸浓缩得到粗品。并用硅胶柱层析分离(二氯甲烷/甲醇=50/1),得到无色透明油状目标产物UBI-1260a(23g,收率27.3%)
1H NMR(400MHz,氯仿-d)δ3.65–3.56(m,2H),3.49–3.40(m,1H),2.84–2.78(m,2H),2.53(t,2H),2.32–2.21(m,2H),1.98–1.88(m,2H),1.74–1.62(m,2H)
步骤2:UBI-1260c(V1685-068)
UBI-1260a(15g,88mmol)溶于THF(300mL)冷却到0℃,加入NaH(4.2g,105.6mmol)。50℃下反应1小时。然后加入UBI-1260b(22.5g,114mmol),70℃反应16小时。反应液冷却就加入HCl(2M)直到PH=8。减压旋蒸浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1),得到无色透明油状目标产物UBI-1260c(11g,收率44%)
1H NMR(400MHz,氯仿-d)δ4.63(t,J=5.3Hz,1H),3.79–3.52(m,6H),3.50(d,J=5.3Hz,2H),3.39(q,J=5.1,4.5Hz,1H),2.82(dd,J=11.2,5.6Hz,2H),2.58(t,J=5.8Hz,2H),2.23(t,J=10.0Hz,2H),1.97–1.85(m,2H),1.68(dtd,J=13.2,9.6,3.7Hz,2H),1.22(t,J=7.1Hz,6H).
步骤3:UBI-1260d(V1685-082)
UBI-1260c(1g,3.5mmol)溶于甲醇(20mL),在N2保护下室温反应16小时。反应完成后,过滤,滤液减压旋蒸浓缩得到粗品,直接用于下一步。LC-MS:[M+H]+=261.2
步骤4:UBI-1260d(V1685-094)
UBI-1260d(1g,3.8mmol),P1(1.6g,3.8mmol),HATU(2.9g,7.7mmol)溶于DIPEA(1.4mL,7.7mmol)和DMF(10mL),室温反应2小时。反应完成后,反应液反相柱分离(水/甲醇=5%/95%45分钟)。得到白色固体UBI-1260d(1.5g,收率60%)。LC-MS:[M+H]+=:668.2
步骤5:UBI-1260f(V1685-095)
UBI-1260d(1.5g,2.25mmol)用于盐酸(3mL)and水(12mL),室温反应16小时。反应完成后,加入饱和NaHCO3水溶液调PH=7。二氯甲烷萃取(5mL*3)。有机相用Na2SO4干燥,浓缩得到粗产品UBI-1260f(1g,收率76.9%)。直接用于下一步。LC-MS:[M+H]+=:594.2
步骤6:UBI-1260g(V1685-096)
炔丙胺(24mg,0.26mmol)溶于MeOH(10mL),加入UBI-1260f(300mg,0.51)和一滴醋酸。室温反应1小时。然后加入NaBH3CN(36mg,0.51mmol),室温反应1小时。反应液用饱和NaHCO3水溶液淬灭,浓缩得到粗产品。该粗产品溶于THF,过滤,滤液直接用于下一步。LC-MS:[M+H]+=633.2。
步骤7:UBI-1260(V1685-098)
UBI-1260g(200mg,0.31mmol),(Boc)2O(200mg,0.93mmol),NaHCO3(78mg,0.93mmol)溶于THF,室温反应1小时。反应液浓缩后用Pre-TLC分离(二氯甲烷/甲醇=10/1)。得到白色固体UBI-1260(40mg,收率17.6%)。LC-MS:[M+H]+=733.4
实施例1.3.23化合物UBI-1261(P1-12h)的合成方法:
步骤1:UBI-1261b(V1685-097)
丁-3-炔-1-胺(34mg,0.26mmol)溶于甲醇(10mL),加入UBI-1260f(300mg,0.51)和一滴醋酸。室温反应1小时。然后加入NaBH3CN(36mg,0.51mmol),室温反应1小时。反应液用饱和NaHCO3水溶液淬灭,浓缩得到粗产品。该粗产品溶于THF,过滤,滤液直接用于下一步。LC-MS:[M+H]+=647.2
步骤2:UBI-1261(V1685-099)
UBI-1261b(200mg,0.31mmol),(Boc)2O(200mg,0.93mmol),NaHCO3(78mg,0.93mmol)溶于THF,室温反应1小时。反应液浓缩后用Pre-TLC分离(二氯甲烷/甲醇=10/1)。得到白色固体UBI-1260(40mg,收率17.6%)。LC-MS:[M+H]+=747.4
实施例1.3.24化合物UBI-1262(P1-9h)的合成方法:
步骤1:UBI-1262a(V1685-111)
UBI-1285g(1.38g,6.45mmol)和K2CO3(890mg,6.45mmol)溶于乙腈(100mL),加入4-溴正丁炔(681mg,5.16mmol).70℃反应16小时,反应完成后,过滤,滤液减压旋蒸浓缩得到粗品。并用硅胶柱层析分离(二氯甲烷/甲醇=20/1),得到黄色透明油状目标产物UBI-1262a(370mg,收率28.4%)。LC-MS:[M+H]+=267.2.
步骤2:UBI-1262b(V1685-112)
UBI-1262a(370mg,1.4mmol),(Boc)2O(606mg,2.8mmol),NaHCO3(176mg,2.1mmol)溶于THF(10mL),室温反应1小时。反应液用乙酸乙酯萃取(10mL*3)。有机相用Na2SO4干燥,
浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1~100%),得到白色固体状目标产物UBI-1262b(337mg,收率65.8%)。
1H NMR(400MHz,氯仿-d)δ3.67–3.29(m,10H),2.43(dt,J=8.5,4.1Hz,2H),1.98(t,J=2.7Hz,1H),1.84(s,2H),1.46(s,9H).
步骤3:UBI-1262c(V1685-113)
UBI-1262b(337mg,0.92mmol)溶于H2O(1mL)和THF(10mL),加入NaOH(73mg,1.8mmol)。室温反应16小时。反应液浓缩得到粗品直接用于下一步。LC-MS:[M+H]+=267.2.
步骤4:UBI-1262(V1685-114)
UBI-1262c(400mg,1.48mmol),P1(630mg,1.48mmol),HATU(1.1g,2.96mmol)溶于DIPEA(545ul,2.96mmol)和DMF(10mL)。室温反应2小时。反应完成后,反应液用反相柱分离(水/甲醇=5%/95%45分钟)。得到白色固体UBI-1262(100mg,收率10%)
1H NMR(400MHz,DMSO-d6)δ8.41(d,J=8.4Hz,1H),8.36–8.32(m,1H),7.84(s,1H),7.60(s,1H),7.48(d,J=7.8Hz,2H),4.45–4.29(m,1H),4.24(dd,J=7.6,3.6Hz,1H),3.94(s,3H),3.45(t,J=5.8Hz,4H),3.38–3.27(m,6H),3.25(s,4H),2.82(d,J=3.5Hz,1H),2.37(d,J=7.6Hz,3H),2.06–1.98(m,1H),1.95–1.72(m,8H),1.63(dd,J=14.2,7.1Hz,3H),1.39(s,9H),0.76(t,J=7.4Hz,3H).
实施例1.3.25化合物UBI-1263的合成方法(P1-13h):
步骤1:UBI-1263b(V1685-121)
UBI-1263b(5g,71.4mmol)溶于DMF(200mL)冷却至0℃,加入NaH(3.4g,85.7mmol)。0℃反应1小时。UBI-1263a(21.6g,85.7mmol)加入到反应液后室温反应16小时。反应加入饱和NH4Cl水溶液,用二氯甲烷萃取(10mL*3)。有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(石油醚/二氯甲烷=3/1),得到物色油状物UBI-1263b(5g,收率29%)。
1H NMR(400MHz,氯仿-d)δ3.65(t,J=6.1Hz,2H),3.50(td,J=6.6,3.4Hz,4H),2.41(t,J=7.0,2.7Hz,2H),1.92(t,J=2.7Hz,1H),1.73(p,J=6.2Hz,2H),0.84(s,9H),0.00(s,6H).
步骤2:UBI-1263c(V1685-123)
UBI-1263b(3g,12.4mmol)溶于THF(100mL)并加入TBAF(4.85g,18.6mmol)。室温反应16小时。反应液加入水,用乙酸乙酯萃取(50mL*3),有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1),得到物色油状物UBI-1263c(1.3g,收率82.2%)
1H NMR(400MHz,氯仿-d)δ3.82–3.75(m,2H),3.67(t,J=5.8Hz,2H),3.58(t,J=6.7Hz,2H),2.47(td,J=6.7,2.7Hz,2H),2.34(s,1H),2.00(t,J=2.6Hz,1H),1.85(p,J=5.7Hz,2H).
步骤3:UBI-1263d(V1685-129)
UBI-1263c(128mg.1mmol)溶于DCM(10mL)后,加入TEA(88ul,2mmol)和MsCl(155ul,2mmol)。室温反应16小时。反应液加入水,用二氯甲烷萃取(10mL*3)。有机相用Na2SO4干燥,浓缩得到粗品直接用于下一步。
步骤4:UBI-1263f(V1685-130)
UBI-1263e(213mg,0.388mmol),UBI-1263d(214mg,0.388mmol),K2CO3(160mg,1.16mmol)溶于DMF(10mL),70℃反应4小时。反应液加入水,用乙酸乙酯萃取(50mL*3),有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1),然后硅胶柱用MeOH/NH3.H2O=1/1冲洗,得到粗品UBI-1263f(200mg收率78.1%)。LC-MS:[M+H]+=661.2
步骤5:UBI-1263(V1685-131)
UBI-1263f(200mg,0.3mmol),(Boc)2O(327mg,1.5mmol),NaHCO3(80mg,0.9mmol)溶于THF。室温反应1小时。反应液加入水,用乙酸乙酯萃取(10mL*3),有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1~100%),得到白色固体目标产物UBI-1263(80mg,收率34.7%)。LC-MS:[M+H]+=761.5
实施例1.3.26化合物UBI-1264的合成方法(P1-14h):
步骤1:UBI-1264a(V1899-108)
P1(1.43g,8.22mmol),N-叔丁氧羰基-1,3-丙二胺(3.5g,8.22mmol),HATU(4.7g,16.44mmol)溶于DIPEA(3.2g,24.66mmol)和DMF(40mL)。室温反应18小时。反应液加入到100mL水中,出现固体,过滤得到黄色目标化合物UBI-1264a(3.5g,收率73%)
1H NMR(400MHz,DMSO-d6)δ8.43(d,J=8.3Hz,1H),8.31(t,J=5.8Hz,1H),7.85(s,1H),7.61(s,1H),7.51–7.43(m,2H),6.82(t,J=5.8Hz,1H),4.35(t,J=8.2Hz,1H),4.24(dd,J=7.6,3.6Hz,1H),3.94(s,3H),3.33(s,1H),3.25(s,4H),2.98(q,J=6.6Hz,2H),2.06–1.97(m,1H),1.90(td,J=7.9,2.5Hz,2H),1.78(qd,J=6.8,4.3,3.5Hz,4H),1.68–1.55(m,5H),1.38(s,9H),0.76(t,J=7.4Hz,3H).LCMS[M+H]+=582
步骤2:UBI-1264b(V1899-110)
UBI-1264a(300mg,0.52mmol)冷却至0℃然后加入4M HCl/二氧六环(0.6mL)。室温反应2小时。反应液浓缩得到黄色油状物UBI-1264b(200mg,收率85%)。LCMS[M+H]+=482
步骤3:UBI-1264c(V1685-134)
UBI-1264b(600mg,1mmol),UBI-1263d(206mg,1mmol),K2CO3(414mg,3mmol)溶于DMF,70℃下反应16小时。反应完成后,反应液直接反相柱分离(水/甲醇=5%/95%45分钟)。得到白色固体粗产品UBI-1264c(200mg,收率29.6%)。LC-MS:[M+H]+=675.5
步骤2:UBI-1264(V1685-135)
UBI-1264c(200mg,0.3mmol),(Boc)2O(327mg,1.5mmol),NaHCO3(80mg,0.9mmol)溶液THF,室温反应1小时。反应液加入水,用乙酸乙酯萃取(10mL*3),有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1~100%),得到白色固体目标产物UBI-1264(80mg,收率34.5%)。LC-MS:[M+H]+=774.5
实施例1.3.27化合物UBI-1265的合成方法(P1-10h):
步骤1:UBI-1265a(V1685-144)
UBI-1264b(200mg,0.41mmol),UBI-1263d(85mg,0.41mmol),K2CO3(113mg,0.82mmol)溶于DMF,70℃下反应16小时。反应液直接反相柱分离(水/甲醇=5%/95%45分钟)。得到白色固体粗产品UBI-1265a(200mg,收率82.6%)。LC-MS:[M+H]+=592.2
步骤2:UBI-1265(V1685-148)
UBI-1265a(200mg,0.3mmol),(Boc)2O(327mg,1.5mmol),NaHCO3(80mg,0.9mmol)溶于THF,室温反应1小时。反应液加入水,用乙酸乙酯萃取(10mL*3),有机相用Na2SO4干燥,浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷/甲醇=20/1~100%),得到白色固体目标产物UBI-1265(90mg,收率34.5%)。LC-MS:[M+H]+=692.5
实施例1.3.28化合物UBI-1258(P1-14h)的合成方法
步骤1:UBI-1258b(V2126-010)
化合物UBI-1258a(0.5g,2.28mmol),化合物TEA(0.7g,6.84mmol)溶于DCM(20mL)。在0℃下向反应液中滴加MsCl(0.4g,3.42mmol),后室温下反应1小时。反应液用水洗,有机相干燥,旋干得到无色油状粗产品UBI-1097c(670mg,收率100%)。LCMS[M+H]+=298.2
步骤2:UBI-1258c(V2126-011)
化合物UBI-1258b(670mg,2.28mmol),化合物UBI-1238(400mg,2.46mmol)和K2CO3(690mg,5mmol),KI(40mg,0.23mmol)溶于CH3CN(20mL),然后90℃反应16小时。反应液有水洗(50mL),二氯甲烷萃取(100mL*3)。有机相无水硫酸钠干燥,减压旋蒸浓缩得到粗产品。粗产品用硅胶柱层析分离(二氯甲烷:甲醇=10:1)得到白色固体目标产物UBI-1258c(600mg,收率80%)。LCMS[M+H]+=328.3
步骤3:UBI-1258d(V2126-012)
化合物UBI-1258c(600mg,1.83mmol)溶于4N HCl/二氧六环(10mL),然后室温反应1小时。反应液减压旋干浓缩得到白色固体目标产物UBI-1258d(500mg,收率90%)。LCMS[M+H]+=228.3
步骤4:UBI-1258f(V2126-017)
化合物UBI-1258d(400mg,1.33mmol),化合物UBI-1258e(215mg,1.33mmol)和K2CO3(550mg,4mmol),KI(25mg,0.13mmol)溶于CH3CN(20mL),后在90℃反应3小时。反应液过滤,滤液减压旋蒸浓缩得到粗品,并用反向C18柱层析分离,冻干得到无色油状目标产物UBI-1258f(350mg,收率90%,纯度50%)。LCMS[M+H]+=294.2
步骤5:UBI-1258g(V2126-022)
化合物UBI-1258f(350mg,1.2mmol),化合物碳酸二叔丁酯(392mg,1.8mmol),NaHCO3(300mg,3.6mmol)溶于THF(10mL),后室温反应2小时。反应液过滤,滤液减压旋蒸浓缩得到粗品,并有硅胶柱层析分离(乙酸乙酯:石油醚=1:1)得到白色固体UBI-1258g(200mg,收率42%)。LCMS[M+H]+=394.3
步骤6:UBI-1258h(V2126-024)
化合物UBI-1258g(200mg,0.51ml),1N三甲基膦的四氢呋喃溶液(1mL,1mmol)溶于CH3CN(10mL),后在室温反应1小时。反应液中加入水(1mL)并在40℃反应2小时。反应液减压旋蒸浓缩得到白色固体目标产物UBI-1258h(180mg,收率100%)。LCMS[M+H]+=368.3
步骤7:UBI-1258(V2126-025)
化合物UBI-1258h(180mg,0.5mmol),化合物P1(210mg,0.50mmol),HATU(230mg,0.6mmol),二异丙基乙胺(190mg,1.5mmol)溶DMF(5mL),后室温反应1小时。反应液减压旋蒸浓缩得到粗品,粗品加入二氯甲烷稀释,水洗。有机相用无水硫酸钠干燥,浓缩,并用硅胶柱层析分离(二氯甲烷:甲醇=0:1)得到白色固体UBI-1258(300mg,收率78%)。LCMS[M+H]+=775.5
实施例1.3.29化合物UBI-1257(P1-12h)的合成方法
步骤1:UBI-1257b(V2126-015)
化合物UBI-1257a(4g,21mmol),三乙胺(6.4g,63mmol)溶于二氯甲烷(200mL),在0℃下向反应液中滴加甲基磺酰氯(3.6g,31.5mmol),后在室温反应1小时。反应液用水洗,有机相无水硫酸钠干燥,减压旋蒸浓缩得到无色油状粗品UBI-1257b(5.6g,收率100%)。LCMS[M+H]+=268.2
步骤2:UBI-1257c(V2126-016)
化合物UBI-1257b(5.6g,21mmol),化合物UBI-1238(3.4g,21mmol)和K2CO3(5.8g,42mmol),KI(400mg,2.1mmol)溶于CH3CN(200mL),后在90℃反应16小时。反应液过滤,滤液减压旋蒸浓缩得到粗品,并用硅胶柱层析分离(二氯甲烷:甲醇=10:1)得到白色固体目标产物UBI-1257c(4.5g,收率72%)。LCMS[M+H]+=298.3
步骤3:UBI-1257d(V2126-020)
化合物UBI-1257c(1.5g,5mmol)溶于4N HCl/二氧六环(30mL),后在室温反应1小时。反应液减压旋蒸浓缩得到粗品UBI-1257d(1.3g,收率95%)。LCMS[M+H]+=198.3
步骤4:UBI-1257f(V2126-023)
化合物UBI-1257d(800mg,2.96mmol),化合物UBI-1257e(480mg,2.96mmol),K2CO3(1.25g,8.88mmol),KI(60mg,0.3mmol)溶于CH3CN(30mL),后在90℃反应3小时。反应液过滤,滤液减压旋蒸浓缩得到粗品,并用反向C18柱层析分离,冻干得到无色油状目标产物UBI-1257f(500mg,收率60%,纯度50%)。LCMS[M+H]+=264.3
步骤5:UBI-1257g(V2126-026)
化合物UBI-1257f(500mg,1.9mmol),化合物碳酸二叔丁酯(620mg,2.8mmol),NaHCO3(480mg,5.7mmol)溶于THF(20mL),后在室温反应2小时。反应液过滤,滤液减压旋蒸浓缩得到粗品,并用硅胶柱层析分离(乙酸乙酯:石油醚=1:1)得到白色固体目标产物UBI-1257g(250mg,36%yield)。LCMS[M+H]+=364.3
步骤6:UBI-1257h(V2126-028)
化合物UBI-1257g(250mg,0.69ml),1N三甲基膦的四氢呋喃溶液(1.4mL,1.4mmol)溶于THF(10mL),后在室温反应1小时。反应液中加入水(1mL)并在40℃反应2小时。反应液减压旋蒸浓缩得到白色固体目标产物UBI-1257h(230mg,收率100%)。LCMS[M+H]+=338.4
步骤7:UBI-1257(V2126-029)
化合物UBI-1257h(230mg,0.69mmol),化合物P1(290mg,0.69mmol),HATU(315mg,0.83mmol),二异丙基乙胺(270mg,2.1mmol)溶DMF(5mL),后室温反应1小时。反应液减压旋蒸浓缩得到粗品,粗品加入二氯甲烷稀释,水洗。有机相用无水硫酸钠干燥,浓缩,并用硅胶柱层析分离(二氯甲烷:甲醇=10:1)得到白色固体UBI-1257(400mg,收率78%)。LCMS[M+H]+=745.5
实施例1.4化合物连接头b-A1的合成方法
实施例1.4.1化合物UBI-1302(NH2-12e-A1)的合成方法
步骤1:UBI-1302b(V1895-009)
化合物UBI-1302a(660mg,2.11mmol)以及HCl/二氧六环(10mL,4N)加入到四氢呋喃(10mL)中,室温反应2小时,反应完成后减压旋蒸浓缩,得到化合物UBI-1302b(525mg,收率100%).
步骤2:UBI-1302c(V1895-015)
化合物UBI-1302b(525mg,2.11mmol)、3-氧代氮杂丁烷-1-羧酸叔丁酯(361mg,2.11mmol)加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1302c(240mg)为白色固体。收率:31%。
步骤3:UBI-1302d(V1895-017)
将UBI-1302c(240mg,0.65mmol)、氯甲酸苄酯(144mg,0.85mmol)和碳酸氢钠(771mg,9.18mmol)加入到四氢呋喃(20ml)中,室温下反应12h后倒入10mL水并用二氯甲烷(10ml*3)萃取。有机层用无水Na2SO4干燥并浓缩得到产物UBI-1302d(198mg,收率77%)。
步骤4:UBI-1302e(V1895-018)
将UBI-1302d(198mg,0.39mmol)、盐酸/二氧六环(10mL,4N)加入到四氢呋喃(10mL)中,室温反应2小时,反应完成后减压浓缩,得到化合物UBI-1302e(159mg,产率100%)。
步骤5:UBI-1302f(V1895-019)
将UBI-1302e(159mg,0.39mmol)、DIEA(50mg,0.39mmol)和2-(2,6-二氧哌啶-3-基)-4-氟异吲哚-1,3-二酮(107mg,0.39mmol)加入到DMF(30mL)中,在80℃下反应拌18h,然后用硅胶柱层析分离,得到化合物UBI-1302f(80mg,产率31%)。
步骤6:UBI-1302(V1895-020)
将UBI-180857f(41mg,0.06mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应2小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1302(19mg,产率49%)。
实施例1.4.2化合物UBI-1303(NH2-12e-A1)的合成方法
步骤1:UBI-1303b(V1895-025)
将1-(叔丁氧羰基)环丙烷羧酸(500mg,2.49mmol)、来那度胺(644mg,2.49mmol)、HATU(1015mg,2.67mmol)和DIPEA(0.3mL)加入到DMF(3mL)中,在室温下搅拌16h,用反相柱(MeOH/H2O=5%~95%,45min)纯化。得到产物UBI-1303b(846mg,77%产率)。
步骤2:UBI-1303c(V1895-028)
UBI-1303b(846mg,1.91mmol)溶于二氯甲烷(5mL)和甲醇(5mL),然后加入HCl/二氧六环(0.5mL),室温反应1小时。反应液浓缩得到粗产品目标化合物UBI-1303c(654mg,收率100%)(76mg,收率100%)。
步骤3:UBI-1303d(V1895-059)
化合物UBI-1303c(305mg,1.44mmol),UBI-1301(492mg,1.44mmol),加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1303d(240mg)为白色固体。收率:31%。
步骤4:UBI-1303e(V1895-061)
将UBI-1303d(240mg,0.45mmol)、二碳酸二叔丁酯(146mg,0.67mmol)加入到二氧六环(30mL)中,室温下反应2h,然后用乙酸乙酯(10mL*3)浓缩提取。过滤浓缩得到所需化合物UBI-1303e(233mg,产率82%)。
步骤5:UBI-1303(V1895-062)
将UBI-1303e(233mg,0.37mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应2小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1303(221mg,产率100%)。
LCMS:(M+H)+=613.3
实施例1.4.3化合物UBI-1304(NH2-12e-A1)的合成方法
步骤1:UBI-1304b(V1685-046)
来那度胺(1g,3.8mmol)溶于AcOH(20ml),然后加入N-Boc-3-羟基氮杂环丁烷(1.31g,7.7mmol),80℃下反应1小时。反应液冷却至30℃,加入NaBH(OAc)3后室温反应16小时。反应液浓缩后硅胶柱分离(二氯甲烷/甲醇=20/1)得到白色固体目标化合物UBI-1304b(1.15g,收率73.2%)。LC-MS:(M+H)+=415.1
步骤2:UBI-1304c(V1685-047)
UBI-1304b(100mg,0.24mmol)溶于二氯甲烷(5mL)和甲醇(5mL),然后加入HCl/二氧六环(0.5mL),室温反应1小时。反应液浓缩得到粗产品目标化合物(76mg,收率100%),该粗品直接用于下一步反应。
步骤3:UBI-1304d(V1895-065)
UBI-1304c(300mg,1.42mmol),UBI-1301(452mg,1.44mmol),,加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1304d(215mg))为白色固体。收率:30%。
步骤4:UBI-1304e(V1895-066)
将UBI-1304d(215mg,0.42mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应16小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1304e((139mg,产率71%)。
LCMS:(M+H)+=485.1
实施例1.4.3化合物UBI-13045(NH2-12e-A1)的合成方法
步骤1:UBI-1305b(V1895-026)
将1-Boc-L-氮杂环丁烷-2-羧酸(500mg,2.49mmol)、来那度胺(644mg,2.49mmol)、HATU(1015mg,2.67mmol)和DIPEA(0.3mL)加入到DMF(3mL)中,在室温下搅拌16h,用反相柱(MeOH/H2O=5%~95%,45min)纯化。得到产物UBI-1305b(846mg,77%产率)。
步骤2:UBI-1305c(V1895-027)
UBI-1303b(846mg,1.91mmol)溶于二氯甲烷(5mL)和甲醇(5mL),然后加入HCl/二氧六环(0.5mL),室温反应1小时。反应液浓缩得到粗产品目标化合物UBI-1303c(654mg,收率100%)(76mg,收率100%)。
步骤3:UBI-1305d(V1895-029)
将化合物UBI-1305c(352mg,1.42mmol),UBI-1301(485mg,1.42mmol),加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1305d(229mg)为白色固体。收率:30%。
步骤4:UBI-1305(V1895-070)
将UBI-1305d(229mg,0.43mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应16小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1305((139mg,产率71%)。
LCMS:(M+H)+=513.1
实施例1.4.4化合物UBI-1306(NH2-12e-A1)的合成方法
步骤1:UBI-1306b(V1895-057)
将1-Boc-R-氮杂环丁烷-2-羧酸(500mg,2.49mmol)、来那度胺(644mg,2.49mmol)、HATU(1015mg,2.67mmol)和DIPEA(0.3mL)加入到DMF(3mL)中,在室温下搅拌16h,用反相柱(MeOH/H2O=5%~95%,45min)纯化。得到产物UBI-1306b(840mg,产率76%)。
步骤2:UBI-1306c(V1895-058)
UBI-1306b(840mg,1.91mmol)溶于二氯甲烷(5mL)和甲醇(5mL),然后加入HCl/二氧六环(0.5mL),室温反应1小时。反应液浓缩得到粗产品目标化合物UBI-1306c(650mg,收率100%)(76mg,收率100%)。
步骤3:UBI-1306d(V1895-072)
将UBI-1301(352mg,1.42mmol),UBI-1306c(485mg,1.42mmol),加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1306d(229mg)白色固体。收率:30%
步骤4:UBI-1306(V1895-073)
将UBI-1306d(229mg,0.43mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应16小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1306((154mg,产率71%)。
LCMS:(M+H)+=513.1
实施例1.4.5化合物UBI-1307(NH2-12e-A1)的合成方法
步骤1:UBI-1307b(V1895-057)
将1-{[(1,1-二甲基乙基)氧基]羰基}-3-羟基氮杂丁烷-3-羧酸(500mg,2.49mmol)、来那度胺(644mg,2.49mmol)、HATU(1015mg,2.67mmol)和DIPEA(0.3mL)加入到DMF(3mL)中,在室温下搅拌16h,用反相柱(MeOH/H2O=5%~95%,45min)纯化。得到产物UBI-1307b(840mg,产率76%)。
步骤2:UBI-1307c(V1895-061)
UBI-1307b(840mg,1.91mmol)溶于二氯甲烷(5mL)和甲醇(5mL),然后加入HCl/二氧六环(0.5mL),室温反应1小时。反应液浓缩得到粗产品目标化合物UBI-1307c(650mg,收率100%)。
步骤3:UBI-1307d(V1895-075)
将化合物UBI-1307c(352mg,1.42mmol),UBI-1301(485mg,1.42mmol),加入到二氯甲烷(10mL)中,加入三乙酰氧基硼氢化钠(530mg,2.51mmol)。反应完成后倒入10mL水,二氯甲烷提取(5mL*3)萃取。合并有机相后用饱和食盐水洗,无水Na2SO4干燥,减压旋蒸浓缩,得到粗品经硅胶柱层析(DCM/MeOH=10/1)纯化,得到化合物UBI-1307d(230mg)为白色固体。收率:30%
步骤4:UBI-1307(V1895-076)
将UBI-1307d(229mg,0.43mmol)、10%钯炭(20mg)加入到甲醇/二氯甲烷(1mL/10mL)混合溶剂中,在氢气环境下室温反应16小时。过滤后浓缩滤液得到粗品,用冷的***洗涤(10mL*3),干燥后得到化合物UBI-1307((154mg,收率71%)。
LCMS:(M+H)+=513.1
实施例1.4.6化合物UBI-1308(NH2-12e-A1)的合成方法
步骤1:UBI-1308b(V1895-091)
将UBI-1308a(1.0g,4.67mmol)、UBI-1308a-1(2.6g,4.67mmol)和N,N-二异丙基乙胺(1.8g,14.01mmol)加入到乙腈(20mL)中,在80℃下反应18小时。反应液用硅藻土过滤,滤液浓缩得到粗品。用快速层析法(DCM/MeOH=0%~10%20min)纯化,得到化合物UBI-1308b(1.5g,产率72%)。
步骤2:UBI-1308c(V1895-092)
将UBI-1308b(1.1g,2.5mmol)溶于MeOH(500mL),加入镁屑(5.6g,2.3mmol),在65℃下反应过夜。反应液用硅藻土过滤,滤液浓缩得到粗品,用快速色谱法纯化(用DCM/MeOH=0%~10%洗脱),得到产物UBI-1308c(0.29g)白色固体。收率:41%。
步骤3:UBI-180889d(V1895-093)
将UBI-180889c(500mg,1.77mmol)和4-溴代-1-炔(280mg,2.12mmol)加入到乙腈(10mL)中,在N2下加入碳酸钾(733mg,5.31mmol)。反应液用硅藻土过滤,滤液浓缩得到粗品,用快速色谱法纯化(DCM/MeOH=0%~10%20分钟洗脱),得到白色固体UBI-180889d(473mg,收率80%)。
步骤4:UBI-1308d(V1895-094)
将化合物UBI-1308c(400mg,1.49mmol)溶于DMF(10mL),加入二氯二(三苯基磷)钯(104mg,0.149mmol)、碘化亚铜(57mg,0.07mmol)和三乙胺(150mg,1.49mmol),在氮气下于80℃反应过夜。反应液经硅藻土过滤,滤液浓缩得到粗品,用快速层析法纯化(用DCM/MeOH=0%~20%30min洗脱),得到产物UBI-1308d(260mg)白色固体。收率:38%。
步骤5:UBI-1308e(V1895-095)
将UBI-1308c(900mg,3.15mmol)、盐酸/二氧六环(10mL,4N)加入到四氢呋喃(10mL)中,室温反应2小时,反应完成后减压浓缩,得到化合物UBI-1308(215mg,收率100%).
实施例1.4.7化合物UBI-1309(NH2-12e-A1)的合成方法
步骤1:UBI-1309b(V2127-011)
将UBI-1309a(20.7g,100mmol)和三乙胺(17.1g,150mmol)溶于DCM(60mL)中,缓慢加入甲基磺酰氯(12.5g,110mmol)。在室温下反应1小时后,用二氯甲烷(50mL×3)萃取,用盐水(50mL)洗涤合并的有机层,有机相用无水Na2SO4干燥,减压浓缩,用快速色谱法(DCM:MeOH=10:1)纯化得到UBI-1309b(26.5g,产率93%),无色油状物。
步骤2:UBI-1309c(V2127-013)
将UBI-1309b(285mg,1.00mmol)、叔丁基哌啶-4-基氨基甲酸酯(200mg,1.00mmol)、碳酸钾(414mg,3.00mmol)溶于DMF(9mL)中,在微波120℃下反应1小时。所得粗品用快速色谱法(石油醚/乙酸乙酯=80%~100%,20min,二氯甲烷/甲醇=0%~10%20min)纯化,得到无色油状物UBI-1309c(110mg,收率28%)。
步骤3:UBI-1309d(V2127-014)
将UBI-1309c(110mg,27.3mmol)、10%钯炭(581mg,5.46mmol)加入到甲醇(20ml)中,在氢气环境中室温下反应12h。反应液用硅藻土过滤,滤液浓缩得到UBI-1309d(72mg,收率100%)白色固体。
步骤4:UBI-1309f(V2127-024)
将UBI-1309d(500mg,1.35mmol)、3-丁炔-1-醇(94mg,1.35mmol)、Pd(PPh3)2Cl2(94mg,0.135mmol)和碘化亚铜(51mg,0.27mmol)加入到DMF(2mL)中,在80℃N2保护下反应16小时。用反相色谱柱(MeOH/H2O=5%95%45min)纯化,60%收集。得到化合物UBI-1309f(215mg,产率54%)白色固体。
步骤5:UBI-1309g(V2127-026)
将化合物UBI-1309f(312mg,1.00mmol)和三乙胺(171mg,1.50mmol)加入到二氯甲烷(60mL)中,缓慢滴加甲基磺酰氯(125mg,1.10mmol)。在室温下反应1小时后,用DCM(50mL×3)萃取反应液,用盐水(50mL)洗涤合并的有机层,用无水Na2SO4干燥,减压浓缩,用色谱柱层析(DCM:MeOH=10:1)纯化得到化合物UBI-1309g(171mg,产率99%)白色固体。
步骤6:UBI-1309h(V2127-027)
将化合物UBI-1309g(78mg,0.20mmol)、N,N-二异丙基乙胺(50mg,0.39mmol)和化合物UBI-1309d(51mg,0.20mmol)加入到乙腈(30mL)中,80℃下反应18h,浓缩得到粗品,然后用硅胶层析(PE/EtOAc=70%~100%20min,MeOH/DCM=0%~10%40min)纯化,得到化合物UBI-1309h(51mg,产率46%)。
步骤7:UBI-1309(V2127-029)
将UBI-1309h(51mg,0.09mmol),、盐酸/二氧六环(10mL,4N)加入到四氢呋喃(10mL)中,室温反应2小时,反应完成后减压浓缩,得到化合物UBI-1309(41mg,收率100%).
实施例1.5化合物P1-连接头h-A1的合成方法
步骤1:UBI-1237(V1782-042)
A1(5.2g,20mmol),NaNO2(4.15g,60mmol)加入到水中(200mL)冰浴下缓慢滴加稀释的H2SO4(20mL浓硫酸加50mL水)大概75分钟滴加完毕。然后室温反应30分钟后,冰浴下滴加KI(16.6g,100mmol)的水溶液100mL,然后80℃反应3小时,静置降温。过滤滤饼用石油醚、水反复洗。固体再用乙醇重结晶得到得到棕黄色固体产物UBI-1237((5.4g,收率72%)。LCMS[M+H]+=371
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.04(d,J=7.7Hz,1H),7.77(t,J=5.6Hz,1H),7.35(t,J=7.6Hz,1H),5.15(m,1H),4.29(d,J=17.5Hz,1H),4.14(d,J=17.5Hz,1H),2.91(m,1H),2.66–2.55(m,1H),2.49–2.42(m,1H),2.02(m,1H).
步骤2:P1-连接头h-A1
化合物P1-连接头h(20mg,1eq.),UBI-1237(1eq.),Pd(PPh3)2Cl2(0.2eq.),CuI(0.2eq.),TEA(1eq.)溶于无水DMF(4mL)在N2保护下,室温至100℃反应1小时至16小时。反应液冷却后倒入5mL水,然后用乙酸乙酯萃取(5mL*3)。有机相先后用饱和食盐水洗,Na2SO4干燥,浓缩得到粗品。该粗品用preP1-TLC(DCM/MeOH=10/1)分离得到目标化合物。
将上述目标化合物溶于二氯甲烷(3mL),然后加入0.5mL(HCl/二氧六环4M),室温反应1小时。将反应液减压旋蒸浓缩得到粗品,用无水***洗(5mL*3),过滤后固体真空干燥得到目标化合物P1-连接头h-A11
化合物UB-180925的合成方法
步骤1:UB-180925b(V2031-110)
将Cbz-Cl(361mg,2.12mmol)加入到UB-180925a(400mg,1.41mmol)和TEA(285mg,2.83mmol)的二氯甲烷(10mL)中,该反应体系在0℃下搅拌搅拌3小时,反应完成后浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%)得到黄色油状物UB-180925b(380mg,收率64%)。LCMS:[M+H]+=418.2
步骤2:UB-180925c(V2031-111)
将4N盐酸二氧六环(2mL)加入到UB-180925b(380mg,0.91mmol)的二氯甲烷(10mL)中。反应体系在20℃下搅拌4小时,反应完成后浓缩得到白色固体UB-180925c(250mg,86.5%收率)LCMS:[M+H]+=318.2
步骤3:UB-180925d(V2031-112)
P1(268mg,0.63mmol)、UB-180925c(250mg,0.79mol)、HATU(450mg,1.18mmol)、二异丙基乙基胺(305mg,2.37mmol)溶解在无水DMF(10mL)中,室温下搅拌16小时。反应完成后将混合物倒入水中(20mL),然后用乙酸乙酯(20mL×3)提取。合并有机相用盐水洗涤,硫酸钠干燥,浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),得到黄色固体UB-180925d(250mg,收率54.8%)。LCMS:[M+H]+=725.4
1H NMR(400MHz,氯仿-d)δ11.22(s,2H),8.65–8.52(m,1H),8.28(dd,J=31.2,8.4Hz,3H),7.59(s,1H),7.46(d,J=1.8Hz,1H),7.35(qd,J=6.4,5.5,1.9Hz,5H),6.62(d,J=7.8Hz,1H),5.30(s,1H),5.14(s,2H),4.46(q,J=8.1Hz,1H),4.27(dd,J=7.7,3.5Hz,1H),3.98(s,7H),3.66(pd,J=6.6,3.1Hz,7H),3.49(s,2H),3.31(s,3H),3.09(qd,J=7.5,3.5Hz,8H),2.29(dd,J=32.4,11.8Hz,4H),2.13(d,J=11.6Hz,1H),2.01–1.62(m,10H),0.87(t,J=7.5Hz,3H).
步骤4:UB-180925e(V2031-113)
将10%钯碳(30mg)加入到UB-180925d(200mg,0.28mol)的甲醇(5mL)溶液中。反应混合物在H2球下搅拌4小时,反应完成后过滤,滤饼用甲醇洗涤。滤液浓缩得到白色固体UB-180925e(110mg,收率67.5%)。LCMS:[M+H]+=591.4
步骤5:UB-180925f(V2031-119)
将UB-180925e(250mg,0.42mmol)、UBI-1282(125mg,0.635mmol)、碘化钾(70.3mg,0.42mmol)、碳酸钾(117mg,0.85mmol)加入乙腈(5mL)溶液中,反应混合物在80℃下搅拌16小时。反应完成后加水(5mL),将有机物分离、干燥(硫酸钠)、过滤、反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),得到黄色固体UB-180925f(200mg,收率66.9%)。LCMS:[M+H]+=707.4
1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.41(d,J=8.6Hz,1H),8.10(s,1H),7.84(s,1H),7.60(s,1H),7.51–7.43(m,2H),4.60(s,1H),4.35(q,J=8.1Hz,1H),4.24(dd,J=7.8,3.6Hz,1H),3.94(s,3H),3.75(s,1H),3.60(t,J=8.2Hz,2H),3.48(t,J=8.3Hz,3H),3.06(s,2H),2.18–1.71(m,12H),1.63(dd,J=14.7,7.2Hz,4H),1.40(d,J=13.2Hz,2H),1.12(t,J=7.0Hz,6H),0.76(t,J=7.4Hz,3H).
步骤6:UB-180925g(V2031-122)
将UB-180925f(150mg,0.21mmol)加入到1N HCl(10mL)中。反应体系在30℃反应4小时,反应完成后,用二氯甲烷萃取,硫酸钠干燥,真过滤浓缩,得到UB-180925g(110mg)。LCMS:[M+H]+=633.4
步骤7:UB-180925i(V2031-121)
将UBI-1237(400mg,1.08mmol)、UB-180925h(274mg,1.62mmol)、PdCl2(PPh3)2(38mg,0.05mmol)、碘化铜(21mg)、三乙胺(491mg)加入无水DMF(5mL)中。反应体系在80℃搅拌2小时,反应完成后冷却至室温。将混合物加入水中,用二氯甲烷萃取,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=10%),得到黄色固体UB-180925i(250mg,收率56.2%)。
LCMS:[M+H]+=412.2 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.71(dd,J
=7.6,1.1Hz,1H),7.64(dt,J=8.1,1.9Hz,1H),7.51(d,J=7.6Hz,1H),7.11–6.97(m,1H),5.15(dd,J=13.3,5.1Hz,1H),3.18(q,J=6.6Hz,2H),3.04(q,J=6.6Hz,1H),2.98–2.89(m,1H),2.62(s,1H),2.61–2.54(m,2H),2.45(dd,J=13.1,4.4Hz,1H),2.39(t,J=6.7Hz,1H),2.02(dd,J=8.9,3.6Hz,1H),1.37(d,J=4.7Hz,9H).
步骤8:UB-180925j(V2031-123)
将4N盐酸二氧六环溶液(1mL)加入至UB-180925i(150mg,0.21mmol)的二氯甲烷(5mL)中。反应体系在20℃搅拌4小时,反应完成后,加水,二氯甲烷萃取,硫酸钠干燥,过滤浓缩得到UB-180925j(110mg,收率97%)LCMS:[M+H]+=312.1
步骤9:UB-180925(V2031-125)
将UBI-180925(50mg,0.17mmol),UBI-180925j(35.7mg,0.17mmol)、乙酸(10mg)加入到甲醇(2mL),该反应体系搅拌一小时后加入氰基硼氢化钠(15mg,0.24mmol),继续在60℃搅拌3小时。反应完成后,制备得到白色固体UBI-180925(2.6mg,收率3.6%)。LCMS:[M+H]+=928.5
化合物UB-180933的合成方法
步骤1:UB-180933b(V2031-124)
将UB-180933a(115mg,0.635mmol)、碘化钾(70.3mg,0.42mmol)、碳酸钾(117mg,0.85mmol)加入到乙腈(5mL)中,反应体系在80℃下搅拌16小时。反应完成后加入水(5mL),乙酸乙酯萃取、干燥(硫酸钠)、过滤、反应液浓缩后通过硅胶柱层析分离(二氯甲烷/甲醇=10%),得到黄色固体UB-180933b(150mg,收率51.3%)。LCMS:[M+H]+=691.4
步骤2:UB-180933c(V2031-126)
将UB-180933b(150mg,0.22mmol)加入到4N盐酸二氧六环(5mL)中。反应体系在30℃反应4小时,反应完成后。加入10mL水,二氯甲烷萃取,硫酸钠干燥,过滤浓缩得到UB-180933c(113mg,收率80.5%)。LCMS:[M+H]+=647.4
步骤3:UB-180933(V2031-133)
将UBI-180925j(50mg,0.45mmol)、UBI-180933c(113mg,0.22mmol)、乙酸(10mg)加入到甲醇(5mL)。体系搅拌室温搅拌1小时小时后氰基硼氢化钠(56mg,0.89mmol),继续搅拌过夜。反应完成后制备得到UBI-180933(5mg,收率3.1%)。LCMS:[M+H]+=942.5
1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),11.01(s,1H),9.69(s,1H),8.38(d,J=7.8Hz,1H),7.82(t,J=4.1Hz,2H),7.74(ddd,J=14.9,7.7,1.1Hz,2H),7.65–7.51(m,3H),5.17(dd,J=13.3,5.1Hz,1H),4.63–4.29(m,3H),4.17(p,J=8.7Hz,1H),3.91(s,3H),3.58(d,J=12.0Hz,4H),3.45(s,2H),3.31(s,1H),3.21(s,3H),3.10(s,2H),3.01–2.86(m,1H),2.63(s,1H),2.19(d,J=9.2Hz,2H),2.08–1.74(m,10H),1.66(t,J=11.9Hz,2H),1.57–1.34(m,6H),0.75(t,J=7.4Hz,3H).
在本文中,化合物编号UB-180XXX,也可简化为编号XXX,例如UB-180925即化合物925。
通过类似的方法制备表A所示的其他化合物。
表A
测试例
测试例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。
本实验使用的部分细胞株,如下表1:
表1.细胞株列表
细胞进行常规培养,细胞铺板前至少传2代以上。收集处于对数生长期细胞,制备成单细胞悬液并计数,调整细胞浓度至所需浓度,以每孔加入100μl接种到96孔细胞培养板内。每孔加入100μL受试化合物的完全培养基,每个浓度皆设2个复孔,5倍梯度往下稀释,继续培养72h。所有细胞都进行相对应受试样品的IC50测定。实验结果如测试例4所示。
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。
测试例2蛋白质印迹
细胞用化合物处理一定时间后,离心收集细胞,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1、图2和图3和测试例4所示。
可见,本发明的偶联物(或TED分子)对靶蛋白表现出浓度相关的降解活性。
测试例3体外激酶活性实验
用1x reaction buffer将化合物、酶、底物和ATP稀释到所需浓度。384孔板中加入1μL不同浓度化合物、2μL酶、2μL底物/ATP混合溶液,室温孵育1小时。然后每孔加入5μLADP1-GloTM试剂,室温孵育40分钟。最后加入10μL检测试剂,室温孵育30分钟后使用Envision检测化学发光信号,结果如测试例4所示。
可见,本发明中合成制备的TED分子,在多种肿瘤细胞系中表现出很强的细胞增殖抑制活性,具有成为抗肿瘤药物的前景。
测试例4
按照前述测试例的方法对表A中部分化合物(或偶联物)进行了活性测试,测试结果汇总如下:
(4.1)被测化合物对MV4;11细胞抑制活性IC50
0nM<IC50≤100nM的化合物如下:928,893,884,888,932,930,883,889,912,927,864,900,903,899,890,882,892,920,913,885,886,866,924,894,865,911,908,923,914,907,921,917,867,916,895,909,910,919,897,926,905,915,933,934,918,901,906,874,898,873,931,925,922,869,904,876,857。
100nM<IC50≤1000nM的化合物如下:868,863,881,891,870,855,856,854,851,859,872,871。
IC50>1000nM的化合物如下:860,850,852,853,858。
(4.2)被测化合物对Hela细胞抑制活性IC50
0nM<IC50≤1000nM的化合物如下:883,889,892,884,888,893。
(4.3)被测化合物对HL-60细胞抑制活性IC50
0nM<IC50≤1000nM的化合物如下:889,900,883,884,899,893,892,890,888,903,902,897,895,874,905,901,891,904。
(4.4)被测化合物对Daudi细胞抑制活性IC50
IC50≤100nM的化合物如下:928,883,884,889,864,900,930,932,865,912,927,890,902,913,899,920,911,926,924,909,903,908,910,893,916,866,923,888,914,907,917,918,867,919,915。
100nM<IC50≤1000nM的化合物如下:906,886,874,892,882,933,922,921,897,895,925,885,931,873,863,857,894,876,869,868,896。
IC50>1000nM的化合物如下:898,881,870,855,856,854,851,859,872,871,850,852,853,858。
(4.5)被测化合物对NCIH82细胞抑制活性IC50
0nM<IC50≤1000nM的化合物如下:864,865,889,928,866,884,883,932,910,902,873,909,927,916,900,863,893,930,912,914,874,891,897,920,913,926,908,903,915,923,911,924,890,906,925,899,867,917,892,918,933,895,919,901,907,922,931,888,857,868,872,882,869,871。
IC50>1000nM的化合物如下:886,921,885,894,876,896,898,881,870,855,856,854,851,859,850,852,853,858,904,905。
(4.6)被测化合物对HT-29细胞抑制活性IC50
0nM<IC50≤300nM的化合物如下:864,865,928,889,902,866,910,932,914,930,900,923,893,925,927,916,909,873,924,899,897。
300nM<IC50≤1000nM的化合物如下:911,883,913,874,912,903,892,891,867,884,906,920,908,926,895,917,915,918,919,882,922,890,907,933,888,901。
IC50>1000nM的化合物如下:863,931,857,868,872,869,871,886,885,921,894,876,896,898,881,870,855,854,851,859,850,852,853,858,904,905。
(4.7)被测化合物对U-87MG细胞抑制活性IC50
0nM<IC50≤100nM的化合物如下:932,864,900,927,930,889,865,902,884,883,928,909,912,899,892,913,893,882,920,911,903,886。
100nM<IC50≤500nM的化合物如下:895,914,916,890,897,926,910,924,906,918,907,908,917,873,874,888,915,923,919,933,901,869,876,894,885,925,866,922,898,891,921,905。
500nM<IC50≤1000nM:896,868,867,931,857,904。
IC50>1000nM:863,872,871,881,870,855,856,854,851,859,850,852,853,858。
(4.8)被测化合物对MDA-MB-231细胞抑制活性IC50
0nM<IC50≤500nM的化合物如下:883,884,890,893,888,889,892。
(4.9)被测化合物对THP-1细胞抑制活性IC50
0nM<IC50≤1000nM的化合物如下:883,884,888,874,889。
(4.10)被测化合物对MOL4-4细胞抑制活性IC50
0nM<IC50≤100nM:883,884,888,889。
(4.11)被测化合物对HUVEC细胞抑制活性EC50
0nM<EC50≤1000nM的化合物如下:889,928,930,932,883,884,927,888,893,892,920,890,924,933,923,926,919,921,922,925。
(4.12)被测化合物在MV4;11细胞内对PLK1降解活性DC50
DC50<100nM的化合物如下:869,874,883,884,889,912。
(4.13)被测化合物(部分)在MV4;11细胞内对BRD4降解活性DC50
DC50<100nM的化合物如下:869,874,883,884,889,912,928。
(4.14)被测化合物在TMD-8细胞内对PLK1降解活性DC50
DC50<100nM的化合物如下:883,884。
(4.15)被测化合物在TMD-8细胞内对BRD4降解活性DC50
DC50<100nM的化合物如下:883,884。
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所示的偶联物或其药学上可接受的盐,其特征在于,
RT-L1-RE3 (I)
其中,
(a)所述RE3为E3连接酶配体部分;
(b)所述RT为靶标分子部分;
(c)所述L1为连接RE3和RT部分的连接头,且L1如式II所示;
-W1-L2-W2- (II)
其中,
W1和W2各自独立地为-(W)s-;
W各自独立地选自为选自下组的二价基团:无、-C(Rb)2-、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-、NR、取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基、取代或未取代的C6-10芳基、取代或未取代的5至10元杂芳基;
s=0、1、2、3、或4;
L2如式III所示,
-(ML)o- (III)
其中,
ML各自独立地为M、MT或MN;
其中,
o为5~50的整数;
M各自独立地为选自下组的二价基团:-C(Rb)2-、、-O-、-S-、-N(Ra)-、-C(=O)-、-SO2-、-SO-、-PO3-、-C(Rb)=C(Rb)-、-C≡C-、取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基、取代或未取代的C6-10芳基、取代或未取代的5至10元杂芳基、氨基酸残基;
MN各自独立地为选自下组的二价基团:-N(R’)-、-N(含N(R’)环原子的4至10元杂环烷基)-、含N(R’)环原子的4至10元杂环烷基、被至少一个-N(Rb)R’(较佳地,-NHR’)所取代的-C(Rb)2-、C3-8环烷基、4至10元杂环烷基、C6-10芳基或5至10元杂芳基;
MT各自独立地为选自下组的二价基团:-N(R”)-、-N(含N(R”)环原子的4至10元杂环烷基)-、含N(R”)环原子的4至10元杂环烷基、被至少一个-N(Rb)R”(较佳地,-NH R”)所取代的-C(Rb)2-、C3-8环烷基、4至10元杂环烷基、C6-10芳基或5至10元杂芳基;
R为R’或R”;
R’各自独立地选自下组:H、C1-6烷基、OH、SH、-COO-C1-6烷基、-OC(O)-C1-6烷基、氨基保护基团;
R”为-W3-L3-W4-(RP)q;
W3和W4各自独立地为-(W)s-;且W和s的定义同W1和W2基团中的定义;
L3为二价连接基团;
RP为多肽元件或者靶标分子T;
q为>0(较佳地,m为0.1~10,更佳地,0.2~5);
Ra各自独立地选自下组:H、OH、SH、取代或未取代的C1-6烷基、氨基保护基团、含N(Rc)环原子的4至10元杂环烷基;
Rb各自独立地选自下组:H、卤素、OH、SH、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷基酰基(-C(O)-C1-6烷基)、羧基、-COO-C1-6烷基、-OC(O)-C1-6烷基;或者,位于相同碳上的2个Rb以及与它们相连的碳共同构成取代或未取代的C3-8环烷基、取代或未取代的4至10元杂环烷基;
Rc各自独立地选自下组:H、OH、SH、取代或未取代的C1-6烷基、氨基保护基团;
除非特别说明,所述的取代是指基团中一个或多个(如1、2、或3个)氢被选自下组的取代基所取代:卤素(较佳地,F、Cl、Br或I)、氰基(CN)、氧代(=O)、硫代(=S)、C1-6烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基酰基(C1-6烷基-C(O)-)、-COO-C1-6烷基、-OC(O)-C1-6烷基、NH2、NH(C1-6烷基)、N(C1-6烷基)2。
2.如权利要求1所述的偶联物,其特征在于,L2为L7,且L7如式IIIb所示;
-(M)o1-(MT)-(M)o2- (IIIb)
其中,M、MT如前定义;
o1和o2各自独立地为1~50的整数且4≤o1+o2≤49。
3.如权利要求1所述的偶联物,其特征在于,所述的偶联物如式1b-1、1b-2、1b-3、2b或3b所示;
RT-W1-L7-Wb-C≡C-RE3 (1b-1);
RT-W1-L7-CO-RE3 (1b-2);
RT-W1-L7-CONH-RE3 (1b-3);
RT-Wa-Cr1-Wa-Cr2-L7-W2-RE3 (2b)
RT-Ar1-L7-W2-RE3 (3b)
其中,
Ar1为五或六元含氮杂芳基;
Cr1为无,或者未取代或被C1-4烷基所取代的C4-7环烷基或4至6元杂环基;
Cr2为未取代或被C1-4烷基所取代的4至6元含氮杂环基,且Cr2中至少一个氮杂原子与L7连接;
Wa和Wb的定义同W;且W、W1、W2、RT、RE3和L7如式I中定义。
5.如权利要求1所述的偶联物,其特征在于,所述的偶联物为选自组1、组2和组3中的偶联物;其中,R和R1为R”。
6.如权利要求1所述的偶联物,其特征在于,L3为-(Ma)p-;其中,Ma的定义同M,p为1~50的整数。
7.一种药物组合物,其特征在于,所述的药物组合物含有如权利要求1所述的偶联物和药学上可接受的载体。
8.如权利要求1所述的偶联物在制备用于治疗或预防与靶标蛋白过量相关的疾病的药物中的的用途。
9.一种减少细胞中靶标蛋白含量的方法,其中,将细胞与如权利要求1所述的偶联物相接触,从而减少细胞中靶标蛋白的含量。
10.一种TED化合物或其药学上可接受的盐,其特征在于,所述的TED化合物如式VI所示;
RT W1-(ML)o-W2-RE3 (VI)
其中,
ML各自独立地为M或MN
M、MN、RE3、RT、W1、W2和下标o如式I中定义。
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