CN114641474B - 一类具有免疫调节功能的含n杂环化合物的制备和应用 - Google Patents
一类具有免疫调节功能的含n杂环化合物的制备和应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
一种结构如式I所示的化合物,具有在调节免疫和抑制PD‑1/PD‑Ll方面的用途。
Description
技术领域
本发明涉及小分子蛋白抑制剂领域,具体地,本发明提供了一种具有免疫调节功能的杂环化合物的制备和应用。
背景技术
免疫系统具有监视、防御、调控等作用。细胞免疫主要参与对胞内寄生的病原微生物的免疫应答及对肿瘤细胞的免疫应答,参与迟发型变态反应和自身免疫病的形成,参与移植排斥反应及对体液免疫的调节。T淋巴细胞被抗原递呈细胞的激活通常受两种不同信号的调节。初级信号由APC细胞上的主要组织相容性复合体(MHC)呈递外来抗原肽通过T细胞受体(TCR)转导。次级信号,又称共刺激信号,通过APC细胞上的共刺激分子与T细胞表面受体结合,传递给T细胞,调节T细胞增殖,细胞因子分泌和效应功能。次级信号包括正调节和负调节两种方式,正信号促进T细胞激活,负信号诱导T细胞耐受,对人体适应和调整自身免疫细胞对外界不同抗原的反应作用至关重要。
程序性细胞死亡蛋白配体1(Programmed death-ligand 1,PD-L1),又可称为分化簇274(cluster of differentiation 274,CD274)或者B7同源蛋白1(B7 homolog1,B7-H1),属于肿瘤坏死因子超家族,是由290个氨基酸残基组成的I型跨膜糖蛋白,包含一个IgV样区、一个IgC样区、一个跨膜疏水区和一个30个L氨基酸的胞内尾部,完整分子量为40kDa。PD-L1 mRNA在几乎所有组织中都有表达,但PD-L1蛋白只在少部分组织中持续表达,包括肝脏、肺脏、扁桃体以及免疫特赦组织如眼、胎盘等。PD-L1也表达于活化的T细胞,B细胞,单核细胞,树突状细胞,巨噬细胞等。
PD-L1的受体为PD-1,主要表达于活化的CD4+T细胞、CD8+T细胞、NK细胞、B细胞和活化的单核细胞等免疫细胞表面。PD-L1与PD-1结合可以启动PD-1胞浆区ITIM(免疫受体酪氨酸抑制作用模块)酪氨酸残基的磷酸化,促使酪氨酸磷脂酶与SHP2结合,活化SHP2,使下游Syk和PI3K发生去磷酸化从而传递终止信号,限制抗原呈递细胞或者树突状细胞与T细胞的相互作用。这种结合还可以进一步抑制T细胞的代谢,抑制抗凋亡蛋白Bcl-2的分泌,减少效应细胞因子IL-2,IFN-γ的分泌,诱导T细胞耗竭和凋亡,从而降低免疫T细胞参与的免疫应答,行使负性调节功能。
T细胞识别抗原并活化后会分泌IFN-γ。T细胞来源的IFN-γ会扩增和维持T细胞功能,比如上调MHC分子,增强目标细胞的抗原处理和呈递,促进T细胞分化。IFN-γ同时也会诱导免疫炎症部位组织的PD-L1表达,防止过度免疫对组织造成伤害。IFN-γ可以诱导常规上皮细胞,血管内皮细胞,髓样细胞,幼稚T细胞等细胞表面PD-L1的表达。IFN-γ诱导产生的干扰素调节因子1(IRF-1)也可以与PD-L1转录起始位点前200bp和320bp处的干扰素调节因子结合位点结合,从转录水平调节PD-L1。PD-L1可以与T细胞表面的PD-1结合行使负调节功能,从而保护炎性部位。
PD-L1的负性调控功能在肿瘤免疫中发挥着重要作用。2004年,Konishi等率先在非小细胞肺癌病人的组织样本中发现PD-L1的表达,随后PD-L1被发现表达于各种肿瘤病人的组织中,包括胃癌,肺癌,肝癌,肝内胆管癌,结肠癌,胰腺癌,卵巢癌,乳腺癌,子宫颈癌,头颈鳞状细胞癌,鼻咽癌,食管癌,膀胱癌,肾细胞癌,皮肤癌,口腔鳞状细胞癌等。细胞恶变过程中,由于基因突变、外源基因(病毒)表达或静止基因激活等原因会产生新的蛋白分子,这些蛋白质在细胞内降解后,某些降解的肽段可以表达于细胞表面,成为肿瘤抗原。免疫系统可以通过免疫监察识别肿瘤抗原并清除肿瘤细胞,而肿瘤细胞则利用PD-L1逃避免疫攻击。
肿瘤部位PD-L1的表达可以通过多种途径保护肿瘤细胞免受伤害。肿瘤浸润淋巴细胞(TIL)分泌IFN-γ可诱导肿瘤细胞及周围基质细胞表达PD-L1。而肿瘤细胞的PD-L1可以与TIL上PD-1结合,抑制TIL细胞的活化,并进一步导致其凋亡。体外实验证明,肿瘤细胞相关PD-L1可以增加肿瘤特异T细胞的调亡,而PD-L1单克隆抗体可以减弱这种作用。肿瘤相关PD-L1可以促进T细胞表达IL-10,进一步抑制免疫反应。PD-L1不仅仅是PD-1的配体,他也可以作为受体传递反向的信号保护肿瘤细胞免受FAS-FASL等其他抗肿瘤途径诱导的凋亡。
目前多个已上市的靶向PD-1或者PD-L1的单克隆抗体药物证实PD-1/PD-L1的阻断剂可用于多种肿瘤的临床治疗。然而抗体药物有其自身的特点,如生产成本高,稳定性较差,需经注射给药及易产生免疫原性等。而小分子药物具有组织渗透性好,储存运输方便,生产成本较低,无免疫原性及通常可口服给药等优势,因此研究开发PD-1/PD-L1的小分子阻断剂具有显著的应用价值和社会价值。
发明内容
本发明的目的是提供一种小分子的PD-1/PD-L1阻断剂。
本发明的第一方面,提供了一种如下式I所示的化合物,其立体异构体或其互变异构体,或其药学上可接受的盐、水合物或溶剂化物:
X1、X3和X4各自独立地选自下组:N、CH;
X5和X6各自独立地选自下组:N、C;
Y1和Y2各自独立地为N、CH、C=O、S(=O)、S(=O)2、CH2、O或S;
Z1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9和Z10各自独立地为N或CH;
R1、R4、R6和R7表示一个或多个位于环上的选自下组的取代基:H、D、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取的C1-C6烷氧基;
R2选自下组:H、D、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基;或所述的R2基团上有一个或多个氢原子被R5取代;且所述的R2基团可以位于X1、X3。
所述的R3为其中,W1为选自下组的基团:CR2、C(O);
所述的R5为其中,W2为选自下组的基团:CR2、C(O);
其中各个R各自独立地选自下组:H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基;
Ra、Rb、Rc和Rd各自独立地选自下组:H、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
或所述的Ra和Rb与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基;
或所述的Rc和Rd与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基;
除非特别说明,所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代:羧基、卤素、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、甲基砜基、-S(=O)2NH2、氧代(=O)、-CN、羟基、-NH2、C1-C6胺基、C1-C6酰胺基(-C(=O)-N(Rc)2或-NH-C(=O)(Rc),Rc为H或C1-C5的烷基)、C1-C6磺酰胺基、(-S(=O)n-N(Rc)2或-NH-S(=O)n(Rc),Rc为H或C1-C5的烷基,n为1或2)、或取代或未取代的选自下组的基团:C1-C6烷基、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、3-10元环烷基、具有1-3个选自N、S和O的杂原子的3-10元杂环基、-(CH2)-C6-C10芳基、-(CH2)-3-10元环烷基、-(CH2)-(具有1-3个选自N、S和O的杂原子的5-10元杂芳基)、-(CH2)-(具有1-3个选自N、S和O的杂原子的3-10元杂环基),且所述的取代基选自下组:卤素、C1-C6烷基、C1-C6烷氧基、羧基、氧代、-CN、-OH、C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基;
为基团的连接位点;
各个各自独立地为单键或双键;
附加条件是式I化合物为化学上稳定的结构。
在另一优选例中,所述的化合物具有如下式II-1或II-2所示的结构:
在另一优选例中,Z1、Z2、Z3、Z4、Z5、Z6为CH;
Z7、Z8、Z9和Z10各自独立地为N或CH;且所述的Z7、Z8、Z9和Z10中有1-2个N。
在另一优选例中,Z7为N,且Z8、Z9和Z10为CH。
在另一优选例中,R6和R7各自独立地为卤素,CN,甲基。
在另一优选例中,所述的具有选自下组的结构(该结构中未包括R3取代基):
在另一优选例中,所述的为选自下组的杂环所形成的结构:
在另一优选例中,所述的R3选自下组:
在另一优选例中,所述的选自下组:
在另一优选例中,所述的R5为:
在另一优选例中,所述的式I化合物选自下组:
本发明的第二方面,提供了一种药物组合物,包含(1)如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物或如本发明第二方面所述的药物组合物用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物的用途。在另一优选例中,所述的疾病选自下组:肿瘤、病原体感染、自身免疫应答相关疾病。
在另一优选例中,所述的药物组合物用于选自下组的疾病的治疗:黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素不应性前列腺腺癌)、乳癌、结肠癌和肺癌(例如非小细胞肺癌)。骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃肠、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金氏病、非何杰金氏淋巴瘤、食道癌、小肠癌、内分泌系统的癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)的赘生物/肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊髓轴(spinalaxis)肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏(Kaposi)肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的那些癌症)、及所述癌症的组合。转移性癌症,尤其是表达PD-L1的转移性癌症
在另一优选例中,所述的药物组合物用于联合用药方案,较佳地,所述的联合用药方案包括:联合肿瘤化疗方案,其他肿瘤免疫治疗剂(小分子化合物及抗体等),放疗方案,肿瘤靶向药,肿瘤疫苗(如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV))。
在另一优选例中,所述的药物组合物用于单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗。其中包括但不限于各种病毒,病原体细菌,病原体真菌,病原体寄生虫等的治疗。如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
在另一优选例中,所述的药物组合物用于诱导治疗性自身免疫应答。
在另一优选例中,所述的药物组合物用于治疗具有不恰当的其他自身抗原积累的患者,如淀粉状蛋白沉积物,包括阿尔茨海默病中的Aβ、细胞因子如TNFa和IgE。
本发明的第四方面,提供了一种PD-1/PD-L1抑制剂,所述抑制剂包含如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,设计并合成了一类新型PD-1小分子抑制剂。在此基础上,发明人完成了本发明。
术语
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“C1-C8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的3-10元杂环基”是指具有3-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一种如下式I所示的化合物,其立体异构体或其互变异构体,或其药学上可接受的盐、水合物或溶剂化物:
为基团的连接位点;
各个各自独立地为单键或双键;
附加条件是式I化合物为化学上稳定的结构。
优选的式I化合物为本申请实施例中所示的具体化合物。
式I化合物的制备
本发明还提供了一种制备如本发明第一方面所述化合物的方法,具体地,所述化合物可以通过用式1化合物经还原胺化得到式2化合物,再经金属催化反应得到式3化合物,同时化合物4经还原胺化反应得到化合物5,然后化合物3和化合物5经金属催化偶联反应得到第一方面所述的化合物。
其中,X1、X3和X4各自独立地选自下组:N、CH;
X5和X6各自独立地选自下组:N、C;
Y1和Y2各自独立地为N、CH、C=O、S(=O)、S(=O)2、CH2、O或S;
Z 1、Z2、Z3、Z4、Z5、Z6、Z7、Z8、Z9和Z10各自独立地为N或CH;
R1、R4、R6和R7表示一个或多个位于环上的选自下组的取代基:H、D、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取的C1-C6烷氧基;
R2选自下组:H、D、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基;或所述的R2基团上有一个或多个氢原子被R5取代;且所述的R2基团可以位于X1或X3;
所述的R3为其中,W1为选自下组的基团:CR2、C(O);
所述的R5为其中,W2为选自下组的基团:CR2、C(O);
其中各个R各自独立地选自下组:H、卤素、CN、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基;
Ra、Rb、Rc和Rd各自独立地选自下组:H、-(C=O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基;
或所述的Ra和Rb与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基;
或所述的Rc和Rd与相邻的N原子共同构成取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基。
药物组合物和施用方法
由于本发明化合物具有优异的PD-1的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗与PD-1/PD-L1信号通路相关的疾病(例如,癌症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
联合给药时,所述药物组合物还包括与一种或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
在本发明的优选实施方式中,所述的药物组合物可以用于:
(1)用于治疗各种肿瘤,包括但不限制于黑素瘤(例如转移性恶性黑素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素不应性前列腺腺癌)、乳癌、结肠癌和肺癌(例如非小细胞肺癌)。骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内恶性黑素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃肠、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金氏病、非何杰金氏淋巴瘤、食道癌、小肠癌、内分泌系统的癌症、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病(包括急性髓细胞样白血病、慢性髓细胞样白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病)、儿童期实体瘤、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾盂癌、中枢神经系统(CNS)的赘生物/肿瘤、原发性CNS淋巴瘤、肿瘤血管发生、脊髓轴(spinalaxis)肿瘤、脑干胶质瘤、垂体腺瘤、卡波西氏(Kaposi)肉瘤、表皮样癌、鳞状细胞癌、T细胞淋巴瘤、环境诱发的癌症(包括由石棉诱发的那些癌症)、及所述癌症的组合。转移性癌症,尤其是表达PD-L1的转移性癌症
(2)用于联合用药方案,例如联合肿瘤化疗方案,其他肿瘤免疫治疗剂(小分子化合物及抗体等),放疗方案,肿瘤靶向药,肿瘤疫苗等,如人类乳头瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV)。可以在所述药剂之前、之后或同时施用,或者可以与其它已知疗法共施用。
(3)用于单独或联合使用用于治疗暴露于特定毒素或病原体的患者的治疗。其中包括但不限于各种病毒,病原体细菌,病原体真菌,病原体寄生虫等的治疗。如HIV、肝炎病毒(甲、乙、丙)、流感病毒、疱疹病毒、贾第虫、疟疾、利什曼原虫、金黄色葡萄球菌、绿脓杆菌等病原体已建立的感染。
(4)用于诱导治疗性自身免疫应答,以治疗具有不恰当的其他自身抗原积累的患者,如淀粉状蛋白沉积物,包括阿尔茨海默病中的Aβ、细胞因子如TNFa和IgE。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
各实施例中:
分析方法I
LCMS仪器:Agilent 6110,UV检测器:G1315D
层析柱:Xbridge C18 3.0×50mm,2.5uM,柱温30℃
流动相:A:H2O(0.05%TFA),B:乙腈,梯度洗脱:0-1min 10%B,1-8min 10-95%B,9min 95%B
中间体A、B的合成:
叔-丁基2-氯-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸酯
化合物A1(25克,86毫摩尔)溶解在500毫升的甲醇中,再在零度下加入甲醇钠(19毫升,5.OM的甲醇溶液),然后反应在室温下搅拌过夜,LCMS检测到反应产物。反应液倒入水中(200毫升),以二氯甲烷萃取(200毫升*3),有机相用无水硫酸钠干燥后过滤蒸除溶剂,残渣通过柱层析(PE∶EA=5∶1)纯化得到化合物A2(23.5克,95%)。
6-(叔-丁基)2-甲基4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-2,6-二羧酸酯
化合物A2(12.5克,43.8毫摩尔)溶解在甲醇(180毫升)中,加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(3.20克,4.38毫摩尔),三乙胺(13.3克,131.5毫摩尔)。反应液在100摄氏度、5.0MPa的-氧化碳氛围中搅拌16小时,LCMS检测到反应产物,过滤出催化剂,滤液旋干浓缩。残渣通过柱层析(PE∶EA=5∶1)纯化得到化合物A3(9.0克,66%)。
叔-丁基2-(羟甲基)-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-羧酸酯
化合物A3(5.0克,16毫摩尔)溶解在甲醇(30毫升)中,加入硼氢化钠(676毫克,17毫摩尔),然后反应液在室温下搅拌30分钟。TLC检测反应完全。反应液旋干浓缩,柱层析(PE∶EA=10∶1)纯化得到化合物A4(4.3克,93%)。
(4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲醇
化合物A4(4.3克,15毫摩尔)溶解在二氯甲烷(10毫升)中,缓慢滴加HCl的1,4-二氧六环溶液(50毫升),然后反应液在室温下搅拌30分钟,TLC检测反应完全。反应液旋干浓缩,pH调到9-10,柱层析(DCM∶甲醇=10∶1)纯化得到化合物A5(4.2克)。
(6-(3-溴-2-氯苯基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲醇
化合物A5(3.4克,43.8毫摩尔)溶解在甲苯(500毫升)中,加入2,6-二溴-1-氯苯(20.1克,75.1毫摩尔),醋酸钯(420毫克,1.88毫摩尔),1,1′-联萘-2,2′-双二苯膦(2.33克,3.76毫摩尔),碳酸铯(18.3克,56.3毫摩尔),反应液在110度氮气氛围中搅拌16小时,LCMS检测到反应产物。反应液过滤,滤液旋干浓缩,柱层析(PE∶EA=5∶1)纯化得到化合物A(5.7克,82%)。
6-(3-溴-2-氯苯基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-甲醛
化合物A(500毫克,1.35毫摩尔)溶解在二氯甲烷(10毫升)中,加入戴斯-马丁氧化剂(1.15克,2.7毫摩尔)然后反应液在室温下搅拌1小时,LCMS检测到反应产物,滤液旋干浓缩,柱层析(PE∶EA=1∶1)纯化得到化合物B(150毫克,31%)。
中间体C的合成:
6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛
2-(3-溴-2-氯-苯基)-4,4,5,5-四甲基-[1,3,2]二噁硼戊环
往1,3-二溴-2-氯苯(5克,18.52毫摩尔)的1,4-二氧六环(200毫升)溶液中加入1,1′-二(二苯膦基)二茂铁二氯化钯(II)(678毫克,0.93毫摩尔),联硼酸频那醇酯(4.7克,18.52毫摩尔),醋酸钾(5.44克,55.56毫摩尔)。混合物在氮气球保护下90摄氏度搅拌过夜。反应液冷却后倒入水中(200毫升),用乙酸乙酯(200毫升*3)萃取。有机相用无水硫酸钠干燥,抽滤,浓缩。残留物通过正相硅胶层析柱(石油醚∶乙酸乙酯=100∶1)纯化得到白色固体目标化合物C1(2.7克,46%)。
1HNMR(400MHz,CDCl3):δ7.67-7.65(m,1H),7.60-7.58(m,1H),7.11-7.07(m,1H),1.36(s,12H).
6-(3-溴-2-氯苯基)-2-甲氧基尼古丁醛
将C1(1.71克,5.39毫摩尔),6-氯-2-甲氧基吡啶-3-甲醛(1.02克,5.93毫摩尔),四-三苯基膦钯(312毫克,0.27毫摩尔),1,4-二氧六环(27毫升),水(2.7毫升),碳酸钾(1.49克,10.77毫摩尔)的混合物在氮气球保护下95摄氏度搅拌3小时。反应液冷却至室温后用二氯甲烷(100毫升)稀释,然后用水(50毫升)和饱和食盐水(50毫升)洗涤。有机相用无水硫酸钠干燥,抽滤,浓缩。残留物通过正相硅胶层析柱(石油醚∶乙酸乙酯=100∶1)纯化得到白色固体目标化合物C2(1.24克,70%)。
1HNMR(400MHz,CDCl3):δ10.41(s,1H),8.20-8.18(m,1H),7.73-7.71(m,1H),7.52-7.50(m,1H),7.30-7.22(m,2H),4.10(s,3H).
6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛
往C2(720毫克,2.2毫摩尔)的1,4-二氧六环(20毫升)溶液中加入1,1′-二(二苯膦基)二茂铁二氯化钯(II)(161毫克,0.22毫摩尔),联硼酸频那醇酯(616毫克,2.43毫摩尔),醋酸钾(606毫克,6.17毫摩尔)。混合物在氮气球保护下95摄氏度搅拌过夜。反应液冷却后倒入水中(50毫升),用乙酸乙酯(50毫升*3)萃取。有机相用无水硫酸钠干燥,抽滤,浓缩。残留物通过正相硅胶层析柱(石油醚∶乙酸乙酯=100∶1)纯化得到白色固体目标化合物C(500毫克,46%)。
1HNMR(400MHz,CDCl3):δ10.41(s,1H),8.16(d,J=8Hz,1H)7.72-7.70(m,1H),7.62-7.60(m,1H),7.37-7.31(m,2H),4.09(s,3H),1.37(s,12H).
中间体D的合成:
2-氯-3-(5-甲酰基-2H-吡唑并[3,4-b]吡啶-2-基)苯基三氟甲磺酸酯
2-叠氮-5-溴尼古丁醛
将化合物D1(15克,73.5毫摩尔),TBAI(2.71克,7.34毫摩尔)溶于DMSO(90毫升)中。向上述溶液中加入叠氮化钠(5.73克,88.1毫摩尔),反应液于室温下搅拌1小时。LCMS检测反应结束后,反应液倒入碎冰(600毫升)中,搅拌过滤,滤饼以冰水(50毫升)洗涤,并在40℃下油泵干燥,得到土黄色固体D2(21克,59%)。ESI-MS m/z=227,229[M+H]+.
5-溴-2-(2-氯-3-甲氧苯基)-2H-吡唑并[3,4-b]吡啶
将化合物D2(10克,44.05毫摩尔),化合物D3(6.96克,44.05毫摩尔)溶于对二甲苯(350毫升),反应液于145℃搅拌过夜。LCMS检测反应结束后,反应液蒸干,粗品用柱纯化(二氯甲烷/乙酸乙酯=5/1),得到黄色固体化合物D4(2克,13%)。ESI-MS m/z=338,340[M+H]+.
甲基2-(2-氯-3-甲氧苯基)-2H-吡唑并[3,4-b]吡啶-5-羧酸酯
将化合物D4(5.3克,15.7毫摩尔),溶于DMF/甲醇(300毫升/50毫升)中,加入Pd(dppf)Cl2(1.14克,1.56毫摩尔),三乙胺(11毫升,79.3毫摩尔),反应液于100摄氏度下,CO(5.0MPa)搅拌过夜。LCMS检测反应~50%,蒸出甲醇,以水(1L)稀释,用二氯甲烷(200毫升x3)萃取,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,粗品用柱纯化(二氯甲烷/石油醚/乙酸乙酯=5/5/2),得到棕色固体化合物D5(2.58克,52%)。ESI-MS m/z=318,320[M+H]+.
(2-(2-氯-3-甲氧苯基)-2H-吡唑并[3,4-b]吡啶-5-基)甲醇
将化合物D5(700毫克,2.21毫摩尔)溶于二氯甲烷(40毫升)中,冷却至-70摄氏度,向其中加入1.5M DIBAl-H的甲苯溶液(2.9毫升,4.35毫摩尔),反应液于-70摄氏度搅拌1h。LCMS检测~20%产物,额外1.5M DIBAl-H的甲苯溶液(15毫升,3.0毫摩尔)滴入反应液中,反应液于-70摄氏度搅拌1h。以反应结束后,以饱和氯化铵溶液(100毫升),酒石酸钾钠/二氯甲烷(200毫升/100毫升)稀释,用二氯甲烷(100毫升x 3)萃取,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,粗品用柱纯化(二氯甲烷/甲醇=10/1),得到黄色固体化合物D6(580毫克,30%)。ESI-MS m/z=290,292[M+H]+.
2-(2-氯-3-甲氧苯基)-2H-吡唑并[3,4-b]吡啶-5-甲醛
将化合物D6(1.06克,3.67毫摩尔)溶于二氯甲烷(80毫升)中,向其中加入Dess-Martin(1.82克,4.29毫摩尔),反应液于室温下搅拌2h。TLC检测反应结束,反应液以饱和碳酸氢钠(40毫升)淬灭,用二氯甲烷(20毫升*3)萃取,合并有机层,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,粗品用柱纯化(二氯甲烷/甲醇=10/1)得到黄色固体化合物D7(0.96克,77%)。ESI-MS m/z=288,290[M+H]+.
2-(2-氯-3-羟基苯基)-2H-吡唑并[3,4-b]吡啶-5-甲醛
将D7(940毫克,3.26毫摩尔)溶于二氯甲烷(2毫升)中,向其中滴加1.0M BBr3的二氯甲烷溶液(10毫升,10毫摩尔),反应液在室温下搅拌3h。LCMS检测反应结束后,用二氯甲烷/四氢呋喃/水(20毫升/10毫升/10毫升)稀释,用二氯甲烷/四氢呋喃(20毫升/4毫升x 3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,粗品用柱纯化(二氯甲烷/石油醚/乙酸乙酯=1/1/1)得到浅黄色固体化合物D8(545毫克,61%)。ESI-MS m/z=274,276[M+H]+.
2-氯-3-(5-甲酰基-2H-吡唑并[3,4-b]吡啶-2-基)苯基三氟甲磺酸酯
将化合物D8(457毫克,1.67毫摩尔),吡啶(530毫克,6.71毫摩尔)溶于二氯甲烷(50毫升)中,反应液冷却至0摄氏度,向其中滴加Tf2O(0.56毫升),反应液在室温搅拌过夜。反应液以2N HCl(40毫升),饱和碳酸氢钠(40毫升),饱和食盐水(40毫升)依次洗涤,合并有机层,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,粗品用柱纯化(二氯甲烷/石油醚/乙酸乙酯=1/1/2)得到黄色固体化合物D(557毫克,68%)。ESI-MS m/z=406,408[M+H]+.
1HNMR(400MHz,CDCl3):10.08(s,1H),9.22(s,1H),8.63(s,2H),7.82(dd,J=8.0Hz,2.0Hz,1H),7.57-7.50(m,2H).
实施例1:(S)-1-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)哌啶-4-羧酸
实施例1-1:(S)-(2-氯-3-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯基)硼酸.
向6-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)-2-甲氧基尼古丁醛(1.00克,2.58毫摩尔),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸(1.94克,12.90毫摩尔),N-乙基-N-异丙基丙烷-2-胺(1.67克,12.90毫摩尔)的混合物中加入无水N,N-二甲基甲酰胺(10毫升)。反应液加热到50℃并搅拌16个小时。然后三乙酰氧基硼氢化钠(2.73克,12.90毫摩尔)分批加入反应液,反应继续在50℃下搅拌2小时。反应结束以后,反应液直接用反相C-18柱分离纯化(乙腈/碳酸氢铵水溶液)得到标题化合物(S)-(2-氯-3-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯基)硼酸(0.92克,92%),为白色絮状固体。MS(ESI):m/z=390.2[M+H]+.
实施例1-2:(S)-6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-甲醛.
把1-1(363毫克,0.93毫摩尔),(6-(3-溴-2-氯苯基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲醛(230毫克,0.62毫摩尔),[1,1′-双(二-苯基膦基)二茂铁]氯化钯(II)的二氯甲烷复合物(1∶1)(50毫克,0.062毫摩尔),碳酸钾(257毫克,1.86毫摩尔),1,4-二氧六环(6毫升)和水(0.6毫升)的混合物在氮气保护下加热到90摄氏度并搅拌2个小时。反应液过滤并用甲醇冲洗两遍,滤液浓缩。残渣通过正相快速分离纯化(石油醚∶乙酸乙酯=1∶1)得到标题化合物(S)-6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-甲醛(240毫克,61%),为淡黄色固体。MS(ESI):m/z=633.1[M+H]+.
实施例1-3:甲基(S)-1-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)哌啶-4-羧酸酯.
把1-2(120毫克,0.19毫摩尔),甲基哌啶-4-羧酸酯(134毫克,0.95毫摩尔),无水N,N-二甲基甲酰胺(5毫升)的混合物加热到50℃并搅拌16个小时。然后三乙酰氧基硼氢化钠(201毫克,0.95毫摩尔)分批加入反应液中。反应继续在50℃下搅拌2小时。反应结束以后,反应液直接用反相C-18柱分离纯化(乙腈/碳酸氢铵水溶液)得到标题化合物甲基(S)-1-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)哌啶-4-羧酸酯(30毫克,4%),为白色絮状固体。MS(ESI):m/z=760.2[M+H]+.
实施例1:(S)-1-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)哌啶-4-羧酸.
向实施例1-3(30毫克,0.039毫摩尔)的甲醇(2毫升),四氢呋喃(2毫升)和水(0.5毫升)的混合溶液中,加入氢氧化锂一水合物(7毫克,0.156毫摩尔)。反应液加热到40℃并搅拌两个小时,中和,浓缩,残渣通过制备型高效液相色谱纯化获得目标产物(S)-1-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)哌啶-4-羧酸(10毫克,34%),为白色固体。MS(ESI):m/z=746.2[M+H]+.
1HNMR(400MHz,DMSO-d6)δ7.79(d,J=7.5Hz,1H),7.67(s,1H),7.61(dd,J=7.7,1.7Hz,1H),7.49(t,J=7.6Hz,1H),7.37-7.30(m,3H),7.24(d,J=7.4Hz,1H),6.92(dd,J=6.0,2.8Hz,1H),4.81-4.60(m,4H),3.96(s,3H),3.89(s,3H),3.68(s,2H),3.61(s,3H),2.86(d,J=12.6Hz,2H),2.52(d,J=6.0Hz,2H),2.22-2.06(m,6H),1.74(d,J=10.7Hz,2H),1.69-1.64(m,1H),1.57-1.49(m,2H).
实施例2:(S)-1-((2-(2,2′-二氯-3′-(6-甲氧基-5-(((((S)-5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-基)甲基)吡咯烷-3-羧酸
实施例2-1:(S)-2-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-甲醛
把2-氯-3-(5-甲酰基-2H-吡唑并[3,4-b]吡啶-2-基)苯基三氟甲磺酸酯(89毫克,0.22毫摩尔),(S)-(2-氯-3-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯基)硼酸(128毫克,0.32毫摩尔),[1,1′-双(二-苯基膦基)二茂铁]氯化钯(II)的二氯甲烷复合物(1∶1)(36毫克,0.044毫摩尔),碳酸钾(136毫克,0.987毫摩尔),1,4-二氧六环(5毫升)和水(1毫升)的混合物,在氮气保护下加热到90摄氏度并搅拌2个小时。反应液过滤,并用甲醇冲洗两遍,滤液浓缩,残渣通过正相快速分离纯化(二氯甲烷∶甲醇=10∶1)得到标题化合物(S)-2-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-甲醛(110毫克,85%),为淡黄色固体。MS(ESI):m/z=601.1[M+H]+.
实施例2-2:甲基(S)-1-((2-(2,2′-二氯-3′-(6-甲氧基-5-(((((S)-5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-基)甲基)吡咯烷-3-羧酸酯
把混合物2-1(100毫克,0.166毫摩尔)和甲基(S)-吡咯烷-3-羧酸酯盐酸(276毫克,1.66毫摩尔)的无水N,N-二甲基甲酰胺(5毫升)的溶液,加热到50℃并搅拌16个小时。然后三乙酰氧基硼氢化钠(351毫克,1.66毫摩尔)分批加入,反应继续在50℃下,搅拌2小时。反应结束以后,反应液直接用反相C-18柱分离纯化(乙腈/碳酸氢铵水溶液),得到标题化合物甲基(S)-1-((2-(2,2′-二氯-3′-(6-甲氧基-5-(((((S)-5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-基)甲基)吡咯烷-3-羧酸酯(85毫克,72%),为棕色固体。MS(ESI):m/z=714.2[M+H]+.
实施例2:(S)-1-((2-(2,2′-二氯-3′-(6-甲氧基-5-(((((S)-5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-基)甲基)吡咯烷-3-羧酸
向2-2(85毫克,0.119毫摩尔)和氢氧化锂一水合物(10毫克,0.238毫摩尔)的混合物中加入甲醇(5毫升)和水(0.2毫升)。反应液室温搅拌16小时,过滤,滤液浓缩。残渣通过制备型高效液相色谱纯化获得目标产物(S)-1-((2-(2,2′-二氯-3′-(6-甲氧基-5-(((((S)-5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-2H-吡唑并[3,4-b]吡啶-5-基)甲基)吡咯烷-3-羧酸(28.8毫克,35%),为白色固体。MS(ESI):m/z=700.1[M+H]+.
1HNMR(400MHz,DMSO-d6)δ8.76(s,1H),8.62(d,J=2.1Hz,1H),8.10(d,J=2.1Hz,1H),7.80(dd,J=7.4,2.2Hz,2H),7.70-7.61(m,4H),7.54(t,J=7.6Hz,1H),7.45(dd,J=7.6,1.7Hz,1H),7.25(d,J=7.5Hz,1H),3.88(s,3H),3.67(d,J=8.7Hz,4H),3.62-3.57(m,1H),2.95-2.86(m,J=14.8,7.9Hz,1H),2.71(t,J=8.7Hz,1H),2.61(q,J=9.3,6.4Hz,1H),2.52(d,J=6.0Hz,4H),2.12-2.01(m,3H),1.93(q,J=14.6,7.6Hz,2H),1.70-1.61(m,J=10.1,4.9Hz,1H).
以下化合物采用与实施例1类似的方法,替换相应原料获得。
实施例5:(S)-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)甘氨酸
实施例5-1:(S)-5-((((6-(2,2′-二氯-3′-(2-(羟甲基)-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)-[1,1′-联苯基]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
把(S)-(2-氯-3-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)苯基)硼酸(180毫克,0.46毫摩尔),(6-(3-溴-2-氯苯基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲醇(114毫克,0.31毫摩尔),[1,1′-双(二-苯基膦基)二茂铁]氯化钯(II)的二氯甲烷复合物(1∶1)(45毫克,0.062毫摩尔),碳酸钾(311毫克,2.25毫摩尔),1,4-二氧六环(5毫升)和水(1毫升)的混合溶液,在氮气保护下加热到90摄氏度并搅拌2个小时。反应液过滤,并用甲醇冲洗两遍,滤液浓缩,残渣通过正相快速分离纯化(二氯甲烷∶甲醇=10∶1)得到标题化合物(S)-5-((((6-(2,2′-二氯-3′-(2-(羟甲基)-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)-[1,1′-联苯基]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮(160毫克,82%),为淡黄色固体。MS(ESI):m/z=634.2[M+H]+。
实施例5-2:(S)-5-((((6-(2,2′-二氯-3′-(2-(氯甲基)-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)-[1,1′-联苯基]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
向混合物5-1(140毫克,0.22毫摩尔)加入二氯甲烷(5毫升)中滴加氯化亚砜(39毫克,0.33毫摩尔)。反应室温搅拌2小时。反应液浓缩,残渣通过正相快速分离纯化(二氯甲烷∶甲醇=10∶1)得到标题化合物(S)-5-((((6-(2,2′-二氯-3′-(2-(氯甲基)-4-甲氧基-5,7-二氢-6H-吡咯并[3,4-d]嘧啶-6-基)-[1,1′-联苯基]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮(60毫克,42%),为棕色固体。MS(ESI):m/z=652.1[M+H]+。
实施例5-3:甲基(S)-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)甘氨酸酸酯
把混合物5-2(60毫克,0.09毫摩尔),甲基甘氨酸酯盐酸盐(34毫克,0.276毫摩尔),碳酸钾(101毫克,0.735毫摩尔),碘化钠(3毫克,0.02毫摩尔)加入无水N,N-二甲基甲酰胺(5毫升)中,反应室温搅拌16小时。反应液加入水(30毫升)稀释,并用乙酸乙酯(15毫升x3)萃取,有机相合并后浓缩,残渣通过正相分离纯化(乙酸乙酯∶石油醚=3∶20)得到标题化合物甲基(S)-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)甘氨酸酸酯(60毫克,93%),为棕色固体。MS(ESI):m/z=706.2[M+H]+。
实施例5:(S)-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)甘氨酸
把混合物5-3(60毫克,0.085毫摩尔),氢氧化锂一水合物(6毫克,0.17毫摩尔),加入甲醇(5毫升)中,加入水(4滴),反应液室温搅拌16小时。过滤,浓缩,残渣通过制备型高效液相色谱纯化获得目标产物(S)-((6-(2,2′-二氯-3′-(6-甲氧基-5-((((5-羰基吡咯烷-2-基)甲基)氨基)甲基)吡啶-2-基)-[1,1′-联苯基]-3-基)-4-甲氧基-6,7-二氢-5H-吡咯并[3,4-d]嘧啶-2-基)甲基)甘氨酸(2.96毫克,5%),为白色固体。MS(ESI):m/z=692.2[M+H]+。
1HNMR(400MHz,DMSO-d6)δ7.79(d,J=7.5Hz,1H),7.66(s,1H),7.61(dd,J=7.7,1.7Hz,1H),7.48(t,J=7.6Hz,1H),7.36-7.30(m,3H),7.23(d,J=7.5Hz,1H),6.92(q,J=5.9,3.0Hz,1H),4.90-4.70(m,J=11.0Hz,4H),4.05(s,2H),3.99(s,3H),3.89(s,3H),3.69(d,2H),3.65-3.55(m,1H),2.52(d,J=6.1Hz,2H),2.13-1.91(m,5H),1.68-1.61(m,1H).
测试例1:检测化合物对PD-1/PD-L1蛋白相互结合的抑制效应
采用PD-1/PD-L1均相时间分辨荧光(Homogenous Time-Resolved Fluorescence,HTRF)检测技术来检测化合物跟PD-L1的结合能力。
选用PD1/PD-L1 binding assay试剂盒(Cisbio,Cat#63ADK000CPDEC),该试剂盒包含Tag 1-PD-L1和Tag 2-PD-1两个蛋白,及Anti-Tag1-Eu3+和Anti-Tag2-XL 665两个抗体。检测原理:Anti-tag1-Eu3+作为HTRF的供体,Anti-Tag2-XL 665作为HTRF的受体,当Tag1-PD-L1和Tag 2-PD-1相互作用时,加入的HTRF供体和受体相互靠近,供体接受到激发能量后,将部分能量转移到受体,会产生665nm发射光。当加入化合物阻断了PD1/PD-L1相互作用时,只产生620nm发射光。通过比较665nm/620nm的比值,来确定化合物的抑制效果。Tag 1-PD-L1用Diluent buffer(cat#62DLBDDF)稀释成工作浓度10nM,Tag 2-PD-1用Diluentbuffer稀释成工作浓度500nM,Anti-Tag1-Eu3+用detection buffer(cat#62DB1FDG)按1∶100稀释,Anti-Tag2-XL 665用detection buffer按1∶20稀释,待检测化合物用diluentbuffer梯度稀释成2X的终浓度。在384孔板中每孔先加入2μL化合物,再分别先后加入4μLTag 1-PD-L1,4μL Tag 2-PD-1,室温孵育15分钟。加入5μL Anti-Tag1-Eu3+和5μL Anti-Tag2-XL 665,室温孵育过夜,用BioTek SynergyTM Neo2多功能酶标仪检测,获得665nm/620nm比值。用PrismGraphd 5.02拟合IC50曲线。
表1本发明部分化合物的IC50值
化合物编号 | PD-L1 IC50 |
1 | A |
2 | A |
3 | A |
4 | A |
5 | A |
字母A代表IC50小于10nM;
字母B代表IC50为10nM至100nM;
字母C代表IC50为大于100nM;
结果显示,本发明中化合物可在不同浓度下有效抑制PD-1/PD-L1的结合。因此可用于与PD-1/PD-L1互相结合相关的疾病治疗中。
测试例2:细胞学NFAT报告基因实验
PD1/PD-L1的细胞学实验需要有两种细胞,PD-1效应细胞和PD-L1 aAPC/CHO-K1细胞,其中PD-1效应细胞表达人PD-1蛋白和由NFAT驱动的荧光素酶报告基因,PD-L1 aAPC/CHO-K1细胞表达PD-L1蛋白和anti-CD3 antibody。当这两种细胞共培养时,PD-1/PD-L1的相互作用会抑制TCR至NFAT-RE的信号传递,中断NFAT-RE介导的荧光信号。当加入PD-1或PD-L1的抑制剂时,阻断了PD-1/PD-L1的相互作用,解除了对TCR至NFAT-RE通路的信号抑制,使荧光信号增强,通过荧光信号的强弱来判断抑制剂的阻断效果。
实验第一天,将复苏的PD-L1 aAPC/CHO-K1细胞消化处理,离心后用培养基(90%Ham’s F-12/10%FBS)将浓度调为2.5*105/mL,按每孔40ul,1*104细胞的量铺在384孔板中,置于培养箱中过夜培养。第二天,先将待测化合物用检测buffer(99%RPMI1640/1%FBS)按梯度稀释到所需检测浓度的2倍,PD-1细胞离心后用检测buffer调成浓度为6.25*105/mL。将过夜培养的384孔板中的培养基吸干,每孔加入20ul稀释好的化合物,再加入20ul PD-1细胞,在细胞培养箱中孵育6小时后,每孔再加入20ul Bio-Glo试剂(Promega,cat#G7940),10分钟后,用多功能酶标仪读板。每块板需设置阴性对照(只加细胞,不加化合物),和空白对照(只加检测buffer)。根据荧光值,用prism5来分析化合物的抑制活性。
结果显示,本发明化合物能够有效阻断PD-1/PD-L1的相互作用,半活抑制浓度与临床阶段的PD1抑制剂相当或更佳。
表2本发明部分化合物的EC50值
化合物编号 | PD-L1 EC50 |
1 | A |
3 | A |
5 | A |
字母A代表IC50小于100nM;
字母B代表IC50为100nM至500nM;
字母C代表IC50为大于500nM
测试例3:本发明中小分子抑制剂小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予ICR小鼠测试化合物,于不同时间点采集血样,LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下:取所需量供试品,溶于5%DMSO+10%Solutol+85%注射用水中,配成所需浓度的溶液,用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间:给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h。口服采血时间:给药后0.25h,0.5h,1h,2h,4h,6h,8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据,运用Phoenix WinNonlin 7.0软件计算药代动力学参数,如AUC(0-t),AUC(0-∞),T1/2,Cmax,Tmax和MRT等。
结果显示,本发明化合物具有优异的药代动力学性质。
测试例4:本发明中小分子抑制剂大鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予SD大鼠测试化合物,于不同时间点采集血样,LC-MS/MS测定大鼠血浆中受试物的浓度并计算相关参数。具体如下:取所需量供试品,溶于5%DMSO+10%Solutol+85%注射用水中,配成所需浓度的溶液,用于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间:给药后0.083h,0.25h,0.5h,1h,2h,4h,8h和24h。口服采血时间:给药后0.25h,0.5h,1h,2h,4h,6h,8h和24h。建立生物样品分析方法及样品检测方法。过不同时间点的血药浓度数据,运用Phoenix WinNonlin 7.0软件计算药代动力学参数,如AUC(0-t),AUC(0-∞),T1/2,Cmax,Tmax和MRT等。
结果显示,本发明化合物具有优异的药代动力学性质。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种如下式II-1或II-2所示的化合物,其立体异构体,或其药学上可接受的盐:
或
R1、R4、R6和R7各自独立地为位于环上的一个或多个取代基;
R1为H;
R4为H、C1-C6烷基、C1-C6烷氧基;
R6和R7为卤素;
R2选自下组:H、D、C1-C6烷氧基;
所述的R3为;其中,W1为CH2;
所述的R5为;其中,W2为CH2;
Ra、Rb各自独立地选自下组:H、取代的C1-C8烷基;所述的“取代”是指被以下取代基所取代:羧基;或所述的Ra和Rb与相邻的N原子共同构成取代的具有1-3个选自N杂原子的5-10元饱和杂环基;所述的“取代”是指被羧基取代;
Rc和Rd各自独立地选自下组:H、取代的C1-C8烷基;所述的“取代”是指被以下取代基所取代:被氧代的具有1-3个选自N的杂原子的3-10元饱和杂环基;
为基团的连接位点;
附加条件是式I化合物为化学上稳定的结构。
2.如权利要求1所述的化合物,其特征在于,所述的R3选自下组:
、、、。
3.如权利要求1所述的化合物,其特征在于,所述的R5为:,,。
4.如权利要求1所述的化合物,其特征在于,R6和R7各自独立地为Cl。
5.如权利要求1所述的化合物,其特征在于,R4为H、甲基或甲氧基。
6.一种选自下组的化合物:
。
7.一种药物组合物,其特征在于,包含(1)如权利要求1所述的化合物或其立体异构体,或其药学上可接受的盐;(2)药学上可接受的载体。
8.如权利要求1所述的化合物或其立体异构体,或其药学上可接受的盐或如权利要求7所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗与PD-1/PD-L1的活性或表达量相关的疾病的药物组合物。
9.如权利要求8所述的用途,其特征在于,所述的疾病选自下组:肿瘤、病原体感染、自身免疫应答相关疾病。
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