CN115677689A - 多取代苯类pd-l1抑制剂、组合物及其应用 - Google Patents
多取代苯类pd-l1抑制剂、组合物及其应用 Download PDFInfo
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- CN115677689A CN115677689A CN202210898831.XA CN202210898831A CN115677689A CN 115677689 A CN115677689 A CN 115677689A CN 202210898831 A CN202210898831 A CN 202210898831A CN 115677689 A CN115677689 A CN 115677689A
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种多取代苯类PD‑L1抑制剂、组合物及其应用,所述化合物具有如通式(I)的结构。本发明发明人通过实验证实,本发明化合物表现出很强的PD‑1/PD‑L1阻断活性,显著的PD‑L1占据活性,同时能够逆转PD‑L1抑制的T细胞功能。同时,本发明化合物可口服吸收,具有良好的药代动力学性质,并且在体内具有较好的抗肿瘤抑制活性。因此,本发明的化合物可以应用于在单独或与其他药物联合应用治疗从PD1或PD‑L1活性的抑制中获益的疾病、障碍或病症中的应用,包括感染性疾病、免疫性疾病、炎性疾病和癌症。
Description
技术领域
本发明属于医药领域,具体是涉及一种多取代苯类的化合物、药物组合物及其应用。所述化合物可阻断PD1与PD-L1的相互作用,并且可用于治疗多种疾病、障碍,包括感染性疾病、免疫性疾病、癌症。
背景技术
人体免疫系统在对包括肿瘤在内的众多的疾病进程中发挥着极其重要的调控作用。在恶性肿瘤的发展过程中,为了逃避人体免疫系统的监视,发展进化出了多种免疫逃逸机制。其中改变肿瘤细胞或者免疫细胞表面共刺激或共抑制分子的表达是最为关键的肿瘤免疫逃逸机制之一。目前通过阻断抑制性免疫检查点分子(如PD1/PD-L1)的相互作用已经成为有效的肿瘤免疫治疗策略之一。(Postow等,J.Clinical Oncology 2015,1-9)。
PD-1是一种可表达于多种免疫细胞的表面受体,在体内发挥着极为重要的免疫负反馈调节作用,可以有效防止T细胞过度活化造成的自身免疫系统疾病(Sharpe等,Nat.Immunol.,2007,8,239-245)。PD-1受体在体内有PD-L1/PD-L2两种相对应内源性配体。PD-L1与PD-L2在表达上有所不同,PD-L1多表达于树突细胞、巨噬细胞、B细胞和T细胞(Greenwald等,Annu.Rev.Immunol.2005,23:515-548;Okazaki和Honjo,Trends Immunol2006,(4):195-201),同时也可以在多种肿瘤细胞上高表达。而PD-L2通常只在树突细胞上表达。药物阻断PD-1/PD-L1的相互作用是目前肿瘤免疫治疗领域最热门的方向。
目前已经有多个PD-1和PD-L1单抗在临床上用于10余种肿瘤适应症的治疗。但是抗体药物存在不可口服给药,组织渗透性较差,容易产生抗药抗体等缺陷。因此开发针对阻断PD1/PD-L1的新型小分子抑制剂有望克服抗体药物的缺陷,成为全新的免疫检查点抑制剂开发方向。
发明内容
本发明的目的在于提供一种新颖的多取代苯类化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐。
本发明还提供了一种包括上述化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐的药物组合物。
本发明同时提供了一种上述化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐用于制备治疗从PD1或PD-L1活性的抑制中获益的疾病、障碍或病症的药物中的应用。
本发明采用如下的技术方案:
一种化合物,具有通式(I)的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐;
X选自:N或CH;
R1选自:C1-C4烷氧基、C3-C5环烷氧基、C1-C4卤代烷氧基、C3-C5环烷基、C1-C4卤代烷基;
R2选自:甲基、氰基、氯原子;
R3选自:甲基、氰基、氯原子;
R4选自:H、C1-C4烷氧基、C3-C5环烷氧基、C1-C4卤代烷氧基、C3-C5环烷基、C1-C4卤代烷基;
n选自:0、1、2;
m选自:1、2。
更进一步地,本发明优选的化合物,具有通式(IIa)、(IIb)的结构:
或其立体异构体或其立体异构体混合物或其药学上可接受的盐。
更进一步地,作为优选的方案:
更进一步地,作为优选的方案:
R2优选自:甲基;
作为优选,本发明优选的化合物,具有通式(IIb)所示的结构。
作为进一步优选,本发明优选的化合物,具有通式(IIb)所示的结构,且:
作为优选,选自下列化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐:
1-((6-环丙基-2-(3'-((3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 001
1-((6-环丙基-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 002
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-)((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 004
4-(2-(((6-环丙基-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙基)双环[2.2.1]庚烷-1-羧酸 005
1-((2-(2'-氯-3'-((3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 006
1-((2-(2'-氯-3'-((3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸甲酯007
1-((2-(2'-氯-3'-((3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)哌啶-2-羧酸 008
(新戊酰氧基)甲基1-((2-(2'-氯-3'-((3-((3-羟基吡咯烷-1-基)甲基)-1,7-萘啶-8-基)氨基)-2-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸酯 009
4-((((6-环丙基-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯基]-3-基)苯并[d]恶唑-5-基)甲基)氨基)甲基)双环[2.2.1]庚烷-1-羧酸 010
1-((2-(2-氯-3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 011
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 012
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-3-羧酸 013
4-((((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)甲基)双环[2.2.1]庚烷-1-羧酸 014
4-(2-(((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙基)双环[2.2.1]庚烷-1-羧酸 015
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氮杂环丁烷-3-羧酸 016
1-((2-(2-氰基-3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 017
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基氮杂环丁烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 018
4-(2-(((2-(2-氯-3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)氨基)乙基)双环[2.2.1]庚烷-1-羧酸 019
(R)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 020
(S)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 021
(S)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((S)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 022
(R)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((S)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 023
4-(2-(((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙基)双环[2.2.1]庚烷-1-羧酸甲酯 024
4-((((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)甲基)双环[2.2.1]庚烷-1-羧酸甲酯 025
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)-3-甲基吡咯烷-3-羧酸 026
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-羧酸 027
((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)脯氨酸 028
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((2-羟丙基)氨基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 029
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((((S)-2-羟丙基)氨基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 030
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((((R)-2-羟丙基)氨基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 031
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 032
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((R)-3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 033
1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((S)-3-羟基-3-甲基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸 034
1-((6-环丙基-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-3-羧酸 035
1-((6-环丙基-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 036
(R)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 037
(S)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 038
(R)-1-((2-(2-氯-3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 039
(R)-1-((2-(2'-氯-3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基-[1,1'-联苯]-3-基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)哌啶-4-羧酸 040
术语说明
除非另有定义,本发明使用的所有技术和科学术语与该领域专业人员通常理解的含义相同。除非另有说明,本发明参考的所有专利文献、公开披露的资料等全文纳入参考文献。如本发明中同一术语有多个定义,以本节中的定义为准。
需要理解的是,前文的一般描述和后文的详细描述仅仅是示范性的和解释性的,对任何权利要求都无限制性。需要注意的是,说明书和所附权利要求书中,除非文中另有说明,单数形式指代如“一”、“一个”、“这个”,包含复数指代。还需注意的是,除非另有说明,“或”代表“和/或”。此外,“包含”、“包括”等类似术语不是限制性的。
“取代”是指氢原子被取代基取代。需要注意的是,特定原子上的取代基是被其价态限制的。在定义部分,“Ci-Cj”是指包括起点和终点的范围,其中i和j都是整数,表示碳原子的数目。例如,C1-C4,C1-C8,C3-C8等。
本发明所用术语“烷基”是指一个具有一至六个碳原子的直链饱和单价烃基或一个具有三至六个碳原子的支链饱和的单价烃基,优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基等。烷基可以是无取代或单取代或多取代,多取代时取代基可以相同也可以不同;烷基的取代基选自卤素、硝基、羟基、羧基、羧酸甲酯、羧酸乙酯、异丙酯、胺甲酰基、C1-C6烷基、C1-C6烷氧基、C3-C10环烷基、烷氧基羰基、烷硫基、烷基磺酰基、烷基酰胺基、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“烷氧基”是指-O-烷基,其中烷基如上所定义。本发明所用“烷氧基”的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基,其取代基可为卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“环烷基”是指具有三个至十个碳原子的单环或多环(两个单环之间用化学键连接或桥环或螺环或稠合)的非芳香性单价烃基,优选为环丙基、环丁基、环戊基、环己基等,其中一个或两个碳原子可以由一个氧代基团替代。该环烷基可以是无取代或取代的,其取代基选自卤素、硝基、羟基、羧基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6羟烷基、卤代C1-C6烷氧基、C3-C6环烷基、卤代C3-C6环烷基、烷氧基羰基(羧酸甲酯、羧酸乙酯)、烷硫基、烷基磺酰基、烷基酰胺基(甲酰胺)、羟烷基酰胺基、磺酰胺基、3至10元杂环基,或者氨基或单取代或多取代氨基,其中氨基的取代基可以相同也可以不同,选自氢、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C3-C10环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“卤代烷基”是指被卤素(优选为氟、氯、溴、碘)取代的烷基基团,其中烷基如上所定义。“卤代烷基”中卤素取代基可以是一个或多个,可以在一个原子上进行取代,也可以在不同的原子上进行取代。
本发明所用术语“环烷氧基”是指-O-环烷基,其中环烷基如上所定义。“环烷氧基”还包括取代环烷氧基,其取代基可为卤素、氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明所用术语“卤代烷氧基”是指-O-卤代烷基基团,其中卤代烷基如上所定义。“卤代烷氧基”还包括取代的卤代烷氧基,其取代基可为氨基、羟基、C1-C6烷基、C1-C6羟烷基、C1-C6烷氧基、C1-C6环烷基、3至10元杂环基、C6-C12芳基、C5-C14杂芳基。
本发明采用本领域技术人员所熟知的方法可以制备本发明所述化合物的盐。所述的盐可以是有机酸盐、无机酸盐等,所述的有机酸盐包括枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等;所述的无机酸盐包括氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如,与低级烷基磺酸,如甲磺酸,三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐;与芳基磺酸,如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐;与有机羧酸,如乙酸,富马酸,酒石酸,草酸,马来酸,苹果酸,琥珀酸或柠檬酸等可形成相应的盐;与氨基酸,如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐。与无机酸,如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸),硝酸,碳酸,硫酸或磷酸等也可形成相应的盐。
本发明所述的化合物包括其某个原子被同位素取代后的化合物。同位素指具有相同原子序数不同原子质量的原子。如氢的同位素包括氘和氚。本发明所述的化合物组成的原子中,一个或多个原子可被天然或非天然的同位素取代。如有的实施例中的氢原子可被一个或多个氘原子取代。包含同位素原子的化合物的合成方法为现有已知技术。
本发明的第二个目的是提供一种药物组合物,包括上述任意一项技术方案所述的化合物中的一种或多种。本发明所述的药物组合物可以是上述任意一项技术方案所述的化合物中的一种或多种与其他化合物组成,或者上述任意一项技术方案所述的化合物中的一种或多种组成。
另一方面,本发明提供的是使用本文公开的通式(I)、通式(IIa)、通式(IIb)所述的化合物或其立体异构体或其立体异构体混合物或其药学上可接受的盐治疗从PD1或PD-L1活性的抑制中获益的疾病、障碍或病症中的应用。
在进一步优选的方案中,本发明提供的是通过给予有需要的治疗者一种含有治疗有效量的至少一种化合物的组合物、从而阻断所述受试者PD1和PD-L1相互作用的方法,其中所述化合物的结构式为通式(I)、通式(IIa)、通式(IIb)。
在一些实施方式中,有需要的受治疗者罹患癌症,所述癌症包括血液肿瘤和实体瘤,例如黑色素瘤、胶质母细胞瘤、食道肿瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性淋巴瘤、原发性中枢神经系统淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、原发性纵隔大B细胞淋巴瘤、前列腺癌、去势抵抗性前列腺癌、慢性粒细胞白血病、卡波西肉瘤纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、脑膜瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、胆道肿瘤、基底细胞癌、胸腺肿瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、默克尔(MeRkel)细胞癌、神经肿瘤、卵泡中心淋巴瘤、结肠癌、霍奇金病、非霍奇金淋巴瘤、白血病、慢性或急性白血病,包括急性髓性白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SClC)、非鳞状非小细胞肺癌、结肠直肠癌、卵巢癌、胃癌、肝细胞癌、胰腺癌、胰腺导管腺癌、头颈部鳞状细胞癌、头颈部癌、胃肠道、骨癌、皮肤癌、直肠癌、肛门癌、睾丸癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、尿道癌、阴茎癌、膀胱癌、肾癌、输尿管癌、肾盂癌、中枢神经系统肿瘤(CNS)、肿瘤血管生成、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、表皮样癌、石棉沉滞症、腺癌、乳头状癌、囊腺癌、支气管肺癌、肾细胞癌、移行细胞癌、绒毛膜癌、精原细胞瘤、胚胎癌、威尔姆氏瘤、多形性腺瘤、肝细胞乳头状瘤、肾小管腺瘤、囊腺瘤、乳头状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤和纤维瘤。
在进一步的实施方式中,有需要的受治疗者罹患感染性疾病、免疫性疾病和炎性疾病,例如败血症、肝脏感染、HIV、甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、疱疹病毒、乳头瘤病毒、流行性感冒、类风湿关节炎、系统性红斑狼疮、多发性硬化、炎性肠炎、克罗恩氏病、结肠炎、自身免疫性溶血性贫血、强直性脊柱炎、天疱疮、荨麻疹、哮喘、视神经炎、银屑病、慢性阻塞性气道疾病、皮炎、秃头症。
本发明还提供本发明所述的化合物或其药学上可用的盐在制备阻断PD1和PD-L1相互作用中的应用,特别是在制备治疗细胞增生疾病中的应用。所述的细胞增生疾病包括癌症。换言之,本发明还提供通式(I)、通式(IIa)、通式(IIb)所述的化合物或其药学上可接受的盐单独或和其他药物联合使用在治疗增生类疾病(如癌症)中的应用。
与本发明所述的化合物或组合物联用的药物,可选自抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化学治疗剂、抗癌剂、抗血管生成剂、免疫治疗剂(比如免疫检查点抑制剂)、抗激素药(比如激酶抑制剂)、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂或抗增殖剂中的一种或多种。
一种制剂,包括上述任一方案所述的化合物中的一种或多种。
所述载体包括药学领域的常规稀释剂,赋形剂,填充剂,粘合剂,湿润剂,崩解剂,吸收促进剂,表面活性剂,吸附载体,润滑剂等,必要时还可以加入香味剂,甜味剂等。
本发明药物可以制成片剂、粉剂、胶囊、注射制剂、颗粒制剂、喷雾剂等多种形式,上述各剂型的药物均可以按照药学领域的常规方法制备。
本发明化合物还可以与治疗癌症,例如通过化学疗法、照射疗法、肿瘤靶向疗法、辅助疗法、免疫疗法或手术的其他方法组合使用。免疫疗法的实例包括细胞激素治疗(例如干扰素、GM-CSF、G-CSF、IL-2)、CRS-207免疫疗法、癌症疫苗、单克隆抗体、授受性T细胞转移、Toll受体促效剂、STING促效剂、溶瘤病毒疗法和免疫调节小分子,包括沙利度胺(thalidomide)或JAK1/2抑制剂等等。
本发明发明人通过实验证实,本发明化合物表现出很强的PD-1/PD-L1阻断活性,同时能够逆转PD-L1抑制的T细胞功能。同时,本发明化合物可口服吸收,具有良好的药代动力学性质,并且在体内具有良好的抗肿瘤效果。因此,本发明的化合物可以应用于在单独或与其他药物联合应用治疗从PD1或PD-L1活性的抑制中获益的疾病、障碍或病症中的应用,包括感染性疾病、免疫性疾病、炎性疾病和癌症。
具体实施方式
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
中间体1的合成路线
中间体1-1的合成
2-溴-4-甲氧基苯甲酸甲酯(0.1mmol)、环丙基硼酸(0.3mmol)、SPhos-Pd-G2(氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II))(0.005mmol)、磷酸钾(0.2mmol)溶于甲苯,N2保护,110℃反应过夜。浓缩反应液,经硅胶柱层析得到中间体1-1:2-环丙基-4-甲氧基苯甲酸甲酯。LC-MS(ESI-MS):207[M+H]+。
中间体1-2的合成
中间体1-1(0.1mmol)溶于无水二氯甲烷,三溴化硼(0.7mmol)稀释于无水DCM,-10℃滴加到中间体1-1的DCM溶液中,保持该温度反应3小时。低温下加入水淬灭反应。经萃取浓缩后经硅胶柱层析得到中间体1-2:2-环丙基-4-羟基苯甲酸甲酯。LC-MS(ESI-MS):193[M+H]+。
中间体1-3的合成
将中间体1-2(10g)溶于40mL冰醋酸,加入醋酸酐10mL,冰浴冷却。滴加浓硝酸和冰醋酸混合液10mL(5mL+5mL),滴加完毕后,缓慢升温至室温继续反应2小时。反应结束后,反应液倒入冰水中,经过滤得到中间体1-3:2-环丙基-4-羟基-5-硝基苯甲酸甲酯,直接进行下一步反应。LC-MS(ESI-MS):238[M+H]+。
中间体1-4的合成
将中间体1-3(5g)溶于甲醇,加入0.5g Pd/C,氢气室温还原过夜。硅藻土过滤Pd/C后,浓缩反应液,经硅胶柱层析得到中间1-4:5-氨基-2-环丙基-4-羟基苯甲酸甲酯。LC-MS(ESI-MS):208[M+H]+。
中间体1-5的合成
中间体1-4(0.1mmol)溶于甲醇,加入3-溴-2甲基苯甲醛(0.09mmol),80℃反应3小时,减压浓缩。浓缩后重新溶于DCM,加入DDQ(2,3-二氯-5,6-二氰基苯醌)(0.15mmol),室温反应1小时。DCM稀释反应液,用硫代硫酸钠溶液洗涤有机相。浓缩有机相,经硅胶柱层析得到中间体1-5:2-(3-溴-2-甲基苯基)-6-环丙基苯并[d]恶唑-5-羧酸甲酯。LC-MS(ESI-MS):386[M+H]+。
中间体1-6的合成
中间体1-5(0.2mmol)溶于无水THF,-20℃加入LiAlH4(0.3mmol)。缓慢升温至室温反应2小时,加入10%氢氧化钠溶液1mL淬灭反应。用盐酸、饱和食盐水洗涤有机相。经硅胶柱层析得到中间体1-6:(2-(3-溴-2-甲基苯基)-6-环丙基苯并[d]恶唑-5-基)甲醇。LC-MS(ESI-MS):358[M+H]+。
中间体1-7的合成
将1g中间体1-6溶于无水THF,加入Dess-Martin试剂1.7g,室温反应2小时后,经硅藻土过滤,经硅胶柱层析得到中间体1-7:2-(3-溴-2-甲基苯基)-6-环丙基苯并[d]恶唑-5-甲醛。LC-MS(ESI-MS):356[M+H]+。
中间体1-8的合成
中间体1-7(1g)溶于甲醇,加入醋酸316mg,吡咯-3-甲酸叔丁酯1.8g,室温搅拌30分钟后,加入氰基硼氢化钠(520mg),60℃反应3小时。冷却至室温,加入DCM稀释反应液,经饱和食盐水洗涤后,过柱纯化得到中间体1-8:1-((2-(3-溴-2-甲基苯基)-6-环丙基苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸叔丁酯。LC-MS(ESI-MS):511[M+H]+。
中间体1的合成
中间体1-8(700mg)溶于1,4-二氧六环溶液中,加入联硼酸频那醇酯(1.2g),醋酸钾(110mg),Pd(dppf)Cl2(100mg),N2保护下100℃反应过夜。反应结束后浓缩反应液,经硅胶柱层析得到中间体1:1-((6-环丙基-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸叔丁酯。LC-MS(ESI-MS):559[M+H]+。
参考中间体1的合成路线和方法,合成得到以下中间体结构:
中间体6的合成
中间体6-1的合成
取单口瓶,加入2,4-二羟基苯甲酸甲酯(10.0g,59.47mmol,1.0eq.),冰乙酸(44mL),乙酸酐(11mL),将溶液冷却至10℃,加入65%硝酸(8.3g,79.20mmol,1.3eq.)和冰乙酸(6mL)的混合物,混合物氮气置换三次,然后10℃搅拌1小时,之后升温到15℃,继续搅拌1小时。取样检测,反应完全。反应液加入水(40mL),搅拌10分钟,过滤并用少量水冲洗,收集固体,加入甲醇(25mL),搅拌10分钟,过滤并用少量甲醇冲洗,收集产物真空干燥,即得2,4-二羟基-5-硝基苯甲酸甲酯(4.5g,20.06mmol,收率33.7%)。LC-MS:(ESI)[M+H]+=214.0tR=1.77min。
中间体6-2的合成
取250mL单口瓶,加入2,4-二羟基-5-硝基苯甲酸甲酯(4.0g,18.77mmol,1.0eq.),和甲醇(100mL),加入10%氢氧化钯碳催化剂(2.0g,50%m/m),混合物氢气置换三次,并保持氢气压力在15psi,25℃搅拌3小时,TLC点板确定反应完成,过滤除去催化剂,并用甲醇(100mL)洗涤滤饼,收集滤液,减压蒸馏浓缩,残余物经Flash柱(石油醚:乙酸乙酯=10:1)纯化,得到5-氨基-2,4-二羟基苯甲酸甲酯(2.0g,9.83mmol,收率52.37%)。LC-MS:(ESI)[M+H]+=184.0tR=1.06min。
中间体6-3的合成
取500mL单口瓶,加入5-氨基-2,4-二羟基苯甲酸甲酯(5.0g,27.30mmol,1.0eq.),3-溴-2-甲基苯甲醛(6.5g,32.76mmol,1.2eq.)和甲醇(150mL)。混合物置换氮气三次,80℃搅拌5小时。然后将反应液减压浓缩,干燥,加入二氯甲烷(150mL),然后加入DDQ(2,3-二氯-5,6-二氰基苯醌)(8.7g,38.22mmol,1.4eq.),25℃搅拌12小时。取样检测,反应完全。将反应液用乙酸乙酯萃取三次(100mL×3),合并有机相,并用水洗涤三次(20mL×3),有机相减压浓缩至40mL,搅拌1小时,过滤,收集得到2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-羧酸甲酯(7.5g,19.67mmol,收率72.0%)。LC-MS:(ESI)[M+H]+=361.6tR=2.02min。
中间体6-4的合成
取100mL单口瓶,加入2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-羧酸甲酯(3.8g,10.49mmol,1.0eq.),N,N-二甲基甲酰胺(40mL),碳酸铯(13.7g,41.97mmol,4.0eq.)和2-溴-2,2-二氟乙酸钠(8.3g,41.97mmol,4.0eq.)。混合物置换氮气三次,100℃搅拌14小时。取样检测,反应完全。反应液使用乙酸乙酯(30mL×3)萃取,合并有机相,减压蒸馏浓缩,残余物用Flash柱(石油醚:乙酸乙酯=20:1)纯化,得到2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-羧酸甲酯(800mg,1.75mmol,收率16.7%)。LCMS:(ESI)[M+H]+=411.7,tR=1.85min。
中间体6-5的合成
取一单口瓶,将2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-羧酸甲酯(100mg,0.24mmol,1.0eq.)溶于THF(5mL)中,0℃冰浴下,缓慢加入四氢铝锂(11mg,0.29mmol,1.2eq.),0℃条下搅拌30分钟,TLC点板确定反应完成,加入少量水(3mL)淬灭,将反应液使用乙酸乙酯(10mL×3)萃取三次,合并有机相,减压蒸馏浓缩,用制备TLC(石油醚:乙酸乙酯=3:1)纯化,得到(2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲醇(40mg,0.09mol,收率38.6%)。LCMS:(ESI)[M+H]+=383.8,tR=1.73min。
中间体6-6的合成
取单口瓶,将(2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲醇(20mg,0.05mmol,1.0eq.)溶于二氯甲烷(5mL)中,加入二氧化锰(226mg,2.60mmol,50.0eq.),25℃搅拌18小时。取样检测,反应完全。反应液过滤除去二氧化锰,用乙酸乙酯(5mL×3)萃取三次,合并有机相,减压浓缩,残余物经制备TLC(石油醚:乙酸乙酯=5:1)纯化,得到2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-甲醛(17mg,0.05mmol,收率85.5%)。LCMS:(ESI)[M+H]+=381.6,tR=1.92min。1H NMR(400MHz,DMSO)δ10.35(s,1H),8.27(s,1H),8.11(d,J=7.6Hz,1H),8.03–7.92(m,2H),7.67–7.25(m,2H),2.83(s,3H).
中间体6-7的合成
在50mL圆底烧瓶中,将2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-甲醛(85mg,0.22mmol,1.0eq.)、三乙胺(68mg,0.67mmol,3.0eq.)和吡咯烷-3-羧酸甲脂(58mg,0.45mmol,2.0eq.)加入到DCM(10mL)中。反应混合物在0℃下搅拌2小时,加入氰基硼氢化钠(17mg,0.27mmol,1.2eq.),25℃搅拌14小时。取样检测,反应完全。反应液用乙酸乙酯萃取3次(10mL×3),合并有机相,浓缩干燥。残余物经制备硅胶板纯化(展开剂:乙酸乙酯),得到1-((2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸甲脂(30mg,0.06mmol,26.8%)。LCMS:(ESI)[M+H]+=495.1。
中间体6的合成
将1-((2-(3-溴-2-甲基苯基)-6-(二氟甲氧基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸甲酯(184mg,0.37mmol,1.0eq.),联硼酸频那醇酯(141mg,0.56mmol,1.5eq.)和醋酸钾(73mg,0.74mmol,2.0eq.)溶解于二氧六环和水(3mL和1mL)中,然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(27mg,0.037mmol,0.1eq.)。室温下置换氮气3次,加热至100℃,搅拌18小时。取样检测,反应完全。冷却至室温,用硅藻土过滤,滤液旋干,残余物用Flash柱(石油醚:乙酸乙酯=3:1)纯化得到1-((6-(二氟甲氧基)-2-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)苯基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸甲酯(141mg,收率:70%)。LC-MS:(ESI)[M+H]+=543.6,tR=1.575min。
参考中间体6的合成路线和方法,合成得到以下中间体结构:
中间体22的合成
中间体22-1的合成
取单口瓶,加入3-溴-8-氯-1,7-萘啶(800mg),碳酸铯(2.14g,),乙烯基氟硼酸钾(572mg),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(268mg),1,4-二氧六环和水。混合物换气三次,然后在90℃搅拌1.5小时。反应液冷却至室温,然后加入水(15mL),用乙酸乙酯萃取三次(30mL*3),合并有机相,用饱和食盐水反洗一次(30mL),经硅胶柱层析纯化即得中间体22-1:8-氯-3-乙烯基-1,7-萘啶。LC-MS(ESI-MS):191[M+H]+。
中间体22-2的合成
取100mL的封管,加入8-氯-3-乙烯基-1,7-萘啶(300mg),3-溴-2-甲基苯胺(325mg),叔丁醇(5mL)和盐酸的1,4-二氧六环溶液。反应混合物在120℃搅拌2h。反应液冷却到室温,然后用饱和的碳酸钠溶液进行中和至pH=7,用乙酸乙酯萃取三次(30mL*3),合并有机相,并用饱和食盐水洗一次(30mL),无水硫酸钠干燥之后,经硅胶柱层析纯化即得中间体22-2:N-(3-溴-2-甲基苯基)-3-乙烯基-1,7-萘啶-8-胺。LC-MS(ESI-MS):340[M+H]+。
中间体22-3的合成
取100mL单口瓶,加入中间体22-2(750mg),锇酸钾(53.0mg),1,4-二氧六环和水。在0℃的条件下,向反应液中加入高碘酸钠(1.33g)。反应的混合物在室温下搅拌3小时。然后用饱和的亚硫酸钠淬灭反应,用乙酸乙酯萃取三次,合并有机相,并用饱和食盐水洗一次后经硅胶柱层析纯化即得中间体22-3:8-((3-溴-2-甲基苯基)氨基)-1,7-萘啶-3-甲醛。LC-MS(ESI-MS):342[M+H]+。
中间体22的合成
取100mL单口瓶,加入中间体22-3(210mg),二氯甲烷,三乙胺(231mg)和吡咯烷-3-醇(63mg)。混合物搅拌1小时,在0℃的条件下,氰基硼氢化钠(56.0mg)加入到上述的混合物中。混合物在室温的条件下,继续搅拌16小时。加水淬灭这个反应,用二氯甲烷萃取,合并有机相,经硅胶柱层析纯化得中间体22:1-((8-((3-溴-2-甲基苯基)氨基)-1,7-萘啶-3-基)甲基)吡咯烷-3-醇。LC-MS(ESI-MS):413[M+H]+。
中间体23的合成
参考中间体22的合成,在中间体22-2的合成中,用3-溴-2-氯苯胺替换3-溴-2-甲基苯胺合成得到中间体23。LC-MS(ESI-MS):433[M+H]+。
中间体24的合成
中间体24-1的合成
取单口瓶,将2,5-二溴-3-硝基吡啶(3.00g,10.64mmol,1.00eq.)溶于乙腈(20mL),加入氰化亚铜(1.05g,11.71mmol,1.10eq.),85℃搅拌16小时,取样检测,反应完全。反应液冷却至室温,过滤,收集滤液,浓缩,加入水(100mL),用二氯甲烷萃取三次(100mL×3),合并有机相,减压蒸馏浓缩得到粗产物,粗产物用Flash柱(石油醚:二氯甲烷=3:1)纯化得到5-溴-3-硝基吡啶-2-甲腈(1.80g,7.11mmol,收率:66.8%)。1H NMR:[M+H]+=227.9。(400MHz,CDCl3)δ9.06(s,1H),8.77(s,1H)。
中间体24-2的合成
取单口瓶,将5-溴-3-硝基吡啶-2-甲腈(1.40g,6.14mmol,1.00eq.)缓慢加入浓硫酸(8mL)中,加热至100℃,搅拌2小时。取样检测,反应完全。反应液冷却至室温,倒入冰水中,析出固体,过滤,滤饼用水洗涤并抽干得5-溴-3-硝基吡啶-2-甲酰胺(1.25g,4.57mmol,收率:74.5%)。LCMS(ESI)[M+H]+=245.9,tR=1.079min。
中间体24-3的合成
取单口瓶,将5-溴-3-硝基吡啶-2-甲酰胺(210mg,0.85mmol,1.00eq.)溶于甲醇(4mL),加入水(2mL),氯化铵(365mg,6.83mmol,8.00eq.)和铁粉(238mg,4.27mmol,5.00eq.),加热至100℃搅拌30min,取样检测,反应完全。反应液过滤,浓缩,加入水(10mL),使用二氯甲烷(10mL×3)萃取3次,浓缩得到粗产物。粗产物使用制备TLC纯化(石油醚:乙酸乙酯=3:1)得到3-氨基-5-溴吡啶-2-甲酰胺(140mg,0.65mmol,收率:75.9%)。LCMS:(ESI)[M+H]+=216.0,tR=1.453min。1H NMR:(400MHz,DMSO)δ7.92(s,1H),7.82(s,1H),7.41(s,2H),7.06(s,2H)。
中间体24-4的合成
在100mL圆底烧瓶中,将3-氨基-5-溴吡啶-2-甲酰胺(6.70g,31.01mmol,1.0eq.)溶于DCM(70mL)和DMF(10mL)中。冰浴下滴加2,2-二氟乙酸酐(10.80g,62.03mmol,2.0eq.)。滴完,反应液在25℃下搅拌18小时,取样检测,反应完全。反应液浓缩干燥得到5-溴-3-(2,2-二氟乙酰胺基)吡啶-2-甲酰胺(7.20g,22.04mmol,收率:71.0%)。LCMS:(ESI)[M+H]+=294.0,tR=1.08min。
中间体24-5的合成
在250mL圆底烧瓶中,加入5-溴-3-[(2,2-二氟乙酰基)氨基]吡啶-2-甲酰胺(9.80g,33.33mmol,1.0eq.),乙醇(45mL)和水(11mL),分批加入氢氧化钠(1.33g,33.33mmol,1.0eq.)。将反应混合物在50℃搅拌2小时。取样LCMS检测,反应转化完全。混合物冷却至室温,将反应混合物倒入水(500mL)中。在室温下搅拌30分钟,过滤得到7-溴-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-醇(6.00g,20.65mmol,62.0%)。LC-MS:(ESI)[M+H]+=275.9,tR=1.401min。
中间体24-6的合成
在250mL圆底烧瓶中,加入7-溴-2-(二氟甲基)吡啶并[3,2-d]嘧啶-4-醇(4.50g,16.30mmol,1.0eq.),碳酸铯(10.62g,32.60mmol,2.0eq.),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.19g,1.63mmol,0.1eq.),乙烯基三氟硼酸钾(3.27g,24.45mmol,1.5eq.)和二氧六环(45mL),水(15mL)。氮气保护下,混合物升温至80℃并搅拌12小时。取样LCMS检测,反应转化完全。过滤反应溶液,滤液经真空浓缩,得到2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-醇(3.03g,12.77mmol,收率:78.3%)粗品,无需纯化直接用于下一步。LC-MS:(ESI)[M+H]+=224.0,tR=1.359min。
中间体24-7的合成
在500mL圆底烧瓶中,2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-醇(15.00g,54.34mmol,1.0eq.)溶解在甲苯(150mL),将二异丙基乙胺(21.07g,163.02mmol,3.0eq.)和三氯氧磷(25.00g,163.02mmol,3.0eq.)加入混合物中。氮气保护下,将混合物升温至80℃并搅拌2小时。取样LCMS检测,反应转化完全。反应混合物冷却至室温,减压浓缩。残余物通过柱色谱法纯化(SiO2,石油醚/乙酸乙酯=20/1—10/1),得到4-氯-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶(6.05g,19.36mmol,收率:35.6%)。LC-MS:(ESI)[M+H]+=242.0,tR=1.957min。1H NMR(400MHz,DMSO)δ9.49(d,J=2.0Hz,1H),8.68(d,J=2.0Hz,1H),7.32–7.00(m,2H),6.52(d,J=17.6Hz,1H),5.81(d,J=11.2Hz,1H).
中间体24-8的合成
将4-氯-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶(1.55g,6.42mmol,1.0eq.)溶解在叔丁醇(15mL)和3-溴-2-甲基苯-1-胺中添加(1.43g,7.70mmol,1.2eq.)。将反应混合物在50℃搅拌12小时。取样LCMS检测,反应转化完全。反应混合物冷却至室温,将反应混合物倒入水(100mL)中。在室温下搅拌30分钟后,过滤,所得滤饼经真空干燥得到N-(3-溴-2-甲基苯基)-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺(2.02g,4.86mmol,收率:75.7%)。LC-MS:(ESI)[M+H]+=391,tR=1.799min。
中间体24-9的合成
三口烧瓶中,将N-(3-溴-2-甲基苯基)-2-(二氟甲基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺(2.01g,5.11mmol,1.0eq.)溶解在二氯甲烷(1000mL)中。将反应混合物冷却至-78℃。然后将臭氧引入反应溶液中,直至反应液呈微蓝色。取样LCMS检测,反应转化完全。然后加入三乙胺(1.55g,15.34mmol,3.0eq.),将反应混合物继续在-78℃搅拌1小时。将反应混合物升温至室温,残余物经柱层析纯化(SiO2,石油醚/乙酸乙酯=20/1—1/3),得到4-((3-溴-2-甲基苯基)氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-甲醛(800mg,1.87mmol,收率:36.6%)。LC-MS:(ESI)[M+H]+=392.6,tR=1.654min。1H NMR(400MHz,DMSO)δ10.81(s,1H),10.35(s,1H),9.36(d,J=1.6Hz,1H),8.80(d,J=1.6Hz,1H),7.60(d,J=8.0Hz,1H),7.53(d,J=7.6Hz,1H),7.25(t,J=8.0Hz,1H),6.74(m,1H),2.29(s,3H).
中间体24的合成
三口烧瓶中,4-((3-溴-2-甲基苯基)氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-甲醛(550mg,1.40mmol,1.0eq.)溶于二氯甲烷(15mL),将吡咯烷-3-醇(244mg,2.80mmol,2.0eq.)和三乙胺(580mg,5.74mmol,4.0eq.)加入混合物中。将混合物在25℃搅拌2小时。然后加入氰基硼氢化钠(132mg,2.10mmol,1.5eq.),将反应混合物继续在25℃搅拌12小时。取样LCMS检测,反应转化完全。将混合物加入水(50mL)中,用乙酸乙酯(100mL×2)萃取。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩。残余物经柱色谱法(SiO2,石油醚/乙酸乙酯=20/1—10/1)纯化,得到1-((4-((3-溴-2-甲基苯基)氨基)-2-(二氟甲基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(320mg,0.63mmol,收率:45.3%)。LC-MS:(ESI)[M+H]+=464.1,tR=1.40,3min。
参考中间体24的合成路线和方法,合成得到以下中间体结构:
实施例001. 1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸(004)
第一步:
在三口烧瓶中,将中间体24(193mg,0.42mmol,1.0eq.)添加到二恶烷(3mL)和H2O(0.4mL)中,然后添加中间体6(271mg,0.50mmol,1.2eq.)、K3PO4(265mg,1.25mmol,3.0eq.)和XPhos Pd G2(氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II))(65mg,0.083mmol,0.2eq.)。将混合物用N2脱气3次,并在100℃下搅拌反应3小时。取样LCMS检测,反应转化完全。将混合物冷却至25℃,过滤,滤液真空浓缩得到中间体020-1:1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸甲酯(330mg,0.21mmol,收率:49.6%)粗品。LC-MS:[M+H]+=800.1,tR=2.337min。
第二步:
在圆底烧瓶中,将中间体020-1(330mg,0.21mmol,1.0eq.)加入MeOH(3mL)和H2O(2mL),然后加入氢氧化锂一水合物(20mg,0.84mmol,4.0eq.)。将混合物在25℃搅拌3小时。取样LCMS检测,反应转化完全。用1N盐酸溶液调节反应液的PH至3-4,残余物经制备HPLC纯化得到1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-((3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸(144mg,0.17mmol,收率:83.6%)。LC-MS:(ESI)[M+H]+=786.2。1H NMR:(400MHz,DMSO)δ10.46(s,1H),8.99–8.96(m,1H),8.16(d,J=1.5Hz,1H),8.15–8.09(m,1H),7.91(s,1H),7.76–7.70(m,2H),7.56–7.52(m,1H),7.46–7.39(m,2H),7.40–7.03(m,2H),6.88–6.58(m,1H),4.74(s,1H),4.28–4.18(m,1H),3.95–3.82(m,2H),3.80–3.65(m,2H),3.33(s,2H),2.99–2.90(m,1H),2.80–2.66(m,4H),2.66–2.55(m,2H),2.47(s,3H),2.45–2.40(m,1H),2.08–1.96(m,6H),1.64–1.55(m,1H).
实施例002.(R)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸(020)
参考实施例001的合成路线和方法,合成得到化合物020:(R)-1-((6-(二氟甲氧基)-2-(3'-((2-(二氟甲基)-7-(((R)-3-羟基吡咯烷-1-基)甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吡咯烷-3-羧酸。LC-MS:(ESI)[M+H]+=786.2.tR=1.288min 1H NMR:(400MHz,DMSO)δ10.45(s,1H),8.97–8.94(m,1H),8.17(d,J=1.6Hz,1H),8.14–8.09(m,1H),7.90(s,1H),7.74–7.69(m,2H),7.57–7.50(m,1H),7.43–7.38(m,2H),7.38–7.03(m,2H),6.87–6.57(m,1H),4.73(s,1H),4.27–4.18(m,1H),3.93–3.81(m,2H),3.79–3.66(m,2H),3.32(s,2H),2.98–2.89(m,1H),2.78–2.65(m,4H),2.64–2.54(m,2H),2.47(s,3H),2.44–2.39(m,1H),2.08–1.98(m,2H),1.96(s,4H),1.63–1.54(m,1H).
参考实施例001的合成路线和方法,合成得到如下具体化合物:
实施例040:PD-1/PD-L1阻断活性(Alphalisa法)
实验步骤:
1.配制化合物:
将化合物配制成50mM(mol/L)的储备液,待用。
2.配制1×Immunoassy Buffer:
用去离子水将10×Immunoassy Buffer稀释成1×Immunoassy Buffer。
3.稀释化合物:
将化合物按照实验方案进行一系列的浓度梯度稀释:首先用DMSO稀释成1000倍终浓度的化合物,再用PBS稀释成100倍终浓度的化合物,最后用1×Immunoassy Buffer稀释成4倍终浓度的化合物,以备后续加样。
4.加样:将已稀释好的化合物以5μL/孔分别加入HTRF 96 well low volumeplate中。
5.配制4×His tagged PD-L1(20nM):取5μL 500nM PD-L1加入120uL 1×Immunoassy Buffer中,吹打混匀,随后,以5μL/孔加入HTRF 96 well low volume plate中。
6.配制4×His tagged PD-1(20nM):取5μL 500nM PD-1加入120μL 1×Immunoassy Buffer中,吹打混匀,随后,以5μL/孔加入HTRF 96 well low volume plate中。
7.配制4×Anti-6×His AlphaLISA Acceptor beads(40μg/mL)和4×Streptavidin(SA)Donor beads(80μg/mL)混合液:取1μL 5mg/mL Anti-6×His AlphaLISAAcceptor beads和2μL 5mg/mL SA-Donor beads加入122uL 1×Immunoassy Buffer中,吹打混匀,随后,5μL/孔加入HTRF 96 well low volume plate中,吹打混匀。
8. 23℃,避光孵育90min。
9.使用EnVision多功能酶标仪的Alpha参数,在615nm处读取吸光值。
表1:PD-1/PD-L1阻断活性实验结果:
注:+:IC50<10nM;++:10nM<IC50<100nM;+++:100nM<IC50<1000nM;++++:1000nM<IC50
由表1可知,本发明制备得到的化合物001~040具有的强效的PD-1/PD-L1阻断活性。
实施例041.PD-L1占据(PBMC)试验
健康人PBMC置于圆底96孔板中,100uL/孔。加入不同浓度待测化合物,随后加入1ng/ml的IFN-g(R&D System)。37℃孵育18小时。随后加入PD-L1流式抗体(PE,M1H1,eBioscience),CD14流式抗体(BV421,),避光染色1小时后。经离心、PBS重悬细胞、过筛等操作后,经流式细胞仪检测CD14+细胞亚群中,PD-L1的平均荧光强度。根据浓度和平均荧光强度作图,并计算IC50。
表2 PD-L1占据(PBMC)
化合物编号 | PBMC(IC<sub>50</sub>) | 化合物编号 | PBMC(IC<sub>50</sub>) |
004 | <1nM | 029 | <1nM |
011 | <1nM | 034 | <1nM |
012 | <1nM | 037 | <1nM |
014 | <1nM | 039 | <1nM |
015 | <1nM | 化合物a | 45nM |
020 | <1nM |
由表2可知:本发明化合物在PBMC占据活性中表现出显著的PD-L1占据活性。
化合物a选自CN110582493A的实施例24:
实施例042.PD-L1占据(MC-38)试验
MC-38细胞置于平底96孔板中,100uL/孔。加入不同浓度待测化合物。37℃孵育18小时。随后加入PD-L1流式抗体(PE,M1H1,eBioscience),避光染色1小时后。经离心、PBS重悬细胞、过筛等操作后,经流式细胞仪检测PD-L1的平均荧光强度。根据浓度和平均荧光强度作图,并计算IC50。
表3 PD-L1占据(MC-38)
注:+:IC50<0.5nM;++:0.5nM<IC50<3nM;+++:3nM<IC50;
由表3可知,本发明化合物在MC-38细胞占据活性中表现出显著的PD-L1占据活性。
实施例043:体外共孵育实验
实验步骤
1. 293T-OS8-hPDL1细胞的预处理:
(1)取1小培养瓶已长满的293T OS8-hPDL1细胞,倒掉培养液,加入4mL PBS清洗后,倒掉PBS,加入1mL胰酶混匀,消化细胞,静置2min后,轻轻拍落细胞,使其完全脱落(可用显微镜观察是否完全脱落),随后加入4mL DMEM-hPDL1完全培养液(DMEM培养液+10%FBS+50μg/mL Hypomycin+0.5ng/mL puromycin)终止消化。
(2)随后,将液体转移至15mL离心管中,转速1000r/min,离心5min。
(3)弃上清,加入2mL DMEM-hPDL1完全培养液,加入2μL丝裂霉素C(Mitomycin C),室温孵育1.5h。
(4)1000r/min,离心5min,弃上清。
(5)加入5mL PBS洗三次(离心,去上清)。
(6)加入2mL 1640-hPDL1完全培养液(1640培养液+10%血清+50μg/mL Hypomycin+0.5ng/mL puromycin)重悬细胞,计数。
2. 293T OS8-hPDL1细胞种板:将293T OS8-hPDL1细胞以5×104个/100μL/孔接种于96孔平板中,混匀。置于37℃5%CO2培养箱中孵育2h。
3. 293T OS8-hPDL1细胞给药。实验组别的设置:
空白对照:PBS(Con)、DMSO(0.1%)
阳性对照:Atezolizumab(10nM)
试验组:待测化合物的各浓度
给药体系:100μL 293T OS8-hPDL1细胞(5万/孔)+1μL化合物(终浓度)给药后,置于37℃5%CO2培养箱中孵育3h。
4.CD3+ T细胞的准备:复苏已购买的CD3+ T细胞,将1mL CD3+ T细胞冻存液加入5mL 1640完全培养液中,1000r/min,离心5min,弃上清。加入5mL1640完全培养液,重悬细胞,计数。
5.CD3+ T细胞种板:将CD3+ T细胞以10×104个/100μL/孔种于原先的96孔平板中,混匀。总体系:200μL 293T OS8-hPDL1细胞和CD3+ T细胞混合液+2μL化合物(终浓度)
6.共孵育培养:细胞置于37℃5%CO2培养箱中,孵育48h。
7.收样:48h后,收取上清液,用于IFN-g的ELISA检测。
8.数据的处理:(化合物检测的数值-空白对照(PBS))/(DMSO-空白对照(PBS))
表4体外共孵育试验结果
化合物编号 | Folds comparing with DMSO(IFN-g) |
012(5nM) | 3.9 |
020(5nM) | 3.2 |
mAb(10nM) | 2.7 |
体外共孵育实验结果表明,本发明制备得到的化合物相比单克隆抗体具有更高的IFN-g表达量,说明本发明化合物能较好的逆转PD-L1抑制的T细胞功能。
实施例044:小鼠吸收试验
以ICR小鼠为实验动物,灌胃给药30mg/kg(采用羧甲基纤维素钠溶液配制成乳白色混悬液)。灌胃给药的取血时间点为0.25、0.5、1、2、4、6、8、24h。取全血0.3ml,离心后取血浆0.1ml采用LC-MS/MS进行分析
表5:小鼠吸收试验实验结果
化合物编号 | 剂量 | C<sub>max</sub> |
012 | 30mg/kg | +++ |
015 | 30mg/kg | +++ |
020 | 30mg/kg | +++ |
029 | 30mg/kg | ++ |
034 | 30mg/kg | ++ |
注:+:Cmax<10ng/ml;++:10ng/ml<Cmax<200ng/ml;+++:200ng/ml<Cmax
由表5可知,本发明得到的化合物具有较好的口服吸收。
实施例045:体内抗肿瘤药效实验
雌性C57BL/6小鼠右前肢接种100万MC38-hPDL1细胞。待肿瘤平均长至90mm3后按肿瘤体积进行随机平均分组。一日两次口服给予不同剂量的化合物。同时一日口服给予2次等体积空白溶媒作为空白对照。一周给予2次Durvalumab单抗(5mg/kg)作为阳性对照。每周3次用游标卡尺测量肿瘤体积,并记录体重。当空白对照组平均肿瘤体积大道2000mm3时,停止实验。根据不同时间个组平均肿瘤体积,绘制肿瘤增长曲线。
试验结果表明,本发明的化合物具有较好的体内抗肿瘤效果。
Claims (12)
7.一种药物组合物,其特征在于,包括权利要求1~6中任意一项所述的化合物的一种或多种。
8.一种药物制剂,其特征在于,包括权利要求1~6中任意一项所述的化合物的一种或多种。
9.根据权利要求8所述的药物制剂,其特征在于,包括片剂、粉剂、胶囊、注射制剂、颗粒制剂、喷雾剂。
10.一种如权利要求1至6任意一项所述化合物在制备单独或与其他药物联合应用治疗从PD1或PD-L1活性的抑制中获益的疾病。
11.如权利要求10所述的应用,其特征在于,所述其他药物选自抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化学治疗剂、抗癌剂、抗血管生成剂、免疫治疗剂、抗激素药、抗纤维化剂、放射治疗剂、抗肿瘤剂或抗增殖剂。
12.如权利要求10所述的应用,其特征在于,所述疾病选自感染性疾病、免疫性疾病、炎性疾病和癌症中的一种或多种。
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CN110582493A (zh) * | 2016-12-22 | 2019-12-17 | 因赛特公司 | 作为免疫调节剂的苯并噁唑衍生物 |
WO2020156323A1 (en) * | 2019-01-31 | 2020-08-06 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods thereof |
CN112135824A (zh) * | 2018-03-30 | 2020-12-25 | 因赛特公司 | 作为免疫调节剂的杂环化合物 |
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CN110582493A (zh) * | 2016-12-22 | 2019-12-17 | 因赛特公司 | 作为免疫调节剂的苯并噁唑衍生物 |
CN112135824A (zh) * | 2018-03-30 | 2020-12-25 | 因赛特公司 | 作为免疫调节剂的杂环化合物 |
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