CN111205268B - 异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用 - Google Patents
异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用 Download PDFInfo
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- CN111205268B CN111205268B CN201910389995.8A CN201910389995A CN111205268B CN 111205268 B CN111205268 B CN 111205268B CN 201910389995 A CN201910389995 A CN 201910389995A CN 111205268 B CN111205268 B CN 111205268B
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Abstract
本发明公开了一种异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用。本发明的异吲哚啉衍生物及其药物组合物能够调节免疫细胞因子的产生或活性,从而有效的治疗癌症和炎症性疾病。
Description
本专利申请是申请号为201510536922.9的专利申请的分案申请,该专利申请的申请日为2015年8月27日,其发明名称为《异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用》。
技术领域
本发明涉及一种异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用。
背景技术
肿瘤坏死因子-α(TNF-α)是一种促炎性细胞因子,在免疫稳态、炎症和宿主防御中起着重要作用。TNF-α已被证明是炎症的主要介质之一。TNF-α也可以由肿瘤产生,并且可以起到促肿瘤形成的作用,也可引起肿瘤细胞的程序性死亡。此外,TNF-α也影响诸如细胞凋亡、坏死、血管生成、免疫细胞活化、分化和细胞迁移过程,所有这些过程在肿瘤发生和肿瘤进展中发挥着重要作用。
无节制TNF-α活性或TNF-α的过度产生与多种疾病的病理学有关,包括但不限于癌症,例如,结肠、直肠、前列腺、乳腺、脑和肠癌;以及炎性疾病,特别是与癌症有关的炎症。TNF-α调节异常也可引起自身免疫性疾病、中毒性休克综合征、恶病质、关节炎、银屑病癣、HIV感染和AIDS、神经系统疾病和中枢神经系统疾病、脓毒症、充血性心力衰竭、移植排斥反应以及病毒感染。因此降低TNF-α水平,或调节TNF-α活性是许多免疫学、炎症性和恶性疾病(如癌症和炎症)治疗的很有前途的策略。例如,Sethi et al.Front.Biosci.(2008)13,5094-5107和Results Prob.Cell Differ.(2009)49,1-15。
来那度胺(3-(4-氨基-1,3-二氢-1-氧代-2H-异吲哚-2-基)-2,6-哌啶二酮)是一种小分子免疫调节剂,已证明其能够抑制TNF-α和其他促炎性细胞因子分泌,并增加抗炎性细胞因子分泌。来那度胺获得批准用于治疗多发性骨髓瘤(2006年)、骨髓增生异常综合征(2005年)和套细胞淋巴瘤(2013年)。此外,在临床试验中,来那度胺可单独或与其它治疗剂联合用药,治疗非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、髓性白血病、难治性浆细胞瘤、慢性粒单核细胞性白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、黑色素瘤眼外蔓延、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病;髓性白血病、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、套细胞淋巴瘤、非小细胞肺癌、卵巢癌、肾细胞癌、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤和巨球蛋白血症(参见WO 2012/015986)。
然而,来那度胺有许多副作用。事实上,来那度胺的处方信息中明确表明:该药物具有骨髓抑制、深静脉血栓形成、肺栓塞和致畸风险。在临床试验期间,大多数服用来那度胺的患者因血液学毒性而需要减少剂量。因此,尽管来那度胺具有有益的活性,但是其有效性受到显著发生的副作用的限制。因此,本领域亟需一种改良结构的来那度胺衍生物,以优化其性能。
发明内容
本发明提供了一种异吲哚啉衍生物、其中间体、制备方法、药物组合物及应用。本发明的异吲哚啉衍生物能够调节细胞因子(如TNF-α)的产生或活性,从而有效的治疗癌症和炎症性疾病。
本发明提供了一种通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药:
通式(I)中,n1选自0或1;
R1、R3、R4、R5、R6、R7、R8和R9独立地选自H或D;
R2选自H、D或卤素;
L1和L2独立地选自CD2、CHD或CH2;
X选自NH、ND或O;
R10为H、D或其中R1’、R2’、R3’、R4’和R5’分别独立地选自H、D、卤素、氰基、羟基、取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2~C20)杂环烷基或氘代(C2~C20)杂环烷基;其中,Ra和Rb独立地为H、(C1-C12)烷基或(C1-C12)烷基酰基;Rc和Rd独立地为H或(C1~C12)烷基;Re为或(C2-C20)杂环烷基;Re1和Re2独立地为H或(C1-C12)烷基;
所述的取代的(C1-C12)烷氧基中的取代基选自下列基团中的一个或多个:D、卤素、羟基、(C1-C12)烷氧基、(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基、 其中Rf和Rg独立地为H或(C1-C12)烷基;Rh为(C2-C20)的杂环烷基;
所述的取代的(C1-C12)烷基中的取代基选自下列基团中的一个或多个:D、(C2-C20)杂环烷基、氘代(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基或氘代(C1-C12)烷基取代的(C2-C20)杂环烷基;
当所述的取代的(C1-C12)烷氧基或所述的取代的(C1-C12)烷基中的取代基为多个时,所述的取代基相同或不同;
上述各基团中,所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C2-C20)杂环烷基中的杂原子选自O、N和S中的一个或多个;
条件是:通式(I)中,当n1为0时,R1、R3和R10为H或D,X为NH或ND,R2为卤素;
较佳地,通式(I)中,所述的不对称中心是指非手性碳、(S)构型碳、富集的(S)构型碳、(R)构型碳、富集的(R)构型碳或者消旋体。
通式(I)中,所述的Z较佳地为下列任一结构:
上述各基团中,所述的(C2-C20)的杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C2-C20)杂环烷基较佳地是指杂原子为N或O,杂原子数为1-2个的(C2-C6)杂环烷基。所述的(C2-C6)杂环烷基较佳地为四氢吡咯(例如)、吗啉基(例如)或哌嗪基(例如)。所述的(C1-C12)烷基取代的(C2-C20)杂环烷基或所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中所述的(C1-C12)烷基较佳地为(C1-C4)烷基。所述的(C1-C4)烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述的氘代(C2-C20)杂环烷基较佳地为所述的(C1-C12)烷基取代的(C2-C20)杂环烷基较佳地为 所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基较佳地为
通式(I)中,当R10为R1’、R2’、R3’、R4’和R5’分别独立地选自 或取代的(C1-C12)烷氧基,Ra和Rb独立地为(C1-C12)烷基或(C1-C12)烷基酰基,Rc和Rd独立地为(C1~C12)烷基,Re为Re1和Re2独立地为(C1-C12)烷基,所述的取代的(C1-C12)烷氧基中的取代基为Rf和Rg独立地(C1-C12)烷基时,所述的(C1-C12)烷基酰基的结构为Ra1为(C1-C12)烷基;Ra、Rb、Ra1、Rc、Rd、Re1、Re2、Rf和Rg中,所述的(C1-C12)烷基较佳地为(C1-C4)烷基。所述的(C1-C4)烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
通式(I)中,当R10为R1’、R2’、R3’、R4’和R5’分别独立地选自取代的(C1-C12)烷氧基,所述的取代的(C1-C12)烷氧基中的取代基选自(C1-C12)烷氧基时,所述的(C1-C12)烷氧基较佳地为(C1-C4)烷氧基。所述的(C1-C4)烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
通式(I)中,当R10为R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C12)烷基时,所述的取代或未取代的(C1-C12)烷基较佳地为取代或未取代的(C1-C4)烷基。所述的取代或未取代的(C1-C4)烷基较佳地为取代或未取代的甲基、取代或未取代的乙基、取代或未取代的正丙基、取代或未取代的异丙基、取代或未取代的正丁基、取代或未取代的异丁基或者取代或未取代的叔丁基。所述的取代的(C1-C12)烷基较佳地为
通式(I)中,当R10为R1’、R2’、R3’、R4’和R5’分别独立地选自取代或未取代的(C1-C12)烷氧基时,所述的取代或未取代的(C1-C12)烷氧基较佳地为取代或未取代的(C1-C4)烷氧基。所述的取代或未取代的(C1-C4)烷氧基较佳地为取代或未取代的甲氧基、取代或未取代的乙氧基、取代或未取代的正丙氧基、取代或未取代的正丁氧基、取代或未取代的异丁氧基或者取代或未取代的叔丁氧基。所述的取代的(C1-C12)烷氧基较佳地为
通式(I)中,较佳地,当n1为1时,R2为H或D。
通式(I)中,较佳地,当n1为1,R2为H或D时,R10为较佳地,R10中,R5’选自H或D,R2’、R3’和R4’其中一个选自卤素、氰基、羟基、 取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2~C20)杂环烷基或氘代(C2~C20)杂环烷基;其余选自H或D;上述情况下,当R2’、R4’和R5’选自H或D时,R3’选自卤素、氰基、取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2~C20)杂环烷基或氘代(C2~C20)杂环烷基。
通式(I)中,当n1为1,R2为H或D,X为NH或ND,R10为时,较佳地,R1’、R4’和R5’为H,R2’选自卤素或取代或未取代的(C1-C12)烷基;R3’选自卤素、取代或未取代的(C1-C12)烷基或取代或未取代的(C1-C12)烷氧基。
氘(D或者2H)是氢的一中稳定形态的非放射性同位素,其原子量为2.0144。天然中的氢是以H(氢或氕)、D(2H或氘)和T(3H或氚)同位素混合物的形式存在的,其中氘的丰度为0.0156%。根据本领域普通技术知识,所有含有天然氢原子的化合物结构式中,氢原子实际上表示的是H、D与T的混合物。因此,化合物中任何位点处的氘丰度大于其自然丰度0.0156%时,这些化合物都应该被认为是非天然的或氘富集的,因此,这些化合物相对于其非富集对应物来说是新颖的。
本发明中,“氘富集”化合物意指在通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药的化合物中的任何相关位点处的氘的丰度大于其在该位点处的自然丰度。因此,在“氘富集”化合物中,其相关位点中的任一者处的氘丰度都可能在大于0.0156%到100%的范围内。氘富集的位点以D表示,非氘富集的位点用H表示。根据本领域普通技术知识,非氘富集的位点还可以省略符号H。获得氘富集化合物的方法的实例是用氘交换氢或者用氘富集起始物质合成化合物。
本发明中,所给出的氘富集中氘的百分含量或氘丰度中氘百分含量均是指摩尔百分含量。
本发明中,非氘富集是指自然中的氢,即以H(氢或氕)、D(2H或氘)和T(3H或氚)同位素混合物的形式存在的。
本发明还提供了一种如前所述的通式(I)所示的异吲哚啉衍生物的制备方法,其可以用商业上可获得的原料,通过已知的方法合成得到,较佳地采用方法A制备,所述的方法A包括下列步骤:将化合物A-06(1)进行如下所示的脱保护反应,制得化合物A-06(a1);再将化合物A-06(a1)进行如下所示的酰胺化反应,制得通式(I)化合物;
方法A中,化合物A-06(1)、A-06(a1)或通式(I)中,L1、L2、X、Z、*、R1~R10、n1的定义均同前所述;Ra和Rb一个为另一个为Ra1和Rb1其中一个为另一个为中,Ra”和Rb”独立地为H或D。
通式(I)中,当n1为0时,所述的通式(I)化合物还可进一步采用方法B制备,所述的方法B较佳地包括下列步骤:将化合物I-RS进行如下所示的还原反应,制得通式(I)化合物;
方法B中,化合物I-RS或通式(I)中,R2为卤素,n1为0,X为NH或ND,R10为H或D;L1、Z、R1和R3的定义均同前所述。
方法C中,化合物P-01或通式(I)中,X为NH或ND,n1为1,Rp1、Rp2和Rp3独立地为H或D;L1、L2、Z、R1、R2和R3的定义均同前所述;中,R10为R1’、R2’、R3’、R4’和R5’的定义均同前所述。
方法A、方法B或方法C中,所述的脱保护反应、所述的酰胺化反应、所述的还原反应或所述的还原胺化反应的方法和条件可为本领域此类反应常规的方法和条件。化合物A-06(1)或化合物A-06(a1)中,以及化合物I-RS、化合物P-01或通式(I)的Z中,当用*标注的碳为不对称中心时,可将化合物A-06(1)、化合物A-06(a1)、化合物I-RS、化合物P-01或通式(I)采用本领域常规的手性拆分的方法进行拆分,分别得到(R)构型化合物、富集的(R)构型化合物、(S)构型化合物或者富集的(S)构型化合物,再进行相应地反应,制得通式(I)化合物。
方法A中,当通式(I)中,n1为0时,所述的通式(I)化合物的制备方法,其还可进一步包含下列步骤:将化合物A-05(1)进行如下所示的还原反应,制得所述的化合物A-06(1);即可;
其中,化合物A-05(1)和A-06(1)中,L1、L2、R1~R8、Ra和Rb的定义均同前所述;化合物A-06(1)中,X为NH或ND,n1为0;R10为H或D。所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中,当通式(I)中,X为NH或ND,n1为1时,所述的通式(I)化合物的制备方法,其还可进一步包含下列步骤:将化合物A-05(2)与进行如下所示的还原胺化反应,制得所述的化合物A-06(1);即可;
其中,化合物A-05(2)和A-06(1)中,L1、L2、R1~R8、Ra和Rb的定义均同前所述;化合物A-06(1)中,X为NH或ND,n1为1;中,Rp3为H或D;R10为R1’、R2’、R3’、R4’和R5’的定义同前所述。所述的还原胺化反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中,当通式(I)化合物中X为O,n1为1时,所述的通式(I)化合物的制备方法,其还可进一步包含下列步骤:将化合物A-05(3)与进行如下所示的亲核取代反应,制得所述的化合物A-06(1);即可;
其中,化合物A-05(3)和A-06(1)中,L1、L2、R1~R8、Ra和Rb的定义均同前所述;化合物A-06(1)中,X为O,n1为1;中,Hal为卤素(例如F、Cl、Br或I);R10为R10中,R1’、R2’、R3’、R4’和R5’的定义同前所述。所述的亲核取代反应的方法和条件可为本领域此类反应常规的方法和条件。
所述的化合物A-06(1)的制备方法,其还可进一步包含下列步骤:将化合物Q-03与化合物A-04(1)进行如下所示的偶合反应再脱保护基后,制得所述的化合物A-05(3);
所述的化合物A-05(3)的制备方法,其还可进一步包含下列步骤:市售所得原料酚Q-01经TBDMS保护后制得Q-02,再与卤代试剂(例如NBS)反应得到苄卤Q-03。
其中,化合物Q-01中,R1~R3和L1的定义均同前所述。
方法B中,所述的通式(I)化合物的制备方法中,化合物I-RS按照本领域制备该类化合物的常规方法制备得到,较佳地为采用方法D或方法E制备得到;所述的方法D较佳地包含下列步骤:将化合物A-03,与化合物A-04(2)或其盐进行如下所示的偶合反应,制得所述的化合物I-RS;
其中,化合物A-03、A-04(2)或I-RS中,L1、Z、*、R1~R8的定义均同前所述;化合物A-03中,Hal为卤素(例如Cl、Br或I)。所述的偶合反应的方法和条件可为本领域此类反应常规的方法和条件。化合物A-04(2)的盐一般是指化合物A-04(2)与酸形成的盐,较佳地为化合物A-04(2)的盐酸盐。
所述的方法E较佳地包含下列步骤:将化合物A-05(1)先后进行如下所示的脱保护,制得化合物A-06(a2),再将化合物A-06(a2)进行如下所示的酰胺化反应,制得所述的化合物I-RS;
其中,A-05(1)、A-06(a2)或I-RS中,L1、Z、*、R1~R8、Ra和Rb的定义均同前所述;Ra2和Rb2其中一个为另一个为中,Ra”和Rb”独立地为H或D。所述的脱保护及酰胺化反应可为本领域此类反应常规的方法和条件。
方法C中,所述的通式(I)化合物的制备方法,其还可进一步包括下列步骤:将I-RS进行如下所示的还原反应,制得化合物P-01;
化合物I-RS或化合物P-01中,R2为H、D或卤素;Rp1和Rp2独立地为H或D;L1、L2、Z、R1和R3的定义均同前所述。所述的还原反应的方法和条件可为本领域此类反应常规的方法和条件。
方法A中,所述的化合物A-06(1)制备方法,较佳地还可进一步包含下列步骤:将化合物A-03与化合物A-04(1)进行如下所示的偶合反应,制得所述的化合物A-05(1);
其中,化合物A03、A-04(1)或A-05(1)中,L1、*、R1~R8、Ra和Rb的定义均同前所述,Hal为卤素(例如Cl、Br或I)。所述的偶合反应的方法和条件可为本领域此类反应常规的方法和条件。
所述的通式(I)所示的异吲哚啉衍生物的制备方法,其包含下列步骤,具体见反应流程式A和反应流程式P:
反应流程式A:苄卤原料A-03与氨基酸衍生物A-04(1)偶合生成的产物A-05(1),经去保护得到化合物A-05(2),通过与醛的还原胺化反应转化为胺A-06(1)。最后进行脱保护关环制得目标产物(I),具体如下:
反应流程式A中:各字母和基团的定义均同前所述。
氨基酸衍生物A-04市售可得或按照公知方法(参见Chen etal.Biotechnol.Lett.(1992)14,269;WO 2012/015986;WO 2012/068512;US 2012/0053159;Manesis et al.J.Org.Chem.(1987)52,5342;Stogniew et al.J.LabelledCompd.RAD.(1981)18,897;Blomquist et al.J.Org.Chem.(1966)31,4121)合成,具体见反应流程式F1、F2和G。
反应流程式F1:
在重水中用Na-Hg还原F1-01得到氘富集物F1-02。二酸F1-02用乙酰氯脱水转化为酸酐F1-03,再分别与无水乙醇、氧化银和溴反应则形成溴代物F1-04。用试剂F1-05(Blomquist et al.J.Org.Chem.(1966)31,4121)处理F1-04得三乙酯F1-06。在D2O-DCl中加热F1-06就形成了氘富集氨基酸F1-07,并通过氨基保护基保护氨基(例如Boc、Cbz)、醋酐脱水转化为酸酐F1-08。以苄醇处理F1-08后再分别与氯甲酸乙酯及氨水反应,最后经脱保护就可以取得目标化合物F1-11。F1-08、F1-09和F1-10中,W1为本领域常规的氨基保护基。
反应流程式F2:
用试剂F2-05(Blomquist et al.J.Org.Chem.(1966)31,4121)处理F2-04(市售可得)得三乙酯F2-06。在D2O-DCl中加热F2-06就形成了氘富集氨基酸F1-07,并通过氨基保护基保护氨基(例如Boc、Cbz)、醋酐脱水转化为酸酐F2-08。以苄醇处理F2-08后再分别与氯甲酸乙酯及氨水反应,最后经脱保护就可以取得目标化合物F2-11。F2-08、F2-09和F2-10中,W1为本领域常规的氨基保护基。
反应流程式G:
酯G-01在氘代乙酸中用苯甲醛处理生成氘富集化合物G-02。用氨基保护基保护G-02中的氨基后,再分别与氯甲酸乙酯和氨水反应得到酰胺G-04。G-04中的氨基保护基可以用本领域常规的去保护方法脱去(例如酸解或还原),从而转化为目标化合物G-05。
原料A-03与氨基化合物P-03反应后得到化合物P-02。再通过还原、与醛的还原胺化反应制得通式(I)化合物。氨基化合物P-03市售可得或可按公知文献方法合成(参见WO 2012/015986;WO 2012/068512;Muller et al.Bioorganic&MedicinalChemistry Letters(1999)9,1625)。
反应流程式P:
反应流程式P中:各字母和基团的定义同前所述。
上述反应路线中涉及的化学反应所采用的条件和步骤均可参照本领域此类反应常规的条件和步骤进行,并且上述方法所得的化合物还可以进一步通过对外周位置进行修饰而获得本发明的其它目标化合物。
本发明还提供了一种制备通式(I)所示的异吲哚啉衍生物的中间体化合物A-06(1)、A-06(a1)、I-RS或P-01:
化合物A-06(1)、A-06(a1)、I-RS或P-01中,L1、L2、n1、Z、*、R1~R10、Ra、Rb、Ra1、Rb1、Rp1和Rp2的定义均同前所述;化合物A-06(1)中,Ra和Rb一个为另一个为化合物A-06(a1)中,Ra1和Rb1其中一个为另一个为 中,Ra”和Rb”独立地为H或D;化合物P-01中,Rp1和Rp2独立地为H或D。
本发明还提供了一种药物组合物,该药物组合物中包括治疗和/或预防有效量的本发明通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物和前药中的一种或多种。
根据本发明的实施例,所述的药物组合物可以配制用于任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂:如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
根据本发明的药物组合物可进一步包含药学上可接受的辅料,如药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。
根据本发明的实施例,药学上可接受的辅料可以包括一种或多种粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂或增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。药学上可接受的载体根据给药所需的制剂形式可以采取多种形式。例如,对于液体口服制剂,合适的载体和添加剂包括水、二醇类、油类、醇类、调味剂、防腐剂、着色剂等。作为另一个说明性示例,对于固体口服制剂、合适的载体和添加剂包括淀粉、糖类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。药学上可接受的载体或辅料通常应该是无毒的。根据本发明的药物组合物可以包含一种或多种合适的载体/辅料。辅料的量和类型将根据需要变化。本领域普通技术人员将能够根据当前的公开内容容易地确定要添加到本发明的药物组合物中的适当载体/辅料。
本发明的药物组合物,即包含治疗或预防有效量的本发明提供的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物和前药中的一种或多种,可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,根据本发明的药物组合物可以通过混合通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药,与药学上可接受的载体,根据常规的药物配料技术来制备,这些技术包括但不限于常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
根据本发明的实施例,药物组合物中除了通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物和前药中的一种或多种之外,可进一步包含一种或多种其他治疗剂。可包括在本发明的药物组合中的其它治疗剂的更多内容将在下文披露。其它治疗剂的量和类型将取决于要进行治疗或预防的疾病、病症或病况;疾病、病症或病况的严重程度;接受组合物给药的受试者的因素,如年龄、体重、身体状况等;给药途径等。
在某些实施例中,本发明涉及通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药的控释剂型。如本文所用,“控释剂型”指的是一种剂型,其中组合物的治疗活性成分的释放速率可控,或者是具有特定的延迟,以控制接受组合物给药的受试者中治疗活性成分的释放部位。一种控释剂型可以包含一种控释剂,如持续释放剂(持续释放或延迟释放)和延迟释放剂(延迟释放)。
如本文所用,术语“持续释放”和“延迟释放”是指治疗活性成分从药物组合物中释放的时间延长。如本文所用,术语“延迟释放”是指受试者接受给药后组合物到达受试者内所需环境后,或受试者接受给药后经过特定时间后,治疗活性组分从药物组合物中释放,使得释放发生在特定部位或所需的环境。
如本文所用,术语“持续释放剂”和“延迟释放剂”是指提供使治疗活性成分从组合物中控制释放的化合物或添加剂,以便释放逐渐发生,并且释放的时间延长。持续或延迟释放剂可使受试者接受组合物给药后治疗活性成分在特定长时间内释放。
根据本发明的实施例,通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药从本发明的组合物中的控制释放可以通过各种条件来实现,这些条件包括但不限于pH值、温度、酶、水或其它生理条件或化合物。例如,根据本发明的药物化合物可以进一步包含肠溶衣,其中肠溶包衣控制通式(I)化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药的释放,使其在所需的一段时间内从组合物中逐渐和连续地释放,使得该化合物能在延长的时间期内发挥治疗或预防作用。
根据本发明的实施例,控释药物组合物可进一步包含一种或多种如下所公开的其它治疗剂或药剂。
本领域技术人员根据公开的内容可以熟知那些合适的控释制剂、持续和延迟释放剂。可以并入本发明的药物组合物以提供控释组合物的控制释放剂的非限制性实例包括聚合物,如羟丙基甲基纤维素;凝胶;渗透膜;微粒;脂质体;微球以及其组合。本文所述的任何组合物可适用于控释制剂,如片剂、胶囊、软胶囊和囊片。
在本发明中的某些实施例中,治疗或预防量的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药、其任何药物组合物、制剂等,可以以本发明中的方法在一段时间(给药周期)内给予受试者,其后是一段不给予化合物的时期(非给药周期)。可以重复所需次数的给药周期和非给药周期。给药周期或者非给药周期的所需长度和次数将取决于正在治疗或预防的疾病、病症或病况的类型和/或严重程度,以及受试者个体的性别、年龄、体重和其他参数(例如,受试者个体的生物学、身体和生理状况等)。根据本文件公开的内容本领域普通技术人员的技术水平将足以确定给药周期和/或非给药周期的适当长度和次数。
根据本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药可用于多种用途,包括但不限于用于制备治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、病症或病况的药物。
因此,在另一个总方面,本发明涉及包含治疗或预防有效量的通式(I)化合物、其药学上可接受的盐、溶剂化物、立体异构体、同位素化合物、代谢物或前药在制备治疗或预防疾病、病症或病况的药物中的应用。在另一方面,本发明涉及一种治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病、病症或病况的方法,所述的方法通过给予受试者治疗或预防有效量的通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、立体异构体、同位素化合物、代谢物和前药中的一种或多种。根据本发明的方法,此类待治疗或预防的疾病、病症和病况的实例包括但不限于癌症:包括实体瘤、TNF-α相关病症、不期望的血管生成相关疾病和病症、疼痛、黄斑变性(MD)相关综合征、皮肤病、角化病、呼吸系统疾病(例如肺部疾病)、免疫缺陷病、中枢神经系统(CNS)疾病、自身免疫性疾病、动脉粥样硬化、遗传、过敏、病毒、睡眠病症及相关综合征、炎性疾病、PDE-4相关疾病或IL-2相关疾病。本领域中众所周知的此类疾病、病症或病况的实例包括但不限于在PCT专利出版物WO2012015986和WO2006018182以及美国专利出版物US20100204227中描述的那些,其中一些在此通过引用将其整体并入本文。
在一个实施例中,疾病、病症或病况选自:瘤原性或癌性疾病;自身免疫性疾病,如阿狄森氏病、强直性脊柱炎、抗磷脂抗体综合征、特应性皮炎、自身免疫性斑秃、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳病、自身免疫性淋巴增生综合征(alps)、白塞氏病、大疱性类天疱疮、心肌病、乳糜泻、慢性疲劳综合征性免疫缺陷综合征(CFIDS)、慢性炎症性脱髓鞘性多发性神经病、瘢痕性类天疱疮、冷凝集素病、CREST综合征、克罗恩病、德戈氏病、皮肌炎、幼年型皮肌炎、盘状红斑狼疮、湿疹、原发性混合型冷球蛋白血症、纤维肌痛-纤维肌炎、Grave’s病、吉兰-巴雷综合征、桥本氏甲状腺炎、化脓性汗腺炎、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、特发性血小板减少性紫癜、IgA肾病、胰岛素依赖型糖尿病(I型)、幼年型关节炎、红斑狼疮、美尼尔氏病、混合性结缔组织病、多发性硬化、重症肌无力、寻常性天疱疮、恶性贫血、结节性多动脉炎、多软骨炎、polyglancular综合征、风湿性多肌痛、多肌炎和皮肌炎、原发性丙种球蛋白血症、原发性胆汁性肝硬化、银屑病、雷诺氏现象、莱特尔氏综合征、风湿热、类风湿性关节炎、结节病、硬皮病、干燥综合征、系统性红斑狼疮、僵人综合征、多发性大动脉炎、颞动脉炎/巨细胞动脉炎、溃疡性结肠炎、葡萄膜炎、血管炎、白癜风、韦格纳氏肉芽肿病以及自身免疫性威尔逊氏病;肺部疾病,如哮喘、慢性阻塞性肺疾病;神经系统疾病,如阿尔茨海默氏病、帕金森氏症、抑郁症、癫痫症和双相型障碍;心血管疾病,如动脉粥样硬化、心肌梗死、骨质疏松症;代谢性疾病,如肥胖、2-型糖尿病;成人呼吸窘迫综合征;骨吸收疾病,如关节炎;高钙血症;移植物抗宿主反应;脑型疟疾;炎性疾病,如寻常痤疮、关节炎、哮喘、动脉粥样硬化、乳糜泻、慢性前列腺炎、结肠炎、克罗恩氏病、皮炎、憩室炎、肾小球肾炎、肝炎、超敏反应、炎性肠病、间质性膀胱炎、肠易激综合征(IBS)、红斑狼疮、肾炎、盆腔炎、再灌注损伤、类风湿性关节炎、结节病、移植排斥、溃疡性结肠炎、脉管炎、慢性肺部炎性疾病、中风、循环性休克;HIV感染、AIDS以及AIDS机会性感染;其他病症,例如,类风湿性脊椎炎、骨关节炎和其他关节炎病症、脓毒性休克、脓毒症、内毒素性休克、移植物抗宿主病、消瘦、克罗恩氏病、溃疡性结肠炎、麻风结节性红斑、cAMP相关病症,如脓毒性休克、脓毒症、内毒素性休克、血液动力学休克和脓毒症综合征、缺血后再灌注损伤、疟疾、分枝杆菌感染、脑膜炎、充血性心力衰竭、纤维化疾病、恶病质、移植排斥、辐射损伤、高氧肺泡损伤;病毒感染,如由疱疹病毒引起的那些感染;病毒性结膜炎;或特应性皮炎。
癌性或瘤原性病症的实例包括但不限于:急性成淋巴细胞白血病、急性髓性白血病、急性骨髓性白血病、核型急性成髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病、慢性粒细胞性白血病、毛细胞白血病、髓性白血病、肾上腺皮质癌、伯基特淋巴瘤、AIDS相关淋巴瘤、皮肤T-细胞淋巴瘤、皮肤B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、低级别滤泡性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、多发性骨髓瘤、冒烟型骨髓瘤、骨髓增生异常综合征、套细胞淋巴瘤、惰性骨髓瘤、慢性骨髓增生性疾病、中枢神经系统(CNS)淋巴瘤、肛门癌、星形细胞瘤、非典型畸胎样/横纹肌样瘤、基底细胞癌、胆管癌、膀胱癌、骨瘤、骨样骨瘤、骨软骨瘤、骨母细胞瘤、骨肉瘤、内生软骨瘤、动脉瘤样骨囊肿、骨纤维异常增殖症、软骨肉瘤、尤因氏肉瘤、纤维肉瘤、多形性未分化肉瘤、脑肿瘤、脑干神经胶质瘤、髓母细胞瘤、髓上皮瘤、成松果体细胞瘤、乳腺癌、支气管肿瘤、类癌瘤、宫颈癌、脊索瘤、结肠癌、结肠直肠癌、颅咽管瘤、胚胎瘤、室管膜母细胞瘤、室管膜瘤、食道癌、嗅神经母细胞瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、眼内黑色素瘤眼癌、视网膜母细胞瘤眼癌、胆囊癌、胃癌、胃肠道间质瘤、妊娠滋养细胞肿瘤、神经胶质瘤、头颈癌、肝癌、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波西肉瘤、肾癌、朗格汉斯细胞组织细胞增生症、喉癌、唇和口腔癌、肺癌、Merkel细胞癌、间皮瘤、多发性内分泌腺瘤综合征、蕈样肉芽肿、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、卵巢癌、卵巢上皮癌、卵巢生殖细胞肿瘤、卵巢低度恶性潜能瘤、胰腺癌、胰岛细胞瘤胰腺癌、乳头状瘤病、副神经节瘤、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、浆细胞瘤、胸膜肺母细胞瘤、激素难治性前列腺癌、雄激素非依赖性前列腺癌、雄激素依赖性IV期非转移性前列腺癌、激素不敏感性前列腺癌、化疗不敏感前列腺癌、直肠癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、软组织肉瘤、子宫肉瘤、皮肤癌(黑色素瘤)、鳞状细胞癌、Merkel细胞皮肤癌、小肠癌、鳞状颈癌、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、尿道癌、子宫内膜癌、子宫肉瘤、阴道癌、外阴癌、星状细胞瘤、肝细胞癌、Waldenstrom巨球蛋白血症、肾母细胞瘤。
在一个优选实施例中,疾病、病症或病况选自骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、中枢神经系统淋巴瘤、非霍奇金淋巴瘤;乳头状和滤泡状甲状腺癌;乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤、实体瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病;髓性白血病、脑肿瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、肾细胞癌、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、星状细胞瘤、肝细胞癌或原发性巨球蛋白血症(Waldenstrom巨球蛋白血症)。在一个具体实施例中,所述癌症是转移性的。在另一个实施例中,所述癌症是化疗或放疗难治或无效的。
本文所述的治疗方法可使用任何合适的方法将药物组合物给予受试者,包括注射、经粘膜、口服、吸入、眼部、直肠、长效植入、脂质体、乳剂或持续释放方法。
本领域技术人员会认识到,本发明中要所用化合物的治疗或预防有效量可以随着因素的不同而不同,对于特定受试者,如年龄、饮食、健康等,寻求治疗或预防的症状或疾病、病症或病况的严重程度以及并发症和类型,所用制剂等。根据本发明公开内容,本领域普通技术人员将能够很容易地确定需给予受试者的化合物的治疗或预防有效量,以便在受试者中引起期望的生物学或医学响应。
根据本发明的实施例,通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药可以用来调节TNF-α或IL-2的活性或产生。在一个实施例中,当使用“调节”来描述特定分子的活性或产生时,是指抑制该分子的活性或产生。在另一个实施例中,当使用“调节”来描述特定分子的活性或产生时,是指增加或促进该分子的活性或产生。然而在另一个实施例中,当使用“调节”来描述特定分子的活性或产生时,是指减少或增加该分子的活性或产生。
因此,本发明还提供了调节TNF-α或IL-2产生或活性的方法。根据本发明的实施例,通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药,或其组合物可以给予受试者以调节TNF-α或IL-2的产生或活性,用于治疗或预防由TNF-α或IL-2调节异常相关或以TNF-α或IL-2调节异常为特征的疾病、病症或病况。
在一个优选实施例中,将根据本发明的通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药,或其组合物给予给受试者,以调节TNF-α或IL-2的产生或活性,用于治疗或预防癌症或炎症。
在本文所述的任何方法中,根据本发明的通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药,可单独使用或与放射疗法或放射免疫疗法等配合使用,还可与一种或多种其它具有药理学活性的治疗剂(以下简称“其它治疗剂”)联合使用。
根据本发明的实施例,根据本发明的通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药与其它治疗剂联合使用,根据本发明公开内容,可以在治疗或预防任何疾病、病症或病况中发挥协同作用。
根据本发明的实施例,其它治疗剂可以是天然存在的、半合成的或合成的化合物。在另一个实施例中,其它治疗剂可以是小分子,如合成的有机或无机分子;或较大的分子或生物分子,例如具有药理活性的蛋白质或核酸。在另一个实施例中,其它治疗剂可以是抗血管生成、免疫调节、免疫治疗、化学治疗或激素化合物。
适合于本发明所用其它治疗剂的实例包括但不限于单克隆和多克隆抗体如obinutuzumabnivolumabpembrolizumabelotuzumab、抗Her2/neu抗体(例如,曲妥珠单抗(trastuzumab,商品名:)和帕妥珠单抗(pertuzumab,商品名:OmnitargTM);阿昔单抗(abciximab,商品名:)、利妥昔单抗(rituximab,商品名:)、巴利昔单抗(basiliximab,商品名:)、帕利珠单抗(palivizumab,商品名:)、英夫利西单抗(infliximab,商品名:)、曲妥珠单抗(Trastuzumab,商品名:)、阿仑单抗(alemtuzumab,商品名:)、替伊莫单抗(ibritumomab tiuxetan,商品名:)、阿达木单抗(adalimumab,商品名:)、奥马珠单抗(omalizumab,商品名:)、托西莫单抗-I-131(tositumomab-I-131,商品名:)、西妥昔单抗(cetuximab,商品名: )、那他珠单抗(natalizumab,商品名:)、托珠单抗(tocilizumab,商品名: )、帕尼单抗(panitumumab,商品名:)、雷珠单抗(ranibizumab,商品名: )、依库珠单抗(eculizumab,商品名:)、赛妥珠单抗(certolizumab pegol,商品名:)、戈利木单抗(golimumab,商品名:)、康纳单抗(canakinumab,商品名:)、优特克单抗(ustekinumab,商品名:)、奥法木单抗(ofatumumab,商品名:)、德尼单抗(denosumab,商品名:)、莫维珠单抗(motavizumab,商品名:)、依决洛单抗(edrecolomab,商品名:)、瑞西巴库(raxibacumab,商品名:)、贝利单抗(belimumab,商品名:)、伊匹单抗(ipilimumab,商品名:)、贝伦妥单抗-维多汀(brentuximab vedotin,商品名:)、帕妥珠单抗(pertuzumab,商品名:或OmnitarTM)、阿恩曲珠单抗(ado-Trastuzumabemtansine,商品名:)、抗-CD40单克隆抗体、抗TNF-α抗体和VEGFR抗体(例如,贝伐单抗(bevacizumab,商品名:安维汀TM);Akt抑制剂;ALK抑制剂;AMPK抑制剂;反义寡核苷酸;烷化化学治疗剂,如氮芥类(例如,环磷酰胺(Cyclophosphamide)、二氯甲基二乙胺(Mechlorethamine)、氮芥气(HN2)(商品名:Mustardgen)、乌拉莫司汀(Uramustine)、尿嘧啶氮芥(uracil mustard)、美法仑(Melphalan)、苯丁酸氮芥(Chlorambucil)、异环磷酰胺(Ifosfamide)和苯达莫司汀(Bendamustine);亚硝基脲类(例如卡莫司汀(Carmustine)、洛莫司汀(Lomustine)和链佐星(Streptozocin);烷基磺酸盐(例如白消安(Busulfan));以及乙撑亚胺类如塞替派(Thiotepa);基于铂的化疗剂(例如顺铂(Cisplatin)、卡铂(Carboplatin)、奈达铂(Nedaplatin)、奥沙利铂(Oxaliplatin)、沙铂(Satraplatin)和四硝酸三钼(Triplatin tetranitrate)、丙卡巴肼(Procarbazine)、六甲蜜胺(Altretamine)、达卡巴嗪(Dacarbazine)米托唑胺(Mitozolomide)和替莫唑胺(Temozolomide);APC抑制剂;细胞凋亡基因调节剂;细胞凋亡调节剂;ATM/ATR抑制剂;极光激酶抑制剂;Axl抑制剂;Bcl-2抑制剂;BCR/ABL拮抗剂;bFGF抑制剂;BTK抑制剂;酪蛋白激酶抑制剂(ICOS);半胱胺酸蛋白酶抑制剂;CAR-T;CDK抑制剂如palbociclib;ChK抑制剂;c-Kit抑制剂;c-Met抑制剂;EGFR抑制剂;c-Myc抑制剂;C-RET抑制剂;CSF-1R抑制剂;细胞因子;DNA-PK抑制剂;动力蛋白抑制剂;EGF受体抑制剂;EGFR抑制剂;EGFR/ERBB抑制剂;肝配蛋白受体抑制剂;ERK抑制剂;雌激素激动剂;雌激素拮抗剂;FAK抑制剂;FGFR抑制剂;FLT3抑制剂;GF受体拮抗剂;谷胱甘肽抑制剂;GSK-3抑制剂;热休克蛋白-90抑制剂(例如17-AAG);造血生长因子;HDAC抑制剂;雄激素受体抑制剂、雄激素生物合成抑制剂、HER2抑制剂;HIF抑制剂;组蛋白去乙酰化酶抑制剂(例如SAHA和LAQ 824);HSP抑制剂;IAP抑制剂;IGF-1R抑制剂;IkB激酶抑制剂;胰岛素样生长因子-1受体抑制剂;整合素抑制剂;干扰素激动剂;干扰素;白介素;JAK抑制剂;JNK抑制剂;白血病抑制因子;白细胞α干扰素;溶血磷脂酸酰基转移酶抑制剂;基质溶解素抑制剂;基质金属蛋白酶抑制剂;Mdm2抑制剂;MEK抑制剂;MIF抑制剂;mTOR抑制剂;寡核苷酸;P13K抑制剂(例如,渥曼青霉素);p38 MAPK抑制剂;p53抑制剂;PAK抑制剂;PARP抑制剂;PDGFR抑制剂;PDK-1抑制剂;PD-1抑制剂;PD-L1抑制剂;磷酸酶抑制剂;Pim抑制剂;PKC抑制剂;PLK抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白质酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;RacGTPase抑制剂;Raf抑制剂;Ras法尼基蛋白转移酶抑制剂;Ras抑制剂;Ras-GAP抑制剂;ROCK抑制剂;S6激酶抑制剂;信号转导抑制剂;去乙酰化酶抑制剂;Src抑制剂;STAT抑制剂;生存素抑制剂;Syk抑制剂;端粒酶抑制剂;TNF-α抑制剂;拓扑异构酶抑制剂;Trk受体抑制剂;酪氨酸激酶抑制剂;尿激酶受体拮抗剂;血管内皮生长因子受体激酶抑制剂(例如,PTK787);VDA抑制剂;VEGFR抑制剂(例如,flk-1特异性激酶抑制剂、SU5416和ptk787/zk222584);Wee1抑制剂;和Wnt信号通路抑制剂。
适合用于本发明的其他具体治疗剂包括,但不限于,阿西维辛(acivicin);阿柔比星(aclarubicin);盐酸阿考达唑(acodazole hydrochloride);阿克罗宁(acronine);acylfulvene(酰基富烯);腺环戊醇(adecypenol);阿多来新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);氨莫司汀(ambamustine);安波霉素(ambomycin);醋酸阿美蒽醌(ametantrone acetate);amidox;阿米福汀(amifostine);氨基乙酰丙酸(aminolevulinic acid);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑;穿心莲内酯;antarelix;anthramycin;抗背部化形态发生蛋白-1(anti-dorsalizing morphogenetic protein-1);抗瘤酮(antineoplaston);甘氨酸阿非迪霉素(aphidicolin glycinate);无嘌呤酸(apurinic acid);ara-CDP-DL-PTBA;天门冬酰胺酶(asparaginase);曲林菌素(asperlin);奥沙那宁(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);阿新司坦汀1;阿新司坦汀2;阿新司坦汀3;阿糖胞苷(azacitidine);阿扎司琼(azasetron);阿扎托新(azatoxin);重氮酪氨酸(azatyrosine);阿扎替派(azetepa);阿佐霉素(azotomycin);班兰诺(balanol);巴马司他(batimastat);苯并二氢卟酚(benzochlorins);苯佐替派(benzodepa);苯甲酰基星形抱菌素(benzoylstaurosPorine);β-内酰胺衍生物(beta lactam derivatives);β-阿立辛(β-alethine);betaclamycin B;白桦脂酸(betulinic acid);比卡鲁胺(bicalutamide);盐酸比生群(bisantrene hydrochloride);二吖丙啶精胺(bisaziridinylspermine);双奈法德二甲磺酸酯(bisnafide dimesylate);双崔特A(bistratene A);bizelesin(比折来新);硫酸博莱霉素(bleomycin sulfate);硼替佐米(吉西他滨(gemcitabine);布喹那钠(brequinar sodium);bretlate;溴匹立明(bropirimine);布度钛(budotitane);布度钛(busulfan);丁硫堇(buthionine sulfoximine);放线菌素(cactinomycin);卡泊三醇(calcipotriol);钙磷酸蛋白C(calphostin C);卡普睾酮(calusterone);喜树碱衍生物(camptothecin derivatives);卡培他滨(capecitabine);卡醋胺(caracemide);卡贝替姆(carbetimer);卡铂(carboplatin);甲酰胺-氨基-三唑(carboxamide-amino-triazole);羧基酰氨基三唑(carboxyamidotriazole);羧胺三唑(carboxyamidotriazole);卡莫司汀(carmustine);carubicin hydrochloride(盐酸卡米诺霉素);卡折来新(carzelesin);澳粟精胺(castanospermine);抗菌肽B(cecropin B);西地芬戈(cedefingol);塞来昔布(celecoxib);西曲瑞克(cetrorelix);苯丁酸氮芥(chlorambucil);二氢卟酚(chlorins);氯代喹喔啉磺胺(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);cirolemycin(西罗霉素);顺铂(cisplatin);顺式卟啉(cis-porphyrin);克拉屈滨(cladribine);氯米芬类似物(clomifene analogues);克霉唑(clotrimazole);克立霉素A(collismycin A);克立霉素B(collismycin B);考布他汀A4(combretastatin A4);考布他汀衍生物(combretastatin derivatives);康纳京尼(conagenin);卡那贝西汀816(crambescidin 816);克立那托甲磺酸(crisnatol mesylate);克立那托(crisnatol);念珠藻环肽8(cryptophycin8);念珠藻环肽A类似物(cryptophycin A analogues);卡拉新A(curacin A);环戊蒽醌(cyclopentanthraquinones);环磷酰胺(cyclophosphamide);环普兰姆(cycloplatam);环孢菌素(cyclosporin);西匹霉素(cypemycin);阿糖胞苷十八烷基磷酸钠(cytarabine ocfosfate);阿糖胞苷(cytarabine);磷酸己烧雌酹(cytostatin);达卡巴嗪(dacarbazine);达昔单抗(dacliximab);更生霉素(dactinomycin);盐酸柔红霉素(daunorubicin hydrochloride);地西他滨(decitabine);去氢膜海鞘素B(dehydrodidemnin B);地洛瑞林(deslorelin);地塞米松(dexamethasone);右异环磷酰胺(dexifosfamide);奥马铂(ormaplatin);右奥马铂(dex奥马铂(ormaplatin);右雷佐生(Dextrazoxane);右旋维拉帕米(dexverapamil);甲磺酸地扎胍宁(dezaguaninemesylate);地扎胍宁(dezaguanine);地吖醌(diaziquone);膜海鞘素B(didemnin B);地多西(didox);二乙基去甲精胺(diethylnorspermine);二氢-5-氮胞苷(dihydro-5-azacytidine);9-二氢紫杉醇(dihydrotaxol,9-)-;二恶霉素(dioxamycin)二苯基螺莫司汀(diphenyl spiromustine);多西他赛(docetaxel);二十二烷醇(docosanol);多拉司琼(dolasetron);去氧氟尿苷(doxifluridine);盐酸表柔比星(doxorubicinhydrochloride);阿霉素(doxorubicin);多西环素(doxycycline);枸橼酸屈洛昔芬(droloxifene citrate);屈洛昔芬(droloxifene);屈他雄酮丙酸酯(dromostanolonepropionate);屈大麻酚(dronabinol);达佐霉素(duazomycin);卡霉素SA(duocarmycinSA);依布硒(ebselen);依考莫司汀(ecomustine);依达曲沙(edatrexate);依地福新(edelfosine);依决洛单抗(edrecolomab);盐酸依氟鸟氨酸(eflornithinehydrochloride);依氟鸟氨酸(eflornithine);榄香烯(elemene);elotuzumab;依沙芦星(elsamitrucin);乙嘧替氟(emitefur);恩洛铂(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);表柔比星(epirubicin);爱普列特(epristeride);爱必妥(erbitux);厄布洛唑(erbulozole);盐酸依索比星(esorubicin hydrochloride);雌莫司汀衍生物(estramustine derivatives);雌莫司汀磷酸钠(estramustine phosphate sodium);雌莫司汀(estramustine);依那西普(etanercept);依他硝唑(etanidazole);磷酸依托泊苷(etoposide phosphate);依托泊苷(etoposide);艾托卜宁(etoprine);依西美坦(exemestane);盐酸法倔唑(fadrozolehydrochloride);法倔唑(fadrozole);法扎拉滨(fazarabine);芬维A胺(fenretinide);非格司亭(filgrastim);非那雄胺(finasteride);夫拉平度(flavopiridol);氟卓斯汀(flezelastine);氟脲苷(floxuridine);夫斯特隆(fluasterone);磷酸氟达拉滨(fludarabine phosphate);氟达拉滨(fludarabine);fluorocitabine;盐酸氟柔红霉素(fluorodaunorunicin hydrochloride);氟尿嘧啶(fluorouracil);福酚美克(forfenimex);福美司坦(formestane);磷喹酮(fosquidone);福司曲星钠(fostriecinsodium);福司曲星(fostriecin);福莫司汀(fotemustine);钆特沙弗林(gadoliniumtexaphyrin);硝酸镓(gallium nitrate);加洛他滨(galocitabine);加尼瑞克(ganirelix);盐酸吉西他滨(gemcitabine hydrochloride);吉西他滨(gemcitabine);和普苏姆(hepsulfam);调蛋白(heregulin);六亚甲基二乙酰胺(hexamethylenebisacetamide);羟基脲(hydroxyurea);金丝桃素(hypericin);伊班膦酸(ibandronicacid);依鲁替尼(ibrutinib);盐酸伊达比星(idarubicin hydrochloride);伊达比星(idarubicin);艾多昔芬(idoxifene);伊决孟酮(idramantone);异环磷酰胺(ifosfamide);伊莫福新(ilmofosine);伊洛马司他(ilomastat);伊马替尼(imatinib,商品名:);咪喹莫特(imiquimod);免疫刺激肽(immunostimulant peptides);碘苄胍(iobenguane);碘阿霉素(iododoxorubicin);4-甘薯苦醇(ipomeanol,4-)-;异丙铂(iproplatin);盐酸伊立替康(irinotecan hydrochloride);伊立替康(irinotecan);伊罗普拉(iroplact);伊索拉定(irsogladine);异苯胍唑(isobengazole);异高软海绵素B(isohomohalicondrin B);伊他司琼(itasetron);jasplakinolide;kahalalide F;片螺素-N三醋酸酯(lamellarin-N triacetate);醋酸兰瑞肽(lanreotide acetate);兰瑞肽(lanreotide);拉帕替尼(lapatinib,商品名: );leinamycin;来格司亭(lenograstim);香菇多糖硫酸酯(lentinan sulfate);leptolstatin;来曲唑(letrozole);醋酸亮丙瑞林(leuprolide acetate);醋酸亮丙瑞林+雌激素+孕激素(leuprolide+estrogen+progesterone);亮丙瑞林(leuprorelin);左旋咪唑(levamisole);盐酸利阿唑(liarozole hydrochloride);利阿唑(liarozole);亲脂性双糖肽(lipophilic disaccharide peptide);脂溶性铂类似物(lipophilic platinumanalogues);立索克林酰胺7(lissoclinamide7);洛铂(lobaplatin);蚯吲磷脂(lombricine);洛美曲索钠(lometrexol sodium);洛美曲索(lometrexol);洛莫司汀(lomustine);氯尼达明(lonidamine);盐酸洛索蒽醌(losoxantrone hydrochloride);洛索蒽醌(losoxantrone);洛索立宾(loxoribine);勒托替康(lurtotecan);镥特沙弗林(lutetium texaphyrin);lysofylline;裂解肽(lytic peptides);美坦新(maitansine);麦洛坦汀A(Amannostatin A);马马司他(marimastat);马索罗酚(masoprocol);乳腺丝抑蛋白(maspin);美登素(maytansine);盐酸氮芥(mechlorethamine hydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美伦孕酮(melengestrol acetate);美法仑(melphalan);美诺立尔(menogaril);麦尔巴隆(merbarone);巯嘌呤(mercaptopurine);美替瑞林(meterelin);蛋氨酸(methioninase);甲氨蝶呤钠(methotrexate sodium);甲氨蝶呤(methotrexate);甲氧氯普胺(metoclopramide);氯苯氨啶(metoprine);美妥替哌(meturedepa);米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);米丁度胺(mitindomide);米托卡星(mitocarcin);丝裂红素(mitocromin);米托洁林(mitogillin);米托胍腙(mitoguazone);二溴卫矛醇(mitolactol);米托马星(mitomalcin);丝裂霉素衍生物(mitomycin derivatives);丝裂霉素(mitomycin);米托萘胺(mitonafide);米托司培(mitosper);米托坦(mitotane);有丝分裂毒素成纤维细胞生长因子-月巴皂草毒蛋白(mitotoxin fibroblast growth factor-saporinmitotoxin);盐酸米托蒽醌(mitoxantrone hydrochloride);米托蒽醌(mitoxantrone);莫法罗汀(mofarotene);莫拉司亭(molgramostim);莫哌达醇(mopidamol);mycaperoxide B;霉酚酸(mycophenolic acid);myriaporone;N-乙酰基地那林(N-acetyldinaline);那法瑞林(nafarelin);nagrestip;纳洛酮+喷他佐辛(naloxone+pentazocine);napavin;naphterpin;那托司亭(nartograstim);奈达铂(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);尼鲁米特(nilutamide);nisamycin;nitrullyn;nivolumab诺考达唑(nocodazole);诺加霉素(nogalamycin);O6-苄基鸟嘌呤(O6-benzylguanine);oblimersen(奥利默森,商品名:);奥曲肽(octreotide);奥克恩(okicenone);奥那司酮(onapristone);昂丹司琼(ondansetron);奥拉新(oracin);奥马铂(ormaplatin);奥沙特隆(osaterone)奥沙利铂(oxaliplatin);厄诺霉素(oxaunomycin);奥昔舒仑(oxisuran);紫杉醇(paclitaxel);紫杉醇衍生物(paclitaxelderivatives);帕诺明(palauamine);palbociclib;棕榈酰根霉素(palmitoylrhizoxin);帕米膦酸(pamidronic acid);人参炔三醇(panaxytriol);帕诺米芬(panomifene);panobinostat;帕拉贝新(parabactin);帕折普汀(pazelliptine);培门冬酶(pegaspargase);皮地新(peldesine);培利霉素(peliomycin);pembrolizumab戊氮芥(pentamustine);多硫酸戊聚糖钠(pentosan polysulfate sodium);喷司他丁(pentostatin);喷唑(pentrozole);硫酸培洛霉素(peplomycin sulfate);全氟溴烷(perflubron);培磷酰胺(perfosfamide);紫苏子醇(perillyl alcohol);苯连氮霉素(phenazinomycin);乙酸苯酯(phenylacetate);溶链菌(picibanil);盐酸毛果芸香碱(pilocarpine hydrochloride);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);吡柔比星(pirarubicin);吡曲克辛(piritrexim);盐酸吡罗蒽醌(piroxantronehydrochloride);普来司汀A(placetin A);普来司汀B(placetin B);铂络合物(platinumcomplex);普卡霉素(plicamycin);普洛美坦(plomestane);卟吩姆钠(porfimer sodium);泊非霉素(porfiromycin);泼尼氮芥(prednimustine);强的松;盐酸丙卡巴肼(procarbazine hydrochloride);丙基双吖啶酮(propyl bis-acridone);前列腺素J2(prostaglandin J2);盐酸嘌呤霉素(puromycin hydrochloride);嘌呤霉素(puromycin);羟基茜草素(purpurins);吡唑呋喃菌素(pyrazofurin);甲氧基吡唑啉吖啶(pyrazoloacridine);雷替曲塞(raltitrexed);雷莫司琼(ramosetron);雷帕霉素(rapamycin);雷帕霉素衍生物(rapamycin derivatives)(例如,依维莫司(everolimus);merilimus;olcorolimus;ridaforolimus;西罗莫司(sirolimus);temsirolimus西罗莫司脂化物(sirolimus,商品名:Torisel);umirolimus和佐他莫司(zotarolimus);去甲基瑞替利汀(retelliptine demethylated);铼186依替膦酸钠(rhenium Re 186etidronate);根霉素(rhizoxin);利波腺苷(riboprine);核酶(ribozymes);RII维甲酸(RII retinamide);罗希吐碱(rohitukine);罗莫肽(romurtide);罗喹美克(roquinimex);鲁滨吉隆B1(rubiginone B1);鲁泊塞(ruboxyl);盐酸沙芬戈(safingol hydrochloride);沙芬戈(safingol);saintopin;SarCNU;肌肉叶绿醇A(sarcophytol A);沙格司亭(sargramostim);Sdi1类似物(Sdi1mimetics);马沙尼(semaxanib);司莫司汀(semustine);辛曲秦(simtrazene);sizofuran;索布佐生(sobuzoxane);硼卡钠(sodiumborocaptate);苯乙酸钠(sodium phenylacetate);索佛罗(solverol);生长调节素结合蛋白(somatomedin binding protein);索纳明(sonermin);斯帕磷酸钠(sparfosatesodium);斯帕磷酸(sparfosate);稀疏霉素(sparsomycin);穗霉素D(spicamycin D);盐酸锗螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺铂(spiroplatin);斯兰罗皮汀(splenopentin);海绵素1(spongistatin1);角鲨胺(squalamine);斯替皮米德(stipiamide);链黑菌素(streptonigrin);链佐星(streptozocin);sulfinosine;磺氯苯脲(sulofenur);suradista;苏拉明(suramin);苦马豆素(swainsonine);他利霉素(talisomycin);他莫司汀(tallimustine);他莫昔芬甲碘化物(tamoxifen methiodide);牛磺莫司汀(tauromustine);泰索帝(taxotere);他扎罗汀(taxotere);替可加兰钠(tecogalan sodium);替加氟(tegafur);tellurapyrylium;盐酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替罗昔隆(teroxirone);睾内酯(teroxirone);四氯十氧化物(tetrachlorodecaoxide);替唑明(tetrazomine);噻立拉斯汀(thaliblastine);硫咪嘌呤(thiamiprine);噻可拉林(thiocoraline);硫鸟嘌呤(thioguanine);噻替哌(thiotepa);血小板生成素模拟物(thrombopoietin mimetics);血小板生成素(thrombopoietin);胸腺法新(thymalfasin);胸腺曲南(thymotrinan);噻唑呋林(tiazofurin);乙基锡初紫红素(tin ethyl etiopurpurin);替拉扎明(tirapazamine);二茂钛二氯化物(titanocenebichloride);托普升替(topsentin);枸橼酸托瑞米芬(toremifene citrate);托瑞米芬(toremifene);醋酸曲托龙(trestolone acetate);维甲酸(tretinoin);三乙酰尿苷(triacetyluridine);磷酸曲西立滨(triciribine phosphate);曲西立滨(triciribine);三甲曲沙葡糖醛酸脂(trimetrexate glucuronate);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司琼(tropisetron);盐酸妥布氯(tubulozole hydrochloride);妥罗雄脲(turosteride);tyrphostins;乌苯美司(ubenimex);尿嘧啶氮芥(uracil mustard);乌瑞替派(uredepa);伐普肽(vapreotide);凡瑞林B(variolin B);维拉雷琐(velaresol);藜芦胺(veramine);verdins;维替泊芬(verteporfin);硫酸长春碱(vinblastinesulfate);硫酸长春新碱(vincristine sulfate);硫酸长春新碱(vindesine sulfate);长春地辛(vindesine);硫酸长春匹定(vinepidine sulfate);硫酸长春甘酯(vinglycinatesulfate);硫酸长春罗新(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbinetartrate);长春瑞滨(vinorelbine);硫酸长春罗定(vinrosidine sulfate);维萨汀(vinxaltine);硫酸长春利定(vinzolidine sulfate);vitaxin;伏氯唑(vorozole);扎诺特隆(zanoterone);折尼铂(zeniplatin);净司他丁(zinostatin);5-乙炔基尿嘧啶(5-ethynyluracil)和盐酸佐柔比星(zorubicin hydrochloride)。
在一个优选实施方案中,其它治疗剂选自elotuzumab、palbociclib、panobinostat、nivolumab、pembrolizumab、培美曲塞(pemetrexed)、托泊替康(拓扑替康)(topotecan)、阿霉素(doxorubicin)、硼替佐米(bortezomib)、吉西他滨(gemcitabine)、达卡巴嗪(dacarbazine)、地塞米松(dexamethasone)、克拉霉素(biaxin)、长春新碱(vincristine)、阿糖胞苷(azacitidine)、CAR-T、利妥昔单抗(rituximab)、曲妥珠单抗(trastuzumab)、PD-1抑制剂、PD-L1抑制剂、HDAC抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂、泼尼松(prednisone)、多西他赛(docetaxel)、氯法拉滨注射液、Ublituximab、romidepsin、BTK抑制剂、红血球生长激素、eltrombopag、米诺四环素和美法仑(melphalan)中的一种或多种。
在本发明的一个实施例中,将一种包含通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药,和另外一种治疗剂的组合物同时给予受试者。在另一个实施例中,通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药,和另外一种治疗剂按顺序依次给药。在另一个实施例中,通式(I)化合物、其药学上可接受的盐、溶剂化物、立体异构体、同位素化合物、代谢物,或前药,和另外一种治疗剂分别单独给药。另外一种治疗剂可以在给予根据本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药之前、连续或之后给予。
根据本发明可与通式(I)化合物或其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药联合给药的一个或多个其它治疗剂将取决于多种因素,例如,需进行预防或治疗的疾病、病症或病况等。本领域普通技术人员能够根据本发明的公开内容,很容易地确定将与通式(I)所示的异吲哚啉衍生物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药联合所用合适的其它治疗剂。
本发明中方法中将所用其它治疗剂的治疗有效量是本领域熟练技术人员所熟知的,并且给药指导可见本文引用的专利和公布的专利申请以及Wells et al,eds.,Pharmacotherapy Handbook,2nd Edition,Appleton and Lange,Stamford,Conn.(2000);PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Deluxe Edition,TarasconPublishing,Loma Linda,Calif.(2000)和其它医学文献。但是,普通技术人员的技术水平完全能够确定其它治疗剂的最佳有效剂量范围。
根据本发明的一个实施方式,当根据本发明通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药与其它治疗剂联合给药时,通式(I)所示的化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药的治疗有效量低于通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药不与其它治疗剂联合给药时将需要的治疗有效量。在另一个实施例中,另一种治疗剂的治疗有效量低于不给予根据本发明通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药时的有效量。以这种方式,与任何一种药物的高剂量相关的副作用可以降至最低。其他潜在的优势,例如,改善给药方案和/或降低药物成本,对于本领域技术人员将是显而易见的。
根据本发明的实施例,当将通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药和其它治疗剂给予受试者以治疗或预防疾病、病症或病况时,通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药和其它治疗剂可通过相同的途径给药,也可通过不同的途径给药。其它治疗剂可通过本文描述的任何途径给药,包括但不限于口服、吸入、注射、眼部、粘膜、直肠、乳剂、脂质体、长效植入或持续缓释方法。其它治疗剂的具体给药途径将依赖于其它治疗剂本身及制剂,以及需预防或治疗的疾病、病症或病况。根据本公开内容,本领域中一名普通技术人员的技能水平足以确定其它治疗剂的给药途径。
本文中引用或描述了各种出版物、文章和专利,引用或描述这些参考文献或将其整体并入本文或对之进行的讨论是为了说明本发明的背景,并非是指其中的内容构成了本发明现有技术的一部分。
除非另有定义,本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。否则,此处所用的某些术语的含义具有本说明书所设定的含义。此处引用的所有专利、已经公开的专利申请和出版物均通过引用并入到本文中,如同在此处全面阐述一样。应当注意的是,除非上下文明确表示另有规定外,用于此处和所附权利要求中的单数形式均包含复数含义。
如本文中所用,当提到具体盐、组合物、辅料等“药学上可接受的”时,是指该盐、组合物、辅料等一般无毒、安全,并且适合于受试者使用,优选哺乳动物受试者,更优选为人受试者。
本文所用术语“药学上可接受的盐”指药学上可接受的有机或无机盐。示例性盐包括但不限于:硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、gentisinate、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐的综述见Handbook ofPharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl andCamille G.Wermuth,ed.,Wiley-VCH,2002)。
如本文所用,术语“代谢物”是指药物分子在体内所经历的化学结构的变化后产生的活性物质,该活性物质一般为前述药物分子的衍生物,其还可被化学修饰。
如本文所用并且除非另有规定,术语“晶型(polymorph)”是指在结晶时,分子在晶格空间的排列不同而形成的一种或多种晶体结构。
如本文所用,术语“溶剂化物”是指通式(I)化合物、其药学上可接受的盐、晶型、立体异构体、同位素化合物、代谢物或前药的一种晶体形式,它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量量的溶剂,并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂化物可能是溶剂化物至少丢失一个(但并非全部)溶剂分子得到的。在一个特定实施例中,一种溶剂化物是一种水合物,意味着化合物的结晶形式进一步包括水分子,以水分子作为溶剂。
如本文所用并且除非另有规定,术语“前药”是指包含生物反应官能团的化合物的衍生物,使得在生物条件下(体外或体内),生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常,前药无活性,或者至少比化合物本身活性低,使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如,前药可包含可生物水解的基团。可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见,例如,J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007)。
本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药可以含有一个或多个不对称中心(“立体异构体”)。如本文所用,术语“立体异构体”是指对映异构体、非对映异构体、差向异构体(epimers)、内向-外向异构体(endo-exo isomers)、阻转异构体(atropisomers)、位向异构体(regioisomers)、顺式-和反式-异构体等在内的所有立体异构体。本文的“立体异构体”也包括前述各种立体异构体的“纯立体异构体”及“富集立体异构体”或“消旋体”。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集,还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。本文的“纯立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于95%。本文的“富集立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于50%。本文的“消旋体”是指所涉化合物的一种立体异构体的质量含量与该化合物的其它种立体异构体的质量含量相等。
本文所用术语“同位素化合物”是指本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、代谢物,或前药中含有一个或多个天然或非天然丰度的原子同位素。非天然丰度的原子同位素包括但不限于氘(2H或D)、氚(3H或T)、碘-125(125I)、磷-32(32P)、碳-13(13C)或碳-14(14C)。前述同位素化合物还可用作治疗或诊断剂(即,体内显影剂),或研究工具。本发明的化合物的所有同位素变体,无论是否具有放射性,都包括在本发明的范围内。
本文所用术语“同位素富集”是指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物或前药中含有一个或多个非天然丰度的原子同位素。“同位素富集”也指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、立体异构体、同位素化合物、代谢物,或前药化合物中至少含有一个非天然丰度同位素原子。
如本文所用,术语“受试者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优,人类最优。如本文所用术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为最优。
在一个实施例中,“治疗”或“正在治疗”是指疾病或病症或其至少一个可辨别症状的改善、预防或逆转,例如通过减少或稳定癌症或病症症状,治疗癌症、不期望的血管生成相关病症或TNF-α相关病症。在另一个实施例中,“治疗”或“正在治疗”是指正在治疗的疾病或病症的至少一个可测量身体参数的改善、预防或逆转,可能并未在哺乳动物中识别所述疾病或病症,例如,通过抑制TNF-α产生或调节TNF-α活性治疗癌症、不期望的血管生成相关病症或TNF-α相关病症。然而在另一个实施例中,“治疗”或“正在治疗”是指减慢疾病或病症的进展,或者是身体上的,例如可辨别症状的稳定,或生理学上的,例如,身体参数的稳定,或两者兼而有之。在另一个实施例中,“治疗”或“正在治疗”是指延迟疾病或病症的发作。
在某些实施例中,关注化合物作为预防措施给药。如本文所用,“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中,将指定化合物作为预防措施给予受试者,例如有癌症或自身免疫性疾病家族病史或倾向的受试者。
如本文所用,“治疗有效量”是指能够引起组织系统、动物或人产生生物学或医学反应(研究员、兽医、医生或其他临床医生正在寻求的)的化合物或组合物的量,其可以包括减轻正在治疗的疾病或病症症状。在一个优选实施例中,治疗有效量是有效治疗、改善治疗或预防癌症、病症或不期望的血管相关病况或TNF-α相关病症的量。
术语“预防有效量”是指能够抑制受试者中病症发作(研究员、兽医、医生或其它临床医生所寻求的)的活性化合物或药剂的量。化合物的预防有效量是指治疗剂单独使用或联合其它治疗活性化合物所用的量,其在治疗或预防疾病、病症或病况中能够提供治疗益处。
如无另外说明,本文所用术语的单数形式“一个”或“一种”也包括复数意义。
如无另外说明,本文使用“或”或“和”指“和/或”。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明通式(I)所示的异吲哚啉衍生物能够调节细胞因子(如TNF-α)的产生和/或活性,从而有效的治疗癌症和炎症性疾病。
具体实施方式
实施例1化合物I-28
步骤A:将5-氟-2-甲基苯甲酸(6.0g,38.9mmol)溶解于98%硫酸(60mL)。降温至-5-0℃,缓慢滴加65%硝酸(3.3g,50.7mmol),加毕维持此温度下搅拌1小时。反应液加入冰水(200g)中,水相用甲基叔丁基醚萃取(150mL×3),有机相用饱和食盐水洗一次(20mL),无水硫酸钠干燥,过滤,旋干溶剂,得到7.0克粗品黄色固体5-氟-2-甲基-3-硝基苯甲酸粗品。粗品未经纯化,直接用于下一步。1H NMR(DMSO-d6,300MHz),δ8.05(dd,J=8.1Hz,3.0Hz,1H),7.85(dd,J=8.7,3.0Hz,1H),2.44(s,3H).
步骤B:将步骤A所得5-氟-2-甲基-3-硝基苯甲酸粗品(7.0g)溶解在甲醇里(70mL),加入98%硫酸(2mL)。混合物于70℃搅拌过夜。反应液浓缩后,加入水(50mL)和乙酸乙酯(150mL)分层,水相乙酸乙酯萃取(100mL×2)。合并有机相并用饱和食盐水洗一次(30mL),无水硫酸钠干燥,过滤,旋干溶剂,柱层析(PE:EtOAc=10:1~3:1)得到淡黄色固体5-氟-2-甲基-3-硝基苯甲酸甲酯(3.5g,两步收率为42%)。1H NMR(DMSO-d6,300M Hz),δ8.10(dd,J=8.1,3.0Hz,1H),7.88(dd,J=8.7,3.0Hz,1H),3.86(s,3H),2.41(s,3H).
步骤C:将5-氟-2-甲基-3-硝基苯甲酸甲酯(3.5g,16.4mmol)、BPO(388mg,1.6mmol)和NBS(3.2g,18.1mmol)溶于CCl4(40mL)中,95℃浴温下反应过夜。混合物冷却至室温后过滤,滤液以饱和食盐水(20mL)洗一次,无水硫酸钠干燥,减压浓缩,硅胶柱层析纯化(PE:EtOAc=10:1~5:1)得到淡黄色油状物2-溴甲基-5-氟-3-硝基苯甲酸甲酯(3.7g,收率:77%)。1H NMR(DMSO-d6,300MHz):δ8.21-8.25(dd,J=8.1,3.0Hz,1H),7.99-8.03(dd,J=8.7,2.7Hz,1H),4.97(s,2H),3.93(s,3H).
步骤D:将3-氨基哌啶-2,6-二酮盐酸盐(2.5g,15.1mmol)和2-溴甲基-5-氟-3-硝基苯甲酸甲酯(4.0g,13.7mmol)和KHCO3(3.5g,34.2mmol)加入CH3CN(80mL)中,95℃浴温反应过夜。反应液浓缩后加入冰水(100g)搅拌0.5h。过滤,固体用水洗(50mL×3),干燥后得到黄色固体I-28A[3-(6-fluoro-4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione](3.8g,收率:90%)。1H NMR(DMSO-d6,400MHz),δ11.04(s,1H),8.38(dd,J=8.8,2.4Hz,1H),8.11(dd,J=6.8,2.4Hz,1H),5.18(dd,J=13.2,5.2Hz,1H),4.88(d,J=19.2Hz,1H),4.78(d,J=19.2Hz,1H),2.87-2.96(m,1H),2.54-2.63(m,2H),2.01-2.05(m,1H)。
步骤E:将化合物I-28A(2.8g,9.1mmol)和Pd/C(10%,280mg,50%水)加于DMF(30mL)中,50Psi氢气下室温反应6h。反应液过滤,固体用DMF(50mL×1洗涤,滤液浓缩,浓缩物加水(100ml)搅拌0.5h,抽滤,固体用水洗涤(50mL×3)后浓缩并干燥,得到类白色粗品(2.1g,收率:84%)。取其中200mg,用制备HPLC纯化得到148.8mg类白色固体I-28[3-(4-amino-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione]。1H NMR(DMSO-d6,400MHz),11.01(s,1H),6.55-6.63(m,2H),5.79(s,2H),5.10(dd,J=13.2,4.8Hz,1H),4.18(d,J=17.2Hz,1H),4.08(d,J=17.2Hz,1H),2.87-2.95(m,1H),2.59-2.63(m,1H),2.27-2.31(m,1H),2.02-2.06(m,1H)。LCMS:278.1([M+1]+)。
化合物I-01~化合物I-27的合成方法参照实施例1。
实施例2化合物I-29和I-30的合成
800mg化合物I-28溶于28mL DMF中,通过HPLC手性拆分(色谱柱:CHIRALPAK IA,5μm,30×250mm;流动相CH3CN;流速21mL/min;温度26-28℃;检测波段230nM;单次进样体积350μL)得到300mg I-29[Rt=4.81min;>99%ee;1H NMR(DMSO-d6,400MHz),δ11.01(s,1H),6.55-6.63(m,2H),5.80(s,2H),5.07-5.12(m,1H),4.18(d,J=16.8Hz,1H),4.08(d,J=16.8Hz,1H),2.87-2.93(m,1H),2.59-2.63(m,1H),2.27-2.31(m,1H),2.02-2.07(m,1H)。LCMS:278.1([M+1]+)]和260mg I-30[Rt=7.08min;>97.5%ee;1H NMR(DMSO-d6,400MHz),δ11.01(s,1H),6.55-6.63(m,2H),5.79(s,2H),5.08-5.12(m,1H),4.19(d,J=17.2Hz,1H),4.08(d,J=17.2Hz,1H),2.87-2.95(m,1H),2.59-2.64(m,1H),2.27-2.31(m,1H),2.04-2.07(m,1H)。LCMS:278.1([M+1]+)]。
实施例3化合物I-31和I-32
步骤A:向含有L-谷氨酸-5-苄酯(50.0g,211mmol)的氘代醋酸AcOD(150mL)中加入苯甲醛(1.34g,12.6mmol),加热至65℃,搅拌18小时。减压浓缩去除溶剂。向剩余固体中加入甲醇(25mL)、乙腈(50mL)和甲基叔丁基醚(200mL),打浆搅拌半小时后过滤,滤饼用甲基叔丁基醚(200mL)淋洗。固体经减压干燥后用同样方法重新反应一次后得I-31A(32.5g,收率65%)。1H NMR[(CD3OD+D2O),300MHz]:δ7.33-7.42(m,5H),5.14(s,2H),3.70(t,<0.05H),2.58-2.63(m,2H),2.13-2.17(m,2H)。
步骤B:将化合物I-31A(32.5g,137mmol)溶于THF(600ml)和水(600ml)的混合溶剂中,冰浴下加入NaHCO3(12.6g,150mmol),10分钟后将(Boc)2O(32.7g,150mmol)缓慢加入反应体系中。自然升温至室温后继续搅拌4小时,减压浓缩,剩余物加入适量饱和NaHCO3溶液使之溶清。用甲基叔丁基醚萃取(200ml×2),水相冰浴冷却后用3N的HCl溶液酸化至pH~1。EtOAc萃取(300ml×2),无水Na2SO4干燥,过滤,浓缩得白色固体中间体I-31B(46.5g,收率:100%)。产品无需进一步纯化直接用于下一步。1H NMR(CD3OD,300MHz):δ7.29-7.35(m,5H),5.12(s,2H),4.13(br s,0.05H),2.45-2.50(m,2H),2.12-2.21(m,1H),1.85-1.94(m,1H),1.42(s,9H)。
步骤C:将化合物I-31B(46.5g,137mmol)溶于THF(300mL)中,反应液冷却至5℃后,加入甲基吗啉(NMM,16.5g,164mmol)和氯甲酸乙酯(17.8g,164mmol),0-5℃搅拌一小时后,将饱和的氨水(150ml)加入反应液中,室温下剧烈搅拌2小时。加入乙酸乙酯(200mL)萃取分液,水相再次用乙酸乙酯(200mL)萃取一次。合并有机相,分别用饱和碳酸氢钠溶液(200mL×2)和饱和食盐水洗涤(200ml),无水硫酸钠干燥,过滤浓缩后得白色固体产品I-31C(41g,收率:90%)。1H NMR(DMSO-d6,300MHz):δ7.30-7.41(m,5H),7.24(s,1H),6.99(s,1H),6.79(s,1H),5.06(s,2H),3.90(m,<0.05H),2.33-2.38(m,2H),1.70-1.94(m,2H),1.35(s,9H)。
步骤D:将化合物I-31C(41.0g,121mmol)溶于1,4-二氧六环(200mL)中,加入6N的HCl/二氧六环溶液(300mL),室温搅拌2小时。反应液浓缩蒸干后加入200mL甲基叔丁基醚打浆,过滤后干燥得白色固体I-31D(31.3g,收率:95%)。1H NMR(DMSO-d6,400MHz):δ8.37(brs,3H),8.04(s,1H),7.56(m,1H),7.33-7.38(m,5H),5.10(s,2H),3.77(t,<0.05H),2.48-2.52(m,2H),2.01-2.05(m,2H)。
步骤E:将2-溴甲基-5-氟-3-硝基苯甲酸甲酯(31.8g,109mmol)和化合物I-31D(29.7g,109mmol)溶于乙腈中(550mL),搅拌下加入TEA(22.1g,218mmol)。升温至75℃反应过夜。减压浓缩至干,剩余物加入CH3CN(100mL)打浆得浅黄色固体化合物I-31E(34.5g,收率:76.2%)。1H NMR(DMSO-d6,300MHz):δ8.33(dd,J=8.7,2.4Hz,1H),8.04(dd,J=6.9,2.4Hz,1H),7.66(s,1H),7.26-7.36(m,6H),4.82-5.05(m,4H),2.20-2.39(m,3H),2.06-2.15(m,1H)。
步骤F:化合物I-31E通过HPLC手性拆分(色谱柱:DAICEL CHIRALPAK IA,10μm,25×250mm;流动相MeOH/DCM80/20(v/v);流速30mL/min;温度35℃;检测波段254nM)得到I-31F1[1H NMR(DMSO-d6,300MHz):δ8.31-8.35(m,1H),8.03(dd,J=7.2,2.1Hz,1H),7.66(s,1H),7.29-7.35(m,6H),4.83-5.04(m,4H),2.22-2.40(m,3H),2.06-2.16(m,1H)]和I-31F2[1H NMR(DMSO-d6,300MHz):δ8.33(dd,J=9.3,2.4Hz,1H),8.03(dd,J=7.2,2.4Hz,1H),7.67(s,1H),7.29-7.36(m,6H),4.83-5.05(m,4H),2.20-2.42(m,3H),2.09-2.16(m,1H)]。
化合物I-32:化合物I-31F2(2.2g,5.3mmol)和Pd/C(10%,200mg,50%水)加入无水甲醇(30mL)中,50Psi氢气压力下室温反应4h。反应液抽滤,滤液浓缩至干,剩余固体加入DCE(15mL)搅拌5分钟,减压浓缩至干。得到类白色粗品(1.4g)。取1.1g(3.7mmol)溶于干燥的THF(10mL)和DCE(40mL)的混合溶剂中,于-30℃下缓慢滴加SOCl2(0.74g,9.3mmol),加毕搅拌反应2h,滴加吡啶(1.1g,9.3mmol)维持此温度搅拌40分钟,加入TEA(1.3g,13mmol),继续反应2h。加水(0.1mL),反应混合物减压浓缩至干后再加水(5mL),EtOAc萃取(70mL×5),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经Pre-HPLC得到浅绿色固体I-32(340mg,收率:33%;99%ee)。1H NMR(DMSO-d6,400MHz),11.00(s,1H),6.56-6.61(m,2H),5.78(s,2H),5.05-5.11(m,0.05H),4.17(d,J=17.1Hz,1H),4.05(d,J=17.1Hz,1H),2.84-2.96(m,1H),2.56-2.62(m,1H),2.20-2.32(m,1H),1.98-2.05(m,1H)。LCMS:279.1([M+1]+)。
化合物I-31:用化合物I-32的同样合成方法,以I-31F1替换I-31F2可以得到化合物I-31(99%ee)。1H NMR(DMSO-d6,400MHz),10.99(s,1H),6.52-6.61(m,2H),5.71(br s,2H),5.08(dd,J=18.0,7.2Hz,0.04H),4.17(d,J=17.4Hz,1H),4.06(d,J=17.4Hz,1H),2.83-2.96(m,1H),2.56-2.62(m,1H),2.21-2.32(m,1H),1.98-2.05(m,1H)。LCMS:279.1([M+1]+)。
实施例4化合物I-01
参照实施例3中化合物的合成方法,用相应的外消旋混合物I-31E为底物,就可以合成实施例4中的化合物I-01。
1H NMR(DMSO-d6,300MHz):δ10.94(br s,1H),6.52-6.61(m,2H),5.78(s,2H),5.05-5.11(m,0.05H),4.16(d,J=16.8Hz,1H),4.05(d,J=16.8Hz,1H),2.84-2.96(m,1H),2.54-2.62(m,1H),2.21-2.31(m,1H),1.98-2.04(m,1H).LCMS:279.1([M+1]+)。
化合物I-33~化合物I-56的合成方法可参照实施例2或3。
实施例5化合物A195
3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A195.
合成路线
实验部分
A340D(40mg,0.096mmol)溶于CH3CN(3mL),加入CDI(20mg,0.13mmol),90℃氮气氛围下搅拌反应过夜。减压浓缩。残液溶于DCM(30mL),依次经0.1N HCl(10mL),饱和NaHCO3水溶液(10mL),饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。残液经制备薄层色谱纯化(DCM/MeOH=25/1)2次,可得白色固体A195(46mg,收率:81%)。
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.23(t,J=7.8Hz,1H),7.11(t,J=9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.66(d,J=7.8Hz,1H),6.24(t,J=5.7Hz,1H),5.10(dd,J=13.2,5.4Hz,1H),4.36(d,J=5.4Hz,2H),4.30(d,J=17.7Hz,1H),4.17(d,J=17.7Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.57-2.64(m,1H),2.24-2.36(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
参照实施例5中化合物的合成方法,用相应的底物替换A340D,就可以合成下列实施例6-7中的化合物。
实施例6化合物A196
3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneA196.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.21(t,J=7.8Hz,1H),7.00-7.04(m,2H),6.90-6.95(m,2H),6.62(d,J=7.8Hz,1H),6.30(t,J=6.0Hz,1H),5.10(dd,J=13.2,5.7Hz,1H),4.40(d,J=6.0Hz,2H),4.28(d,J=17.4Hz,1H),4.16(d,J=17.4Hz,1H),3.81(s,3H),2.85-2.97(m,1H),2.56-2.63(m,1H),2.26-2.32(m,1H),1.99-2.07(m,1H).LCMS:398.1([M+1]+).
实施例7化合物A197
3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneA197.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.19-7.31(m,2H),6.92(d,J=7.2Hz,1H),6.80(dd,J=12.0,2.4Hz,1H),6.71(dd,J=8.4,2.4Hz,1H),6.65(d,J=7.8Hz,1H),6.20(t,J=5.7Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.24-4.33(m,3H),4.14(d,J=17.1Hz,1H),3.72(s,3H),2.85-2.97(m,1H),2.57-2.62(m,1H),2.21-2.36(m,1H),1.98-2.05(m,1H).LCMS:398.1([M+1]+).
实施例8化合物A318
3-(6-fluoro-4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-di one A318.
合成路线
实验部分
步骤A:将Pd/C(0.18g,10%,50%wet)加入到I-28A(1.0g,3.3mmol)的DMF溶液(10mL)中,氢气置换三次后于50psi,25℃下反应5小时。过滤,滤液减压浓缩至干,剩余物用PE/EtOAc(5:1,10mL)打浆三次,得绿色固体产品I-28(粗品0.9g)。
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),6.52-6.61(m,2H),5.77(s,2H),5.07(dd,J=5.4,13.2Hz,1H),4.17(d,J=17.1Hz,1H),4.06(d,J=17.1Hz,1H),2.83-2.95(m,1H),2.55-2.62(m,1H),2.20-2.34(m,1H),1.97-2.07(m,1H).
步骤B:向化合物I-28和2-氟-3-甲氧基苯甲醛(85mg,0.551mmol)的HOAc(3mL)溶液中加入DCE(15mL),搅拌1小时。加入NaBH(OAc)3(235mg,1.09mmol)反应18小时后未反应完全,补加NaBH(OAc)3(50mg,0.236mmol后30℃反应8小时。再补加2-氟-3-甲氧基苯甲醛(30mg,0.195mmol)后于40℃反应16小时。蒸干溶剂,Prep-TLC纯化到粗品后用1mL MeOH打浆得类白色固体产品(A318,30mg,收率:20%)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.05-7.07(m,2H),6.91-6.94(m,1H),6.61-6.65(m,2H),6.44(dd,J=1.8,12.9Hz,1H),5.06-5.12(m,1H),4.39(d,J=5.7Hz,2H),4.26(d,J=17.1Hz,1H),4.13(d,J=17.1Hz,1H),3.81(s,3H),2.86-2.90(m,1H),2.57-2.63(m,1H),2.24-2.30(m,1H),2.02-2.06(m,1H).LCMS:416.1([M+1]+).
参照前述实施例8中的合成方法,用相应的底物替换步骤B中的2-氟-3-甲氧基苯甲醛。就可以合成下列实施例9-10中的化合物。
实施例9化合物A319
3-(6-fluoro-4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione,A319.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.30(t,J=9.0Hz,1H),6.71-6.84(m,2H),6.55-6.64(m,2H),6.47(dd,J=2.1,12.6Hz,1H),5.05-5.11(m,1H),4.31(d,J=5.1Hz,2H),4.24(d,J=17.4Hz,1H),4.11(d,J=17.4Hz,1H),3.73(s,3H),2.84-2.96(m,1H),2.57-2.62(m,1H),2.19-2.34(m,1H),2.03-2.06(m,1H).LCMS:416.1([M+1]+).
实施例10化合物A320
3-(6-fluoro-4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)-piperidine-2,6-dioneA320.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.12(t,J=9.3Hz,1H),6.81-6.94(m,2H),6.60-6.66(m,2H),6.48(dd,J=2.4,12.6Hz,1H),5.06-5.12(m,1H),4.36(d,J=5.4Hz,2H),4.27(d,J=17.7Hz,1H),4.14(d,J=17.7Hz,1H),3.67(s,3H),2.83-2.97(m,1H),2.57-2.62(m,1H),2.20-2.35(m,1H),2.00-2.08(m,1H).LCMS:416.1([M+1]+).
实施例11化合物A327
3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione,A327.
合成路线
实验部分
步骤A:将4-(吗啉甲基)苯甲醇1.5g,7.2mmol)溶解于二氯甲烷(20mL)中,降温至0℃,缓慢滴加氯化亚砜(2.6g,21.8mmol),滴加完毕后,25℃下反应过夜。LCMS检测反应完成。反应液浓缩后,得到类白色固体4-(4-氯甲基)苯基吗啉盐酸盐1.9g粗品)。
1H NMR(DMSO-d6,400MHz):δ11.70(br s,1H),7.65-7.67(m,2H),7.50-7.52(m,2H),4.79(s,2H),4.32-4.33(m,2H),3.81-3.93(m,4H),3.16-3.19(m,2H),3.02-3.11(m,2H).
步骤B:5-氟-2-甲基-3-硝基-苯甲酸甲酯(2.0g,9.4mmol)和Pd/C(10%,200mg,50%water)溶于MeOH(20mL)中,50Psi氢气下温室搅拌过夜。TLC和LCMS检测反应完成。反应液抽滤,固体用甲醇洗涤(50mL×1),滤液浓缩,得到无色液体3-氨基-5-氟-2-甲基-苯甲酸甲酯(1.3g粗品)。
1H NMR(DMSO-d6,300MHz):δ6.57-6.60(m,1H),5.44(s,2H),3.77(s,3H),2.11(s,3H).
步骤C:3-氨基-5-氟-2-甲基-苯甲酸甲酯(1.3g crude)和10%H2SO4(43g,42.6mmol)溶解在MeOH(20mL)中,0℃氮气下反应下滴加亚硝酸钠(750mg,10.87mmol)溶液,滴加完毕后,在此温度下反应1小时。加入50%H2SO4(42.6g,213mmol)溶液,100℃下反应1小时。TLC检测反应完成。反应液浓缩,浓缩液用水(20mL)和EtOAc(100mL)摇匀分液,水相用EtOAc萃取(100mL×3),合并有机相,无水硫酸钠干燥,减压浓缩,硅胶柱层析纯化(PE:EtOAc=5:1)得到淡黄色固体5-氟-3-羟基-2-甲基-苯甲酸甲酯(660mg,两步收率:38%)。
1H NMR(DMSO-d6,400MHz):δ10.25(s,1H),6.93-6.96(m,1H),6.78-6.82(m,1H),3.81(s,3H),2.23(s,3H).
步骤D:5-氟-3-羟基-2-甲基-苯甲酸甲酯(1.2g,6.5mmol)和咪唑(1.33g,19.5mmol)溶解在DCM(20mL)中,然后在氮气保护下0℃分批加入TBDMSCl(1.96g,13mmol),加入完毕后搅拌10分钟,升至25℃搅拌2小时。TLC检测反应完成。反应液加入水(50mL)洗一次,水相用DCM萃取(150mL×3),合并有机相,无水硫酸钠干燥浓缩,硅胶柱层析纯化(PE:EtOAc=20:1~10:1),得到淡黄色油状物3-(叔丁基-二甲基-硅氧基)-5-氟-2-甲基-苯甲酸甲酯(1.4g,收率:72%)。
1H NMR(DMSO-d6,400MHz):δ7.12-7.15(m,1H),6.84-6.87(m,1H),3.82(s,3H),2.26(s,3H),0.98(s,9H),0.23(s,6H).
步骤E:将3-(叔丁基-二甲基-硅氧基)-5-氟-2-甲基-苯甲酸甲酯(1.4g,4.7mmol)和NBS(1.0g,5.6mmol)溶解在CCl4(20mL)中,然后加入过氧化苯甲酰(0.12g,0.5mmol),氮气下80℃反应过夜。TLC检测反应完成。反应液抽滤,固体用DCM(50mL)洗涤后,滤液水(50mL)洗涤,水相用DCM萃取(100mL×3),合并有机相,干燥、浓缩,硅胶柱层析纯化(PE:EtOAc=100:1),得到白色固体2-溴甲基-3-(叔丁基-二甲基-硅氧基)-5-氟-苯甲酸甲酯(1.4g,纯度:90%)。
1H NMR(DMSO-d6,400MHz):δ7.28-7.31(m,1H),7.00-7.03(m,1H),4.93(s,2H),3.91(s,3H),1.07(s,9H),0.36(s,6H).
步骤F:2-溴甲基-3-(叔丁基-二甲基-硅氧基)-5-氟-苯甲酸甲酯(500mg,1.33mmol)和异谷酰胺叔丁酯盐酸盐(349mg,1.46mmol)和三乙胺(405mg,4.0mmol)溶解在CH3CN(10mL)中,氮气保护下80℃下反应过夜。TLC检测反应完成。反应液浓缩后,溶于THF(10mL)中,然后滴加TBAF(4mL,1M in THF),混合物室温搅拌0.5小时,TLC检测反应完成。反应液浓缩,硅胶柱层析纯化(PE:EtOAc=5:1~1:1~EA),得到淡黄色固体A327A(200mg,3步收率:34%)。
1H NMR(MeOD,400MHz):δ6.95-6.98(m,1H),6.72-6.76(m,1H),4.90-4.94(m,1H),4.54(d,J=17.6Hz,1H),4.42(d,J=17.6Hz,1H),2.25-2.30(m,3H),2.16-2.21(m,1H),1.39(s,9H).
步骤G:将A327A(200mg,0.57mmol)和4-(4-(chloromethyl)benzyl)morpholinehydrochloride(445mg,粗品)溶于干燥的DMF(10mL)中,室温氮气下加入K2CO3(393mg,2.90mmol)。加入完毕后,室温搅拌,反应过夜。LCMS检测反应未完,补加4-(4-Chloromethyl-benzyl)-morpholine(445mg,粗品),继续反应6小时。反应液浓缩后,加入水(10mL)和EtOAc(30mL)摇匀分液,水相用EtOAc萃取(10mL×3),合并有机相,干燥、浓缩,硅胶柱层析纯化(PE:EtOAc=5:1~1:1~EtOAc),得到白色固体A327B(250mg,收率:81%)。
1H NMR(DMSO-d6,400MHz):δ7.57(s,1H),7.44-7.46(m,2H),7.34-7.36(m,2H),7.19-7.27(m,2H),7.06-7.08(m,1H),5.23(s,2H),4.68-4.72(m,1H),4.50(d,J=17.6Hz,1H),4.39(d,J=17.6Hz,1H),3.56-3.58(m,4H),3.47(s,2H),2.30-2.38(m,4H),2.13-2.17(m,3H),2.00-2.05(m,1H),1.32(s,9H).
步骤H:将A327B(250mg,0.46mmol)溶解在干燥的DCM(10mL)中,0℃氮气下加入TFA(4mL),加入完毕后,混合物搅拌4小时。TLC检测反应完成。反应液浓缩后,得到淡黄色固体A327C(230mg粗品)。
步骤I:将A327C(230mg crude)溶解在CH3CN(15mL)中,室温氮气下加入CDI(115mg,0.71mmol),加入完毕后,混合物95℃下反应过夜。LCMS检测反应完成。反应液浓缩后,Prep-HPLC纯化得到黄色固体A327(24mg,两步收率:11%)。
1H NMR(DMSO-d6,400MHz):δ10.98(s,1H),7.43-7.45(m,2H),7.28-7.35(m,3H),7.11-7.13(m,1H),5.23(s,2H),5.08-5.13(m,1H),4.39(d,J=17.2Hz,1H),4.23(d,J=17.2Hz,1H),3.55-3.58(m,4H),3.47(s,2H),2.87-2.91(m,1H),2.54-2.59(m,1H),2.42-2.45(m,1H),2.35-2.41(m,4H),1.97-1.99(m,1H).LCMS:468.2([M+1]+).
实施例12化合物A329
3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A329.
合成路线
步骤A:将2-氟-4-甲氧基苯甲醛(1.0g,6.49mmol)溶于MeOH(10mL)中,加入NaBH4(370mg,9.74mmol),室温搅拌反应1h,TLC显示反应完成。加入1N HCl淬灭反应和调pH(4-5),加入DCM(50mL)和水(40mL),水相用DCM萃取(50mL×2),合并的有机相用食盐水洗一次(50mL),无水硫酸钠干燥,过滤,母液减压浓缩,得淡黄色油状产品2-氟-4-甲氧基苯甲醇(910mg,收率:90%),无需纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.31(t,J=8.4Hz,1H),6.72-6.76(m,2H),5.08(t,J=5.7Hz,1H),4.43(d,J=5.7Hz,2H),3.73(m,3H).
步骤B:将2-氟-4-甲氧基苯甲醇(400mg,2.56mmol)溶于干燥的DCM(10mL)中,加入SOCl2(458mg,3.85mmol),室温搅拌反应3h。LCMS显示反应完成。反应液直接减压浓缩,得淡黄色油状物2-氟-4-甲氧基苄氯(450mg),无需纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.42(t,J=8.7Hz,1H),6.85(dd,J=12.0,2.7Hz,1H),6.77(dd,J=11.4,2.7Hz,1H),4.72(s,2H),3.76(s,3H).
步骤C:将化合物A329B(200mg,0.68mmol)溶于DMF(15mL)中,加入K2CO3(283mg,2.05mmol)和2-氟-4-甲氧基苄氯(239mg,1.37mmol),室温搅拌反应过夜。LCMS显示反应有原料剩余,加入2-氟-4-甲氧基苄氯(100mg,0.57mmol),继续搅拌反应3小时。LCMS显示反应完全。减压浓缩掉溶剂,加入EtOAc(50mL)和水(30mL)溶解分层,水相用EtOAc萃取(50mL×2),合并的有机相用食盐水洗一次(50mL),无水硫酸钠干燥,过滤,母液减压浓缩得剩余物,剩余物用制备TLC纯化(MeOH/DCM=1/20)得白色固体产物A329A(190mg,收率:65%)。
1H NMR(DMSO-d6,300MHz):δ7.57(br s,1H),7.45-7.54(m,2H),7.36(d,J=8.1Hz,1H),7.30(d,J=7.5Hz,1H),7.17(br s,1H),6.87-6.92(m,1H),6.81-6.85(m,1H),5.19(s,2H),4.69-4.74(m,1H).4.47(d,J=17.7Hz,1H),4.33(d,J=17.7Hz,1H),3.79(s,3H),3.50(s,3H),2.13-2.27(m,3H),2.00-2.10(m,1H),
步骤D:将A329A(190mg,0.44mmol)溶解于DMF(10mL)中,后向反应瓶中加入K2CO3(183mg,1.33mmol),氮气保护加热至80℃搅拌反应过夜。LCMS显示反应完成。反应液减压抽滤,母液减压浓缩,剩余物制备HPLC纯化冻干得白色固体产物A329(120mg,收率:68%)。
1H NMR(DMSO-d6,300MHz):δ10.79(br s,1H),7.48-7.54(m,2H),7.33-7.41(m,2H),6.89(dd,J=12.3,2.4Hz,1H),6.81(dd,J=8.4,2.4Hz,1H),5.19(s,2H),5.08-5.13(m,1H),4.35(d,J=17.7Hz,1H),4.18(d,J=17.7Hz,1H),3.78(s,3H),2.84-2.94(m,1H),2.57-2.61(m,1H),2.38-2.46(m,1H),1.92-2.00(m,1H).
LCMS:399.1([M+1]+).
参照前述实施例12中的合成方法,用相应的底物替换步骤A中的2-氟-4-甲氧基苯甲醛。就可以合成下列实施例13-14中的化合物。
实施例13化合物A331
3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A331.
1H NMR(DMSO-d6,300MHz):δ10.65(br s,1H),7.51(t,J=7.8Hz,1H),7.34-7.40(m,2H),7.13-7.23(m,2H),6.93-6.99(m,1H),5.25(s,2H),5.10(dd,J=10.2,5.1Hz,1H),4.39(d,J=17.7Hz,1H),4.23(d,J=17.7Hz,1H),3.74(s,3H),2.84-2.96(m,1H),2.54-2.60(m,1H),2.39-2.47(m,1H),1.93-2.00(m,1H).LCMS:399.1([M+1]+).
实施例14化合物A334
3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A334.
1H NMR(DMSO-d6,400MHz):10.96(s,1H),7.50(t,J=7.6Hz,1H),7.34-7.38(m,2H),7.13-7.20(m,3H),5.28(s,2H),5.10(dd,J=12.8,4.4Hz,1H),4.38(d,J=17.6Hz,1H),4.22(d,J=17.6Hz,1H),3.85(s,3H),2.87-2.90(m,1H),2.50-2.58(m,1H),2.40-2.43(m,1H),1.95-1.98(m,1H).LCMS:399.1([M+1]+).
实施例15化合物A336
3-[4-(2-Fluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione,A336.
1H NMR(DMSO-d6,400MHz):10.92(s,1H),6.53-6.63(m,1H),7.50(t,J=8.0Hz,1H),7.40-7.47(m,2H),7.36(t,J=8.0Hz,1H),7.23-7.29(m,2H),5.30(s,2H),5.11(dd,J=12.8,5.2Hz,1H),4.38(d,J=17.6Hz,1H),4.23(d,J=17.6Hz,1H),2.86-2.95(m,1H),2.54-2.59(m,1H),2.38-2.47(m,1H),1.97-2.00(m,1H).LCMS:369.1([M+1]+).
实施例16化合物A340
(S)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A340.
合成路线
实验部分
步骤A:氮气保护下将(S)-异谷酰胺叔丁酯盐酸盐(1.91g,8.00mmol)加入到2-溴甲基-3-硝基苯甲酸甲酯(2.00g,7.30mmol)的CH3CN溶液中(40mL),然后加入Et3N(1.63g,16.1mmol),反应混合物加热至75℃搅拌反应过夜。TLC显示反应完成。反应液减压浓缩,剩余物溶解在EtOAc(50mL)和水(50mL)中,分层,水相用EtOAc萃取(50mLx2),合并有机相,食盐水洗一次(50mL),有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用石油醚和EtOAc的混合溶液(4/1,v/v)打浆,过滤得白色固体产物A340A(2.2g,收率:83%)。
1H NMR(DMSO-d6,300MHz):δ8.45(dd,J=0.9,8.1Hz,1H),8.16(dd,J=0.9,8.1Hz,1H),7.82(t,J=8.1Hz,1H),7.65(br s,1H),7.27(br s,1H),5.05(d,J=19.5Hz,1H),4.90(d,J=19.5Hz,1H),4.75-4.80(m,1H),2.14-2.27(m,3H),2.00-2.10(m,1H),1.33(s,9H).
步骤B:将A340A(1.20g,3.30mmol)溶解在甲醇中,后加入Pd/C(10%,200mg,50%water),氢气换气三次,50Psi氢气压力下25℃氢化反应过夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C,滤液减压浓缩至干。得淡黄色固体产物A340B(1.19g,粗品)直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.50(br s,1H),7.11-7.16(m,2H),6.85(d,J=7.2Hz,1H),6.74(d,J=7.2Hz,1H),5.41(br s,2H),4.68-4.73(m,1H),4.38(d,J=17.7Hz,1H),4.16(d,J=17.7Hz,1H),2.09-2.19(m,3H),1.92-2.01(m,1H),1.32(s,9H).
步骤C:将A340B(1.00g,粗品)和2-氟-5-甲氧基苯甲醛(601mg,3.90mmol)溶解于甲醇中,后向反应瓶中加入HOAc(0.5mL),25℃搅拌3小时。加入Pd/C(10%,100mg,50%water),氢气换气三次,25℃氢化(氢气球)反应过夜。LCMS显示反应完全。减压抽滤除掉Pd/C,滤液减压浓缩,剩余物用硅胶柱纯化(石油醚/EtOAc=1/4)得淡黄色固体A340C(1.15g,两步收率:88%)。
1H NMR(DMSO-d6,300MHz):δ7.56(br s,1H),7.09-7.24(m,3H),6.91-6.96(m,2H),6.80-6.85(m,1H),6.63(d,J=8.4Hz,1H),6.34-6.38(m,1H),4.74(dd,J=10.2,4.5Hz,1H),4.50(d,J=18.0Hz,1H),4.37(d,J=6.0Hz,2H),4.28(d,J=18.0Hz,1H),3.67(s,3H),2.12-2.21(m,3H),1.91-2.02(m,1H),1.33(s,9H).
步骤D:将A340C(1.15g,2.44mmol)溶解于DCM(20mL)中,冷却至0℃,后向反应瓶中滴加TFA(4mL),慢慢升至25℃搅拌反应过夜。反应液减压浓缩,剩余物用C18柱层析纯化(40%乙腈的水溶液),冷冻干燥得淡黄色固体A340D(800mg,收率:79%)。
1H NMR(DMSO-d6,400MHz):δ12.14(br s,1H),7.57(br s,1H),7.10-7.23(m,3H),6.91-6.96(m,2H),6.81-6.85(m,1H),6.63(d,J=8.0Hz,1H),6.35(t,J=6.0Hz,1H),4.72-4.76(m,1H),4.51(d,J=17.6Hz,1H),4.37(d,J=5.6Hz,2H),4.31(d,J=17.6Hz,1H),3.67(s,3H),2.18-2.23(m,3H),1.96-2.02(m,1H).
步骤E:将A340D(700mg,1.69mmol)溶于干燥的DCM(70mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(1.00g,8.40mmol),滴加完毕后,加入DMF(10mg)的DCM(1mL)溶液加毕搅拌反应2h,滴加吡啶(666mg,8.42mmol)维持此温度搅拌40分钟,加入Et3N(852mg,8.42mmol),加毕,继续反应2h。LCMS显示反应完成。加入H2O(10mL)淬灭反应,水相用DCM萃取(20mL×2),食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经Prep-HPLC得到浅绿色固体A340(460mg,收率:68%,ee:98%)。
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J=7.8Hz,1H),7.11(t,J=9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J=8.1Hz,1H),6.26(t,J=6.0Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.37(d,J=6.0Hz,2H),4.30(d,J=17.1Hz,1H),4.17(d,J=17.1Hz,1H),3.65(s,3H),2.85-2.96(m,1H),2.56-2.63(m,1H),2.24-2.37(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
实施例17化合物A341
(R)-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A341.
合成路线
实验部分
步骤A:将2-溴甲基-3-硝基苯甲酸甲酯(1.00g,3.65mmol)溶解于CH3CN(50mL)中,后向反应瓶中加入(R)-异谷酰胺叔丁酯盐酸盐(955mg,4.00mmol)和Et3N(815mg,8.05mmol),氮气保护,加热至75℃搅拌反应过夜。TLC显示反应完成。反应液减压浓缩,剩余物溶解在EtOAc(50mL)和水(50mL)中,分层,水相用EtOAc萃取(50mL×2),合并有机相,食盐水洗一次(50mL),无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱纯化(石油醚/EtOAc=1/4)得白色固体A341A(800mg,收率:60%)。
1H NMR(DMSO-d6,300MHz):δ8.45(d,J=6.0Hz,1H),8.16(d,J=5.4Hz,1H),7.82(t,J=6.0Hz,1H),7.64(br s,1H),7.27(br s,1H),5.05(d,J=14.4Hz,1H),4.91(d,J=14.4Hz,1H),4.76-4.80(m,1H),2.15-2.25(m,3H),2.02-2.11(m,1H),1.33(s,9H).
步骤B:将A341A(800mg,2.20mmol)溶解在甲醇中,后加入Pd/C(10%,80mg,50%water),50 Psi氢气压力下25℃氢化反应过夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C,滤液减压浓缩至干,得淡黄色固体A341C(680mg,收率:93%),直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ7.54(br s,1H),7.13-7.18(m,2H),6.88(d,J=7.2Hz,1H),6.76(d,J=7.8Hz,1H),5.44(br s,2H),4.70-4.75(m,1H),4.41(d,J=17.7Hz,1H),4.18(d,J=17.7Hz,1H),2.09-2.21(m,3H),1.92-2.06(m,1H),1.34(s,9H).
步骤C:将A341C(680mg,2.04mmol)和2-氟-5-甲氧基苯甲醛(472mg,3.06mmol)溶解于MeOH中,后向反应瓶中加入HOAc(0.5mL),25℃搅拌3小时。加入Pd/C(10%,50mg,50%water),氢气换气三次,25℃氢化反应过夜(气球)。LCMS显示反应完全,减压抽滤掉Pd/C,滤液减压浓缩,剩余物用硅胶柱纯化(石油醚/EtOAc=1/4),得淡黄色固体A341E(650mg,收率:68%)。
1H NMR(DMSO-d6,400MHz):δ7.56(br s,1H),7.18-7.23(m,2H),7.12(t,J=9.2Hz,1H),6.91-6.95(m,2H),6.81-6.85(m,1H),6.63(d,J=8.0Hz,1H),6.36(t,J=5.6Hz,1H),4.72-4.76(m,1H),4.50(d,J=17.6Hz,1H),4.37(d,J=6.0Hz,2H),4.29(d,J=17.6Hz,1H),3.67(s,3H),2.14-2.22(m,3H),1.94-2.04(m,1H),1.33(s,9H).
步骤D:将A341E(650mg,1.38mmol)溶解于DCM(20mL)中,冷却至0℃,后向反应瓶中滴加TFA(4mL),慢慢升至25℃搅拌反应过夜。反应液减压浓缩,剩余物用C18柱层析纯化(40%乙腈的水溶液)冷冻干燥得淡黄色固体A341G(450mg,收率:79%)。
1H NMR(DMSO-d6,300MHz):δ7.56(br s,1H),7.07-7.22(m,3H),6.89-6.94(m,2H),6.78-6.83(m,1H),6.61(d,J=7.8Hz,1H),6.34(t,J=6.3Hz,1H),4.69-4.73(m,1H),4.50(d,J=17.7Hz,1H),4.35(d,J=5.7Hz,2H),4.29(d,J=17.7Hz,1H),3.65(s,3H),2.12-2.19(m,3H),1.93-1.98(m,1H).
步骤E:将A341G(450mg,1.08mmol)溶于干燥的DCM(50mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(644mg,5.41mmol),毕,加入DMF(10mg)的DCM(1mL)溶液加毕搅拌反应2h,滴加吡啶(428mg,5.41mmol)维持此温度搅拌40分钟,加入Et3N(547mg,5.41mmol),加毕,继续反应2h,LCMS显示反应完成。加入H2O(10mL)淬灭反应,水相用DCM萃取(30mL×2),食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经Prep-HPLC得到浅绿色固体A341(260mg,收率:61%,ee:96%)。
1H NMR(DMSO-d6,300MHz):δ10.98(br s,1H),7.23(t,J=7.8Hz,1H),7.11(t,J=9.3Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J=8.1Hz,1H),6.26(t,J=6.0Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.36(d,J=5.7Hz,2H),4.30(d,J=17.1Hz,1H),4.17(d,J=17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.56-2.63(m,1H),2.22-2.35(m,1H),2.00-2.07(m,1H).LCMS:398.1([M+1]+).
实施例18化合物A342
(R)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A342.
合成路线
实验部分:
步骤A.将A343F(31.7g,115.5mmol)悬浊于CH3CN(560mL)中,后向反应瓶中加入A343G(31.5g,115.5mmol)和Et3N(23.3g,231.0mmol),氮气保护,加热至75℃搅拌反应过夜。反应液减压浓缩,剩余物溶解在EtOAc(50mL)和4M HCl水溶液(150mL)中搅拌,过滤,滤饼水洗(30mL)。滤液用EtOAc萃取(250mL×2),合并有机相,食盐水洗(30mL),无水硫酸钠干燥,过滤,滤液减压浓缩,合并所得两批固体用CH3CN(40mL×2)打浆,过滤得白色固体A343E(37g,收率:81%)。通过手性拆分得到类白色固体Peak1 A343E(S)(14.4g,yield(收率):77.8%,Rt=7.30min,100%ee)and Peak2A343E(R)(14.8g,yield:80%,Rt=11.87min,100%ee)
手性拆分制备条件:手性柱:CHIRALPAK IE,柱子粒径:10μm,柱子型号:50×250mm;检测波长:254nm;流动相:MeOH/DCM=80/20(V/V);进样量:48mL;流速:60mL/min;柱温:35℃;溶剂:流动相17.1mg/mL。
A343E(S):1H NMR(DMSO-d6,300MHz):δ8.43(d,J=8.1Hz,1H),8.13(d,J=7.5Hz,1H),7.79(t,J=8.1Hz,1H),7.66(br s,1H),7.26-7.35(m,6H),4.86-5.07(m,4H),2.42-2.21-2.43(m,3H),2.06-2.16(m,1H).
A343E(R):1H NMR(DMSO-d6,300MHz):δ8.43(d,J=8.4Hz,1H),8.13(d,J=7.2Hz,1H),7.77-7.82(m,1H),7.65(br s,1H),7.35-7.23-7.35(m,6H),4.86-5.07(m,4H),2.20-2.42(m,3H),2.06-2.15(m,1H).
步骤B.将A343E(R)(2.5g,6.3mmol)溶解在MeOH(150mL)/THF(150mL)中,后加入Pd/C(10%,500mg,50%water),氢气换气三次,50 Psi氢气压力下25℃氢化反应过夜。LCMS显示反应完成。反应液减压抽滤掉Pd/C,滤液减压浓缩至干。加入CH3CN/DCE(50mL/150mL)减压浓缩至干,再用THF(300mL)溶解减压浓缩至干,除去残余的甲醇得白色固体A342C(1.68g,收率:97%)直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ12.11(br s,1H),7.54(s,1H),7.11-7.16(m,2H),6.85(d,J=7.8Hz,1H),6.74(d,J=7.8Hz,1H),5.43(br s,2H),4.68-4.73(m,0.02H),4.41(d,J=17.4Hz,1H),4.17(d,J=17.4Hz,1H),2.10-2.18(m,3H),1.94-1.97(m,1H).
步骤C:将A342C和2-氟-5-甲氧基苯甲醛(831mg,5.39mmol)溶解于MeOH中,后向反应瓶中加入HOAc(0.5mL),25℃搅拌20小时。加入Pd/C(10%,100mg,50%water),氢气换气三次,25℃氢化反应过夜(氢气球)。LCMS显示反应完全。减压抽滤掉Pd/C,滤液减压浓缩,剩余物用C18柱层析纯化(CH3CN:H2O=5%-35%,30min;35%-45%,30min;45%-55%20min)冷冻干燥得淡黄色固体A342A(800mg,收率:53%)。
1H NMR(DMSO-d6,300MHz):δ12.10(br s,1H),7.56(br s,1H),7.07-7.22(m,3H),6.89-6.94(m,2H),6.78-6.83(m,1H),6.61(d,J=8.1Hz,1H),6.34(t,J=6.0Hz,1H),4.70-4.74(m,0.03H),4.50(d,J=17.7Hz,1H),4.35(d,J=5.7Hz,2H),4.28(d,J=17.7Hz,1H),3.65(s,3H),2.10-2.21(m,3H),1.92-2.02(m,1H).
步骤D.将A342A(450mg,1.10mmol)溶于干燥的DCM(50mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(572mg,4.81mmol),毕,加入DMF(10mg)的DCM(1mL)溶液加毕,搅拌反应2hr,滴加吡啶(380mg,4.80mmol)维持此温度搅拌40分钟,加入Et3N(486mg,4.80mmol),加毕,继续反应2h,LCMS显示反应完成。加入H2O(10mL)淬灭反应,水相用DCM萃取(30mL×2),食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经C18柱(CH3CN:H2O=5%-35%,30min;35%-45%,30min;45%-55%20min)纯化得到淡黄色固体A342(220mg,收率:58%,ee:99%)。
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J=7.8Hz,,1H),7.11(t,J=9.6Hz,,1H),6.90-6.95(m,2H),6.79-6.84(m,1H),6.65(d,J=7.8Hz,1H),6.26(t,J=5.4Hz,1H),5.07-5.14(m,0.01H),4.36(d,J=5.7Hz,2H),4.30(d,J=17.1Hz,1H),4.17(d,J=17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.24-2.34(m,1H),2.00-2.06(m,1H).LCMS:399.1([M+1]+).
参照前述实施例18中的合成方法,用相应的底物替换步骤B中的A343E(R)。就可以合成下列实施例19中的化合物。
实施例19化合物A343
(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A343.
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.23(t,J=8.1Hz,,1H),7.11(t,J=9.6Hz,1H),6.90-6.95(m,2H),6.78-6.84(m,1H),6.65(d,J=8.1Hz,1H),6.26(t,J=6.3Hz,1H),5.07-5.13(m,0.02H),4.36(d,J=5.7Hz,2H),4.29(d,J=17.1Hz,1H),4.17(d,J=17.1Hz,1H),3.65(s,3H),2.85-2.97(m,1H),2.56-2.64(m,1H),2.24-2.34(m,1H),2.00-2.05(m,1H).LCMS:399.1([M+1]+).
实施例20化合物A346
(S)-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A346.
合成路线
实验部分
30℃下将A346A(119mg,0.58mmol)和A308A(100mg,0.39mmol)溶解于醋酸(2.5mL)和二氯甲烷(2.5mL)的混合溶液中搅拌1小时,加入NaBH(OAc)3(246mg,1.16mmol),氮气保护下搅拌18小时。TLC显示反应完成。反应液减压浓缩至干加入饱和碳酸氢钠水溶液(5mL)调pH至8,加入DCM萃取(25mL×5),有机相无水Na2SO4干燥,过滤,滤液减压浓缩,剩余物用石油醚和乙酸乙酯的混合溶液(1/1)(25mL×2)打浆得250mg粗品,用Prep-HPLC制备得白色固体产物A346(140mg,收率:80%)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),.7.16-7.33(m,5H),6.90(d,J=7.2Hz,1H),6.62(d,J=7.8Hz,1H),6.33(t,J=5.7Hz,1H),5.07-5.13(m,1H),4.35(d,J=5.4Hz,2H),4.29(d,J=17.1Hz,1H),4.16(d,J=17.1Hz,1H),3.53(t,J=4.5Hz,4H),3.39(s,2H),2.85-2.93(m,1H),2.58-2.63(m,1H),2.28-2.31(m,5H),2.01-2.06(m,1H).LCMS:449.2([M+1]+).
参照前述实施例20中的合成方法,用相应的底物替换实施例20中的A346A。就可以合成下列实施例21-45中的化合物
实施例21化合物A359
3-(4-((2-fluoro-3-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A359.
1H NMR(DMSO-d6,300MHz):δ10.96(br,1H),9.79(br,1H),7.21(t,J=7.8Hz,1H),6.73-6.93(m,4H),6.63(d,J=7.8Hz,1H),6.25(t,J=6.0Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.37(d,J=5.7Hz,2H),4.28(d,J=17.4Hz,1H),4.15(d,J=17.4Hz,1H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.22-2.36(m,1H),2.01-2.05(m,1H).LCMS:384.1([M+1]+).
实施例22化合物A360
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzonitrile,A360.
1H NMR(300MHz,DMSO-d6):δ11.03(s,1H),7.81-7.86(m,1H),7.71-7.76(m,1H),7.36(t,J=7.8Hz,1H),7.25(t,J=7.8Hz,1H),6.97(d,J=7.5Hz,1H),6.66(d,J=7.8Hz,1H),6.41(t,J=5.7Hz,1H),5.13,(dd,J=12.9,5.1Hz,1H),4.50(d,J=5.7Hz,1H),4.32(d,J=17.1Hz,1H),4.19(d,J=17.1Hz,1H),2.87-2.95(m1H),2.50-2.65(m1H),2.29-2.34(m1H),2.02-2.07(m1H).
实施例23化合物A361
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzamide,A361.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.75(s,1H),7.63(s,1H),7.45-7.53(m,2H),7.16-7.27(m,2H),6.96(d,J=7.2Hz,1H),6.64(d,J=8.1Hz,1H),6.35-6.38(m,1H),5.13(dd,J=13.2,4.8Hz,1H),4.46(d,J=5.4Hz,2H),4.33(d,J=17.4Hz,1H),4.20(d,J=17.4Hz,1H),2.87-2.98(m,1H),2.60-2.65(m,1H),2.25-2.39(m,1H),2.03-2.07(m,1H).LCMS:411.1([M+1]+).
实施例24化合物A362
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluoro-N-methylbenzamide,A362.
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),8.28(d,J=3.3Hz,1H),7.46(t,J=7.2Hz,2H),7.15-7.26(m,2H),6.95(d,J=7.5Hz,1H),6.63(d,J=8.4Hz,1H),6.37(t,J=5.7Hz,1H),5.12(dd,J=13.5,4.8Hz,1H),4.45(d,J=5.1Hz,2H),4.32(d,J=17.4Hz,1H),4.20(d,J=17.4Hz,1H),2.87-2.99(m,1H),2.78(d,J=4.8Hz,3H),2.60-2.65(m,1H),2.25-2.39(m,1H),1.99-2.11(m,1H).LCMS:425.1([M+1]+)
实施例25化合物A363
3-(4-((5-(2-(Dimethylamino)ethoxy)-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A363.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.24(t,J=8.1Hz,1H),7.11(t,J=9.3Hz,1H),6.90-6.96(m,2H),6.80-6.86(m,1H),6.65(d,J=8.4Hz,1H),6.29(t,J=6.0Hz,1H),5.12(dd,J=13.2,4.8Hz,1H),4.29-4.39(m,3H),4.19(d,J=17.1Hz,1H),3.94(t,J=5.7Hz,2H),2.87-2.99(m,1H),2.51-2.65(m,3H),2.24-2.38(m,1H),2.15(s,6H),2.00-2.10(m,1H).LCMS:455.2([M+1]+).
实施例26化合物A364
3-(4-((2-fluoro-5-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A364.
1H NMR(300MHz,DMSO-d6):δ11.01(s,1H),9.24(s,1H),7.22(t,J=7.8Hz,1H),6.92-6.99(m,2H),6.70-6.73(m,1H),6.55-6.60(m,2H),6.31(t,J=5.7Hz,1H),5.11,(dd,J=13.2,5.1Hz,1H),4.27-4.34(m,3H),4.17(d,J=17.1Hz,1H),2.86-2.96(m1H),2.57-2.64(m1H),2.24-2.33(m1H),2.02-2.06(m1H).
实施例27化合物A367
3-(4-((2-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A367.
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.14-7.26(m,3H),6.93-7.04(m,2H),6.64(d,J=7.5Hz,1H),6.30(br s,1H),5.09-5.16(m,1H),4.42(s,2H),4.31(d,J=17.4Hz,1H),4.18(d,J=17.4Hz,1H),2.89-2.98(m,1H),2.59-2.65(m,1H),2.25-2.46(m,4H),2.02-2.07(m,1H).LCMS:382.2([M+1]+).
实施例28化合物A368
3-(4-((2-fluoro-5-(2-morpholinoethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A368.
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.23(t,J=7.5Hz,1H),7.09(t,J=9.6Hz,1H),6.79-6.95(m,3H),6.64(d,J=7.5Hz,1H),6.24(br,1H),5.10(dd,J=13.2,5.1Hz,1H),4.36(d,J=5.7Hz,2H),4.30(d,J=17.1Hz,1H),4.18(d,J=17.1Hz,1H),3.97(t,J=5.7Hz,2H),3.51(t,J=4.5Hz,4H),2.85-2.97(m,1H),2.56-2.63(m,3H),2.27-2.39(m,5H),2.00-2.05(m,1H).LCMS:497.2([M+1]+).
实施例29化合物A369
3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A369.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.22(t,J=7.8Hz,1H),7.09(t,J=9.3Hz,1H),6.88-6.95(m,2H),6.77-6.83(m,1H),6.63(d,J=8.1Hz,1H),6.27(t,J=5.7Hz,1H),5.11(dd,J=13.2,5.4Hz,1H),4.36(d,J=5.7Hz,2H),4.30(d,J=17.4Hz,1H),4.17(d,J=17.4Hz,1H),3.88(t,J=6.3Hz,2H),3.52(t,J=3.9Hz,4H),2.85-2.96(m,1H),2.57-2.63(m,1H),2.22-2.41(m,7H),1.99-2.05(m,1H),1.73-1.84(m,2H).LCMS:511.2([M+1]+).
实施例30化合物A370
3-(4-((2-fluoro-5-(2-methoxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A370.
1H NMR(300MHz,DMSO-d6):δ10.98(s,1H),7.23(t,J=7.8Hz,1H),7.06-7.12(m,1H),6.90-6.95(m,2H),6.79-6.84(m,1H),6.64(d,J=8.1Hz,1H),6.24(t,J=5.4Hz,1H),5.10(dd,J=13.2,5.1Hz,1H),4.28-4.38(m,3H),4.19(d,J=17.1Hz,1H),3.96-3.99(m,2H),3.55-3.58(m,2H),3.23(s,3H),2.85-2.95(m1H),2.57-2.64(m1H),2.24-2.36(m1H),1.98-2.09(m1H).
实施例31化合物A371
3-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenylmethylcarbamate,A371.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.52-7.56(m,1H),7.15-7.25(m,2H),6.93-7.06(m,3H),6.63(d,J=7.8Hz,1H),6.28-6.32(m,1H),5.10(dd,J=13.5,4.5Hz,1H),4.40(d,J=4.8Hz,2H),4.30(d,J=17.4Hz,1H),4.18(d,J=17.4Hz,1H),2.84-2.97(m,1H),2.59-2.69(m,4H),2.23-2.37(m,1H),1.99-2.08(m,1H).LCMS:441.1([M+1]+).
实施例32化合物A372
3-(4-((2-fluoro-3-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A372.
1H NMR(DMSO-d6,300MHz):δ10.99(s,1H),7.21(t,J=7.8Hz,1H),6.85-6.92(m,2H),6.63(d,J=8.1Hz,1H),6.48-6.55(m,2H),6.21(t,J=5.4Hz,1H),5.48-6.49(m,1H),5.09(dd,J=13.2,5.1Hz,1H),4.35(d,J=5.4Hz,2H),4.27(d,J=17.4Hz,1H),4.15(d,J=17.4Hz,1H),2.85-2.97(m,1H),2.69(d,J=4.5Hz,3H),2.49-2.63(m,1H),2.21-2.35(m,1H),1.98-2.05(m,1H).LCMS=397.1([M+1]+)
实施例33化合物A375
3-(4-((2-fluoro-5-(2-hydroxyethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A375.
1H NMR(DMSO-d6,300MHz):δ9.35(br s,1H),7.22(t,J=8.1Hz,1H),7.10(t,J=9.3Hz,1H),6.88-6.95(m,2H),6.78-6.83(m,1H),6.63(d,J=8.4Hz,1H),6.31(t,J=6.0Hz,1H),5.11(dd,J=13.5,5.1Hz,1H),4.82(br s,1H),4.37(d,J=5.7Hz,2H),4.30(d,J=17.1Hz,1H),4.17(t,J=17.1Hz,1H),3.85(t,J=4.8Hz,2H),3.62(t,J=4.8Hz,2H),2.85-2.97(m,1H),2.55-2.65(m,1H),2.24-2.36(m,1H),2.01-2.05(m,1H).LCMS:428.1[(M+1)+].
实施例34化合物A376
3-(4-((2-fluoro-5-(2-(pyrrolidin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A376.
1H NMR(300MHz,DMSO-d6):δ11.02(s,1H),7.22(t,J=8.1Hz,1H),7.06-7.13(m,1H),6.89-6.95(m,2H),6.78-6.84(m,1H),6.63(d,J=7.8Hz,1H),6.29(t,J=5.7Hz,1H),5.11,(dd,J=13.2,5.1Hz,1H),4.27-4.37(m,3H),4.17(d,J=17.1Hz,1H),3.94(t,J=6.0Hz,1H),2.85-2.97(m1H),2.57-2.69(m3H),2.22-2.42(m5H),1.98-2.06(m1H),1.56-1.66(m4H).
实施例35化合物A377
3-(4-((2-fluoro-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A377.
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.22(t,J=7.8Hz,1H),7.09(t,J=9.6Hz,1H),6.91-6.95(m,2H),6.79-6.89(m,1H),6.63(d,J=8.1Hz,1H),6.29(t,J=6.0Hz,1H),5.11(dd,J=13.5,4.8Hz,1H),4.27-4.37(m,3H),4.17(d,J=17.4Hz,1H),3.94(t,J=5.7Hz,2H),2.85-2.98(m,1H),2.55-2.62(m,4H),2.20-2.42(m,8H),2.12(s,3H),1.98-2.07(m,1H).LCMS:510.2([M+1]+).
实施例36化合物A378
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenyldimethylcarbamate,A378.
1H NMR(300MHz,DMSO-d6):δ11.00(s,1H),7.17-7.26(m,2H),7.08-7.11(m,1H),6.94-7.04(m,2H),6.78-6.84(m,1H),6.62(d,J=8.1Hz,1H),6.30(t,J=5.9Hz,1H),5.11,(dd,J=13.2,5.4Hz,1H),4.40(d,J=5.7Hz,1H),4.31(d,J=17.4Hz,1H),4.18(d,J=17.4Hz,1H),2.84-2.96(m7H),2.57-2.63(m1H),2.23-2.37(m1H),2.00-2.05(m1H).
实施例37化合物A382
3-(4-((2-fluoro-5-(3-morpholinopropoxy)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A382.
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.32(t,J=7.8Hz,1H),7.22(t,J=7.8Hz,1H),7.05-7.13(m,2H),6.93(d,J=7.5Hz,1H),6.64(d,J=7.8Hz,1H),6.28(t,J=6.3Hz,1H),5.07-5.13(m,1H),4.38(d,J=5.7Hz,2H),4.28(d,J=17.4Hz,1H),4.16(d,J=17.4Hz,1H),3.54(t,J=4.5Hz,4H),3.42(s,2H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.26-2.38(m,5H),2.00-2.09(m,1H).LCMS:467.2([M+1]+).
实施例38化合物A383
3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A383.
1H NMR(DMSO-d6,300MHz):δ10.98(br s,1H),7.34(d,J=0.9Hz,1H),7.10-7.32(m,3H),6.95(d,J=7.5Hz,1H),6.64(d,J=7.8Hz,1H),6.27(br s,1H),5.12(dd,J=13.5,5.1Hz,1H),4.43(d,J=5.7Hz,2H),4.32(d,J=17.1Hz,1H),4.21(d,J=17.1Hz,1H),3.45-3.48(m,4H),3.38(s,2H),2.87-2.99(m,1H),2.30-2.36(m,1H),2.23-2.25(m,4H),2.22-2.36(m,1H),2.01-2.09(m,1H).LCMS=467.2[(M+1)+].
实施例39化合物A381
3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A381.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20-7.31(m,3H),7.10(t,J=7.8Hz,1H),6.95(d,J=7.5Hz,1H),6.65(d,J=8.1Hz,1H),6.31(t,J=5.7Hz,1H),5.12(dd,J1=13.8Hz,J2=5.4Hz,1H),4.43(d,J=5.4Hz,2H),4.31(d,J=17.4Hz,1H),4.19(d,J=17.4Hz,1H),3.53-3.58(m,6H),2.87-2.99(m,1H),2.57-2.66(m,1H),2.24-2.39(m,5H),2.00-2.10(m,1H).LCMS=467.2[(M+1)+].
实施例40化合物A384
3-(4-((3-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A384.
1H NMR(DMSO-d6,300MHz):δ9.76(br s,1H),7.23(t,J=8.1Hz,1H),6.93(d,J=7.5Hz,1H),6.77(t,J=7.8Hz,1H),6.61-6.67(m,2H),6.49-6.54(m1H),6.22(t,J=5.7Hz,1H),5.09-5.15(m,3H),4.35(d,J=5.4Hz,2H),4.29(d,J=17.4Hz,1H),4.17(d,J=17.4Hz,1H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.23-2.36(m,1H),2.00-2.10(m,1H).LCMS=383.1([M+1]+).
实施例41化合物A388
N-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorophenyl)acetamide,A388.
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),9.71(s,1H),7.74(t,J=6.9Hz,1H),7.22(t,J=7.8Hz,1H),7.02-7.13(m,2H),6.93(d,J=7.5Hz,1H),6.64(d,J=7.8Hz,1H),6.31(t,J=6.0Hz,1H),5.10(dd,J=12.9,5.1Hz,1H),4.42(d,J=5.4Hz,2H),4.29(d,J=17.1Hz,1H),4.16(d,J=17.1Hz,1H),2.85-2.95(m,1H),2.55-2.64(m,1H),2.22-2.36(m,1H),1.99-2.07(m,4H).LCMS=425.1[(M+1)+].
实施例42化合物A389
3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide,A389.
1H NMR(300MHz,DMSO-d6):δ11.02(s,1H),7.85-7.88(m,1H),7.73-7.78(m,1H),7.39-7.45(m,3H),7.24(t,J=7.8Hz,1H),6.96(d,J=7.5Hz,1H),6.63(d,J=8.1Hz,1H),6.43(t,J=6.0Hz,1H),5.11,(dd,J=13.2,5.1Hz,1H),4.46(d,J=5.4Hz,2H),4.29(d,J=17.4Hz,1H),4.18(d,J=17.4Hz,1H),2.85-2.97(m1H),2.58-2.63(m1H),2.24-2.36(m5H),2.02-2.07(m1H).
实施例43化合物A387
3-(4-((2-fluoro-5-(methylamino)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A387.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.22(t,J=7.5Hz,1H),6.87-6.93(m,2H),6.62(d,J=8.1Hz,1H),6.50-6.53(m,1H),6.31-6.36(m,1H),6.25(t,J=5.7Hz,1H),5.47-5.52(m,1H),5.11(dd,J=4.8,13.2Hz,1H),4.25-4.30(m,3H),4.15(d,J=17.4Hz,1H),2.85-2.97(m,1H),2.54-2.63(m,4H),2.22-2.37(m,1H),1.99-2.06(m,1H).LCMS:397.21([M+1]+).
实施例44化合物A396
3-(4-((2-fluoro-4-hydroxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A396.
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),9.74(br s,1H),7.14-7.25(m,2H),6.92(d,J=7.2Hz,1H),6.66(d,J=8.1Hz,1H),6.52-6.55(m,2H),6.13(t,J=6.0Hz,1H),5.07-5.13(m,1H),4.24-4.29(m,3H),4.14(d,J=17.1Hz,1H),2.87-2.97(m,1H),2.56-2.65(m,1H),2.21-2.36(m,1H),1.98-2.06(m,1H).LCMS:384.1[(M+1)+]
实施例45化合物A391
[3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione],A391.
步骤A:参照前述实施例20中的合成方法,用相应的底物替换实施例20中的A346A,就可以合成下列化合物A391G。
1H NMR(DMSO-d6,400MHz):δ11.03(s,1H),9.31(s,1H),7.37-7.44(m,2H),7.24(t,J=7.6Hz,1H),7.09(t,J=9.2Hz,1H),6.95(d,J=7.2Hz,1H),6.62(d,J=8.0Hz,1H),6.33(t,J=5.6Hz,1H),5.11-5.16(m,1H),4.36(t,J=5.2Hz,2H),4.29(d,J=16.8Hz,1H),4.19(d,J=17.2Hz,1H),2.89-2.98(m,1H),2.60-2.64(m,1H),2.26-2.37(m,1H),2.03-2.06(m,1H),1.42(s,9H).
步骤B:向A391G(400mg,0.83mmol)的DCM(12mL)溶液中滴加TFA(4m L)后35℃搅拌0.5小时。反应液浓缩干并用CH3CN(4mL)、Et3N(100mg)溶解后HPLC制备得白色固体产物A391(130mg,yield:41%)。
1H NMR(DMSO-d6,400MHz):δ10.83(s,1H),9.37(t,J=5.6Hz,1H),8.03(d,J=8.8Hz,2H),7.78-7.86(m,3H),7.58(s,1H),7.50(d,J=8.0Hz,2H),7.17(s,1H),4.64(d,J=5.6Hz,2H),4.50-4.54(m,1H),2.37-2.41(m,1H),2.21-2.26(m,1H),1.89-1.93(m,2H).LCMS:523.1([M+1]+).
实施例46化合物A397
3-(4-((5-amino-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A397.
步骤A:参照前述实施例20中的合成方法,用相应的底物替换实施例20中的A346A,就可以合成下列化合物A397A。
1H NMR(DMSO-d6,400MHz):δ11.04(br s,1H),9.54(br s,1H),7.38(d,J=12.8Hz,1H),7.22-7.28(m,2H),7.13(d,J=8.4Hz,1H),6.94(d,J=7.6Hz,1H),6.65(d,J=8.0Hz,1H),6.24(t,J=5.6Hz,1H),5.10-5.14(m,1H),4.27-4.34(m,3H),4.17(d,J=17.2Hz,1H),2.89-2.97(m,1H),2.64-2.67(m,1H),2.25-2.36(m,1H),2.03-2.06(m,1H),1.46(s,9H).
步骤B:将A397A(100mg,0.21mmol)溶解在二氧六环(20mL)中,向反应瓶中滴加6 NHCl二氧六环溶液,搅拌反应2.5小时,反应液浓缩,溶解在DMF(10mL)中,饱和NaHCO3调节pH=7-8,过滤,母液浓缩,剩余物Prep-HPLC纯化得淡黄色固体产物A397(35mg,收率:44%)。
1H NMR(DMSO-d6,400MHz):δ11.02(br s,1H),7.24(t,J=8.4Hz,1H),7.02(t,J=8.4Hz,1H),6.93(d,J=7.6Hz,1H),6.69(d,J=8.0Hz,1H),6.04(t,J=5.6Hz,1H),5.30(brs,2H),5.09-5.14(m,1H),4.25(d,J=17.2Hz,1H),4.20(d,J=5.6Hz,1H),4.14(d,J=17.2Hz,1H),2.88-2.97(m,1H),2.59-2.64(m,1H),2.24-2.35(m,1H),2.02-2.08(m,4H).LCMS:383.2[(M+1)+].
实施例47化合物A373
(S)-3-deuterium-3-(4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidi ne-2,6-dione,A373.
步骤A:向A373C4-(morpholinomethyl)benzaldehyde(0.8g,3.9mmol)和A356C(0.7g,2.5mmol)的甲醇(100mL)溶液中加入1mL HOAc。N2保护下40℃反应过夜。然后加入Pd/C(50%wet,10%,150mg),氢气置换后1atm压力下反应5h。约90%原料反应完。过滤,滤液浓缩干反相HPLC制备得浅黄色固体产品A373A(1.0g,收率:86%)。
1H NMR(DMSO-d6,300MHz):δ9.96(br,1H),7.59(s,1H),7.41-7.49(m,4H),7.11-7.18(m,2H),6.87(d,J=7.2Hz,1H),6.54(d,J=8.1Hz,1H),4.25-4.55(m,7H),3.93(d,J=12.0Hz,2H),3.58(t,J=12.3Hz,2H),3.01-3.24(m,4H),2.13-2.21(m,3H),1.93-2.00(m,1H).
步骤B:-40℃向A373A(200mg,0.428mmol)的DCM(12mL)/THF(12mL)溶液中加入SOCl2(204mg,1.71mmol)的DCM溶液(1.7mL)。N2保护下-40℃反应2小时。然后加入吡啶(135mg,1.71mmol)搅拌30分钟,再加入三乙胺(173mg,1.71mmol)升至室温搅拌。加0.5mL水淬灭反应。蒸干溶剂后用反相Prep-HPLC制备两次(流动相为纯水/乙腈)得白色固体产品A373(20mg,收率:10%)。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.15-7.34(m,5H),6.89(d,J=7.2Hz,1H),6.61(d,J=7.8Hz,1H),6.38(t,J=4.8Hz,1H),5.08-5.14(m,0.04H),4.35(d,J=5.1Hz,2H),4.29(d,J=17.4Hz,1H),4.16(d,J=17.4Hz,1H),3.55(br s,4H),3.42(br.s,2H),2.85-2.98(m,1H),2.57-2.63(m,1H),2.24-2.34(m,5H),1.99-2.05(m,1H).
LCMS:450.2([M+1]+).
实施例48化合物A374
2-(3-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)-4-fluorophenoxy)ethyl pyrrolidine-1-carboxylate,A374.
合成路线
实验部分
步骤A.氮气保护下将四氢吡咯(3.77g,53mmol),2-溴乙醇(6.25g,50mmol),K2CO3(6.9g,50mmol)的乙腈溶液(70mL)加热至回流反应过夜。过滤,蒸干溶剂,柱层析(DCM:MeOH=100:1to10:1)得浅黄油状产品A374A(4g,收率:50%)。
1H NMR(CDCl3,300MHz):δ4.25-4.28(m,2H),3.80-3.85(m,2H),3.36-3.43(m,4H),2.92(t,J=5.7,1H),1.88-1.92(m,4H).
步骤B.将SOCl2(3.6g,30.0mmol)加入到A374A(2.3g,14.4mmol)的氯仿溶液(50mL)中,加完回流反应1.5h。浓缩得白色固体A374C(2.0g,收率:78%)。
1H NMR(CDCl3,300MHz):δ4.21(t,J=5.7,2H),3.77(t,J=5.7,2H),3.21-3.32(m,4H),1.75-1.83(m,4H).
步骤C.氮气保护下将A374C(802mg,4.52mmol),2-氟-5-羟基苯甲醛(280mg,2.0mmol),K2CO3(828mg,6.0mmol)的DMF(10mL)溶液加热至90℃反应过夜。反应液倒入冰水(100mL)中搅拌,过滤,滤饼经水(20mL)洗后溶解于EtOAc(50mL),干燥,蒸干后得白色固体产品A374E(560mg)。直接用于下一步。
1H NMR(CDCl3,300MHz):δ10.32(s,1H),7.31-7.34(m,1H),7.09-7.17(m,2H),4.42(t,J=5.1Hz,2H),4.20(t,J=5.1Hz,2H)3.30-3.41(m,4H),1.85(br s,4H).
步骤D.室温下将A374E(206mg,0.732mmol)和A308A(150mg,0.578mmol)溶解于醋酸(6mL)和二氯甲烷(6mL)的混合溶液中搅拌4小时后加入NaBHCN(109mg,1.74mmol),氮气保护下反应过夜。反应液减压浓缩用乙腈溶解后HPLC制备得白色固体产物A374(105mg,收率35%)。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.20-7.25(m,1H),7.11(t,J=9.3Hz,1H),6.93-6.95(m,2H),6.82-6.87(m,1H),6.64(d,J=8.1Hz,1H),6.24-6.29(m,1H),5.11(dd,J=13.5,5.1Hz,1H),4.33-4.37(m,2H),4.20-4.27(m,4H),4.08-4.14(m,2H),3.12-3.22(m,4H),2.86-2.97(m,1H),2.62-2.71(m,1H),2.24-2.33(m,1H),2.01-2.06(m,1H),1.69-1.77(m,4H).LCMS:525.2([M+1]+).
实施例49化合物A349
[3-(4-((3,4-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione],A349.
N2保护下,向A349A(100mg,0.23mmol)的DMF(5mL)溶液中加入K2CO3(47.0mg,0.34mmol),于80℃(油浴)搅拌过夜。TCL显示反应完成。过滤,滤液减压浓缩,剩余物用反相HPLC纯化得白色固体A349(40mg,收率43%)。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20(t,J=7.5Hz,1H),7.01(s,1H),6.85-6.92(m,3H),6.68(d,J=7.8Hz,1H),6.24-6.28(m,1H),5.08-5.14(m,1H),4.25-4.33(m,3H),4.18(d,J=17.1Hz,1H),3.72(s,3H),3.70(s,3H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.24-2.37(m,1H),2.00-2.08(m,1H).LCMS:410.2([M+1]+).
实施例50化合物A350
3-(4-((3,4-dimethylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A350.
N2保护下,向A350A(100mg,0.25mmol)的CH3CN(5mL)溶液中加入CDI(62.0mg,0.38mmol),于95℃(油浴)搅拌过夜。TCL显示反应完成。过滤,滤液减压浓缩,剩余物用反相HPLC纯化得白色固体A350(61mg,收率65%)。
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.15-7.21(m,2H),7.04-7.10(m,2H),6.91(d,J=7.2Hz,1H),6.62(d,J=8.1Hz,1H),6.27-6.31(m,1H),5.11(dd,J=13.2,5.1Hz,1H),4.28-4.33(m,3H),4.18(d,J=17.7Hz,1H),2.87-2.99(m,1H),2.60-2.65(m,1H),2.24-2.37(m,1H),2.19(s,3H),2.17(s,3H),2.02-2.07(m,1H).LCMS:378.2([M+1]+).
参照前述实施例50中的合成方法,用相应的底物替换实施例50中的A350A,就可以合成下列实施例51-55中的化合物。
实施例51化合物A351
3-(4-((4-fluoro-3-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A351.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.29(d,J=6.0Hz,1H),7.18-7.23(m,2H),7.06(t,J=9.6Hz,1H),6.92(d,J=7.2Hz,1H),6.63(d,J=7.8Hz,1H),6.34(t,J=6.0Hz,1H),5.12(dd,J=13.2,5.1Hz,1H),4.28-4.33(m,3H),4.18(d,J=17.4Hz,1H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.26-2.37(m,1H),2.21(s,3H),2.01-2.08(m,1H).LCMS:382.1([M+1]+).
实施例52化合物A352
3-(4-((3-chloro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A352.
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.41(s,1H),7.17-7.30(m,3H),6.92(d,J=7.5Hz,1H),6.61(d,J=8.1Hz,1H),6.39(t,J=6.0Hz,1H),5.12(dd,J=13.2,5.4Hz,1H),4.29-4.37(m,3H),4.18(d,J=17.1Hz,1H),2.87-2.99(m,1H),2.59-2.65(m,1H),2.25-2.39(m,4H),2.02-2.07(m,1H).LCMS:398.1([M+1]+).
实施例53化合物A353
3-(4-((3-fluoro-4-methylbenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A353.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.11-7.24(m,4H),6.92(d,J=7.2Hz,1H),6.61(d,J=7.5Hz,1H),6.36-6.40(m,1H),5.12(dd,J=13.5,5.1Hz,1H),4.29-4.37(m,3H),4.19(d,J=17.4Hz,1H),2.86-2.99(m,1H),2.59-2.65(m,1H),2.24-2.39(m,1H),2.18(s,3H),2.01-2.07(m,1H).LCMS:382.1([M+1]+).
实施例54化合物A354
3-(4-((3-chloro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A354.
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.44(d,J=1.8Hz,1H),7.32(dd,J=8.4,1.8Hz,1H),7.21(t,J=7.8Hz,1H),7.09(d,J=8.7Hz,1H),6.93(d,J=7.2Hz,1H),6.65(d,J=8.1Hz,1H),6.35(t,J=5.9Hz,1H),5.09-5.15(m,1H),4.28-4.33(m,3H),4.18(d,J=16.8Hz,1H),3.81(s,3H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.24-2.37(m,1H),2.01-2.09(m,1H).LCMS:414.1([M+1]+).
实施例55化合物A355
3-(4-((3,5-dimethoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A355.
1H NMR(DMSO-d6,300MHz):δ11.03(s,1H),7.18-7.24(m,1H),6.92(d,J=7.5Hz,1H),6.64(d,J=8.4Hz,1H),6.55(d,J=2.1Hz,2H),6.31-6.35(m,2H),5.12(dd,J=13.2,4.8Hz,1H),4.28-4.34(m,3H),4.19(d,J=16.8Hz,1H),3.33(s,6H),2.87-2.99(m,1H),2.58-2.67(m,1H),2.26-2.37(m,1H),2.02-2.08(m,1H).LCMS:410.2([M+1]+).
实施例56化合物A356
(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A356.
合成路线:
实验部分
步骤A:将A356C(300mg,1.08mmol)和2-氟-4-甲氧基苯甲醛(249mg,1.62mmol)溶解于甲醇(30mL)中,后向反应瓶中加入冰醋酸(0.5mL),加热30℃(外温)搅拌5小时。加入Pd/C(10%,100mg,50%water),30℃(外温)氢化反应过夜(氢气球)。减压抽滤掉Pd/C,滤液减压浓缩,剩余物用反向C18(CH3CN:H2O=5%-35%,30min;35%-45%,30min;45%-55%20min)冻干得淡黄色固体A356A(160mg,yield:35%)。
1H NMR(DMSO-d6,300MHz):δ12.06(br s,1H),7.55(br s,1H),7.29(t,J=9.0Hz,1H),7.16-7.22(m,2H),6.88(d,J=7.5Hz,1H),6.80(dd,J=12.6,2.4Hz,1H),6.71(dd,J=8.7,2.7Hz,1H),6.61(d,J=8.1Hz,1H),6.28(t,J=6.0Hz,1H),4.68-4.74(m,0.01H),4.48(d,J=17.7Hz,1H),4.23-4.31(m,3H),3.72(s,3H),2.10-2.19(m,3H),1.93-2.01(m,1H).
步骤B:将A356A(160mg,0.39mmol)溶于干燥的DCM(20mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(229mg,1.92mmol),毕,加入DMF(5mg)的DCM(1mL)溶液加毕,搅拌反应2h,滴加吡啶(152mg,1.92mmol)维持此温度搅拌40分钟,加入Et3N(195mg,1.92mmol),加毕,继续反应2h,LCMS显示反应完成。加入H2O(10mL)淬灭反应,水相用DCM萃取(30mL×2),合并有机相,食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经反向C18制备柱纯化(CH3CN:H2O=5%-35%,30min;35%-45%,30min;45%-55%20min)纯化得到白色固体A356(70mg,收率:46%,ee:97%)。
1H NMR(DMSO-d6,300MHz):δ10.99(br s,1H),7.31(t,J=9.0Hz,,1H),7.24(t,J=7.8Hz,1H),6.94(d,J=7.2Hz,1H),6.82(dd,J=12.3,2.7Hz,1H),6.71-6.75(m,1H),6.68(d,J=7.8Hz,1H),6.20(t,J=6.0Hz,1H),5.08-5.14(m,0.04H),4.26-4.35(m,3H),4.17(d,J=16.8Hz,1H),3.74(s,3H),2.87-2.97(m,1H),2.57-2.66(m,1H),2.25-2.34(m,1H),2.00-2.09(m,1H).LCMS:399.1([M+1]+).
参照前述实施例56中的合成方法,用相应的底物替换步骤A中的2-氟-4-甲氧基苯甲醛,就可以合成下列实施例57中的化合物。
实施例57化合物A357
(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A357.
1H NMR(DMSO-d6,300MHz):δ11.00(br s,1H),7.21(t,J=7.8Hz,,1H),7.00-7.07(m,2H),6.89-6.93(m,2H),6.78-6.84(m,1H),6.61(d,J=8.4Hz,1H),6.30(t,J=5.4Hz,1H),5.07-5.13(m,0.03H),4.40(d,J=5.7Hz,2H),4.28(d,J=17.1Hz,1H),4.16(d,J=17.1Hz,1H),3.81(s,3H),2.85-2.97(m,1H),2.57-2.63(m,1H),2.24-2.34(m,1H),2.00-2.06(m,1H).LCMS:399.1([M+1]+).
实施例58化合物A379
(S)-3-deuterium-3-(4-((2-fluoro-5-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A379.
合成路线
实验部分
步骤A:将A379A1(10.0g,27.8mmol)和A379A2(8.01g,33.4mmol)悬浮于CH3CN(250mL)中,后向反应瓶中加入DIPEA(7.92g,61.3mmol),氮气保护,加热至45℃搅拌反应过夜。反应液减压浓缩,剩余物溶解在DCM(300mL)和水(100mL)中搅拌,水层用DCM萃取(200mL×1),合并有机相,食盐水(200mL)洗,无水硫酸钠干燥,过滤,滤液减压浓缩,得黄色固体粗产物A379A(12.3g)。
步骤B.将A379A(12.3g,粗品)溶解在THF(100mL)中,加入1N TBAF的THF溶液(100mL),25℃氢化反应过夜。LCMS显示反应完成。向反应液中加入EtOAc(200mL)和H2O(200mL),分层,水相用EtOAc(200mL×2)萃取,合并有机相,用食盐水洗(300mL),无水硫酸钠干燥,过滤母液减压浓缩至干,剩余物用EtOAc(20mL)打浆,EtOAc(10mL)洗滤饼,固体干燥得白色固体产物A379B(5.7g)。或者母液硅胶柱层析纯化(PE/EtOAc=1:4)得白色固体产物A379B(1.5g,两步收率:77%)。
1H NMR(DMSO-d6,300MHz):δ10.01(s,1H),7.54(br s,1H),7.29(t,J=7.8Hz,1H),7.12-7.16(m,2H),6.96(dd,J=8.1,0.6Hz,1H),4.66-4.71(m,0.01H),4.47(d,J=17.7Hz,1H),4.29(d,J=17.7Hz,1H),2.08-2.17(m,3H),1.95-2.02(m,1H),1.31(s,9H).
步骤C:将A379B(1.18g,3.52mmol)和2-氟-5-甲氧基苄氯(1.23g,7.04mmol)溶解于DMF(20mL)中,后向反应瓶中加入K2CO3(972mg,7.03mmol),室温搅拌反应过夜。LCMS显示反应完全。减压浓缩掉DMF,剩余物加入EtOAc(50mL)和H2O(30mL)溶解,水相用EtOAc(50mL)萃取,合并有机相,食盐水洗(50mL),无水Na2SO4干燥,过滤,母液减压浓缩,剩余物用硅胶柱纯化(MeOH/DCM=1/30),得白色固体产物(1.46g,收率:87%)。白色固体产物用手性柱拆分A379C(650mg)和A379D(650mg)。
手性拆分制备条件:
流动相:Hexane/EtOH=40/60(V/V).样品浓度:100mg/ml(在流动相中).手性柱:IC;柱子型号:20mm(I.D)×250mm(L);柱子粒径:5um;柱温:35℃;进样量:250μL;流速:10ml/min;检测波长:205nm。
A379C:1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.46(t,J=8.1Hz,1H),7.28-7.34(m,2H),7.11-7.21(m,3H),6.92-6.97(m,1H),5.22(s,2H),4.49(d,J=18.0Hz,1H),4.36(d,J=18.0Hz,1H),3.73(s,3H),2.05-2.13(m,3H),1.96-2.02(m,1H),1.30(s,9H).
步骤D:将A379C(650mg,1.37mmol)溶解于二氯甲烷(20mL)中,冷却至0℃,后向反应瓶中滴加三氟乙酸(10mL),慢慢升至室温搅拌反应过夜。反应液减压浓缩,剩余物溶解在4mL CH3CN中用反向C18柱纯化(40%乙腈的水溶液)冻干得淡黄色固体A379E(566mg,收率:99%)。
1H NMR(DMSO-d6,300MHz):δ12.08(br s,1H),7.58(br s,1H),7.46(t,J=8.1Hz,1H),7.28-7.35(m,2H),7.11-7.21(m,3H),6.92-6.97(m,1H),5.22(s,2H),4.51(d,J=17.7Hz,1H),4.37(d,J=17.7Hz,1H),3.73(s,3H),2.08-2.20(m,3H),1.96-2.05(m,1H).
步骤E:将A379E(366mg,0.88mmol)溶于干燥的DCM(35mL)和THF(5mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(522mg,4.39mmol),毕,加入DMF(5mg)的DCM(1mL)溶液加毕搅拌反应1h,滴加吡啶(347mg,4.39mmol)维持此温度搅拌40分钟,加入Et3N(444mg,4.39mmol),加毕,继续反应1h。LCMS显示反应完成。加入H2O(10mL)淬灭反应,水相用DCM萃取(50mL),食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经C18柱纯化得到白色固体A379(270mg,yield:77%,ee:100%)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.49(t,J=8.1Hz,1H),7.32-7.38(m,2H),7.11-7.21(m,2H),6.91-6.97(m,1H),5.23(s,2H),5.06-5.12(m,0.01H),4.37(d,J=17.4Hz,1H),4.21(d,J=17.4Hz,1H),3.72(s,3H),2.82-2.94(m,1H),2.57-2.60(m,1H),2.38-2.48(m,1H),1.92-1.97(m,1H).LCMS=400.1([M+1]+).
参照前述实施例58中的合成方法,用相应的底物替换步骤C中的2-氟-5-甲氧基苄氯,就可以合成下列实施例59中的化合物。
实施例59化合物A380
(S)-3-deuterium-3-(4-((2-fluoro-3-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A380.
1H NMR(DMSO-d6,300MHz):δ10.95(br s,1H),7.49(t,J=7.8Hz,1H),7.31-7.37(m,2H),7.07-7.19(m,3H),5.26(s,2H),5.05-5.11(m,0.01H),4.36(d,J=17.4Hz,1H),4.20(d,J=17.4Hz,1H),3.83(s,3H),2.82-2.94(m,1H),2.51-2.60(m,1H),2.37-2.46(m,1H),1.92-1.99(m,1H).LCMS=400.1([M+1]+).
实施例60化合物A393
(S)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A393.
步骤A:向化合物A379B(2.0g,6.0mmol)的DCM(30mL)溶液中加入TFA(5mL)25℃下搅拌3小时,减压浓缩后得粗产品(1.7g)。将2-三甲基硅基乙醇(3.55g,30mmol),EDCI(2.3g,12.0mmol)和DMAP(733mg,6.0mmol)加入到上述粗产品(1.7g)的DMF(5mL)溶液中,35℃下搅拌过夜,反应液减压浓缩后经硅胶柱层析纯化(DCM/MeOH=40/1)得到产品A393A(1.6g,两步收率70%).
1H NMR(DMSO-d6,300MHz):δ9.99(s,1H),7.54(s,1H),7.28(t,J=7.8Hz,1H),7.11-7.14(m,2H),6.96(d,J=7.8Hz,1H),4.47(d,J=18.0Hz,1H),4.28(d,J=18.0Hz,1H),3.92-3.99(m,2H),2.00-2.25(m,4H),0.80-0.85(m,2H),0.04(s,9H).
步骤B:将K2CO3(750mg,5.40mmol)和2-氟-4-甲氧基苄氯(720mg,4.10mmol)加入到A393A(1.02g,2.70mmol)的DMF(20mL)溶液中,反应液加热到30℃,搅拌17小时后过滤去除固体,滤液浓缩后得到粗品,硅胶柱层析纯化(DCM/MeOH=60/1)得到产品A393C(1.0g,72%).
1H NMR(DMSO-d6,300MHz):δ7.43-7.54(m,3H),7.26-7.35(m,2H),7.14(s,1H),6.80-6.90(m,2H),5.16(s,2H),4.45(d,J=17.4Hz,1H),4.30(d,J=17.4Hz,1H),3.92-3.98(m,2H),3.77(s,3H),2.01-2.22(m,4H),0.79-0.84(m,2H).
步骤C:手性拆分
手性拆分制备条件:
流动相:MeOH/EtOH=50/50(V/V).样品浓度:120mg/mL.手性柱:IF;柱子型号:20mm(I.D)×250mm(L);柱子粒径:5um;柱温:35℃;进样量:300μL;流速:9mL/min;检测波长:205nm。
A393E
1H NMR(DMSO-d6,300MHz):δ7.59(s,1H),7.45-7.54(m,2H),7.36(d,J=7.8Hz,1H),7.29(d,J=7.2Hz,1H),7.20(s,1H),6.80-6.92(m,2H),5.18(s,2H),4.47(d,J=17.4Hz,1H),4.32(d,J=17.4Hz,1H),3.92-4.01(m,2H),3.78(s,3H),2.01-2.20(m,4H),0.80-0.85(m,2H),0.04(s,9H).
步骤D:
将TBAF(1N/THF,5mL)加入到A393E(500mg,0.97mmol)的THF(5mL)溶液中,加热50℃搅拌过夜,冷却后过滤,浓缩母液后经C18制备柱纯化得到粗品(420mg),将300mg粗品的DCM(15mL)溶液冷却到-40℃后滴加DMF(1mL)和SOCl2(428mg,3.60mmol),搅拌2小时后加入吡啶(281mg,3.60mmol),继续搅拌30分钟后,将Et3N(363mg,3.60mmol)加入反应液,-40℃下继续搅拌1小时后,将反应液倒入水(80mL)中淬灭反应,用DCM(80mL×3)萃取,合并有机相后,无水硫酸钠干燥,过滤浓缩后经Prep-HPLC制备分离得到产品A393(200mg,两步收率72%).
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.48-7.53(m,2H),7.32-7.40(m,2H),6.80-6.91(m,2H),5.19(s,2H),4.35(d,J=17.4Hz,1H),4.19(d,J=17.4Hz,1H),3.78(s,3H),2.84-2.96(m,1H),2.37-2.59(m,2H),1.93-1.99(m,1H).LCMS:400.1([M+1]+).
参照前述实施例60中的合成方法,用相应的底物替换A393E。就可以合成下列实施例61中的化合物。
实施例61化合物A392
(R)-3-deuterium-3-(4-((2-fluoro-4-methoxybenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A392.
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.48-7.53(m,2H),7.32-7.40(m,2H),6.80-6.91(m,2H),5.19(s,2H),5.07-5.13(m,0.05H),4.35(d,J=17.7Hz,1H),4.19(d,J=17.7Hz,1H),3.78(s,3H),2.84-2.96(s,1H),2.36-2.59(m,2H),1.93-1.98(m,1H).LCMS:400.1([M+1]+).
实施例62化合物A385
3-(4-((2-fluoro-3-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A385.
合成路线
实验部分
步骤A:将化合物2-氟-3-甲氨基苯甲醇溶解在DCM(10mL)中,加入SOCl2(0.5mL),搅拌反应4小时。反应液浓缩得黄色固体3-氯甲基2-氟-N-甲基苯胺盐酸盐(430mg),不纯化直接用于下一步。
1H NMR(DMSO-d6,300MHz):δ9.97(br s,2H),7.05(t,J=8.1Hz,1H),6.84-6.92(m,2H),4.72(s,2H),2.74(s,3H).
步骤B:将A329B(300mg,1.03mmol)溶解在DMF(10mL)中,加入3-氯甲基2-氟-N-甲基苯胺盐酸盐(259mg)和K2CO3(355mg,2.57mmol),搅拌反应过夜,LCMS显示大量原料剩余,补加3-氯甲基2-氟-N-甲基苯胺盐酸盐(150mg)和K2CO3(100mg,0.72mmol),搅拌反应过夜,原料基本反应完全。减压浓缩掉DMF,剩余物中加入EtOAc(20mL)和水(10mL),分层,水相用EtOAc(20mL×2)萃取,合并的有机相用食盐水(20mL)洗,无水Na2SO4干燥,过滤,滤液减压浓缩,剩余物Prep-TLC(乙酸乙酯/石油醚=4/1)纯化得白色固体A385A(242mg,收率:55%)。
1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.45(t,J=7.8Hz,1H),7.27-7.33(m,2H),7.15(br s,1H),6.99(t,J=8.1Hz,1H),6.61-6.71(m,2H),5.59(br s,1H),5.20(s,2H),4.70(dd,J=10.5,4.5Hz,1H),4.47(d,J=17.7Hz,1H),4.33(d,J=17.7Hz,1H),3.48(s,3H),2.71(d,J=4.2Hz,3H),2.12-2.25(m,3H),1.99-2.09(m,1H).
步骤C:将A385A(242mg,0.56mmol)溶解在DMF(10mL)中,加入K2CO3(234mg,1.69mmol),80℃搅拌反应过夜。反应物浓缩,剩余物制备HPLC纯化,冻干得白色固体产物A385(100mg,收率:45%)。
1H NMR(DMSO-d6,300MHz):δ10.71(br s,1H),7.50(t,J=8.1Hz,1H),7.32-7.38(m,2H),7.00(t,J=7.8Hz,1H),6.63-6.72(m,2H),5.61-5.62(m,1H),5.23(s,2H),5.10(dd,J=13.2,5.1Hz,1H),4.37(d,J=17.7Hz,1H),4.21(d,J=17.7Hz,1H),2.84-2.96(m,1H),2.72(d,J=4.8Hz,3H),2.51-2.60(m,1H),2.37-2.47(m,1H),1.93-2.00(m,1H).LCMS=398.1([M+1]+).
参照前述实施例62中的合成方法,用相应的底物替换步骤B中的3-氯甲基2-氟-N-甲基苯胺盐酸盐,就可以合成下列实施例63-66中的化合物。
实施例63化合物A390
3-(4-((2-fluoro-5-(methylamino)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A390.
1H NMR(DMSO-d6,300MHz):δ10.97(s,1H),7.48(t,J=7.8Hz,1H),7.33(t,J=7.2Hz,2H),6.96(t,J=9.3Hz,1H),6.63-6.66(m,1H),6.46-6.51(m,1H),5.58-5.63(m,1H),5.16(s,2H),5.06-5.12(m,1H),4.35(d,J=17.4Hz,1H),4.19(d,J=17.4Hz,1H),2.83-2.95(m,1H),2.54-2.62(m,4H),2.34-2.45(m,1H),1.91-1.99(m,1H).LCMS:398.1([M+1]+).
实施64化合物A398
3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-di one,A398.
1H NMR(DMSO-d6,300MHz):δ10.92(br s,1H),7.46-7.51(m,2H),7.31-7.37(m,3H),7.16-7.22(m,1H),5.27(s,2H),5.05-5.11(m,1H),4.35(d,J=17.4Hz,1H),4.20(d,J=17.4Hz,1H),3.50-3.53(m,4H),3.43(s,2H),2.82-2.92(m,1H),2.53-2.60(m,1H),2.34-2.44(m,1H),2.23-2.29(m,4H),1.90-2.00(m,1H).LCMS=468.2[(M+1)+].
实施例65化合物A399
3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dio ne,A399.
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.49-7.54(m,2H),7.34-7.45(m,3H),7.19-7.24(m,1H),5.29(s,2H),5.08-5.14(m,1H),4.39(d,J=17.7Hz,1H),4.22(d,J=17.7Hz,1H),3.50-3.57(m,6H),2.84-2.98(m,1H),2.54-2.60(m,1H),2.34-2.47(m,5H),1.92-2.01(m,1H).LCMS:468.2([M+1]+).
实施例66化合物A407
3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A407.
合成路线:
实验部分
步骤A:将A327A(300mg,0.85mmol)和4-(4-氯甲基)-3-氟苯基吗啉盐酸盐(359mg,1.28mmol)溶解于DMF(15mL)中,后向反应瓶中加入K2CO3(352mg,2.55mmol),40℃搅拌过夜。过滤,浓缩掉DMF,剩余物用Prep-TLC(MeOH/DCM=1/15)纯化,得白色固体产物A407B(430mg,收率:90%)。
1H NMR(DMSO-d6,300MHz):δ7.51-7.56(m,2H),7.33(dd,J=11.4,1.5Hz,1H),7.17-7.21(m,3H),7.07(dd,J=7.5,1.5Hz,1H),5.24(s,2H),4.66-4.69(m,1H),4.44(d,J=17.7Hz,1H),4.32(d,J=17.7Hz,1H),3.55-3.58(m,4H),3.48(s,2H),2.29-2.39(m,4H),2.05-2.18(m,3H),1.95-2.01(m,1H),1.29(s,9H).
步骤B:将A407B(430mg,0.77mmol)溶解于DCM(20mL)中,室温向反应瓶中滴加TFA(5mL),25℃搅拌反应3h。LCMS显示原料消失。反应液减压浓缩得黄色固体A407C(387mg,收率:100%)。
1H NMR(DMSO-d6,300MHz):δ10.33(br s,1H),7.71(t,J=7.8Hz,1H),7.61(s,1H),7.33-7.47(m,3H),7.19(s,1H),7.09-7.11(m,1H),5.31(s,2H),4.69-4.72(m,1H),4.48(d,J=17.7Hz,1H),4.38(s,2H),4.35(d,J=17.7Hz,1H),3.89-3.99(m,2H),3.57-3.67(m,2H),3.14-3.34(m,4H),3.10-2.17(m,3H),1.95-2.01(m,1H).
步骤C:将A407C(215mg,0.39mmol)溶于CH3CN(15mL)中,加入CDI(190mg,1.17mmol),氮气保护下加热回流过夜。LCMS显示原料消失。减压浓缩至干,剩余物经Prep-HPLC纯化得到白色固体A407(80mg,yield:43%)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.51-7.56(m,1H),7.34-7.39(m,1H),7.11-7.21(m,3H),5.25(s,2H),5.05-5.11(m,1H),4.33(d,J=18.0Hz,1H),4.16(d,J=18.0Hz,1H),3.54-3.57(m,4H),3.48(s,2H),2.82-2.94(m,1H),2.49-2.56(m,1H),2.30-2.44(m,5H),1.91-1.99(m,1H).LCMS:486.2([M+1]+).
实施例67化合物A403
(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)p iperidine-26-dione,A403.
步骤A:将A379B(1.0g,3.59mmol)和4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐(1.23g,7.05mmol)溶解于DMF(20mL)中,向反应瓶中加入K2CO3(972mg,7.04mmol),25℃搅拌过夜。过滤,浓缩掉DMF,剩余物用硅胶柱纯化,得白色固体产物A403A(1.3g,收率:80%)。
[A403A]1H NMR(DMSO-d6,300MHz):δ7.54(br s,1H),7.43-7.49(m,2H),7.28-7.34(m,3H),7.14-7.22(m,2H),5.26(s,2H),4.67-4.72(m,0.05H),4.50(d,J=17.4Hz,1H),4.33(d,J=17.4Hz,1H),3.49-3.56(m,4H),3.44(s,2H),2.25-2.34(m,4H),2.09-2.15(m,3H),1.94-2.03(m,1H),1.29(s,9H).
步骤B:手性拆分.
A403A用手性硅胶柱拆分得到A403C(500mg)和A403E(500mg)。
手性拆分制备条件:流动相:Hexane/IPA=70/30(V/V)。样品浓度:100mg/mL;手性柱:IA;柱子型号:30mm(I.D)×250mm(L);柱子粒径:5um;柱温:35℃;进样量:250μL;检测波长:205nm;流速:50mL/min。
A403C:
(S)-tert-butyl5-amino-4-deuterium-4-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate
1H NMR(DMSO-d6,300MHz):δ7.55(br s,1H),7.43-7.49(m,2H),7.28-7.34(m,3H),7.16-7.22(m,2H),5.26(s,2H),4.66-4.71(m,1H),4.49(d,J=17.4Hz,1H),4.33(d,J=17.4Hz,1H),3.51-3.53(m,4H),3.43(s,23H),2.26-2.33(m,4H),2.02-2.16(m,3H),1.94-1.99(m,1H),1.29(s,9H).
步骤C:将A403C(500mg,1.0mmol)溶解于二氯甲烷(12mL)中,冷却至0℃,后向反应瓶中滴加三氟乙酸(3mL),慢慢升至25℃搅拌反应过夜。反应液减压浓缩,剩余物溶解在CH2Cl2(20mL)中,加入饱和NaHCO3调节pH=8-9,浓缩,剩余物用反向C18柱纯化(CH3CN:H2O=5-40%,40min)冻干得淡黄色固体A403D(400mg,收率:82%)。
1H NMR(DMSO-d6,300MHz):δ7.93(br s,1H),7.41-7.49(m,2H),7.26-7.32(m,3H),7.16-7.22(m,1H),7.06(br s,1H),5.25(s,2H),5.05-5.13(m,0.00H),4.60(d,J=17.7Hz,1H),4.30(d,J=17.7Hz,1H),3.50-3.52(m,4H),3.42(s,2H),2.22-2.32(m,4H),2.03-2.10(m,1H),1.81-1.94(m,3H).
步骤D:将A403D(400mg,0.82mmol)溶于干燥的DMF(1mL)、DCM(40mL)和THF(20mL)中,氮气保护下冷至-40℃,缓慢滴加SOCl2(488mg,4.1mmol),毕,搅拌反应1h,滴加吡啶(324mg,4.1mmol)维持此温度搅拌40分钟,加入Et3N(415mg,4.1mmol),加毕,继续反应1h。LCMS显示反应完成。DCM(50mL)和加入H2O(2mL)淬灭反应,水相用DCM萃取(50mL×2),食盐水洗(50mL×1),无水硫酸钠干燥,过滤,减压浓缩至干,剩余物经C18柱纯化(CH3CN:H2O=5%-45%,40min)得到白色固体A403(300mg,yield:78%,ee:99%)。
1H NMR(DMSO-d6,300MHz):δ10.96(br s,1H),7.46-7.51(m,2H),7.31-7.37(m,3H),7.16-7.22(m,1H),5.27(s,2H),5.05-5.13(m,0.04H),4.35(d,J=17.7Hz,1H),4.19(d,J=17.7Hz,1H),3.5.-3.53(m,4H),3.43(s,2H),2.82-2.94(m,1H),2.49-2.58(m,1H),2.36-2.41(m,1H),2.26-2.32(m,4H),1.91-1.98(m,1H).LCMS:469.2([M+1]+).
参照前述实施例67中的合成方法,用相应的底物替换4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐。就可以合成下列实施例68-69中的化合物。
实施例68化合物A404
(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A404.
1H NMR(DMSO-d6,300MHz):δ10.94(s,1H),7.45-7.53(m,2H),7.31-7.42(m,3H),7.17-7.21(m,1H),5.28(s,2H),4.37(d,J=18.0Hz,1H),4.21(d,J=18.0Hz,1H),3.51-3.62(m,6H),2.82-2.95(m,1H),2.57-2.62(m,1H),2.28-2.42(m,5H),1.91-2.01(m,1H).LCMS:469.2([M+1]+).
实施例69化合物A406
(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A406.
1H NMR(DMSO-d6,300MHz):δ10.98(s,1H),7.47-7.55(m,2H),7.31-7.38(m,2H),7.16-7.20(m,2H),5.24(s,2H),5.06-5.12(m,0.04H),4.35(d,J=18.0Hz,1H),4.19(d,J=18.0Hz,1H),3.55(br,4H),3.47(s,2H),2.82-2.94(m,1H),2.48-2.57(m,1H),2.33-2.42(m,5H),1.91-1.96(m,1H).LCMS:469.2([M+1]+).
实施例70化合物A400
(S)-3-deuterium-3-(4-((2-fluoro-3-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A400.
合成路线:
实验部分
步骤A:向化合物A356C(400mg,1.44mmol)的MeOH溶液(30mL)中加入2-氟-3-(吗啉甲基)苯甲醛(481mg,2.16mmol)和HOAc(0.5mL),30℃下搅拌过夜,将Pd/C(150mg,10%,50%water)加入到反应液中,氢气环境下剧烈搅拌3小时,过滤去除固体,减压浓缩滤液后得到产品A400A(580mg).
1H NMR(DMSO-d6,300MHz):δ7.57(br s,1H),7.06-7.31(m,5H),6.88-6.90(m,1H),6.58-6.60(m,1H),6.37(s,1H),4.26-4.54(m,4H),3.47-3.66(m,6H),2.23-2.37(m,4H),2.07-2.15(m,3H),1.85-1.97(m,1H).
步骤B:将A400A(480mg,0.99mmol)的DCM(20mL)溶液冷却到-40℃后滴加DMF(1mL)和SOCl2(589mg,4.95mmol),搅拌2小时后加入吡啶(383mg,4.95mmol),再搅拌30分钟后,将Et3N(501mg,4.95mmol)加入反应液,-40℃下继续搅拌1小时后将反应液倒入水(80mL)中淬灭反应,用DCM(80mL×3)萃取,合并有机相后,无水硫酸钠干燥,过滤、减压浓缩后经柱层析纯化(DCM/MeOH=40/1)得到产品A400(251mg,54%).
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.20-7.31(m,3H),7.10(t,J=7.8Hz,1H),6.95(d,J=7.5Hz,1H),6.65(d,J=7.8Hz,1H),6.29-6.32(m,1H),5.09-5.15(m,0.05H),4.43(d,J=5.1Hz,2H),4.31(d,J=17.1Hz,1H),4.19(d,J=17.1Hz,1H),3.49-3.64(m,6H),2.87-2.99(m,1H),2.58-2.65(m,1H),2.25-2.44(m,5H),2.01-2.06(m,1H).LCMS:468.2([M+1]+).
参照前述实施例70中的合成方法,用相应的底物替换步骤A中的2-氟-3-(吗啉甲基)苯甲醛。就可以合成下列实施例71-72中的化合物。
实施例71化合物A401
(S)-3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione A401.
1H NMR(DMSO-d6,400MHz):δ11.03(br s,1H),7.32(d,J=6.8Hz,1H),7.12-7.23(m,3H),6.94(d,J=7.6Hz,1H),6.62(d,J=8.0Hz,1H),6.34(t,J=6.0Hz,1H),5.11-5.16(m,0.4H),4.42(d,J=5.6Hz,2H),4.31(d,J=16.8Hz,1H),4.20(d,J=17.2Hz,1H),3.42-3.49(m,4H),3.37(s,2H),2.89-2.98(m,1H),2.58-2.67(m,1H),2.28-2.35(m,1H),2.18-2.26(m,4H),2.02-2.06(m,1H).LCMS:468.2[(M+1)+].
实施例72化合物A402
(S)-3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A402.
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.30-7.35(m,1H),7.22(t,J=7.8Hz,1H),7.05-7.13(m,2H),6.92(d,J=7.5Hz,1H),6.64(d,J=8.1Hz,1H),6.27-6.31(m,1H),5.08-5.14(m,0.05H),4.38(d,J=5.4Hz,2H),4.28(d,J=17.4Hz,1H),4.16(d,J=17.4Hz,1H),3.54(br s,4H),3.42(s,2H),2.85-2.97(m,1H),2.56-2.62(m,1H),2.24-2.31(m,5H),1.98-2.06(m,1H).LCMS:468.2([M+1]+).
实施例73化合物A405
3-(6-fluoro-4-((4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A405.
合成路线:
步骤A:-70℃氮气保护下将(COCl)2(152mg,1.2mmol)加入到DMSO(156mg,2.0mmol)的DCM溶液(10mL)中,维持温度-70℃继续搅拌30分钟,然后加入4-(吗啉甲基)-苯甲醇(207mg,1.0mmol)的3mL DCM溶液继续搅拌1小时。滴入Et3N(405mg,4.0mmol),维持温度-70℃继续搅拌1小时后升至25℃,滴加水(10mL)淬灭反应,加入NaHCO3溶液(5mL)。分液,水相用10mL DCM萃取,合并有机相浓缩后柱层析(PE:EtOAc=2:1)得浅黄色油状产品A405A(180mg,收率:88%)。
1H NMR(CDCl3,300MHz):δ9.99(s,1H),7.84(d,J=7.8Hz,2H),7.51(d,J=8.1Hz,2H),3.70-3.73(m,4H),3.57(s,2H),2.46(t,J=4.2Hz,4H).
步骤B:25℃下将A405A(111mg,0.54mmol)和I-28(100mg,0.36mmol)溶解于HOAc(6mL)和DCM(6mL)的混合溶液中搅拌3小时后加入NaBH3CN(45mg,0.72mmol),室温反应过夜。补加A405A(40mg,0.14mmol),40℃反应6小时。减压浓缩除去溶剂,加入NaHCO3(10mL)和DCM(25mL),分液,水相用DCM萃取(20mL×2),合并有机相,。减压浓缩除去溶剂Prep-HPLC纯化(含0.5%TFA)后,冷冻干燥所得固体加入5mL NaHCO3饱和溶液调pH值为8,用DCM萃取(5mL×5)蒸干得白色固体产物A405(50mg,收率:30%)。
1H NMR(DMSO-d6,300MHz):δ11.01(s,1H),7.23-7.33(m,4H),6.72(br s,1H),6.60(dd,J=1.8Hz,7.5Hz,1H),6.42(dd,J=2.1Hz,12.6Hz,1H),5.09(dd,J=5.1Hz,13.2Hz,1H),4.35(d,J=5.4Hz,2H),4.27(d,J=17.4Hz,1H),4.14(d,J=17.4Hz,1H),3.53(br s,4H),3.41(s,2H),2.84-2.96(m,1H),2.57-2.63(m,1H),2.21-2.31(m,5H),2.01-2.05(m,1H).LCMS:467.2([M+1]+).
实施例74化合物A386
3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A386.
合成路线:
实验部分:
步骤A.向2-氟-4-吗啉甲基苯甲醇(1.0g,4.4mmol)的氯仿溶液(25mL)中加入SOCl2(1.1g,9.2mmol)。加热回流反应2小时后蒸干溶剂,用25mL氯仿带蒸两次得白色固体产品A386A(1.2g,收率:97%)。
1H NMR(DMSO-d6,400MHz):δ11.98(br s,1H),7.70(d,J=10.8Hz,1H),7.63(t,J=8.0Hz,1H),7.70(d,J=7.6Hz,1H),4.82(s,2H),4.37(d,J=4.8Hz,2H),3.86-3.93(m,4H),3.07-3.21(m,4H).
步骤B:A386A、A386B(0.8g,2.4mmol),K2CO3(1.3g,9.6mmol)的DMF(20mL)溶液氮气置换后加热至40℃反应18小时。反应液倒入100mL冰水中用EtOAc萃取(20mL×5),合并有机相用水(20mL),食盐水(20mL)洗,干燥后浓缩,硅胶柱层析纯化(PE:EtOAc=2:1至1:1)得白色固体产品A386C(1.2g,收率:92%)。
1H NMR(CDCl3,300MHz):δ7.37-7.47(m,3H),7.10-7.16(m,3H),6.30(br s,1H),5.33(br s,1H),5.18(s,2H),4.86-4.91(m,1H),4.36-4.51(m,2H),3.71-3.74(m,4H),3.51(s,2H),2.45-2.48(m,4H),2.09-2.40(m,4H),1.42(s,9H).
步骤C:向A386C(1.2g,2.2mmol)的DCM(30mL)溶液加入TFA(15mL),35℃下搅拌反应2小时。反应液减压浓缩至干,剩余物经Prep-HPLC纯化得浅黄色固体产品A386E(1.4g,收率:64%)。
1H NMR(DMSO-d6,300MHz):δ12.05(br s,1H),7.56(br s,2H),7.47(t,J=8.1Hz,1H),7.29-7.36(m,4H),7.15-7.22(m,1H),5.25(s,2H),4.68-4.73(m,1H),4.50(d,J=17.7Hz,1H),4.36(d,J=17.7Hz,1H),3.56-3.60(m,6H),2.26-2.45(m,2H),1.94-2.16(m,4H),1.72-1.77(m,2H).
步骤D:A386E(421mg,0.867mmol)溶于DCM/THF(50mL/5mL)后降温至-40℃加入SOCl2(516mg,4.33mmol)的DCM(10mL)溶液。-40至-20℃反应2小时后加入吡啶(339mg,4.33mmol),-40℃搅拌半小时后加入Et3N(438mg,4.33mmol)。缓慢升至25℃,加入0.5mL水淬灭反应。过滤,滤饼用5mL CH3CN溶解,滤除不溶物蒸干得粗品;DCM用水(25mL×2)洗,食盐水(25mL)洗,蒸干。合并粗品用prep-HPLC纯化两次得白色固体产物A386(105mg,收率:26%)。
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.49-7.58(m,2H),7.34-7.40(m,2H),7.17-7.21(m,2H),5.26(s,2H),5.07-5.13(m,1H),4.38(d,J=17.7Hz,1H),4.22(d,J=17.7Hz,1H),3.58(br s,4H),3.49(br s,2H),2.84-2.96(m,1H),2.56-2.60(m,1H),2.30-2.43(m,5H),1.92-2.02(m,1H).
实施例75化合物A425
3-deuterium-3-(4-((2-fluoro-5-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A425.
参照前述实施例67中的合成方法,用相应的外消旋混合物A403A为底物,就可以合成实施例75中的化合物A425。
1H NMR(DMSO-d6,300MHz):δ10.95(s,1H),7.49-7.57(m,2H),7.33-7.40(m,2H),7.18-7.22(m,2H),5.26(s,2H),4.37(d,J=17.7Hz,2H),4.21(d,J=17.7Hz,1H),3.58-3.62(m,4H),3.49(s,2H),2.84-2.96(m,1H),2.27-2.58(m,6H),1.93-1.99(m,1H).LCMS=469.2([M+1]+).
实施例76化合物A427
3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A427.
参照前述实施例67中的合成方法,用相应的底物替换4-(3-(氯甲基)-4-氟苯基)吗啉盐酸盐[4-(3-(chloromethyl)-4-fluorobenzyl)morpholine hydrochloride]。就可以合成实施例76中的化合物,A427。
1H NMR(DMSO-d6,300MHz):δ10.97(s,1H),7.49-7.58(m,2H),7.34-7.41(m,2H),7.17-7.21(m,2H),5.26(s,2H),4.38(d,J=17.7Hz,1H),4.21(d,J=17.7Hz,1H),3.54-3.61(m,2H),3.47(s,2H),2.84-2.96(m,1H),2.53-2.68(m,3H),2.38-2.44(m,1H),1.93-1.99(m,1H),1.66(t,J=10.5Hz,2H),1.02(d,J=6.0Hz,6H).LCMS:497.2([M+1]+).
实施例77化合物A426
3-deuterium-3-(4-((2-fluoro-4-(morpholinomethyl)benzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A426.
参照前述实施例70中的合成方法,用相应的外消旋混合物A400A为底物,就可以合成实施例77中的化合物A426。
1H NMR(DMSO-d6,300MHz):δ11.00(s,1H),7.32(t,J=8.1Hz,1H),7.22(t,J=7.8Hz,1H),7.05-7.13(m,2H),6.93(d,J=7.5Hz,1H),6.64(d,J=8.1Hz,1H),6.27(t,J=6.0Hz,1H),5.07-5.13(m,0.01H),4.38(d,J=5.4Hz,2H),4.28(d,J=17.1Hz,1H),4.16(d,J=17.1Hz,1H),3.52-3.55(m,4H),3.42(s,2H),2.85-2.97(m,1H),2.56-2.65(m,1H),2.23-2.35(m,5H),1.99-2.06(m,1H).LCMS:468.2([M+1]+).
实施例78化合物A428
3-deuterium-3-(4-((4-((2,6-dimethylmorpholino)methyl)-2-fluorobenzyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione,A428.
参照前述实施例70中的合成方法,用相应的底物替换步骤A中的2-氟-3-(吗啉甲基)苯甲醛,就可以合成实施例78中的化合物,A428。
1H NMR(DMSO-d6,300MHz):δ11.02(s,1H),7.34(t,J=7.8Hz,1H),7.24(t,J=7.8Hz,1H)7.06-7.13(m,2H),6.95(d,J=7.5Hz,1H),6.67(d,J=7.8Hz,1H),6.28(t,J=5.7Hz,1H),4.40(d,J=5.1Hz,2H),4.30(d,J=17.1Hz,1H),4.18(d,J=17.1Hz,1H),3.52-3.61(m,2H),3.42(s,2H),2.87-2.99(m,1H),2.59-2.65(m,3H),2.35-2.25(m,1H),2.01-2.06(m,1H),1.63(t,J=10.5Hz,2H),1.01(d,J=6.0Hz,6H).LCMS:496.2([M+1]+).
效果实施例
TNF-α活性抑制实验方法
采集健康志愿者的外周血并用EDTA抗凝管收集。将血液用1640培养基(Gibco,产品目录号11875-093,USA)稀释5倍后加入到96孔细胞培养板中(Costar,产品目录号3599,USA),然后用10μL本发明通式(I)化合物的DMSO(Sigma,产品目录号D2650,USA)溶液处理,化合物的终浓度为100nM,DMSO的终浓度为0.2%。在37℃,5%CO2培养箱中孵育60分钟后,于反应体系中加入10μL LPS(Sigma,产品目录号L-2880,USA),终浓度10ng/mL,再在37℃,5%CO2条件下继续培养6小时后。收集上清液,TNF-α含量通过ELISA方法(BD Biosciences,产品目录号555212,USA)测定。用读板仪器检测吸收光强度,检测OD450 nm值,以OD650 nm值作为参考,以含0.2%DMSO培养基的溶液对照组作为0%抑制。记录原始数据和标准曲线。通过XL-fit软件,绘制四参数药物抑制曲线并计算每个化合物的抑制率,具体见表1。
表1
细胞增殖实验方法
将MM.1S细胞(骨髓瘤细胞)(ATCC,产品目录号CRL-2974)按每孔1.8×103个接种至含有RPMI-1964培养基(Gibco,产品目录号A10491-01)的96-孔培养板中,置于37℃,5%CO2培养箱内培养24小时。化合物用DMSO(Sigma,产品目录号D2650)配成20mM的储备液,用培养基稀释至所需浓度(DMSO终浓度为0.5%)后加入各孔,在37℃,5%CO2培养箱内孵育72小时。之后,每孔加入20μl MTS(Promega,产品目录号G3581),在37℃,5%CO2培养箱内再培养1-4小时。检测OD490 nm,以OD650 nm值作为参考,以含0.5%DMSO培养基的溶液对照组作为0%抑制。用GraphPad Prism5软件,允许变斜率制作量效曲线并计算IC50值,具体见表2。
表2
注:A:<300nM;B::≥300nM。
CTG细胞增殖实验方法
将Rec-1细胞(套细胞淋巴瘤细胞)(ATCC,产品目录号CRL-3004),Namalwa.CSN/70细胞(伯基特淋巴瘤细胞)(DSMZ,产品目录号ACC-70),WSU-DLCL-2细胞(弥漫性大B细胞淋巴瘤细胞)(DSMZ,产品目录号ACC-575),按每孔(5-15)×103个接种至含有特定培养基的底透壁白的96-孔培养板(Corning,产品目录号CLS3903)中,置于37℃,5%CO2培养箱内培养24小时。化合物用DMSO(Sigma,产品目录号276855)配成150mM的储备液,用培养基稀释至所需浓度(DMSO终浓度为0.2%)后加入各孔,在37℃,5%CO2培养箱内孵育72-120小时。之后,每孔加入100μl CellTiter-细胞活性检测试剂(Promega,产品目录号G7570),在振板机上混匀10分钟,诱导细胞溶解。将96孔板在室温中放置10分钟,使其发光信号稳定。粘贴白色的底膜于培养板底部,使用EnSpire测板。通过XLfit软件进行数据处理,获得IC50值,具体见表3。
表3
注:A:<100nM;B:100-400nM;C:401nM-300μM;D:>300μM。
Claims (8)
2.药物组合物,其特征在于,其包括治疗和/或预防有效量的如权利要求1所述的异吲哚啉衍生物或其药学上可接受的盐。
3.如权利要求2所述的药物组合物,其特征在于,所述的药物组合物还进一步包含其他治疗剂,所述的其它治疗剂为elotuzumab、palbociclib、nivolumab、pembrolizumab、panobinostat、培美曲塞、托泊替康、阿霉素、硼替佐米、吉西他滨、达卡巴嗪、地塞米松、克拉霉素、长春新碱、阿糖胞苷、利妥昔单抗、曲妥珠单抗、泼尼松、多西他赛、氯法拉滨注射液、Ublituximab、romidepsin、红血球生长激素、eltrombopag、米诺四环素、CAR-T和美法仑中的一种或多种。
4.如权利要求2所述的药物组合物,其特征在于,所述的药物组合物还进一步包含其他治疗剂,所述的其它治疗剂为PD-1抑制剂、PDL-1抑制剂、HDAC抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂和BTK抑制剂中的一种或多种。
5.如权利要求1所述的异吲哚啉衍生物或其药学上可接受的盐在制备治疗或预防由TNF-α产生的、或由TNF-α活性调节异常相关的疾病的药物中的应用。
6.如权利要求5所述的应用,其特征在于,所述的疾病为实体瘤。
7.如权利要求5所述的应用,其特征在于,所述的疾病选自骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、慢性淋巴细胞白血病、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、骨髓纤维化、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、慢性粒单核细胞白血病、滤泡性淋巴瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、甲状腺癌、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、伯基特淋巴瘤、霍奇金淋巴瘤、大细胞淋巴瘤、弥漫性大B细胞淋巴瘤、星状细胞瘤、肝细胞癌和原发性巨球蛋白血症中的一种或多种。
8.如权利要求5所述的应用,其特征在于,所述的疾病选自脑肿瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、眼外延伸黑色素瘤中的一种或多种。
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AU2015341301B2 (en) | 2019-05-16 |
CN105566290A (zh) | 2016-05-11 |
ES2812877T3 (es) | 2021-03-18 |
DK3643709T3 (da) | 2021-12-20 |
EP3214081A1 (en) | 2017-09-06 |
EP3643709A1 (en) | 2020-04-29 |
NZ731789A (en) | 2019-04-26 |
US10017492B2 (en) | 2018-07-10 |
PL3214081T3 (pl) | 2021-04-06 |
CN111205268A (zh) | 2020-05-29 |
EP3643709B1 (en) | 2021-10-20 |
JP2017533955A (ja) | 2017-11-16 |
CA2966038C (en) | 2020-04-21 |
KR102191256B1 (ko) | 2020-12-15 |
JP6546997B2 (ja) | 2019-07-17 |
AU2015341301A1 (en) | 2017-06-01 |
CA2966038A1 (en) | 2016-05-06 |
PL3643709T3 (pl) | 2022-02-21 |
CN105566290B (zh) | 2020-05-22 |
RU2695521C9 (ru) | 2019-08-19 |
CY1123361T1 (el) | 2021-12-31 |
DK3214081T3 (da) | 2020-09-28 |
PT3214081T (pt) | 2020-08-31 |
RU2017118453A (ru) | 2018-12-04 |
RU2017118453A3 (zh) | 2019-01-17 |
EP3214081B1 (en) | 2020-07-08 |
WO2016065980A1 (zh) | 2016-05-06 |
ES2901509T3 (es) | 2022-03-22 |
US20170313676A1 (en) | 2017-11-02 |
PT3643709T (pt) | 2021-12-20 |
RU2695521C2 (ru) | 2019-07-23 |
EP3214081A4 (en) | 2018-08-15 |
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Address after: Room 401, 4th Floor, Building B1, Block B, Yungu Innovation Park, No. 868 Sichuan Road, Baohe District, Hefei City, Anhui Province, 230022 Patentee after: Kangpu Biopharmaceutical Technology (Hefei) Co.,Ltd. Country or region after: China Address before: Room 818, 780 Cailun Road, Zhangjiang High-tech Park, Pudong New Area, Shanghai, 201203 Patentee before: KANGPU BIOPHARMACEUTICALS, Ltd. Country or region before: China |