CN105705489B - 用作免疫调节剂的化合物 - Google Patents

用作免疫调节剂的化合物 Download PDF

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CN105705489B
CN105705489B CN201480060895.6A CN201480060895A CN105705489B CN 105705489 B CN105705489 B CN 105705489B CN 201480060895 A CN201480060895 A CN 201480060895A CN 105705489 B CN105705489 B CN 105705489B
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methyl
phenyl
methoxyl group
amino
dimethoxy
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CN105705489A (zh
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L·S·丘帕克
X·郑
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Abstract

本申请公开了式(I)化合物。本申请还公开了使用所述化合物作为免疫调节剂的方法以及包含所述化合物的药物组合物。这些化合物用于治疗、预防病毒学疾病或病症和癌症或减缓其进展。

Description

用作免疫调节剂的化合物
相关申请的交叉引用
本申请要求2013年9月4日提交的美国临时专利申请61/873,398的优先权，将其全部内容通过引用的方式并入本申请。
技术领域
本公开一般地涉及用作PD-1/PD-L1蛋白/蛋白相互作用的抑制剂的化合物。本申请提供了化合物、包含所述化合物的组合物及其使用方法。本公开还涉及药物组合物，其包含本公开的用于治疗各种疾病包括癌症和感染性疾病的至少一种化合物。
背景技术
程序性死亡-1(CD279)为T细胞上的受体，其已经显示当经其配体程序性死亡-配体1(PD-L1,CD274,B7-H1)或PD-L2(CD273,B7-DC)结合时，抑制来自T细胞受体的信号激活(Sharpe et al.,Nat.Imm.2007)。当表达PD-1的T细胞接触表达其配体的细胞时，对抗原刺激应答的机能活动，包括增殖、细胞因子分泌和细胞毒性得到减弱。PD-1/PD-配体相互作用在感染或肿瘤消退过程中或在发展自身耐受性过程中下调免疫应答(Keir Me,Butte MJ,Freeman GJ,et al.PD-1and its ligands in tolerance andimmunity.Annu.Rev.Immunol.2008；26:Epub)。长期抗原刺激，诸如在肿瘤疾病或慢性感染过程中发生的那些，会导致T细胞表达升高水平的PD-1且在针对长期抗原的活性方面功能失调(reviewed in Kim and Ahmed,Curr Opin Imm,2010)。这称为“T细胞耗竭”。B细胞也显示了对PD-1/PD-配体的抑制和“耗竭”。
使用PD-L1的抗体对PD-1/PD-L1连接的阻断已经显示在许多系统中修复和促进T细胞激活。具有晚期癌症的患者受益于使用PD-L1的单克隆抗体的疗法(Brahmer et al.,New Engl J Med 2012)。肿瘤和慢性感染的临床前动物模型已经显示了单克隆抗体对PD-1/PD-L1途径的阻断可增强免疫应答且导致肿瘤排斥或控制感染。经PD-1/PD-L1阻断的抗肿瘤免疫疗法可促进对众多组织学上不同的肿瘤的治疗免疫应答(Dong H,Chen L.B7-H1pathway and its role in the Evasion of tumor immunity.J Mol Med.2003；81(5):281-287；Dong H,Strome SE,Salamoa DR,et al.Tumor-associated B7-H1 promotes T-cell apoptosis:a potential mechanism of immune evasion.Nat Med.2002；8(8):793-800)。
对PD-1/PD-L1的相互作用的干扰也显示了在慢性感染系统中的增强的T细胞活性。小鼠的慢性淋巴细胞脉络丛脑膜炎病毒感染也显示了经阻断PD-L1而导致的改善的病毒清除和恢复的免疫性(Barber DL,Wherry EJ,Masopust D,et al.Restoring functionin exhausted CD8T cells during chronic viral infection.Nature.2006；439(7077):682-687)。感染有HIV-1的人源化小鼠显示了针对病毒血症的增强的保护以及CD4+T细胞的病毒耗竭(Palmer et al.,J.Immunol 2013)。经PD-L1的单克隆抗体对PD-1/PD-L1的阻断可修复对来自以下患者的T细胞的体外抗原特异性功能：HIV患者(Day,Nature 2006；Petrovas,J.Exp.Med.2006；Trautman,Nature Med.2006；D’Souza,J.Immunol.2007；Zhang,Blood 2007；Kaufmann,Nature Imm.2007；Kasu,J.Immunol.2010；Porichis,Blood2011)、HCV患者[Golden-Mason,J.Virol.2007；Jeung,J.Leuk.Biol.2007；Urbani,J.Hepatol.2008；Nakamoto,PLoS Path.2009；Nakamoto,Gastroenterology 2008]或HBV患者(Boni,J.Virol.2007；Fisicaro,Gastro.2010；Fisicaro et al.,Gastroenterology,2012；Boni et al.,Gastro.,2012；Penna et al.,J.Hep.,2012；Raziorrough,Hepatology2009；Liang,World J Gastro.2010；Zhang,Gastro.2008)。
除了增强对长期抗原的免疫应答之外，对PD-1/PD-L1途径的阻断还显示了增强对接种疫苗，包括在慢性感染情况下的治疗性接种疫苗的应答(S.J.Ha,S.N.Mueller,E.J.Wherry et al.,“Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection,”The Journal ofExperimental Medicine,vol.205,no.3,pp.543-555,2008.；A.C.Finnefrock,A.Tang,F.Li et al.,“PD-1blockade in rhesus macaques:impact on chronic infection andprophylactic vaccination,”The Journal of Immunology,vol.182,no.2,pp.980-987,2009；M.-Y.Song,S.-H.Park,H.J.Nam,D.-H.Choi,and Y.-C.Sung,“Enhancement ofvaccine-induced primary and memory CD8+ t-cell responses by soluble PD-1,”TheJournal of Immunotherapy,vol.34,no.3,pp.297-306,2011)。
PD-1途径为在由慢性感染和肿瘤疾病过程中的长期抗原刺激引起的T细胞耗竭中的关键抑制分子。通过靶标PD-L1蛋白阻断PD-1/PD-L1的相互作用已经显示了修复体外和体内抗原特异性T细胞免疫功能，包括在肿瘤或慢性感染情况下增强对接种疫苗的应答。
因此，阻断PD-L1与PD-1的相互作用的药物是理想的。
申请人发现了具有作为PD-L1与PD-1的相互作用的抑制剂的活性的有效化合物，且因此可用于治疗性给药以增强癌症或慢性感染的免疫性，包括治疗疫苗。提供这些化合物以用作药物，其具有对它们的药物性(drugability)而言重要的期望稳定性、生物利用度、治疗指数和毒性值。
发明内容
本公开提供了式(I)化合物，包括其盐和前药，其用作PD-1/PD-L1蛋白/蛋白相互作用的抑制剂。
本公开还提供了药物组合物，其包含式(I)化合物和/或其药用盐，以及药用载体。
本公开还提供了治疗与PD-L1活性包括其与其他蛋白诸如PD-1和B7-1(CD80)的相互作用相关的疾病或病症的方法，所述方法包括向哺乳动物患者给予式(I)化合物和/或其药用盐。
本公开还提供了制备式(I)化合物和/或其盐的方法和中间体。
本公开还提供了式(I)化合物和/或其药用盐，其用于治疗。
本公开还提供了式(I)化合物和/或其药用盐在制备用于治疗或预防PD-L1相关病症诸如癌症和感染性疾病的药物中的用途。
式(I)化合物以及包含式(I)化合物的组合物可用于治疗、预防或治愈各种感染性疾病和癌症。包含这些化合物的药物组合物用于治疗、预防各种治疗领域的疾病或病症诸如癌症和感染性疾病或减缓其进展。
本公开的这些和其他特征将随着披露内容继续而以展开形式阐述。
具体实施方式
本公开的第一方面提供了至少一种式(I)化合物或其盐:
其中:
环B为苯基或噻吩基；
环A为:
其中A”为CH或N，且其中R1和R2中的一者为Q且R1和R2中的另一者为Rb；
R3为H或-CH2C(O)OH；
R4为-NHCH2CH2NHC(O)CH3；
Q为:
(i)
其中Ry为-OH、-CH3、-CH2OH、-C(O)OH、-CH2C(O)OH或-C(O)NHCH2CH2OH、-C(O)NH2、-NHC(O)CH3，且Rz为-OH、-CH3、-OCH3、-OC(O)CH3或-CH2CH＝CH2且Rh为-CH3或-C(O)CH3；
(ii)-CH2NH-Rx，其中Rx为环丁基、任选取代有两个氟原子的-(CH2)环丁基、环丙基、羟基环戊基、环戊基、环己基、羟基环己基、羟基四氢呋喃基、N-甲基哌啶基、N-乙基哌啶基、羟基四氢噻吩基或
(iii)-CH2NRa-CRaRa-(CH2)n-Rx，其中Rx为氢、氮杂环丁烷酮基、环己基、羟基苯基、吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、咪唑基、N-甲基咪唑基、-C(O)(吗啉基)；任选取代有甲基、苯基、烷氧基苯基、羟基苯基、吡啶基、嘧啶基或-C(O)OC(CH3)3基团的哌嗪基；吡咯烷基、吡啶基、二氧化硫吗啉基或甲基三唑基；或
(iv)-CHRa-NRa-CRaRa-(CHRa)n-Rx，其中Rx为-OH、-OCH3、-C(O)OH、-OPh,-CH(CO2H)-NHC(O)CH3、-O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H-O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、-C(O)CH3、-C(O)NRaRa、-C(O)NRqRq、-N(CH3)2、-NHC(O)CH3,-NHC(O)Ph、--C(O)NH(CH2)2-咪唑基、NHC(O)OCH2Ph、-N(CH3)S(O)2CH3、-NHC(O)CH＝CH2、-NHC(O)CH＝CHC(O)CH2CH3,-NHS(O)2CH3或
每个Ra独立为H、-CH(OH)CH3、OH、-(CH2)2OH、-CH2OH,-(CH2)2NH2、-CH2CH3或-CH3；或同一个碳原子上的两个Ra基团可形成四、五或六元碳环、N-甲基哌啶环或吡喃环；
每个Rb独立为H、F、Cl、Br、-CF3、-CN、CH3或-OCH3；
每个Rc独立为-OCH3、-OH、-OCH2CH3、-O(CH2)OCH3、-OCH2CH＝CH2、-O(CH2)2CH3、-O(CH2)2-吗啉基或F；
或连接于相邻碳原子的两个Rc形成-O-(CH2)v-O-，其中v为1或2；
每个Rq选自氢、-CH2C(O)NHCH2CO2H、-(CH2)C(O)NHCH(CO2H)CH2CH(CH3)2、-CH(Bn)-C(O)NHCH(CO2H)(CH2)3NHC(NH)NH2；
m为0或1；
n为0、1、2或3；
每个p独立为0或1；且
q为0、1或2。
在第一方面的第一个实施方案中，环A为:
在第二个实施方案中，本公开提供了式(I)化合物或其盐，其中环A为:
且Q为
在第三个实施方案中，本公开提供了式(I)化合物或其盐，其中环A为:
且Q为-CH2NH-Rx，其中Rx为环丁基、任选取代有两个氟原子的-(CH2)环丁基、环丙基、羟基环戊基、环戊基、环己基、羟基环己基、羟基四氢呋喃基、N-甲基哌啶基、N-乙基哌啶基、羟基四氢噻吩基或
在第一方面的第四个实施方案中，本公开提供了式(I)化合物或其盐，其中环A为:
且Q为-CH2NRa-CRaRa-(CH2)n-Rx，其中Rx为氢、氮杂环丁烷酮基、环己基、羟基苯基、吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、咪唑基、N-甲基咪唑基、-C(O)(吗啉基)；任选取代有甲基、苯基、烷氧基苯基、羟基苯基、吡啶基、嘧啶基或-C(O)OC(CH3)3基团的哌嗪基；吡咯烷基、吡啶基、二氧化硫吗啉基或甲基三唑基。
在第一方面的第五个实施方案中，本公开提供了式(I)化合物或其盐，其中环A为:
且Q为-CHRa-NRa-CRaRa-(CHRa)n-Rx，其中Rx为-OH、-OCH3、-C(O)OH、-OPh,-CH(CO2H)-NHC(O)CH3、-O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H-O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、-C(O)CH3、-C(O)NRaRa、-C(O)NRqRq、-N(CH3)2、-NHC(O)CH3,-NHC(O)Ph、--C(O)NH(CH2)2-咪唑基、NHC(O)OCH2Ph、-N(CH3)S(O)2CH3、-NHC(O)CH＝CH2、-NHC(O)CH＝CHC(O)CH2CH3,-NHS(O)2CH3或
在第一方面的第六个实施方案中，本公开提供了式(I)化合物或其盐，其中环A为:
在第二方面，本公开提供了药物组合物，其包含式(I)化合物或其药用盐以及药用载体。
在第三方面，本公开提供了治疗与抑制PD-1/PD-L1的相互作用相关的疾病或病症的方法，所述方法包括向哺乳动物患者给予式(I)化合物或其药用盐。在第三方面的第一个实施方案中，所述疾病或病症为病毒感染或癌症。
在另一方面，本公开提供了式(II)化合物或其盐
其中：
环A为:
R1和R2中的一者为Q且R1和R2中的另一者为Rb；
R3为H或-CH2C(O)OH；
R4为-NHCH2CH2NHC(O)CH3；
Q为:
(i)
其中Ry为-CH2OH、-C(O)OH、-CH2C(O)OH或-C(O)NHCH2CH2OH，且Rz为-OH、-CH3、-OCH3、-OC(O)CH3或-CH2CH＝CH2；
(ii)-CH2NH-Rx，其中Rx为环丁基、羟基环己基、N-甲基哌啶基或N-乙基哌啶基；
(iii)-CH2NRa-CRaRa-(CH2)n-Rx，其中Rx为吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、-C(O)(吗啉基)、N-甲基哌嗪基或甲基三唑基；或
(iv)-CHRa-NRa-CRaRa-(CH2)n-Rx，其中Rx为-OH、-C(O)OH、-C(O)CH3、-C(O)NRaRa、-NHC(O)CH3或-NHS(O)2CH3；
每个Ra独立为H或-CH3；
每个Rb独立为H、F、Cl、Br、-CH3或-OCH3；
每个Rc独立为-OCH3或F；
或连接于相邻碳原子的两个Rc形成-O-CH2-O-；
m为0或1；
n为0、1或2；
每个p独立为0或1；且
q为0、1或2。
一个实施方案提供了式(II)化合物，其中环A为
该实施方案的化合物具有式(III)化合物:
其中R1、R2、Rb、Rc和q如在第一方面中定义。在该实施方案中包括式(IIIA)化合物，其中R1为Q且R2为Rb:
在该实施方案中还包括式(IIIB)化合物，其中R1为Rb；且R2为Q:
一个实施方案提供了式(III)化合物，其中Q为:
且其中R1、R2、Rb、Rc、Ry、Rz、m和q如在第一方面所定义。在该实施方案中包括式(IIIA)化合物和式(IIIB)化合物。在该实施方案中还包括其中m为0的化合物。此外，在该实施方案中包括其中m为0且q为0的化合物。
一个实施方案提供了式(III)化合物，其中Q为:
Ry为-C(O)OH或-CH2C(O)OH；且R1、R2、Rb、Rc、Rz、m和q如在第一方面所定义。在该实施方案中包括其中m为0的化合物。在该实施方案中还包括其中m为0且q为0的化合物。
一个实施方案提供了式(III)化合物，其中m为0；且R1、R2、Rb、Rc和q如在第一方面所定义。在该实施方案中包括其中Q为的化合物。
一个实施方案提供了式(III)化合物，其中m为1；且R1、R2、Rb、Rc和q如在第一方面所定义。
一个实施方案提供了式(III)化合物，其中Q为:Ry为-CH2OH或-C(O)OH；Rz为-OH、-CH3、-OCH3、-OC(O)CH3或-CH2CH＝CH2；且R1、R2、Rb、Rc、m和q如在第一方面所定义。在该实施方案中包括式II化合物，其中Q为:
且Rz为-OH、-CH3、-OCH3或-OC(O)CH3。在该实施方案中还包括其中p为0且Q为:的化合物。
一个实施方案提供了式(III)化合物，其中Q为:且Ry为-C(O)OH、-CH2C(O)OH或-C(O)NHCH2CH2OH；且R1、R2、Rb、Rc、Ry和q如在第一方面所定义。在该实施方案中包括其中Ry为-C(O)OH的化合物。
一个实施方案提供了式(III)化合物，其中Q为:Ry为-C(O)OH或-CH2C(O)OH；且R1、R2、Rb、Rc、Ry和q如在第一方面所定义。在该实施方案中包括式III化合物，其中Q为:
一个实施方案提供了式(III)化合物，其中Ry为-C(O)OH且Q为:
且R1、R2、Rb、Rc、Rz、m和q如在第一方面所定义。
一个实施方案提供了式(III)化合物，其中Q为:
Ry为-C(O)OH；且R1、R2、Rb、Rc和q如在第一方面所定义。
一个实施方案提供了式(III)化合物，其中Q为:-CH2NH-Rx；且Rx为环丁基、羟基环己基、N-甲基哌啶基或N-乙基哌啶基；且其中R1、R2、Rb、Rc、m和q如在第一方面所定义。在该实施方案中包括式(IIA)化合物和式(IIB)化合物。
一个实施方案提供了式(III)化合物，其中Q为:-CH2NRa-CRaRa-(CH2)n-Rx；Rx为吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、-C(O)(吗啉基)、N-甲基哌嗪基或甲基三唑基；且R1、R2、Ra、Rb、Rc、n、p和q如在第一方面所定义。在该实施方案中包括式(IIIA)化合物和式(IIIB)化合物。此外，在该实施方案中包括式(III)化合物，其中n为1或2。
一个实施方案提供了式(III)化合物，其中Q为-CH2NHCH2(吡咯烷酮基)、-CH2NHCH2CH2(吡咯烷酮基)、-CH2NHCH2CH2CH2(吡咯烷酮基)、-CH2NHCH2CH2(哌啶酮基)、-CH2NHCH2CH2(吗啉基)、-CH2NHCH2C(O)(吗啉基)、-CH2NHCH2CH2(N-甲基哌嗪基)、-CH2NHCH2CH2(哌嗪酮基)或-CH2NHCH(CH3)(甲基三唑基)；且R1、R2、Ra、Rb、Rc、n、p和q如在第一方面所定义。
一个实施方案提供了式(III)化合物，其中Q为:-CH2NH-CH2-Rx；Rx为吡咯烷酮基；且R1、R2、Rb、Rc和q如在第一方面所定义。在该实施方案中包括其中q为0的化合物。
一个实施方案提供了式(III)化合物，其中Q为:-CH2NRa-CRaRa-(CH2)n-Rx；Rx为吡咯烷酮基或哌啶酮基；n为1或2；且R1、R2、Ra、Rb、Rc和p如在第一方面所定义。在该实施方案中包括其中q为0的化合物。
一个实施方案提供了式(IIIa)化合物，其中Q为:-CH2NRa-CRaRa-(CH2)n-Rx；且Rx为吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、-C(O)(吗啉基)、N-甲基哌嗪基或甲基三唑基；且R1、R2、Ra、Rb、Rc、p和q如在第一方面所定义。
一个实施方案提供了式(IIIb)化合物，其中Q为:-CH2NRa-CRaRa-(CH2)n-Rx；且Rx为吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、-C(O)(吗啉基)、N-甲基哌嗪基或甲基三唑基；且R1、R2、Ra、Rb、Rc和q如在第一方面所定义。
一个实施方案提供了式(III)化合物，其中Q为:-CHRa-NRa-CRaRa-(CH2)n--Rx且Rx为-OH、-C(O)OH、-C(O)CH3、-C(O)NRaRa、-NHC(O)CH3或-NHS(O)2CH3；且R1、R2、Ra、Rb、Rc、n和q如在第一方面所定义。在该实施方案中包括其中Q为-CH2-NH-CH2-(CH2)n-C(O)NRaRa且n为0或1的化合物。在该实施方案中还包括其中Q为:-CH2-NRa-CRaRa-(CH2)n-Rx；Rx为-OH、-C(O)OH、-NHC(O)CH3或-NHS(O)2CH3的化合物。
一个实施方案提供了式(III)化合物，其中Q为:-CH2N(CH3)CH2C(O)OH、-CH2N(CH3)CH(CH3)C(O)OH、-CH2NHCH(CH3)C(O)OH、-CH2NHC(CH3)2C(O)OH、-CH2NHCH(CH3)CH2C(O)OH、-CH2NHCH2CH2C(O)CH3、-CH2NHCH2CH2C(O)NH2、-CH2NHCH2C(O)N(CH3)2、-CH2NHCH2CH2NHC(O)CH3、-CH2NHCH2CH2CH2NHC(O)CH3、-CH(CH3)NHCH2CH2NHC(O)CH3或-CH2NHCH2CH2N(CH3)S(O)2CH3；且R1、R2、Ra、Rb、Rc、n和q如在第一方面所定义。
一个实施方案提供了式(IIIA)化合物，其中每个Rb为H。在该实施方案中包括具有以下结构的式(IIIA-1)化合物:
其中Q、Rc和q如在第一方面所定义。
一个实施方案提供了式(IIIA)化合物，其中R2为H。在该实施方案中包括具有以下结构的式(IIIA-2)化合物:
其中Q、Rb、Rc和q如在第一方面所定义。在该实施方案中还包括具有以下结构的式(IIIA-3)化合物:
该实施方案的实例包括其中Rb为F、Cl、Br或-CH3的化合物。
一个实施方案提供了式(IIIA)化合物，其中R2为Rb，且其具有式(IIIA-4)结构:
其中Q、R2、Rc和q如在第一方面所定义。在该实施方案中包括其中R2为-OCH3的化合物。
一个实施方案提供了式(IIIA)化合物，其中一个Rb为H。在该实施方案中包括具有式(IIIA-5)结构的化合物:
其中Q、R2、Rb、Rc和q如在第一方面所定义。式(IIIA-5)化合物的实例包括这样的化合物，其中(i)R2为-OCH3；(ii)R2为-CH3或-OCH3；(iii)Rb为-CH3且R2为-CH3；(iv)Rb为-OCH3且R2为-OCH3；且(v)Rb为-CH3或-OCH3且R2为-CH3或-OCH3。
一个实施方案提供了式(IIIA)化合物，其中每个R2为H。该实施方案的化合物具有式(IIIA-6)化合物:
其中Q、Rb、Rc和q如在第一方面所定义。在该实施方案中包括其中Rb独立为-CH3或-OCH3的化合物。
一个实施方案提供了式(IIIA)化合物，其中每个R2为H。该实施方案的化合物具有式(IIIA-7)结构:
其中Q、R2、Rb、Rc和q如在第一方面所定义。在该实施方案中包括其中每个Rb为Br且R2为-OCH3的化合物。
一个实施方案提供了式(III)化合物，其中p为1。在该实施方案中包括具有以下结构的式(II-1)化合物:
其中R1、R2和Rb如在第一方面所定义。
一个实施方案提供了式(IIIA)化合物，其中q为2且连接至相邻碳原子的两个Rc形成-O-CH2-O-。在该实施方案中包括具有以下结构的式(IIIA-8)化合物:
其中Q、R2和Rb如在第一方面所定义。
一个实施方案提供了式(IIIA)化合物，其选自(S)-1-(2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苄基)哌啶-2-羧酸(1)；1-(4-((2'-氟-2-甲基联苯-3-基)甲氧基)苄基)氮杂环丁烷(3)；N-{2-[({3-溴-2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(4)；({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺(5)；N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}-N-甲基甲磺酰胺(6)；1-({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(7)；2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-(吗啉-4-基)乙-1-酮(8)；({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-(4-甲基哌嗪-1-基)乙基]胺(9)；1-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}哌啶-2-酮(10)；1-{3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(11)；4-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}哌嗪-2-酮(12)；({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-(吗啉-4-基)乙基]胺(13)；1-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(14)；N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1-乙基哌啶-3-胺(16)；1-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}吡咯烷-2-酮(17)；(2S,4R)-4-(乙酰基氧基)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(18)；N-(2-羟基乙基)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-甲酰胺(19)；({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[1-(5-甲基-4H-1,2,4-三唑-3-基)乙基]胺(20)；N-{2-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(21)；(2S,4R)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-4-甲氧基吡咯烷-2-羧酸(22)；N-{3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}乙酰胺(23)；(1R,2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇(24)；N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1-甲基哌啶-3-胺(25)；(2S)-1-({2-甲氧基-3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(26)；(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-2-(丙-2-烯-1-基)吡咯烷-2-羧酸(27)；3-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(28)；4-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吗啉-3-羧酸(30)；3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁酸(31)；1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-羧酸(32)；(2R)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(33)；(2S)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(34)；2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-N,N-二甲基乙酰胺(35)；N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(36)；1-({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(37)；(2S,4R)-4-甲氧基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(39)；1-({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(40)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环庚烷-2-羧酸(41)；2-[1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-基]乙酸(42)；1-{3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(43)；N-{2-[(1-{3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}乙基)氨基]乙基}乙酰胺(44)；2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙酸(45)；3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(46)；(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(47)；1-({3-氟-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(49)；(2R,4R)-4-羟基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(50)；(2R,4S)-4-羟基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(51)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(52)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-3-羧酸(53)；(3R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-3-羧酸(54)；(2R,4R)-4-甲基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(55)；(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(56)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-羧酸(57)；(2R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(58)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1,2,5,6-四氢吡啶-3-羧酸(63)；2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丙酸(64)；N-{2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(65)；1-({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(66)；N-{2-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(67)；N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)环丁胺(68)；N-{2-[({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(69)；N-{2-[(1-{3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}乙基)氨基]乙基}乙酰胺(70)；(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(71)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(72)；(1R,2R)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇(73)；1-({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(74)；(2R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(75)；5-{[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(76)；(2S)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(77)；(2R)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(78)；N-{2-[({3-氟-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(79)；(2S)-2-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(80)；3-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(82)；1-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(83)；3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁酸(84)；(2R)-2-[甲基({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(85)；3-[({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(86)；N-{2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(87)；N-{2-[({4-甲基-3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(88)；(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷-2-羧酸(90)；5-{[({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(91)；5-{[({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(92)；(2S)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(93)；2-[甲基({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酸(94)；3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(95)；(2R)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(96)；1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(97)；1-({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(98)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(99)；1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(100)；2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇(102)；2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇(103)；(2S)-2-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(104)；(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(105)；(2R)-2-{[(2,6-二甲氧基-4-{[3-(3-甲氧基苯基)-2-甲基苯基]甲氧基}苯基)甲基]氨基}丙酸(106)；(2R)-2-{[(4-{[3-(3-氟-5-甲氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸(107)；(2R)-2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸(108)；以及它们的盐。
一个实施方案提供了式(III-B)化合物，其选自2-[甲基({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酸(15)；3-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(29)；1-({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(38)；1-({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(48)；(2S)-1-({4-甲基-3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(59)；1-{3-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(60)；(2S)-2-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(81)；[(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-基]甲醇(89)；以及它们的盐。
一个实施方案提供了式(II)化合物，其中环A为:
其中R4、Rb、Rc、p和q如在第一方面所定义。在该实施方案中包括式(IVA)化合物，其中环A为
在该实施方案中还包括式(IVB)化合物，其中环A为
一个实施方案提供了式(IVA)和式(IVB)化合物，其中q为0。
一个实施方案提供了式(IVA)和式(IVB)化合物，其中p为0。
一个实施方案提供了式(IVA)和式(IVB)化合物，其中p为0且q为0。
一个实施方案提供了化合物，其选自N-[2-({5-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢萘-1-基}氨基)乙基]乙酰胺(61)；N-[2-({6-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢萘-1-基}氨基)乙基]乙酰胺(62)；以及它们的盐。
一个实施方案提供了式(II)化合物，其中环A为:其中R3、Rb、Rc和p如在第一方面所定义。该实施方案的化合物具有式(V)的结构:
一个实施方案提供了式(V)化合物，其中q为0。
一个实施方案提供了式(V)化合物，其中p为0。
一个实施方案提供了式(V)化合物，其中p为0且q为0。
一个实施方案提供了化合物，其选自2-(6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢异喹啉-2(1H)-基)乙酸(2)；6-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢异喹啉(101)；以及它们的盐。
一个实施方案提供了化合物，其选自第一方面范围内的示例性实例及其盐。
一个实施方案提供了化合物，其选自任一上述实施方案范围内的任何亚组的化合物。
一个实施方案提供了组合物，其包含本公开的至少一种化合物或其盐。
一个实施方案提供了药物组合物，其包含:药用载体；和本公开的至少一种化合物或其盐。
一个实施方案提供了药物组合物，其包含；药用载体；和治疗有效量的至少一种本公开的化合物或其盐。
一个实施方案提供了制备本公开化合物或其盐的方法。
一个实施方案提供了制备本公开化合物或其盐的中间体。
本发明可在不背离本发明的精神或基本特性下以其它特定形式体现。本发明涵盖本申请所述的本发明的方面和/或实施方案的所有组合。应了解，本发明的任何和所有实施方案可连同任何其它实施方案一起来描述其它实施方案。也应了解，实施方案的各个别要素意欲与任何实施方案的任何和所有其它要素组合以描述其它实施方案。
本发明的特征和优势可由本领域技术人员在阅读以下详细描述后更容易地了解。应了解，出于清楚原因上文和下文在各个实施方案的情况下描述的本发明的某些特征也可组合形成单一实施方案。反之，出于简洁原因在单一实施方案的情况下描述的本发明的各种特征也可组合形成其子组合。本申请确定为示例性或优选的实施方案意欲具说明性而非具限制性。
除非本申请另外特定说明，否则以单数形式提及也可包括复数。举例而言，“一个”和“一种”可指一个或一种，也可指一个或多个，或一种或多种。
本申请使用的短语“化合物或其盐”是指至少一种化合物、化合物的至少一种盐或其组合。例如，式(I)化合物或其盐包括式(I)化合物；两种式(I)化合物；式(I)化合物的盐；式(I)化合物以及式(I)化合物的一种或多种盐；和式(I)化合物的两种或多种盐。
除非另外指示，否则任何具有不饱和价数的杂原子被认为具有足以满足这种价数的氢原子。
用于描述本发明的各种术语的定义列于下文中。当术语在整篇说明书(除非其在特定情况下另外限制)中个别地或作为较大团体的一部分使用时，这些定义均适用于这种术语。本申请所阐述的定义优先于以引用方式并入本申请中的任何专利、专利申请和/或专利申请公开中所阐述的定义。
在整篇说明书中，基团和其取代基可由本领域技术人员选择以提供稳定的部分和化合物。
短语“药学上可接受”在本申请中用于指在正确医学判断范畴内适用于与人类和动物组织接触而无过度毒性、刺激性、过敏反应或其它问题或并发症且与合理效益/风险比率相称的那些化合物、物质、组合物和/或剂型。
式(I)化合物可形成盐，其也落入到本公开的范围内。除非另作说明，应当理解的是提及本发明化合物包括提及其一种或多种盐。术语“盐”是指由无机酸和碱和/或有机酸和碱形成的酸性和/或碱性盐。此外，术语“盐可包括两性离子(内盐)，例如在式(I)化合物同时含有碱性部分(诸如胺或吡啶或咪唑环)和酸性部分(诸如羧酸)时。优选为药用盐(即无毒、生理学可接受的盐)，例如可接受的金属和胺盐，其中阳离子并不显著导致该盐的毒性或生物学活性。然而，可使用其他盐，例如在制备过程中可采用的分离或纯化步骤中，且因此认为其在本公开的范围内。式(I)化合物的盐可通过例如如下形成：使式(I)化合物与一定量(诸如当量)的酸或碱在诸如使盐沉淀的介质中或在水性介质中反应，随后冻干。
示例性酸加成盐包括乙酸盐(诸如由乙酸或三卤代乙酸例如三氟乙酸形成的盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、葡糖二酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(由盐酸形成)、氢溴酸盐(由溴化氢形成)、氢碘酸盐、马来酸盐(由马来酸形成)、2-羟基乙磺酸盐、乳酸盐、甲磺酸盐(由甲磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如由硫酸形成的盐)、磺酸盐(诸如本申请提及的盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐诸如甲苯磺酸盐(tosylate)、十一碳酸盐等。
示例性碱性盐包括铵盐；碱金属盐，诸如钠、锂和钾盐；碱土金属盐，诸如钙和镁盐；钡、锌和铝盐；与有机碱(例如有机胺)形成的盐，所述有机碱诸如三烷基胺诸如三乙胺、普鲁卡因、二苄基胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N,N′-二苄基亚乙基-二胺、去氢枞胺、N-乙基哌啶、苄基胺、二环己基胺或相似的药用胺；以及与氨基酸诸如精氨酸、赖氨酸等形成的盐。碱性含氮基团可用诸如以下的试剂进行季铵化：低级烷基卤化物(例如甲基氯、甲基溴、甲基碘、乙基氯、乙基溴、乙基碘、丙基氯、丙基溴、丙基碘、丁基氯、丁基溴和丁基碘)、硫酸二烷基酯(例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯)、长链卤化物(例如癸基氯、癸基溴、癸基碘、月桂基氯、月桂基溴、月桂基碘、肉豆蔻基氯、肉豆蔻基溴、肉豆蔻基碘、硬脂基氯、硬脂基溴和硬脂基碘)、芳烷基卤化物(例如苄基溴和苯乙基溴)等。优选的盐包括一盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
式(I)化合物可作为无定形固体或晶状固体提供。可采用低压冻干以提供作为固体的式(I)化合物。
还应当理解式(I)化合物的溶剂化物(例如，水合物)也在本发明的范围内。术语“溶剂化物”意指式(I)化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合。该物理缔合包括氢键。在一些情况中，该溶剂化物能够分离，例如当一个或多个溶剂分子掺入至结晶固体的晶格中时。“溶剂化物”涵盖溶液相溶剂化物和可分离的溶剂化物。示例性溶剂化物包括水合物、乙醇合物、甲醇合物、异丙醇合物、乙腈溶剂化物和乙酸乙酯溶剂化物。溶剂化的方法是本领域已知的。
各种前药形式在此项技术中为熟知的且描述于以下文献中：
a)The Practice of Medicinal Chemistry,Camille G.Wermuth et al.,Ch 31,(Academic Press,1996)；
b)Design of Prodrugs,edited by H.Bundgaard,(Elsevier,1985)；
c)A Textbook of Drug Design and Development,P.Krogsgaard-Larson andH.Bundgaard,eds.Ch 5,pgs 113-191(Harwood Academic Publishers,1991)；和
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa and JoachimM.Mayer,(Wiley-VCH,2003)。
另外，式(I)化合物在制备之后可被分离和纯化，以获得含有等于或大于99重量％的量的式(I)化合物(“实质上纯”)的组合物，接着如本申请所述使用或配制。这种“实质上纯”的式(I)化合物在本申请中也涵盖作为本发明的一部分。
“稳定化合物”和“稳定结构”意欲指示足够稳固而能够自反应混合物中分离出达适用纯度且能够配制成有效治疗剂的化合物。本发明意欲包含稳定化合物。
“治疗有效量”意欲包括有效充当PD-1抑制剂或有效治疗或预防癌症或慢性感染诸如乙型肝炎和丙型肝炎的单独本发明化合物的量，或所主张的化合物组合的量，或与其它活性成分组合的本发明化合物的量。
本申请所用的“治疗(treating)”或“治疗(treatment)”涵盖治疗哺乳动物(尤其人类)的疾病状态，且包括：(a)预防哺乳动物出现疾病状态，尤其在所述哺乳动物易患所述疾病状态但尚未诊断为患有所述疾病状态时；(b)抑制疾病状态，也即阻止其发展；和/或(c)减轻疾病状态，也即使疾病状态消退。
本发明化合物意欲包括本发明化合物中存在的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。作为一般实例且非限制性地，氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。通常，同位素标记的本发明化合物可通过本领域技术人员已知的常规技术或通过类似于本申请所述的方法的方法，使用适当的同位素标记试剂替代否则使用的未经标记的试剂来制备。例如，甲基(-CH3)也包括氘化甲基诸如-CD3。
式(I)化合物和/或其药用盐可通过任何适于待治疗病症的方式给药，其可取决于对位点特异性治疗或待递送的式(I)化合物的量的需求。本发明也涵盖一类药物组合物，其包含至少一种式(I)化合物；和一种或多种无毒的药学上可接受的载体和/或稀释剂和/或辅料(本申请统称作“载体”物质)和必要时选用的其它活性成分。式(I)化合物可通过任何适合途径，优选以适于所述途径的药物组合物形式且以有效用于预期治疗的剂量给予。本发明的化合物和组合物可以含有常规药学上可接受的载体、辅料和媒介物的剂量单位制剂形式，例如口服、经粘膜或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌内和胸骨内)给予。举例而言，药物载体可含有甘露糖醇或乳糖和微晶纤维素的混合物。混合物可含有其它组分，诸如润滑剂，例如硬脂酸镁；和崩解剂，诸如交聚维酮(crospovidone)。载体混合物可填充至明胶胶囊中或压制成片剂。药物组合物可以例如口服剂型或输注剂形式给予。
对于口服给药，药物组合物可呈例如片剂、胶囊剂、液体胶囊剂、混悬剂或液体形式。药物组合物优选以含有特定量的活性成分的剂量单位形式制成。举例而言，药物组合物可以包含约0.1mg至1000mg，优选约0.25mg至250mg，且更优选约0.5mg至100mg范围内的量的活性成分的片剂或胶囊剂形式提供。虽然适用于人类或其它哺乳动物的日剂量可视患者的病症和其它因素而广泛变化，但可使用常规方法确定。
本申请涵盖的任何药物组合物可例如经由任何可接受且适合的口服制剂来口服递送。示例性口服制剂包括(但不限于)例如片剂、糖衣锭(troches)、口含锭(lozenges)、水性和油性混悬剂、液体胶囊剂、可分散性散剂或颗粒剂、乳剂、硬胶囊剂和软胶囊剂、糖浆剂和酏剂。意欲口服给予的药物组合物可根据此项技术中已知用于制造意欲口服给予的药物组合物的任何方法来制备。为提供药学上可口的制剂，本发明药物组合物可含有至少一种选自甜味剂、矫味剂、着色剂、缓和剂、抗氧化剂和防腐剂的试剂。
片剂可例如通过混合至少一种式(I)化合物和/或其至少一种药用盐与至少一种适用于制造片剂的无毒的药学上可接受的赋形剂来制备。示例性赋形剂包括(但不限于)例如惰性稀释剂，诸如碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠；粒化剂和崩解剂，诸如微晶纤维素、交联羧甲纤维素钠、玉米淀粉和海藻酸；粘合剂，诸如淀粉、明胶、聚乙烯-吡咯烷酮和阿拉伯胶(acacia)；和润滑剂，诸如硬脂酸镁、硬脂酸和滑石。另外，片剂可无包衣，或通过已知技术包覆包衣以掩蔽味道令人不悦的药物的不良味道，或延迟活性成分在胃肠道中的崩解和吸收，从而使活性成分的作用持续较长时段。示例性水溶性味觉掩蔽物质包括(但不限于)羟基丙基甲基纤维素和羟基丙基纤维素。示例性时间延迟物质包括(但不限于)乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊剂可例如通过混合至少一种式(I)化合物和/或其至少一种盐与至少一种惰性固体稀释剂(诸如碳酸钙；磷酸钙；和高岭土(kaolin))来制备。
软明胶胶囊剂可例如通过混合至少一种式(I)化合物和/或其至少一种药用盐与至少一种水溶性载体(诸如聚乙二醇)；和至少一种油介质(诸如花生油、液体石蜡和橄榄油)来制备。
水性混悬剂可例如通过混合至少一种式(I)化合物和/或其至少一种药用盐与至少一种适用于制造水性混悬剂的赋形剂来制备。适用于制造水性混悬剂的示例性赋形剂包括(但不限于)例如助悬剂，诸如羧甲基纤维素钠、甲基纤维素、羟基丙基甲基纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶；分散剂或湿润剂，诸如天然存在的磷脂，例如卵磷脂；环氧烷与脂肪酸的缩合产物，诸如聚氧乙烯硬脂酸酯；环氧乙烷与长链脂族醇的缩合产物，诸如十七亚乙基-氧基十六醇；环氧乙烷与源自脂肪酸和己糖醇的偏酯的缩合产物，诸如聚氧乙烯山梨糖醇单油酸酯；和环氧乙烷与源自脂肪酸和己糖醇酐的偏酯的缩合产物，诸如聚乙烯脱水山梨糖醇单油酸酯。水性混悬剂也可含有至少一种防腐剂，诸如对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯；至少一种着色剂；至少一种矫味剂；和/或至少一种甜味剂，包括(但不限于)例如蔗糖、糖精和阿斯巴甜(aspartame)。
油性混悬剂可例如通过将至少一种式(I)化合物和/或其至少一种药用盐悬浮于植物油(诸如花生油；橄榄油；芝麻油；和椰子油)；或矿物油(诸如液体石蜡)中来制备。油性混悬剂也可含有至少一种增稠剂，诸如蜂蜡；硬石蜡；和十六醇。为提供可口的油性混悬剂，可将至少一种上文已描述的甜味剂和/或至少一种矫味剂添加至油性混悬剂中。油性混悬剂可进一步含有至少一种防腐剂，包括(但不限于)例如抗氧化剂，诸如丁基化羟基苯甲醚和α-生育酚。
可分散性散剂和颗粒剂可例如通过混合至少一种式(I)化合物和/或其至少一种药用盐与至少一种分散剂和/或湿润剂；至少一种助悬剂；和/或至少一种防腐剂来制备。适合的分散剂、湿润剂和助悬剂如上文已描述。示例性防腐剂包括(但不限于)例如抗氧化剂，例如抗坏血酸。另外，可分散性散剂和颗粒剂也可含有至少一种赋形剂，包括(但不限于)例如甜味剂；矫味剂；和着色剂。
至少一种式(I)化合物和/或其至少一种药用盐的乳剂可例如制备成水包油乳剂。包含式(I)化合物的乳剂的油相可由已知成分以已知方式构成。油相可由(但不限于)例如植物油(诸如橄榄油和花生油)；矿物油(诸如液体石蜡)；和其混合物提供。虽然所述相可仅包含乳化剂，但其可包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。适合的乳化剂包括(但不限于)例如天然存在的磷脂，例如大豆卵磷脂；源自脂肪酸和己糖醇酐的酯或偏酯，诸如脱水山梨糖醇单油酸酯；和偏酯与环氧乙烷的缩合产物，诸如聚氧乙烯脱水山梨糖醇单油酸酯。优选地，亲水性乳化剂连同用作稳定剂的亲脂性乳化剂一起包括在内。也优选包括油和脂肪两者。具有或不具有稳定剂的乳化剂一起组成所谓乳化蜡，且所述蜡与油和脂肪一起组成所谓乳化软膏基质，所述乳化软膏基质形成乳膏剂制剂的油性分散相。乳剂也可含有甜味剂、矫味剂、防腐剂和/或抗氧化剂。适用于本发明制剂中的乳化剂和乳剂稳定剂包括吐温(Tween)60、斯潘(Span)80、十六醇十八醇混合物(cetostearylalcohol)、十四烷醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯，或此项技术中熟知的其它物质。
式(I)化合物和/或其至少一种药用盐也可例如经由任何药学上可接受且适合的可注射形式静脉内、皮下和/或肌内递送。示例性可注射形式包括(但不限于)例如包含可接受的媒介物和溶剂(诸如水、林格溶液(Ringer's solution)和等张氯化钠溶液)的无菌水溶液；无菌水包油微乳剂；和水性或油性混悬剂。
用于肠胃外给予的制剂可为水性或非水性等张无菌注射溶液剂或混悬剂的形式。这种溶液剂和混悬剂可使用所提及的用于口服给予的制剂的一种或多种载体或稀释剂或通过使用其它适合的分散剂或湿润剂和助悬剂由无菌粉末或颗粒制备。这种化合物可溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、黄蓍胶和/或各种缓冲液中。其它辅料和给药方式在医药技术中为广泛熟知的。活性成分也可以作为含适合载体(包括盐水、右旋糖或水)或含环糊精(也即Captisol)、共溶剂溶解(也即丙二醇)或胶束溶解(也即吐温80)的组合物形式通过注射给予。
无菌可注射制剂也可为于无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液剂或混悬剂，例如于1,3-丁二醇中的溶液剂。可使用的可接受的媒介物和溶剂为水、林格溶液和等张氯化钠溶液。另外，无菌不挥发性油惯常用作溶剂或悬浮介质。出于此目的，可使用任何温和的不挥发性油，包括合成单酸甘油酯或二酸甘油酯。另外，在可注射剂制备中可使用脂肪酸，诸如油酸。
无菌可注射水包油微乳剂可例如通过以下来制备：1)将至少一种式(I)化合物溶解于油相(诸如大豆油与卵磷脂的混合物)中；2)组合含有式(I)的油相与水和甘油混合物；和3)加工所述组合，形成微乳剂。
无菌水性或油性混悬剂可根据此项技术早已已知的方法来制备。举例而言，无菌水溶液剂或混悬剂可用无毒肠胃外可接受的稀释剂或溶剂来制备，诸如1,3-丁二醇；且无菌油性混悬剂可用无菌无毒可接受的溶剂或悬浮介质来制备，诸如无菌不挥发性油，例如合成单酸甘油酯或二酸甘油酯；和脂肪酸，诸如油酸。
可用于本发明药物组合物中的药学上可接受的载体、辅料和媒介物包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂；自乳化药物递送系统(SEDDS)，诸如d-α-生育酚聚乙二醇1000丁二酸酯；用于药物剂型中的表面活性剂，诸如吐温、聚乙氧基蓖麻油，诸如CREMOPHOR表面活性剂(BASF)，或其它类似聚合递送基质；血清蛋白，诸如人血清白蛋白；缓冲物质，诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质，诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。环糊精(诸如α-环糊精、β-环糊精和γ-环糊精)或经化学修饰的衍生物(诸如羟基烷基环糊精，包括2-羟基丙基-环糊精和3-羟基丙基-环糊精)或其它溶解的衍生物也宜用于增强本申请所述式的化合物的递送。
本发明的药物活性化合物可根据常规药学方法加工以产生用于向患者(包括人类和其它哺乳动物)给予的医药药剂。药物组合物可经受常规医药操作(诸如杀菌)和/或可含有常规辅料，诸如防腐剂、稳定剂、湿润剂、乳化剂、缓冲剂等。片剂和丸剂可另外用肠溶包衣制备。这些组合物也可包含辅料，诸如湿润剂、甜味剂、矫味剂和香化剂。
所给予的化合物的量和以本发明的化合物和/或组合物治疗疾病病症的给药方案视多种因素而定，包括个体的年龄、体重、性别、医学病症、疾病类型、疾病严重度、给药途径和频率和所采用的特定化合物。因此，给药方案可广泛不同，但可常规地使用标准方法来确定。每公斤体重约0.001mg至100mg，优选每公斤体重约0.0025mg至约50mg和最优选每公斤体重约0.005mg至10mg的日剂量可为适当的。日剂量可以每天一至四次给药给予。其他给药方案包括每周一次给予以及每两天周期一次给予。
为达治疗目的，通常将本发明的活性化合物与适用于所示给药途径的一种或多种辅料组合。若口服给予，则可将化合物与乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合，接着制成片剂或胶囊剂以方便给予。这些胶囊剂或片剂可含有控制释放制剂，如可以活性化合物于羟基丙基甲基纤维素中的分散液的形式提供。
本发明的药物组合物包含式(I)化合物和/或其至少一种药用盐和任选地其它选自任何药学上可接受的载体、辅料和媒介物的试剂。本发明的替代组合物包含本申请所述的式(I)化合物或其前药和药学上可接受的载体、辅料或媒介物。
本发明的化合物抑制PD-1/PDL-1蛋白/蛋白相互作用，从而导致PD-1阻断。PD-1阻断可增强对哺乳动物包括人的癌性细胞和感染性疾病的免疫应答。在一方面，本发明涉及使用式(I)化合物或其盐体内治疗受试者以使得癌性肿瘤的生长得到抑制。式(I)化合物或其盐可单独使用以抑制癌性肿瘤的生长。可选择地，式(I)化合物或其盐可与如下所述的其他免疫源性药物或标准癌症治疗组合使用。
在一个实施方案中，本发明提供了抑制受试者的肿瘤细胞生长的方法，包括向该受试者给予治疗有效量的式(I)化合物或其盐。
在一个实施方案中，提供了治疗癌症的方法，包括向有此需要的患者给予治疗有效量的式(I)化合物或其盐。癌症的实例包括这样的癌症，可使用本发明的化合物抑制其生长，包括通常对免疫疗法应答的癌症。用于治疗的优选的癌症的非限制性实例包括黑色素瘤(例如转移性恶性黑色素瘤)、肾癌(例如透明细胞癌)、前列腺癌(例如激素难治性前列腺腺癌)、乳腺癌、结肠癌和肺癌(例如非小细胞肺癌)。此外，本发明包括难治性或复发性恶性肿瘤，可使用本发明化合物抑制其生长。
可使用本发明方法治疗的其他癌症的实例包括骨癌、胰腺癌、皮肤癌、头颈癌、皮肤或眼内恶性黑色素瘤、子宫癌、卵巢癌、直肠癌、肛区癌、胃癌、睾丸癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、何杰金病、非何杰金淋巴瘤、食道癌、小肠癌、内分泌系统癌、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、肾或尿道癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性中枢神经的淋巴瘤、肿瘤血管发生、脊髓轴肿瘤、脑干胶质瘤、垂体腺瘤、卡波西肉瘤、表皮样癌、鳞状细胞癌症、T细胞淋巴瘤、环境诱导的癌症包括由石棉诱导的癌症，以及上述癌症的组合。本发明还用于治疗转移性癌症，特别是表达PD-L1的转移性癌症(Iwai et al.(2005)Int.Immunol.17:133-144)。
任选地，式(I)化合物或其盐可与其他免疫源性剂组合，诸如癌性细胞、纯化的肿瘤抗原(包括重组蛋白、肽和碳水化合物分子)、细胞和转染有基因编码的免疫刺激细胞因子的细胞(He et al(2004)J.Immunol.173:4919-28)。可使用的肿瘤疫苗的非限制性实例包括黑色素瘤抗原的肽，诸如gp100、MAGE抗原、Trp-2、MART1和/或酪氨酸酶的肽，或转染以表达细胞因子GM-CSF的肿瘤细胞。在人中，某些肿瘤已经显示为免疫源性的，诸如黑色素瘤。可以预期的是，通过由PD-1阻断提高T细胞激活的阈值，期望肿瘤应答在宿主中被激活。
PD-1阻断可与接种疫苗方案组合。已经提议了针对抗肿瘤接种疫苗的许多实验策略(参见Rosenberg,S.,2000,Development of Cancer Vaccines,ASCO Educational BookSpring:60-62；Logothetis,C.,2000,ASCO Educational Book Spring:300-302；Khayat,D.2000,ASCO Educational Book Spring:414-428；Foon,K.2000,ASCO Educational BookSpring:730-738；也参见Restifo,N.and Sznol,M.,Cancer Vaccines,Ch.61,pp.3023-3043in DeVita,V.et al.(eds.),1997,Cancer:Principles and Practice ofOncology.Fifth Edition)。在这些策略中的一者中，使用自体同源的或同种异体的肿瘤细胞制备疫苗。这些细胞疫苗已经显示在转导肿瘤细胞以表达GM-CSF时是最有效的。GM-CSF已经显示为针对肿瘤接种疫苗的抗原呈递的有效活化剂(Dranoff et al.(1993)Proc.Natl.Acad.Sci.U.S.A.90:3539-43)。
在各种肿瘤中的基因表达和大规模基因表达模式的研究已经导致对所谓的肿瘤特异性抗原的限定(Rosenberg,S A(1999)Immunity 10:281-7)。在血多情况下，这些肿瘤特异性抗原为表达于肿瘤中和该肿瘤所来源的细胞中的分化抗原，例如黑色素细胞抗原gp100、MAGE抗原和Trp-2。更重要的是，这些抗原中的许多可显示为存在于宿主中的肿瘤特异性T细胞的靶标。PD-1阻断可与表达于肿瘤中的重组蛋白和/或肽的整体组合使用以产生对这些蛋白的免疫应答。这些蛋白通常被免疫系统视为自体抗原且因此对其耐受。该肿瘤抗原也可包括蛋白端粒末端转移酶，其对于合成染色体的调聚物而言是必须的，并且在多于85％的人癌症中表达且仅在有限数目的体细胞组织中表达(Kim,N et al.(1994)Science 266:2011-2013)(这些体细胞组织可以各种方式而受到保护以防免疫攻击)。肿瘤抗原也可为表达于癌症细胞中的"新抗原"，这是由于体细胞突变改变了蛋白序列或在两种不相关序列间(即费城染色体中的bcr-abl)产生融合蛋白，或来自B细胞肿瘤的个体基因型。
其他肿瘤疫苗可包括来自人癌症中所涉及的病毒的蛋白，诸如人乳头状瘤病毒(HPV)、肝炎病毒(HBV和HCV)和卡波西疱疹肉瘤病毒(KHSV)。可与PD-1阻断组合使用的其他形式的肿瘤特异性抗原为经纯化的热休克蛋白(HSP)，其由肿瘤组织自身分离。这些热休克蛋白含有来自肿瘤细胞的蛋白片段且这些HSP在递送至抗原呈递细胞时是高度有效的以用于产生肿瘤免疫性(Suot,R&Srivastava,P(1995)Science 269:1585-1588；Tamura,Y.etal.(1997)Science 278:117-120)。
树突细胞(DC)为有效的抗原呈递细胞，其可用于引起抗原特异性应答。DC可离体产生且载有各种蛋白和肽抗原以及肿瘤细胞提取物(Nestle,F.et al.(1998)NatureMedicine 4:328-332)。DC也可由遗传方式转导以同样表达这些肿瘤抗原。针对免疫接种的目的，DC也已经直接与肿瘤细胞融合(Kugler,A.et al.(2000)Nature Medicine 6:332-336)。作为疫苗接种的方法，DC免疫接种可有效地与PD-1阻断组合以激活更有效的抗-肿瘤应答。
PD-1阻断也可与标准癌症治疗组合。PD-1阻断可有效地与化学治疗方案组合。在这些情况下，其可有效地降低所给予的化学治疗试剂的剂量(Mokyr,M.et al.(1998)Cancer Research 58:5301-5304)。所述组合的实例为本发明的化合物与用于治疗黑色素瘤的达卡巴嗪的组合。所述组合的另一个实例为本发明的化合物与用于治疗黑色素瘤的白细胞介素-2(IL-2)的组合。PD-1阻断与化学疗法的组合使用的科学原理为细胞死亡，其为大多数化学治疗化合物的细胞毒素作用的结果，其应导致肿瘤抗原在抗原呈递途径中的水平增加。通过细胞死亡可导致与PD-1阻断的协同作用的其他组合疗法为放射、手术和激素抑制疗法。这些方案中的每个在宿主中产生了肿瘤抗原的来源。血管发生抑制剂也可与PD-1阻断组合。血管发生的抑制导致肿瘤细胞死亡，其可使得肿瘤抗原融入宿主抗原呈递途径。
本发明的化合物也可与双特异性大环类肽组合使用，后者使得Fcα或Fcγ受体表达效应器细胞靶标至肿瘤细胞(参见例如美国专利5,922,845和5,837,243)。双特异性大环类肽可用于靶标两种分离的抗原。例如抗-Fc受体/抗肿瘤抗原(例如Her-2/neu)双特异性大环类肽已经用于将巨噬细胞靶标至肿瘤位点。该靶标可更有效地激活肿瘤特异性应答。这些应答的T细胞分支可通过使用PD-1阻断而得到增强。可选择地，通过使用结合至肿瘤抗原和树突细胞特异性细胞表面标记物的双特异性大环类肽，抗原可直接递送至DC。
肿瘤通过各种机制躲避宿主免疫监视。这些机制中的许多可通过使肿瘤表达的且免疫抑制的蛋白失活而得到克服。这些包括其他TGF-β(Kehrl,J.et al.(1986)J.Exp.Med.163:1037-1050)、IL-10(Howard,M.&O'Garra,A.(1992)Immunology Today 13:198-200)和Fas配体(Hahne,M.et al.(1996)Science 274:1363-1365)。对于以上各实体的大环类肽可与本发明的化合物组合使用以抵消免疫抑制剂的作用且有利于宿主的肿瘤免疫应答。
激活宿主免疫应答的大环类肽可与抗-PD-1组合使用。这些包括树突细胞表面上的分子，其激活DC功能和抗原呈递。抗-CD40大环类肽能够有效替代T细胞辅助细胞活性(Ridge,J.et al.(1998)Nature 393:474-478)且可与PD-1大环类肽组合使用(Ito,N.etal.(2000)Immunobiology 201(5)527-40)。激活大环类肽至T细胞辅刺激分子诸如CTLA-4(例如美国专利5,811,097)、OX-40(Weinberg,A.et al.(2000)Immunol 164:2160-2169)、4-1BB(Melero,I.et al.(1997)Nature Medicine 3:682-685(1997)和ICOS(Hutloff,A.etal.(1999)Nature 397:262-266)也可针对T细胞激活的水平增加来提供。
骨髓移植通常用于治疗各种造血来源的肿瘤。尽管移植物抗宿主病为该治疗的后果，治疗益处可由移植物抗肿瘤应答获得。PD-1阻断可用于提高供体移入的肿瘤特异性T细胞的有效性。本发明的其他方法用于治疗已经暴露于特定毒素或病原体的患者。因此，本发明的另一方面提供了治疗受试者的感染性疾病的方法，包括向该受试者给予治疗有效量的式(I)化合物或其盐。与如上所讨论的其对肿瘤的应用类似，式(I)化合物或其盐可单独使用或作为辅剂与疫苗组合使用，以刺激对病原体、毒素或自体抗原的免疫应答。可特别使用该治疗方法所针对的病原体的实例包括这样的病原体，针对该病原体目前没有有效的疫苗，或针对该病原体常规疫苗并不完全有效。这些包括但不限于HIV、肝炎(A,B,&C)、流感、疱疹、贾第虫(Giardia)、疟疾、利什曼原虫(Leishmania)、金黄色葡萄球菌(Staphylococcus aureus)、铜绿假单胞菌(Pseudomonas Aeruginosa)。PD-1阻断特别用于对抗按照因素确定的感染，所述因素诸如在感染过程中呈递改变的抗原的HIV。这些新的抗原表位在给药时被识别为异质的，因此引起强的T细胞应答，其不会被负信号经PD-1阻断而抑制。
可由本发明方法治疗的引起感染的病原性病毒的某些实例包括HIV、肝炎(A、B或C)、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II和CMV、EB病毒)、腺病毒、流感病毒、虫媒病毒、埃可病毒、鼻病毒、柯萨奇病毒、豇豆花叶病毒(cornovirus)、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、痘苗病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病毒、JC病毒和虫媒病毒性脑炎病毒。
可由本发明方法治疗的引起感染的病原性细菌的某些实例包括衣原体、立克次体细菌、分枝杆菌、葡萄球菌、链球菌、肺炎双球菌、脑膜炎球菌和淋球菌、克雷白杆菌、变形菌、灵杆菌、假单胞菌、军团杆菌、白喉、沙门菌、杆菌、霍乱、破伤风、肉毒杆菌、炭疽、鼠疫杆菌、钩端螺旋体和莱姆病菌。
可由本发明方法治疗的引起感染的病原性真菌的某些实例包括念珠菌(白色念珠菌、克鲁斯氏念珠菌、光滑念株菌、热带念珠菌等)、新型隐球菌、曲霉菌(烟曲霉、黑曲霉等)、属毛霉菌(毛霉、腐化米霉菌、根霉)、申克孢子丝菌、申克孢子丝菌、巴西副球孢子菌、粗球孢子菌和夹膜组织胞浆菌。
可由本发明方法治疗的引起感染的病原性寄生虫的某些实例包括痢疾内变形虫、结肠小袋虫、福勒耐格里原虫、棘阿米巴原虫、蓝氏贾第虫、隐孢子虫、卡氏肺囊虫、间日疟原虫、果氏巴贝虫、布氏锥虫、克氏锥虫、杜氏利什曼原虫、刚地弓形虫和巴西钩虫。
在所有以上方法中，PD-1阻断可与其他形式的免疫疗法组合，诸如细胞因子治疗(例如干扰素、GM-CSF、G-CSF,IL-2)或双特异性抗体疗法，其提供肿瘤抗原的增强的呈递(参见例如Holliger(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448；Poljak(1994)Structure 2:1121-1123)。
本发明的化合物可引起并增强自身免疫应答。事实上，使用肿瘤细胞和肽疫苗诱导抗肿瘤应答表明了许多抗-肿瘤应答涉及抗自体反应性(depigmentation observed inanti-CTLA-4+GM-CSF-modified B 16 melanoma in van Elsas et al.supra；depigmentation in Trp-2vaccinated mice(Overwijk,W.et al.(1999)Proc.Natl.Acad.Sci.U.S.A.96:2982-2987)；由TRAMP肿瘤细胞疫苗引起的自身免疫性前列腺炎(Hurwitz,A.(2000)supra)、黑色素瘤肽抗原疫苗接种和在人临床试验中观察的白癜风(Rosenberg,S A and White,D E(1996)J.Immunother Emphasis Tumor Immunol 19(1):81-4)。
因此，可以考虑使用抗-PD-1阻断与各种自体蛋白的组合以设计疫苗接种方案，从而有效地产生针对疾病治疗的这些自体蛋白的免疫应答。例如，阿尔兹海默病包括A.β.肽在脑中淀粉样沉着物中的不适当累积；针对淀粉状蛋白的抗体反应能够清除这些淀粉样沉着物(Schenk et al.,(1999)Nature 400:173-177)。
其他自体蛋白也可用作靶标，诸如针对治疗变态反应和哮喘的IgE，以及针对治疗类风湿性关节炎的TNF.α.。最后，针对各种激素的抗体反应可通过使用式(I)化合物或其盐来诱导。使针对生殖激素的抗体反应失效可用于避孕。使针对激素和具体肿瘤生长所需的其他可溶性因子的抗体反应失效也可作为可能的疫苗接种靶标。
如上针对使用抗-PD-1抗体所述的类似方法可用于诱导治疗性自身免疫应答以治疗具有其他自体抗原的不适当累积的患者，所述其他自体抗原诸如淀粉样沉着物，包括阿尔及海默病中的A.β.；细胞因子，诸如TNF.α.，和IgE。
通过共同给予式(I)化合物或其盐以及所研究的抗原(例如疫苗)，本发明的化合物可用于刺激抗原特异性免疫应答。因此，在本发明的另一方面，提供了在受试者中增强对抗原的免疫应答的方法，包括向所述受试者给予：(i)抗原；和(ii)式(I)化合物或其盐，以使得在受试者中对所述抗原的免疫应答得到增强。抗原可为例如肿瘤抗原、病毒抗原、细菌抗原或来自病原体的抗原。所述抗原的非限制性实例包括在如上段落所讨论的那些，诸如如上讨论的肿瘤抗原(或肿瘤疫苗)或如上讨论的来自病毒、细菌或其他病原体的抗原。
如前所述，本发明的化合物可与一种或多种其他治疗剂例如细胞毒素剂、放射毒性剂或免疫抑制剂共同给药。本发明的化合物可在其他治疗剂之前、之后或共同给药，或可与其他已知的疗法例如抗癌疗法例如放射疗法共同给予。所述治疗剂包括抗肿瘤药物诸如多柔比星(阿霉素)、顺铂、硫酸博来霉素、卡莫司汀、苯丁酸氮芥、达卡巴嗪和环磷酰胺羟基脲，其本身仅在对患者有毒性或亚毒性的水平有效。顺铂以100mg/剂每四周一次经静脉内给予，且阿霉素以60-75mg/ml剂量每21天一次经静脉内给予。式(I)化合物或其盐与化学治疗剂的共同给药提供了两种抗癌药物，其经不同的机制起效，从而产生对人肿瘤细胞的细胞毒性作用。所述共同给药可解决由于发展对药物的抵抗或肿瘤细胞抗原性的变化(这会导致其不与所述抗体反应)所导致的问题。
本发明范围内还包括试剂盒，其包含式(I)化合物或其盐以及使用说明书。该试剂盒还可进一步包含至少一种额外的试剂。试剂盒通常包括指明试剂盒内容物的意在用途的标签。术语标签包括提供于该试剂盒上或其中的任何书写或记录的材料，或其以其他方式依附于所述试剂盒。
上述其它治疗剂在与本发明化合物组合使用时，可例如依医师参考手册(Physicians'Desk Reference，PDR)中所指示，或如由本领域技术人员以其它方式所确定的量使用。在本发明方法中，可在给予本发明化合物之前、同时或之后给予所述其它治疗剂。
在一个实施方案中，式(I)化合物抑制PD-1/PD-L1的相互作用，其所具有的IC50值为10μM或更低，例如0.01至10μM，如经PD-1/PD-L1均相时间分辨荧光(Homogenous Time-Resolved Fluorescence,HTRF)结合测定所测量。优选地，式(I)化合物抑制PD-1/PD-L1的相互作用，其所具有的IC50值为1μM或更低，例如0.01至1μM。
实施例
在以下实施例中进一步定义本发明。应理解的是，实施例仅以示例方式给出。从上述讨论和实施例，本领域技术人员能够确定本发明的基本特征，且在不背离本发明精神和范畴的情况下，可作出各种变化和修饰以使本发明适用于各种用途和情况。因而，本发明不受以下阐述的示例性实施例的限制，而是由所附的权利要求所限定。
缩写
Ac 乙酰基
anhyd. 无水
aq. 水性
Bn 苄基
Bu 丁基
CV 柱体积
Et 乙基
h,hr或hrs 小时
HPLC 高效液相色谱
LC 液相色谱
M 摩尔
mM 毫摩尔
Me 甲基
MHz 兆赫
min. 分钟
mins 分钟
M+1 (M+H)+
MS 质谱
n或N 当量浓度
nM 纳摩尔
Ph 苯基
Ret Time或RT 保留时间
sat. 饱和
SFC 超临界流体色谱
实施例1
(S)-1-(2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苄基)哌啶-2-羧酸
中间体1A:(2-甲基联苯-3-基)甲醇
将(3-溴-2-甲基苯基)甲醇(2.071g,10.3mmol)、苯基硼酸(2.51g,20.60mmol)和[1,1'-二(二苯基膦基)二茂铁]二氯化钯(II)-二氯甲烷络合物(0.084g,0.103mmol)在甲苯(15.45ml)和乙醇(5.15ml)中的混合物置于氩气下。向该溶液中加入碳酸氢钠,2M(15.45ml,30.9mmol)并将混合物在80℃加热30分钟。将反应混合物用20mL乙酸乙酯和5mL水稀释。将有机部分经旋转蒸发浓缩。将粗产物进行硅胶色谱纯化(用0-40％乙酸乙酯/己烷洗脱)得到2g灰白色固体。1H NMR(400MHz,氯仿-d)δ7.47-7.29(m,7H),7.23(s,1H),4.80(d,J＝5.6Hz,2H),2.27(s,3H),1.63-1.59(m,1H).
中间体1B:2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苯甲醛
将偶氮二羧酸二异丙酯(2.158mL,11.10mmol)在THF(50mL)中的溶液逐滴加入至4-羟基-2,6-二甲氧基苯甲醛(1.838g,10.09mmol)、三苯基膦(2.91g,11.10mmol)和2-甲基-[1,1'-联苯]-3-基)甲醇(2g,10.09mmol)在无水THF(50mL)中的冷却的(0℃)溶液中。将所得的黄色溶液在搅拌下缓慢温热至室温过夜。1H NMR(500MHz,氯仿-d)δ10.40(s,1H),7.48-7.42(m,3H),7.40(d,J＝7.6Hz,1H),7.36-7.30(m,4H),6.23(s,2H),5.19(s,2H),3.94-3.89(m,6H),2.30(s,3H)。Rf＝0.55 1:1乙酸乙酯:己烷.
实施例1:
将2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苯甲醛(20mg,0.055mmol)、(S)-哌啶-2-羧酸和三乙酰氧基硼氢化钠(35.1mg,0.166mmol)在二氯甲烷(4mL)中的溶液在85℃搅拌45分钟。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:Waters XBridge C18,19x200mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:25-65％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为20.3mg,且经LCMS分析评估的其纯度为99％。LC/MS方法A:2.8分钟,M+1:476.3,M-1:474.4,准确质量:475.2。1H NMR(500MHz,DMSO-d6)δ7.55-7.15(m,8H),6.43(s,2H),5.20(s,2H),4.12(s,2H),3.80(s,6H),3.20-3.04(m,3H),3.22-3.02(m,3H),2.65(br.s.,1H),2.22(s,3H),1.82(br.s.,2H),1.57(br.s.,2H),1.40(d,J＝6.7Hz,2H).
表中的实施例6、7、9-15、17、18、21、24-26、32、36、37、46-48、69、84、103、105、111、163-190、195、196、233-244和246-284由中间体1B，即2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苯甲醛和适当的胺根据如实施例1所述的一般合成方法制备。
实施例2
2-(6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢异喹啉-2(1H)-基)乙酸
中间体2A:6-羟基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
将1,2,3,4-四氢异喹啉-6-醇HCl(1g,5.39mmol)和BOC2O(2.251ml,9.70mmol)在饱和碳酸氢钠水溶液(10mL)和氯仿(10mL)中的溶液在室温搅拌过夜。将水相用浓HCl中和并用乙酸乙酯萃取。将合并的有机部分用0.1N HCl洗涤，经MgSO4干燥，滤过并浓缩得到1.6g黄色油状物。将油状物进行硅胶色谱纯化(0-60％乙酸乙酯/己烷)得到0.58g产物。1HNMR(400MHz,氯仿-d)δ6.99(d,J＝8.3Hz,1H),6.70(dd,J＝8.3,2.5Hz,1H),6.64(d,J＝2.5Hz,1H),4.52(s,2H),3.64(t,J＝5.9Hz,2H),2.80(t,J＝5.9Hz,2H),1.62-1.46(m,13H).
中间体2B:6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯
将偶氮二羧酸二异丙酯(0.503mL,2.59mmol)在THF(11.800mL)中的溶液逐滴加入至6-羟基-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(586mg,2.351mmol)、三苯基膦(678mg,2.59mmol)和(2-甲基-[1,1'-联苯]-3-基)甲醇(513mg,2.59mmol)在无水THF(11.800mL)中的冷却的(0℃)溶液中。将所得的黄色溶液缓慢温热至室温并搅拌过夜。除去过量的溶剂并将残留物经硅胶色谱法纯化(0-35％乙酸乙酯/己烷)。1H NMR(400MHz,氯仿-d)δ7.48-7.42(m,3H),7.41-7.33(m,3H),7.30-7.26(m,2H),7.07(d,J＝8.3Hz,1H),6.90(dd,J＝8.3,2.7Hz,1H),6.83(d,J＝2.4Hz,1H),5.09(s,2H),4.55(s,2H),3.66(t,J＝5.6Hz,2H),2.85(t,J＝5.7Hz,2H),2.69(br.s.,2H),2.27(s,3H),1.52(s,9H).
中间体2C:6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-1,2,3,4-四氢异喹啉HCl
在室温将化合物，即6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢异喹啉-2(1H)-羧酸叔丁酯(580mg,1.350mmol)溶于过量的2N HCl/乙醚,3mL。将溶液静置过夜。收集黄色析出物，用乙醚洗涤一次并在真空条件(house vacuum)下干燥过夜得到黄色固体(425mg)。1H NMR(500MHz,DMSO-d6)δ7.49-7.42(m,3H),7.41-7.36(m,1H),7.32(d,J＝7.6Hz,2H),7.28(t,J＝7.6Hz,1H),7.19(d,J＝7.6Hz,1H),6.98(d,J＝8.5Hz,1H),6.88-6.77(m,2H),5.10(s,2H),3.04-2.98(m,2H),2.74(t,J＝5.6Hz,2H),2.19(s,3H),1.90(s,2H)。中间体2C为实施例101。
实施例2:
混合物通过将碳酸钾(0.055g,0.400mmol)和6-((2-甲基-[1,1’-联苯]-3-基)甲氧基)-1,2,3,4-四氢异喹啉(0.066g,0.2mmol)在乙腈(2.000ml)中混合制备。将2-溴乙酸甲酯经少量碳酸钾填料滤过除去任何溴化氢。将2-溴乙酸甲酯(0.034g,0.220mmol)加入至混合物中。将所得的混合物搅拌3小时。经确定反应程度为约20％。将混合物加热至35℃且保持1小时。消耗剩余的起始物质。该物质无需进一步纯化即可使用。
将一半未经纯化的物质用2mL甲醇和1mL 1N氢氧化钠稀释。将混合物在室温搅拌过夜。LCMS显示起始物质消耗且存在产物。使用旋转蒸发除去溶剂。将固体物质溶于DMF。留下不溶的部分。将所得的混合物滤过。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:Waters Xbridge C18,19x200mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:15-100％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为10.7mg，且经LCMS分析评估的其纯度为97％。LC/MS方法M:2.8分钟,M+1:388.2,M-1:386.1,准确质量:387.2。1H NMR(500MHz,DMSO-d6)δ7.49-7.43(m,3H),7.41-7.36(m,1H),7.32(d,J＝7.3Hz,2H),7.28(t,J＝7.5Hz,1H),7.19(d,J＝7.3Hz,1H),7.00(d,J＝9.2Hz,1H),6.85(s,2H),5.11(s,2H),3.72(s,2H),3.30(s,2H),2.85(dd,J＝10.8,4.4Hz,4H),2.19(s,3H).
实施例3
2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇
中间体3A:3-氯-4-((2-甲基联苯-3-基)甲氧基)苯甲醛
将偶氮二羧酸二异丙酯(1.01g,5mmol)在THF(30mL)中的溶液逐滴加入至4-羟基-3-氯苯甲醛(0.782g,5mmol)、三苯基膦(1.3g,4.99mmol)和中间体1A,2-甲基-[1,1'-联苯]-3-基)甲醇(0.90g,4.54mmol)在无水THF(30mL)中的冷却的(0℃)溶液中。将所得的黄色溶液在搅拌下缓慢温热至室温过夜。将溶剂经旋转蒸发器除去。将残留物在40g硅胶柱上纯化(10:1己烷:乙酸乙酯)。分离出0.97g预期产物，其为白色固体。1H NMR(400MHz,氯仿-d)δ9.90(s,1H),7.98(d,J＝2.0Hz,1H),7.81(dd,J＝8.6,2.0Hz,1H),7.53-7.49(m,1H),7.49-7.43(m,2H),7.39(d,J＝7.1Hz,1H),7.36-7.29(m,4H),7.20(d,J＝8.3Hz,1H),5.30(s,2H),2.30(s,3H).
实施例3:
将3-氯-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(20mg,0.059mmol)和2-氨基乙醇(3.99mg,0.065mmol)在二氯甲烷(5mL)中的溶液在室温搅拌1小时。除去溶剂并加入甲苯(3mL)且用旋转蒸发器除去。向残留物中加入二氯甲烷(5mL)和三乙酰氧基硼氢化钠(37.8mg,0.178mmol)。将所得的浅黄色混合物在室温搅拌过夜。除去溶剂并将残留物溶于甲醇以用于纯化。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:20-60％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为10.7mg,且经LCMS分析评估的其纯度为100％。LC/MS方法A:2.7分钟,M+1:382.4准确质量:381.2。1H NMR(500MHz,DMSO-d6)δ7.51(d,J＝7.6Hz,1H),7.49-7.44(m,2H),7.42(s,1H),7.41-7.36(m,1H),7.34-7.28(m,3H),7.27(s,2H),7.21(d,J＝7.6Hz,1H),5.23(s,2H),3.65(s,2H),3.46(t,J＝5.8Hz,2H),2.55(t,J＝5.8Hz,2H),2.23(s,3H),1.90(s,1H,乙酸酯).
实施例23、31、33-35、65、66、78、79、98、115、116、117和197根据在实施例3中所述的一般操作制备，除了在还原胺化中使用适当的、可商购得到的胺代替哌啶-2-羧酸。
实施例162根据在实施例3中所述的一般操作制备，除了在还原胺化中使用(S)-5-(叔丁氧基羰基)-1,2,5-三氮杂螺[2.4]庚-1-烯-6-羧酸(Van Der Meijden,B.Robinson,J.A.ARKIVOC,2011,vi,130-136)代替哌啶-2-羧酸。
实施例102根据在实施例3中所述的一般方法制备，除了在第一步使用4-羟基-3-甲基苯甲醛代替4-羟基-3-氯苯甲醛。
实施例4
1-(4-((3'-甲氧基-2-甲基联苯-3-基)甲氧基)苄基)氮杂环丁烷
中间体4A:4-(3-溴-2-甲基苄基氧基)苯甲醛
将偶氮二羧酸二异丙酯(4.25mL,21.88mmol)在THF(100mL)中的溶液加入至4-羟基苯甲醛(2.67g,21.88mmol)、三苯基膦(5.74g,21.88mmol)和(3-溴-2-甲基苯基)甲醇(4.0g,19.89mmol)在无水THF(100mL)中的冷却的(0℃)溶液中。将所得的黄色溶液缓慢温热至室温并搅拌过夜。经旋转蒸发除去溶剂。将残留物经硅胶色谱法纯化(用0-100％乙酸乙酯/己烷洗脱)得到4.9克标题化合物(81％)。1H NMR(500MHz,氯仿-d)δ9.93(s,1H),7.92-7.85(m,2H),7.61(dd,J＝8.0,0.9Hz,1H),7.38(d,J＝7.6Hz,1H),7.15-7.07(m,3H),5.17(s,2H),2.48(s,3H).
中间体4B:1-(4-(3-溴-2-甲基苄基氧基)苄基)氮杂环丁烷
将四甲基三乙酰氧基硼氢化铵(345mg,1.311mmol)和氮杂环丁烷盐酸盐(123mg,1.311mmol)在二氯甲烷(12mL)中的溶液加入至4-((3-溴-2-甲基苄基)氧基)苯甲醛(200mg,0.655mmol)在二氯甲烷(12mL)中的溶液中。将反应混合物在室温搅拌过夜。将反应混合物通过加入饱和碳酸氢钠淬灭。将有机层用饱和氯化钠水溶液洗涤并干燥(Na2SO4)。然后将粗残留物经制备性HPLC纯化(使用甲醇-H2O-TFA缓冲系统)。收集馏分并使用Speed-vac浓缩过夜得到102mg白色固体。分析性LC/MS用于确定最终纯度：柱:Phenomenex Luna2.0x30mm,流动相A:含有0.1％三氟乙酸的10:90甲醇:水；流动相B:含有0.1％三氟乙酸的90:10甲醇:水；梯度:0％B,0-100％B，历时2分钟；流速:1.0mL/分钟。保留时间:1.8分钟,M+1:348.
实施例4:
制备1-(4-((3-溴-2-甲基苄基)氧基)苄基)氮杂环丁烷(330mg,880μmol)在二噁烷(22mL)中的溶液。接下来，制备碳酸铯(568mg,1.8mmol)在水(4.4mL)中的溶液。向2mL微波小瓶中的3-甲氧基苯基硼酸中加入1mL(S)-2-((4-((3-溴-2-甲基苄基)氧基)苄基)氨基)丙酸溶液、200μL碳酸铯溶液和1,1'-二(二苯基膦基)二茂铁二氯化钯(II),二氯甲烷(3.56mg,4.33μmol)。将小瓶封盖并在Biotage Initiator(400W)上在140℃微波加热10分钟，其中使用20秒搅拌并使用固定的保持时间。将内容物转移至6-mL PL-Thiol SPE柱(用甲醇调节)。将反应小瓶用500μL甲醇淋洗并将淋洗液转移至SPE柱。将产物用4mL甲醇洗脱并收集于16x100mm培养管。将样品在Zymark Tabletop干燥器在35℃干燥3小时。接下来，将1mL DMF加入至各小瓶中并经反相HPLC纯化:柱:Waters Xbridge C18,19x200mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:15-100％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。LC/MS方法M:3.9分钟,M+1:374.4,准确质量:373.2。1H NMR(500MHz,DMSO-d6)δ7.44(d,J＝7.0Hz,1H),7.36(t,J＝7.5Hz,1H),7.26(t,J＝7.5Hz,1H),7.20(d,J＝5.5Hz,3H),6.99(d,J＝8.2Hz,2H),6.95(d,J＝8.5Hz,1H),6.87(d,J＝7.9Hz,1H),6.84(br.s.,1H),5.11(s,2H),3.79(s,3H),3.49(br.s.,2H),3.14(t,J＝6.9Hz,4H),2.19(s,3H),2.02-1.95(m,2H).
实施例75、92和93根据在实施例4中所述的一般操作制备，除了在还原胺化步骤中使用适当的胺代替氮杂环丁烷并在钯催化偶联步骤中使用适当的硼酸。
实施例5
N-{2-[({3-溴-2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺
实施例5经实施例37的溴化制备：在0℃向溴化钾(26.5mg,0.223mmol)和溴(14.25mg,0.089mmol)在水中的溶液中加入N-(2-((2,6-二甲氧基-4-((2-甲基-[1,1’-联苯]-3-基)甲氧基)苄基)氨基)乙基)乙酰胺(20mg,0.045mmol)。将混合物在0℃搅拌2hr并形成黄色析出物。加入水并收集黄色析出物(19mg)。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:Waters Xbridge C18,19x200mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:30-70％B，历时10分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为7.0mg,且经LCMS分析评估的其纯度为100％。1H NMR(500MHz,DMSO-d6)δ7.81(br.s.,1H),7.58(d,J＝7.6Hz,1H),7.51-7.44(m,2H),7.40(d,J＝7.0Hz,1H),7.34-7.29(m,3H),7.23(d,J＝7.6Hz,1H),6.83(s,1H),5.29(s,2H),3.88(s,3H),3.77(s,3H),3.71(s,2H),3.14(d,J＝6.1Hz,2H),2.58(t,J＝6.0Hz,2H),2.26(s,3H),1.79(s,3H).
实施例8、22、29、67和104根据在实施例1中所述的一般操作制备，除了使用3-溴-4-羟基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛且在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例16、30、39、49、61和82根据在实施例1中所述的一般操作制备，除了使用3-羟基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例60和89根据在实施例1中所述的一般操作制备，除了使用3-羟基-4-甲基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例19、20、28、40、42-44、51-59、64、72-74、76、77、85、86、88、90、91、94-97、100和110根据在实施例1中所述的一般操作制备，除了使用4-羟基-3-甲基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例27根据在实施例1中所述的一般操作制备，除了使用4-羟基-2-甲氧基-3-甲基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛。
实施例38、68、81、83和99根据在实施例1中所述的一般操作制备，除了使用4-羟基-2-甲氧基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例41、70和87根据在实施例1中所述的一般操作制备，除了使用4-羟基-2,6-二甲基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例50和80根据在实施例1中所述的一般操作制备，除了使用3-氟-4-羟基苯甲醛代替4-羟基-2,6-二甲氧基苯甲醛并在还原胺化中使用适当的胺代替哌啶-2-羧酸。
实施例106、107和108根据在实施例4中所述的一般操作制备，除了使用4-羟基-2,6-二甲氧基苯甲醛代替4-羟基苯甲醛，在还原胺化步骤中使用丙氨酸代替氮杂环丁烷并在钯催化偶联步骤中使用适当的硼酸。
实施例45
N-{2-[(1-{3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}乙基)氨基]乙基}乙酰胺
中间体45A:1-(3-氯-4-((2-甲基联苯-3-基)甲氧基)苯基)乙酮
中间体45A由1-(3-氯-4-羟基苯基)乙酮和中间体1A根据制备中间体1B所述的一般操作制备。
实施例45:
向1-(3-氯-4-((2-甲基-[1,1’-联苯]-3-基)甲氧基)苯基)乙酮(20mg,0.057mmol)在THF(2mL)中的溶液中加入N-乙酰基乙二胺(12.94mg,0.114mmol)和原钛酸四叔丁酯(0.050mL,0.143mmol)。将所得的白色混合物在85℃在微波加热1小时。加入另外的原钛酸四叔丁酯(0.050mL,0.143mmol)并在100℃加热1小时。加入硼氢化钠(6.47mg,0.171mmol)，随后加入乙醇(2mL)。将混合物在室温搅拌2小时。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:Waters Xbridge C18,19x200mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:10-100％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为12.6mg,且经LCMS分析评估的其纯度为98％。1H NMR(500MHz,DMSO-d6)δ7.77(br.s.,1H),7.51(d,J＝7.3Hz,1H),7.49-7.43(m,2H),7.43-7.35(m,2H),7.35-7.24(m,5H),7.21(d,J＝7.6Hz,1H),5.22(s,2H),3.66(d,J＝6.4Hz,1H),3.14-2.99(m,2H),2.42-2.28(m,2H),2.23(s,3H),1.77(s,3H),1.26-1.18(m,3H).
实施例71根据在实施例45中所述的一般操作制备，除了使用1-(4-羟基-3-甲基苯基)乙酮代替1-(3-氯-4-羟基苯基)乙酮。
实施例62根据在实施例45中所述的一般操作制备，除了使用5-羟基-3,4-二氢萘-1(2H)-酮代替1-(3-氯-4-羟基苯基)乙酮。
实施例63根据在实施例45中所述的一般操作制备，除了使用6-羟基-3,4-二氢萘-1(2H)-酮代替1-(3-氯-4-羟基苯基)乙酮。
实施例109根据在实施例45中所述的一般操作制备，除了使用1-氨基-2,3-二氢-1H-茚-4-醇代替1-(3-氯-4-羟基苯基)乙酮。
实施例112
(2S)-1-[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-3-(三氟甲基)苯基)甲基]哌啶-2-羧酸
中间体112A:(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苯基)甲醇
将(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)硼酸(0.537g,2.98mmol)、(3-溴-2-甲基苯基)甲醇(0.5g,2.487mmol)和二代XPhos前催化剂(0.059g,0.075mmol)用THF(24ml)覆盖并脱气。加入磷酸钾(12.43ml,6.22mmol)的0.5M水溶液。将反应混合物在室温搅拌，在氩气下密封过夜。经旋转蒸发除去溶剂。将残留物使用3:1己烷:乙酸乙酯在24g硅胶柱上纯化。含有预期产物的馏分得到0.59g标题化合物，其为无色油状物。1H NMR(400MHz,氯仿-d)δ7.39(d,J＝7.3Hz,1H),7.25(t,J＝7.6Hz,1H),7.22-7.18(m,1H),6.92(d,J＝8.1Hz,1H),6.83(d,J＝1.7Hz,1H),6.78(dd,J＝8.2,1.8Hz,1H),4.79(d,J＝5.9Hz,2H),4.33(s,4H),2.28(s,3H).
中间体112B:4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-3-(三氟甲基)苯甲醛
将4-羟基-3-(三氟甲基)苯甲醛(35.9mg,0.189mmol)、三苯基膦(49.5mg,0.189mmol)和(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苯基)甲醇(44mg,0.172mmol)在无水THF(1ml)中混合。冷却至0℃。逐滴加入偶氮二羧酸二异丙酯(0.037ml,0.189mmol)在THF(1ml)。将所得的黄色溶液缓慢温热至室温，同时搅拌过夜。经旋转蒸发器除去溶剂。将粗残留物在24g硅胶柱上用5:1己烷:乙酸乙酯纯化。合并馏分得到0.046g预期产物，其为浅黄色固体。
实施例112:
将4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-3-(三氟甲基)苯甲醛(15mg,0.035mmol)和(S)-哌啶-2-羧酸(13.57mg,0.105mmol)的DMF(1.5mL)溶液在室温搅拌1小时。加入氰基硼氢化钠(6.60mg,0.105mmol)和3滴乙酸(2.004μl,0.035mmol)。将反应混合物在室温搅拌过夜。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:40-80％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为14.3mg,且经LCMS分析评估的其纯度为100％。1H NMR(500MHz,DMSO-d6)d 7.67-7.55(m,2H),7.52-7.37(m,2H),7.27(t,J＝7.5Hz,1H),7.18(d,J＝7.3Hz,1H),6.93(d,J＝8.1Hz,1H),6.79-6.73(m,2H),5.28(s,2H),4.29(s,4H),3.87(d,J＝13.2Hz,1H),3.51(d,J＝13.6Hz,3H),2.86(br.s.,1H),2.26-2.22(m,1H),2.21(s,3H),1.80(br.s.,1H),1.70(d,J＝9.2Hz,1H),1.50(d,J＝18.7Hz,3H),1.37(br.s.,1H).
实施例113根据在实施例112中所述的一般操作制备，除了在还原胺化中使用N-(2-氨基乙基)乙酰胺代替哌啶-2-羧酸。
实施例114根据在实施例112中所述的一般操作制备，除了在还原胺化中使用(S)-4-氨基-3-羟基丁酸代替哌啶-2-羧酸。
实施例118
2-[({5-[(2-甲基-3-苯基苯基)甲氧基]噻吩-2-基}甲基)氨基]乙-1-醇
在8mL透明小瓶中，将(2-甲基-[1,1'-联苯]-3-基)甲醇(50mg,0.252mmol)、碳酸铯(123mg,0.378mmol)、2-(二-叔丁基膦基)-3-甲氧基-6-甲基-2'-4'-6'-三异丙基-1,1'-联苯(7.09mg,0.015mmol)、4A分子筛(50mg)和甲苯(0.4mL)混合。将反应混合物用氩气脱气。加入5-氯噻吩-2-甲醛(55.5mg,0.378mmol,Cole,Andrew G.；Letourneau,JeffreyJohn；Ho,Koc-Kan WO 2010059922 A1)和烯丙基二氯化钯(II)二聚体(2.77mg,7.57μmol)。然后将反应混合物在90℃加热24hrs。将反应混合物用乙酸乙酯稀释，经硅藻土滤过并浓缩。将残留物在4gm硅胶柱上纯化(使用0至15％乙酸乙酯/石油醚的梯度)。合并含有产物的馏分并浓缩得到预期的醛(0.039g)。实施例118由该醛和2-氨基乙醇根据如实施例1所述的还原胺化条件制备。
实施例119
2-[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]乙-1-醇
中间体119A:2-甲基-5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶
向6-甲基吡啶-3-醇(0.209g,1.915mmol)和碳酸铯(1.248g,3.83mmol)在DMF(5mL)中的溶液中加入3-(溴甲基)-2-甲基-1,1'-联苯(0.5g,1.915mmol)并将反应混合物在室温搅拌3小时。使用40％乙酸乙酯/石油醚的TLC分析显示消耗起始物质。将反应混合物用水(50ml)淬灭并用乙酸乙酯(2x50ml)萃取。将合并的有机萃取物用水(50ml)、饱和氯化钠水溶液(50ml)洗涤，经硫酸钠干燥并浓缩得到粗残留物(500mg)。将粗残留物在12g硅胶柱上纯化(25-30％乙酸乙酯/石油醚的梯度)得到预期化合物(0.365g,65％)。1H NMR(400MHz,DMSO-d6)d 8.25(s,1H),7.50-7.30(m,5H),7.30-7.25(m,3H),7.18(d,J＝7.6Hz,2H),5.19(s,2H),2.40(s,3H),2.19(s,3H).
中间体119B:2-甲基-5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶1-氧化物
在0℃向2-甲基-5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶(365mg,1.261mmol)和碳酸氢钠(318mg,3.78mmol)在氯仿(8mL)中的溶液中加入间氯过苯甲酸(435mg,2.52mmol)。将反应混合物温热至室温然后在室温搅拌3h，在该过程中反应混合物变为稠的乳液。使用50％乙酸乙酯/石油醚的TLC分析显示消耗起始物质。向反应混合物中加入水(20ml)并用二氯甲烷(3x30ml)萃取。将合并的有机部分用10％碳酸氢钠(40ml)、水(40ml)、饱和氯化钠水溶液(30ml)洗涤，经硫酸钠干燥并浓缩得到粗物质，其无需纯化即可使用。1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),7.45(m,3H),7.34(d,J＝8.4Hz,2H),7.29(m,3H),7.20(d,J＝7.2Hz,1H),7.20(dd,J＝8.8,2.4Hz,1H),5.20(s,2H),2.28(s,3H),2.19(s,3H).
中间体119C:(5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-基)甲醇
将2-甲基-5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶1-氧化物(0.38g,1.244mmol)在乙酸酐(3ml,31.8mmol)中的溶液加热至100℃且保持30分钟。使用50％乙酸乙酯/石油醚的TLC分析显示消耗起始物质，得到符合中间体乙酸酯的具有较高rf的化合物。将反应混合物用乙酸乙酯(50ml)稀释并用饱和碳酸氢钠溶液(30ml)、水(30ml)、饱和氯化钠水溶液(30ml)洗涤，经硫酸钠干燥并浓缩得到粗物质乙酸酯(380mg)。将粗物质乙酸酯(380mg)溶于甲醇(20mL)并加入碳酸钾(0.602g,4.36mmol)。将反应混合物在室温搅拌过夜。使用50％乙酸乙酯/石油醚的TLC分析显示消耗乙酸酯，得到具有较低rf的化合物。将溶剂浓缩并将残留物溶于EtOAc(30ml)，用水(20ml)、饱和氯化钠水溶液(20ml)洗涤，经硫酸钠干燥并浓缩。将粗残留物在4g硅胶柱上纯化(30％EtOAc/石油醚的梯度)，分离得到预期产物。1H NMR(300MHz,DMSO-d6)d 8.30(s,1H),7.15-7.60(m,10H),5.30(t,J＝7.6Hz,1H),5.22(s,2H),4.50(d,J＝7.6Hz,2H),2.20(s,3H).
中间体119D:5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛
在RT向(5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-基)甲醇(190mg,0.622mmol)在甲醇(5mL)中的溶液中加入二氧化锰(541mg,6.22mmol)并将反应混合物在室温搅拌4小时。使用30％乙酸乙酯/石油醚的TLC分析显示消耗起始物质。将反应混合物经硅藻土滤过并将填料用二氯甲烷(50ml)洗涤。将滤液浓缩得到粗产物。将产物(0.13g,67％)经4g硅胶柱色谱法分离(使用10-12％乙酸乙酯/石油醚)。1H NMR(400MHz,DMSO-d6)δ9.90(s,1H,CHO),8.6(s,1H),7.97(d,J＝8.8Hz,1H),7.74(dd,J＝8.4,2.8Hz,1H),7.50-7.40(m,3H),7.39(m,1H),7.36(m,3H),7.23(dd,J＝7.6,1.2Hz,1H),5.38(s,2H),2.21(s,3H).
实施例119由中间体119D,5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛和2-氨基乙醇根据如实施例1所述的还原胺化条件制备。
实施例120由中间体119D,5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛和(1-氨基环戊基)甲醇根据如实施例1所述的还原胺化条件制备。
实施例121由中间体119D,5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛和甲胺根据如实施例1所述的还原胺化条件制备。
实施例122由中间体119D,5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛和5-(氨基甲基)吡咯烷-2-酮根据如实施例1所述的还原胺化条件制备。
实施例123-161和295
中间体123A:2-氯-6-(羟基甲基)苄腈
向1000ml单颈圆底烧瓶中加入3-氯-2-氰基苯甲酸乙酯(8.0g,38.2mmol,Dean,David Kenneth；Munoz-Muriedas,Jorge；Sime,Mairi；Steadman,Jon Graham Anthony；Thewlis,Rachel Elizabeth Anne；Trani,Giancarlo；Walter,Daryl Simon WO2010125102 A1)和四氢呋喃(390mL)。将混合物搅拌直到获得澄清的溶液。将溶液冷却至-40℃并历时15分钟分批加入硼氢化锂(1.663g,76mmol)。在加入全部硼氢化锂后，使反应混合物缓慢达到室温并搅拌过夜。使用4:6乙酸乙酯:石油醚的TLC分析显示消耗起始物质。将饱和氯化铵水溶液加入至2000ml多颈圆底烧瓶中并冷却至-5℃(内部温度)。历时15分钟缓慢加入粗反应混合物。加入完成后，将温度保持在-5℃达20分钟。将反应混合物用二氯甲烷(500ml)稀释并分离各层。将水层用二氯甲烷(1X300ml)萃取并将合并的有机部分用1.5N盐酸水溶液(1x50ml)、饱和氯化钠水溶液(1x50ml)洗涤并经硫酸钠干燥。减压除去溶剂得到黄色固体(7.0g)。将粗物质溶于最少量的二氯甲烷并在冰浴中冷却。加入石油醚直到形成白色固体。将固体经滤过收集，用石油醚洗涤并真空干燥得到标题化合物(3.5g)。1H NMR(300MHz,CDCl3)δ7.55(m,J＝2.6Hz,2H),4.99(s,2H),2.14(bs,1H,OH).
中间体123B:3-(羟基甲基)-[1,1'-联苯]-2-甲腈
向2-氯-6-(羟基甲基)苄腈,123A,(2g,11.93mmol)在THF(80mL)中的溶液中加入苯基硼酸(2.183g,17.90mmol)和二代Xphos前催化剂(0.263g,0.334mmol,CAS编号1310584-14-5)。使氮气鼓泡经过反应混合物达5分钟以净化氧气。将反应混合物冷却至0℃并将0.5M磷酸钾(47.9mL,23.94mmol)在水中的溶液加入至反应混合物中，并继续用氮气净化5分钟。将反应混合物在室温搅拌过夜。使用1:1乙酸乙酯:石油醚的TLC分析显示消耗起始物质。将反应混合物用75mL二氯甲烷稀释并分离各层。将水层用15mL二氯甲烷萃取。将合并的有机部分用20mL饱和氯化钠水溶液洗涤，经硫酸钠干燥并在40℃真空蒸发得到粗产物。将残留物在120g硅胶柱上纯化(使用石油醚和乙酸乙酯作为洗脱剂)。将产物在10％乙酸乙酯/石油醚洗脱。将收集的馏分蒸发得到产物，其为灰白色固体(1.82g)。1H NMR(400MHz,CDCl3)δ7.60-7.70(m,2H),7.40-7.55(m,6H),4.99(d,J＝6.0Hz,2H),2.13(t,J＝6.0,1H,OH).
中间体123C:3-((4-甲酰基-3,5-二甲氧基苯氧基)甲基)-[1,1'-联苯]-2-甲腈
在氮气气氛下向3-(羟基甲基)-[1,1'-联苯]-2-甲腈,123B,(300mg,1.434mmol)在四氢呋喃(10mL)中的溶液中加入4-羟基-2,6-二甲氧基苯甲醛(261mg,1.434mmol)和三苯基膦(489mg,1.864mmol)。反应混合物似乎为棕色且浑浊。冷却至0℃，然后加入偶氮二羧酸二异丙酯(0.367mL,1.864mmol)在1ml THF中的溶液。在室温搅拌反应混合物过夜。TLC分析显示未形成产物。在室温加入四氢呋喃(10mL)、三苯基膦(489mg,1.864mmol)和偶氮二羧酸二异丙酯(0.367mL,1.864mmol)。反应混合物变为澄清的溶液。在室温搅拌3小时。将溶剂真空蒸发并将残留物在40g硅胶柱上纯化(使用石油醚和乙酸乙酯作为洗脱剂)。将产物在40％-45％乙酸乙酯洗脱。将产物洗脱为含有极性三苯基膦氧化物杂质的混合物。将收集的馏分蒸发得到化合物，其为灰白色固体(500mg)。将500mg化合物在5ml异丙醇中制成浆状物并搅拌30分钟。将固体经滤过收集，用2.5ml异丙醇洗涤并真空干燥2小时得到标题化合物(180mg)。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H,CHO),7.80(m,2H),7.65(dd,J＝1.2,7.6Hz,1H),7.60(m,5H),6.44(s,2H),5.45(s,2H),3.84(s,6H).
实施例123-161和295由中间体123C,3-((4-甲酰基-3,5-二甲氧基苯氧基)甲基)-[1,1'-联苯]-2-甲腈根据如实施例1所述的还原胺化条件使用适当的胺制备，得到预期产物。
实施例190
N1-(2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)-N1-甲基乙-1,2-二胺
中间体190A:(2-((2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)(甲基)氨基)乙基)氨基甲酸叔丁酯
将(2-(甲基氨基)乙基)氨基甲酸叔丁酯(0.348g,2.000mmol)、三乙酰氧基硼氢化钠(0.636g,3.00mmol)和2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(0.362g,1mmol)在DMF(5ml)中混合。在室温搅拌过夜。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:50-90％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为600mg，且经LCMS分析评估的其纯度为100％。LC\MS方法A:2.2分钟,M+1＝521.6,EM＝520.3。LC\MS方法M:3.1分钟,M+1＝521.6,EM＝520.3。1H NMR(500MHz,DMSO-d6)δ7.52-7.44(m,3H),7.41-7.37(m,1H),7.35-7.28(m,3H),7.21(d,J＝7.0Hz,1H),6.45-6.25(m,3H),5.17(s,2H),3.82-3.73(m,6H),3.41(br.s.,2H),3.06(d,J＝5.8Hz,2H),2.38(br.s.,2H),2.28-2.18(m,3H),2.07(s,3H),1.43-1.34(m,9H).
实施例191:
将中间体191A(2-((2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)(甲基)氨基)乙基)氨基甲酸叔丁酯(0.6g,1.15mmol)溶于5mL 0.5N盐酸/乙醚。在室温搅拌1小时。用乙醚稀释并使氮气鼓泡经过反应混合物达10分钟。经旋转蒸发除去溶剂。将残留物置于真空过夜。
经反相HPLC色谱法纯化，其使用以下条件：起始％B＝5至最终％B＝100,梯度时间＝10分钟,流速＝40mL/分钟,波长＝220nm,溶剂A＝含有0.1％TFA的10％甲醇,90％水，溶剂B＝含有0.1％TFA的90％甲醇,10％水，柱＝Phenomenex-Luna 30X50mm S10。
在8.6分钟的主峰符合预期产物。合并含有预期产物的馏分并经离心蒸发干燥得到标题化合物，其为二三氟乙酸盐(0.61g,82％)。1H NMR(400MHz,氯仿-d)δ7.47-7.41(m,3H),7.38(d,J＝7.1Hz,1H),7.33(d,J＝6.8Hz,2H),7.30(d,J＝3.2Hz,1H),6.28(s,2H),5.48(br.s.,4H),5.12(s,2H),4.29(q,J＝13.0Hz,2H),3.92-3.77(m,6H),3.70-3.39(m,5H),2.86-2.73(m,3H),2.29(s,3H).
1H NMR(500MHz,DMSO-d6)δ7.52-7.44(m,3H),7.42-7.37(m,1H),7.35-7.27(m,3H),7.22(d,J＝7.6Hz,1H),6.38(s,2H),5.17(s,2H),3.77(s,6H),3.40(s,2H),2.74(br.s.,2H),2.45-2.38(m,2H),2.25-2.19(m,3H),2.07(s,3H).
实施例191
1-(2-((2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)(甲基)氨基)乙基)-3-苯基脲
向5mL反应小瓶中加入异氰酰基苯(0.012g,0.100mmol)在二氯甲烷(0.5mL)中的溶液。加入实施例190,N1-(2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)-N1-甲基乙-1,2-二胺,2TFA(0.032g,0.05mmol)和许尼希碱(0.027mL,0.155mmol)在二氯甲烷(0.5mL)中的溶液。在室温搅拌过夜。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:35-75％B，历时25分钟，然后7分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为5.9mg,且经LCMS分析评估的其纯度为99％。1H NMR(500MHz,DMSO-d6)δ8.82(br.s.,1H),7.55-7.45(m,3H),7.39(d,J＝7.3Hz,3H),7.37-7.28(m,3H),7.25-7.16(m,3H),6.88(t,J＝7.2Hz,1H),6.38(s,2H),6.05(br.s.,1H),5.18(s,2H),3.76(s,6H),3.47(br.s.,2H),3.23(d,J＝5.2Hz,2H),2.48-2.42(m,2H),2.24(s,3H),2.13(s,3H).
实施例192
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}-2-氧代-2H-色烯-6-磺酰胺
向5mL反应小瓶中加入2-氧代-2H-色烯-6-磺酰氯(0.024g,0.100mmol)。加入实施例190,N1-(2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)-N1-甲基乙-1,2-二胺,2TFA(0.032g,0.05mmol)和许尼希碱(0.027mL,0.155mmol)在二氯甲烷(0.5mL)中的溶液。在室温搅拌30分钟。反应经LCMS监测，显示出大部分预期产物。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:40-80％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为19.3mg,且经LCMS分析评估的其纯度为97％。1H NMR(500MHz,DMSO-d6)δ8.25(s,1H),8.20(d,J＝9.8Hz,1H),7.97(d,J＝8.2Hz,1H),7.60(d,J＝8.5Hz,1H),7.53-7.45(m,3H),7.43-7.37(m,1H),7.36-7.27(m,3H),7.22(d,J＝7.3Hz,1H),6.63(d,J＝9.8Hz,1H),6.36(s,2H),5.17(s,2H),3.73(s,6H),3.36(s,2H),2.91(t,J＝6.7Hz,2H),2.35(t,J＝6.9Hz,2H),2.23(s,3H),1.99(s,3H).
实施例193
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}丙-2-烯酰胺
将实施例190,N1-(2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)-N1-甲基乙-1,2-二胺(0.021g,0.05mmol)与许尼希碱(0.026mL,0.150mmol)和丙烯酰氯(0.014g,0.150mmol)在二氯甲烷(1mL)中混合。1小时后，LC/MS显示预期产物。加入甲醇并在空气流下除去溶剂。再溶于甲醇并滤过。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:30-70％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为19.2mg,且经LCMS分析评估的其纯度为98％。1H NMR(500MHz,DMSO-d6)δ7.91-7.86(m,1H),7.47(s,3H),7.42-7.37(m,1H),7.33(d,J＝7.9Hz,3H),7.24-7.19(m,1H),6.37(s,2H),6.27-6.16(m,1H),6.13-5.97(m,1H),5.61-5.52(m,1H),5.17(s,2H),3.75(s,6H),3.30-3.22(m,2H),2.44-2.37(m,2H),2.23(s,3H),2.10(s,3H).
实施例194
(2E)-3-({2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}氨甲酰基)丙-2-烯酸乙酯
将实施例190,N1-(2,6-二甲氧基-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苄基)-N1-甲基乙-1,2-二胺(0.021g,0.05mmol)、许尼希碱(0.026mL,0.150mmol)和(E)-4-氯-4-氧代丁-2-烯酸乙酯(0.024g,0.150mmol)在二氯甲烷(1mL)中混合。30分钟后，反应经LC/MS监测，显示了预期产物。加入甲醇并在空气流下除去溶剂。再溶于甲醇并滤过。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:40-100％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为17.8mg,且经LCMS分析评估的其纯度为97％。1H NMR(500MHz,DMSO-d6)δ8.40(br.s.,1H),7.52-7.45(m,3H),7.42-7.37(m,1H),7.35-7.27(m,3H),7.21(d,J＝7.3Hz,1H),7.02(d,J＝15.3Hz,1H),6.56(d,J＝15.6Hz,1H),6.37(s,2H),5.16(s,2H),4.18(q,J＝7.2Hz,2H),3.75(s,6H),3.30(d,J＝5.8Hz,2H),2.43(t,J＝6.6Hz,2H),2.23(s,3H),2.12(s,3H),1.24(t,J＝7.0Hz,3H).
实施例198
N-{2-[({3-氰基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺
中间体198A:3-溴-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛
向3-溴-4-羟基苯甲醛(101mg,0.5mmol)、三苯基膦(146mg,0.555mmol)和(2-甲基-[1,1'-联苯]-3-基)甲醇(100mg,0.504mmol)在无水THF(3mL)中的冷却的(0℃)溶液中逐滴加入偶氮二羧酸二异丙酯(0.108mL,0.555mmol)在THF(3mL)中的溶液。将所得的黄色溶液缓慢温热至室温，同时搅拌过夜。将过量的溶剂旋转蒸发。将粗残留物溶于甲醇并经制备性LC/MS纯化，其采用以下条件：柱:Waters XBridge C18,19x200mm,5-μm颗粒；保护柱:Waters XBridge C18,19x10mm,5-μm颗粒；流动相A:含有20-mM乙酸铵的水；流动相B:含有20-mM乙酸铵的95:5乙腈:水；梯度:30-100％B，历时20分钟，然后4分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为106.9mg,且经LCMS分析评估的其纯度为100％。LC/MS方法A:3.1分钟,M+1＝381.0,EM＝380.0.
实施例198:
将氰化亚铜(I)(18mg,0.201mmol)和3-溴-4-((2-甲基-[1,1'-联苯]-3-基)甲氧基)苯甲醛(50mg,0.131mmol)在DMF(1311μl)中在氩气下混合。密封并在120℃加热72小时。滤过并将该溶液直接与三乙酰氧基硼氢化钠(84mg,0.394mmol)和N-(2-氨基乙基)乙酰胺(26.8mg,0.263mmol)在DMF(657μl)中混合。在室温搅拌过夜并经0.45μm PVDF Whatman注射过滤器滤过。
将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:35-75％B，历时20分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为16.1mg,且经LCMS分析评估的其纯度为91％。1H NMR(500MHz,DMSO-d6)δ7.80(br.s.,1H),7.69(s,1H),7.63(d,J＝8.4Hz,1H),7.53-7.44(m,3H),7.42-7.36(m,2H),7.34-7.28(m,3H),7.23(d,J＝7.7Hz,1H),5.33(s,2H),3.66(s,2H),3.38(d,J＝11.7Hz,2H),3.18-3.06(m,2H),2.23(s,3H),1.79(s,3H).
实施例199
N-(2-((4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2,5-二氟苄基)氨基)乙基)乙酰胺
中间体199A
4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2,5-二氟苯甲醛
将2,5-二氟-4-羟基苯甲醛(204mg,1.288mmol)、三苯基膦(338mg,1.288mmol)和(3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苯基)甲醇(300mg,1.171mmol)在无水THF(5853μl)中混合并在冰/水浴上冷却。逐滴加入偶氮二羧酸二异丙酯(250μl,1.288mmol)在THF(5853μl)中的溶液。历时周末将所得的黄色溶液在搅拌下缓慢温热至室温。经LCMS显示主峰不具有产物质量。将过量的溶剂经旋转蒸发器蒸发。在40g硅胶柱上进行色谱法纯化(0-30％乙酸乙酯/己烷，经历20倍柱体积)得到340mg白色固体。在CDCl3中一些芳香化合物的峰缺失且最可能的是由残留滤过掩蔽。DMSO中的NMR证实了该结构。1H NMR(400MHz,DMSO-d6)δ10.09(d,J＝2.2Hz,1H),7.66(dd,J＝10.9,6.5Hz,1H),7.57(dd,J＝12.2,6.6Hz,1H),7.45(d,J＝7.3Hz,1H),7.32-7.25(m,1H),7.24-7.19(m,1H),6.93(d,J＝8.1Hz,1H),6.79(s,1H),6.78-6.74(m,1H),5.37(s,2H),4.29(s,4H),2.22(s,3H).
实施例199:
将N-(2-氨基乙基)乙酰胺(12.37mg,0.121mmol)和4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2,5-二氟苯甲醛(40mg,0.101mmol)的混合物在二氯乙烷(505μl)中混合。固体未溶解。加入三乙酰氧基硼氢化钠(42.8mg,0.202mmol)并将混合物在室温搅拌过夜。大部分固体已经溶解。LCMS显示了产物:亚胺:起始物质:二烷基化物的1:1:5:2混合物。加入10当量的N-(2-氨基乙基)乙酰胺(100mg,1mmol)和氰基硼氢化钠并搅拌2小时。LCMS仅显示预期产物：将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:30-80％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为29.6mg,且经LCMS分析评估的其纯度为96％。1H NMR(500MHz,DMSO-d6)δ7.79(br.s.,1H),7.42(d,J＝7.7Hz,1H),7.36-7.23(m,3H),7.19(d,J＝7.0Hz,1H),6.93(d,J＝8.1Hz,1H),6.78(s,1H),6.76(d,J＝8.1Hz,1H),5.21(s,2H),4.29(s,4H),3.12(q,J＝6.1Hz,2H),2.21(s,3H),1.92(br.s.,2H),1.82-1.74(m,3H)。认为2个缺失的氢处于DMSO或水的峰的下方。
实施例200由中间体199A,4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2,5-二氟苯甲醛和(S)-4-氨基-3-羟基丁酸根据如实施例1所述的还原胺化条件制备。
实施例201由中间体199A,4-((3-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-2-甲基苄基)氧基)-2,5-二氟苯甲醛和(S)-哌啶-2-羧酸根据如实施例1所述的还原胺化条件制备。
实施例202
N-{2-[({2-甲氧基-6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]乙基}乙酰胺
中间体202A:2-甲氧基-6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-甲醛
将碳酸铯(223mg,0.683mmol)、乙酸钯(II)(7.67mg,0.034mmol)、2-二-叔丁基膦基-2',4',6'-三异丙基联苯(叔丁基Xphos)(29mg,0.068mmol)、6-氯-2-甲氧基吡啶-3-甲醛(58.6mg,0.341mmol)和(2-甲基-[1,1'-联苯]-3-基)甲醇(88mg,0.444mmol)在配备有搅拌棒的25mL圆底烧瓶中混合。加入甲苯(2mL)并将混合物用氩气流净化5分钟。将反应混合物密封并在80℃加热过夜。LC/MS显示具有相似强度的11个峰。在4分钟的峰所具有的M+1为334，其符合预期产物。将粗反应混合物的可溶部分加入至25g硅胶柱(二氯甲烷)。用0-60％乙酸乙酯/己烷进行色谱法纯化。使用2,4-二硝基苯基肼染色测试含有至少两个混合物的馏分针对醛为阳性。分离该醛-阳性的馏分且无需进一步纯化即可使用。
实施例202:
在1:00pm将氰基硼氢化钠(20mg,0.318mmol)、N-(2-氨基乙基)乙酰胺(25mg,0.245mmol)和粗的2-甲氧基-6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-甲醛(20mg,0.060mmol)在DMF(2mL)和乙酸(0.100mL)中混合。在室温搅拌过夜。LC/MS显示产物：3.5分钟,M+1＝420.3,EM＝419.2。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridgeC18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:35-75％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为11.0mg,且经LCMS分析评估的其纯度为96％。1H NMR(600MHz,DMSO-d6)δ7.80(br.s.,1H),7.62(d,J＝8.1Hz,1H),7.48-7.43(m,3H),7.41-7.36(m,1H),7.31(d,J＝7.3Hz,2H),7.26(t,J＝7.5Hz,1H),7.18(d,J＝7.7Hz,1H),6.42(d,J＝7.7Hz,1H),5.41(s,2H),3.89(s,3H),3.58(s,1H),3.18-3.05(m,2H),2.22(s,3H),1.82-1.72(m,3H)。认为二氨基乙酰胺的亚甲基处于2.5ppm的DMSO峰的下方。
实施例203至226
中间体203A:5-溴-2-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶
将2,5-二溴吡啶(5g,21.11mmol)、(2-甲基-[1,1'-联苯]-3-基)甲醇(5.44g,27.4mmol)、二苯并-18-冠-6(0.380g,1.055mmol)、氢氧化钾(2.84g,50.7mmol)和甲苯(50mL)的混合物用Dean-Stark阱(用甲苯预填充)回流搅拌。1.5小时后，停止加热。TLC分析显示消耗起始物质。LC/MS符合粗的预期产物。将溶剂经旋转蒸发减压除去。加入水(50mL)并将产物在二氯乙烷(3x50mL)中萃取。将合并的有机部分经硫酸镁干燥并滤过。将溶剂经旋转蒸发减压除去，得到9.7g黄色油状物。LC/MS符合粗的预期产物。黄色油状物在静置时变为灰白色固体。在330g硅胶柱上进行色谱法纯化(0-20％乙酸乙酯/己烷)得到产物(6.3g,84％)。1H NMR(400MHz,DMSO-d6)δ8.34(dd,J＝2.8,0.5Hz,1H),7.95(dd,J＝8.8,2.5Hz,1H),7.50-7.43(m,3H),7.42-7.37(m,1H),7.34-7.31(m,2H),7.28(t,J＝7.5Hz,1H),7.23-7.18(m,1H),6.95(dd,J＝8.8,0.5Hz,1H),5.41(s,2H),2.20(s,3H).
中间体203B:6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-甲醛
在-78℃将N-丁基锂(1.140mL,2.96mmol)(2.6M在甲苯中)加入至5-溴-2-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶(1.0g,2.82mmol)的THF(10mL)溶液中。将反应混合物搅拌1小时，之后加入DMF(0.437mL,5.65mmol)。30分钟后，将反应混合物温热至室温。LC/MS符合预期产物。将反应混合物倒入20mL 5％碳酸氢钠水溶液中并用乙醚(3x20mL)萃取。将合并的有机物经硫酸镁干燥并滤过。将溶剂经旋转蒸发减压除去得到840mg黄色固体。该化合物无需进一步纯化即可使用。1H NMR(400MHz,DMSO-d6)d 9.99(s,1H),8.81(d,J＝2.4Hz,1H),8.16(dd,J＝8.6,2.4Hz,1H),7.53-7.16(m,8H),7.09(d,J＝8.6Hz,1H),5.55(s,2H),2.24-2.16(m,3H).
实施例203-226由中间体203B,6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-3-甲醛根据如实施例1所述的还原胺化条件使用适当的胺制备，得到预期产物。
实施例227
(2R)-2-{[(4-{[3-(3-氟-5-甲氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸
中间体227A:(R)-2-((4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苄基)氨基)丙酸甲酯
将4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛(1.15g,3.15mmol)在二氯乙烷(50mL)中的溶液与D-丙氨酸甲酯盐酸盐(1.319g,9.45mmol)和三乙酰氧基硼氢化钠(2.002g,9.45mmol)混合。将反应混合物在85℃加热3小时。浓缩粗物质，再溶于乙酸乙酯并用水、盐水洗涤，并经硫酸镁干燥。除去溶剂并且粗产物无需纯化即可直接用于下一步。
中间体227B:(R)-2-((4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苄基)氨基)丙酸
将氢氧化钠水溶液(1N)(3.15mL,3.15mmol)加入至中间体227A,(R)-2-((4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苄基)氨基)丙酸甲酯(1.425g,3.15mmol)在THF(20mL)和甲醇(20mL)中的溶液中。将混合物在室温搅拌过夜。除去溶剂得到浅黄色固体。经制备性HPLC纯化得到淡红色、浅棕色固体(1.2g)。
实施例227:
将中间体227B,(S)-2-(((3'-溴-3,5-二甲氧基-2'-甲基-[1,1'-联苯]-4-基)甲基)氨基)丙酸(714mg,1.8mmol)溶于二噁烷(35mL)。将碳酸铯(1.7gm,5.3mmol)溶于水(3.5mL)。将(3-氟-5-甲氧基苯基)硼酸(18mg,0.1mmol)在0.5-2mL微波小瓶中称重。加入(S)-2-(((3'-溴-3,5-二甲氧基-2'-甲基-[1,1'-联苯]-4-基)甲基)氨基)丙酸溶液(1mL,0.052mmol)100μL碳酸铯溶液和1,1'-二(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(4.25mg,0.0052mmol)。将反应混合物在Biotage InitiatorTM(400W)微波中在150℃加热15分钟，其中20秒预先搅拌并使用固定保持时间。将内容物转移至6mL MP-Thiol SPE柱(用甲醇调节)。将反应小瓶用2x500μL甲醇淋洗，将淋洗液转移至SPE柱。将产物用4mL甲醇洗脱。在1小时内将样品在Zymark Tabletop干燥器中在40℃吹下。向每个小瓶中加入1mLDMF。将内容物转移至16x48mm螺纹小瓶中。用500μL DMF淋洗培养管。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95甲醇:水；流动相B:含有10-mM乙酸铵的95:5甲醇:水；梯度:10-100％B，历时18分钟,然后7分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为8.1mg,且经LCMS分析评估的其纯度为100％。1H NMR(500MHz,DMSO-d6)d 7.52(d,J＝7.9Hz,1H),7.29(d,J＝7.3Hz,1H),7.24(d,J＝7.9Hz,1H),6.86(d,J＝11.3Hz,1H),6.76-6.68(m,2H),6.44(s,2H),5.20(s,2H),3.97(br.s.,2H),3.82(d,J＝3.7Hz,9H),3.05(d,J＝6.7Hz,1H),2.23(s,3H),1.27(d,J＝6.7Hz,3H).
实施例228,(2R)-2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸由中间体227B,(S)-2-(((3'-溴-3,5-二甲氧基-2'-甲基-[1,1'-联苯]-4-基)甲基)氨基)丙酸和苯并[d][1,3]二氧杂环戊烯-5-基硼酸使用如合成实施例227所采用的相同反应条件制备。
实施例229
3-[3-(4-{[(2-羟基乙基)氨基]甲基}-3,5-二甲氧基苯氧基甲基)-2-甲基苯基]苯酚
中间体229A:4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛
将4-羟基-2,6-二甲氧基苯甲醛(3.99g,21.88mmol)、三苯基膦(6g,22.88mmol)和(3-溴-2-甲基苯基)甲醇(4g,19.89mmol)在无水THF(50mL)中的溶液在冰浴中冷却。逐滴加入偶氮二羧酸二异丙酯(4.25mL,21.88mmol)在THF(50mL)中的溶液。将所得的黄色溶液在搅拌下缓慢温热至室温过夜。经旋转蒸发器除去过量的溶剂。将粗产物在360g硅胶柱上经色谱法纯化(用乙酸乙酯/己烷洗脱)。合并含有预期产物的馏分并将溶剂真空除去得到标题化合物(4.0g,55％)。1H NMR(400MHz,氯仿-d)δ10.39(s,1H),7.62(d,J＝8.0Hz,1H),7.37(d,J＝7.3Hz,1H),7.12(t,J＝7.8Hz,1H),6.18(s,2H),5.13(s,2H),3.91(s,6H),2.49(s,3H).
实施例229:
制备4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛(310mg,850μmol)在DCE(8.5mL)中的溶液。另外制备2-氨基乙醇(77uL,1.3mmol)在DCE(7.5mL)中的溶液。将各溶液的0.5mL等分溶液加入至反应小瓶中。将乙酸(2.86μl,50.0μmol)加入至小瓶中，封盖并在40℃振摇1hr。在40℃在Zymark Tabletop干燥器中除去溶剂达1小时。加入甲苯(0.5mL)并在40℃在Zymark Tabletop干燥器中除去溶剂达1小时。制备四甲基三乙酰氧基硼氢化铵(672mg,2.6mmol)在DCE(17mL)中的溶液并将1mL加入至反应混合物中。将反应小瓶封盖并在室温振摇过夜。将内容物转移至6-mL PL-SO3H SPE柱(用甲醇调节)。将反应小瓶用500μL甲醇淋洗并将淋洗液转移至SPE柱。将柱用4mL甲醇洗涤。将产物用4mL 1N氨/甲醇洗脱，在35℃在Zymark Tabletop干燥器中除去溶剂达1小时。将残留物溶于二噁烷(1mL)并转移至含有(3-羟基苯基)硼酸(13.8mg,0.1mmol)的小瓶中。加入碳酸铯(831mg,2.6mmol)在水(1.7mL)中的溶液(0.1mL)和固体1,1'-二(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(4.08mg,0.005mmol)。将反应混合物在搅拌下在100℃加热过夜。将反应内容物转移至6-mL PL-Thiol SPE柱(用甲醇调节)。将反应小瓶用甲醇(0.5mL)淋洗并将淋洗液加入至SPE柱。将产物用4mL甲醇洗脱。在35℃在Zymark Tabletop干燥器中除去溶剂达2小时。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95甲醇:水；流动相B:含有10-mM乙酸铵的95:5甲醇:水；梯度:50-90％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟，合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为2.4mg,且经LCMS分析评估的其纯度为96％。1H NMR(500MHz,DMSO-d6)δ7.47(d,J＝7.3Hz,1H),7.30-7.22(m,2H),7.18(d,J＝7.3Hz,1H),6.78(d,J＝8.2Hz,1H),6.71(d,J＝7.3Hz,1H),6.68(br.s.,1H),6.38(s,2H),5.16(s,2H),3.91(s,1H),3.78(s,6H),3.67(br.s.,2H),3.47-3.43(m,2H),2.56-2.53(m,2H),2.22(s,3H).
实施例230、231、232和245由4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛和2-氨基乙醇使用如实施例229阐述的相同操作制备，除了用适当的硼酸代替(3-羟基苯基)硼酸，以获得预期产物。
实施例285、286、287和289由4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛和N-(2-氨基乙基)乙酰胺使用如实施例229阐述的相同操作制备，除了用适当的硼酸代替(3-羟基苯基)硼酸，以获得预期产物。
实施例288、290、291、292、293和294由4-((3-溴-2-甲基苄基)氧基)-2,6-二甲氧基苯甲醛和2-甲基-1-(4-甲基哌嗪-1-基)丙-2-胺使用如实施例229阐述的相同操作制备，除了用适当的硼酸代替(3-羟基苯基)硼酸，以获得预期产物。
实施例296
(3S)-3-羟基-4-[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]丁酸
将(S)-4-氨基-3-羟基丁酸(35.7mg,300μmol)和5-((2-甲基-[1,1'-联苯]-3-基)甲氧基)吡啶-2-甲醛(30.3mg,100μmol)溶于DMF(0.5mL)和乙酸(5.72μl,100μmol)的混合物。将反应混合物在40℃搅拌1小时并加入氰基硼氢化钠(18.85mg,300μmol)在DMF(0.5mL)中的溶液。在室温搅拌过夜。将反应混合物用500μL MeOH稀释。在35℃在Zymark Tabletop干燥器中除去溶剂达1小时。将残留物再溶于1mL DMF并使用注射过滤器滤过。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:20-60％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为9.1mg,且经LCMS分析评估的其纯度为94％。1H NMR(500MHz,DMSO-d6)d 8.33(d,J＝2.6Hz,1H),7.50(d,J＝8.8Hz,1H),7.46(t,J＝7.5Hz,3H),7.41-7.36(m,2H),7.32(d,J＝7.3Hz,2H),7.29(t,J＝7.7Hz,1H),7.21(d,J＝7.7Hz,1H),5.22(s,2H),3.89-3.83(m,1H),3.78(br.s.,2H),3.45(br.s.,3H),2.28(dd,J＝15.0,5.1Hz,1H),2.21(s,3H),2.17-2.09(m,1H).
实施例297
N-(2-{[(3-氯-4-{[2-甲基-3-(噻吩-3-基)苯基]甲氧基}苯基)甲基]氨基}乙基)乙酰胺
中间体297A:(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)苯基)甲醇
将二噁烷(200mL)加入至500mL圆底烧瓶中并使氮气鼓泡通过反应混合物达10分钟。加入(3-溴-2-甲基苯基)甲醇(9.0g,44.8mmol)并使氮气鼓泡通过反应混合物达10分钟。加入乙酸钾(13.18g,134mmol)并使氮气鼓泡通过反应混合物达10分钟。加入二(频哪醇合)二硼(18.19g,71.6mmol)并使氮气鼓泡通过反应混合物达10分钟。加入PdCl2(dppf)-CH2Cl2(4.75g,5.82mmol)并使氮气鼓泡通过反应混合物达10分钟。将反应混合物在80℃加热过夜。
将反应混合物用乙酸乙酯(200ml)稀释，经硅藻土填料滤过并将填料用乙酸乙酯洗涤。将合并的有机部分真空浓缩得到黑色粘稠残留物。将粗残留物吸附于硅胶上并在120g硅胶柱上进行色谱法纯化(使用丙酮/石油醚)。将产物在5.0％丙酮洗脱。合并含有产物的馏分，并真空除去溶剂。得到灰白色固体。将固体与石油醚搅拌并真空滤过除去硼杂质。标题化合物(8.7g,77％)经NMR分析为纯的。1H NMR(500MHz,DMSO-d6)δ7.33(dd,J＝0.9,7.5Hz,1H),7.45(d,J＝6.9Hz,1H),7.22(t,J＝7.5Hz,1H),4.73(d,J＝3.0Hz,2H),2.58(s,3H),1.58(br.s.,1H,OH),1.37(s,12H).
中间体297B:3-氯-4-((2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)苄基)氧基)苯甲醛
将3-氯-4-羟基苯甲醛(126mg,0.806mmol)、三苯基膦(233mg,0.887mmol)和(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)苯基)甲醇(200mg,0.806mmol)在无水THF(5mL)中的溶液在冰浴中冷却。逐滴加入偶氮二羧酸二异丙酯(0.172mL,0.887mmol)在THF(5mL)中的溶液。将所得的黄色溶液缓慢温热至室温，同时搅拌过夜。除去溶剂并将残留物在24g硅胶柱上纯化(用2:1己烷:乙酸乙酯)。收集馏分得到预期产物(0.305g,98％)。1HNMR(400MHz,氯仿-d)d 9.86(s,1H),7.94(d,J＝2.0Hz,1H),7.81(dd,J＝7.5,1.1Hz,1H),7.75(dd,J＝8.4,2.1Hz,1H),7.55(d,J＝7.5Hz,1H),7.25(t,J＝7.6Hz,1H),7.12(d,J＝8.6Hz,1H),5.24(s,2H),2.61(s,3H),1.39(s,12H).
实施例297:
将(3-((2-氯-4-甲酰基苯氧基)甲基)-2-甲基苯基)硼酸(352mg,1.2mmol)在二噁烷(16mL)中的溶液用氮气脱气。将磷酸三钾(613mg,2.9mmol)溶于水(4mL)并用氮气脱气。向反应小瓶中加入2-溴噻吩(23.6mg,0.144mmol)、1mL(3-((2-氯-4-甲酰基苯氧基)甲基)-2-甲基苯基)硼酸溶液、250μL磷酸三钾溶液和固体二代Xphos前催化剂(2.84mg,3.61μmol,CAS编号1310584-14-5)。将小瓶密封并在室温振摇过夜。将反应混合物转移至6mL PL-Thiol SPE柱(用甲醇调节)。将反应小瓶用500μL甲醇淋洗并将淋洗液转移至SPE柱。将中间体产物用4mL甲醇洗脱并在40℃在Zymark Tabletop干燥器中除去溶剂达3小时。中间体无需进一步纯化即可使用。
制备N-(2-氨基乙基)乙酰胺(336μL,3.5mmol)在DCE(8.0mL)中的溶液并将500μLN-(2-氨基乙基)乙酰胺溶液加入至干燥的醛中间体。加入乙酸(4.14μl,0.072mmol)并将密封的反应混合物在40℃搅拌1小时。在40℃在Zymark Tabletop干燥器中除去溶剂达2小时。加入甲苯(500μL)并在40℃在Zymark Tabletop干燥器中除去溶剂达1小时。将四甲基三乙酰氧基硼氢化铵(1.4gm,5.2mmol)溶于DCE(16mL)并将1.0mL该溶液加入至反应混合物中。将密封的反应混合物在室温振摇过夜。LCMS基本上符合亚胺中间体。在40℃在ZymarkTabletop干燥器中除去溶剂达3小时。制备N-(2-氨基乙基)乙酰胺(336μL,3.5mmol)在DMF(8.0mL)中的溶液并将500μL加入至反应混合物中。加入乙酸(4.14μl,0.072mmol)。将密封的反应混合物在室温振摇1小时。将氰基硼氢化钠(327mg,5.2mmol)溶于DMF(8.0mL)并将500μL加入至反应混合物。将密封的反应混合物在室温振摇过夜。将反应内容物转移至6-mLPL-SO3H SPE柱(用甲醇调节)。将反应小瓶用500μL甲醇淋洗并将淋洗液转移至SPE柱。将柱用4mL甲醇淋洗。将产物用4mL 1N氨/甲醇洗脱。在40℃在Zymark Tabletop干燥器中除去溶剂达2小时并将残留物溶于DMF(1mL)。将粗物质经制备性LC/MS纯化，其采用以下条件：柱:XBridge C18,19x200mm,5-μm颗粒；流动相A:含有10-mM乙酸铵的5:95乙腈:水；流动相B:含有10-mM乙酸铵的95:5乙腈:水；梯度:40-80％B，历时15分钟,然后5分钟保持在100％B；流速:20mL/分钟。合并含有预期产物的馏分并经离心蒸发干燥。产物的收率为6.3mg,且经LCMS分析评估的其纯度为97％。1H NMR(500MHz,DMSO-d6)δ7.64(d,J＝5.1Hz,1H),7.55(s,1H),7.52(d,J＝7.3Hz,1H),7.40-7.34(m,3H),7.33-7.27(m,1H),7.20-7.16(m,1H),7.14(d,J＝3.3Hz,1H),5.28(s,2H),3.92(br.s.,2H),3.25(d,J＝6.2Hz,2H),2.77(br.s.,2H),2.36(s,3H),1.82(s,3H).
HPLC方法
方法A:柱:Waters BEH C18,2.0x50mm,1.7-μm颗粒；流动相A:含有10mM乙酸铵的5:95乙腈:水；流动相B:含有10mM乙酸铵的95:5乙腈:水；温度:40℃；梯度:0.5分钟保持在0％B,0-100％B，历时4分钟,然后0.5分钟保持在100％B；流速:1mL/分钟.
方法M:柱:Waters BEH C18,2.0x50mm,1.7-μm颗粒；流动相A:含有10mM乙酸铵的5:95甲醇:水；流动相B:含有10mM乙酸铵的95:5甲醇:水；温度:40℃；梯度:0.5分钟保持在0％B,0-100％B，历时4分钟,然后0.5分钟保持在100％B；流速:0.5mL/分钟.
方法AA:Ascentis Express C18,4.6X50mm,2.7μm柱；4ml/分钟流速；4分钟梯度，0％B至100％B；A＝5％ACN-95％H2O 10mM NH4OAc,B＝95％ACN-5％H2O 10mM NH4OAc；UV检测，220nm；且柱加热器设置在45℃.
方法AT:Ascentis Express C18,2.1X50mm,2.7μm柱；1.1ml/分钟流速；3分钟梯度，0％B至100％B；A＝5％ACN-95％H2O 0.1％TFA,B＝95％ACN-5％H2O 0.1％TFA；UV检测，220nm；且柱加热器设置在50℃.
方法A50:柱:Waters BEH C18,2.0x50mm,1.7-μm颗粒；流动相A:含有10mM乙酸铵的5:95乙腈:水；流动相B:含有10mM乙酸铵的95:5乙腈:水；温度:50℃；梯度:0％B,0-100％B，历时3分钟，然后0.5分钟保持在100％B；流速:1mL/分钟；检测:UV，220nm.
方法M50:柱:Waters BEH C18,2.0x50mm,1.7-μm颗粒；流动相A:含有10mM乙酸铵的5:95甲醇:水；流动相B:含有10mM乙酸铵的95:5甲醇:水；温度:50℃；梯度:0％B,0-100％B，历时3分钟，然后0.5分钟保持在100％B；流速:0.5mL/分钟；检测:UV，220nm.
生物学测定
使用PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定研究式(I)化合物结合PD-L1的能力。
均相时间分辨荧光(HTRF)结合测定
所有结合研究在HTRF测定缓冲液中进行，该缓冲液由补充有0.1％(withv)牛血清白蛋白的dPBS和0.05％(v/v)Tween-20组成。对于PD-1-Ig/PD-L1-His结合测定，将抑制剂与PD-L1-His(10nM最终)在4μl测定缓冲液中预先培养15m，随后加入在1μl测定缓冲液中的PD-1-Ig(20nM最终)并进一步培养15m。使用来自人、狗或小鼠的PD-L1。使用铕穴状化合物-标记的抗-Ig(1nM最终)和别藻蓝素(APC)标记的抗-His(20nM最终)完成HTRF检测。将抗体稀释于HTRF检测缓冲液并将5μl分配于结合反应混合物的上方。将反应混合物平衡30分钟并使用EnVision荧光计得到信号(665nm/620nm比)。在PD-1-Ig/PD-L2-His(分别为20&5nM)、CD80-His/PD-L1-Ig(分别为100&10nM)和CD80-His/CTLA4-Ig(分别为10&5nM)之间进行额外的结合测定。生物素化SEQ ID NO:71和人PD-L1-His之间的竞争研究如下进行。将抑制剂与PD-L1-His(10nM最终)在4μl测定缓冲液中预先培养60m，随后加入在1μl测定缓冲液中的生物素化的SEQ ID NO:71(0.5nM最终)。结合平衡30m，随后加入在5μl HTRF缓冲液中的铕穴状化合物-标记的链霉亲和素(2.5pM最终)和APC-标记的抗-His(20nM最终)。将反应混合物平衡30m并使用EnVision荧光计得到信号(665nm/620nm比)。
下表列出了如在PD-1/PD-L1均相时间分辨荧光(HTRF)结合测定中测量的本发明的实施例1-108的IC50。如经实施例1-297所示的本发明的化合物显示了具有如下范围的IC50值：A＝0.006-0.10μM；B＝0.11-1.00μM；C＝1.01-10μM.
式(I)化合物具有作为PD-1/PD-L1的相互作用的抑制剂的活性，且因此可用于治疗与PD-1/PD-L1的相互作用相关的疾病。通过抑制PD-1/PD-L1的相互作用，本发明化合物可用于治疗感染性疾病，诸如丙型肝炎和癌症。

Claims (12)

1.式(I)化合物或其盐：
其中：
环B为苯基或噻吩基；
环A为:
其中A”为CH或N，且其中R1和R2中的一者为Q且R1和R2中的另一者为Rb；
R3为H或-CH2C(O)OH；
R4为-NHCH2CH2NHC(O)CH3；
Q为:
(i)
其中Ry为-OH、-CH3、-CH2OH、-C(O)OH、-CH2C(O)OH或-C(O)NHCH2CH2OH、-C(O)NH2、-NHC(O)CH3，且Rz为-OH、-CH3、-OCH3、-OC(O)CH3或-CH2CH＝CH2且Rh为-C(O)CH3；
(ii)-CH2NH-Rx，其中Rx为环丁基、任选取代有两个氟原子的-(CH2)环丁基、环丙基、羟基环戊基、环戊基、环己基、羟基环己基、羟基四氢呋喃基、N-甲基哌啶基、N-乙基哌啶基、羟基四氢噻吩基，或
(iii)-CH2NRa-CRaRa-(CH2)n-Rx，其中Rx为氢、氮杂环丁烷酮基、环己基、羟基苯基、吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、咪唑基、N-甲基咪唑基、-C(O)(吗啉基)；任选取代有甲基、羟基苯基、吡啶基、嘧啶基或-C(O)OC(CH3)3基团的哌嗪基；吡咯烷基、吡啶基、二氧化硫吗啉基或甲基三唑基；或
(iv)-CHRa-NRa-CRaRa-(CHRa)n-Rx，其中Rx为-OH、-OCH3、-C(O)OH、-OPh,-CH(CO2H)-NHC(O)CH3、-O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H-O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、-C(O)CH3、-C(O)NRaRa、-C(O)NRqRq、-N(CH3)2、-NHC(O)CH3、-NHC(O)Ph、-C(O)NH(CH2)2-咪唑基、NHC(O)OCH2Ph、-N(CH3)S(O)2CH3、-NHC(O)CH＝CH2、-NHC(O)CH＝CHC(O)CH2CH3，或
每个Ra独立为H、-CH(OH)CH3、OH、-(CH2)2OH,-CH2OH、-(CH2)2NH2、-CH2CH3或-CH3；或同一个碳原子上的两个Ra基团可形成四、五或六元碳环、N-甲基哌啶环或吡喃环；
每个Rb独立为H、F、Cl、Br、-CF3、-CN、CH3或-OCH3；
每个Rc独立为-OCH3、-OH、-OCH2CH3,-O(CH2)OCH3、-OCH2CH＝CH2、-O(CH2)2CH3、-O(CH2)2-吗啉基或F；
或连接于相邻碳原子的两个Rc形成-O-(CH2)v-O-，其中v为1或2；
每个Rq选自氢、-CH2C(O)NHCH2CO2H、-(CH2)C(O)NHCH(CO2H)CH2CH(CH3)2、-CH(Bn)-C(O)NHCH(CO2H)(CH2)3NHC(NH)NH2；
m为0或1；
n为0、1、2或3；
每个p独立为0；且
q为0、1或2。
2.权利要求1的化合物或其盐，其中环A为:
3.权利要求2的化合物或其盐，其中Q为:
4.权利要求2的化合物或其盐，其中Q为:-CH2NH-Rx，其中Rx为环丁基、任选取代有两个氟原子的-(CH2)环丁基、环丙基、羟基环戊基、环戊基、环己基、羟基环己基、羟基四氢呋喃基、N-甲基哌啶基、N-乙基哌啶基、羟基四氢噻吩基或
5.权利要求2的化合物或其盐，其中Q为:-CH2NRa-CRaRa-(CH2)n-Rx，其中Rx为氢、氮杂环丁烷酮基、环己基、羟基苯基、吡咯烷酮基、哌啶酮基、哌嗪酮基、吗啉基、咪唑基、N-甲基咪唑基、-C(O)(吗啉基)；任选取代有甲基、羟基苯基、吡啶基、嘧啶基或-C(O)OC(CH3)3基团的哌嗪基；吡咯烷基、吡啶基、二氧化硫吗啉基或甲基三唑基。
6.权利要求2的化合物或其盐，其中Q为-CHRa-NRa-CRaRa-(CHRa)n-Rx，其中Rx为-OH、-OCH3、-C(O)OH、-OPh、-CH(CO2H)-NHC(O)CH3、-O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2OH、-O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H
-O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、-C(O)CH3、-C(O)NRaRa、-C(O)NRqRq、-N(CH3)2、-NHC(O)CH3,-NHC(O)Ph、--C(O)NH(CH2)2-咪唑基、NHC(O)OCH2Ph、-N(CH3)S(O)2CH3、-NHC(O)CH＝CH2、-NHC(O)CH＝CHC(O)CH2CH3或
7.化合物或其盐，所述化合物选自：
(S)-1-(2,6-二甲氧基-4-((2-甲基联苯-3-基)甲氧基)苄基)哌啶-2-羧酸(1)；
1-(4-((2'-氟-2-甲基联苯-3-基)甲氧基)苄基)氮杂环丁烷(3)；
N-{2-[({3-溴-2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(4)；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺(5)；
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}-N-甲基甲磺酰胺(6)；
1-({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(7)；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-(吗啉-4-基)乙-1-酮(8)；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-(4-甲基哌嗪-1-基)乙基]胺(9)；
1-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}哌啶-2-酮(10)；
1-{3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(11)；
4-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}哌嗪-2-酮(12)；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[2-(吗啉-4-基)乙基]胺(13)；
1-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(14)；
2-[甲基({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酸(15)；
N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1-乙基哌啶-3-胺(16)；
1-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}吡咯烷-2-酮(17)；
(2S,4R)-4-(乙酰基氧基)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(18)；
N-(2-羟基乙基)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-甲酰胺(19)；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[1-(5-甲基-4H-1,2,4-三唑-3-基)乙基]胺(20)；
N-{2-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(21)；
(2S,4R)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-4-甲氧基吡咯烷-2-羧酸(22)；
N-{3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}乙酰胺(23)；
(1R,2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇(24)；
N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1-甲基哌啶-3-胺(25)；
(2S)-1-({2-甲氧基-3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(26)；
(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-2-(丙-2-烯-1-基)吡咯烷-2-羧酸(27)；
3-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(28)；
3-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(29)；
4-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吗啉-3-羧酸(30)；
3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁酸(31)；
1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-羧酸(32)；
(2R)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(33)；
(2S)-1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(34)；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-N,N-二甲基乙酰胺(35)；
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(36)；
1-({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(37)；
1-({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(38)；
(2S,4R)-4-甲氧基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(39)；
1-({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(40)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环庚烷-2-羧酸(41)；
2-[1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-基]乙酸(42)；
1-{3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(43)；
N-{2-[(1-{3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}乙基)氨基]乙基}乙酰胺(44)；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙酸(45)；
3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(46)；(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(47)；
1-({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(48)；
1-({3-氟-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(49)；
(2R,4R)-4-羟基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(50)；
(2R,4S)-4-羟基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(51)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(52)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-3-羧酸(53)；
(3R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-3-羧酸(54)；
(2R,4R)-4-甲基-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(55)；
(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(56)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-4-羧酸(57)；
(2R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(58)；
(2S)-1-({4-甲基-3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(59)；
1-{3-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}吡咯烷-2-酮(60)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1,2,5,6-四氢吡啶-3-羧酸(63)；
2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丙酸(64)；
N-{2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(65)；
1-({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(66)；
N-{2-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(67)；
N-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)环丁胺(68)；
N-{2-[({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(69)；
N-{2-[(1-{3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}乙基)氨基]乙基}乙酰胺(70)；
(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(71)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(72)；
(1R,2R)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇(73)；
1-({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)哌啶-2-羧酸(74)；
(2R)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-羧酸(75)；
5-{[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(76)；
(2S)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(77)；
(2R)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(78)；
N-{2-[({3-氟-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(79)；
(2S)-2-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(80)；
(2S)-2-[({3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(81)；
3-[({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(82)；
1-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(83)；
3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁酸(84)；
(2R)-2-[甲基({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(85)；
3-[({2,6-二甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(86)；
N-{2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(87)；
N-{2-[({4-甲基-3-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺(88)；
[(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)吡咯烷-2-基]甲醇(89)；
(2S)-1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷-2-羧酸(90)；
5-{[({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(91)；
5-{[({4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}吡咯烷-2-酮(92)；
(2S)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(93)；
2-[甲基({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酸(94)；
3-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酰胺(95)；
(2R)-2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(96)；
1-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(97)；
1-({2-甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(98)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(99)；
1-({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氮杂环丁烷(100)；
2-[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇(102)；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇(103)；
(2S)-2-[({3-溴-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(104)；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙酸(105)；
(2R)-2-{[(2,6-二甲氧基-4-{[3-(3-甲氧基苯基)-2-甲基苯基]甲氧基}苯基)甲基]氨基}丙酸(106)；
(2R)-2-{[(4-{[3-(3-氟-5-甲氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸(107)；
(2R)-2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸(108)；
2-(6-((2-甲基-[1,1'-联苯]-3-基)甲氧基)-3,4-二氢异喹啉-2(1H)-基)乙酸(2)；
N-[2-({5-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢萘-1-基}氨基)乙基]乙酰胺(61)；
N-[2-({6-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢萘-1-基}氨基)乙基]乙酰胺(62)；或6-[(2-甲基-3-苯基苯基)甲氧基]-1,2,3,4-四氢异喹啉(101)。
8.化合物或其盐，选自
N-[2-({4-[(2-甲基-3-苯基苯基)甲氧基]-2,3-二氢-1H-茚-1-基}氨基)乙基]乙酰胺；
4-{[({3-甲基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}氮杂环丁烷-2-酮；
(3S)-4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
(2S)-1-[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-3-(三氟甲基)苯基)甲基]哌啶-2-羧酸；
N-(2-{[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-3-(三氟甲基)苯基)甲基]氨基}乙基)乙酰胺；
(3S)-4-{[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-3-(三氟甲基)苯基)甲基]氨基}-3-羟基丁酸；
(2R,3S)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
(2R,3R)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
(2S,3S)-2-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
2-[({5-[(2-甲基-3-苯基苯基)甲氧基]噻吩-2-基}甲基)氨基]乙-1-醇；
2-[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]乙-1-醇；
{1-[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]环戊基}甲醇；
甲基({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)胺；
5-{[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]甲基}吡咯烷-2-酮；
2-(3,5-二甲氧基-4-{[(吡啶-2-基甲基)氨基]甲基}苯氧基甲基)-6-苯基苄腈；
2-{4-[(环丙基氨基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-{3,5-二甲氧基-4-[(3-甲基哌啶-1-基)甲基]苯氧基甲基}-6-苯基苄腈；
2-[3,5-二甲氧基-4-({[2-(吡咯烷-1-基)乙基]氨基}甲基)苯氧基甲基]-6-苯基苄腈；
2-{4-[(4-羟基哌啶-1-基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-[3,5-二甲氧基-4-(吗啉-4-基甲基)苯氧基甲基]-6-苯基苄腈；
2-(3,5-二甲氧基-4-{[(吡啶-3-基甲基)氨基]甲基}苯氧基甲基)-6-苯基苄腈；
2-(3,5-二甲氧基-4-{[(吡啶-4-基甲基)氨基]甲基}苯氧基甲基)-6-苯基苄腈；
2-[4-({[(3-羟基苯基)甲基]氨基}甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-[4-({[(2-羟基苯基)甲基]氨基}甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-[4-({[(4-羟基苯基)甲基]氨基}甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-{4-[(环丁基氨基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-{4-[(环戊基氨基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-{4-[(环己基氨基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-[3,5-二甲氧基-4-({[3-(2-氧代吡咯烷-1-基)丙基]氨基}甲基)苯氧基甲基]-6-苯基苄腈；
2-(3,5-二甲氧基-4-{[(丙-2-基)氨基]甲基}苯氧基甲基)-6-苯基苄腈；
N-{2-[({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)氨基]乙基}乙酰胺；
2-[4-({[2-(二甲基氨基)乙基]氨基}甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-(3,5-二甲氧基-4-{[(2-甲氧基乙基)氨基]甲基}苯氧基甲基)-6-苯基苄腈；
2-(4-{[(2-羟基乙基)氨基]甲基}-3,5-二甲氧基苯氧基甲基)-6-苯基苄腈；
2-[4-({[1-(羟基甲基)环戊基]氨基}甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-(4-{[(4-羟基环己基)氨基]甲基}-3,5-二甲氧基苯氧基甲基)-6-苯基苄腈；
3-[({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)氨基]丙酰胺；
2-{3,5-二甲氧基-4-[(甲基氨基)甲基]苯氧基甲基}-6-苯基苄腈；
2-[3,5-二甲氧基-4-({[2-(吡啶-2-基)乙基]氨基}甲基)苯氧基甲基]-6-苯基苄腈；
2-{3,5-二甲氧基-4-[(2-甲基吡咯烷-1-基)甲基]苯氧基甲基}-6-苯基苄腈；
2-{4-[(4-乙酰基哌嗪-1-基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-[3,5-二甲氧基-4-(吡咯烷-1-基甲基)苯氧基甲基]-6-苯基苄腈；
2-(4-{[3-(羟基甲基)哌啶-1-基]甲基}-3,5-二甲氧基苯氧基甲基)-6-苯基苄腈；
N-[(3S)-1-({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)吡咯烷-3-基]乙酰胺；
2-[4-(氮杂环丁烷-1-基甲基)-3,5-二甲氧基苯氧基甲基]-6-苯基苄腈；
2-{4-[(4-乙酰基-1,4-二氮杂环庚烷-1-基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-(4-{[乙基(吡啶-4-基甲基)氨基]甲基}-3,5-二甲氧基苯氧基甲基)-6-苯基苄腈；
2-(4-{[(2S)-2-(羟基甲基)吡咯烷-1-基]甲基}-3,5-二甲氧基苯氧基甲基)-6-苯基苄腈；
2-{4-[(2,5-二甲基吡咯烷-1-基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
2-{4-[(3-羟基哌啶-1-基)甲基]-3,5-二甲氧基苯氧基甲基}-6-苯基苄腈；
1-({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)哌啶-3-羧酸；
(2S)-1-({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)吡咯烷-2-甲酰胺；
(2S)-1-({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)哌啶-2-羧酸；
(6S)-5-({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1,2,5-三氮杂螺[2.4]庚-1-烯-6-羧酸；
{2-[2-(2-氨基乙氧基)乙氧基]乙基}({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)胺；
2-(2-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙氧基}乙氧基)乙-1-醇；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)({2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基})胺；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)({2-[4-(吡啶-2-基)哌嗪-1-基]乙基})胺；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)({2-[4-(嘧啶-2-基)哌嗪-1-基]乙基})胺；
4-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}哌嗪-1-羧酸叔丁酯；
4-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}-1λ6,4-硫吗啉-1,1-二酮；
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}氨基甲酸苄酯；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[3-(4-甲基哌嗪-1-基)丙基]胺；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[3-(吗啉-4-基)丙基]胺；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[3-(1H-咪唑-1-基)丙基]胺；
4-{[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}氮杂环丁烷-2-酮；
3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-N-[2-(1H-咪唑-4-基)乙基]丙酰胺；
2-({3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}(2-羟基乙基)氨基)乙-1-醇；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(3-苯氧基丙基)胺；
4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-羟基丁酸；
3-(4-{3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙基}哌嗪-1-基)苯酚；
[2-(苄基氧基)乙基]({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)胺；
1-{2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}-5,8,11-三氧杂-2-氮杂十三烷-13-醇；
1-{2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}-5,8,11,14,17,20-六氧杂-2-氮杂二十三烷-23-酸；
1-{2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}-5,8,11,14-四氧杂-2-氮杂十七烷-17-酸；
(2S)-5-甲脒基-2-[(2R)-2-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酰氨基}-3-苯基丙酰氨基]戊酸；
2-(2-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酰氨基}乙酰氨基)乙酸；
(2S)-5-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-乙酰氨基戊酸；
[(3,3-二氟环丁基)甲基]({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)胺；
(环丁基甲基)({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)胺；
(2S)-2-(2-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙酰氨基}乙酰氨基)-4-甲基戊酸；
(2-氨基乙基)({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)甲基胺；
3-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}-1-苯基脲；
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}-2-氧代-2H-色烯-6-磺酰胺；
N-{2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}丙-2-烯酰胺；
(2E)-3-({2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)(甲基)氨基]乙基}氨甲酰基)丙-2-烯酸乙酯；
(6S)-5-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-1,2,5-三氮杂螺[2.4]庚-1-烯-6-羧酸；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-(羟基甲基)丙-1,3-二醇；
(3S)-4-[({3-氯-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
N-{2-[({3-氰基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙基}乙酰胺；
N-(2-{[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-2,5-二氟苯基)甲基]氨基}乙基)乙酰胺；
(3S)-4-{[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-2,5-二氟苯基)甲基]氨基}-3-羟基丁酸；
(2S)-1-[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-2,5-二氟苯基)甲基]哌啶-2-羧酸；
N-{2-[({2-甲氧基-6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]乙基}乙酰胺；
5-(氮杂环丁烷-1-基甲基)-2-[(2-甲基-3-苯基苯基)甲氧基]吡啶；
N-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)环丁胺；
N-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)环戊胺；
1-{3-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]丙基}吡咯烷-2-酮；
({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)[2-(吡啶-2-基)乙基]胺；
2-[(2-甲基-3-苯基苯基)甲氧基]-5-(吡咯烷-1-基甲基)吡啶；
[(2S)-1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)吡咯烷-2-基]甲醇；
(2S)-1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)哌啶-2-羧酸；
1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)哌啶-3-羧酸；
[1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)哌啶-3-基]甲醇；
1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)哌啶-4-醇；
2-[(2-甲基-3-苯基苯基)甲氧基]-5-[(2-甲基吡咯烷-1-基)甲基]吡啶；
({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)(丙-2-基)胺；
甲基({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)胺；
N-{2-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]乙基}乙酰胺；
[2-(二甲基氨基)乙基]({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)胺；
(2-甲氧基乙基)({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)胺；
2-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]乙-1-醇；
{1-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]环戊基}甲醇；
4-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]环己-1-醇；
3-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]丙酰胺；
(2S)-2-[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]丙酸；
5-{[({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)氨基]甲基}吡咯烷-2-酮；
N-[(3S)-1-({6-[(2-甲基-3-苯基苯基)甲氧基]吡啶-3-基}甲基)吡咯烷-3-基]乙酰胺；
(2R)-2-{[(4-{[3-(3-氟-5-甲氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸；
(2R)-2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}丙酸；
3-[3-(4-{[(2-羟基乙基)氨基]甲基}-3,5-二甲氧基苯氧基甲基)-2-甲基苯基]苯酚；
2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}乙-1-醇；
2-{[(4-{[3-(3-乙氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}乙-1-醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-{3-[2-(哌啶-1-基)乙氧基]苯基}苯基)甲氧基]苯基}甲基)氨基]乙-1-醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丙-1,3-二醇；
(2S,3S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-甲基戊-1-醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-4-甲基戊-1-醇；
1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-2-醇；
{1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环戊基}甲醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-1,3-二醇；
1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-2-醇；
(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-4-甲基戊-1-醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-甲基丁-1-醇；
(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-甲基丁-1-醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-1-醇；
(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-1-醇；
2-{[(2,6-二甲氧基-4-{[2-甲基-3-(3-丙氧基苯基)苯基]甲氧基}苯基)甲基]氨基}乙-1-醇；
(2S)-3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-1,2-二醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丁酸；
1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丙-2-醇；
(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]戊-1-醇；
3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-2-醇；
(2R)-3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-1,2-二醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-1-醇；
(2S)-1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丙-2-醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇；
(1S,2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇；
(3R,4S)-4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]氧杂环戊烷-3-醇；
1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-甲基丁-2-醇；
({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)[3-(二甲基氨基)-2-羟基丙基]胺；
(2R)-2-环丙基-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇；
3-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-甲基丁-2-醇；
(2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-苯基乙-1-醇；
1-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2,3-二氢-1H-茚-2-醇；
(1S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-苯基乙-1-醇；
(3S)-4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]硫杂环戊烷-3-醇；
(1R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-苯基乙-1-醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-(吡啶-3-基)乙-1-醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-(吡啶-4-基)乙-1-醇；
(2S)-2-环己基-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]乙-1-醇；
{4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]氧杂环己烷-4-基}甲醇；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-1-(1-甲基-1H-咪唑-2-基)乙-1-醇；
1-{[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}环己-1-醇；
(1R,2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环戊-1-醇；
4-{[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}-1-甲基哌啶-4-醇；
(1R,2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环己-1-醇；
(1S,2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环戊-1-醇；
(1R,2R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]环戊-1-醇；
(2R,3S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-1,3-二醇；
(2S,3R)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]丁-1,3-二醇；
1-{[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]甲基}环丁-1-醇；
(3R)-4-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-3-羟基丁酸；
2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-乙基丙-1,3-二醇；
(2S)-2-[({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)氨基]-2-苯基乙-1-醇；
1-({2,6-二甲氧基-4-[(2-甲基-3-苯基苯基)甲氧基]苯基}甲基)-4-羟基哌啶-4-甲酰胺；
N-(2-{[(2,6-二甲氧基-4-{[3-(3-甲氧基苯基)-2-甲基苯基]甲氧基}苯基)甲基]氨基}乙基)乙酰胺；
N-(2-{[(4-{[3-(3-乙氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}乙基)乙酰胺；
N-(2-{[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}乙基)乙酰胺；
[(4-{[3-(2H-1,3-苯并二氧杂环戊烯-5-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基][2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
N-(2-{[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基]氨基}乙基)乙酰胺；
[(4-{[3-(3-乙氧基苯基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基][2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
[(4-{[3-(2,3-二氢-1,4-苯并二氧杂环己烯-6-基)-2-甲基苯基]甲氧基}-2,6-二甲氧基苯基)甲基][2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
{[2,6-二甲氧基-4-({3-[3-(甲氧基甲氧基)苯基]-2-甲基苯基}甲氧基)苯基]甲基}[2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
{[2,6-二甲氧基-4-({2-甲基-3-[3-(丙-2-烯-1-基氧基)苯基]苯基}甲氧基)苯基]甲基}[2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
{[4-({3-[2-氟-5-(2-甲氧基乙氧基)苯基]-2-甲基苯基}甲氧基)-2,6-二甲氧基苯基]甲基}[2-甲基-1-(4-甲基哌嗪-1-基)丙-2-基]胺；
(3S)-4-[({4-[(2-氰基-3-苯基苯基)甲氧基]-2,6-二甲氧基苯基}甲基)氨基]-3-羟基丁酸；
(3S)-3-羟基-4-[({5-[(2-甲基-3-苯基苯基)甲氧基]吡啶-2-基}甲基)氨基]丁酸；和
N-(2-{[(3-氯-4-{[2-甲基-3-(噻吩-3-基)苯基]甲氧基}苯基)甲基]氨基}乙基)乙酰胺。
9.权利要求1的化合物或其盐，其中环A为:
10.药物组合物，包含权利要求1的化合物或其盐，以及药用载体。
11.权利要求1的化合物在制备用于治疗与抑制PD-1/PD-L1的相互作用相关的疾病或病症的药物中的用途。
12.权利要求11的用途，其中所述疾病或病症为病毒感染或癌症。
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