CN112424194B - 免疫调节剂及其组合物和制备方法 - Google Patents
免疫调节剂及其组合物和制备方法 Download PDFInfo
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- CN112424194B CN112424194B CN201980046611.0A CN201980046611A CN112424194B CN 112424194 B CN112424194 B CN 112424194B CN 201980046611 A CN201980046611 A CN 201980046611A CN 112424194 B CN112424194 B CN 112424194B
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- methyl
- biphenyl
- oxazol
- acetic acid
- benzo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
本发明涉及式I化合物，使用所述化合物作为免疫调节剂的方法，以及包含该化合物的药物组合物。所述化合物可用于治疗，预防或改善疾病或病症，例如癌症或感染。
Description
技术领域
本发明涉及药物活性化合物。本发明提供了该化合物及其组合物和应用方法。该化合物可调节PD-1/PD-L1蛋白质/蛋白质相互作用，并且可用于治疗包括传染病和癌症在内的各种疾病。
背景技术
免疫***在控制和消除癌症等疾病中起着重要作用。但是，癌细胞通常会通过一些策略逃逸或抑制免疫***，从而促进其生长。其中一种机制是改变免疫细胞上共刺激和共抑制分子的表达(Postowetal，J.Clinical Oncology 2015，1-9)。事实证明，阻断PD-1等抑制性免疫检查点的信号是一种有希望的，有效的治疗方式。
PD-1和PD-L1之间的相互作用导致肿瘤浸润淋巴细胞的减少，T细胞受体介导的细胞增殖的减少以及癌细胞的免疫逃逸(Dong et al，J.Mol Med.，81:281-287(2003)；Blanket al，Cancer Immunol Immunother.，54:307-314(2005)；Konishi et al，Clin.CancerRes..10:5094-5100(2004))。可以通过阻断PD-1与PD-L1的局部相互作用来逆转这种免疫抑制作用，并且当PD-1与PD-L2的相互作用被阻断时效果更加明显(Iwai et al.，Proc.Natl.Acad.Sci.USA，99:12293-12297(2002)；Brown et al，J.Immunol，170:1257-1266(2003))。
程序性死亡受体1，也被称作CD279，是在活性T细胞，自然杀伤细胞，B细胞和巨噬细胞上表达的细胞表面受体(Greenwald et al，Annu.Rev.Immunol2005，23:515-548；Okazaki和Honjo，Trends Immunol 2006，(4):195-201)。具有负反馈调节***的功能，可以阻止T细胞的活化来降低自身免疫性同时增强自我耐受性。另外，还已知PD-1在诸如癌症和病毒感染的疾病中在抑制抗原特异性T细胞应答中起关键作用。(Sharpe et al，NatImmunol 2007 8，239-245；Postow et al，J.Clinical Oncol 2015，1-9)。
PD-1由细胞外免疫球蛋白可变样结构域，跨膜区和细胞内结构域组成(Parry etal，Mol Cell Biol 2005，9543-9553)。细胞内结构域包含位于基于免疫受体酪氨酸的抑制基序和基于免疫受体酪氨酸的开关基序中的两个磷酸化位点，这表明PD-1负调节T细胞受体介导的信号。PD-1具有两个配体PD-L1和PD-L2(Parry等，Mol Cell Biol 2005，9543-9553；Latchman等，Nat Immunol 2001，2，261-268)，它们的表达方式不同。在脂多糖和GM-CSF处理后，PD-L1蛋白在巨噬细胞和树突状细胞上表达上调，并在T细胞受体和B细胞受体信号传导后在T细胞和B细胞上调。PD-L1几乎在所有肿瘤细胞中高度表达，并且在IFN-γ处理后表达进一步增加(Iwai等，PNAS2002，99(19)：12293-7；Blank等，Cancer Res 2004，64(3)：1140-5)。实际上，已经证明肿瘤PD-L1表达状态在多种肿瘤类型中是预后的(Wang等人，Eur J Surg Oncol 2015；Huang等人，Oncol Rep 2015；Sabatier等人，Oncotarget2015，6(7)：5449-5464)。相反地，PD-L2的表达更受限制并且主要由树突细胞表达(Nakae等人，J Immunol 2006，177：566-73)。PD-1及其配体PD-L1和PD-L2在T细胞上的连接可产生相关信号来抑制IL-2和IFN-γ的产生以及T细胞受体激活后诱导的细胞增殖(Carter等，EurJ Immunol 2002，32(3)：634-43；Freeman等，J Exp Med 2000，192(7)：1027-34)。该机制涉及募集SHP-2orSHP-1磷酸酶以抑制T细胞受体信号转导例如Syk和Lck的磷酸化(Sharpe etal，Nat Immunol2007，8，239-245)。PD-1信号轴的激活还减弱了PKC-θ激活环的磷酸化，这对于NF-κΒ和API途径的激活以及IL-2，IFN-γ和TNF等细胞因子的产生是必不可少的(Sharpe等人，Nat Immunol 2007，8，239-245；Carter等，Eur J Immunol 2002，32(3)：634-43；Freeman等，J Exp Med 2000，192(7)：1027-134)。
临床前动物研究的一些证据表明，PD-1及其配体会对免疫反应产生负调节作用。PD-1敲除小鼠会发展出狼疮样肾小球肾炎和扩张性心肌病(Nishimura等，Immunity 1999，11：41-151；Nishimura等，Science 2001，291：319-322)。在慢性LCMV病毒感染模型中，已显示PD-1/PD-L1相互作用可抑制病毒特异性CD8 T细胞的效应子功能的激活，扩展和获得(Barber等，自然2006，439，682-7))。
这些数据支持我们开发一种通过阻断PD-1介导的抑制性信号传导级联反应来增强or“拯救”T细胞反应的治疗方法。目前在免疫疗法中批准的大多数药物都是单克隆抗体。但是，直接靶向PD-1orPD-L1的小分子抑制剂仍未被批准，只有CA170进行了临床评估。
因此仍然强烈需要针对PD-1和PD-L1蛋白/蛋白相互作用的更有效更易于施用的治疗药物。在本发明中，申请人发现了一种有效的小分子可以作为PD-L1与PD-1的相互作用的抑制剂，因此可用于治疗性给药以增强针对癌症和/or传染病的免疫力。这些小分子有望成为具有良好稳定性，溶解性，生物利用度，治疗指数和毒性值的药物，这对于成为促进人类健康的有效药物至关重要。
发明内容
本发明涉及用作PD-L1和PD-1相互作用的抑制剂的化合物。PD-1和PD-L1相互作用的抑制剂可以用于治疗癌症和其他感染病。
本发明化合物具有如式Ⅰ所示的一般结构。一种式Ⅰ所示的化合物，或其立体异构体，互变异构体，药学上可接受的盐，前药，螯合物，非共价复合物或溶剂化物，
其中，
W和U分别独立地选自NR10，CR10，C(R10)2，O，或S；
R10是H，或C1-8烷基；
代表单键或双键包括其顺反异构体；
X和Y分别独立地选自不存在，＝(CH)n-，(CH2)n-，-S-，-O-，-NR18-，-CO-，-CONR19-，或-NR20CO-，-SO2-，其中＝(CH)n-，-(CH2)n-，-NR18-，-CONR19-，或-NR20CO-任选地被C1-8烷基，或-OC1-8烷基所取代；其中R18，R19，R20分别独立地选自H，-C1-4烷基，-C1-4卤代烷基，-C1-8杂烷基，-C1-4烷基-COOH，或-C1-4烷基-OH；
R1和R2分别独立地H，-CONH2,-C1-8烷基，-C1-8烯基，-C1-8卤代烷基，-C1-8杂烷基，-C3-10环烷基，-C3-6杂环基，-C5-6杂芳基，-C1-4烷基-C5-6芳基，-CO-C1-4烷基，-SO2-C1-4烷基，-C1-4烷基-COOH，-C1-4烷基-NHCONH-C1-6烷基，-C1-4烷基-OH；或
R1和R2和与它们连接的原子组成5-至6-元杂环；所述杂环任选地包含1，2或3个独立选自N，S或O的杂原子；所述杂环任选地被-C1-8烷基，-C0-4烷基-COOH,-C0-4烷基-OH所取代；
R3，R4和R11分别独立地选自H，卤素，CN，C1-8烷基，或-OC1-8烷基；
R3和X和与它们连接的原子组成5-至6-元杂环；所述杂环任选地包含1，2或3个独立选自N，S或O的杂原子；所述杂环任选地被-C1-8烷基，-C0-4烷基-COOH，或-C0-4烷基-OH所取代；或
R11和Y和与它们连接的原子组成5-至6-元杂环；所述杂环任选地包含1，2或3个独立选自N，S或O的杂原子；所述杂环任选地被-C1-8烷基，-C0-4烷基-COOH，-C0-4烷基-OH所取代；
R5和R6分别独立地选自H，-C1-8烷基，-C1-8杂烷基，-C3-6杂环基，或-C3-10环烷基，其中-C1-8烷基,-C1-8杂烷基，-C3-6杂环基，或C3-10环烷基任选地被-COOH或–OH所取代；或
R5和R6和与它们连接的原子组成4-至6-元杂环；所述杂环任选地包含1，2或3个独立选自N，S或O的杂原子；所述杂环任选地被-C0-4烷基-COOH，或-C0-4烷基-OH所取代；
M是O，S，NR’，C(R’)2或卤素，其中R’是H，或C1-8烷基；
R7是-C1-4烷基，-C1-4卤代烷基，或-C1-4杂烷基，条件为如果M是卤素，则R7为不存在；
R8和R9分别独立地选自H，卤素，CN，或-C1-8烷基；或
R8和R9和与它们连接的原子组成3-至4-元杂环或碳环；
n是0或1。
在式Ⅰ的一些实施例中，W和U分别独立地选自N，O，S，或-NCH3。
在式Ⅰ的一些实施例中，X和Y分别独立地选自不存在，-O-，＝CH-，-CH2，-NH-，-CONH-，或-CO-。
在式Ⅰ的一些实施例中，如权利要求1-3任一项所述的化合物，其中R1和R2分别独立地选自H，甲基，
在式Ⅰ的一些实施例中，R1和R2和与它们连接的原子组成6-元杂环。
在式Ⅰ的一些实施例中，R1和R2和与它们连接的原子组成
在式Ⅰ的一些实施例中，R3和R4分别独立地选自H，-CH3，F，Cl，或CN。
在式Ⅰ的一些实施例中，R3和X和与它们连接的原子组成5-至6-元杂环；所述杂环任选地包含1或2个独立选自N，S或O的杂原子。
在式Ⅰ的一些实施例中，R3和X和与它们连接的原子组成
在式Ⅰ的一些实施例中，R5和R6和与它们连接的原子组成
在式Ⅰ的一些实施例中，其中R5和R6分别独立地选自H，-CH3，
在式Ⅰ的一些实施例中，其中M是O，或-NCH3。
在式Ⅰ的一些实施例中，R7分别独立地选自-CH3，-CH2CH3，
在式Ⅰ的一些实施例中，其中R8和R9和与他们连接的原子组成
关于式Ⅰ的化合物，本发明还提供了更多的优选的技术方案，所述化合物为：
1)2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙烷-1-醇
2)1-(6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)-N,N-二甲基甲胺
3)1-((2-(2,2'-二甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
4)1-((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
5)1-((2-(3'-(3-(2-((2-羟乙基)氨基)乙基)尿素)-2-甲基-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
6)(E)-1-((2-(2,2'-二甲基-3'-(4-吗啉代丁基-2-烯-1-基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
7)(E)-1-((2-(2,2'-二甲基-3'-(4-吗啉代丁基-1-烯-1-基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
8)1-((2-(2,2'-二甲基-3'-(3-吗啉丙酰胺)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
9)1-((2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
10)1-((6-甲氧基-2-(2-甲基-3'-(4-吗啉代丁基yl)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
11)1-((2-(4'-氯-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
12)1-(2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-5-甲氧基-1-甲基-1H-苯并[d]咪唑-6-基)哌啶-2-乙酸
13)1-((2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)甲基)哌啶-2-乙酸
14)4-((6-甲氧基-1-甲基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-1H-苯并[d]咪唑-5-基)甲基)吗啉-3-乙酸
15)4,4-二氟-1-((6-甲氧基-1-甲基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-1H-苯并[d]咪唑-5-基)甲基)哌啶-2-乙酸
16)4,4-二氟-1-((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
17)4-((6-甲氧基-2-(2-甲基-3'-(3-吗啉丙酰胺)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
18)4-((2-(2'-氰基-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
19)N-((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)-N-甲基甘氨酸
20)((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)脯氨酸
21)3-羟基-2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)-2-甲基丙酸
22)1-((2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-(吡啶-2-基甲氧基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
23)1-((6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
24)1-((6-异丙氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
25)((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-5-基)甲基)脯氨酸
26)((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-6-基)甲基)脯氨酸
27)1-((2-(2,2'-二甲基-3'-((3-(吗啉代甲基)环氧乙烷基-2-基)甲基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
28)1-((2-(2,2'-二甲基-3'-((2-(吗啉代甲基)环丙基)甲基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
29)1-((2-(3'-(3-((4-羟丁基)(甲基)氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
30)1-((2-(3'-(3-(二甲基氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
31)1-((6-甲氧基-2-(3'-(3-((2-甲氧基乙基)(甲基)氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
32)1-((2-(2,2'-二甲基-3'-(3-(甲基(2-(3-丙基尿素)乙基)氨基)丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
33)1-((5-甲氧基-1-甲基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-1H-苯并[d]咪唑-6-基)甲基)哌啶-2-乙酸
34)1-((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-6-基)甲基)哌啶-2-乙酸
35)1-((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-6-基)甲基)哌啶-2-乙酸
36)((2-(2,2'-二甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-(二甲基氨基)苯并[d]噻唑-5-基)甲基)甘氨酸
37)N-((2-(2,2'-二甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-(二甲基氨基)苯并[d]恶唑-5-基)甲基)-N-甲基甘氨酸
38)4-((6-甲氧基-2-(2-甲基-3-(1-(3-吗啉代丙酰基)吲哚啉-4-基)苯基)苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
39)1-((6-乙氧基-2-(2-甲基-3-(1-(3-吗啉代丙酰基)吲哚啉-4-基)苯基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
40)1-((6-甲氧基-2-(2-甲基-3-(1-(2-吗啉代乙酰基)吲哚啉-4-基)苯基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
本发明还提供了一种包含本发明任一种化合物的药用组合物和一种药学上可接受的辅料，比如说羟丙基甲基纤维素。在该组合物中，所述化合物与所述辅料的重量比大约为0.0001至10。
本发明还提供了式Ⅰ化合物的药用组合物在用于制备治疗受试者疾病的药物中的用途。
本发明还提供了与上述用途相关的一些优选的技术方案。
在一些实施例中，制备的药物可用于治疗，预防或者延迟癌症，癌症的转移，免疫***相关疾病的发生或进展。所述癌症包括胃癌，甲状腺癌，肺癌，白血病，胰腺癌，黑色素瘤，多发性黑色素瘤，脑癌，肾癌，***癌，卵巢癌或乳腺癌。
本发明还提供了一种抑制PD-1/PD-L1之间相互作用的方法，所述方法包括向患者施用权利要求1-12任一项中的化合物或其药学上可接受的盐或其立体异构体。
本发明提供了一种治疗与PD-1/PD-L1之间相互作用有关的疾病的治疗方法，所述方法包括向所需患者施用治疗有效量的本发明中的任一化合物，或其药学上可接受的盐或其立体异构体。所述疾病包括结肠癌，胃癌，甲状腺癌，肺癌，白血病，胰腺癌，黑色素瘤，多发性黑色素瘤，脑癌，肾癌，***癌，卵巢癌或乳腺癌。
本发明提供了一种提高，刺激或增加患者免疫***的方法，所述方法包括向所需患者施用治疗有效量的本发明中的任一化合物，或其药学上可接受的盐或其立体异构体。
本发明还提供了一种该化合物或其药用组合物在制备药物中的用途。
在一些实施例中，该药物可用于治疗或预防癌症。
在一些实施例中，所述癌症为结肠癌，胃癌，甲状腺癌，肺癌，白血病，胰腺癌，黑色素瘤，多发性黑色素瘤，脑癌，肾癌，***癌，卵巢癌或乳腺癌。
在一些实施例中，该药物可用作PD-1/PD-L1相互作用的抑制剂的药物。
上述通式中使用的一般化学术语具有其通常的含义。例如，如本文所用，除非另有说明，否则本文术语“卤素”指的是氟，氯，溴或碘。优选的卤素为F，Cl和Br。
如本文所用，除非另有说明，烷基包括具有直链，支链或环状部分的饱和一价烃基。例如，烷基包括甲基，乙基，丙基，异丙基，环丙基，正丁基，异丁基，仲丁基，叔丁基，环丁基，正戊基，3-(2-甲基)丁基，2-戊基，2-甲基丁基，新戊基，环戊基，正己基，2-己基，2-甲基戊基和环己基。类似地，如C1-8烷基，定义C1-8基团具有1、2、3、4、5、6、7或8个线性或支链排列的碳原子。
烯基和炔基包括直链，支链或环状的烯烃和炔烃。同样地，“C2-8烯基”和“C2-8炔基”是指具有2、3、4、5、6、7或8个碳原子的线性或分支排列的烯基或炔基。
烷氧基是由前述直链，支链或环状烷基形成的氧醚。
除非另有说明，否则本文所用的术语“芳基”是指含有碳环原子的未取代或取代的单环或多环***。优选的芳基是单环或双环6-10元芳族环***。苯基和萘基是优选的芳基。最优选的芳基是苯基。
除非另有说明，否则本文所用的术语“杂环基”表示未取代或取代的稳定的三至八元单环饱和环***，其由碳原子和选自N，O或S的一个至三个杂原子组成，其中氮或硫杂原子可任选地被氧化，并且氮杂原子可任选被季铵化。杂环基可以连接在任何杂原子或碳原子上，以形成稳定的结构。此类杂环基的实例包括但不限于氮杂环丁烷基，吡咯烷基，哌啶基，哌嗪基，氧代哌嗪基，氧代哌啶基，氧杂庚基，庚基，四氢呋喃基，二氧戊环基，四氢咪唑基，四氢吡唑基，四氢恶唑基，硫代吡啶基，四氢萘基，噻吗啉基亚砜，噻吗啉基砜和恶二唑基。
除非另有说明，否则本文所用的术语“杂芳基”表示未取代或取代的稳定的五或六元单环芳族环***或未取代或取代的九或十元苯并稠合的杂芳族环***或双环杂芳族环***，其由碳原子和选自N，O或S的1-4个杂原子组成，其中氮或硫杂原子可以任选地被氧化，并且氮杂原子可以任选地被季铵化。杂芳基可以连接在任何杂原子或碳原子上，以形成稳定的结构。杂芳基的实例包括但不限于噻吩基，呋喃基，咪唑基，恶唑基，恶唑基，吡唑基，吡咯基，噻唑基，噻二唑基，***基，吡啶基，哒嗪基，吲哚基，氮杂吲哚基，吲唑基，苯并咪唑基，苯并呋喃基，苯并噻吩基，苯并恶唑基，苯并恶唑基，苯并吡唑基，苯并噻唑基，苯并噻二唑基，苯并***基腺嘌呤基，喹啉基或异喹啉基。
术语“烯基氧基”是指基团-O-烯基，其中烯基如上定义。
术语“炔基氧基”是指基团-O-炔基，其中炔基如上定义。
术语“环烷基”是指具有3至12个碳原子的环状饱和烷基链，例如环丙基，环丁基，环丁基，环丁基。
术语“取代的”是指其中一个或多个氢原子各自独立地被相同或不同的取代基取代的基团。典型的取代基包括但不限于，卤素(F，Cl，Br或I)，C1-8烷基，C3-12环烷基，-OR1，SR1，＝O，＝S，-C(O)R1，-C(S)R1，＝NR1，-C(O)OR1，-C(S)OR1，-NR1R2，-C(O)NR1R2，氰基，硝基，-S(O)2R1，-OS(O2)OR1，-OS(O)2R1，-OP(O)(OR1)(OR2)；其中R1和R2分别独立地选自-H，低级烷基，低级卤代烷基。在一些实施例中，取代基分别独立选自-F，-Cl，-Br，-I，-OH，三氟甲氧基，乙氧基，丙氧基，异丙氧基，正丁氧基，异丁氧基，叔丁氧基，-SCH3，-SC2H5，甲醛基，-C(OCH3)，氰基，硝基，CF3，-OCF3，氨基，二甲基氨基,甲基硫，磺酰基和乙酰基。
如本文所用的术语，“组合物”指的是包括由指定量的指定成分组成的产品，以及由指定量的指定成分组合直接或间接产生的任何产品。因此，含有本发明化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的某些晶型可以多晶型物的形式存在，因此旨在包括在本发明中。另外，一些化合物可以与水(即水合物)或普通有机溶剂形成溶剂化物，并且这些溶剂化物也意图包括在本发明的范围内。
取代的烷基的实例包括但不限于2-氨基苄基，2-羟乙基，五氯苯乙烯，三氟甲基，甲氧基甲基，五氟甲苯和哌嗪基甲基。
取代的烷氧基的实例包括但不限于氨基甲氧基，三氟甲氧基，2-二苯基氨基乙氧基，2-乙氧基羰基乙氧基，3-羟基丙氧基。
本发明的化合物也可以药学上可接受的盐的形式存在。为了用于医学，本发明化合物的盐是指无毒的“药学上可接受的盐”。药学上可接受的盐形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐。药学上可接受的酸性/阴离子盐通常采用碱性氮被无机或有机酸质子化的形式。代表性的有机或无机酸包括盐酸，氢溴酸，氢碘酸，高氯酸，硫酸，硝酸，磷酸，乙酸，丙酸，乙醇酸，乳酸，琥珀酸，顺丁烯二酸，富马酸，苹果酸，酒石酸，柠檬酸，苯甲酸，扁桃酸，甲磺酸，羟基乙磺酸，苯磺酸，草酸，帕莫酸，萘磺酸，对甲苯磺酸，环己烷氨基磺酸，水杨酸，糖精或三氟乙酸。药学上可接受的碱性/阳离子盐包括但不限于铝，钙，氯普鲁卡因，胆碱，二乙醇胺，乙二胺，锂，镁，钾，钠和锌。
本发明在其范围内包括本发明化合物的前药。通常，此类前药是化合物的功能性衍生物，其易于在体内转化为所需化合物。因此，在本发明的治疗方法中，术语“施用”应涵盖应用具体公开的化合物或可能未具体公开但给予对象后体内转化为特定化合物的化合物对所述各种疾病的治疗。合适的前药衍生物的选择和制备的常规程序描述于例如“Design of Prodrugs”(ed。)。H.Bundgaard，爱思唯尔，1985年。
需要指出的是分子的特定位置处的任何取代基或变量的定义独立于该分子中其他位置的定义。可以理解的是，本发明化合物的取代基和取代方式可以由本领域普通技术人员选择，以提供化学上稳定的化合物，并且可以通过本领域已知的技术以及在此阐述的那些方法容易地合成。
本发明包括的化合物含有一个或者多个不对称中心，因此产生非对映异构体和旋光异构体。本发明包括所有可能的非对映异构体和他们的外消旋混合物，基本上纯的对映体，所有的几何异构体和其药学上可接受的盐。
上述式Ⅰ所示的化合物在特定位置没有确定的立体化学。本发明包括式Ⅰ所有的立体异构体和其药学上可接受的盐。另外地，本发明也包括立体异构体的混合物和分离的特定异构体。在用于制备此类化合物的合成程序过程中，或在使用本领域技术人员已知的外消旋或差向异构程序的过程中，此类程序的产物可以是立体异构体的混合物。
当存在式I化合物的互变异构体时，除非另有特别说明，否则本发明包括任何可能的互变异构体及其药学上可接受的盐，及其混合物。
当式Ⅰ化合物和其药学上可接受的盐以溶剂化物或多晶型形式存在的时候，本发明包括了任何一种溶剂化物和多晶型物。形成溶剂化物的溶剂的类型没有特别限制，只要该溶剂是药理学上可接受的即可。例如，可以使用水，乙醇，丙醇，丙酮等。
术语“药学上可接受的盐”是指由药学上可接受的无毒碱或酸制备的盐。当本发明的化合物为酸性时，其相应的盐可以方便地由药学上可接受的无毒碱，包括无机碱和有机碱制备。衍生自此类无机碱的盐包括铝，铵，钙，铜(一价和二价)，铁，亚铁，锂，镁，锰(一价和二价)，钾，钠，锌等盐。特别优选地是铵，钙，镁，钾和钠盐。衍生自药学上可接受的有机无毒碱的盐包括伯，仲，和叔胺的盐，以及环胺和取代的胺，例如天然和合成的取代胺。可以形成盐的其他药学上可接受的有机无毒碱包括离子交换树脂，例如精氨酸，甜菜碱，咖啡因，胆碱，N',N'-二苄基苯二胺，二叔胺，2-二甲苯氨基乙醇，2-二甲基氨基乙醇，乙醇胺，苯二胺，N-苯吗啉，N-苯甲酸，葡萄糖胺，葡糖胺，组氨酸，肼苯达明，异丙胺，赖氨酸，甲基葡糖胺，吗啉，哌嗪，苯基吡啶，多胺树脂，普鲁卡因，嘌呤，可可碱，三丁胺，三甲基胺，三丙基胺，三甲胺等。
当本发明的化合物为碱性时，其相应的盐可以方便地由药学上可接受的无毒酸，包括无机和有机酸制备。这样的酸包括，例如，乙酸，苯磺酸，苯并甲酸，樟脑磺酸，柠檬酸，乙磺酸，甲酸，富马酸，葡萄糖酸，谷氨酸，氢溴酸，盐酸，等离子，乳酸，马来酸，苹果酸，扁桃酸，甲烷磺酸，粘液，硝酸，帕莫酸，泛酸，磷酸，琥珀酸，硫酸，酒石酸，对甲苯磺酸等。优选的是柠檬酸，氢溴酸，甲酸，盐酸，马来酸，磷酸，硫酸和酒石酸，特别优选的是甲酸和盐酸。由于式I化合物旨在用于药物用途，因此它们优选以基本上纯的形式提供，例如至少60％的纯度，更合适地至少75％的纯度，尤其是至少98％的纯度(％以重量计)基础)。
本发明药用组合物含有式Ⅰ所示化合物(或其药学上可接受的盐)作为活性成分，一种药学上可接受的载体和任选的其他有治疗效果的成分或佐剂。所述组合物包括适合于口服，直肠，局部和/或肠胃外(包括皮下，肌内，和静脉内)施用的组合物，尽管在任何给定情况下最合适的途径将取决于具体的宿主，和/或所处条件的严重性。活性成分正在服用。药物组合物可以方便地以单位剂型和通过药学领域公知的任何方法制备。
在实践中，本发明式Ⅰ所示的化合物或其前药，或其代谢物，或其药学上可接受的盐，可以作为活性成分通过传统的药物混合技术与一种药学上的载体进行充分混合。载体可根据所需的给药方式采取多种形式，例如，口服或肠胃外(包括静脉注射)。因此，本发明的药用组合物可以制备成独立地可用于口服的制剂，例如，每个均包含预定量活性成分的胶囊，扁囊剂或片剂。另外地，该组合物也可作为粉末剂，颗粒剂，溶液和分散剂存在与水性溶液中，在非水性溶液中，可以作为水包油乳液或油包水乳液。除了上述常见剂型外，式Ⅰ所示化合物或其药学上可接受的盐也可一毛缓释制剂或递送装置的形式给药。该组合物可通过药学中的任一方法制备。通常，这些方法包括使活性成分与一种或多种必要成分的载体结合的步骤。通常，通过将活性成分与液体载体或细分的固体载体或与两者均匀和紧密地混合来制备组合物。然后可以将产品方便地成形为所需的外观。
因此，本发明的药用组合物可包含一种药学上可接受的载体和式Ⅰ化合物或其药学上可接受的盐。式Ⅰ化合物或其药学上可接受的盐可被包含在其他药用组合物中与其他一种或多种活性成分联合使用。
应用的药用载体可为，例如，固体，液体或气体。固体载体包括乳糖，白土，蔗糖，滑石粉，明胶，琼脂，果胶，***胶，硬脂酸镁和和硬脂酸。液体载体包括糖浆，花生油，橄榄油和水。气态载体的实例包括例如二氧化碳和氮气。在制备口服剂型的组合物时，可使用任何方便的药物介质。例如，水，乙二醇，油，醇，调味剂，防腐剂，着色剂等可用于形成口服液制剂，例如混悬剂，酊剂和溶液；而诸如淀粉，糖，微晶纤维素，稀释剂，制粒剂，润滑剂，粘合剂，崩解剂等的载体可用于形成口服固体制剂，如粉剂，胶囊剂和片剂。因为给药方便，药物和胶囊是最优的口服剂型，其中使用固体的药用载体。任选地，可以通过标准的水性或非水性技术将片剂包衣。
含有该组合物和任选地一种或多种必要成分和佐剂的片剂可通过压制或者模制来制备。可以通过在合适的机器中将自由流动形式的活性成分例如粉末或颗粒压缩，任选地与粘合剂，润滑剂，惰性稀释剂，表面活性剂或分散剂混合来制备压制片剂。可以通过在合适的机器中将用惰性液体稀释剂润湿过的粉末状化合物来制备模制片剂。每一片剂，扁囊剂和胶囊含有约0.05mg至5mg的活性成分。例如，给人服用的口服制剂可包含0.5mg至5g的活性成分，其与合适的方便量的载体材料混合，所述载体材料占混合物总量的比例5％至95％。单位剂量通常含有约1mg至2g的活性成分，经常为25mg，50mg，l00mg，200mg，300mg，400mg，500mg，600mg，800mg，或l000mg。
用作肠胃外给药的本发明药用组合物其活性成分可制备成在水中的溶液或分散剂。可以使用合适的表面活性剂，例如，羟丙基纤维素。分散体也可由甘油，液态聚乙二醇，及其在油中的混合物制备。另外地，此外，可以包含防腐剂以防止微生物的有害生长。
用于注射的本发明药用组合物包括无菌水溶液和分散体。另外地，该组合物可以是无菌粉末的形式，用于临时制备这种无菌注射溶液或分散液。在所有情况下，最终的注射形式必须为无菌形式并且必须可以有效的流动以易于注射。该药用组合物必须在生产和储存条件下稳定；因此，应该注意保存以防止微生物例如细菌和真菌的污染。载体可以是溶剂或分散介质，其包含例如水，乙醇，多元醇(例如甘油，丙二醇和液态聚乙二醇)，植物油及其合适的混合物。
本发明的药用组合物可作为局部应用，例如，气雾剂，霜剂，软膏剂，洗剂，除尘粉等。此外，该组合物可以是适合用于透皮装置的形式。这些制剂可使用本发明式Ⅰ化合物或其药学上可接受的盐通过传统的方法来制备。例如，通过将亲水性材料和水与约5wt％至约10wt％的化合物混合以制备具有所需稠度的乳膏或软膏，可以制备乳膏或软膏。
本发明药用组合物可制备成植入剂，其载体为固体。优选地是混合物形成单位剂量的栓剂。合适的载体包括可可脂和其他本领域常用材料。栓剂可通过以下方式方便地形成：首先将组合物与软化或熔融的载体混合，然后在模具中冷却和成形。
除了前面提到的载体材料，前面描述的药用制剂还可能包括合适的一种或多种其他的载体成分，例如，稀释剂，缓冲剂，调味剂，粘合剂，表面活性剂，增稠剂，润滑剂，防腐剂(包括抗氧化剂)等。此外，也可包括其他佐剂使得制剂与预期接受者的血液等渗。含有式Ⅰ化合物或其药学上可接受的盐的组合物也可制备为粉末或液体浓缩物形式。
通常，在上述疾病的治疗中剂量水平为每天约体重水平的0.01mg/kg到150mg/kg，或每位患者每天约0.5mg至7g。例如，对于结肠癌，直肠癌，套细胞淋巴瘤，多发性骨髓瘤，乳腺癌，***癌，胶质母细胞瘤，鳞状细胞食道癌，脂肪肉瘤，T细胞淋巴瘤黑素瘤，胰腺癌，胶质母细胞瘤或肺癌可通过以下药物有效治疗：每公斤体重每天约0.01至50mg化合物，或每位患者每天约0.5mg至3.5g化合物。
然而应当理解的是，也有可能会用到比上述剂量高或低的剂量。对于具体受试者的具体的剂量水平和治疗方式取决于很多因素，包括所施用的具体化合物，患者的年龄，体重，健康状况，性别，饮食，给药时间，给药方式，***率，药物组合，接受治疗的特定疾病的严重程度和病程，疾病的治疗对象以及治疗医师的判断。
通过以下对本发明的书面描述，这些和其他方面将变得显而易见。
提供以下实施例来对本发明进行更好的说明。除非另有明确说明，所有份数和百分比均以重量计，所有温度均为摄氏度。
将会通过具体的实施例更细节地描述本发明。提供以下实施例用于说明性目的，并且无意以任何方式限制本发明。本领域技术人员将容易认识到可以改变或修改以产生基本相同结果的各种非关键参数。根据本文所述的至少一种测定法，发现实施例的化合物抑制PD-1/PD-L1蛋白/蛋白相互作用的活性。
实施例
制备本发明化合物的实验步骤如下所述。利用开放获取制备型LCMS在Waters质量导向分馏***上纯化了一些制备的化合物。用于这些***操作的基本设备设置，协议和控制软件已在文献中进行了详细描述。参见，例如，Blom，“用于制备型LC-MS的两泵在柱稀释配置中”，K.Blom，J.Combi.Chem，2002，4，295-301；Blom等人，“优化用于平行合成纯化的制备型LC-MS配置和方法”，J.Combi.Chem，2003，5，670-83；和Blom等人，“制备型LC-MS纯化：改进的化合物特异性方法优化”，J.Combi.Chem，2004，6，874-883。
实施例中使用了下列缩略语：
ACN:乙腈；
AcOH:乙酸；
BSA:牛血清白蛋白；
DCM:二氯甲烷；
DDQ:2,3-二氯-5,6-二氰基-p-苯醌；
DMSO:二甲基亚砜；
EtOAc:乙酸乙酯；
h or hrs:小时；
HTRF:均相时间分辨荧光；
MeOH:甲醇；
min:分钟；
rt or r.t.:室温；
THF:四氢呋喃。
实施例1化合物23的合成
1-((6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
步骤1：3-溴-2-甲基苯甲醛的制备
10℃下向(3-溴-2-甲基苯基)甲醇(20.1g)的干燥二氯甲烷溶液(300mL)分批加入戴斯-马丁试剂(51.1g)。室温下搅拌所得溶液1小时。通过硅藻土过滤混合物。固体用DCM洗涤后，混合滤液用碳酸氢钠水溶液，水和盐水洗涤后干燥浓缩。残留物通过柱色谱法纯化(正己烷-乙酸乙酯以50:1至15:1的比例进行洗脱)得到3-溴-2-甲基苯甲醛为白色固体。(16.3g)
步骤2：5-氨基-2,4-二羟基苯甲酸甲酯的制备
在氢气的环境压力下，使用在碳上的氢氧化钯碳(10wt％,8.2g)的MeOH(200mL)溶液将2,4-二羟基-5-硝基苯甲酸甲酯(15g)氢化过夜。混合物通过硅藻土过滤，用DCM洗涤，减压除去溶剂。粗品经柱色谱纯化(DCM-MeOH以50:1至10:1的比例进行洗脱)得到5-氨基-2,4-二羟基苯甲酸甲酯为棕色固体。(8.6g)
步骤3：2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-羧酸甲酯的制备
将3-溴-2-甲基苯甲醛(6.01g)，5-氨基-2,4-二羟基苯甲酸甲酯(5.54g)于MeOH(80mL)的混合物置于小瓶中，搅拌并回流1小时。浓缩混合物，残留物重新溶解于DCM(150mL)，加入DDQ(10.32g)。混合物于室温下搅拌1小时。用DCM稀释反应然后用Na2S2O3溶液和NaHCO3溶液洗涤。有机相通过MgSO4干燥,过滤并且浓缩滤液。得到2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-羧酸甲酯为棕色固体(10g)。
步骤4：2-(3-溴-2-甲基苯基)-5-(羟甲基)苯并[d]恶唑-6-醇的制备
0℃下2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-羧酸甲脂(3.01g)的DCM(40mL)和THF(100mL)溶液中逐滴加入LiAlH4的THF(2.5M,5mL)溶液。混合物加热至室温。1小时后，用1mL水和1mL10％NaOH溶液淬灭反应，用1M HCl，水和盐水洗涤。有机相通过Na2SO4干燥，过滤并浓缩滤液。得到2-(3-溴-2-甲基苯基)-5-(羟基甲基)苯并[d]恶唑-6-醇为黄色固体。(2.7g)
步骤5：2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-甲醛的制备
10℃下2-(3-溴-2-甲基苯基)-5-(羟基甲基)苯并[d]恶唑-6-醇(1.01g)的干燥THF(15mL)溶液中分批加入Dess-Martin试剂(1.79g)。所得溶液室温下搅拌1小时。硅藻土过滤混合物。DCM洗涤固体，合并的滤液使用碳酸氢钠水溶液，水和盐水进行洗涤，干燥，浓缩。残留物通过柱色谱法纯化(正己烷-EtOAc以20:1至5:1的比例进行洗脱)得到2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-甲醛为黄色固体(320mg)。
步骤6：2-(3-溴-2-甲基苯基)-6-甲氧基苯并[d]恶唑-5-甲醛的制备
向2-(3-溴-2-甲基苯基)-6-羟基苯并[d]恶唑-5-甲醛(151mg)的ACN(4mL)的溶液中加入K2CO3(188mg)，碘甲烷(3滴)，80℃下搅拌过夜。反应冷却至室温后用DCM稀释并用水和NaCl溶液洗涤。有机相通过MgSO4干燥，过滤并浓缩滤液。残留物通过柱色谱法纯化(正己烷-EtOAc以20:1至5:1的梯度洗脱)得到2-(3-溴-2-甲基苯基)-6-甲氧基苯并[d]恶唑-5-甲醛为白色固体(121mg)。
步骤7：6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛的制备
将2-(3-溴-2-甲基苯基)-6-甲氧基苯并[d]恶唑-5-甲醛(70mg)，苯硼酸(40mg)和醋酸钾(83mg)于1,4-二氧六环(2mL)和水(0.5mL)中的混合物吹氮气10分钟。加入[1,1'-双(二苯基膦基)二茂铁]-二氯钯DCM(17mg)，混合物另吹氮气5分钟然后加热回流2小时。混合物冷却后通过硅藻土过滤。EtOAc洗涤固体，混合滤液用水和盐水洗涤，干燥，浓缩。残留物通过柱色谱法纯化(正己烷-EtOAc以20:1至5:1的梯度洗脱)得到6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛为白色固体。(61mg)
步骤8：1-((6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸(化合物23)的制备
6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛(61mg),哌啶-2-乙酸(46mg)和AcOH(11mg)的MeOH溶液在室温小搅拌0.5小时。混合物中加入NaBH3CN(34mg)，然后加热至60℃并持续2小时。冷却混合物后用DCM稀释并用水和NaCl溶液洗涤。有机相通过MgSO4干燥，过滤并浓缩滤液。残留物通过柱色谱法纯化得到1-((6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸(化合物23)为白色固体。(33mg)
实施例2化合物1的合成
步骤1：4-(3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丙基)吗啉的制备
1)向3-溴酚(50mg)的ACN(20mL)溶液中加入1-溴-3-氯丙烷(100mg)和K2CO3(100mg)。混合物搅拌12小时。浓缩所得溶液，所得固体通过柱色谱法纯化得到1-溴-3-(3-氯丙氧基)苯，50mg。
2)向1-溴-3-(2-氯乙氧基)-2-甲基苯(50mg)的ACN(20mL)溶液中加入吗啉(100mg)和K2CO3(100mg)和KI(60mg)。84℃下搅拌混合物12小时。浓缩所得溶液，所得固体通过柱色谱法纯化得到4-(3-(3-苯氧基)丙基)吗啉，60mg。
3)向4-(3-(3-溴苯氧基)丙基)吗啉(200mg)的二氧六环(56mL)溶液，加入4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧杂硼烷)(180mg)，KOAC(100mg)，Pd(dppf)Cl2(40mg)。氮气保护下混合物在90℃搅拌12小时。反应用水(50mL)淬灭并用EtOAc萃取3次。合并有机相并用盐水洗涤。浓缩所得溶液并用硅胶纯化(正己烷-EtOAc以8:1至5:1的梯度进行洗脱)得到4-(3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丙基)吗啉(100mg)。
步骤2：6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛的制备
如实施例1所述制备2-(3-溴-2-甲基苯基)-6-甲氧基苯并[d]恶唑-5-甲醛(6-1)。
将2-(3-溴-2-甲基苯基)-6-甲氧基苯并[d]恶唑-5-甲醛(70mg)，4-(3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基)丙基)吗啉(78mg)和醋酸钾(83mg)于1,4-二氧六环(2mL)和水(0.5mL)中的混合物吹氮气10分钟。加入[1,1'-双(二苯基膦基)二茂铁]-二氯钯DCM(17mg)，混合物再次吹氮气5分钟然后加热回流2小时。冷却混合物后用硅藻土过滤。用EtOAc洗涤固体，合并的滤液用水和盐水洗涤，干燥，浓缩。残留物通过柱色谱法纯化(正己烷-EtOAc以20:1至5:1的梯度洗脱)得到6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛为白色固体(61mg)。
步骤3:2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙烷-1醇(化合物1)的制备
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6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-甲醛(68mg)，2-氨基乙烷-1醇(86mg)和AcOH(11mg)的MeOH溶液室温下搅拌0.5小时。混合物中加入NaBH3CN(34mg)，然后加热至60℃保持2小时。冷却混合物并用DCM稀释，并用水和NaCl溶液洗涤。有机相通过MgSO4干燥，过滤，浓缩滤液。残留物通过柱色谱法纯化(DCM-甲醇以50:1至10:1的梯度进行洗脱)得到2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙烷-1醇(化合物1)为白色固体。(33mg)使用相应的中间体，基本上如实施例1所述的方法制备下列化合物，
表1
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均相时间分辨荧光(HTRF)结合试验
测试在标准黑色384孔聚苯乙烯平板中进行，最终体积为20μL。首先在DMSO中连续稀释抑制剂，然后在添加其他反应组分之前将其添加到板孔中。测定DMSO的最终浓度为1％。该测定是在25℃，含0.05％吐温-20和0.1％BSA的PBS缓冲液(pH 7.4)中进行的。C端带有His-标签的重组人PD-L1蛋白(19-238)购自AcroBiosy stems(PD1-H5229)。C末端带有Fc标签的重组人PD-1蛋白(25-167)同样购自AcroBiosy stems(PD1-H5257)。在测定缓冲液中稀释PD-L1和PD-1蛋白，并向板孔中加入10μL。将板离心，并将蛋白质与抑制剂预孵育40分钟。孵育后，添加10μL HTRF检测缓冲液，该缓冲液中补充了对Fc有特异性的加密标记的抗人IgG(PerkinElmer-AD0212)和与-别藻蓝蛋白(Allophycocyanin)(APC，PerkinElmer-AD0059H)偶联的抗His抗体。离心后，将孔板在25℃下孵育60分钟。在PHERAstar FS读板器(665nm/620nm比率)上阅读之前。测定中的最终浓度为-3nM PD1、10nMPD-L1、1nM抗人IgG和20nM抗His-别藻蓝蛋白。使用GraphPad Prism5.0软件拟合控制活性百分比与抑制剂浓度对数的曲线来进行IC50测定。
如实施例中所例示的，本发明的化合物的IC50值在以下范围内：“*”代表“IC50≤2nM”；“**”代表“2nM<IC50≤10nM”；“***”代表“10nM<IC50≤150nM”；“****”代表“IC50＞150nM”.
表1提供了使用PD-1/PD-L1均相时间分辨荧光(HTRF)结合方法测定获得的实施例A中所述化合物的数据。
表2
| 实施例序号 | IC50 | 实施例序号 | IC50 |
| 1 | * | 21 | * |
| 2 | ** | 22 | ** |
| 3 | 1nM | 23 | 0.61nM |
| 4 | * | 24 | * |
| 5 | ** | 25 | * |
| 6 | * | 26 | * |
| 7 | * | 27 | ** |
| 8 | * | 28 | ** |
| 9 | * | 29 | * |
| 10 | ** | 30 | * |
| 11 | ** | 31 | * |
| 12 | * | 32 | * |
| 13 | * | 33 | * |
| 14 | * | 34 | * |
| 15 | ** | 35 | * |
| 16 | ** | 36 | ** |
| 17 | * | 37 | * |
| 18 | * | 38 | * |
| 19 | ** | 39 | * |
| 20 | * | 40 | *** |
Claims (6)
1.一种式I所示的化合物，或其药学上可接受的盐，
其中，
W和U分别独立地选自N或O；
为单键或双键；
X和Y分别独立地选自不存在、-O-、＝CH-、-CH2-、-NH-、-CONH-或-CO-；
R1和R2分别独立地选自H、甲基、 或
R1和R2和与它们连接的原子组成
R3，R4和R11分别独立地选自H、-CH3、F、Cl或CN；
R5和R6和与它们连接的原子组成
M为O；
R7选自-CH3、-CH2CH3、
R8和R9为H；
n为1。
2.一种化合物或其药学上可接受的盐，其中化合物为：
1)2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)乙烷-1-醇
3)1-((2-(2,2'-二甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
4)1-((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
6)(E)-1-((2-(2,2'-二甲基-3'-(4-吗啉代丁基-2-烯-1-基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
7)(E)-1-((2-(2,2'-二甲基-3'-(4-吗啉代丁基-1-烯-1-基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
8)1-((2-(2,2'-二甲基-3'-(3-吗啉丙酰胺)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
9)1-((2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
12)1-(2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-5-甲氧基-1-甲基-1H-苯并[d]咪唑-6-基)哌啶-2-乙酸
13)1-((2-(2'-氟-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)甲基)哌啶-2-乙酸
14)4-((6-甲氧基-1-甲基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-1H-苯并[d]咪唑-5-基)甲基)吗啉-3-乙酸
17)4-((6-甲氧基-2-(2-甲基-3'-(3-吗啉丙酰胺)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
18)4-((2-(2'-氰基-2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
20)((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)脯氨酸
21)3-羟基-2-(((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)氨基)-2-甲基丙酸
23)1-((6-甲氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
24)1-((6-异丙氧基-2-(2-甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
25)((6-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-5-基)甲基)脯氨酸
26)((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-6-基)甲基)脯氨酸
29)1-((2-(3'-(3-((4-羟丁基)(甲基)氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
30)1-((2-(3'-(3-(二甲基氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
31)1-((6-甲氧基-2-(3'-(3-((2-甲氧基乙基)(甲基)氨基)丙氧基)-2,2'-二甲基-[1,1'-联苯]-3-基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
32)1-((2-(2,2'-二甲基-3'-(3-(甲基(2-(3-丙基尿素)乙基)氨基)丙氧基)-[1,1'-联苯]-3-基)-6-甲氧基苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
33)1-((5-甲氧基-1-甲基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-1H-苯并[d]咪唑-6-基)甲基)哌啶-2-乙酸
34)1-((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]恶唑-6-基)甲基)哌啶-2-乙酸
35)1-((5-甲氧基-2-(2-甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)苯并[d]噻唑-6-基)甲基)哌啶-2-乙酸
37)N-((2-(2,2'-二甲基-3'-(3-吗啉代丙氧基)-[1,1'-联苯]-3-基)-6-(二甲基氨基)
苯并[d]恶唑-5-基)甲基)-N-甲基甘氨酸
38)4-((6-甲氧基-2-(2-甲基-3-(1-(3-吗啉代丙酰基)吲哚啉-4-基)苯基)苯并[d]恶唑-5-基)甲基)吗啉-3-乙酸
39)1-((6-乙氧基-2-(2-甲基-3-(1-(3-吗啉代丙酰基)吲哚啉-4-基)苯基)苯并[d]恶唑-5-基)甲基)哌啶-2-乙酸
3.一种药物组合物，包括权利要求1或2所述的化合物，或其药学上可接受的盐，和至少一种药学上可接受的载体或辅料。
4.权利要求3的药物组合物或权利要求1-2所述的化合物在制备用于治疗或预防癌症药物中的用途。
5.如权利要求4所述的用途，所述癌症包括结肠癌，胃癌，甲状腺癌，肺癌，白血病，胰腺癌，黑色素瘤，脑癌，肾癌，***癌，卵巢癌或乳腺癌。
6.如权利要求4所述的用途，其中所述药物用作PD-1/PD-L1相互作用的抑制剂。
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| CNPCT/CN2018/096342 | 2018-07-19 | ||
| CN2018096342 | 2018-07-19 | ||
| PCT/CN2019/096653 WO2020015717A1 (en) | 2018-07-19 | 2019-07-19 | Immunomodulators, compositions and methods thereof |
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| JP7185532B2 (ja) | 2016-06-27 | 2022-12-07 | ケモセントリックス，インコーポレイティド | 免疫調節化合物 |
| AU2018306619B2 (en) | 2017-07-28 | 2022-06-02 | Chemocentryx, Inc. | Immunomodulator compounds |
| CN111225665B (zh) | 2017-08-08 | 2023-12-08 | 凯莫森特里克斯股份有限公司 | 大环免疫调节剂 |
| EP3755311A4 (en) | 2018-02-22 | 2021-11-10 | ChemoCentryx, Inc. | USEFUL INDANE-AMINES AS AN AGONISTS OF PD-L1 |
| CN112654617A (zh) * | 2018-09-13 | 2021-04-13 | 贝达药业股份有限公司 | 免疫调节剂及其组合物和制备方法 |
| CN111793077B (zh) * | 2019-04-01 | 2023-08-04 | 东莞市东阳光新药研发有限公司 | Pd-1/pd-l1小分子抑制剂及其在药物中的应用 |
| SG11202112310TA (en) | 2019-05-15 | 2021-12-30 | Chemocentryx Inc | Triaryl compounds for treatment of pd-l1 diseases |
| JP2022536845A (ja) | 2019-06-20 | 2022-08-19 | ケモセントリックス，インコーポレイティド | Ｐｄ－ｌ１疾患の治療のための化合物 |
| JP2022539830A (ja) | 2019-07-10 | 2022-09-13 | ケモセントリックス，インコーポレイティド | Ｐｄ－ｌ１阻害剤としてのインダン |
| US11713307B2 (en) | 2019-10-16 | 2023-08-01 | Chemocentryx, Inc. | Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases |
| PE20221764A1 (es) | 2019-10-16 | 2022-11-11 | Chemocentryx Inc | Aminas de heteroaril-bifenilo para el tratamiento de enfermedades pd-l1 |
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| WO2004062661A1 (en) * | 2003-01-08 | 2004-07-29 | Axys Pharmaceuticals, Inc. | 2-‘5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl!- carboxylic acid derivatives as factor viia inhibitors |
| WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
| WO2020052650A1 (en) * | 2018-09-13 | 2020-03-19 | Betta Pharmaceuticals Co., Ltd | Immunomodulators, compositions and methods there of |
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| CA2984971A1 (en) * | 2015-05-11 | 2016-11-17 | Kancera Ab | Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity |
| MD3377488T2 (ro) * | 2015-11-19 | 2023-02-28 | Incyte Corp | Compuși heterociclici ca imunomodulatori |
| ES2934230T3 (es) * | 2016-12-22 | 2023-02-20 | Incyte Corp | Derivados de benzooxazol como inmunomoduladores |
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- 2019-07-19 US US17/261,013 patent/US20210300909A1/en not_active Abandoned
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| WO2004062661A1 (en) * | 2003-01-08 | 2004-07-29 | Axys Pharmaceuticals, Inc. | 2-‘5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl!- carboxylic acid derivatives as factor viia inhibitors |
| WO2018119224A1 (en) * | 2016-12-22 | 2018-06-28 | Incyte Corporation | Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers |
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| CN112424194A (zh) | 2021-02-26 |
| US20210300909A1 (en) | 2021-09-30 |
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