CN114555080A - 用于治疗pd-l1疾病的杂芳基联苯胺 - Google Patents
用于治疗pd-l1疾病的杂芳基联苯胺 Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Pyridine Compounds (AREA)
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Abstract
提供了可用作免疫调节剂的化合物。该化合物具有包括其立体异构体和药学上可接受的盐的式(I),其中R2a,R2b,R3,R3a,R4,R6,R7,R8,A,Z,X1和n如本文所定义。还公开了与此类化合物的制备和使用相关的方法,以及包含此类化合物的药物组合物。
Description
相关申请的交叉引用
根据《美国法典》第35条第119(e)款的规定,本申请要求2019年10月16日提交的美国临时申请号62/915,771的优先权,其公开内容通过引用全部并入本文。
联邦资助研发下作出发明的权属声明
不适用
引用“序列表”、表格或以光盘形式提交的计算机程序列表附件
不适用
发明背景
程序性细胞死亡蛋白-1(PD-1)是CD28超家族的成员,在与其两个配体PD-L1或PD-L2相互作用时传递负信号。PD-1及其配体在T细胞活化和耐受中广泛表达,并发挥广泛的免疫调节作用。PD-1及其配体参与减弱感染免疫和肿瘤免疫,促进慢性感染和肿瘤进展。
PD-1通路的调节在各种人类疾病中具有治疗潜力(Hyun-Tak Jin等人,Curr TopMicrobiol Immunol.(2011);350:17-37)。阻断PD-1通路已成为癌症治疗的一个有吸引力的靶点。阻断程序性细胞死亡蛋白-1(PD-1)免疫检查点通路的治疗性抗体防止T细胞下调并促进针对癌症的免疫反应。几种PD-1通路抑制剂在临床试验的各个阶段都显示出强大的活性(R·D·哈维,临床药理学与治疗学(2014);96(2),214-223)。
需要阻断PD-L1与PD-1或CD80相互作用的药物。一些抗体已经被开发和商业化。一些公开非肽类小分子的专利申请已经公开(来自BMS的WO 2015/160641、WO 2015/034820和WO 2017/066227和WO2018/009505;来自Aurigene的WO 2015/033299和WO 2015/033301;来自Incyte的WO 2017/070089,US 2017/0145025,WO 2017/106634,US2017/0174679,WO2017/192961,WO2017/222976,WO2017/205464,WO2017/112730,WO2017/041899和WO2018/013789;来自Maxinovel的WO2018/006795;来自我们,ChemoCentryx的WO2018/005374)。然而,仍然需要替代化合物,例如小分子作为PD-L1的抑制剂,并且在口服给药、稳定性、生物利用度、治疗指数和毒性方面可能具有有利的特性。
发明概述
在一方面,本文提供了具有式(I)的化合物或其药学上可接受的盐、前药或生物电子等排体:
其中A、Z、X1、R2a、R2b、R3、R3a、R4、R6、R7、R8和下标n如本文所定义。
除了本文提供的化合物之外,本公开还提供了含有一种或多种这些化合物的药物组合物,以及与这些化合物的制备和使用相关的方法。在一些实施例中,化合物被用于PD-1/PD-L1通路相关疾病的治疗方法中。
附图说明
不适用。
发明详述
缩写和定义
这里使用的术语“一”、“一个”或“该”不仅包括具有一个成员的方面,还包括具有多个成员的方面。如这里所使用的,除非上下文清楚地指出,否则单数形式“一”,“一个”,和“该”包括复数形式。因此,例如,对“一个细胞”的提及包括多个这样的细胞,对“试剂”的提及包括对本领域技术人员已知的一种或多种试剂的提及,等等。
术语“约”和“大约”通常是指给定测量的性质或精确度的测量量可接受的误差程度。典型的示例性误差程度在给定值或值范围的20%(%)以内,优选地在10%以内,更优选地在5%以内。或者,特别是在生物系统中,术语“约”和“大约”可以表示在一个数量级内的值,优选地在给定值的5倍内,更优选地在2倍内。除非另有说明,否则本文给出的数字量是近似值,这意味着在未明确说明时可以推断出术语“约”或“大约”。
除非另有说明,术语“烷基”本身或作为另一取代基的一部分是指直链或支链烃基,其具有指定的碳原子数(即C1-8表示1-8个碳)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基等。术语“烯基”是指具有一个或多个双键的不饱和烷基。类似地,术语“炔基”是指具有一个或多个三键的不饱和烷基。烯基的实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基和3-(1,4-戊二烯基)。炔基的实例包括乙炔基、1-和3-丙炔基、3-丁炔基以及更高级的同系物和异构体。术语“环烷基”是指具有指定数量的环原子的烃环(例如,C 3-6环烷基)并且是完全饱和的或在环顶点之间具有不超过一个双键。“环烷基”还意指双环和多环烃环,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。双环或多环可以是稠合、桥连、螺环、或其组合。术语“杂环烷基”或“杂环基”是指含有1至5个选自N、O和S的杂原子的环烷基,其中氮和硫原子任选地被氧化,并且氮原子任选地被季铵化。杂环烷基可以是单环、双环或多环系统。双环或多环可以是稠合、桥连、螺环或它们的组合。应当理解,C4-12杂环基的叙述是指具有4至12个环成员的基团,其中至少一个环成员是杂原子。杂环烷基的非限制性实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、四唑酮、乙内酰脲、二氧戊环、邻苯二甲酰亚胺、哌啶、1,4-二恶烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环等。杂环烷基可以通过环碳或杂原子连接到分子的其余部分。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷烃的二价基团,例如-CH2CH2CH2CH2-。亚烷基可以是直链或支链的。后者的例子是-CH2C(CH3)2CH2-、-CH2C(CH3)2-或-CH(CH3)CH2CH2-。通常,烷基(或亚烷基)基团将具有1至12个碳原子,在本公开中优选地具有8个或更少碳原子的那些基团。类似地,“亚烯基”和“亚炔基”分别是指具有双键或三键的“亚烷基”的不饱和形式。
除非另有说明,术语“杂烷基”本身或与另一术语组合是指,稳定的直链或支链或环状烃基或其组合,由所述碳原子数和一到三个选自O、N、Si和S的杂原子组成,其中氮和硫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。杂原子O、N和S可以位于杂烷基的任何内部位置。杂原子Si可以位于杂烷基的任何位置,包括烷基与分子其余部分连接的位置。实例包括-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3和-CH=CH-N(CH3)-CH3。最多两个杂原子可以是连续的,例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。类似地,除非另有说明,术语“杂烯基”和“杂炔基”本身或与另一个术语组合是指分别包含所述碳数并具有一到三个选自O、N、Si和S的杂原子的烯基或炔基,其中氮和硫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。杂原子O、N和S可以位于杂烷基的任何内部位置。
术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的饱和或不饱和或多不饱和的二价基团,例如-CH2-CH2-S-CH2CH2-和-CH2-S-CH2-CH2-NH-CH2-、-O-CH2-CH=CH-、-CH2-CH=C(H)CH2-O-CH2-和-S-CH2-C≡C-。对于杂亚烷基,杂原子也可以占据一个或两个链末端(例如,亚烷基氧基、亚烷基二氧基、亚烷基氨基、亚烷基二氨基等)。
术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)以其常规含义使用,指的是那些通过氧原子、氨基或硫原子连接到分子其余部分的烷基。此外,对于二烷基氨基,烷基部分可以相同或不同,也可以与每个所连接的氮原子结合形成3-7元环。因此,表示为-NRaRb的基团意味着包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基等。
除非另有说明,术语“卤”或“卤素”本身或作为另一取代基的一部分是指氟、氯、溴或碘原子。此外,诸如“卤代烷基”之类的术语意味着包括单卤代烷基和多卤代烷基。例如,术语“C1-4卤代烷基”意思是包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
术语“羟基烷基”或“烷基-OH”是指如上定义的烷基,其中至少一个(最多三个)氢原子被羟基取代。至于烷基,羟烷基可以具有任何合适数量的碳原子,例如C1-6。示例性的羟烷基包括但不限于羟甲基、羟乙基(其中羟基位于1或2位)、羟丙基(其中羟基位于1、2或3位)和2,3-二羟丙基。
术语“C1-3烷基-胍基”是指如上定义的C1-3烷基,其中至少一个氢原子被胍基(-NHC(NH)NH2)取代。
除非另有说明,否则术语“芳基”是指多不饱和的、通常为芳族的烃基,其可以是稠合在一起或共价连接的单环或多环(最多三个环)。术语“杂芳基”是指含有一到五个选自N、O和S的杂原子的芳基(或环),其中氮和硫原子任选地被氧化,并且氮原子任选地被季铵化。杂芳基可以通过杂原子连接到分子的其余部分。应当理解,C5-10杂芳基的叙述是指具有5至10个环成员的杂芳基部分,其中至少一个环成员是杂原子。芳基的非限制性实例包括苯基、萘基和联苯,而杂芳基的非限制性实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、肉桂基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异恶唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、恶唑基、异恶唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。上述芳基和杂芳基环系统中的每一个的取代基选自下述可接受的取代基组。
术语“碳环(carbocyclic ring/carbocyclic)”或“碳环基”是指仅具有碳原子作为环顶点的环状部分。碳环部分是饱和的或不饱和的并且可以是芳族的。通常,碳环部分具有3至10个环成员。具有多环结构(例如双环)的碳环部分可以包括稠合到芳环(例如1,2,3,4-四氢萘)的环烷基环。因此,碳环包括环戊基、环己烯基、萘基和1,2,3,4-四氢萘基。术语“杂环”是指“杂环烷基”和“杂芳基”部分。因此,杂环是饱和的或不饱和的,并且可以是芳族的。通常,杂环为4至10个环成员并且包括哌啶基、四嗪基、吡唑基和吲哚基。
当任何上述术语(例如,“烷基”、“芳基”和“杂芳基”)被称为“取代的”而不对取代基作进一步说明时,所示基团的取代形式将如下提供。
烷基(包括通常称为亚烷基、烯基、炔基和环烷基的那些基团)的取代基可以是选自以下的多种基团:-卤素,-OR',-NR'R”,-SR',-SiR'R”R”',-OC(O)R',-C(O)R',-CO2R',-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)2R'、-NH-C(NH2)=NH,-NR'C(NH2)=NH,-NH-C(NH2)=NR',-S(O)R',-S(O)2R',-S(O)2NR'R”、-NR'S(O)2R”、-CN和-NO2,数量范围从零到(2m'+1),其中m'是此类基团中碳原子的总数。R'、R”和R”'各自独立地指氢、未取代的C1-8烷基、未取代的杂烷基、未取代的芳基、被1-3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基基团,或未取代的芳基-C1-4烷基。当R’和R”连接到同一个氮原子上时,它们可以与氮原子结合形成3元、4元、5元、6元或7元环。例如,-NR'R”意味着包括1-吡咯烷基和4-吗啉基。单独使用或作为另一基团的一部分使用的术语“酰基”是指烷基基团,其中最接近该基团的连接点的碳上的两个取代基被取代基=O替换(例如,-C(O)CH3、-C(O)CH2CH2OR'等)。
类似地,芳基和杂芳基的取代基是多种多样的,通常选自:-卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R',-OC(O)NR'R”,-NR”C(O)R',-NR”C(O)2R',-NR'-C(O)NR”R”',-NH-C(NH2)=NH,-NR'C(NH2)=NH,-NH-C(NH2)=NR',-S(O)R',-S(O)2R',-S(O)2NR'R”,-NR'S(O)2R”、-N3、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基,数量范围从零到芳环系统上的开放价总数;其中R'、R”和R”'独立地选自氢、C1-8烷基、C3-6环烷基、C2-8烯基、C2-8炔基、未取代的芳基和杂芳基、(未取代的芳基)-C1-4烷基和未取代的芳氧基-C1-4烷基。其他合适的取代基包括通过1-4个碳原子的亚烷基链连接到环原子的上述芳基取代基中的每一个。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被式-T-C(O)-(CH2)q-U-的取代基取代,其中T和U独立地为-NH-、-O-、-CH2-或单键,q为0~2的整数。或者,芳基或杂芳基环的相邻原子上的两个取代基可任选被式-A-(CH2)r-B-的取代基取代,其中A和B独立地为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR'-或单键,r为1~3的整数。如此形成的新环的单键之一可以任选地被双键代替。或者,芳基或杂芳基环的相邻原子上的两个取代基可以任选地被下式的取代基取代-(CH2)s-X-(CH2)t-,其中s和t独立地为0到3的整数,X为-O-,-NR'-,-S-、-S(O)-、-S(O)2-或-S(O)2NR'-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”意思是包括氧(O)、氮(N)、硫(S)和硅(Si)。
本文的公开进一步涉及其前药和生物电子等排体。例如,合适的生物电子等排物将包括羧酸盐替代物(膦酸、次膦酸、磺酸、亚磺酸和酸性杂环基团,例如四唑)。合适的前药将包括那些已知在生理条件下水解和/或氧化以提供式I化合物的常规基团。
术语“患者”和“受试者”包括灵长类动物(尤其是人类)、驯养的伴侣动物(例如狗、猫、马等)和家畜(例如牛、猪、羊等)。
如本文所用,术语“处理”或“治疗”包括改善疾病的治疗和对症治疗,其中任何一种都可以是预防性的(即,在症状发作之前,以预防、延迟或减轻症状的严重性)或治疗性的(即,在症状出现后,以减轻症状的严重程度和/或持续时间)。
术语“药学上可接受的盐”意在包括用相对无毒的酸或碱制备的活性化合物的盐,这取决于在本文描述的化合物上发现的特定取代基。当本公开的化合物含有相对酸性的官能团时,碱加成盐可通过使此类化合物的中性形式与足量的所需碱(纯碱或在合适的惰性溶剂中)接触而获得。衍生自药学上可接受的无机碱的盐的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、三价锰、二价锰、钾、钠、锌等。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,包括取代的胺、环状胺、天然存在的胺等,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺,二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本公开的化合物含有相对碱性的官能团时,酸加成盐可通过使此类化合物的中性形式与足量的所需酸(纯酸或在合适的惰性溶剂中)接触而获得。药学上可接受的酸加成盐的实例包括衍生自无机酸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等的那些,以及衍生自相对无毒的有机酸,如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等的盐。还包括氨基酸如精氨酸等的盐,以及有机酸如葡糖醛酸或半乳糖醛酸等的盐(参见例如,Berge,S.M.等人,“药用盐(Pharmaceutical Salts)”,药学杂志(Journal of Pharmaceutical Science),1977,66,1-19)。本公开的某些特定化合物既包含碱性官能团又包含酸性官能团,其允许化合物转化为碱或酸加成盐。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生。化合物的母体形式在某些物理性质上不同于各种盐形式,例如在极性溶剂中的溶解度,但就本公开的目的而言,盐与化合物的母体形式等价。
本公开的某些化合物可以以非溶剂化形式以及溶剂化形式存在,包括水合形式。通常,溶剂化形式等同于非溶剂化形式,并且旨在包含在本公开的范围内。本公开的某些化合物可以多种结晶或无定形形式存在。一般而言,所有物理形式对于本公开所设想的用途都是等效的,并且旨在落入本公开的范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体、几何异构体、区域异构体和单独的异构体(例如,单独的对映异构体)都旨在涵盖在本发明的范围内。当显示立体化学描述时,其意指其中存在一种异构体并且基本上不含另一种异构体的化合物。“基本上不含”另一种异构体表示两种异构体的比率至少为80/20,更优选为90/10,或95/5或更高。在一些实施方案中,一种异构体将以至少99%的量存在。
本公开的化合物还可在构成此类化合物的一个或多个原子处包含非自然比例的原子同位素。例如,可以用放射性同位素例如氚(3H)、碘-125(125I)或碳-14(14C)对化合物进行放射性标记。本公开的化合物的所有同位素变体,无论是否具有放射性,都旨在涵盖在本公开的范围内。例如,可以制备化合物使得任意数量的氢原子被氘(2H)同位素取代。本公开的化合物还可在构成此类化合物的一个或多个原子处包含非自然比例的原子同位素。同位素的非自然比例可以定义为从自然界中发现的数量到由所讨论的原子100%组成的数量。例如,化合物可以包含放射性同位素,例如氚(3H)、碘125(125I)或碳14(14C),或非放射性同位素,例如氘(2H)或碳13(13C)。这种同位素变化可以为本申请中其他地方描述的那些提供额外的效用。例如,本公开的化合物的同位素变体可以发现额外的用途,包括但不限于作为诊断和/或成像试剂,或作为细胞毒性/放射性毒性治疗剂。此外,本公开化合物的同位素变体可具有改变的药代动力学和药效学特征,这可有助于提高治疗期间的安全性、耐受性或功效。本公开的化合物的所有同位素变体,无论是否具有放射性,都旨在涵盖在本公开的范围内。
化合物
在一方面,本文提供了具有式(I)的化合物或其药学上可接受的盐、前药或
生物电子等排体:
其中:
A是5至10元杂芳基,其未被取代或被1至5个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN;
X1为C1-3亚烷基,其未被取代或被一个或两个独立地选自下组的成员取代:C1-2烷基和CO2H;
R2a和R2b各自独立地选自下组:H、C1-8烷基、C1-8卤代烷基、-Y、-X2-CO2Ra、-X2-ORa、-X2-NRaRb、-X2-C(O)NRaRb,-X2-SO2Ra,-X2-SO2NRaRb、-X2-SO3Ra和-X2-Y,其中每个X2是C1-6亚烷基和任何C1-8烷基或C1-6亚烷基,是未被取代或被一个或两个独立地选自下组的成员取代:OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基和CO2H,每个Y选自下组:C3-6环烷基、C4-8杂环基和5至6元杂芳基,其各自未被取代或被一至四个独立地选自下组的取代基取代:氧代、OH、C1-4烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基、SO3H和CO2H;
或R2a和R2b组合形成4至9元环或螺环,具有零至两个选自O、N和S的附加杂原子环顶点;
其中通过结合R2a和R2b形成的环未被取代或被1至4个独立地选自下组的取代基取代:氧代、C1-8烷基、C1-8卤代烷基、C1-8羟烷基、-X3-CO2Ra、-X3-ORa,-X3-NRaRb,
-X3-C(O)NRaRb、-X3-SO2Ra、-X3-SO2NRaRb和-X3-SO3Ra;其中X3是键或C1-6亚烷基;
R3和R4各自独立地选自下组:H、F、Cl、CN、CH3、OCH3、CH2CH3和CF3;
下标n为0、1、2或3;
每个R3a独立地选自下组:H、F、Cl、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3卤代烷氧基、C2-3烯基和CN;
R6、R7和R8各自独立地选自下组:H、F、Cl、CN、CH3、OCH3、CH2CH3和CF3;
Z是稠合双环杂芳环,未被取代或被1-3个Rc取代;
每个Ra独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H;
每个Rb独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H,它们各自是未取代的或被一个或两个独立地选自以下的成员取代:OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2Cl-8烷基和CO2H;
并且,Ra和Rb当连接到相同的氮原子时,任选地结合形成4至8元环或螺环,其未被取代或被卤素、OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基或CO2H取代;
每个Rc独立地选自下组:H、卤素、CN、C1-6烷基、C1-6卤代烷基、-Y1、-X4-CO2Ra、-O-X4-CO2Ra、-X4-ORa、-X4-NRaRb、-X4-C(O)NRaRb、-O-X4-C(O)NRaRb、-X4-SO2Ra、-X4-SO2NRaRb、-X4-SO3Ra和-N(Ra)-X4-CO2Ra,其中每个X4为键或C1-6亚烷基,每个Y1选自下组:C3-6环烷基和C4-8杂环基;并且任选地,相邻环顶点上的两个Rc结合以形成稠合的5或6元杂环。
在一些实施例中,本公开提供由式(Ia)表示的式(I)化合物:
其中基团R2a、R2b、R3、R4、A、X1和Z具有式(I)提供的含义。
在一些实施例中,本公开提供由式(Ib)表示的式(I)化合物:
其中基团R2a、R2b、R3、R4、A和Z具有式(I)提供的含义。
在一些选定的实施例中,式(I)、(Ia)或(Ib)的化合物是其中Z是具有选自下组的式的稠合双环杂芳环的那些化合物:
在一些选定的实施例中,式(I)、(Ia)或(Ib)的化合物是其中Z是单环5或6元杂芳基环,任选地被1至3个Rc取代的那些化合物;所述杂环选自下组:吡啶基、嘧啶基、吡嗪基、恶唑基、噻唑基和吡唑基。
在一些实施例中,A基团未被取代或被一个或两个独立地选自下组的成员取代:CF3,OH,Et,CN,OCH3和F。在一些实施例中,A基团未被取代或被一个或两个独立地选自下组的成员取代:OCH3和F。
在选定的实施方例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A是5或6元杂芳基并且是未取代或被一个或两个独立地选自卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、OH和CN的成员取代。在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)的化合物的任何实施例,进一步的实施例是其中基团A是5或6元杂芳基,并且是未被取代或被一个或两个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基和CN。在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施方案,进一步的实施例是其中基团A是5或6元杂芳基并且是未取代或被一个或两个独立地选自OCH3和F的成员取代。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A是6元杂芳基,其未被取代或被1-3个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、OH和CN。选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A是6元杂芳基,其未被取代或被1-3个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基和CN。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A选自下组:吡啶基、嘧啶基、吡嗪基、恶唑基、噻唑基和吡唑基,它们各自未被取代或被一个或两个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN。在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A选自下组:吡啶基、嘧啶基、吡嗪基、恶唑基、噻唑基和吡唑基,它们各自未被取代或被一个或两个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和CN。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A是选自下组的6元杂芳基:吡啶、嘧啶、吡嗪和1,2,4-三嗪,它们各自未被取代或被一个或两个独立地选自下组的成员取代:CF3,OH,Et,CN,OCH3和F。在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中基团A是选自下组的6元杂芳基:吡啶、嘧啶、吡嗪和1,2,4-三嗪,它们各自未被取代或被一个或两个独立地选自下组的成员取代:OCH3和F。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R2a和R2b各自为H的实施方案。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R2a和R2b组合形成4至9元环或螺环,任选地具有一个或两个选自O、N或S的附加环顶点的实施方案;其中所述环或螺环被0至4个独立地选自下组的取代基取代:氧代、C1-8烷基、C1-8卤代烷基、C1-8羟烷基、-X2-CO2Ra、-X2-ORa、-X2-NRaRb、-X2-CONRaRb、-X2-SO2Ra、-X2-SO2NRaRb和–X2-SO3Ra;其中X2是键或C1-6亚烷基。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中-N(R2a)(R2b)选自下组的实施例:
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中-N(R2a)(R2b)选自下组的实施例:
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中-N(R2a)(R2b)选自下组的实施例:
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R2a是H或C1-8烷基;R2b是–Y或–X2-Y的那些实施例。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R2a是H或C1-8烷基;R2b是-Y或-X2-Y;Y选自下组:C3-6环烷基和C4-8杂环基,其各自进一步任选地被一至四个独立地选自下组的取代基取代:氧代、OH、C1-4烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、C(O)2C1-8烷基和CO2H的那些实施方案。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R3和R4各自独立地选自下组:F、Cl、CN、CH3、OCH3、CH2CH3和CF3。在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中R3和R4各自独立地选自下组:Cl,CN,CH3,和CF3。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是5或6元非芳族杂环的实施例,任选地被一个或两个氧代基团取代并且任选地被Ra和/或Rb取代。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是单环5或6元杂芳基环,任选地被1-3个Rc取代。
在选定的实施例中,包括上述关于式(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是5或6元非芳族杂环,任选地被一个或两个氧代基团取代,并且任选地被Ra和/或Rb取代。
在选定的实施例中,包括上述关于式(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是单环5或6元杂芳基环,任选地被1-3个Rc取代。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是5或6元非芳族杂环的实施例,任选地被一个或两个氧代基团取代,并且任选地被Ra和/或Rb取代;所述非芳族杂环选自下组:哌啶基、吗啉基、四氢吡喃基和四氢呋喃基。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例,进一步的实施例是其中Z是单环5或6元杂芳环,任选被1-3个Rc取代;所述杂环选自下组:吡啶基、嘧啶基、吡嗪基、恶唑基、噻唑基和吡唑基。
在选定的实施方案中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施方案,进一步的实施方案是其中化合物选自表1的实施方案。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例中,进一步的实施例是从表1中选择的具有++或+++活性的化合物。
在选定的实施例中,包括上述关于式(I)、(Ia)或(Ib)化合物的任何实施例中,进一步的实施例是从表1中选择的具有+++活性的化合物。
除了以上提供的化合物之外,还提供了这些化合物的药学上可接受的盐。在一些实施例中,药学上可接选自铵、钙、镁、钾、钠、锌、精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺,N-乙基吗啉,N-乙基哌啶,葡糖胺,葡萄糖胺,组氨酸,海巴胺,异丙胺,赖氨酸,甲基葡糖胺,吗啉,哌嗪,哌拉定,普鲁卡因,嘌呤,可可碱,三乙胺,三甲胺,三丙胺,氨丁三醇,盐酸,碳酸,一氢碳酸,磷酸、磷酸一氢、磷酸二氢、乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、酒石酸、甲磺酸、精氨酸、葡萄糖醛酸和半乳糖醛酸。在一些实施例中,药学上可接受的盐选自铵盐、钙盐、镁盐、钾盐、钠盐、盐酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、丙酸盐、异丁酸盐、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、精氨酸、葡萄糖醛酸和半乳糖醛酸。在一些实施例中,药学上可接受的盐是钠盐或盐酸盐。
除了盐形式之明还提供了前药形式的化本文所述的化合物的前药是那些在生理条件下容易发生化学变化以提供本公开的化合物的化合物。此外,前药可以在离体环境中通过化学或生化方法转化为本公开的化合物。例如,当放置在具有合适的酶或化学试剂的透皮贴剂储库中时,前药可以缓慢地转化为本公开的化合物。
酯可以用作相应羧酸的前药。C1-10烷基酯或C1-10卤代烷基酯可用作相应羧酸的前药。可以使用以下酯类:叔丁酯、甲酯、乙酯、异丙酯。
制备方法
除了以下实施例中描述的方法外,方案1和2中提供了制备式(I)化合物的一般方法。
方案1
方案1说明了制备具有式(I)的化合物的一般方法。在上述反应方案中,A为六元含氮杂芳环(如吡啶基、嘧啶基),X1为CH2,Rs代表杂芳环上的一个或多个取代基。
在催化剂存在的情况下,(a)与(b)的铃木型偶联则提供联苯化合物(c)。在取代反应中将来自试剂(d)的Z基团加到化合物(c)的外环胺上以形成化合物(e)。然后可以将化合物(e)转化为硼酸盐化合物(f),然后进行第二次铃木式偶联(与卤代-杂芳基化合物(g)),得到三芳基醛化合物(h)。然后用HNR2aR2b对醛进行还原胺化可以提供式(Ia)的化合物。
或者,化合物(c)在化合物(g')和催化剂存在下的第二次铃木型偶联提供三芳基醛化合物(h),其可用于如上所述的还原胺化,以提供下式化合物(Ia)。
方案2
在另一种基于铃木型偶联的方法中,化合物(a)的外环胺首先用试剂(d)取代,得到化合物(j)。在催化剂存在的情况,(j)与(k)的铃木式偶联就能得到化合物(h)。三芳基醛化合物(h)可用于如方案I中所述的还原胺化以提供式(Ia)的化合物。
药物组合物
除了本文提供的化合物之外,这些化合物的组合物通常包含药物载体或稀释剂。
如本文所用,术语“组合物”旨在涵盖包含指定量的指定成分的产品,以及直接或间接由指定量的指定成分的组合产生的任何产品。所谓“药学上可接受”,是指载体、稀释剂或赋形剂必须与配方中的其他成分相容,且对接受者无害。
在另一个实施方案中,提供了一种药物组合物,其包含本公开的化合物,包括式(I)、(Ia)或(Ib)的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂。
在一些实施方案中,药物组合物还包含一种或多种额外的治疗剂。在一些实施例中,一种或多种额外的治疗剂选自抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化疗剂、抗癌剂、抗血管生成剂剂、免疫治疗剂、抗激素剂、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂和抗增殖剂。在一些实施例中,一种或多种额外的治疗剂是趋化因子和/或趋化剂受体的拮抗剂,其包括但不限于CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CCR12、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、C3aR和/或C5aR。趋化因子和/或趋化受体拮抗剂是本领域已知的并且描述于例如WO2007/002667,WO2007/002293,WO/2003/105853,WO/2007/022257,WO/2007/059108,WO/2007/044804,WO2007/115232,WO2007/115231,WO2008/147815,WO2010/030815,WO2010/075257,WO2011/163640,WO2010/054006,WO2010/051561,WO2011/035332,WO2013/082490,WO2013/082429,WO2014/085490,WO2014/100735,WO2014/089495,WO2015/084842,WO2016/187393,WO2017/127409,WO2017/087607,WO2017/087610,WO2017/176620,WO2018/222598,WO2018/222601,WO2013/130811,WO2006/076644,WO2008/008431,WO2009/038847,WO2008/008375,WO2008/008374,WO2008/010934,WO2009/009740,WO2005/112925,WO2005/112916,WO2005/113513,WO2004/085384,WO2004/046092。趋化因子和/或趋化受体拮抗剂还包括CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX3587、CCX3624、CCX 2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168、CCX168-M1、CCX3022和/或CCX3384。
用于施用本公开的化合物的药物组合物可以方便地以单位剂型存在并且可以通过药学和药物递送领域中众所周知的任何方法制备。所有方法都包括使活性成分与构成一种或多种辅助成分的载体结合的步骤。通常,药物组合物通过将活性成分与液体载体或细碎的固体载体或两者均匀且紧密地结合,然后,如果需要,将产品成型为所需的制剂来制备。在药物组合物中,活性目标化合物的含量足以对疾病的过程或状况产生所需的效果。
含有活性成分的药物组合物可以以适合口服的形式存在,例如,如美国专利申请2002-0012680所述的片剂、糖锭、锭剂、水性或油性混悬剂、可分散粉剂或颗粒剂、乳剂和自乳化剂、硬胶囊或软胶囊、糖浆剂、酏剂、溶液、口腔贴剂、口服凝胶、口香糖、咀嚼片、泡腾粉和泡腾片。可根据本领域已知的用于制备药物组合物的任何方法制备旨在用于口服的组合物,并且此类组合物可包含一种或多种选自甜味剂、调味剂、着色剂、抗氧化剂和防腐剂的试剂,以提供药学上优雅和可口的制剂。片剂含有活性成分与适合于制造片剂的无毒药学上可接受的赋形剂的混合物。这些赋形剂可以是例如惰性稀释剂,例如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨糖醇、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如PVP、纤维素、PEG、淀粉、明胶或阿拉伯胶,以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,也可以是包衣的,肠溶的或其他的,通过已知的技术来延缓崩解和胃肠道吸收,从而提供较长时间的持续作用。例如,可以使用诸如单硬脂酸甘油酯或二硬脂酸甘油酯的延时材料。它们也可以通过美国专利号4,256,108;4,166,452;和4,265,874中描述的技术进行涂覆,形成用于控制释放的渗透治疗片剂。
用于口服的制剂也可以作为硬明胶胶囊提供,其中活性成分与惰性固体稀释剂混合,例如碳酸钙、磷酸钙或高岭土、各种平均尺寸的聚乙二醇(PEG)(例如,PEG400、PEG4000))和某些表面活性剂如克列莫佛或solutol,或作为软明胶胶囊,其中活性成分与水或油介质混合,如花生油、液体石蜡或橄榄油。此外,乳液可以用非水混溶性成分如油制备并用表面活性剂如甘油单酯或甘油二酯、PEG酯等稳定。
水性悬浮液含有与适合于制造水性悬浮液的赋形剂混合的活性物质。这样的赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以是天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七亚乙基氧十六醇,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯,例如聚氧乙烯山梨糖醇单油酸酯的缩合产物,或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯,例如聚山梨糖醇单油酸酯的缩合产物。水性悬浮液还可以含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂,例如蔗糖或糖精。
油性悬浮液可以通过将活性成分悬浮在植物油例如花生油、橄榄油、芝麻油或椰子油或矿物油例如液体石蜡中来配制。油性悬浮液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加诸如上述那些的甜味剂和调味剂以提供可口的口服制剂。这些组合物可以通过添加抗氧化剂如抗坏血酸来保存。
适用于制备水悬浮液的可分散粉末和颗粒通过加水提供与分散剂或润湿剂、悬浮剂和一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂和悬浮剂例如上面已经提到的那些。也可以存在其他赋形剂,例如甜味剂、调味剂和着色剂。
本公开的药物组合物还可以是水包油乳剂的形式。油相可以是植物油,例如橄榄油或花生油,或矿物油,例如液体石蜡或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄蓍胶,天然存在的磷脂,例如大豆、卵磷脂,以及衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,以及所述部分酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨醇单油酸酯。乳液还可以含有甜味剂和调味剂。
糖浆和酏剂可以用甜味剂配制,例如甘油、丙二醇、山梨糖醇或蔗糖。这样的制剂还可以包含缓和剂、防腐剂以及调味剂和着色剂。口服溶液可以与例如环糊精、PEG和表面活性剂组合制备。
药物组合物可以是无菌可注射水性或油质悬浮液的形式。该悬浮液可以根据已知技术使用上面提到的那些合适的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的载体和溶剂有水、林格溶液和等渗氯化钠溶液。此外,无菌的不挥发油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸如油酸可用于制备注射剂。
本公开的化合物也可以以栓剂的形式给药,用于药物的直肠给药。这些组合物可以通过将药物与合适的无刺激性赋形剂混合来制备,该赋形剂在常温下为固体但在直肠温度下为液体,因此将在直肠中熔化以释放药物。这种材料包括可可脂和聚乙二醇。此外,化合物可以通过溶液或软膏的方式通过眼部给药来给药。更进一步,主题化合物的透皮递送可以通过离子电渗贴片等来实现。对于局部使用,使用含有本公开的化合物的乳膏、软膏、凝胶、溶液或悬浮液等。如本文所用,局部应用也意味着包括使用漱口水和漱口药。
本公开的化合物还可以与作为可靶向药物载体的合适聚合物的载体偶联。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基-丙基-甲基丙烯酰胺-苯酚、聚羟乙基-天冬酰胺-苯酚或被棕榈酰基残基取代的聚环氧乙烷-聚赖氨酸。此外,本公开的化合物可以与载体偶联,该载体是可用于实现药物控制释放的一类生物可降解聚合物,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。聚合物和半透性聚合物基质可以形成成形制品,例如瓣膜、支架、管材、假体等。在本发明的一个实施例中,本发明的化合物与形成为支架或支架移植装置的聚合物或半透性聚合物基质偶联。
治疗疾病和失调的方法
本公开的化合物可以用作免疫调节剂。本公开的化合物可以在体外和体内的多种情况下用作PD-1和/或PD-L1的激动剂、拮抗剂、部分激动剂、反向激动剂、抑制剂。在一些实施例中,本公开的化合物可以用作PD-1/PD-L1蛋白相互作用的抑制剂。在一些实施例中,本公开的化合物可以用作PD-L1的抑制剂。在一些实施例中,本公开的化合物可以用作CD80/PD-L1蛋白相互作用的抑制剂。在一些实施例中,本公开的化合物可用于在体外或体内抑制PD-1与PD-L1和/或PD-1与CD80和/或PD-1与PD-L2之间的相互作用。在一些实施例中,本公开的化合物可用于抑制VISTA和/或TIM-3。在一些实施例中,本公开的化合物可以是PD-1/PD-L1蛋白相互作用的抑制剂和VISTA和/或TIM-3的抑制剂。在一些实施例中,除了作为PD-1/PD-L1蛋白相互作用的抑制剂之外,本公开的化合物可以是CTLA-4和/或BTLA和/或LAG-3和/或KLRG-1和/或2B4和/或CD160和/或HVEM和/或CD48和/或E-钙粘蛋白和/或MHC-II和/或半乳糖凝集素-9和/或CD86和/或PD-L2和/或VISTA和/或TIM-3和/或CD80的抑制剂。
本公开的化合物可以在水溶液中和在另外适于配体与受体结合的条件下与它们相互作用的受体接触。受体可以存在于悬浮液中(例如,在分离的膜或细胞制剂中)、在培养的或分离的细胞中、或在组织或器官中。
优选地,与受体接触的本公开的化合物的量应足以抑制体外的PD-1/PD-L1结合,如例如使用ELISA所测量的。受体可以存在于溶液或悬浮液中、培养或分离的细胞制剂中或患者体内。
在一些实施例中,本公开的化合物可用于恢复和增强T细胞活化。在一些实施例中,本公开的化合物可用于增强患者的免疫反应。在一些实施例中,本公开的化合物可用于治疗、预防多种治疗领域中的疾病或病症或减缓其进展,例如癌症和传染病。
在一些实施例中,本公开的化合物可用于治疗患有对PD-1/PD-L1蛋白相互作用调节有反应的病症的患者。
在一些实施例中,提供了调节受试者中由PD-1信号通路介导的免疫应答的方法,包括向受试者施用治疗有效量的本公开的化合物,包括式(I)、(Ia)或(Ib)的化合物,或其药学上可接受的盐或包含式(I)、(Ia)或(Ib)的化合物或其药学上可接受的盐的组合物。
在一些实施例中,提供了增强、刺激、调节和/或增加有需要的受试者的免疫反应的方法,包括向受试者施用治疗有效量的本公开的化合物,包括式(I)、(Ia)或(Ib)的化合物,或其药学上可接受的盐或本公开的化合物的组合物,包括式(I)、(Ia)或(Ib)的化合物或其药学上可接受的盐。
在一些实施例中,提供了一种在有需要的受试者中抑制癌细胞生长、增殖或转移的方法,包括向受试者施用治疗有效量的本公开的化合物,包括式(I)、(Ia)或(Ib)的化合物,或其药学上可接受的盐或包含式(I)、(Ia)或(Ib)的化合物或其药学上可接受的盐的本公开的化合物的组合物。
在一些实施例中,提供了治疗有需要的受试者的方法,包括向受试者施用治疗有效量的本公开的化合物,包括式(I)、(Ia)或(Ib)的化合物,或其药学上可接受的盐或包含式(I)、(Ia)或(Ib)的化合物或其药学上可接受的盐的本公开的化合物的组合物。
在一些实施例中,受试者患有选自下组的疾病或病症:传染病、细菌传染病、病毒传染病、真菌传染病、实体瘤、恶性血液病、免疫障碍、炎症疾病和癌症。在一些实施例中,所述疾病或病症选自黑素瘤、成胶质细胞瘤、食道肿瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性淋巴瘤、原发性CNS淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤、原发性纵隔大B细胞淋巴瘤、前列腺癌、去势抵抗性前列腺癌、慢性粒细胞白血病、卡波西肉瘤、纤维肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、血管肉瘤、淋巴管肉瘤、滑膜瘤、脑膜瘤、平滑肌肉瘤、横纹肌肉瘤、软组织肉瘤、肉瘤、败血症、胆道肿瘤、基底细胞癌、胸腺肿瘤、甲状腺癌、甲状旁腺癌、子宫癌、肾上腺癌、肝脏感染、默克尔细胞癌、神经肿瘤、滤泡中心淋巴瘤、结肠癌、霍奇金病、非霍奇金淋巴瘤、白血病、慢性或急性白血病,包括急性髓性白血病、慢性髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SCLC)、非鳞状非小细胞肺癌、结直肠癌、卵巢癌、胃癌、肝细胞癌、胰腺癌、胰腺癌、胰腺导管腺癌、头颈部鳞状细胞癌、头颈部癌、胃肠道癌、胃癌,艾滋病毒,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,疱疹病毒,乳头瘤病毒,流感,骨癌,皮肤癌,直肠癌,肛门癌,睾丸癌,输卵管癌,子宫内膜癌、宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、尿道癌,阴茎癌,膀胱癌,肾癌,输尿管癌,肾盂癌,中枢神经系统(CNS)肿瘤,肿瘤血管生成,脊髓肿瘤,脑干神经胶质瘤,垂体腺瘤,表皮样癌,失禁,癌,腺癌,乳头状癌,囊腺癌,支气管癌,肾细胞癌,移行细胞癌,绒毛膜癌,精原细胞瘤,胚胎癌,威尔姆瘤,多形性腺瘤,肝细胞乳头状瘤,肾小管腺瘤、囊腺瘤、乳头状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤和纤维瘤。
在一些实施例中,进一步向受试者施用治疗有效量的一种或多种另外的治疗剂。在一些实施例中,一种或多种另外的治疗剂选自抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化疗剂、抗癌剂、抗血管生成剂、免疫治疗剂、抗激素剂、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂和抗增殖剂。在一些实施例中,一种或多种另外的治疗剂是趋化因子和/或趋化剂受体的拮抗剂,其包括但不限于CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CCR12、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、C3aR和/或C5aR。趋化因子和/或趋化受体拮抗剂是本领域已知的并且描述于例如WO2007/002667,WO2007/002293,WO/2003/105853,WO/2007/022257,WO/2007/059108,WO/2007/044804,WO2007/115232,WO2007/115231,WO2008/147815,WO2010/030815,WO2010/075257,WO2011/163640,WO2010/054006,WO2010/051561,WO2011/035332,WO2013/082490,WO2013/082429,WO2014/085490,WO2014/100735,WO2014/089495,WO2015/084842,WO2016/187393,WO2017/127409,WO2017/087607,WO2017/087610,WO2017/176620,WO2018/222598,WO2018/222601,WO2013/130811,WO2006/076644,WO2008/008431,WO2009/038847,WO2008/008375,WO2008/008374,WO2008/010934,WO2009/009740,WO2005/112925,WO2005/112916,WO2005/113513,WO2004/085384,WO2004/046092。趋化因子和/或趋化受体拮抗剂还包括CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX3587、CCX3624、CCX 2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168、CCX168-M1、CCX3022和/或CCX3384。
在一些实施例中,本公开的化合物可用于抑制传染病。传染病包括但不限于HIV、流感、疱疹、贾第虫、疟疾、利什曼原虫、由肝炎病毒(甲型、乙型和丙型)、疱疹病毒(例如,VZV、HSV-I、HAV-6、HSV-II和CMV、爱泼斯坦巴尔病毒)、腺病毒、流感病毒、黄病毒、埃可病毒、鼻病毒、柯萨奇病毒、冠状病毒、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、牛痘病毒、HTLV病毒、登革热病毒、乳头瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒和虫媒病毒性脑炎病毒的致病性感染、由衣原体、立克次氏菌、分枝杆菌、葡萄球菌、链球菌、肺炎球菌、脑膜炎球菌和球菌、克雷伯氏菌、变形杆菌、沙雷氏菌,假单胞菌,大肠杆菌,军团菌,白喉,沙门氏菌,杆菌,霍乱,破伤风,肉毒杆菌,炭疽,鼠疫,钩端螺旋体病和莱姆病细菌的致病性感染,由真菌念珠菌(白色念珠菌,克氏菌、光滑菌、热带菌等),新型隐球菌,曲霉(烟曲霉,尼日尔等),毛霉属(毛霉,犁头霉,根霉),申基孢子丝菌,皮炎芽生菌,巴西副球孢子菌,球孢子菌和荚膜组织胞浆菌的致病性感染,以及由寄生虫溶组织内阿米巴、结肠小袋纤毛虫、福(勒)氏耐格里阿米巴、棘阿米巴、贾第鞭毛虫、隐孢子虫、卡氏肺孢子、间日疟原虫、果氏巴贝虫、布氏锥虫、克氏锥虫、多诺瓦尼利什曼原虫、刚地弓形虫、巴西日圆线虫的致病性感染。
在一些实施例中,本公开的化合物可用于抑制HIV感染、延缓AIDS进展、耗尽HIV病毒库或降低症状或HIV感染和AIDS的严重程度。
本公开的化合物可用于治疗受试者的癌症和癌前病症。
本文提供的治疗方法通常包括向患者施用有效量的一种或多种本文提供的化合物。合适的患者包括患有或易患(即预防性治疗)本文鉴定的病症或疾病的那些患者。用于本文所述治疗的典型患者包括哺乳动物,特别是灵长类动物,尤其是人类。其他合适的患者包括驯养的伴侣动物如狗、猫、马等,或家畜如牛、猪、羊等。
一般而言,本文提供的治疗方法包括向患者施用有效量的化合物,一种或多种本文提供的化合物。在一个优选的实施例中,本公开的化合物优选通过静脉内、口服或局部施用于患者(例如人)。有效量可以是足以调节PD-1/PD-L1相互作用的量和/或足以减少或减轻患者呈现的症状的量。优选地,施用的量足以产生足以充分调节PD-1/PD-L1相互作用的化合物(或其活性代谢物,如果该化合物是前药)的血浆浓度。治疗方案可能会根据所使用的化合物和要治疗的特定病症而有所不同;对于大多数疾病的治疗,优选每天4次或更少的给药频率。一般而言,更优选地每天2次的给药方案,特别优选每天一次给药。然而,应当理解,任何特定患者的具体剂量水平和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、治疗时间、给药途径、排泄率、药物组合(即,给予患者的其他药物)和正在接受治疗的特定疾病的严重程度,以及开药医生的判断。通常,优选地使用足以提供有效治疗的最小剂量。通常可以使用适合被治疗或预防的病症的医学或兽医标准来监测患者的治疗效果。
组合
包含本公开的化合物和其他药物的伴随药物可以作为其中两种组分包含在单一制剂中的组合制剂施用,或作为单独的制剂施用。通过分开的制剂给药包括同时给药和以一定时间间隔给药。在以一些时间间隔给药的情况下,可以先给药本公开的化合物,然后是另一种药物,或者可以先给药另一种药物,然后是本公开的化合物。各个药物的给药方法可以相同或不同。
其他药物的剂量可根据临床使用的剂量适当选择。根据待施用对象的年龄和重量,给药方法,给药时间,待治疗的病症,症状和其组合,可以适当地选择本公开的化合物和其他药物的复合比。例如,基于1质量份的本公开的化合物,可以使用0.01至100质量份的量的其他药物。其他药物可以是两种或多种任意药物按适当比例组合而成。
本文所述的化合物可以与一种或多种治疗剂一起使用或组合,例如抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化疗剂、抗癌剂、抗血管生成剂、免疫治疗剂、抗激素剂、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂和抗增殖剂。这些治疗剂可以是化合物、抗体、多肽或多核苷酸的形式。
本文所述的化合物可以与一种或多种治疗性抗体、双特异性抗体和“抗体样”治疗性蛋白质(例如Fab衍生物)、抗体-药物偶联物(ADC)、病毒、溶瘤病毒、基因修饰剂或编辑器,例如CRISPR(包括CRISPRCas9)、锌指核酸酶或合成核酸酶(TALEN)、CAR(嵌合抗原受体)T细胞免疫治疗剂,或其任何组合一起使用或组合。
化学治疗剂的实例包括烷化剂、亚硝基脲剂、抗代谢物、抗癌抗生素、植物来源的生物碱、拓扑异构酶抑制剂、激素药物、激素拮抗剂、芳香酶抑制剂、P-糖蛋白抑制剂、铂络合物衍生物、其他免疫治疗药物和其他抗癌药物。
本文所述的化合物可以与癌症治疗辅助剂如白细胞减少症(中性粒细胞减少症)治疗药物、血小板减少症治疗药物、止吐药和癌症疼痛干预药物同时或以混合物形式使用或组合。
本文所述的化合物可以与激酶抑制剂一起使用或组合。
在一个实施例中,本公开的化合物可以与其他免疫调节剂和/或增强剂同时使用或以混合物形式使用。免疫调节剂的实例包括各种细胞因子、疫苗和佐剂。这些刺激免疫反应的细胞因子、疫苗和佐剂的例子包括但不限于GM-CSF、M-CSF、G-CSF、干扰素-α、β或γ、IL-1、IL-2、IL-3、IL-12、聚(I:C)和CPG。增强剂包括环磷酰胺和环磷酰胺类似物、抗TGF和伊马替尼(格列卫)、有丝分裂抑制剂,例如紫杉醇、舒尼替尼(Sutent)或其他抗血管生成剂、芳香酶抑制剂,例如来曲唑、A2a腺苷受体(A2AR))拮抗剂、血管生成抑制剂、蒽环类、奥沙利铂、阿霉素、TLR4拮抗剂和IL-18拮抗剂。
在一些实施例中,本文描述的化合物可用于或与CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CCR11、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、CXCR6、CXCR7、ChemR23、C5aR、C5a和C5的一个或多个调节剂组合使用。在一些实施例中,调节剂是拮抗剂。
在一些实施例中,本文所述的化合物可以与一种或多种在例如WO2007/002667、WO2007/002293、WO/2003/105853、WO/2007/022257、WO/2007/059108,WO/2007/044804,WO2007/115232,WO2007/115231,WO2008/147815,WO2010/030815,WO2010/075257,WO2011/163640,WO2010/054006,WO2010/051561,WO2011/035332,WO2011/035332,WO2013/082490,WO2013/082429,WO2013/085490,WO2014/100735,WO2014/089495,WO2015/084842,WO2016/187393,WO2017/127409,WO2017/087607,WO2017/087610,WO2017/176620,WO2018/222598,WO2018/222601,WO2013/130811,WO2006/076644,WO2008/008431,WO2009/038847,WO2008/008375,WO2008/008374,WO2008/010934,WO2009/009740,WO2005/112925,WO2005/112916,WO2005/113513,WO2004/085384,WO2004/046092描述的趋化因子和/或趋化受体拮抗剂一起使用或组合。可用于本公开的趋化因子和/或趋化受体拮抗剂还包括CCX354、CCX9588、CCX140、CCX872、CCX598、CCX6239、CCX9664、CCX2553、CCX3587、CCX3624、CCX 2991、CCX282、CCX025、CCX507、CCX430、CCX765、CCX224、CCX662、CCX650、CCX832、CCX168、CCX168-M1、CCX3022和/或CCX3384。
剂量
每天每千克体重约0.1mg至约140mg量级的剂量水平可用于治疗或预防涉及PD-1/PD-L1相互作用的病症(每人约0.5mg至约7g每天一个病人)。可与载体材料组合以产生单一剂型的活性成分的量将根据所治疗的宿主和特定的给药方式而变化。单位剂型通常含有大约1毫克到大约500毫克的活性成分。对于口服、透皮、静脉内或皮下给药的化合物,优选地给予足够量的化合物以达到5ng(纳克)/mL-10μg(微克)/mL血清的血清浓度,更优选地足够的化合物为了达到20ng-1μg/ml血清的血清浓度,应给予足够的化合物以达到50ng/ml-200ng/ml血清的血清浓度。对于直接注射到滑膜中(用于治疗关节炎),应给予足够的化合物以达到约1微摩尔的局部浓度。
给药频率也可以根据使用的化合物和治疗的特定疾病而变化。然而,对于大多数疾病的治疗,优选地每天4次、每天3次或更少的给药方案,特别优选地每天1次或每天2次的给药方案。然而,应当理解,任何特定患者的具体剂量水平将取决于多种因素,包括所用具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、治疗时间、给药途径、排泄率、药物组合(即,给予患者的其他药物)和正在接受治疗的特定疾病的严重程度,以及包括开药医生的判断的其他因素。
在本公开的另一个方面,本公开的化合物可以用于多种非药物的体外和体内应用。本公开的化合物还可以用作PD-1/PD-L1相互作用活性测定中的阳性对照,即,作为确定候选试剂结合PD-1和/或PD-L1的能力的标准,或作为正电子发射断层扫描(PET)成像或单光子发射计算机断层扫描(SPECT)的放射性示踪剂。
包含本公开的化合物或其药学上可接受的盐和使用说明的试剂盒也在本公开的范围内。该试剂盒可以进一步包含至少一种额外的试剂。试剂盒通常包括一个标签,表明试剂盒内容物的预期用途。术语标签包括试剂盒上或随试剂盒提供的任何书写或记录材料,或以其他方式伴随试剂盒。
实施例
以下实施例说明制备本公开的化合物的各种方法,包括式(I)、(Ia)或(Ib)的化合物。提供以下实施例以说明而非限制要求保护的公开。
下面使用的试剂和溶剂可以从商业来源获得,例如Aldrich化学公司(密尔沃基,威斯康星州,美国)。在Varian Mercury 400MHz NMR光谱仪上记录1H-NMR光谱。提供了相对于TMS的显著峰,并按以下顺序列出:多重性(s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰)和质子数。质谱结果报告为质荷比。在示例中,报告了包含最常见原子同位素的M+H(或如前所述的M-H)离子的单个m/z值。同位素模式在所有情况下都对应于预期的公式。电喷雾电离(ESI)质谱分析在Hewlett-Packard MSD电喷雾质谱仪上使用HP1100 HPLC进行样品输送。常将分析物以0.1mg/mL溶解在甲醇或CH3CN中,并将1微升与输送溶剂一起注入质谱仪,扫描范围为100到1000道尔顿。所有化合物都可以在正或负ESI模式下进行分析,使用乙腈/水和1%甲酸作为传递溶剂。
在实施例和本公开的整个描述中使用以下缩写:TLC表示薄层色谱法。
本公开范围内的化合物可以如下所述使用技术人员已知的多种反应合成。本领域技术人员还将认识到,可采用替代方法来合成本公开的目标化合物,并且本文件正文中描述的方法并非详尽无遗,但确实为感兴趣的化合物提供了广泛适用和实用的途径。
本专利中要求保护的某些分子可以以不同的对映异构体和非对映异构体形式存在,并且这些化合物的所有此类变体都被要求保护,除非指定了特定的对映异构体。
在本文中,用于合成关键化合物的实验过程的详细描述导致了分子,这些分子由识别它们的物理数据以及与它们相关的结构描述来描述。
本领域技术人员还将认识到,在有机化学的标准后处理程序中,酸和碱经常被使用。在本专利所述的实验过程中,如果母体化合物具有必要的固有酸性或碱性,有时会产生盐。
实施例1:(S)-5-((((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(10g,39.44mmol),1,3-二溴-2-氯苯(32g,118.3mmol),K2CO3(18.53g,134mmol)和Pd(dppf)Cl2与DCM(3.22g,3.94mmol)的二恶烷(200mL)和水(30mL)的复合物的混合物在N2下在90℃下搅拌3小时。将内容物冷却至室温并通过硅胶快速色谱法纯化以提供3'-溴-2,2'-二氯-[1,1'-联苯]-3-胺。MS:(ES)m/z C12H9BrCl2N[M+H]+计算值为315.9,实测值为315.9。
步骤b:5-氯吡啶并[3,4-b]吡嗪(7.20克,22.7毫摩尔),3'-溴-2,2'-二氯-[1,1'-联苯]-3-胺(3.76克,22.7毫摩尔)和Cs2CO3(11.09g,34mmol)的DMSO(80mL)溶液的混合物在75℃下搅拌过夜。将内容物冷却至室温,用EtOAc稀释并通过塞过滤。收集滤液,用水洗涤并通过硅胶快速色谱法纯化,得到N-(3'-溴-2,2'-二氯-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺。MS:(ES)m/z C19H12BrCl2N4[M+H]+计算值为445.0,实测值为445.0。
步骤c:N-(3'-溴-2,2'-二氯-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺(4.88g,10.94mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧硼烷)(3.05g,12mmol),KOAc(2.68g,27.35mmol)和Pd(dppf)Cl2与DCM(893mg,1.09mmol)的二恶烷(100mL)复合物的混合物在N2下在100℃下搅拌10小时。将内容物冷却至室温并通过硅胶快速色谱法纯化,得到N-(2,2'-二氯-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-)基)-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺。MS:(ES)m/z C25H24BCl2N4O2[M+H]+计算值为493.1,实测值为492.9。
步骤d:N-(2,2'-二氯-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺(340毫克,0.69毫摩尔),5-溴-3-甲氧基吡嗪-2-甲醛(180毫克,0.83毫摩尔),K2CO3(238mg,1.73mmol)和Pd(dppf)Cl2与DCM(81mg,0.10mmol)的二恶烷(5mL)和水(0.75mL)复合物的混合物在N2下在90℃下搅拌3小时。将内容物冷却至室温并通过硅胶快速色谱法纯化以提供5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-甲醛。MS:(ES)m/z C25H17Cl2N6O2[M+H]+计算值为503.1,实测值为503.0。
步骤e:5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-甲醛(40毫克,0.080毫摩尔),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(15mg,0.10mmol)、Et3N(15mg,0.15mmol)和AcOH(90mg,1.5mmol)的EtOH(1mL)和DCM(1mL)溶液的混合物在65℃下加热0.5小时。将内容物冷却至室温并加入NaBH(OAc)3(45mg,0.71mmol)。搅拌30分钟后,用饱和NaHCO3淬灭反应并用DCM萃取。收集有机层并真空浓缩。将获得的残余物通过硅胶快速色谱法和制备型HPLC纯化,得到(S)-5-((((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.25(s,1H),9.06(s,1H),8.54(s,1H),8.03(d,J=7.6Hz,1H),7.93(d,J=6.4Hz,1H),7.40(d,J=7.6Hz,1H),7.68(dd,J=7.6,7.6Hz,1H),7.61(dd,J=7.6,7.6Hz,1H),7.53(m,2H),7.47(d,J=6.8Hz,1H),4.53(s,2H),4.12(s,2H),4.11(s,3H),3.41–3.21(m,1H),2.50–2.32(m,3H),2.04–1.92(m,1H)。MS:(ES)m/zC30H27Cl2N8O2[M+H]+计算值为601.2,实测值为600.9。
实施例2:(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)吡咯烷-3-醇
使用类似于实施例1的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-吡咯烷-3-醇盐酸盐为原料制备该化合物。粗品经硅胶柱色谱纯化得到(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4)-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)吡咯烷-3-醇。
粗品经硅胶柱色谱纯化得到(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4))-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)吡咯烷-3-醇。1HNMR(400MHz,CD3OD)δ8.81(dd,J=4.2,1.5Hz,1H),8.09–8.01(m,2H),7.84–7.74(m,2H),7.61(dd,J=7.6,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.41–7.31(m,2H),7.26(d,J=7.5Hz,1H),7.14–7.07(m,1H),4.38(m,1H),4.00(s,3H),3.89–3.75(m,2H),2.94(ddd,J=16.8,9.4,6.7Hz,2H),2.71(ddd,J=23.4,10.2,4.7Hz,2H),2.57(s,3H),2.15(s,4H),1.78(d,J=8.7Hz,1H).MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.5。
实施例3:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:在N2下,向N-(2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺(370mg,0.76mmol),6-氯-2-甲氧基烟醛(160mg,0.91mmol),和K3PO4(570mg,2.7mmol)的1,4-二恶烷/H2O(8mL)1:1溶液的搅拌溶液中加入Pd(PPh3)4(110mg,0.091mmol)。在90℃搅拌16小时后,将混合物用水稀释并用EtOAc萃取。合并的有机层用MgSO4干燥,过滤并真空浓缩。粗残余物经硅胶柱色谱纯化得到6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C28H23ClN5O2[M+H]+计算值为496.2,实测值为496.2。
步骤b:向6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(53毫克,0.106毫摩尔),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(64毫克,0.42毫摩尔),和三乙胺(60μL,0.42mmol)的DCM/MeOH(2mL)4:1溶液的搅拌溶液中加入NaBH(OAc)3(230mg,1.1mmol)。搅拌30分钟后,通过硅藻土过滤混合物并真空除去挥发物。粗残余物经硅胶柱色谱纯化,得到所需产物(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.72(dd,J=4.3,1.5Hz,1H),8.58(dd,J=8.2,1.3Hz,1H),8.09(dd,J=8.4,1.5Hz,1H),7.67(dd,J=8.5,4.2Hz,1H),7.63(dd,J=7.7,1.8Hz,1H),7.58(d,J=7.4Hz,1H),7.42(d,J=7.6Hz,1H),7.38(d,J=8.1Hz,1H),7.29(dd,J=7.5,1.8Hz,1H),7.26(d,J=1.3Hz,1H),7.09–7.03(m,1H),6.42(s,1H),4.02(s,3H),3.80(s,2H),3.78–3.71(m,1H),2.78(dd,J=12.0,4.2Hz,1H),2.72(s,3H),2.57(dd,J=12.0,8.5Hz,1H),2.39–2.32(m,3H),2.26(s,3H),2.25–2.16(m,1H),1.83–1.67(m,1H)。MS:(ES)m/zC33H33ClN7O2[M+H]+计算值为594.2,实测值为594.2。
实施例4:N-(3'-(5-((((1H-咪唑-2-基)甲基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(1H-咪唑-2-基)甲胺盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物N-(3'-(5-((((1H-咪唑-2-基)甲基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CDCl3)δ9.84(s,1H),8.93(dd,J=4.3,1.4Hz,1H),8.73(dd,J=8.6,1.4Hz,1H),8.15(d,J=8.1Hz,1H),7.92(dd,J=8.6,4.3Hz,1H),7.84(d,J=7.6Hz,1H),7.65(dd,J=7.7,1.7Hz,1H),7.48(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.34(dd,J=7.6,1.7Hz,2H),7.31(s,2H),4.66(s,2H),4.32(s,2H),4.06(s,3H),2.89(s,3H),2.24(s,3H)。MS:(ES)m/z C32H30ClN8O[M+H]+计算值为577.2,实测值为577.2。
实施例5:N-(3'-(5-(((2-(1H-咪唑-1-基)乙基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-(1H-咪唑-1-基)乙烷-1-胺二盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物N-(3'-(5-(((2-(1H-咪唑-1-基)乙基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CDCl3)δ9.90(s,1H),9.23(s,1H),8.97–8.88(m,1H),8.70(d,J=8.5Hz,1H),8.10–8.03(m,1H),7.90(dd,J=8.6,4.4Hz,1H),7.73(d,J=7.6Hz,1H),7.58(dd,J=7.6,1.1Hz,1H),7.49–7.39(m,3H),7.32(dd,J=7.6,1.1Hz,1H),7.23(dd,J=7.5,2.3Hz,2H),7.18(s,1H),4.81–4.72(m,2H),4.23(s,2H),3.98(s,3H),3.75–3.64(m,2H),2.86(s,3H),2.19(s,3H)。MS:(ES)m/z C33H32ClN8O[M+H]+计算值为591.2,实测值为591.2。
实施例6:(S)-5-((((6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐为原料制备该化合物。产物经硅胶柱层析纯化得到所需产物(S)-5-((((6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),8.92(d,J=4.1Hz,1H),8.88–8.80(m,1H),8.24–8.16(m,1H),7.96–7.90(m,1H),7.87–7.80(m,1H),7.69(s,1H),7.60–7.53(m,2H),7.45(d,J=7.2Hz,1H),7.30(d,J=7.4Hz,1H),7.23(dd,J=7.7,5.9Hz,1H),7.17(d,J=7.7Hz,1H),3.93(s,3H),3.75(s,2H),3.66(s,1H),2.64(s,3H),2.59(s,1H),2.30(s,2H),2.19–2.04(m,3H),1.70(dt,J=14.2,7.7Hz,1H)。MS:(ES)m/z C32H30Cl2N7O2[M+H]+计算值为614.2,实测值为614.2。
实施例7:1-((6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基))-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-甲基氮杂环丁烷-3-羧酸为原料制备该化合物。产物经硅胶柱层析纯化得到所需产物1-((6-(2,2'-二氯-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸。1H NMR(400MHz,CDCl3)δ9.99(s,1H),9.12(d,J=8.4Hz,1H),8.78(d,J=4.2Hz,1H),8.11(d,J=8.5Hz,1H),7.87(s,1H),7.68(dd,J=17.8,7.8Hz,2H),7.50(m,2H),7.37–7.28(m,2H),7.08(d,J=7.3Hz,1H),4.36(s,2H),4.08–4.00(m,5H),3.39(d,J=12.8Hz,2H),2.79(s,3H),1.46(s,3H),1.31(d,J=6.4Hz,2H)。MS:(ES)m/z C32H29Cl2N6O2[M+H]+计算值为615.2,实测值为615.2。
实施例8:(1S,2S)-2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)环丁-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(1S,2S)-2-氨基环丁-1-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(1S,2S)-2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d])嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)环丁-1-醇。1H NMR(400MHz,DMSO-d6)δ9.01(d,J=4.4Hz,1H),8.89(s,1H),8.22(d,J=8.5Hz,1H),8.05(dd,J=8.5,4.4Hz,1H),7.93(d,J=7.6Hz,1H),7.68–7.61(m,2H),7.58(dd,J=7.6,7.6Hz,1H),7.48–7.36(m,3H),7.23(d,J=7.6Hz,1H),4.50–4.40(m,1H),4.17–4.03(m,2H),4.01–3.92(m,3H),3.80–3.67(m,1H),2.55(s,3H),2.20–2.07(m,2H),2.04(s,3H),1.99–1.82(m,2H)。MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.5。
实施例9:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙氧基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CDCl3)δ9.86(s,1H),8.96–8.89(m,1H),8.68(d,J=8.5Hz,1H),8.11(d,J=8.1Hz,1H),8.05(s,1H),7.92(dd,J=8.6,4.4Hz,1H),7.80(d,J=7.6Hz,1H),7.62(dd,J=7.7,1.7Hz,1H),7.50–7.40(m,2H),7.35–7.29(m,2H),4.51(q,J=7.0Hz,2H),4.35–4.24(m,2H),4.22–4.07(m,1H),3.24–3.03(m,2H),2.86(s,3H),2.42–2.26(m,2H),2.22(s,3H),1.41(t,J=7.0Hz,3H),1.25(s,2H)。MS:(ES)m/z C34H35ClN7O2[M+H]+计算值为608.3,实测值为608.3。
实施例10:(S)-5-((((6-(2,2'-二氯-3'-(吡啶并[3,2-d]嘧啶-4-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:向4-氯吡啶并[3,2-d]嘧啶(600mg,3.6mmol)和2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(920mg,3.6mmol)的7mL MeCN溶液的搅拌溶液中加入AcOH(0.68mL,12毫摩尔)。将反应搅拌30分钟,然后真空除去挥发物。粗残余物经硅胶柱层析纯化,得到N-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡啶并[3,2-d]嘧啶-4-胺。MS:(ES)m/z C19H21BClN4O2[M+H]+计算值为383.1,实测值为383.2。
步骤b:在N2下,向N-(2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)吡啶并[3,2-d]嘧啶-4-胺(550mg,1.4mmol),6-(3-溴-2-氯苯基)-2-甲氧基烟醛(470毫克,1.4毫摩尔),和K2CO3(710mg,4.9mmol)的二恶烷/H2O(14mL)1:1溶液的搅拌溶液中加入Pd(dppf)Cl2与DCM(140mg,0.17mmol)的络合物。将混合物在90℃在N2下搅拌4小时,然后用H2O稀释。水性混合物用CHCl3萃取,合并的有机层用MgSO4干燥,过滤,真空浓缩。粗残渣经硅胶柱层析纯化得到6-(2-氯-2'-甲基-3'-(吡啶并[3,2-d]嘧啶-4-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C26H18Cl2N5O2[M+H]+计算值为502.1,实测值为502.1。
步骤c:向6-(2,2'-二氯-3'-(吡啶并[3,2-d]嘧啶-4-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(58mg,0.12mmol),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(72mg,0.48mmol),和三甲胺(64μL,0.46mmol)的DCM/MeOH(2.5mL)4:1溶液的搅拌溶液中加入NaBH(OAc)3(240mg,1.2mmol)。30分钟后,混合物通过硅藻土过滤并浓缩滤液。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2,2'-二氯-3'-(吡啶并[3,2-d]嘧啶-4-基氨基))-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CDCl3)δ10.01(s,1H),9.07–8.98(m,1H),8.86(d,J=2.3Hz,2H),8.22(d,J=8.4Hz,1H),7.81–7.71(m,2H),7.68(d,J=7.6Hz,1H),7.50–7.27(m,2H),7.37–7.27(m,2H),7.10(d,J=7.4Hz,1H),7.00(s,1H),4.05(d,J=1.9Hz,3H),3.98(s,3H),3.02–2.65(m,3H),2.40–2.20(m,3H),1.76(d,J=8.6Hz,1H)。MS:(ES)m/z C31H28Cl2N7O2[M+H]+计算值为600.2,实测值为600.2。
实施例11:(S)-5-((((6-(2-氯-2'-甲基-3'-((7-甲基吡啶并[3,4-b]吡嗪-5-基)氨基)-[1,1'-联苯]-3-基)-2-羟基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:向2,4-二氯-6-甲基-3-硝基吡啶(2.5g,12mmol)的24mL THF的搅拌悬浮液中加入7N NH3的MeOH(14mL,98mmol)溶液。搅拌3小时后,真空除去挥发物。粗残余物通过硅胶柱色谱纯化,得到2-氯-6-甲基-3-硝基吡啶-4-胺。C6H7ClN3O2[M+H]+188.0,实测值为188.0。
步骤b:向2-氯-6-甲基-3-硝基吡啶-4-胺(760mg,4.1mmol)和Fe(1.1g,20mmol)的5:1EtOH/H2O(24mL)溶液的搅拌混合物中加入4.4mL浓盐酸。将内容物回流30分钟,然后冷却至室温并用100mL饱和NaHCO3(aq)淬灭。混合物用EtOAc萃取,合并的有机层用MgSO4干燥,过滤,真空浓缩,得到2-氯-6-甲基吡啶-3,4-二胺。MS:(ES)m/z C6H9ClN3[M+H]+计算值为158.0,实测值为158.0。
步骤c:向2-氯-6-甲基吡啶-3,4-二胺(0.49g,3.1mmol)在3mL EtOH中的搅拌溶液中加入40%w/w乙二醛水溶液(2.0mL,12mmol)。回流16小时后,混合物用H2O稀释并用EtOAc萃取。合并有机层并用MgSO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱法纯化,得到5-氯-7-甲基吡啶并[3,4-b]吡嗪。MS:(ES)m/z C8H7ClN3[M+H]+计算值为180.0,实测值为180.1。
步骤d:向5-氯-7-甲基吡啶并[3,4-b]吡嗪(200mg,1.0mmol)和2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-胺(350mg,1.0mmol)的2mLMeCN溶液的搅拌溶液中加入AcOH(0.18mL,3.1mmol)。30分钟后,真空浓缩挥发物。粗残余物经硅胶柱色谱纯化得到N-(2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)-7-甲基吡啶并[3,4-b]吡嗪-5-胺。MS:(ES)m/z C27H29BClN4O2[M+H]+计算值为487.2,实测值为487.2。
步骤e:在N2下,向N-(2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)-7-甲基吡啶并[3,4-b]吡嗪-5-胺(390mg,0.66mmol),6-氯-2-甲氧基烟醛(240mg,1.4mmol),和K3PO4(490mg,2.3mmol)的1,4-二恶烷/H2O(3.3mL)1:1溶液的搅拌溶液中加入Pd(PPh3)4(76mg,0.066mmol)。将混合物在N2(g)下在90℃搅拌3小时。混合物用H2O稀释,然后用EtOAc萃取。合并的有机层用MgSO4干燥,过滤并浓缩。粗残余物经硅胶柱色谱纯化得到6-(2-氯-2'-甲基-3'-((7-甲基吡啶并[3,4-b]吡嗪-5-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C28H23ClN5O2[M+H]+计算值为496.2,实测值为496.2。
步骤f:向6-(2-氯-2'-甲基-3'-((7-甲基吡啶并[3,4-b]吡嗪-5-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(120mg,0.25mmol),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(150mg,0.99mmol),和三甲胺(0.14mL,0.99mmol)的DCM/MeOH(5mL)4:1溶液的搅拌混合物中加入NaBH(OAc)3(530mg,2.5mmol)。搅拌30分钟后,混合物通过硅藻土过滤,滤液真空浓缩。产物通过制备型HPLC纯化,得到产物(S)-5-((((6-(2-氯-2'-甲基-3'-((7-甲基吡啶并[3,4-b]吡嗪-5-基)氨基)-[1,1'-联苯]-3-基)-2-羟基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),9.32(s,1H),9.07(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.23(d,J=8.7Hz,1H),7.76(d,J=7.0Hz,1H),7.62(s,1H),7.55(d,J=7.5Hz,1H),7.50–7.43(m,1H),7.35(dd,J=7.9,7.9Hz,1H),7.12(s,1H),6.96(d,J=7.5Hz,1H),6.55(s,2H),6.43(d,J=7.1Hz,1H),4.07(s,3H),3.95–3.84(m,1H),2.48(s,4H),2.26–2.15(m,3H),2.11(s,3H),1.86–1.70(m,1H)。MS:(ES)m/z C32H31ClN7O2[M+H]+计算值为580.2,实测值为580.1。
实施例12:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:在-78℃和N2下,向3-氨基吡啶甲酰胺(5.0g,36mmol)和吡啶(4.4mL,55mmol)的70mL DCM搅拌溶液中滴加三氟乙酸酐(7.7mL,55mmol)。将反应在室温搅拌18小时。除去挥发物,得到3-(2,2,2-三氟乙酰胺基)吡啶酰胺。MS:(ES)m/z C8H7F3N3O2[M+H]+计算值为234.0,实测值为234.1。
将3-(2,2,2-三氟乙酰胺基)吡啶酰胺和吡啶(7.7mL,55mmol)的35mL 1,2-二氯乙烷溶液在115℃下搅拌72小时。将混合物冷却至室温并用NaCl溶液(水溶液)淬灭。分离各层并用10%MeOH的DCM溶液萃取水层。合并的有机层用MgSO4干燥,过滤并真空浓缩。粗残余物通过硅胶柱色谱法纯化,得到2-(三氟甲基)吡啶并[3,2-d]嘧啶-4(1H)-酮。MS:(ES)m/zC8H5F3N3O[M+H]+计算值为216.0,实测值为216.0。
步骤b:在N2下,向2-(三氟甲基)吡啶并[3,2-d]嘧啶-4(1H)-酮(2.5g,11mmol)的50mL DCM搅拌溶液中加入0.2mL DMF,然后逐滴加入草酰氯(1.4mL,17mmol)。搅拌18小时后,真空除去挥发物。粗残余物通过硅胶柱色谱纯化,得到4-氯-2-(三氟甲基)吡啶并[3,2-d]嘧啶。MS:(ES)m/z C8H4ClF3N3[M+H]+计算值为234.0,实测值为234.0。
步骤c:向4-氯-2-(三氟甲基)吡啶并[3,2-d]嘧啶(1.9g,8.0mmol)和2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(1.9mg,8.0mmol)的16毫升MeCN的搅拌溶液中加入AcOH(1.4mL,24mmol)。30分钟后,真空浓缩挥发物。粗残余物通过硅胶柱色谱纯化得到N-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-胺。MS:(ES)m/z C21H23BF3N4O2[M+H]+计算值为431.2,实测值为431.2。
步骤d:在N2下,向N-(2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-胺(730mg,1.7mmol),6-(3-溴-2-氯苯基)-2-甲氧基烟醛(590mg,1.9mmol),和K2CO3(690mg,5.0mmol)的1,4-二恶烷/H2O(14mL)1:1溶液的搅拌溶液中加入Pd(dppf)Cl2与DCM(160mg,0.20mmol)的络合物。将混合物在N2下于90℃搅拌4小时,然后用100mL H2O稀释。内容物用EtOAc萃取,合并的有机层用MgSO4干燥,过滤,真空浓缩。粗残余物经硅胶柱色谱纯化得到6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C28H20ClF3N5O2[M+H]+计算值为550.1,实测值为550.1。
步骤e:向6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(200mg,0.36mmol),(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(220mg,1.5mmol),和三甲胺(0.21mL,1.5mmol)的DCM/MeOH(7mL)4:1溶液的搅拌溶液中加入NaBH(OAc)3(760mg,3.6mmol)。搅拌30分钟后,混合物通过硅藻土过滤,滤液真空浓缩。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CDCl3)δ9.50(s,1H),8.91(dd,J=4.3,1.5Hz,1H),8.59–8.53(m,1H),8.33(dd,J=8.5,1.5Hz,1H),7.83(dd,J=8.5,4.3Hz,1H),7.66(dd,J=7.7,1.8Hz,1H),7.59(d,J=7.4Hz,1H),7.44(t,J=7.7Hz,2H),7.31(dd,J=7.5,1.8Hz,1H),7.29(m,1H),7.12(dd,J=7.6,1.2Hz,1H),5.99(s,1H),4.04(s,3H),3.81(s,2H),3.76(d,J=13.4Hz,1H),2.81(dd,J=12.0,4.2Hz,1H),2.57(dd,J=12.0,8.7Hz,1H),2.41–2.33(m,2H),2.29(s,3H),2.28–2.19(m,1H),1.84–1.71(m,1H)。MS:(ES)m/zC33H30ClF3N7O2[M+H]+计算值为648.2,实测值为648.2。
实施例13:1-((6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-甲基氮杂环丁烷-3-羧酸为原料制备该化合物。产物经硅胶柱色谱纯化得到所需产物1-((6-(2-氯-2'-甲基-3'-((2-(三氟甲基)吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸。1H NMR(400MHz,CDCl3)δ9.48(s,1H),8.89(d,J=4.4Hz,1H),8.55(d,J=8.1Hz,1H),8.31(d,J=8.5Hz,1H),7.89(s,1H),7.81(dd,J=8.4,4.4Hz,1H),7.62(d,J=7.5Hz,1H),7.41(dd,J=7.8,7.8Hz,2H),7.30(d,J=7.4Hz,2H),7.09(d,J=7.7Hz,1H),4.42(s,1H),4.09(s,1H),4.02(s,3H),3.43(s,2H),2.28–2.23(m,8H)。MS:(ES)m/z C33H29ClF3N6O3[M+H]+计算值为649.2,实测值为649.5。
实施例14:(S)-5-((((6-(2-氯-3'-((2-异丙基吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1))'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:在N2下,向3-氨基吡啶甲酰胺(2.5g,18mmol)和三乙胺(5.8mL,42mmol)的3:1DCM/THF(80mL)溶液的搅拌溶液中滴加异丁酰氯(2.9mL,27mmol)。将反应混合物在室温搅拌3.5小时,然后用1N HCl(水溶液)调节至pH=7。内容物用DCM萃取并浓缩。粗残余物用EtOH稀释并用NaOH(3.8g,54mmol)搅拌。6小时后,混合物用AcOH的H2O溶液中和,然后用EtOAc萃取。合并的有机层用MgSO4干燥,过滤并真空浓缩。残余物通过硅胶柱色谱法纯化,得到2-异丙基吡啶并[3,2-d]嘧啶-4(1H)-酮。MS:(ES)m/z C10H12N3O[M+H]+计算值为190.1,实测值为190.2。
步骤b:在N2下,向2-异丙基吡啶并[3,2-d]嘧啶-4(1H)-酮(2.0g,11mmol)的DCM(70mL)溶液中加入草酰氯(1.1mL,13mmol),然后加入DMF(4滴)。在室温下搅拌4小时后,真空除去挥发物。残余物通过硅胶柱色谱纯化,得到4-氯-2-异丙基吡啶并[3,2-d]嘧啶。MS:(ES)m/z C10H11ClN3[M+H]+计算值为208.1,实测值为208.1。
步骤c:向4-氯-2-异丙基吡啶并[3,2-d]嘧啶(180mg,0.85mmol)和2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-胺(300毫克,0.87毫摩尔)的1.7毫升MeCN溶液的搅拌混合物中加入AcOH(0.15mL,2.6mmol)。将混合物搅拌1.5小时,然后将挥发物真空浓缩。残余物通过硅胶柱色谱纯化得到N-(2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)-2-异丙基吡啶并[3,2-d]嘧啶-4-胺。MS:(ES)m/z C29H33BClN4O2[M+H]+计算值为515.2,实测值为515.2。
步骤d:在N2下,向N-(2'-氯-2-甲基-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)-2-异丙基吡啶并[3,2-d]嘧啶-4-胺(200mg,0.39mmol)、6-氯-2-甲氧基烟醛(130mg,0.77mmol)和K3PO4(280mg,1.3mmol)的二恶烷/H2O(2mL)1:1溶液的搅拌混合物中加入Pd(PPh3)4(45mg,0.039mmol)。将反应在N2下在90℃搅拌2小时,冷却至室温并用5mL H2O稀释。内容物用EtOAc萃取,合并有机层并用MgSO4干燥,过滤并浓缩。残余物经硅胶柱层析纯化得到6-(2-氯-3'-((2-异丙基吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C30H27ClN5O2[M+H]+计算值为524.2,实测值为524.2。
步骤e:向6-(2-氯-3'-((2-异丙基吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-2-甲氧基烟醛(100mg,0.19mmol)、(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐(120mg,0.77mmol)和三甲胺(0.11mL,0.76mmol)的DCM/甲醇(4毫升)4:1溶液的搅拌溶液中加入NaBH(OAc)3(410mg,1.9mmol)。搅拌30分钟后,混合物通过硅藻土过滤,然后真空浓缩。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氯-3'-((2-异丙基吡啶并[3,2-d]嘧啶-4-基)氨基)-2'-甲基-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,DMSO-d6)δ9.06–8.90(m,1H),8.73(s,1H),8.26(dd,J=8.6,1.5Hz,1H),8.04(dd,J=8.5,4.3Hz,1H),7.96(d,J=7.6Hz,1H),7.68(d,J=8.5Hz,1H),7.66(dd,J=7.7,1.8Hz,1H),7.61(s,1H),7.58(t,J=7.6Hz,1H),7.45–7.38(m,3H),7.23–7.18(m,1H),4.30–4.17(m,2H),3.98(s,3H),3.90(ddd,J=6.7,6.7,6.7Hz,1H),3.23–3.12(m,1H),3.12–3.02(m,2H),2.27–2.12(m,3H),2.03(s,3H),1.87–1.68(m,1H),1.23(d J=6.8Hz,3H),1.21(d,J=6.8Hz,3H)。MS:(ES)m/z C35H37ClN7O2[M+H]+计算值为622.3,实测值为622.3。
实施例15:N-(2'-氯-3'-(6-甲氧基-5-((甲基氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(50mg,0.10mmol)、甲胺氯化氢(35mg,0.052mmol)和AcOH(0.10mL,0.71mmol)的DCM(2mL)溶液的混合物在室温下搅拌1.5小时。向混合物中加入NaBH(OAc)3(40mg,0.18mmol)。再搅拌1.5小时后,用饱和NaHCO3淬灭反应并用DCM萃取。分离有机层,用Na2SO4干燥,真空浓缩并通过硅胶色谱法纯化,得到N-(2'-氯-3'-(6-甲氧基-5-((甲基氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1HNMR(400MHz,CDCl3)δ9.23(s,1H),8.73(dd,J=4.0,1.6Hz,1H),8.59(d,J=7.6Hz,1H),8.09(dd,J=8.8,1.6Hz,1H),7.66–7.58(m,1H),7.60(d,J=7.2Hz,1H),7.40(dd,J=7.6,2.0Hz,1H),7.44–7.37(m,2H),7.31–7.24(m,3H),7.06(dd,J=7.6,1.2Hz,1H),4.03(s,3H),3.76(s,2H),2.73(s,3H),2.48(s,3H),2.27(s,3H)。MS:(ES)m/z C29H28ClN6O[M+H]+计算值为511.2,实测值为511.5。
实施例16:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)乙酰胺
6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(50mg,0.10mmol),2-氨基乙酰胺氯化氢(30mg,0.27mmol),Et3N(0.070mL,0.50mmol)和AcOH(0.080mL,1.37mmol)的DCM(2mL)溶液的混合物在室温下搅拌1.5小时。向混合物中加入NaBH(OAc)3(80mg,0.36mmol)。再搅拌1.5小时后,用饱和NaHCO3淬灭反应并用DCM萃取。分离有机层,用Na2SO4干燥,真空浓缩并通过硅胶色谱法纯化,得到2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)乙酰胺。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.72(dd,J=4.0,1.2Hz,1H),8.58(d,J=8.4Hz,1H),8.09(dd,J=8.4,1.6Hz,1H),7.70–7.65(m,1H),7.63(dd,J=8.0,1.6Hz,1H),7.55(d,J=7.6Hz,1H),7.44–7.37(m,2H),7.30(dd,J=5.6,2.0Hz,1H),7.32–7.24(m,2H),7.06(d,J=7.2Hz,1H),4.03(s,3H),3.79(s,2H),3.31(s,2H),2.36(s,br,2H),2.26(s,3H),2.04(s,3H).。MS:(ES)m/z C30H29ClN7O2[M+H]+计算值为554.2,实测值为554.1。
实施例17:N-(2'-氯-3'-(6-甲氧基-5-(吗啉代甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(50mg,0.10mmol),吗啉(30mg,0.57mmol)和AcOH(80mg,1.37mmol)的DCM(2mL)溶液的混合物在室温下搅拌1小时。向混合物中加入NaBH(OAc)3(75mg,0.35mmol)。再搅拌40分钟后,反应用饱和NaHCO3淬灭并用DCM萃取。分离有机层,用Na2SO4干燥,真空浓缩并通过硅胶色谱法纯化,得到N-(2'-氯-3'-(6-甲氧基-5-(吗啉代甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.73(dd,J=4.4,1.6Hz,1H),8.59(d,J=8.0Hz,1H),8.09(dd,J=8.8,1.6Hz,1H),7.73(d,J=7.2Hz,1H),7.70–7.63(m,2H),7.44–7.37(m,2H),7.31–7.25(m,2H),7.06(d,J=6.8Hz,1H),4.01(s,3H),3.75(dd,J=4.8,4.8Hz,4H),3.56(s,2H),2.73(s,3H),2.55(dd,J=4.4,4.4Hz,4H),2.27(s,3H)。MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.5。
实施例18:N-(2'-氯-3'-(6-甲氧基-5-(((四氢-2H-吡喃-4-基)氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(60mg,0.12mmol)、四氢-2H-吡喃-4-胺(25mg,0.24mmol)和AcOH(28mg,0.48mmol)的DCM(1.5mL)溶液的混合物在室温下搅拌1小时。向混合物中加入NaBH(OAc)3(88mg,0.41mmol)。再搅拌40分钟后,反应用饱和NaHCO3淬灭并用DCM萃取。分离有机层,用Na2SO4干燥,真空浓缩并通过硅胶色谱法纯化,得到N-(2'-氯-3'-(6-甲氧基-5-(((四氢-2H-吡喃-4-)基)氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.73(dd,J=4.0,1.2Hz,1H),8.58(d,J=7.6Hz,1H),8.09(dd,J=8.8,1.6Hz,1H),7.70–7.61(m,3H),7.44–7.37(m,2H),7.31–7.25(m,2H),7.06(d,J=7.2Hz,1H),4.03(s,3H),4.04–3.96(m,2H),3.84(s,2H),3.41(ddd,J=11.6,11.6,2.0Hz,2H),2.73(s,3H),2.80–2.70(m,1H),2.27(s,3H),1.80–1.94(m,4H)。MS:(ES)m/z C33H34ClN6O2[M+H]+计算值为581.2,实测值为581.5。
实施例19:(S)-5-((((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-乙基吡嗪-2-基)甲基)氨基)甲基)吡咯烷-2-酮
步骤a:2-氯-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺(15g,59.2mmol),1,3-二溴-2-氯苯(48g,177.5mmol)、K2CO3(27.8g,201mmol)和Pd(dppf)Cl2与DCM(4.83g,5.9mmol)的二恶烷(300mL)和水(45mL)复合物的混合物在N2下在90℃下搅拌3小时。将内容物冷却至室温,经硅藻土/Na2SO4垫过滤,真空浓缩并通过硅胶色谱法纯化,得到3'-溴-2,2'-二氯-[1,1'-联苯]-3-胺。
步骤b:3'-溴-2,2'-二氯-[1,1'-联苯]-3-胺(6.0g,14.6mmol),5-氯吡啶并[3,4-b]吡嗪(2.42g,14.6mmol)和Cs2CO3(7.14g,21.9mmol)的DMSO(100mL)溶液的混合物在75℃下搅拌过夜。将内容物冷却至室温,用水和EtOAc稀释,然后经硅藻土过滤。分离滤液的有机层,用Na 2SO 4干燥,真空浓缩并通过硅胶色谱法纯化,得到N-(3'-溴-2,2'-二氯-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺。MS:(ES)m/z C19H12BrCl2N4[M+H]+计算值为445.0,实测值为444.7。
步骤c:N-(3'-溴-2,2'-二氯-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺(2.80g,6.3mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧硼烷)(1.76g,6.94mmol),KOAc(1.55g,15.75mmol)和Pd(dppf)Cl2与DCM(1.30g,1.6mmol)的二恶烷(100mL)溶液的复合物的混合物在N2下在98℃下搅拌过夜。将内容物冷却至室温并经硅藻土过滤。收集滤液,真空浓缩并通过硅胶快速色谱法纯化,得到N-(2,2'-二氯-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2)-基)-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺。MS:(ES)m/z C25H24BCl2N4O2[M+H]+计算值为493.1,实测值为493.1。
步骤d:N-(2,2'-二氯-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺(125mg,0.25mmol),5-溴-3-乙基吡嗪-2-甲醛(54mg,0.25mmol)、K3PO4(161mg,0.76mmol)和X-PhosPdGen2(40mg,0.050mmol)的THF(2.5mL)和水(2.5mL)溶液的混合物在室温下搅拌3h。内容物通过硅藻土和Na2SO4垫过滤。收集滤液,真空浓缩并通过硅胶快速色谱法纯化,得到5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-乙基吡嗪-2-甲醛。MS:(ES)m/z C26H19Cl2N6O[M+H]+计算值为501.1,实测值为501.1。
步骤e:5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-乙基吡嗪-2-甲醛(40mg,0.080mmol),(S)-5-(氨基甲基)吡咯烷-2-酮氯化氢(15mg,0.10mmol),Et3N(60mg,0.60mmol)和AcOH(90mg,1.5mmol)的EtOH(1mL)和DCM(1mL)溶液的混合物在65℃下加热20分钟。将内容物冷却至室温并加入NaBH(OAc)3(40mg,0.19mmol),然后再搅拌15分钟。真空除去挥发物,所得残余物通过HPLC纯化,得到(S)-5-((((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-乙基吡嗪-2-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.14(s,1H),8.97(s,1H),8.83(s,1H),8.57(d,J=8.4Hz,1H),8.16(d,J=6.8Hz,1H),7.71(d,J=8.0Hz,1H),7.64–7.50(m,3H),7.40(d,J=6.8Hz,1H),7.29(d,J=7.6Hz,1H),4.72–4.60(m,2H),4.20–4.10(m,1H),3.41–3.40(m,2H),2.94(q,J=7.6Hz,2H),2.50–2.32(m,3H),2.04–1.90(m,1H),1.40(t,J=7.4Hz,3H)。MS:(ES)m/z C31H29Cl2N8O[M+H]+计算值为599.2,实测值为599.5。
实施例20:1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸
步骤a:N-(2,2'-二氯-3'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-[1,1'-联苯]-3-基)吡啶并[3,4-b]吡嗪-5-胺(250mg,0.50mmol),6-氯-2-甲氧基烟醛(94mg,0.55mmol),K3PO4(265mg,2.5mmol)和X-PhosPdGen2(70mg,0.090mmol)的THF(4mL)和水(4mL)溶液的混合物在室温下搅拌5小时。内容物通过硅藻土和Na2SO4垫过滤。收集滤液,真空浓缩并通过硅胶快速色谱法纯化,得到6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛。MS:(ES)m/z C26H18Cl2N5O2[M+H]+计算值为502.1,实测值为502.1。
步骤b:6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(40mg,0.080mmol),3-甲基氮杂环丁烷-3-羧酸(30mg,0.26mmol)和AcOH(75mg,1.25mmol)的DMF(1mL)溶液的混合物在室温下搅拌。1小时后,加入NaBH(OAc)3(70mg,0.33mmol)并将内容物再搅拌1小时。真空除去挥发物,所得残余物通过HPLC纯化,得到1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.15(d,J=1.6Hz,1H),8.97(s,1H),8.48(d,J=7.6Hz,1H),8.12(d,J=6.4Hz,1H),7.88(d,J=8.0Hz,1H),7.67(d,J=8.0Hz,1H),7.60–7.51(m,2H),7.46–7.35(m,3H),7.30(d,J=6.8Hz,1H),4.53(d,J=14.4Hz,1H),4.51(s,3H),4.14(d,J=10.8Hz,2H),4.08(s,3H),1.61(s,3H)。MS:(ES)m/z C31H27Cl2N6O3[M+H]+计算值为601.1,实测值为600.9。
实施例21:(S)-5-((((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛(30mg,0.060mmol)、(S)-5-(氨基甲基)吡咯烷-2-酮氯化氢(15mg,0.10mmol)、Et3N(60mg,0.60mmol)和AcOH(90mg,1.5mmol)的EtOH(1mL))和DCM(1毫升)溶液的混合物在65℃下加热30分钟。将内容物冷却至室温并加入NaBH(OAc)3(40mg,0.19mmol)。再搅拌30分钟后,真空除去挥发物。将所得残余物通过HPLC纯化得到(S)-5-((((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.11(s,1H),8.93(s,1H),8.80(d,J=7.6Hz,1H),8.27(d,J=6.0Hz,1H),7.90(d,J=7.2Hz,1H),7.67(d,J=7.6Hz,1H),7.56–7.49(m,2H),7.46–7.37(m,3H),7.17(d,J=6.8Hz,1H),4.34(s,2H),4.11(s,3H),4.10–4.02(m,1H),3.30–3.20(m,2H),2.48–2.30(m,3H),1.96–1.84(m,1H)。MS:(ES)m/z C31H28Cl2N7O2[M+H]+计算值为600.2,实测值为599.8。
实施例22:(3R,4R)-4-(((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氨基)四氢-2H-吡喃-3-醇
5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-甲醛(50毫克,0.10毫摩尔),(3R,4R)-4-氨基四氢-2H-吡喃-3-醇氯化氢(20mg,0.13mmol)、Et3N(75mg,0.75mmol)和AcOH(120mg,2.0mmol)的EtOH(2mL)和DCM(2mL)溶液的混合物在65℃加热40分钟。将内容物冷却至室温并加入NaBH(OAc)3(65mg,0.30mmol)。再搅拌10分钟后,真空除去挥发物。将得到的残渣用HPLC纯化,得到(3R,4R)-4-(((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ9.14(d,J=1.2Hz,1H),8.96(d,J=1.6Hz,1H),8.58–8.56(m,1H),8.54(s,1H),8.15(d,J=6.4Hz,1H),7.73(d,J=7.2Hz,1H),7.62–7.54(m,2H),7.51(d,J=6.8Hz,1H),7.40(d,J=6.8Hz,1H),7.29(d,J=7.6Hz,1H),4.84(s,2H),4.12(s,3H),4.08–3.94(m,3H),3.64–3.53(m,2H),3.46(dd,J=11.2,11.2Hz,1H),2.24–2.10(m,1H),1.93(dd,J=12.0,3.6Hz,1H)。MS:(ES)m/z C30H28Cl2N7O3[M+H]+计算值为604.2,实测值为603.9。
实施例23:1-((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氮杂环丁烷-3-羧酸
5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-甲醛(35mg,0.10mmol)、氮杂环丁烷-3-羧酸(25mg,0.25mmol)和AcOH(60mg,1.0mmol)的DMF(0.5mL)溶液的混合物在室温下搅拌。40分钟后,加入NaBH(OAc)3(65mg,0.30mmol)并将内容物再搅拌1小时。真空除去挥发物,所得残余物通过HPLC纯化,得到1-((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.15(d,J=1.6Hz,1H),8.97(s,1H),8.48(s,1H),8.46(d,J=8.4Hz,1H),8.11(d,J=6.8Hz,1H),7.71(d,J=7.2Hz,1H),7.60–7.55(m,2H),7.50(d,J=7.2Hz,1H),7.40(d,J=6.4Hz,1H),7.31(d,J=7.2Hz,1H),4.74(s,2H),4.74–4.30(m,4H),4.11(s,3H),3.84–3.72(m,1H)。MS:(ES)m/zC29H24Cl2N7O3[M+H]+计算值为588.1,实测值为588.0。
实施例24:1-((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)-3-甲基氮杂环丁烷-3-羧酸
5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-甲醛(37mg,0.10mmol)、3-甲基氮杂环丁烷-3-羧酸(25mg,0.25mmol)和AcOH(60mg,1.0mmol)的DMF(1mL)溶液的混合物在室温下搅拌。1小时后,加入NaBH(OAc)3(50mg,0.23mmol)并将内容物再搅拌15分钟。真空除去挥发物,所得残余物通过HPLC纯化,得到1-((5-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-3-甲氧基吡嗪-2-基)甲基)-3-甲基氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.14(d,J=1.6Hz,1H),8.96(d,J=1.6Hz,1H),8.54(d,J=8.0Hz,1H),8.49(s,1H),8.15(d,J=6.0Hz,1H),7.71(d,J=6.8Hz,1H),7.61–7.54(m,2H),7.50(d,J=7.6Hz,1H),7.40(d,J=6.4Hz,1H),7.28(d,J=7.2Hz,1H),4.75(s,2H),4.70–4.10(m,4H),4.11(s,3H),1.65(s,3H)。MS:(ES)m/z C30H26Cl2N7O3[M+H]+计算值为602.1,实测值为602.0。
实施例25:1-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯])-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)环丙-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和1-(氨基甲基)-环丙-1-醇为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物1-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-)基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)环丙-1-醇。1H NMR(400MHz,CD3OD)δ9.03(d,J=3.9Hz,1H),8.17–8.13(m,1H),8.06–8.01(m,1H),7.88(d,J=7.6Hz,1H),7.66–7.62(m,2H),7.53(dd,J=8.0,8.0Hz,1H)7.46–7.38(m,2H),7.36(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),4.37(s,2H),4.09(s,3H),3.20(s,2H),2.65(s,3H),2.12(s,3H),0.94–0.90(m,2H),0.76–0.72(m,2H)。MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.5。
实施例26:3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基丙-1-醇为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基))氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙-1-醇。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8.6,4.3Hz,1H),7.87(d,J=7.5Hz,1H),7.68–7.48(m,3H),7.48–7.24(m,4H),4.28(s,2H),4.08(s,3H),3.75(t,J=5.7Hz,2H),3.25(t,J=6.9Hz,2H),2.65(s,3H),2.12(s,3H),2.00–1.89(m,2H)。MS:(ES)m/zC31H32ClN6O2[M+H]+计算值为555.2,实测值为555.5。
实施例27:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-甲基氮杂环丁烷-3-醇盐酸盐为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-醇。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.5Hz,1H),7.68–7.48(m,3H),7.40(ddd,J=18.2,16.1,7.6Hz,3H),7.28(dd,J=7.7,1.3Hz,1H),4.52(s,1H),4.46(s,1H),4.22(d,J=10.9Hz,2H),4.07(s,5H),2.66(s,3H),2.11(s,3H),1.53(s,3H)。MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.6。
实施例28:(3R,4R)-4-(((6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1步骤e的方法,以6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(3R,4R)-4-氨基四氢-2H-吡喃-3-醇盐酸盐为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物(3R,4R)-4-(((6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ9.03(dd,J=4.4,1.4Hz,1H),8.33(dd,J=8.3,1.5Hz,1H),8.24–8.15(m,2H),8.04(dd,J=8.6,4.4Hz,1H),7.87(d,J=7.7Hz,1H),7.64–7.52(m,2H),7.50–7.39(m,3H),4.34(d,J=13.2Hz,1H),4.24(d,J=13.3Hz,1H),4.15(s,3H),4.06–3.93(m,3H),3.61–3.40(m,3H),2.75(s,3H),2.16–2.03(m,1H),1.86(d,J=12.8Hz,1H)。MS:(ES)m/z C32H31ClFN6O3[M+H]+计算值为601.2,实测值为601.5。
实施例29:(S)-5-((((6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1)'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-5-氨基甲基吡咯烷-2-酮盐酸盐为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2'-氯-2-氟-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1)'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.04(dd,J=4.3,1.4Hz,1H),8.32(d,J=8.2Hz,1H),8.24–8.15(m,2H),8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.7Hz,1H),7.64–7.54(m,2H),7.51–7.40(m,3H),4.34(d,J=2.9Hz,2H),4.16(s,3H),4.09–4.01(m,1H),3.30–3.21(m,2H),2.75(s,3H),2.46–2.32(m,3H),1.91(d,J=6.4Hz,1H)。MS:(ES)m/z C32H30ClFN7O2[M+H]+计算值为598.2,实测值为598.5。
实施例30:(3R,4R)-4-(((6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(3R,4R)-4-氨基四氢-2H-吡喃-3-醇盐酸盐为原料制备该化合物。粗物质通过制备型HPLC纯化,得到所需产物(3R,4R)-4-(((6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ9.08–9.02(m,1H),8.21–8.11(m,2H),8.05(dd,J=8.6,4.4Hz,1H),7.87(d,J=7.7Hz,1H),7.65–7.51(m,2H),7.50–7.34(m,4H),4.34(d,J=13.3Hz,1H),4.24(d,J=13.3Hz,1H),4.14(s,3H),4.06–3.93(m,3H),3.61–3.40(m,3H),2.67(s,3H),2.19(s,3H),2.18–2.05(m,1H),1.91–1.82(m,1H)。MS:(ES)m/z C33H34FN6O3[M+H]+计算值为581.3,实测值为581.5。
实施例31:(S)-5-((((6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐为原料制备该化合物。粗产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氟-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ8.83(d,J=4.3Hz,1H),8.15–7.99(m,3H),7.82(dd,J=8.6,4.3Hz,1H),7.70(d,J=7.5Hz,1H),7.48–7.33(m,4H),7.21(d,J=7.5Hz,1H),4.07(s,3H),3.88–3.79(m,3H),2.73–2.63(m,2H),2.59(s,3H),2.38–2.23(m,3H),2.23(s,3H),1.81(s,1H)。MS:(ES)m/z C33H33FN7O2[M+H]+计算值为578.3,实测值为578.5。
实施例32:N-(3'-(5-((氮杂环丁烷-3-基氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基氮杂环丁烷-1-羧酸叔丁酯为原料制备该化合物。粗物质通过硅胶色谱法纯化得到3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)氮杂环丁烷-1-羧酸叔丁酯。向Boc保护的中间体中加入10%TFA的DCM溶液。将内容物冻干得到产品N-(3'-(5-((氮杂环丁烷-3-基氨基)甲基)-6-甲氧基吡啶-2-基)-2'-氯-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.3,1.4Hz,1H),8.21–8.09(m,1H),8.05(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.6Hz,1H),7.69–7.48(m,3H),7.48–7.25(m,4H),4.45–4.34(m,5H),4.24(s,2H),4.08(s,3H),2.66(s,3H),2.12(s,3H)。MS:(ES)m/z C31H31ClN7O[M+H]+计算值为552.2,实测值为552.5.。
实施例33:N-(2'-氯-3'-(6-甲氧基-5-((哌啶-4-基氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和4-氨基哌啶-1-羧酸叔丁酯为原料制备该化合物。粗物质通过硅胶色谱法纯化得到4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)哌啶-1-羧酸叔丁酯。Boc保护的中间体用10%TFA的DCM溶液处理,然后将溶液冻干,得到纯产物N-(2'-氯-3'-(6-甲氧基-5-((哌啶-4-基氨基))甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.4,1.4Hz,1H),8.16(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.90(d,J=7.6Hz,1H),7.67–7.48(m,3H),7.48–7.32(m,3H),7.28(dd,J=7.6,1.3Hz,1H),4.35(s,2H),4.09(s,3H),3.59(dd,J=9.9,6.4Hz,3H),3.19–3.08(m,2H),2.66(s,3H),2.47(d,J=13.6Hz,2H),2.12(s,3H),1.97(q,J=14.2,12.4Hz,2H)。MS:(ES)m/z C33H35ClN7O[M+H]+计算值为580.3,实测值为580.5.。
实施例34:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)(甲基)氨基)乙烷-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-(甲氨基)乙烷-1-醇为原料制备该化合物。粗品经硅胶色谱纯化,得到产物2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)(甲基)氨基)乙烷-1-醇。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=10.4,8.5,1.4Hz,2H),7.86–7.75(m,2H),7.62(dd,J=7.7,1.8Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42–7.32(m,2H),7.25(d,J=7.5Hz,1H),7.16–7.09(m,1H),3.99(s,3H),3.72(t,J=6.0Hz,2H),3.66(s,2H),2.65(t,J=6.1Hz,2H),2.58(s,3H),2.33(s,3H),2.16(s,3H)。MS:(ES)m/z C31H32ClN6O2[M+H]+计算值为555.2,实测值为555.5。
实施例35:(S)-3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,2-二醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-3-氨基丙烷-1,2-二醇为原料制备该化合物。粗品经硅胶色谱纯化,得到产物(S)-3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,2-二醇。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.2,1.5Hz,1H),8.10–8.00(m,2H),7.82(dd,J=8.5,4.2Hz,1H),7.71(d,J=7.4Hz,1H),7.61(dd,J=7.7,1.7Hz,1H),7.48(t,J=7.6Hz,1H),7.42–7.32(m,2H),7.24(d,J=7.4Hz,1H),7.12(dd,J=7.6,1.2Hz,1H),4.02(s,3H),3.92–3.75(m,3H),3.56–3.46(m,2H),2.77(dd,J=12.1,3.8Hz,1H),2.63(dd,J=12.1,8.3Hz,1H),2.58(s,3H),2.16(s,3H)。MS:(ES)m/z C31H32ClN6O3[M+H]+计算值为571.2,实测值为571.5。
实施例36:(R)-3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,2-二醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-3-氨基丙烷-1,2-二醇为原料制备该化合物。粗品经硅胶色谱纯化得到产物(R)-3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶))-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,2-二醇。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.2,1.5Hz,1H),8.05(ddd,J=8.5,7.4,1.4Hz,2H),7.81(dd,J=8.5,4.2Hz,1H),7.71(d,J=7.5Hz,1H),7.60(dd,J=7.6,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.41–7.32(m,2H),7.24(d,J=7.4Hz,1H),7.15–7.08(m,1H),4.02(s,3H),3.93–3.74(m,3H),3.58–3.46(m,2H),2.79(dd,J=12.1,3.7Hz,1H),2.69–2.55(m,1H),2.58(s,3H),2.15(s,3H)。MS:(ES)m/z C31H32ClN6O3[M+H]+计算值为571.2,实测值为571.5。
实施例37:(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-3-甲基吡咯烷-3-羧酸为原料制备该化合物。粗物质通过硅胶色谱纯化得到产物(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基吡咯烷-3-羧酸。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=9.7,8.3,1.4Hz,2H),7.92–7.78(m,2H),7.63(dd,J=7.7,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.43–7.32(m,3H),7.16–7.08(m,1H),4.49–4.36(m,2H),4.10(s,3H),3.71(s,1H),3.50(s,1H),3.38(s,1H),2.98(d,J=10.7Hz,1H),2.58(s,3H),2.39(s,1H),2.15(s,3H),1.96(s,1H),1.34(s,3H)。MS:(ES)m/z C34H34ClN6O3[M+H]+计算值为609.2,实测值为609.5。
实施例38:(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基吡咯烷-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-3-甲基吡咯烷-3-醇盐酸盐为原料制备该化合物。粗物质通过硅胶色谱纯化得到产物(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基吡咯烷-3-醇。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=9.4,8.4,1.4Hz,2H),7.86–7.75(m,2H),7.61(dd,J=7.7,1.8Hz,1H),7.48(t,J=7.6Hz,1H),7.42–7.32(m,2H),7.25(d,J=7.5Hz,1H),7.15–7.08(m,1H),4.00(s,3H),3.83–3.70(m,2H),2.96(q,J=7.9Hz,1H),2.79–2.61(m,3H),2.58(s,3H),2.16(s,3H),1.90(t,J=7.0Hz,2H),1.36(s,3H)。MS:(ES)m/zC33H34ClN6O2[M+H]+计算值为581.2,实测值为581.5。
实施例39:(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)(甲基)氨基)四氢-2H-吡喃-3-醇
(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇(43mg,0.072mmol)和福尔马林(37%的水溶液,0.15mL,2.0mmol)的MeOH(1mL)和DCE(1mL)溶液在室温下搅拌30分钟。向反应中加入NaBH(OAc)3(80mg,0.38mmol)。再过30分钟后,将混合物用水淬灭并用2:1v/v CHCl3:IPA萃取。有机相经硅胶色谱分离纯化得到产物(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)(甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.2,1.5Hz,1H),8.05(ddd,J=8.1,6.0,1.4Hz,2H),7.85–7.73(m,2H),7.62(dd,J=7.7,1.8Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.15–7.08(m,1H),4.06–3.87(m,4H),3.99(s,3H),3.62(d,J=13.9Hz,1H),3.54–3.37(m,2H),2.66–2.56(m,1H),2.58(s,3H),2.32(s,3H),2.16(s,3H),2.08–1.95(m,1H),1.79–1.70(m,1H)。MS:(ES)m/z C34H36ClN6O3[M+H]+计算值为611.3,实测值为611.5。
实施例40:(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)吡咯烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-吡咯烷-3-羧酸为原料制备该化合物。粗物质通过硅胶色谱纯化得到产物(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)吡咯烷-3-羧酸。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=8.2,5.4,1.4Hz,2H),7.90(d,J=7.6Hz,1H),7.81(dd,J=8.5,4.2Hz,1H),7.63(dd,J=7.7,1.7Hz,1H),7.50(dd,J=7.6,7.6Hz,1H),7.42–7.32(m,3H),7.15–7.07(m,1H),4.40(s,2H),4.08(s,3H),3.57(dd,J=11.3,5.6Hz,1H),3.40(m,3H),3.16–3.04(m,1H),2.57(s,3H),2.31(m,2H),2.15(s,3H)。MS:(ES)m/z C33H32ClN6O3[M+H]+计算值为595.2,实测值为595.5。
实施例41:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,3-二醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-氨基丙烷-1,3-二醇为原料制备该化合物。粗品经硅胶色谱纯化,得到产物2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)丙烷-1,3-二醇。1H NMR(400MHz,CD3OD)δ9.07–9.01(m,1H),8.16(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8.6,4.3Hz,1H),7.94–7.87(m,1H),7.68–7.58(m,2H),7.53(dd,J=7.6,7.6Hz,1H),7.48–7.32(m,3H),7.28(d,J=7.6Hz,1H),4.41(s,2H),4.09(s,3H),3.90(dd,J=12.0,4.4Hz,2H),3.80(dd,J=11.9,6.3Hz,2H),3.38–3.32(m,1H),2.65(s,3H),2.12(s,3H)。MS:(ES)m/z C31H32ClN6O3[M+H]+计算值为571.2,实测值为571.5。
实施例42:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)乙烷-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-氨基乙烷-1-醇为原料制备该化合物。粗物质通过快速色谱法纯化,得到产物2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)乙烷-1-醇。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.4Hz,1H),8.16(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.93–7.85(m,1H),7.68–7.49(m,3H),7.48–7.25(m,4H),4.32(s,2H),4.09(s,3H),3.89–3.81(m,2H),3.24–3.16(m,2H),2.66(s,3H),2.12(s,3H)。MS:(ES)m/z C30H30ClN6O2[M+H]+计算值为541.2,实测值为541.5。
实施例43:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-(羟甲基)丙烷-1,3-二醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-氨基-2-(羟甲基)丙烷-1,3-二醇为原料制备该化合物。粗品经硅胶色谱纯化,得到产物2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-(羟甲基)丙烷-1,3-二醇。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.4,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.93–7.86(m,1H),7.67–7.48(m,3H),7.48–7.25(m,4H),4.43(s,2H),4.08(s,3H),3.83(s,6H),2.66(s,3H),2.12(s,3H)。MS:(ES)m/z C32H34ClN6O4[M+H]+计算值为601.2,实测值为601.5。
实施例44:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-4-甲基哌啶-4-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和4-甲基哌啶-4-醇为原料制备该化合物。粗品经硅胶色谱纯化得到产物1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-4-甲基哌啶-4-醇。1HNMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.5Hz,1H),8.17(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.99–7.88(m,1H),7.66(dd,J=7.8,1.7Hz,1H),7.62–7.49(m,2H),7.48–7.36(m,3H),7.29(d,J=7.5Hz,1H),4.39(s,2H),4.09(s,3H),3.44–3.66(m,4H),2.66(s,3H),2.12(s,3H),1.90–1.77(m,4H),1.29(s,3H)。MS:(ES)m/z C34H36ClN6O2[M+H]+计算值为595.3,实测值为595.5。
实施例45:(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(3R,4R)-4-氨基四氢-2H-吡喃-3-醇盐酸盐为原料制备该化合物。粗品经硅胶色谱纯化得到产物(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.2,1.5Hz,1H),8.10–8.00(m,2H),7.86–7.72(m,2H),7.61(dd,J=7.7,1.7Hz,1H),7.48(dd,J=7.6Hz,1H),7.42–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.15–7.08(m,1H),4.02(s,3H),3.96–3.82(m,5H),3.54–3.38(m,2H),2.88(d,J=10.9Hz,1H),2.58(s,3H),2.16(s,3H),1.92–1.78(m,1H),1.71(d,J=13.2Hz,1H)。MS:(ES)m/z C33H34ClN6O3[M+H]+计算值为597.2,实测值为597.6。
实施例46:2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,5,7-三氮杂螺[3.4]辛烷-6-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2,5,7-三氮杂螺[3.4]辛烷-6-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基))-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,5,7-三氮杂螺[3.4]辛烷-6-酮。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.88(dd,J=4.3,1.5Hz,1H),8.14(dd,J=8.5,1.5Hz,1H),7.93–7.87(m,2H),7.65(dd,J=7.7,1.8Hz,1H),7.56(dd,J=7.6,7.6Hz,1H),7.42–7.33(m,3H),7.13(dd,J=7.6,1.3Hz,1H),7.00(s,1H),3.95(s,3H),3.62–3.50(m,8H),2.50(s,3H),2.08(s,3H)。MS:(ES)m/zC33H32ClN8O2[M+H]+计算值为607.2,实测值为607.2。
实施例47:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸
使用类似于实施例1的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-甲基氮杂环丁烷-3-羧酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-3-甲基氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.4,1.4Hz,1H),8.26(dd,J=8.6,1.4Hz,1H),8.07(dd,J=8.6,4.4Hz,1H),8.03–7.93(m,2H),7.64(dd,J=7.7,1.7Hz,1H),7.62–7.57(m,1H),7.53(dd,J=7.6,7.6Hz,1H),7.49–7.42(m,1H),7.42–7.37(m,1H),7.35(d,J=7.5Hz,1H),7.27(dd,J=7.8,1.3Hz,1H),4.63–4.43(m,4H),4.18(dd,J=16.9,11.5Hz,2H),4.07(s,3H),2.68(s,3H),2.10(s,3H),1.63(s,3H)。MS:(ES)m/zC33H32ClN6O3[M+H]+计算值为595.2,实测值为595.5。
实施例48:3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙酰胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基-2,2-二甲基丙酰胺为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙酰胺。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.87(d,J=7.6Hz,1H),7.68–7.51(m,3H),7.48–7.29(m,4H),4.29(s,2H),4.12(s,3H),3.14(s,2H),2.66(s,3H),2.12(s,3H),1.35(s,6H)。MS:(ES)m/zC33H34ClN7O2[M+H]+计算值为596.3,实测值为596.5。
实施例49:(S)-5-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)哌啶-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-5-氨基哌啶-2-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-5-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)哌啶-2-酮。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=8.1,5.3,1.4Hz,2H),7.83–7.74(m,2H),7.61(dd,J=7.7,1.7Hz,1H),7.50–7.34(m,3H),7.24(d,J=7.5Hz,1H),7.12(dd,J=7.6,1.3Hz,1H),4.02(s,3H),3.90–3.81(m,2H),3.49(ddd,J=12.1,4.6,1.5Hz,1H),3.13(dd,J=12.2,7.6Hz,1H),3.04–2.98(m,1H),2.58(s,3H),2.50–2.29(m,2H),2.16(s,3H),2.16–2.04(m,1H),1.83–1.73(m,1H)。MS:(ES)m/zC33H33ClN7O2[M+H]+计算值为594.2,实测值为594.6。
实施例50:(R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-4-氨基吡咯烷-2-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.2,1.5Hz,1H),8.06(ddd,J=8.2,6.0,1.4Hz,2H),7.83–7.73(m,2H),7.61(dd,J=7.6,1.7Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.39–7.35(m,2H),7.25(d,J=7.4Hz,1H),7.13–7.11(m,1H),4.02(s,3H),3.82(d,J=2.3Hz,2H),3.69–3.60(m,2H),3.27–3.24(m,1H),2.64–2.60(m,1H),2.58(s,3H),2.30–2.24(m,1H),2.16(s,3H)。MS:(ES)m/z C32H31ClN7O2[M+H]+计算值为580.2,实测值为580.5。
实施例51:(R)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-5-(氨基甲基)吡咯烷-2-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(R)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶))-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ8.85(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=11.5,8.3,1.4Hz,2H),7.83(dd,J=8.5,4.3Hz,1H),7.74(d,J=7.5Hz,1H),7.61(dd,J=7.6,1.8Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.40–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.13(dd,J=7.6,1.2Hz,1H),4.03(s,3H),3.86(s,3H),2.78–2.68(m,2H),2.59(s,3H),2.37–2.13(m,6H),1.85–1.75(m,1H)。MS:(ES)m/z C33H33ClN7O2[M+H]+计算值为594.2,实测值为594.5。
实施例52:N-(2'-氯-3'-(5-((异丙基氨基)甲基)-6-甲氧基吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和丙-2-胺为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物N-(2'-氯-3'-(5-((异丙基氨基)甲基)-6-甲氧基吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=8.2,3.1,1.4Hz,2H),7.81(dd,J=8.5,4.2Hz,1H),7.73(d,J=7.5Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.41–7.32(m,2H),7.25(d,J=7.4Hz,1H),7.11(dd,J=7.6,1.2Hz,1H),4.03(s,3H),3.84(s,2H),2.91(sep,J=6.3Hz,1H),2.58(s,3H),2.16(s,3H),1.16(d,J=6.3Hz,6H)。MS:(ES)m/z C31H32ClN6O[M+H]+计算值为539.2,实测值为539.2.。
实施例53:2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-甲基丙酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2-氨基-2-甲基丙酸为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物2-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-甲基丙酸。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.4,1.5Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.91(d,J=7.6Hz,1H),7.65–7.48(m,3H),7.46–7.28(m,4H),4.29(s,2H),4.09(s,3H),2.66(s,3H),2.13(s,3H),1.70(s,6H)。MS:(ES)m/zC32H32ClN6O3[M+H]+计算值为583.2,实测值为583.2。
实施例54:((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基))-2-甲氧基吡啶-3-基)甲基)甘氨酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和甘氨酸为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)甘氨酸。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.4,1.4Hz,1H),8.18(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.6Hz,1H),7.67–7.48(m,3H),7.46–7.28(m,4H),4.35(s,2H),4.09(s,3H),3.96(s,2H),2.66(s,3H),2.12(s,3H)。MS:(ES)m/z C30H28ClN6O3[M+H]+计算值为555.2,实测值为555.2。
实施例55:N-(2'-氯-3'-(5-((二甲基氨基)甲基)-6-甲氧基吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和二甲胺为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物N-(2'-氯-3'-(5-((二甲基氨基)甲基)-6-甲氧基吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=8.3,8.3,1.4Hz,2H),7.82(dd,J=8.5,4.2Hz,1H),7.72(d,J=7.5Hz,1H),7.63(dd,J=7.7,1.8Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.43–7.33(m,2H),7.26(d,J=7.5Hz,1H),7.12(dd,J=7.5,1.3Hz,1H),4.00(s,3H),3.61(s,2H),2.59(s,3H),2.34(s,6H),2.16(s,3H)。MS:(ES)m/z C30H30ClN6O[M+H]+计算值为525.2,实测值为525.2.。
实施例56:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3–基)-2-甲氧基吡啶-3-基)甲基)哌啶-4-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和哌啶-4-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)哌啶-4-醇。1HNMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=9.5,8.2,1.4Hz,2H),7.86–7.72(m,2H),7.62(dd,J=7.6,1.7Hz,1H),7.48(dd,J=7.6,7.6Hz,1H),7.42–7.31(m,2H),7.27(d,J=7.5Hz,1H),7.13(dd,J=7.6,1.2Hz,1H),4.00(s,3H),3.67(s,3H),2.95–2.91(m,2H),2.59(s,3H),2.42–2.34(m,2H),2.16(s,3H),1.92–1.87(m,2H),1.67–1.58(m,2H)。MS:(ES)m/z C33H34ClN6O2[M+H]+计算值为581.2,实测值为581.2。
实施例57:(3S,4S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(3S,4S)-4-氨基四氢-2H-吡喃-3-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(3S,4S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d])嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.06(ddd,J=12.0,8.3,1.4Hz,2H),7.86–7.76(m,2H),7.62(dd,J=7.7,1.8Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.42–7.33(m,2H),7.29(d,J=7.4Hz,1H),7.13(dd,J=7.7,1.2Hz,1H),4.09–3.87(m,8H),3.56–3.39(m,1H),3.08(d,J=11.2Hz,1H),2.59(s,3H),2.16(s,3H),1.98–1.88(m,1H),1.77(d,J=12.2Hz,1H),1.29(t,J=7.3Hz,1H)。MS:(ES)m/z C33H34ClN6O3[M+H]+计算值为597.2,实测值为597.6。
实施例58:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ8.84(dd,J=4.3,1.5Hz,1H),8.07(ddd,J=16.4,8.3,1.4Hz,2H),7.92–7.78(m,2H),7.56–7.33(m,5H),7.12(dd,J=7.5,1.2Hz,1H),4.02–3.82(m,2H),3.24–3.19(m,1H),2.89–2.78(m,2H),2.64(s,3H),2.58(s,3H),2.40–2.22(m,3H),2.17(s,3H),1.93–1.84(m,1H)。MS:(ES)m/z C33H33ClN7O[M+H]+计算值为578.2,实测值为578.5。
实施例59:1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇
使用类似于实施例1步骤e的方法,以6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇。1H NMR(400MHz,CD3OD)δ9.14(d,J=1.8Hz,1H),8.96(d,J=1.9Hz,1H),8.69–8.62(m,1H),8.21(d,J=6.4Hz,1H),7.89(d,J=7.7Hz,1H),7.68(dd,J=7.8,1.9Hz,1H),7.57–7.52(m,2H),7.48–7.34(m,3H),7.28–7.20(m,1H),4.78–4.60(m,1H),4.49–4.39(m,4H),4.11–3.98(m,5H)。MS:(ES)m/z C29H25Cl2N6O2[M+H]+计算值为559.1,实测值为559.1。
实施例60:(S)-4-(((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-4-氨基吡咯烷-2-酮为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-4-(((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮。1HNMR(400MHz,CD3OD)δ9.10(s,1H),8.93(s,1H),8.86(d,J=8.3Hz,1H),8.30(d,J=6.4Hz,1H),7.91(d,J=7.6Hz,1H),7.70–7.63(m,1H),7.58–7.35(m,5H),7.16(d,J=7.6Hz,1H),4.33(s,2H),4.28–4.21(m,1H),4.12(s,3H),3.91–3.83(m,1H),3.61–3.57(m,1H),2.95–2.87(m,1H),2.66–2.55(m,1H)。MS:(ES)m/zC30H26Cl2N7O2[M+H]+计算值为586.2,实测值为586.1。
实施例61:1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-羧酸为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物1-((6-(2,2'-二氯-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.13(s,1H),8.95(s,1H),8.70–8.63(m,1H),8.21(d,J=6.3Hz,1H),7.89(d,J=7.5Hz,1H),7.68(dd,J=7.7,1.8Hz,1H),7.56–7.52(m,2H),7.47–7.34(m,3H),7.23(dd,J=7.7,1.7Hz,1H),4.5(s,2H),4.43–4.41(m,4H),4.09(s,3H),3.78–3.69(m,1H)。MS:(ES)m/z C30H25Cl2N6O3[M+H]+计算值为587.1,实测值为587.1。
实施例62:3-(5-((((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-2-腈
使用类似于实施例1步骤e的方法,以3-(5-甲酰基-6-甲氧基吡啶-2-基)-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-2-腈和(3R,4R)-4-氨基四氢吡喃-3-醇盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物3-(5-((((3R,4R)-3-羟基四氢-2H-吡喃-4-基)氨基)甲基)-6-甲氧基吡啶-2-基)-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-2-甲腈。1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.74(dd,J=4.3,1.5Hz,1H),8.63(dd,J=8.4,1.5Hz,1H),8.10(dd,J=8.4,1.5Hz,1H),7.82(dd,J=7.9,1.2Hz,1H),7.76–7.64(m,3H),7.49–7.40(m,2H),7.37(d,J=7.9Hz,1H),7.14(d,J=7.9Hz,1H),4.11(s,3H),4.05(dd,J=12.8,2.8Hz,1H),3.98–3.77(m,3H),3.43(ddd,J=23.8,12.0,2.0Hz,2H),2.84–2.78(m,1H),2.74(s,3H),2.34(s,3H),1.89–1.75(m,1H),1.70–1.50(m,2H)。MS:(ES)m/z C34H34N7O3[M+H]+计算值为588.3,实测值为588.2。
实施例63:(S)-5-((((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(S)-5-((((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基))-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.01(s,1H),8.85(s,1H),8.14(d,J=6.2Hz,1H),8.04(d,J=8.4Hz,1H),7.72(d,J=7.5Hz,1H),7.59(d,J=8.0Hz,1H),7.46(dd,J=7.7,7.7Hz,1H),7.39–7.32(m,2H),7.25–7.19(m,2H),7.07(d,J=7.4Hz,1H),4.01(s,3H),3.87–3.77(m,3H),2.77–2.61(m,2H),2.36–2.20(m,3H),2.15(s,3H),1.85–1.75(s,1H)。MS:(ES)m/zC32H31ClN7O2[M+H]+计算值为580.2,实测值为580.5。
实施例64:(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基烟醛和(3R,4R)-4-氨基四氢-2H-吡喃-3-醇盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,CDCl3)δ9.35(s,1H),8.77(dd,J=4.2,1.5Hz,1H),8.50(d,J=7.9Hz,1H),8.18(dd,J=8.5,1.5Hz,1H),7.80(d,J=7.9Hz,1H),7.72(dd,J=8.5,4.0Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.53(d,J=8.0Hz,1H),7.46–7.36(m,2H),7.31(dd,J=7.6,1.8Hz,1H),7.09(d,J=7.6Hz,1H),4.17–3.89(m,4H),3.55–3.39(m,2H),3.12–3.00(m,2H),2.96(q,J=7.2Hz,2H),2.75(s,3H),2.25(s,3H),1.95–1.85(m,1H),1.80–1.73(m,1H),1.36(t,J=7.3Hz,3H)。MS:(ES)m/z C34H36ClN6O2[M+H]+计算值为595.3,实测值为595.2。
实施例65:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮盐酸盐为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-乙基吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CDCl3)δ9.26(s,1H),8.74(dd,J=4.3,1.5Hz,1H),8.57(d,J=8.2Hz,1H),8.11(dd,J=8.5,1.5Hz,1H),7.76–7.65(m,2H),7.61(dd,J=7.7,1.8Hz,1H),7.50(d,J=8.2Hz,1H),7.45–7.36(m,2H),7.30(dd,J=7.5,1.8Hz,1H),7.06(d,J=8.2Hz,1H),6.35(s,1H),3.95(m,2H),3.83(bs,1H),3.09(q,J=7.3Hz,2H),2.99–2.88(m,2H),2.73(s,3H),2.42–2.30(m,2H),2.25(s,3H),2.04(d,1H),1.83(m,1H),1.36(t,J=7.3Hz,3H)。MS:(ES)m/z C34H35ClN7O[M+H]+计算值为592.3,实测值为592.2。
实施例66:3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-甲基丁-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基-3-甲基丁-1-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-甲基丁-1-醇。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.4,1.5Hz,1H),8.17(dd,J=8.7,1.5Hz,1H),8.06(dd,J=8.6,4.3Hz,1H),7.89(d,J=7.5Hz,1H),7.66–7.48(m,3H),7.48–7.25(m,4H),4.26(s,2H),4.07(s,3H),3.92(t,J=5.8Hz,2H),2.66(s,3H),2.12(s,3H),1.96(t,J=5.8Hz,2H),1.53(s,6H),1.38(d,J=4.2Hz,1H)。MS:(ES)m/z C33H36ClN6O2[M+H]+计算值为583.3,实测值为583.5。
实施例67:3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙-1-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基-2,2-二甲基丙-1-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙-1-醇。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.4,1.4Hz,1H),8.18(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.86(d,J=7.5Hz,1H),7.68–7.49(m,3H),7.48–7.25(m,4H),4.26(s,2H),4.08(s,3H),3.48(s,2H),3.09(s,2H),2.66(s,3H),2.12(s,3H),1.02(s,6H)。MS:(ES)m/z C33H36ClN6O2[M+H]+计算值为583.3,实测值为583.5。
实施例68:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基))-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇。1H NMR(400MHz,CD3OD)δ9.04(dd,J=4.3,1.4Hz,1H),8.16(dd,J=8.6,1.4Hz,1H),8.04(dd,J=8.6,4.3Hz,1H),7.90(d,J=7.5Hz,1H),7.68–7.58(m,2H),7.53(dd,J=7.6Hz,1H),7.46–7.39(m,2H),7.36(d,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),4.63(b,1H),4.49(s,2H),4.41(bs,2H),4.08(s,3H),4.03(b,2H),2.65(s,3H),2.12(s,3H)。MS:(ES)m/zC31H30ClN6O2[M+H]+计算值为553.2,实测值为553.5。
实施例69:(S)-N-(2'-氯-3'-(6-甲氧基-5-(((四氢呋喃-3-基)氨基)甲基)吡啶-2-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-四氢呋喃-3-胺为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物(S)-N-(2'-氯-3'-(6-甲氧基-5-(((四氢呋喃-3-基)氨基)甲基)吡啶-2)-基)-2-甲基-[1,1'-联苯]-3-基)-2-甲基吡啶并[3,2-d]嘧啶-4-胺。1H NMR(400MHz,CDCl3)δ9.24(s,1H),8.73(dd,J=4.3,1.5Hz,1H),8.58(dd,J=8.2,1.3Hz,1H),8.11(dd,J=8.5,1.5Hz,1H),7.73–7.59(m,3H),7.41(dd,J=7.8Hz,2H),7.33–7.24(m,2H),7.06(dd,J=7.8,1.3Hz,1H),4.04(s,3H),3.98(m,1H),3.90–3.78(m,4H),3.71(dd,J=9.6,3.6Hz 1H),3.55–3.45(m,1H),2.73(s,3H),2.27(s,3H),2.22–2.09(m,1H),1.90–1.80(m,1H)。MS:(ES)m/z C32H32ClN6O2[M+H]+计算值为567.2,实测值为567.5。
实施例70:3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和3-氨基-2,2-二甲基丙酸为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物3-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2,2-二甲基丙酸。1H NMR(400MHz,CDCl3)δ9.23(s,1H),8.73(dd,J=4.1,1.5Hz,1H),8.58(d,J=8.3Hz,1H),8.10(dd,J=8.4,1.5Hz,1H),7.73–7.60(m,3H),7.46–7.36(m,2H),7.32–7.28(m,2H),7.06(d,J=7.6Hz,1H),4.10(s,3H),4.00(s,2H),2.75(s,2H),2.73(s,3H),2.26(s,3H),2.06(s,1H),1.23(s,6H)。MS:(ES)m/z C33H34ClN6O3[M+H]+计算值为597.2,实测值为597.5。
实施例71:1-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-甲基丙-2-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和1-氨基-2-甲基丙-2-醇为原料制备该化合物。产物通过制备型HPLC纯化,得到所需产物1-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-2-甲基丙-2-醇。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.4Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.90(d,J=7.6Hz,1H),7.66(dd,J=7.6,1.4Hz,1H),7.60(d,J=8.6Hz,1H),7.53(dd,J=7.6Hz,1H),7.46–7.38(m,2H),7.37(d,J=7.6Hz,1H),7.28(dd,J=7.6,1.4Hz,1H),4.34(s,2H),4.09(s,3H),3.03(s,2H),2.66(s,3H),2.12(s,3H),1.31(s,6H)。MS:(ES)m/z C32H34ClN6O2[M+H]+计算值为569.2,实测值为569.5。
实施例72:(R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-4-氨基-3-羟基丁酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(R)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-)基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸。1H NMR(400MHz,CD3OD)δ9.03(dd,J=4.4,1.4Hz,1H),8.15(dd,J=8.6,1.4Hz,1H),8.03(dd,J=8.6,4.3Hz,1H),7.88(d,J=7.5Hz,1H),7.64(ddd,J=7.7,1.9,1.9Hz,2H),7.53(dd,J=7.6,7.6Hz,1H),7.48–7.38(m,2H),7.35(d,J=7.5Hz,1H),7.25(d,J=7.6Hz,1H),4.37–4.31(m,3H),4.09(s,3H),3.30–3.26(m,1H),3.07(dd,J=12.7,9.8Hz,1H),2.65(s,3H),2.57(d,J=6.3Hz,2H),2.12(s,3H)。MS:(ES)m/z C32H32ClN6O4[M+H]+计算值为599.2,实测值为599.4。
实施例73:(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-(三氟甲基)吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-(三氟甲基)烟醛和(S)-5-(氨基甲基)吡咯烷-2-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(S)-5-((((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4)-基)氨基)-[1,1'-联苯]-3-基)-2-(三氟甲基)吡啶-3-基)甲基)氨基)甲基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.3,1.5Hz,1H),8.30(d,J=8.2Hz,1H),8.06(ddd,J=9.5,8.3,1.4Hz,2H),7.94(d,J=8.2Hz,1H),7.82(dd,J=8.5,4.3Hz,1H),7.61(dd,J=7.7,1.8Hz,1H),7.53(dd,J=7.6,7.6Hz,1H),7.44(dd,J=7.5,1.8Hz,1H),7.39(dd,J=7.9,7.9Hz,1H),7.14(dd,J=7.7,1.3Hz,1H),4.06(s,2H),3.88–3.79(m,1H),2.83–2.62(m,2H),2.58(s,3H),2.42–2.21(m,3H),2.17(s,3H),1.91–1.80(m,1H)。MS:(ES)m/z C33H30ClF3N7O[M+H]+计算值为632.2,实测值为632.5。
实施例74:(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)哌啶-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-哌啶-3-羧酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(R)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)哌啶-3-羧酸。1H NMR(400MHz,CD3OD)δ8.83(dd,J=4.2,1.5Hz,1H),8.07(dd,J=8.5,1.5Hz,1H),8.04(d,J=8.0Hz,1H),7.87(d,J=7.5Hz,1H),7.82(dd,J=8.5,4.3Hz,1H),7.66(dd,J=7.6,1.6Hz),7.51(dd,J=7.6,7.6Hz,1H),7.43–7.33(m,3H),7.12(dd,J=7.5,1.3Hz,1H),4.25(t,J=13.7Hz,2H),4.10(s,3H),3.30–3.24(m,1H),3.17–3.04(m,3H),2.70(bs,1H),2.58(s,3H),2.16(s,3H),2.08–1.74(m,3H),1.28(t,J=7.3Hz,1H)。MS:(ES)m/z C34H34ClN6O3[M+H]+计算值为609.2,实测值为609.6。
实施例75:(S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-4-氨基-3-羟基丁酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)-3-羟基丁酸。1H NMR(400MHz,CD3OD)δ8.74(dd,J=16.8,4.4Hz,1H),8.11–7.94(m,2H),7.82–7.66(m,2H),7.54(dt,J=7.7,2.3Hz,1H),7.38(ddd,J=7.6,7.6,1.6Hz,1H),7.35–7.24(m,2H),7.12(dd,J=7.6,1.5Hz,1H),7.03(dd,J=7.6,3.0Hz,1H),4.62(bs,2H),4.30(bs,1H),3.96(s,3H),4.08–3.72(m,2H),3.34(s,3H),2.82(m,1H),2.53(s,3H),2.52–2.28(m,1H)。MS:(ES)m/z C32H32ClN6O4[M+H]+计算值为599.2,实测值为599.5。
实施例76:(S)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)哌啶-2-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-哌啶-2-羧酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(S)-1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)哌啶-2-羧酸。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.06(dd,J=8.8,1.6Hz,1H),8.04(d,J=8.0Hz,1H),7.97(d,J=7.6Hz,1H),7.81(dd,J=8.5,4.2Hz,1H),7.63(dd,J=7.7,1.7Hz,1H),7.49(dd,J=7.6,7.6Hz,1H),7.43–7.33(m,3H),7.11(d,J=7.6Hz,1H),4.51–4.15(m,2H),4.04(s,3H),3.48–3.33(m,2H),2.88(bs,1H),2.58(s,3H),2.25–2.16(m,1H),2.15(s,3H),1.93–1.63(m,4H),1.58–1.45(m,1H)。MS:(ES)m/zC34H34ClN6O3[M+H]+计算值为609.2,实测值为609.6。
实施例77:2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,6-二氮杂螺[3.4]辛烷-5-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(2,6-二氮杂螺[3.4]辛烷-5-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,6-二氮杂螺[3.4]辛烷-5-酮。1H NMR(400MHz,CD3OD)δ8.82(dd,J=4.3,1.5Hz,1H),8.05(ddd,J=7.9,6.5,1.4Hz,2H),7.81(dd,J=8.4,4.3Hz,1H),7.68(d,J=7.5Hz,1H),7.59(dd,J=7.7,1.7Hz,1H),7.47(dd,J=7.6,7.6Hz,1H),7.43–7.31(m,2H),7.22(d,J=7.5Hz,1H),7.11(dd,J=7.6,1.3Hz,1H),3.99(s,3H),3.73(s,2H),3.53(d,J=8.8Hz,2H),3.40(d,J=8.4Hz,2H),3.34(s,2H),2.58(s,3H),2.49(t,J=6.8Hz,2H),2.15(s,3H)。MS:(ES)m/zC34H33ClN7O2[M+H]+计算值为606.2,实测值为606.5。
实施例78:2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,5-二氮杂螺[3.4]辛烷-6-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和2,5-二氮杂螺[3.4]辛烷-6-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到2-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)-2,5-二氮杂螺[3.4]辛烷-6-酮。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.4Hz,1H),8.17(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.92(dd,J=7.3,7.3Hz,1H),7.64(dd,J=7.7,1.9Hz,1H),7.58(d,J=7.7Hz,1H),7.53(dd,J=6.8Hz,1H),7.48–7.37(m,2H),7.37(dd,J=7.6,2.0Hz,1H),7.28(d,J=7.7Hz,1H),4.66–4.44(m,3H),4.39–4.23(m,3H),4.09(s,3H),3.37–3.32(m,2H),2.66(s,3H),2.54(t,J=6.8Hz,2H),2.11(s,3H)。MS:(ES)m/zC34H33ClN7O2[M+H]+计算值为606.2,实测值为606.5。
实施例79:(R)-5-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)哌啶-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(R)-5-氨基哌啶-2-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(R)-5-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)哌啶-2-酮。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.4,1.4Hz,1H),8.17(dd,J=8.6,1.5Hz,1H),8.05(dd,J=8.6,4.3Hz,1H),7.95(d,J=7.6Hz,1H),7.64(dd,J=7.7,1.8Hz,1H),7.61(d,J=7.9Hz,1H),7.53(dd,J=7.7,7.7Hz,1H),7.47–7.39(m,2H),7.37(d,J=7.5Hz,1H),7.28(d,J=8.8Hz,1H),4.40(d,J=12.8Hz,1H),4.35(d,J=13.2Hz,1H),4.10(s,3H),3.81–3.73(m,2H),3.53–3.46(m,1H),2.66(s,3H),2.52(d,J=6.4,Hz,1H),2.50(d,J=6.0Hz,1H),2.43–2.35(bs,1H),2.16–2.06(m,1H)2.12(s,3H)。MS:(ES)m/z C33H33ClN7O2[M+H]+计算值为594.2,实测值为594.5。
实施例80:(S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(S)-4-氨基吡咯烷-2-酮为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(S)-4-(((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)吡咯烷-2-酮。1H NMR(400MHz,CD3OD)δ9.06(dd,J=4.3,1.4Hz,1H),8.18(dd,J=8.6,1.5Hz,1H),8.06(dd,J=8.6,4.4Hz,1H),7.94(d,J=7.6Hz,1H),7.64(dd,J=7.7,1.7Hz,1H),7.58(dd,J=8.0,1.2Hz,1H),7.53(dd,J=7.6,7.6Hz,1H),7.48–7.39(m,2H),7.37(d,J=7.5Hz,1H),7.28(dd,J=7.7,1.3Hz,1H),4.33(s,2H),4.24(dq,J=8.4,4.2Hz,1H),4.10(s,3H),3.88(dd,J=11.6,7.6Hz,1H),3.61(dd,J=11.6,4.0Hz,1H),2.91(dd,J=17.7,8.8Hz,1H),2.66(s,3H),2.59(dd,J=17.7,4.7Hz,1H),2.12(s,3H)。MS:(ES)m/zC32H31ClN7O2[M+H]+计算值为580.2,实测值为580.5。
实施例81:1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-羧酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到1-((6-(2-氯-2'-甲基-3'-((2-甲基吡啶并[3,2-d]嘧啶-4-基)氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸。1H NMR(400MHz,CD3OD)δ9.05(dd,J=4.4,1.4Hz,1H),8.19(dd,J=8.6,1.4Hz,1H),8.05(dd,J=8.6,4.4Hz,1H),7.89(d,J=7.5Hz,1H),7.64(dd,J=7.8,1.7Hz,1H),7.59(dd,J=8.0,1.3Hz,1H),7.53(ddd,J=7.6,7.6,3.4Hz,1H),7.44(d,J=8.1Hz,1H),7.40(ddd,J=7.6,2.9,1.6Hz,1H),7.36(d,J=7.6Hz,1H),7.28(d,J=7.7Hz,1H),4.60–4.30(m,4H),4.08(s,3H),3.74(p,J=8.6Hz,1H),2.92(s,2H),2.66(s,3H),2.11(s,3H)。MS:(ES)m/zC32H29ClN6O3[M+H]+计算值为581.2,实测值为581.5。
实施例82:(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇
使用类似于实施例1中步骤e的方法,以6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和(3R,4R)-4-氨基四氢-2H-吡喃-3-醇为原料制备该化合物。粗产物通过制备型HPLC纯化,得到(3R,4R)-4-(((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基))-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氨基)四氢-2H-吡喃-3-醇。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.11(s,1H),8.93(s,1H),8.22(d,J=5.9Hz,1H),8.14(d,J=8.1Hz,1H),7.82(d,J=7.5Hz,1H),7.61(d,J=7.1Hz,1H),7.51(dd,J=7.7,7.7Hz,1H),7.40–7.29(m,2H),7.29–7.19(m,2H),7.01(d,J=7.6Hz,1H),4.63(bs,1H),3.90(s,3H),3.79–3.58(m,4H),3.36–3.25(m,4H),2.67(s,1H),2.09(s,3H),1.65(t,J=10.2Hz,1H),1.51(d,J=13.2Hz,1H)。MS:(ES)m/z C32H32ClN6O3[M+H]+计算值为583.2,实测值为583.5。
实施例83:1-((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-羧酸为原料制备该化合物。粗产物通过制备型HPLC纯化,得到1-((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-羧酸。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.12(s,1H),8.93(s,1H),8.22(d,J=6.1Hz,1H),8.13(d,J=8.0Hz,1H),7.74–7.63(m,1H),7.61(d,J=7.4Hz,1H),7.51(dd,J=7.7,7.7Hz,1H),7.40–7.29(m,2H),7.24(dd,J=8.3,6.6Hz,2H),7.08–6.96(m,1H),3.89(s,3H),3.54(s,2H),3.49–3.15(m,6H),2.08(s,3H)。MS:(ES)m/z C31H28ClN6O3[M+H]+计算值为567.2,实测值为567.5。
实施例84:1-((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇
使用类似于实施例1步骤e的方法,以6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基烟醛和氮杂环丁烷-3-醇为原料制备该化合物。粗产物通过制备型HPLC纯化,得到1-((6-(2-氯-2'-甲基-3'-(吡啶并[3,4-b]吡嗪-5-基氨基)-[1,1'-联苯]-3-基)-2-甲氧基吡啶-3-基)甲基)氮杂环丁烷-3-醇。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.11(d,J=1.8Hz,1H),8.93(d,J=1.9Hz,1H),8.22(d,J=6.0Hz,1H),8.17–8.14(d,J=8.0Hz,1H),7.66(d,J=7.6Hz,1H),7.61(dd,J=7.8,1.7Hz,1H),7.50(dd,J=7.7,7.7Hz,1H),7.40–7.30(m,2H),7.26–7.21(m,2H),7.02(d,J=7.2Hz,1H),5.31(d,J=6.5Hz,1H),4.20(q,J=6.2Hz,1H),3.89(s,3H),3.64–3.49(m,4H),2.91–2.75(m,2H),2.08(s,3H)。MS:(ES)m/z C30H28ClN6O2[M+H]+计算值为539.2,实测值为539.4。
生物学例子:酶联免疫吸附测定-ELISA
96孔板在4℃下在PBS中用1μg/mL的人PD-L1(R&D获得)包被过夜。然后用2%BSA的0.05%TWEEN-20的PBS(W/V),在37℃下封闭孔1小时。用PBS/0.05%TWEEN-20洗涤板3次,将化合物在稀释介质中连续稀释(1:5)并添加到ELISA板中。加入人PD-1和生物素0.3μg/mL(ACRO Biosystems),在37℃下孵育1小时,然后用PBS/0.05%TWEEN-20洗涤3次。用2%BSA在PBS(W/V)/0.05%TWEEN-20中,在37℃下进行第二次封闭10分钟,然后用PBS/0.05%TWEEN-20洗涤板3次。在37℃下加入链霉亲和素-HRP 1小时,然后用PBS/0.05%TWEEN-20将板洗涤3次。加入TMB底物并在37℃下反应20分钟。添加终止溶液(2N H2SO4水溶液)。使用微板分光光度计在450nm处读取吸光度。结果如表1所示:IC50值提供如下:从1000到10,000nM(+);从10到1000nM(++);小于10nM(+++)。
表1:
本文描述了本发明的特定实施例,包括发明人已知的用于实施本发明的最佳模式。在阅读了上述描述后,所公开的实施例的变化对于本领域的工作人员来说是显而易见的,并且期望那些技术人员可以适当地采用这样的变化。因此,旨在以不同于本文具体描述的方式实施本发明,并且本发明包括在适用法律允许的情况下在所附权利要求中记载的主题的所有修改和等同物。除非本文另有说明或与上下文有明显矛盾,否则本发明涵盖其范围。
本说明书中引用的所有出版物、专利申请、登录号和其他参考文献均以引用方式并入本文,就好像每个单独的出版物或专利申请被具体地和单独地指示以引用方式并入一样。
Claims (31)
1.式(I)所示的化合物或其药学上可接受的盐、前药或生物电子等排体:
其中:
A是5至10元杂芳基,其未被取代或被1至5个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN;
X1为C1-3亚烷基,其未被取代或被一个或两个独立地选自下组的成员取代:C1-2烷基和CO2H;
R2a和R2b各自独立地选自下组:H、C1-8烷基、C1-8卤代烷基、-Y、-X2-CO2Ra、-X2-ORa、-X2-NRaRb、-X2-C(O)NRaRb,-X2-SO2Ra,-X2-SO2NRaRb、-X2-SO3Ra和-X2-Y,其中每个X2是C1-6亚烷基和任何C1-8烷基或C1-6亚烷基,是未被取代或被一个或两个独立地选自下组的成员取代:OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基和CO2H,每个Y选自下组:C3-6环烷基、C4-8杂环基和5至6元杂芳基,其各自未被取代或被一至四个独立地选自下组的取代基取代:氧代、OH、C1-4烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基、SO3H和CO2H;
或R2a和R2b组合形成4至9元环或螺环,具有零至两个选自O、N或S的附加杂原子环顶点;
其中通过结合R2a和R2b形成的环未被取代或被1至4个独立地选自下组的取代基取代:氧代、C1-8烷基、C1-8卤代烷基、C1-8羟烷基、-X3-CO2Ra、-X3-ORa,-X3-NRaRb,-X3-C(O)NRaRb、-X3-SO2Ra、-X3-SO2NRaRb和-X3-SO3Ra;其中X3是键或C1-6亚烷基;
R3和R4各自独立地选自下组:H、F、Cl、CN、CH3、OCH3、CH2CH3和CF3;
下标n为0、1、2或3;
每个R3a独立地选自下组:H、F、Cl、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3卤代烷氧基、C2-3烯基和CN;
R6、R7和R8各自独立地选自下组:H、F、Cl、CN、CH3、OCH3、CH2CH3和CF3;
Z是稠合双环杂芳环,未被取代或被1-3个Rc取代;
每个Ra独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H;
每个Rb独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H,各自未被取代或被一个或两个独立地选自下组的成员取代:OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基和CO2H;
且Ra和Rb当连接到相同的氮原子时,任选地结合形成4至8元环或螺环,其未被取代或被卤素、OH、SO2NH2,C(O)NH2,C(O)NHOH,PO3H2,CO2C1-8烷基或–CO2H取代;
每个Rc独立地选自下组:H、卤素、CN、C1-6烷基、C1-6卤代烷基、-Y1、-X4-CO2Ra、-O-X4-CO2Ra、-X4-ORa、-X4-NRaRb、-X4-C(O)NRaRb、-O-X4-C(O)NRaRb、-X4-SO2Ra、-X4-SO2NRaRb、-X4-SO3Ra和-N(Ra)-X4-CO2Ra,其中每个X4为键或C1-6亚烷基,每个Y1选自下组:C3-6环烷基和C4-8杂环基;并且任选地,相邻环顶点上的两个Rc结合以形成稠合的5或6元杂环。
2.式(I)所示的化合物或其药学上可接受的盐、前药或生物电子等排体:
其中:
A是5至10元杂芳基,其未被取代或被1至5个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和CN;
X1为C1-3亚烷基,其未被取代或被一个或两个独立地选自下组的成员取代:C1-2烷基和CO2H;
R2a和R2b各自独立地选自下组:H、C1-8烷基、C1-8卤代烷基、-Y、-X2-CO2Ra、-X2-ORa、-X2-NRaRb、-X2-C(O)NRaRb,-X2-SO2Ra,-X2-SO2NRaRb、-X2-SO3Ra和-X2-Y,其中每个X2是C1-6亚烷基和任何C1-8烷基或C1-6亚烷基,是未被取代或被一个或两个独立地选自下组的成员取代:OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基和CO2H,每个Y选自下组:C3-6环烷基、C4-8杂环基和5至6元杂芳基,其各自未被取代或被一至四个独立地选自下组的取代基取代:氧代、OH、C1-4烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基、SO3H和CO2H;
或R2a和R2b组合形成4至9元环或螺环,具有零至两个选自O、N和S的附加杂原子环顶点;
其中通过结合R2a和R2b形成的环未被取代或被1至4个独立地选自下组的取代基取代:氧代、C1-8烷基、C1-8卤代烷基、C1-8羟烷基、-X3-CO2Ra、-X3-ORa,-X3-NRaRb,-X3-C(O)NRaRb、-X3-SO2Ra、-X3-SO2NRaRb和-X3-SO3Ra;其中X3是键或C1-6亚烷基;
R3和R4各自独立地选自下组:F、Cl、CN、CH3、OCH3、CH2CH3和CF3;
下标n为0、1、2或3;
每个R3a独立地选自下组:H、F、Cl、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、C1-3卤代烷氧基、C2-3烯基和CN;
R6、R7和R8各自独立地选自下组:H、F、Cl、CN、CH3、OCH3、CH2CH3和CF3;Z是稠合双环杂芳环,未被取代或被1-3个Rc取代;
每个Ra独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H;
每个Rb独立地选自下组:H、C1-6烷基、C3-6环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6亚烷基-CO2H和C1-6亚烷基-SO3H,各自未被取代或被一个或两个独立地选自下组的成员取代:OH、SO2NH2,C(O)NH2,C(O)NHOH,PO3H2,CO2C1-8烷基和CO2H;
且Ra和Rb当连接到相同的氮原子时,任选地结合形成4至8元环或螺环,其未被取代或被卤素、OH、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基或CO2H取代;
每个Rc独立地选自下组:H、卤素、CN、C1-6烷基、C1-6卤代烷基、-Y1、-X4-CO2Ra、-O-X4-CO2Ra、-X4-ORa、-X4-NRaRb、-X4-C(O)NRaRb、-O-X4-C(O)NRaRb、-X4-SO2Ra、-X4-SO2NRaRb、-X4-SO3Ra和-N(Ra)-X4-CO2Ra,其中每个X4为键或C1-6亚烷基,每个Y1选自下组:C3-6环烷基和C4-8杂环基;并且任选地,相邻环顶点上的两个Rc结合以形成稠合的5或6元杂环。
4.如权利要求1或2所述的化合物或其药学上可接受的盐,其中A是5或6元杂芳基,其是未取代的或被1至3个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、OH和CN。
5.如权利要求1或2所述的化合物或其药学上可接受的盐,其中A是6元杂芳基,其是未取代的或被1至3个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、OH和CN。
7.如权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中A未被取代或被一个或两个独立地选自下组的成员取代:CF3、OH、Et、CN、OCH3和F。
8.如权利要求1-6中任一项所述的化合物或其药学上可接受的盐,其中A是选自下组的6元杂芳基:吡啶、嘧啶、吡嗪和1,2,4-三嗪,它们各自未被取代或被一个或两个独立地选自下组的成员取代:CF3、OH、Et、CN、OCH3和F。
13.如权利要求1-13中任一项所述的化合物或其药学上可接受的盐,其中Y选自下组:C3-6环烷基和C4-8杂环基,它们各自未被取代或被1至4个独立地选自下组的取代基取代:氧代、OH、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4羟基烷氧基、SO2NH2、C(O)NH2、C(O)NHOH、PO3H2、CO2C1-8烷基、SO3H和CO2H。
14.如权利要求1所述的化合物或其药学上可接受的盐,其中A选自下组:吡啶基、嘧啶基、吡嗪基、恶唑基、噻唑基和吡唑基,它们各自未被取代或被一个或两个独立地选自下组的成员取代:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN。
15.如权利要求1-14中任一项所述的化合物或其药学上可接受的盐,其中所述化合物是光学纯的或富集的异构体。
16.如权利要求1所述的化合物,其中所述化合物选自表1中的化合物。
18.一种药物组合物,其包含如权利要求1-17中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂。
19.如权利要求18所述的药物组合物,进一步包含一种或多种额外的治疗剂。
20.如权利要求19所述的药物组合物,其中所述一种或多种额外的治疗剂选自下组:抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化疗剂、抗癌剂、抗血管生成剂、免疫治疗剂、抗激素剂、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂和抗增殖剂。
21.一种在受试者中调节由PD-1信号通路介导的免疫反应的方法,包括向受试者施用治疗有效量的如权利要求1-14中任一项所述的化合物,或其药学上可接受的盐或如权利要求18-20中任一项所述的组合物。
22.一种增强、刺激、调节和/或增加有需要的受试者的免疫反应的方法,包括向受试者施用治疗有效量的如权利要求1-14中任一项的化合物或其药学上可接受的盐或权利要求18-20中任一项所述的组合物。
23.在有需要的受试者中抑制癌细胞生长、增殖或转移的方法,包括向所述受试者施用治疗有效量的权利要求1-14中任一项的化合物或其药学上可接受的盐或权利要求18-20中任一项所述的组合物。
24.一种治疗患有或易患由PD-1信号通路介导的疾病或病症的对象的方法,包括向所述对象施用治疗有效量的权利要求1-14中任一项的化合物或其药学上可接受的盐或权利要求18-20中任一项所述的组合物。
25.如权利要求21-24中任一项所述的方法,其中所述受试者患有选自下组的疾病或病症:传染病、细菌性传染病、病毒性传染病、真菌性传染病、实体瘤、恶性血液病、免疫紊乱、炎症性疾病和癌症。
26.如权利要求24所述的方法,其中所述疾病或病症选自下组:黑色素瘤、成胶质细胞瘤、食道肿瘤、鼻咽癌、葡萄膜黑色素瘤、淋巴瘤、淋巴细胞性淋巴瘤、原发性CNS淋巴瘤、T细胞淋巴瘤、弥漫性大B细胞淋巴瘤,原发性纵隔大B细胞淋巴瘤,前列腺癌,去势抵抗性前列腺癌,慢性粒细胞白血病,卡波西肉瘤,纤维肉瘤,脂肪肉瘤,软骨肉瘤,成骨肉瘤,血管肉瘤,淋巴管肉瘤,滑膜瘤,脑膜瘤,平滑肌肉瘤,横纹肌肉瘤,软肉瘤组织,肉瘤,败血症,胆管肿瘤,基底细胞癌,胸腺肿瘤,甲状腺癌,甲状旁腺癌,子宫癌,肾上腺癌,肝脏感染,默克尔细胞癌,神经肿瘤,滤泡中心淋巴瘤,结肠癌,霍奇金病,非霍奇金淋巴瘤,白血病,慢性或急性白血病,包括急性髓性白血病,慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、多发性骨髓瘤、卵巢肿瘤、骨髓增生异常综合征、皮肤或眼内恶性黑色素瘤、肾细胞癌、小细胞肺癌、肺癌、间皮瘤、乳腺癌、鳞状非小细胞肺癌(SCLC),非鳞状非小细胞肺癌,结直肠癌,卵巢癌,胃癌,肝细胞癌,胰腺癌,胰腺癌,胰腺导管腺癌,头颈部鳞状细胞癌,头颈部癌症,胃肠道,胃癌,HIV,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,疱疹病毒,乳头瘤病毒,流感,骨癌,皮肤癌,直肠癌,肛门癌,睾丸癌,输卵管癌,子宫内膜癌、宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌,尿道癌,阴茎癌,膀胱癌,肾癌,输尿管癌,肾盂癌,中枢神经系统(CNS)肿瘤,肿瘤血管生成,脊柱轴肿瘤,脑干神经胶质瘤,垂体腺瘤,表皮样癌,失禁,癌,腺癌,乳头状癌,囊腺癌,支气管癌,肾细胞癌,移行细胞癌,绒毛膜癌,精原细胞瘤,胚胎癌,威尔姆氏瘤,多形性腺瘤,肝细胞乳头状瘤,肾小管腺瘤、囊腺瘤、乳头状瘤、腺瘤、平滑肌瘤、横纹肌瘤、血管瘤、淋巴管瘤、骨瘤、软骨瘤、脂肪瘤和纤维瘤。
27.如权利要求21-26中任一项所述的方法,进一步包括向受试者施用治疗有效量的一种或多种额外的治疗剂。
28.如权利要求27所述的方法,其中所述一种或多种额外的治疗剂选自下组:抗微生物剂、抗病毒剂、细胞毒剂、基因表达调节剂、化疗剂、抗癌剂、抗血管生成剂、免疫治疗剂、抗激素剂、抗纤维化剂、放射疗法、放射治疗剂、抗肿瘤剂和抗增殖剂。
29.一种制备式(II)化合物的方法,
该方法包括:
(a)用硼酸盐试剂和第一催化剂将具有式(2e1)的化合物转化为具有式(2f1)的化合物;
(b)使具有式(2f1)的化合物与具有式(2g1)的化合物和第二催化剂在铃木型条件下接触以制备具有式(2h1)的化合物;
(c)用HN(R2a)(R2b)和氢化物试剂将具有式(2h1)的化合物还原胺化以提供具有式(II)的化合物,
其中上式(2e1)、(2f1)、(2g)、(2h1)和(II)中,Z、R2a,R2b,R3,R3a、下标n、R4,R5,R6,R7,R8中的每一个具有权利要求1中提供的含义;
每个R'独立地选自下组:H和C1-C6烷基;
X选自下组:Br和Cl;
X'选自下组:I、Br和Cl;
带有Rs的环是选自下组的六元氮杂芳基环:吡啶、嘧啶和吡嗪,
Rs是0、1、2或3个独立地选自下组的取代基:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN。
30.一种制备式(II)化合物的方法,
该方法包括:
(a)使具有式(2e1)的化合物与具有式(2g'1)的化合物和催化剂在铃木型条件下接触以制备具有式(2h1)的化合物;
(b)用HN(R2a)(R2b)和氢化物试剂将具有式(2h1)的化合物还原胺化以提供具有式(II)的化合物,
其中上式(2e1)、(2g'1)、(2h1)和(II)中,Z、R2a,R2b,R3,R3a,、下标n、R4,R5,R6,R7,R8分别具有权利要求1中提供的含义;
每个R'独立地选自下组:H和C1-C6烷基;
X选自下组:I、Br和Cl;
带有Rs的环是选自下组的六元氮杂芳基环:吡啶、嘧啶和吡嗪,
Rs是0、1、2或3个独立地选自下组的取代基:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN。
31.一种制备式(II)化合物的方法,
该方法包括:
(a)使具有式(2j1)的化合物与具有式(2k1)的化合物和第一催化剂在铃木型条件下接触以制备具有式(2h1)的化合物;
(b)用HN(R2a)(R2b)和氢化物试剂将具有式(2h1)的化合物还原胺化以提供具有式(II)的化合物,
其中上式(2j1)、(2k1)、(2h1)和(II)中,Z、R2a,R2b,R3,R3a、下标n、R4,R5,R6,R7,R8分别具有权利要求1中提供的含义;
每个R和R'独立地选自下组:H和C1-C6烷基;
X选自下组:I,Br和Cl;
带有Rs的环是选自下组的六元氮杂芳基环:吡啶、嘧啶和吡嗪,
Rs是0、1、2或3个独立地选自下组的取代基:卤素、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、OH和CN。
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