CN105916845B - 用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物 - Google Patents
用于抑制shp2活性的n-氮杂螺环烷取代的n-杂芳基化合物和组合物 Download PDFInfo
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- CN105916845B CN105916845B CN201580004708.7A CN201580004708A CN105916845B CN 105916845 B CN105916845 B CN 105916845B CN 201580004708 A CN201580004708 A CN 201580004708A CN 105916845 B CN105916845 B CN 105916845B
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及能够抑制SHP2活性的式I化合物,其中p、q、Y1、Y2、R1、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R7和R8如发明内容中所定义。发明还提供用于制备本发明化合物的方法、包含此类化合物的药物制剂和使用此类化合物和组合物控制与异常SHP2活性相关的疾病或病症的方法。
Description
背景
发明领域
本发明涉及能够抑制SHP2活性的化合物。本发明还提供用于制备本发明化合物的方法、包含此类化合物的药物制剂和使用此类化合物和组合物控制与异常SHP2活性相关的疾病或病症的方法。
发明背景
Src同源-2磷酸酶(SHP2)是有助于多种细胞功能包括增殖、分化、细胞周期维护和迁移的由PTPN11基因编码的非受体蛋白酪氨酸磷酸酶。SHP2 涉及通过Ras-丝裂原活化的蛋白激酶(JAK-STAT或磷酸肌醇3-激酶-AKT 途径)的信号传导。
SHP2具有两个N-末端Src同源2结构域(N-SH2和C-SH2)、催化结构域(PTP)和C-末端尾部。这两个SH2结构域控制SHP2的亚细胞定位和功能调节。所述分子以通过涉及来自N-SH2和PTP结构域两者的残基的结合网络稳定的无活性、自我抑制构象存在。由例如细胞因子或生长因子的刺激导致催化位点的曝露,致使SHP2酶促活化。
已在多种人类疾病中鉴定PTPN11基因和随后SHP2的突变,所述疾病例如努南(Noonan)综合征、豹(Leopard)综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病以及乳腺癌、肺癌和结肠癌。因此,SHP2代表了用于开发治疗各种疾病的新疗法的具有高度吸引力的靶点。本发明的化合物满足抑制SHP2活性的小分子的需求。
发明内容
在一个方面,本发明提供式I化合物:
其中:p选自0和1;q选自0和1;Y1选自CH和N;Y2选自CR6和 N;R1是–XR1a;其中R1a选自C6-10芳基、C3-8环烷基、C3-8环烯基和含有1 至4个独立地选自N、C(O)、O和S的杂原子或基团的5-9元杂芳基基团;其中所述R1a的芳基或杂芳基被1至5个独立地选自以下的R9基团取代:卤代、氨基、羟基、N3、C1-4烷基、二甲基-氨基、羟基-取代的-C1-4烷基、卤代-取代的-C1-4烷基、氨基-取代的-C1-4烷基、-C(O)OR10和-NHC(O)R10;且X选自键、S(O)m、O、C(O)、COR11、CR10aR10b、NR11;其中m选自0、 1和2;各R10a和R10b独立地选自卤代和C1-4烷基;且R11选自氢和C1-4烷基;R2a和R2b独立地选自氢、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R3a和R3b独立地选自卤代、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R4a和R4b独立地选自氢、卤代、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R5a和R5b独立地选自氢、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;其中选自R2a、R2b、R3a、R3b、 R4a、R4b、R5a、R5b和R7的任何两个基团能够形成5至6元不饱和的或部分饱和的环;R6选自氢、卤代、氰基、C1-4烷基、C1-4烷氧基、氨基-羰基、卤代-取代的C1-4烷基、卤代-取代的C1-4烷氧基、羟基-取代的C1-4烷基、氨基-取代的C1-4烷基、-S(O)1-2R6a、-C(S)R6a、-C(O)NR6aR6b、-C(NH)NR6aR6b和–NR6aC(O)R6b;其中R6a和R6b独立地选自氢和C1-4烷基;R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有1至3个独立地选自N、C(O)、O和S(O)m的杂原子或基团;其中 m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被1-3个独立地选自以下的基团取代:氨基、羟基、甲氧基、卤代、甲基、甲基-氨基和异丁酰氧基。
在第二个方面,本发明提供药物组合物,其包含式I化合物或其N-氧化物衍生物、互变异构体、单独的异构体和异构体混合物或其药学上可接受的盐与一种或多种适合的赋形剂的混合物。
在第三个方面,本发明提供治疗动物疾病的方法,其中SHP2活性的调控可以预防、抑制或改善疾病的病理学和/或症状学情况,该方法包括对所述动物施用治疗有效量的式I化合物或其N-氧化物衍生物、单独的异构体和异构体混合物或其药学上可接受的盐。
在第四个方面,本发明提供治疗动物疾病的方法,其中SHP2活性的调控可以预防、抑制或改善疾病的病理学和/或症状学情况,该方法包括以与抗癌治疗剂同时或顺序组合的方式对所述动物施用治疗有效量的式I化合物或其N-氧化物衍生物、单独的异构体和异构体混合物或其药学上可接受的盐。
在第五个方面,本发明提供式I化合物在制备用于治疗动物疾病的药剂中的用途,所述疾病中SHP2活性促成疾病的病理学和/或症状学。
在第六个方面,本发明提供用于制备式I化合物或其N-氧化物衍生物、前药衍生物、被保护的衍生物、单独的异构体和异构体混合物及其药学上可接受的盐的方法。
定义
除非另有指示,否则上下文中所用的通用术语优选具有本公开文本上下文中的如下含义,其中无论何处使用,更宽泛的术语可以彼此独立地被更具体的定义替代或保留,由此定义本发明更具体的实施方案:
“烷基”是指具有至多20个碳原子的完全饱和支链或无支链烃基团。除非另外提供,否则烷基是指具有1-7个碳原子(C1-7烷基)或1-4个碳原子(C1-4烷基)的烃基团。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。取代的烷基是包含一个或多个如1、2或3个取代基的烷基,所述取代基选自卤素、羟基或烷氧基。卤代-取代的-烷基和卤代-取代的-烷氧基可以为直链或支链的且包括甲氧基、乙氧基、二氟甲基、三氟甲基、五氟乙基、二氟甲氧基、三氟甲氧基等。
“芳基”是指包含6-10个环碳原子的单环或稠合双环芳族环组合 (ringassembly)。例如,芳基可以是苯基或萘基,优选苯基。“亚芳基”是指衍生自芳基的二价基团。
“杂芳基”如上述对芳基所定义,其中环成员的一个或多个是杂原子。例如,C5-10杂芳基最少是如碳原子所示的5个成员,但这些碳原子可以被杂原子替代。因此,C5-10杂芳基包括吡啶基、吲哚基、吲唑基、喹喔啉基、喹啉基、苯并呋喃基、苯并吡喃基、苯并噻喃基、苯并[1,3]间二氧杂环戊烯、咪唑基、苯并-咪唑基、嘧啶基、呋喃基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、噻吩基等。
“环烷基”是指包含所示环原子数的饱和或部分不饱和单环、稠合双环或桥连多环组合。例如,C3-10环烷基包括环丙基、环丁基、环戊基、环己基、环己烯基等。
“杂环烷基”是指如本申请中所定义的环烷基,前提是所指的环碳的一个或多个被选自-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-或-S(O)2-的部分替代,其中R是氢、C1-4烷基或氮保护基。例如,本申请中用于描述本发明化合物的C3-8杂环烷基包括吗啉代、吡咯烷基、吡咯烷基-2-酮、哌嗪基、哌啶基、哌啶酮、1,4-二氧杂-8-氮杂-螺[4.5]癸-8-基、硫代吗啉代、亚砜(sulfano)吗啉代、砜代(sulfono)吗啉代等。
“卤素”(或卤代)优选表示氯或氟,但还可以是溴或碘。
“SHP2”意指“Src同源-2磷酸酶”,并也称为SH-PTP2、SH-PTP3、Syp、 PTP1D、PTP2C、SAP-2或PTPN11。
携有“PTPN11突变”的癌症包括但不限于:N58Y;D61Y,V;E69K; A72V,T,D;E76G,Q,K(ALL);G60A;D61Y;E69V;F71K;A72V; T73I;E76G,K;R289G;G503V(AML);G60R,D61Y,V,N;Y62D;E69K; A72T,V;T73I;E76K,V,G,A,Q;E139D;G503A,R;Q506P(JMML); G60V;D61V;E69K;F71L;A72V;E76A(MDS);Y63C(CMML);Y62C; E69K;T507K(成神经细胞瘤);V46L;N58S;E76V(肺癌);R138Q(黑色素瘤);E76G(结肠癌)。
式I化合物具有不同的异构体形式。例如。任意不对称碳原子可以以 (R)-、(S)-或(R,S)-构型存在,优选(R)-或(S)-构型存在。双键或尤其是环上的取代基可以以顺式-(=Z-)或反式(=E-)形式存在。由此该化合物可以作为异构体混合物存在或优选作为纯异构体、优选作为纯非对映体或纯对映体存在。
如果使用复数形式(例如化合物、盐),则该形式包括单数(例如单一化合物、单一盐)。“一种(A)化合物”不排除(例如在药物制剂中)存在式I的一种以上化合物(或其盐),“一种(a)”仅代表不确定的物品。“一种(A)”由此可以优选解读为“一种或多种(one ormore)”,而较不优选为“一种 (one)”。
无论何时提及式I化合物,其还旨在包括此类化合物的N-氧化物和/ 或其互变异构体。
术语“和/或其N-氧化物、其互变异构体和/或其(优选药学上可接受的) 盐”尤其是指式I化合物可以就此存在或作为与其N-氧化物、互变异构体 (例如归因于酮-烯醇、内酰胺-内酰亚胺、酰胺-亚氨酸或烯胺-亚胺互变异构现象)的混合物或与(例如等效反应引起)其互变异构体的混合物或作为式 I化合物的盐和/或任意这些形式或两种或多种这样形式的混合物存在。
对于下面的化合物,与吡嗪环连接的NH2基团对于效力是关键的。结晶学结构的分析显示该NH2基团与SHP2残基E250的骨架羰基基团发生分子内相互作用:
本发明还包括本发明化合物的所有适合的同位素变化形式或其药学上可接受的盐。本发明化合物或其药学上可接受的盐的同位素变体定义为:其中至少一个原子被具有相同原子数、但原子量不同于通常天然发现的原子量的原子替代。可以掺入本发明化合物及其药学上可接受的盐的同位素的实例包括但不限于氢、碳、氮和氧的同位素,例如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl和123I。本发明化合物及其药学上可接受的盐的一些同位素变体、例如其中掺入放射性同位素如3H或14C的那些可用于药物和/或底物组织分布研究。在具体的实例中,3H和14C同位素可以因其易于制备和可检测性而使用。在其它实例中,使用同位素如2H取代可以提供一些治疗优势,这归因于其较大的代谢稳定性,例如体内半衰期增加或剂量需求降低。本发明化合物及其药学上可接受的盐的一些同位素变体一般可以通过常规方法、使用适合的试剂的同位素变体制备。例如,本发明化合物可以作为如下所示的氘代形式存在:
优选实施方案的描述
本发明涉及能够抑制SHP2活性的化合物。在本发明的一个方面,对于式I化合物,–XR1a是–SR1a且选自:
在本发明的另一方面,–XR1a是–SR1a且选自:
在本发明的另一方面,对于式I化合物:
选自:
在另一方面中,式I化合物是式Ia化合物:
其中:n选自1、2、3和4;p选自0和1;q选自0和1;Y1选自CH 和N;Y2选自CR6和N;Y4独立地选自N、C(O)和CR9;其中仅一个Y4是C(O);R6选自氢、卤代、甲基和氨基-羰基;R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自 N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被选自以下的基团取代:氨基、氨基- 甲基和甲基-氨基;R9选自卤代、氨基、二甲基-氨基、羟基、N3、C1-4烷基、卤代-取代的-C1-4烷基、C1-4烷氧基、-C(O)OR10和-NHC(O)R10;R10选自氢、苯基和萘基;其中所述R10的苯基未被取代或被甲氧基取代;或其药学上可接受的盐。
在本发明的进一方面中,R7和R8与它们都相连的碳原子一起形成5 元饱和的或部分不饱和的环,该环可任选包含1-2个独立地选自N、O、 C(O)和S(O)m的杂原子或基团;其中m选自0、1和2;其中所述由R7和 R8形成的饱和的环被1-3个独立地选自以下的基团取代:氨基、羟基、甲氧基、卤代、甲基、甲基-氨基和异丁酰氧基;或其药学上可接受的盐。
本发明的进一方面是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是如下的化合物或其药学上可接受的盐,其中 R7和R8与它们都相连的碳原子一起形成6元饱和的或部分不饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被选自以下的基团取代:氨基、氨基- 甲基和甲基-氨基。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是如下的化合物或其药学上可接受的盐,其中 R7和R8与它们都相连的碳原子一起形成4元饱和的或部分不饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被选自以下的基团取代:氨基、氨基- 甲基和甲基-氨基。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是其中p和q都是0的化合物;或其药学上可接受的盐。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是式II化合物:
其中:p选自0和1;q选自0和1;Y1选自CH和N;Y2选自CR6和 N;R1选自C6-10芳基、C3-8环烷基、C3-8环烯基和含有1-4个选自N、O和 S的杂原子的5-9元杂芳基基团;其中所述R1a的芳基或杂芳基被1至5个独立地选自以下的R9基团取代:卤代、氨基、羟基、N3、C1-4烷基、羟基 -取代的-C1-4烷基、卤代-取代的-C1-4烷基、氨基-取代的-C1-4烷基、-C(O)OR10和-NHC(O)R10;其中m选自0、1和2;各R10a和R10b独立地选自卤代和 C1-4烷基;且R11选自氢和C1-4烷基;R2a和R2b独立地选自氢、C1-4烷基、 C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R3a和R3b独立地选自卤代、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R4a和R4b独立地选自氢、卤代、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;R5a和R5b独立地选自氢、羰基、C1-4烷基、C1-4烷氧基、氨基、羟基、C3-8环烷基和C1-4烷基-氨基;其中选自R2a、R3a、R4、R5、R6a和R7a的任何两个基团可以形成5-6元不饱和的或部分不饱和的环;R6选自氢、卤代、氰基、C1-4烷基、C1-4烷氧基、氨基-羰基、卤代-取代的C1-4烷基、卤代-取代的C1-4烷氧基、羟基-取代的C1-4烷基和氨基-取代的C1-4烷基;R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自N、O和 S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被选自以下的基团取代:氨基、氨基-甲基和甲基- 氨基;或其药学上可接受的盐。
在本发明的进一方面中是式IIa化合物:
其中:n选自1、2、3和4;p选自0和1;q选自0和1;Y1选自CH 和N;Y2选自CR6和N;Y4选自N和CR9;R6选自氢、卤代、甲基和氨基-羰基;R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被选自以下的基团取代:氨基、氨基-甲基和甲基-氨基;R9选自卤代、氨基、羟基、N3、C1-4烷基、卤代-取代的-C1-4烷基、C1-4烷氧基、-C(O)OR10和 -NHC(O)R10;R10选自氢、苯基和萘基;其中所述R10的苯基未被取代或被甲氧基取代;或其药学上可接受的盐。
在本发明的进一方面中是如下的化合物或其药学上可接受的盐,其中 R7和R8与它们都相连的碳原子一起形成5元饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和 R8形成的饱和的环被选自以下的基团取代:氨基、氨基-甲基和甲基-氨基。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是如下的化合物或其药学上可接受的盐,其中 R7和R8与它们都相连的碳原子一起形成6元饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和 R8形成的饱和的环被选自以下的基团取代:氨基、氨基-甲基和甲基-氨基。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是如下化合物或其药学上可接受的盐,其中R7和R8与它们都相连的碳原子一起形成4元饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和 R8形成的饱和的环被氨基取代。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
在本发明的另一方面中是其中p和q都是0的化合物;或其药学上可接受的盐。
在本发明的进一方面中是选自以下的化合物或其药学上可接受的盐:
药理学和用途
Src同源-2磷酸酶(SHP2)是有助于多种细胞功能包括增殖、分化、细胞周期维护和迁移的由PTPN11基因编码的蛋白酪氨酸磷酸酶。SHP2涉及通过Ras-丝裂原活化的蛋白激酶的信号传导,即JAK-STAT或磷酸肌醇3- 激酶-AKT途径。SHP2通过受体酪氨酸激酶例如ErbBl、ErbB2和c-Met 介导Erkl和Erk2(Erkl/2,Erk)MAP激酶的活化。
SHP2具有两个N末端Src同源2结构域(N-SH2和C-SH2)、催化结构域(PTP)和C-末端尾部。这两个SH2结构域控制SHP2的亚细胞定位和功能调节。所述分子以无活性构象存在,通过涉及来自N-SH2和PTP结构域两者的残基的结合网络抑制抑制其自身活性。响应生长因子刺激,SHP2 通过其SH2结构域在停靠蛋白(docking proteins)例如Gab1和Gab2上与特异的酪氨酸-磷酸化的位点结合。这诱导导致SHP2活化的构象变化。
已在多种人类疾病中鉴定PTPN11的突变,所述疾病例如努南综合征、豹综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病以及乳腺癌、肺癌和结肠癌。SHP2为多种受体酪氨酸激酶包括血小板衍生生长因子的受体(PDGF-R)、成纤维细胞生长因子的受体(FGF-R) 和表皮生长因子的受体(EGF-R)的重要下游信号分子。SHP2还是能够导致细胞转化(癌症发展的先决条件)的有丝分裂原活化蛋白(MAP)激酶途径的活化的重要下游信号分子。SHP2的击倒显著抑制具有SHP2突变或 EML4/ALK易位的肺癌细胞系的细胞生长以及EGFR扩增的乳腺癌和食道癌。SHP2还在胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤中激活致癌基因的下游。
努南综合征(NS)和豹综合征(LS)-PTPN11基因突变导致LS(Multiplelentigenes、心电图传导异常、眼距过宽、肺动脉狭窄(pulmonic stenosis)、生殖器异常、生长迟缓、感觉神经性耳聋)和NS(先天性异常包括心脏缺陷、颅面骨畸形和身材矮小症)。该两种疾病是对于正常细胞生长和分化所需的 RAS/RAF/MEK/ERK丝裂原活化蛋白激酶途径的组件的种系突变引起的常染色体显性综合征家族的一部分。该通路的异常调节具有深刻的影响,特别是对心脏发育,从而导致各种异常,包括valvuloseptal缺陷和/或肥厚性心肌病(HCM)。MAPK信号通路的扰动已被确立为这些疾病的核心,并且在人类已经确定沿着这条通路的几种候选基因,包括KRAS、NRAS、SOS1、 RAF1、BRAF、MEK1、MEK2、SHOC2和CBL中的突变。在NS和LS 最常见的突变基因是PTPN11。在~50%具有NS的病例中发现 PTPN11(SHP2)种系突变,并且几乎所有具有LS的患者都与NS共享某些特征。对于NS,在蛋白质中的Y62D和Y63C取代是基本上不变的,并且是最常见的突变之一。这两种突变影响SHP2的催化非活性构象,而不扰动所述磷酸酶与其磷酸化信号搭档的结合。
青少年髓单核细胞白血病(JMML)–在约35%的患有JMML的患者中存在PTPN11(SHP2)的体细胞突变,一种儿童骨髓增生性疾病(MPD)。这些功能获得性突变典型地是N-SH2结构域或磷酸酶结构域中的点突变,这阻止催化结构域和N-SH2结构域间的自抑制,从而导致SHP2活性。
急性髓性白血病–已在:~10%的小儿急性白血病例如骨髓增生异常综合征(MDS);~7%的B细胞急性淋巴细胞白血病(B-ALL);和~4%的急性髓性白血病(AML)中确定PTPN11突变。
NS和白血病突变导致位于由处于自抑制SHP2构象的N-SH2和PTP 结构域形成的界面处的氨基酸的变化,破坏抑制性的分子内相互作用,导致催化结构域的活动过度。
SHP2充当受体酪氨酸激酶(RTK)信号的正调节蛋白。含有RTK改变 (EGFRamp、Her2amp、FGFRamp、Metamp、易位/活化的RTK,即ALK、BCR/ABL) 的癌症包括食道癌、乳腺癌、肺癌、结肠癌、胃癌、胶质瘤、头颈癌。
食道癌(或食管癌)是食道的恶性肿瘤。有各种亚型,原发鳞状细胞癌 (<50%)和腺癌。在食管腺癌和鳞状细胞癌中有高的RTK表达率。本发明的 SHP2抑制剂因此可以被用于创新的治疗策略。
乳腺癌是癌症的一重要类型,并且是妇女死亡的主因,其中患者对目前的药物发展出抗性。乳腺癌有四个主要亚型包括Luminal A、Luminal B、 Her2样和三阴性/基本样。三阴性乳腺癌(TNBC)是缺乏特异性靶向治疗的侵袭性乳腺癌。表皮生长因子受体I(EGFR)已成为TNBC中的一个充满希望的靶点。经由SHP2的Her2以及EGFR的抑制可能是乳腺癌的有希望的治疗。
肺癌-NSCLC是目前癌症相关死亡的主要原因。占肺癌的约85%(主要是腺癌和鳞状细胞癌)。虽然细胞毒性化疗仍然是治疗的一个重要组成部分,基于肿瘤中的遗传改变例如EGFR和ALK的靶向治疗更可能从靶向治疗中获益。
结肠癌-大约30%至50%的结肠直肠肿瘤已知有突变的(异常的)KRAS,和在10%至15%的结肠直肠癌中存在BRAF突变。对于已证明其结肠直肠肿瘤中过度表达EGFR的患者子集,这些患者表现出抗-EGFR 治疗的有利的临床响应。
胃癌是最普遍的癌症类型之一。通过胃癌细胞中的异常酪氨酸磷酸化所反映的酪氨酸激酶的异常表达是本领域中已知的。三种受体酪氨酸激酶 c-met(HGF受体)、FGF受体2和erbB2/neu在胃癌中经常扩增。因此,不同的信号通路的颠覆可能促进不同类型的胃癌的恶化。
成神经细胞瘤是正发育的交感神经系统的小儿肿瘤,占儿童癌症的大约8%。间变性淋巴瘤激酶(ALK)基因的基因组改变已经被假定促进成神经细胞瘤的发病。
头颈鳞状细胞癌(SCCHN)。高水平的EGFR表达在多种癌症中与不良预后和对放射治疗的抵抗有关,在头颈鳞状细胞癌(SCCHN)中大多如此。 EGFR信号的阻断导致受体的刺激、细胞增殖的抑制和减少的侵袭力及转移。EGFR因此是SCCHN的新抗癌治疗的主要靶点。
本发明涉及能够抑制SHP2的活性的化合物。本发明还提供了用于制备本发明化合物的方法和包含此类化合物的药物制剂。本发明的另一方面涉及治疗SHP2-介导的病症的方法,其包括向有其需要的患者施用治疗有效量的如发明内容中定义的式I化合物的步骤。
在某些实施方案中,本发明涉及上述方法,其中所述SHP2介导的病症是癌症,选自但不限于:JMML;AML;MDS;B-ALL;成神经细胞瘤;食道癌;乳腺癌;肺癌;结肠癌;胃癌、头颈癌。
本发明的化合物还可用于治疗与异常SHP2活性相关的其它疾病或疾患。因此,作为另一方面,本发明涉及治疗选自以下的病症的方法:NS; LS;JMML;AML;MDS;B-ALL;成神经细胞瘤;食道癌;乳腺癌;肺癌;结肠癌;胃癌;头颈癌。
本发明的SHP2抑制剂可以与另一种药理学活性化合物或与两种或更多种另外的药理学活性化合物联用,特别用于治疗癌症。例如,如上述所定义的式(I)化合物或其药学上可接受的盐可以与一种或多种活性剂同时、依次或分别组合施用,所述一种或多种活性剂选自化疗剂,例如有丝分裂抑制剂,例如紫杉烷、长春花生物碱、紫杉醇、多西他赛、长春新碱、长春碱、长春瑞滨或长春氟宁;和其它抗癌药,例如顺铂、5-氟尿嘧啶或5- 氟-2-4(1H,3H)-嘧啶二酮(5FU)、氟他胺或吉西他滨。
此类组合可以在治疗中提供显著的优势,包括协同作用活性。
在一些实施方案中,本发明涉及上述的方法,其中通过胃肠外施用所述化合物。
在一些实施方案中,本发明涉及上述的方法,其中通过肌内、静脉内、皮下、口服、肺、鞘内、局部或鼻内施用所述化合物。
在一些实施方案中,本发明涉及上述的方法,其中通过全身施用所述化合物。
在一些实施方案中,本发明涉及上述的方法,其中所述患者是哺乳动物。
在一些实施方案中,本发明涉及上述的方法,其中所述患者是灵长类。
在一些实施方案中,本发明涉及上述的方法,其中所述患者是人。
在另一个方面,本发明涉及治疗由SHP2介导的病症的方法,包括以下步骤:对有需要的患者施用治疗有效量的化疗剂与治疗有效量的如发明内容中所定义的式I化合物的组合。
药物组合物
在另一个方面,本发明提供药学上可接受的组合物,其包含与一种或多种药学上可接受的载体(添加剂)和/或稀释剂一起配制的治疗有效量的一种或多种上述化合物。如下文详细描述的,可以将本发明的药物组合物专门配制成用于以固体或液体形式施用,包括适合于以下的那些施用方式: (1)口服施用,例如兽用顿服药(drenches)(水或非水溶液或混悬液);片剂,例如靶向口含、舌下和全身吸收的那些;大丸药(boluses);粉末;颗粒;适用于舌的糊剂;(2)胃肠外施用,例如通过皮下、肌内、静脉内或硬膜外注射,例如无菌溶液或混悬液或缓释制剂;(3)局部施用,例如为施用于皮肤的霜剂、软膏剂或控释贴剂或喷雾剂;(4)阴道内或直肠内,例如为阴道药栓、霜剂或泡沫剂;(5)舌下;(6)眼;(7)透皮;(8)鼻;(9)肺;或(10)鞘内。
本文所用的术语“治疗有效量”是指在动物的至少细胞亚群中以适合于任意医学治疗的合理益处/风险比有效地产生一些期望的治疗作用的化合物、材料或包含本发明化合物的组合物的量。
本文所用的术语“药学上可接受的”是指那些化合物、材料、组合物和/或剂型,在合理的医学判断范围内,它们适用于接触人和动物组织,而没有过度的毒性、刺激性、过敏反应或其它问题或并发症,具有合理的益处/风险比。
本文所用的术语“药学上可接受的载体”是指药学上可接受的材料、组合物或媒介物,例如液体或固体填充剂、稀释剂、赋形剂、配制助剂(例如润滑剂、滑石粉、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或牵涉将主题化合物从身体的一器官或部分携带或转运至身体另一器官或部分的溶剂包囊材料。载体各自必须是“可接受的”,其含义是与制剂的其它成分相容且对患者无害。可以用作药学上可接受的载体的材料的一些实例包括: (1)糖类,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉; (3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素; (4)西黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,例如可可脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇类,例如丙二醇;(11)多元醇类,例如甘油、山梨醇、甘露糖醇和聚乙二醇;(12)酯类,例如油酸乙酯和月桂酸乙酯;(13)琼脂; (14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯类、聚碳酸酯类和/或聚酐类;和(22)其它用于药物制剂的无毒性相容性物质。
如上所述,本发明化合物的一些实施方案可以包含碱性官能团,例如氨基或烷基氨基,且由此能够与药学上可接受的酸形成药学上可接受的盐。在这方面术语“药学上可接受的盐”是指本发明化合物的相对无毒性的无机酸和有机酸加成盐。这些盐可以在施用媒介物中或剂型制备方法中原位制备,或通过单独地使游离碱形式的纯化的本发明化合物与适合的有机酸或无机酸反应并且在随后的纯化过程中分离由此形成的盐来制备。有代表性的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等(参见例如Berge等人(1977)“Pharmaceutical Salts”,J.Pharm.Sci.66: 1-19)。
主题化合物的药学上可接受的盐包括这些化合物的常用的例如来自无毒性有机酸或无机酸的无毒性盐或季铵盐。例如,此类常用无毒性盐包括衍生自无机酸的那些,所述无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等;和由有机酸制备的盐,所述有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸(isothionic)等。
在其它情况中,本发明的化合物可以包含一种或多种酸性官能团且由此能够与药学上可接受的碱形成药学上可接受的盐。在这些情况中,术语“药学上可接受的盐”是指本发明化合物的相对无毒性的无机碱和有机碱加成盐。同样,这些盐可以在施用媒介物中或剂型制备方法中原位制备;或单独地使游离酸形式的纯化的化合物与适合的碱如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐、氨或药学上可接受的有机伯胺、仲胺或叔胺反应制备。代表性的碱金属或碱土金属盐包括锂、钠、钾、钙、镁和铝盐等。用于形成碱加成盐的代表性的有机胺类包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等(参见例如Berge等人,上文)。
组合物中还可以存在湿润剂、乳化剂和润滑剂,例如月桂基硫酸钠和硬脂酸镁,以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂。
药学上可接受的抗氧化剂的实例包括:(1)水溶性抗氧化剂,例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α生育酚等;和(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括适合于口服、鼻部、局部(包括口含和舌下)、直肠、阴道和/或胃肠外施用的那些。可以将制剂便利地制成单位剂型且可以通过制药领域众所周知的任意方法制备。可以与载体材料合并产生单一剂型的活性成分的量根据所治疗的宿主、具体施用模式的不同而改变。可以与载体材料合并产生单一剂型的活性成分的量一般是产生治疗效果的化合物的用量。一般地,百分比中,该用量约为0.1%至约99%的活性成分,优选约 5%至约70%、最优选约10%至约30%。
在一些实施方案中,本发明的制剂包含选自环糊精、纤维素、脂质体、胶束形成剂例如胆汁酸和聚合物载体例如聚酯类和聚酐类的赋形剂和本发明的化合物。在一些实施方案中,上述的制剂使得本发明的化合物口服可生物利用。
制备这些制剂或组合物的方法包括使本发明的化合物与载体和任选的一种或多种辅助成分混合的步骤。一般地,通过均匀和紧密地混合本发明的化合物与液体载体或固体载体细粉或它们两者且然后如果必要使产物成形来制备所述制剂。
适合于口服施用的本发明制剂可以是胶囊、扁囊剂、丸剂、片剂、锭剂(使用矫味基质,通常是蔗糖和阿拉伯胶或黄蓍胶)、粉末、颗粒或为在水或非水液体中的溶液或混悬液的形式或为水包油型或油包水型液体乳剂或为酏剂或糖浆剂或软锭剂(使用惰性基质,例如明胶和甘油或蔗糖和阿拉伯胶)和/或漱口剂的形式等,它们各自包含预定量的本发明化合物作为活性成。还可以将本发明的化合物作为大丸药、药糖剂或糊剂施用。
在用于口服施用的本发明固体剂型(胶囊、片剂、丸剂、锭剂、粉末、颗粒、药片(trouches)等)中,活性成分与一种或多种药学上可接受的载体混合,例如柠檬酸钠或磷酸二钙和/或如下的任意种:(1)填充剂或增充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸;(2)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、一些硅酸盐和碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收加速剂,例如季铵化合物和表面活性剂,例如泊洛沙姆和月桂基硫酸钠;(7)湿润剂,例如鲸蜡醇、单硬脂酸甘油酯和非离子表面活性剂;(8)吸收剂,例如高岭土和膨润土粘土;(9)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠、硬脂酸锌、硬脂酸钠、硬脂酸及其混合物;(10)着色剂;和(11)控释剂,例如交聚维酮或乙基纤维素。在胶囊、片剂和丸剂的情况中,药物组合物还可以包含缓冲剂。相似类型的固体组合物也可以作为填充剂用于软胶壳和硬壳胶囊,使用赋形剂例如乳糖或奶糖以及高分子量聚乙二醇等。
可以通过任选地与一种或多种辅助成分一起压制或模制来制备片剂。可以使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如淀粉羟乙酸钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备压制片。可以通过在适合的机器中模塑用惰性液体稀释剂湿润的粉状化合物混合物来制备模制片。
可以任选地给本发明药物组合物的片剂和其它固体剂型例如糖衣剂、胶囊、丸剂和颗粒剂刻痕或用包衣剂和壳例如肠溶衣和其它制药领域众所周知的衣料制备。还可以配制它们以便提供其中活性成分的缓释或控释,使用例如不同比例的羟丙基甲基纤维素提供期望的释放特性、其它聚合物基质、脂质体和/或微球。可以将它们配制用于快速释放,例如冷冻干燥。例如,可以通过经截留细菌的滤膜过滤或通过掺入无菌固体组合物形式的灭菌剂给它们灭菌,所述无菌固体组合物形式的灭菌剂可以溶于无菌水或在使用前即刻使用的一些其它无菌可注射介质。这些组合物还可以任选地包含遮光剂,且可以是仅仅或优选在胃肠道一些部分中释放活性成分的组合物,任选地以延迟方式。可以使用的包埋组合物的实例包括聚合物和蜡。如果适合,活性成分还可以是具有上述赋形剂的一种或多种的微囊形式。
用于口服施用本发明化合物的液体剂型包括药学上可接受的乳剂、微乳、溶液、混悬液、糖浆剂和酏剂。除活性成分外,液体剂型还可以包含本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇(tetrahydrofuryl alcohol)、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。
除惰性稀释剂外,口服组合物还可以包括辅助剂,例如湿润剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、芳香剂和防腐剂。
除活性化合物外,混悬液还可以包含助悬剂,例如乙氧基化异硬脂醇类、聚氧乙烯山梨醇和脱水山梨醇酯类、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂和黄蓍胶及其混合物。
可以将用于直肠或阴道施用的本发明药物组合物制剂制成栓剂,其可以通过混合本发明的一种或多种化合物与一种或多种适合的无刺激性赋形剂或载体制备,所述适合的无刺激性赋形剂或载体包含例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯,且所述栓剂在室温下为固体,而在体温下为液体且由此在直肠或阴道腔中熔化并且释放活性化合物。
适合于阴道施用的本发明制剂还包括阴道栓、棉塞、霜剂、凝胶、糊剂、泡沫剂或喷雾剂,其包含例如本领域已知适合的此类载体。
用于局部或透皮施用本发明化合物的剂型包括散剂、喷雾剂、软膏剂、糊剂、霜剂、洗剂、凝胶、溶液、贴剂和吸入剂。可以在无菌条件下将活性化合物与药学上可接受的载体和可能需要的任意防腐剂、缓冲剂或抛射剂混合。
软膏剂、糊剂、霜剂和凝胶除本发明的活性化合物外还可以包含赋形剂,例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌或其混合物。
粉末和喷雾剂除本发明的化合物外还可以包含赋形剂,例如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂还可以包含常用抛射剂,例如氯氟烃类和挥发性未取代的烃类,例如丁烷和丙烷。
透皮贴剂具有将本发明化合物受控递送至身体的附加优点。可以通过在适当的介质中溶解或分散化合物制备此类剂型。吸收促进剂也可以用于增加化合物流过皮肤。此类流速可以通过提供速率控制膜或将化合物分散于聚合物基质或凝胶中控制。
眼用制剂、眼软膏剂、粉末、溶液等还考虑在本发明的范围内。
适合于胃肠外施用的本发明的药物组合物包含一种或多种本发明化合物与一种或多种药学上可接受的无菌等渗水或非水溶液、分散体、混悬液或乳剂或无菌粉末的组合,可以在恰好在使用前将其再溶解成无菌可注射溶液或分散体中,其可以包含糖类、醇类、抗氧化剂、缓冲剂、抑菌剂、赋予制剂与预期接受者血液等渗的溶质或助悬剂或增稠剂。
可以用于本发明药物组合物的适合的水和非水载体的实例包括水、乙醇、多元醇类(例如甘油、丙二醇、聚乙二醇等)及其适合的混合物、植物油例如橄榄油和可注射有机酯类,例如油酸乙酯。例如,可以通过使用包衣材料例如卵磷脂,通过在分散体的情况中维持所需的粒度和通过使用表面活性剂来维持适当的流动性。
这些组合物还可以包含辅助剂,例如防腐剂、湿润剂、乳化剂和分散剂。可以通过包含不同的抗菌剂和抗真菌剂例如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等来确保防止微生物对主题化合物的作用。还期望在组合物中包括等渗剂,例如糖类、氯化钠等。此外,可以通过包含延迟吸收的物质例如单硬脂酸铝和明胶来延长可注射药物剂型的吸收。
在一些情况中,为了延长药物的作用,期望减缓药物从皮下或肌内注射吸收。通过使用具有差水溶性的结晶或无定形材料的液体混悬液实现这一目的。药物的吸收速率随后取决于溶出速率,而溶出速率可能取决于晶体大小和晶型。或者,通过将药物溶于或混悬于油媒介物使胃肠外施用的药物形式延迟吸收。
可以通过将主题化合物在生物可降解聚合物例如聚丙交酯-聚乙醇酸交酯中形成微囊基质来制备可注射储库剂型。根据药物与聚合物之比和所用具体聚合物性质的不同,可以控制药物释放速率。其它生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。还通过将药物俘获在与身体组织相容的脂质体或微乳中制备储库可注射制剂。
当将本发明的化合物作为药物施用于人和动物时,可以将它们自身或作为药物组合物给予,所述药物组合物包含例如0.1-99%(更优选10-30%) 的活性成分与药学上可接受的载体的组合。
可以通过口服、胃肠外、局部或直肠给予本发明的制剂。当然以适合于各自施用途径的形式给予它们。例如,可以用片剂或胶囊形式、通过注射、吸入、洗眼液、软膏剂、栓剂等施用它们;通过注射、输注或吸入施用;通过洗剂和软膏剂局部施用;和通过栓剂直肠施用。优选口服施用。
本文所用的术语“胃肠外施用”和“通过胃肠外施用”是指非肠和非局部的施用模式,通常通过注射,且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下腔、脊柱内和胸骨内注射和输注。
本文所用的术语“全身施用”、“经全身施用”、“外周施用”和“经外周施用”是指将化合物、药物或其它材料以非直接进入中枢神经系统的方式施用,使得它进入患者系统且由此进行代谢和其它类似过程,例如皮下施用。
可以将这些化合物施用于人和其它动物用于通过任意适合的施用途径的疗法,包括口服、鼻部,作为例如喷雾剂,直肠、阴道内、胃肠外、池内和局部,作为粉末、软膏剂或滴剂,包括口含和舌下。
与所选择的施用途径无关,可以通过本领域技术人员公知的常规方法,将以适当水化形式使用的本发明化合物和/或本发明的药物组合物配制成药学上可接受的剂型。
可以改变本发明药物组合物中活性成分的实际剂量水平,以便得到有效地实现对于特定患者、组合物和施用模式而言期望的治疗响应的活性成分用量,而不会对患者产生毒性。
所选择的剂量水平依赖于各种因素,包括所用的本发明具体化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用具体化合物的排泄或代谢速率、吸收速率和程度、治疗期限、用于与所用具体化合物组合的其它药物、化合物和/或材料、所治疗患者的年龄、性别、体重、情况、一般健康状况和在先的医学史等医学领域众所周知的因素。
本领域普通的临床医师或兽医易于决定所需药物组合物的有效量并且开据其处方。例如,临床医师或兽医可以以低于所需的水平开始给药药物组合物中使用的本发明化合物,以便实现期望的治疗效果,并且逐步增加剂量,直到达到期望的效果为止。
一般地,本发明化合物的适合每日剂量为有效地产生治疗效果的最低剂量的化合物的量。此类有效剂量一般取决于上述因素。一般地,对于患者,当用于指示的止痛效果时,本发明化合物的口服、静脉内、脑室内和皮下剂量可以在约0.0001-约100mg/千克体重/天。
如果期望,活性化合物的有效每日剂量可以作为2次、3次、4次、5 次、6次或以上的亚剂量在全天内适当的间隔分别施用,任选地以单位剂型的形式。优选给药是每天施用1次。
尽管能够单独地施用本发明的化合物,但是优选将该化合物作为药物制剂(组合物)施用。
可以以任意便利的用于人或兽药的方式、按照与其它药物类似的方式配制用于施用的本发明化合物。
在另一个方面,本发明提供药学上可接受的组合物,其包含治疗有效量的如上所述的一种或多种主题化合物,与一种或多种药学上可接受的载体(添加剂)和/或稀释剂一起配制。如下文详细描述,可以将本发明的药物组合物专门配制成以固体或液体形式施用,包括适合于如下的那些:(1)口服施用,例如兽用顿服药(水或非水溶液或混悬液);片剂;大丸药;粉末;颗粒;适用于舌的糊剂;(2)胃肠外施用,例如通过皮下、肌内或静脉内注射,例如无菌溶液或混悬液;(3)局部施用,例如为施用于皮肤、肺或粘膜的霜剂、软膏剂或喷雾剂;或(4)阴道内或直肠内,例如为阴道栓、霜剂或泡沫剂;(5)舌下或口含;(6)眼;(7)透皮;或(8)鼻。
术语“治疗”预以还包括预防、治疗和治愈。
接受这种治疗的患者是任意需要的动物,包括灵长类,特别是人类,和其它哺乳动物,例如马、牛、猪和绵羊;且一般还有家禽和宠物。
本发明的化合物可以就此施用或与药学上可接受的载体混合施用,且其还可以与抗微生物剂结合施用,例如青霉素类、头孢菌素类、氨基糖苷类和糖肽类。联合疗法由此包括依次、同时和单独施用活性化合物,其施用方式为首先施用的活性化合物的治疗效果尚未完全消失时随即施用另一种化合物。
微乳化技术可以改善一些亲脂性(水不溶性)药物活性剂的生物利用度。实例包括Trimetrine(Dordunoo,S.K.等人,Drug Development and Industrial Pharmacy,17(12),1685-1713,1991和REV 5901(Sheen,P.C.等人, J Pharm Sci 80(7),712-714,1991)。其中,微乳化通过优先导向吸附至淋巴系统而不是循环系统提供增强的生物利用度,由此绕过肝并且防止化合物在肝胆循环中被破坏。
尽管关注所有适合的两亲载体,但是目前优选的载体一般是具有公认为安全的(GRAS)状态且可以增溶本发明化合物并且在该溶液接触复合水相(例如在人胃肠道中发现的)时在随后阶段微乳化本发明化合物的那些。通常,满足这些要求的两亲成分具有HLB(亲水与亲油平衡值)值为2-20,且其结构包含C-6至C-20的直链脂族基团。实例是聚乙二醇化的 (glycolized)脂肪酸甘油酯类和聚乙二醇类。
商购的两亲载体是特别关注的,包括Gelucire-系列、Labrafil、Labrasol 或Lauroglycol(均由Gattefosse Corporation,Saint Priest,France制造和调配)、PEG-单-油酸酯、PEG-二-油酸酯、PEG-单-月桂酸酯和二-月桂酸酯、卵磷脂、聚山梨醇酯80等(由USA和全世界的大量公司生产和调配)。
适用于本发明的亲水性聚合物是易于水溶性的、可以与囊泡形成脂质共价结合并且在体内耐受无毒性作用的(即生物相容性的)那些。适合的聚合物包括聚乙二醇(PEG)、聚乳酸(也称为聚丙交酯)、聚乙醇酸(也称作聚乙醇酸交酯)、聚乳酸-聚乙醇酸共聚物和聚乙烯醇。优选的聚合物是具有约 100或120道尔顿至约5,000或10,000道尔顿且更优选约300道尔顿至约 5,000道尔顿分子量的那些。在一个特别优选的实施方案中,所述聚合物是具有约100至约5,000道尔顿分子量且更优选具有约300至约5,000道尔顿分子量的聚乙二醇。在一个特别优选的实施方案中,所述聚合物是具有750 道尔顿(PEG(750))的聚乙二醇。还可以根据其中单体的数量定义聚合物;本发明优选的实施方案使用至少约3个单体的聚合物,此类PEG聚合物由 3个单体组成(约150道尔顿)。
可以适用于本发明的其它亲水性聚合物包括聚乙烯吡咯烷酮、聚甲噁唑啉(polymethoxazoline)、聚乙噁唑啉(polyethyloxazoline)、聚羟丙基甲基丙烯酰胺、聚甲基丙烯酰胺、聚二甲基丙烯酰胺和衍生的纤维素例如羟甲基纤维素或羟乙基纤维素。
在一些实施方案中,本发明的制剂包含生物相容性聚合物,其选自聚酰胺类、聚碳酸酯类、聚亚烷基化合物、丙烯酸和甲基丙烯酸酯类的聚合物、聚乙烯基聚合物、聚乙醇酸交酯、聚硅氧烷、聚氨基甲酸酯类及其共聚物、纤维素、聚丙烯、聚乙烯、聚苯乙烯、乳酸和乙醇酸的聚合物、聚酐类、聚(原酸)酯类、聚(丁酸)、聚(戊酸)、聚(丙交酯-共-己内酯)、多糖类、蛋白质、聚透明质酸、聚氰基丙烯酸酯类及其配混物、混合物或共聚物。
环糊精是环寡糖类,其由6、7或8个葡萄糖单元组成,分别命名为希腊字母α、β或γ。具有低于6个葡萄糖单元的环糊精是现存未知的。葡萄糖单元通过α-1,4-葡萄糖苷键连接。作为糖单元椅型构型的结果,所有仲羟基 (在C-2、C-3上)位于环的一侧上,而C-6上的所有伯羟基位于另一侧上。因此,外侧是亲水性的,使得环糊精为水溶性的。相反,环糊精的腔为疏水性的,这归因于它们内衬有C-3和C-5原子的氢以及醚-样氧。这些基质允许与各种相对疏水性的化合物络合,包括例如甾体化合物,例如17β-雌二醇(参见例如van Uden等人,Plant Cell Tiss.Org.Cult.38:1-3-113(1994))。络合通过范德华相互作用和氢键形成发生。有关环糊精化学的一般综述,参见Wenz,Agnew.Chem.Int.Ed.Engl.,33:803-822(1994)。
环糊精衍生物的物理-化学特性主要依赖于取代的种类和取代度。例如,其在水中的溶解性从不溶性(例如三乙酰基-β-环糊精)到147%可溶性 (w/v)(G-2-β-环糊精)。此外,它们可溶于许多有机溶剂。环糊精的特性能够通过增加或减少其溶解度控制不同制剂成分的溶解度。
已经描述了大量环糊精及其制备方法,例如,Parmeter(I)等人(美国专利US3,453,259)和Gramera等人(美国专利US 3,459,731)描述了电中性环糊精。其它衍生物包括具有阳离子特性的环糊精[Parmeter(II)美国专利US 3,453,257]、不溶性交联环糊精(Solms,美国专利US 3,420,788)和具有阴离子特性的环糊精[Parmeter(III),美国专利US3,426,011]。在具有阴离子特性的环糊精衍生物中,已经将羧酸、亚磷酸、三价膦酸、膦酸、磷酸、硫代膦酸、硫代亚磺酸和磺酸附加在母体环糊精上[参见Parmeter(III),上文]。此外,磺基烷基醚环糊精衍生物由Stella等人描述(美国专利US 5,134,127)。
脂质体由至少一层脂质双层膜组成,该膜包封水性内部隔室。脂质体的特征可以在于膜的类型和大小。小型单层囊泡(SUVs)具有单一膜且典型地为0.02-0.05μm直径;大单层囊泡(LUVS)典型地大于0.05μm。寡层大囊泡和多层囊泡具有多个、通常是同心的膜层且典型地大于0.1μm。具有几个非同心膜的脂质体即包含在较大囊泡中的几个较小囊泡称作多层囊泡。
本发明的一个方面涉及包含含有本发明化合物的脂质体的制剂,其中配制脂质体膜以提供具有增加的携带能力的脂质体。或者或此外,本发明的化合物可以包含在脂质体的脂质体双层内或吸附在其上。可以用脂质表面活性剂使本发明的化合物聚集并且携带在脂质体内部空间中;在这些情况中,配制脂质体膜以抵抗活性剂-表面活性剂聚集物的破坏效应。
根据本发明的一个实施方案,脂质体的脂质双层包含用聚乙二醇(PEG) 衍生的脂质,使得PEG链从脂质双层的内表面延伸入被脂质体包囊的内腔,并且从脂质双层的外部延伸进入周围环境。
本发明脂质体内包含的活性剂是溶解形式的。表面活性剂和活性剂的聚集物(例如包含所关注的活性剂的乳剂或胶束)可以被俘获在本发明脂质体的内部空间内。表面活性剂起分散和增溶活性剂的作用且可以选自任意适合的脂族、脂环族或芳族表面活性剂,包括但不限于不同链长(例如约 C14至约C20)的生物相容性溶血磷脂酰胆碱类(LPCs)。聚合物衍生的脂质例如PEG-脂质也可以用于胶束形成,因为它们起抑制胶束/膜融合的作用且因为将聚合物添加到表面活性剂分子中降低了表面活性剂的CMC并且有助于胶束形成。优选具有微摩尔范围的CMCs的表面活性剂;较高的CMC 表面活性剂可以用于制备俘获在本发明脂质体内的胶束,然而,胶束表面活性剂单体可影响脂质体双层的稳定性并将是设计具有期望稳定性的脂质体的因素。
可以通过本领域公知的任意各种技术制备本发明的脂质体。参见例如美国专利US4,235,871;公布的PCT申请WO 96/14057;New RRC, Liposomes:A practical approach,IRL Press,Oxford(1990),33-104页;Lasic DD,Liposomes from physics toapplications,Elsevier Science Publishers BV, Amsterdam,1993。
例如,本发明的脂质体可通过将用亲水性聚合物衍生的脂质扩散入预形成的脂质体中来制备,如将预形成的脂质体暴露于脂质-接枝的聚合物组成的胶束,脂质浓度相当于脂质体中期望的衍生脂质的最终摩尔百分比。还可以通过匀化、脂质-场水化或挤出技术形成包含亲水性聚合物的脂质体,如本领域中公知。
在本发明的一个方面中,制备具有选择大小范围的基本上均匀大小的脂质体。一种有效选择大小的方法包括将脂质体的水性混悬液挤出通过一系列具有所选均匀孔径的聚碳酸酯膜;膜的孔径基本上相当于通过该膜挤出产生的脂质体的最大尺寸。参见例如美国专利US 4,737,323(1988年4 月12日)。
本发明制剂的释放特性取决于包囊材料、包囊药物的浓度和存在的释放调节剂。例如,可以使用仅在低pH如在胃中或较高pH如在肠中释放的 pH敏感性包衣,可以将释放控制为pH依赖性的。肠溶衣可以用于防止释放发生,直到通过胃为止。用不同材料包囊的氰胺的多层包衣层或混合物可以用于得到最初在胃中释放,然后在肠中释放。还可以通过包含盐或孔形成剂控制释放,所述盐或孔形成剂通过从胶囊中扩散可以增加药物的吸水或释放。改变药物溶解度的赋形剂也可以用于控制释放速率。还可以掺入增强从基质中降解或从其中释放的物质。可以将它们加入到药物中,作为单独的相加入(即作为颗粒)或可以根据化合物的不同共溶于聚合物相中。在所有情况中,用量应为0.1-30%(w/w聚合物)。降解促进剂的类型包括无机盐,例如硫酸铵和氯化铵;有机酸,例如柠檬酸、苯甲酸和抗坏血酸;无机碱,例如碳酸钠、碳酸钾、碳酸钙、碳酸锌和氢氧化锌;和有机碱,例如硫酸鱼精蛋白、精胺(spermine)、胆碱、乙醇胺、二乙醇胺和三乙醇胺;和表面活性剂,例如和将显微结构添加到基质中的孔形成剂(即水溶性化合物如无机盐和糖类)作为颗粒添加。范围应在 1-30%(w/w聚合物)。
摄取还可以通过改变颗粒在肠中的停留时间来操控。例如,可以通过用粘膜粘附聚合物给颗粒包衣或将其选作包囊材料实现这一目的。实例包括大部分带有游离羧基的聚合物,例如脱乙酰壳多糖、纤维素且尤其是聚丙烯酸酯类(本文所用的聚丙烯酸酯类是指包括丙烯酸酯基团和修饰的丙烯酸酯基团的聚合物,例如氰基丙烯酸酯类和甲基丙烯酸酯类)。
药物组合
本发明尤其涉及式I化合物(或包含式I化合物的药物组合物)在治疗一种或多种本文所述的疾病中的用途;其中对治疗的响应是有益性的,例如通过该疾病的一种或多种症状部分或完全消退直到完全治愈或恢复所证实。
式(I)化合物还可与下面的化合物和抗体-药物缀合物组合使用:
BCR-ABL抑制剂:伊马替尼盐酸Inilotinib; NilotinibDasatinib(BMS-345825);Bosutinib(SKI-606); Ponatinib(AP24534);Bafetinib(INNO406);Danusertib(PHA-739358), AT9283(CAS 1133385-83-7);Saracatinib(AZD0530);和 N-[2-[(1S,4R)-6-[[4-(环丁基氨基)-5-(三氟甲基)-2-嘧啶基]氨基]-1,2,3,4-四氢萘-1,4-亚氨-9-基]-2-氧代乙基]-乙酰胺(PF-03814735,CAS942487-16-3);和LGX818。
ALK抑制剂:PF-2341066(crizotinib);5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶 -2,4-二胺;GSK1838705A;和CH5424802。
BRAF抑制剂:Vemurafanib(PLX4032);和Dabrafenib。
FLT3抑制剂–苹果酸舒尼替尼(由Pfizer以商品名出售); PKC412(米哚妥林);tanutinib、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、米哚妥林(midostaurin)、lestaurtinib、KW-2449、quizartinib(AC220)和 crenolanib。
MEK抑制剂–trametinib。
血管内皮细胞生长因子(VEGF)受体抑制剂:贝伐珠单抗(由 Genentech/Roche以商品名销售)、阿昔替尼(axitinib)(N-甲基 -2-[[3-[(E)-2-吡啶-2-基乙烯基]-1H-吲唑-6-基]硫烷基]苯甲酰胺,也称作 AG013736且描述在PCT公开号WO 01/002369中)、丙氨酸布立尼布 (Brivanib)((S)-((R)-1-(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并 [2,1-f][1,2,4]三嗪-6-基氧基)丙-2-基)2-氨基丙酸酯,也称作BMS-582664)、莫替沙尼(motesanib)(N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺且描述在PCT公开号WO 02/066470中)、帕瑞肽 (pasireotide)(也称作SOM230且描述在PCT公开号WO 02/010192中);索拉非尼(以商品名销售);
HER2受体抑制剂:曲妥珠单抗(由Genentech/Roche以商品名销售)、奈拉替尼(也称作HKI-272,(2E)-N-[4-[[3-氯-4-[(吡啶-2- 基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺且描述在PCT公开号WO 05/028443中)、拉帕替尼或二甲苯磺酸拉帕替尼(在商品名下由GlaxoSmithKline销售);曲妥珠单抗emtansine (在美国,ado-trastuzumab emtansine,商品名Kadcyla)–由与细胞毒性剂 mertansine(DM1)连接的单克隆抗体曲妥珠单抗(Herceptin)构成的抗体-药物缀合物;
CD20抗体:利妥昔单抗(由Genentech/Roche以商标和销售)、托西莫单抗(由GlaxoSmithKline以商标销售)、奥法木单抗(由GlaxoSmithKline以商标销售);
酪氨酸激酶抑制剂:盐酸厄洛替尼(由Genentech/Roche以商标销售)、Linifanib(N-[4-(3-氨基-1H-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲,也称作ABT869,购自Genentech)、苹果酸舒尼替尼(由Pfizer 以商品名销售)、波舒替尼(4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-腈,也称作SKI-606且描述在美国专利US 6,780,996中)、达沙替尼(由Bristol-MyersSquibb以商品名销售)、armala(也称作帕唑帕尼,由GlaxoSmithKline以商品名销售)、伊马替尼和甲磺酸伊马替尼(由Novartis以商品名和销售);
DNA合成抑制剂:卡培他滨(由Roche以商标销售)、盐酸吉西他滨(由EliLilly&Company以商标销售)、奈拉滨 ((2R,3S,4R,5R)-2-(2-氨基-6-甲氧基-嘌呤-9-基)-5-(羟基甲基)氧杂戊环-3,4- 二醇,由GlaxoSmithKline以商品名和销售);
抗肿瘤药:奥沙利铂(由Sanofi-Aventis以商品名销售且描述在美国专利US 4,169,846中);
表皮生长因子受体(EGFR)抑制剂:Gefitnib(以商品名销售)、 N-[4-[(3-氯-4-氟苯基)氨基]-7-[[(3”S”)-四氢-3-呋喃基]氧基]-6-喹唑啉基]-4(二甲基氨基)-2-丁烯酰胺,由Boehringer Ingelheim以商品名销售)、西妥昔单抗(由Bristol-Myers Squibb以商品名销售)、帕木单抗(由Amgen以商品名销售);
HER二聚化抑制剂:培妥珠单抗(由Genentech以商标销售);
人粒细胞集落刺激因子(G-CSF)调节剂:非格司亭(由Amgen以商品名销售);
免疫调制剂:阿托珠单抗(Afutuzumab)(购自)、聚乙二醇化非格司亭(以商品名由Amgen销售)、来那度胺(也称作CC-5013,以商品名销售)、沙立度胺(以商品名销售);
CD40抑制剂:达西珠单抗(也称作SGN-40或huS2C6,购自Seattle Genetics,Inc);
促细胞凋亡受体激动剂(PARAs):度拉纳明(Dulanermin)(也称作 AMG-951,购自Amgen/Genentech);
Hedgehog拮抗剂:2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)- 苯甲酰胺(也称作GDC-0449且描述在PCT公开号WO 06/028958中);
PI3K抑制剂:4-[2-(1H-吲唑-4-基)-6-[[4-(甲基磺酰基)哌嗪-1-基]甲基] 噻吩并[3,2-d]嘧啶-4-基]吗啉(也称作GDC 0941且描述在PCT公开号WO 09/036082和WO 09/055730中)、2-甲基-2-[4-[3-甲基-2-氧代-8-(喹啉-3- 基)-2,3-二氢咪唑并[4,5-c]喹啉-1-基]苯基]丙腈(也称作BEZ 235或 NVP-BEZ 235且描述在PCT公开号WO 06/122806中);
磷脂酶A2抑制剂:阿那格雷(在商品名下销售);
BCL-2抑制剂:4-[4-[[2-(4-氯苯基)-5,5-二甲基-1-环己烯-1-基]甲基]-1- 哌嗪基]-N-[[4-[[(1R)-3-(4-吗啉基)-1-[(苯基硫基)甲基]丙基]氨基]-3-[(三氟甲基)磺酰基]苯基]磺酰基]苯甲酰胺(也称作ABT-263且描述在PCT公开号 WO 09/155386中);
促分裂原活化蛋白激酶激酶(MEK)抑制剂:XL-518(Cas No. 1029872-29-4,购自ACC Corp.);
芳香酶抑制剂:依西美坦(以商标由Pfizer销售)、来曲唑 (以商品名由Novartis销售)、阿那曲唑(以商品名销售);
拓扑异构酶I抑制剂:伊立替康(以商标由Pfizer销售)、盐酸托泊替康(以商品名由GlaxoSmithKline销售);
拓扑异构酶II抑制剂:依托泊苷(也称作VP-16和磷酸依托泊苷,以商品名和销售)、替尼泊苷(也称作 VM-26,以商品名销售);
mTOR抑制剂:坦罗莫司(Temsirolimus)(以商品名由Pfizer销售)、地磷莫司(ridaforolimus)(在先称作deferolimus,(1R,2R,4S)-4-[(2R)-2 [(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-二羟基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五氧代-11,36- 二氧杂-4-氮杂三环[30.3.1.04 ,9]三十六碳-16,24,26,28-四烯-12-基]丙基]-2-甲氧基环己基二甲基亚膦酸酯,也称作AP23573和MK8669且描述在PCT 公开号WO 03/064383中)、依维莫司(以商品名由Novartis销售);
破骨性骨吸收抑制剂:1-羟基-2-咪唑-1-基-膦酰基乙基)膦酸一水合物 (以商品名由Novartis销售);
CD33抗体药物缀合物:吉姆单抗奥佐米星(以商品名由 Pfizer/Wyeth销售);
CD22抗体药物缀合物:伊珠单抗奥佐米星(Inotuzumab ozogamicin) (也称作CMC-544和WAY-207294,购自Hangzhou Sage Chemical Co., Ltd.);
CD20抗体药物缀合物:替伊莫单抗(以商品名销售);
生长抑素类似物:奥曲肽(也称作醋酸奥曲肽,以商品名和Sandostatin销售);
合成白细胞介素-11(IL-11):奥普瑞白介素(以商品名由 Pfizer/Wyeth销售);
合成红细胞生成素:达依泊汀α(以商品名由Amgen销售);
核因子κB受体激活物(RANK)抑制剂:地舒单抗(以商品名由 Amgen销售);
血小板生成素拟肽:Romiplostim(以商品名由Amgen销售);
细胞生长刺激剂:帕利夫明(以商品名由Amgen销售);
抗胰岛素样生长因子-1受体(IGF-1R)抗体:芬妥木单抗(也称作 CP-751,871,购自ACC Corp)、罗妥木单抗(CAS No.934235-44-6);
抗-CS1抗体:依洛珠单抗(HuLuc63,CAS No.915296-00-3);
CD52抗体:阿仑珠单抗(以商品名销售);
CTLA-4抑制剂:曲美木单抗(Tremelimumab)(IgG2单克隆抗体,购自 Pfizer,在先称作ticilimumab,CP-675,206)、ipilimumab(CTLA-4抗体,也称作MDX-010,CASNo.477202-00-9);
PD1抑制剂:公开在例如US 8,008,449中的Nivolumab(在文中也称为 MDX-1106、MDX-1106-04、ONO-4538、BMS0936558、CAS登记号: 946414-94-4),并具有文中公开的序列(或与其基本相同或类似的序列,例如,与US 8,008,449中指定的序列具有至少85%、90%、95%或更大的同一性的序列);公开在例如US 8,354,509和WO 2009/114335中的Pembrolizumab(文中也被称为Lambrolizumab、MK-3475、MK03475、 SCH-900475或KEYTRUDA),并且具有文中公开的序列(或与其基本相同或类似的序列,例如,与US 8,354,509和WO2009/114335中指定的序列具有至少85%、90%、95%或更大的同一性的序列);免疫粘附素(例如,包含融合到恒定区(例如,免疫球蛋白序列的Fc区)的PD-L1或PD-L2的胞外或 PD-1结合部分的免疫粘附素);Pidilizumab(CT-011;Cure Tech)是结合PD1 的人源化IgG1k单克隆抗体(Pidilizumab和其它人源化抗-PD-1单克隆抗体公开于WO2009/101611中);和在WO2010/027827和WO2011/066342)中公开的AMP-224(B7-DCIg;Amplimmune)是阻断PD1和B7-H1之间的相互作用的PD-L2Fc融合可溶性受体;其他PD-1的抑制剂,例如在US8,609,089、US 2010028330和/或US 20120114649中公开的抗-PD1抗体。
PDL1抑制剂:MSB0010718C(也称为A09-246-2;Merck Serono)是与 PD-L1结合的单克隆抗体,并公开在例如WO 2013/0179174中(并具有与其基本上相同或类似的序列,例如,与WO 2013/0179174中指定的序列具有至少85%、90%、95%或更高的同一性的序列);以及选自YW243.55.S70、 MPDL3280A(Genetech/Roche)的抗-PD-L1的结合拮抗剂是与PD-L1结合的人Fc优化的IgG1单克隆抗体(MDPL3280A和PD-L1的其它人单克隆抗体公开在U.S.专利号:7,943,743和U.S公开号:20120039906中);MEDI- 4736、MSB-0010718C或MDX-1105(MDX-1105,也被称为BMS-936559 是在WO2007/005874中描述的抗-PD-L1抗体;抗体YW243.55.S70是在WO 2010/077634中描述的抗-PD-L1);.
LAG-3抑制剂:BMS-986016(也称为BMS986016;Bristol-Myers Squibb) 是与LAG-3结合的单克隆抗体。BMS-986016和其他人源化抗-LAG-3抗体公开在US 2011/0150892、WO2010/019570和WO2014/008218中。
GITR激动剂:示例性GITR激动剂包括例如GITR融合蛋白和抗-GITR 抗体(例如,二价抗-GITR抗体)如在美国专利号:6,111,090、欧洲专利号: 090505B1、US专利号:8,586,023、PCT公开号:WO 2010/003118和 2011/090754中所描述的GITR融合蛋白,或描述于例如在U.S.专利号: 7,025,962、欧洲专利号:1947183B1、U.S.专利号:7,812,135、U.S.专利号:8,388,967、U.S.专利号:8,591,886、欧洲专利号:EP 1866339、PCT公开号: WO 2011/028683、PCT公开号:WO 2013/039954、PCT公开号: WO2005/007190、PCT公开号:WO 2007/133822、PCT公开号: WO2005/055808、PCT公开号:WO 99/40196、PCT公开号:WO 2001/03720、PCT公开号:WO99/20758、PCT公开号:WO2006/083289、 PCT公开号:WO 2005/115451、U.S.专利号:7,618,632和PCT公开号: WO 2011/051726中的抗-GITR抗体。
组蛋白脱乙酰基酶抑制剂(HDI):Voninostat(以商品名由 Merck销售);
抗-CTLA4抗体包括Tremelimumab(可从Pfizer获得的IgG2单克隆抗体,原名ticilimumab,CP-675,206);以及Ipilimumab(CTLA-4抗体,也被称为MDX-010,CAS号477202-00-9)。
抗-TIM-3抗体或其抗原结合片段。
烷化剂:替莫唑胺(以商品名和由 Schering-Plough/Merck销售)、更生霉素(也称作放线菌素-D且以商品名销售)、美法仑(也称作L-PAM、L-沙可来新和苯丙氨酸氮芥,以商品名销售)、六甲蜜胺(也称作六甲基蜜胺(HMM),以商品名销售)、卡莫司汀(以商品名销售)、苯达莫司汀(以商品名销售)、白消安(以商品名和销售)、卡铂(以商品名销售)、洛莫司汀(也称作CCNU,以商品名销售)、顺铂(也称作CDDP,以商品名和销售)、苯丁酸氮芥(以商品名销售)、环磷酰胺(以商品名和销售)、达卡巴嗪(也称作DTIC、DIC和咪唑羧酰胺,以商品名销售)、六甲蜜胺(也称作六甲基蜜胺(HMM),以商品名销售)、异环磷酰胺(以商品名销售)、丙卡巴肼(以商品名销售)、氮芥(也称作氮芥、mustine和mechloroethamine盐酸盐,以商品名销售)、链脲菌素(以商品名销售)、噻替派(也称作硫代环磷酰胺,TESPA和TSPA,以商品名销售;
生物反应调节剂:卡介苗(以商品名和BCG销售)、地尼白介素2(以商品名销售);
抗肿瘤抗生素:多柔比星(以商品名和销售)、博来霉素(以商品名销售)、柔红霉素(也称作盐酸柔红霉素 (dauorubicinhydrochloride)、道诺霉素和柔红霉素盐酸盐,以商品名销售)、柔红霉素脂质体(柠檬酸柔红霉素脂质体,以商品名销售)、米托蒽醌(也称作DHAD,以商品名销售)、表柔比星(以商品名EllenceTM销售)、伊达比星(以商品名 Idamycin销售)、丝裂霉素C(以商品名销售);
抗微管剂:雌莫司汀(以商品名销售);
组织蛋白酶K抑制剂:奥当卡替(Odanacatib)(也称作MK-0822,N-(1- 氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲基磺酰基)联苯-4-基]乙基}-L-亮氨酰胺,购自Lanzhou Chon Chemicals,ACC Corp.和ChemieTek 且描述在PCT公开号WO 03/075836中);
埃坡霉素B类似物:Ixabepilone(以商品名由Bristol-Myers Squibb销售);
热激蛋白质(HSP)抑制剂:坦螺旋霉素(Tanespimycin,17-烯丙基氨基 -17-去甲氧基格尔德霉素,也称作KOS-953和17-AAG,购自SIGMA且描述在美国专利US 4,261,989中);
TpoR激动剂:艾曲泊帕(Eltrombopag)(以商品名和由GlaxoSmithKline销售);
抗有丝分裂药:多西他赛(以商品名由Sanofi-Aventis销售);
肾上腺类固醇抑制剂:氨鲁米特(以商品名销售);
抗雄激素药:尼鲁米特(以商品名和销售)、比卡鲁胺(以商品名销售)、氟他胺(以商品名FulexinTM销售);
雌激素:氟甲睾酮(以商品名销售);
蛋白酶体抑制剂:硼替佐米(以商品名销售);
CDK1抑制剂:阿伏西地(Alvocidib)(也称作flovopirdol或HMR-1275, 2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4-色烯酮且描述在美国专利US5,621,002中);
促性腺素释放素(GnRH)受体激动剂:亮丙瑞林或醋酸亮丙瑞林(以商品名由Bayer AG、由Sanofi-Aventis和由Abbott Lab销售);
紫杉烷抗肿瘤药:卡巴他赛(Cabazitaxel)(1-羟基-7β,10β-二甲氧基-9-氧代-5β,20-环氧紫杉-11-烯-2α,4,13α-三基-4-乙酸酯-2-苯甲酸酯 -13-[(2R,3S)-3-{[(叔丁氧基)羰基]氨基}-2-羟基-3-苯基丙酸酯]、拉罗他赛 (larotaxel)(苯甲酸(2α,3ξ,4α,5β,7α,10β,13α)-4,10-双(乙酰基氧基)-13-({(2R,3S)-3-[(叔丁氧羰基)氨基]-2-羟基-3-苯基丙酰基}氧基)-1-羟基 -9-氧代-5,20-环氧-7,19-环紫杉-11-烯-2-基酯);
5HT1a受体激动剂:扎利罗登(也称作SR57746,1-[2-(2-萘基)乙基]-4-[3-(三氟甲基)苯基]-1,2,3,6-四氢吡啶且描述在美国专利US 5,266,573 中);
HPC疫苗:由GlaxoSmithKline销售的由Merck销售的
铁螯合剂:Deferasinox(以商品名由Novartis销售);
抗代谢药:Claribine(2-氯脱氧腺苷,以商品名销售)、5-氟尿嘧啶(以商品名销售)、6-硫代鸟嘌呤(以商品名销售)、培美曲塞(以商品名销售)、阿糖胞苷(也称作阿糖胞嘧啶 (Ara-C),以商品名销售)、阿糖胞苷脂质体(也称作Liposomal Ara-C,以商品名DepoCytTM销售)、地西他滨(以商品名销售)、羟基脲(以商品名DroxiaTM和MylocelTM销售)、氟达拉滨(以商品名销售)、氟尿苷(以商品名销售)、克拉屈滨(也称作2-氯脱氧腺苷(2-CdA),以商品名LeustatinTM销售)、甲氨蝶呤(也称作氨甲蝶呤、甲氨蝶呤钠(MTX),以商品名和TrexallTM销售)、喷司他丁(以商品名销售);
二膦酸盐:帕米膦酸(以商品名销售)、唑来膦酸(以商品名销售);
去甲基化剂:5-阿扎胞苷(以商品名销售)、地西他滨(以商品名销售);
植物生物碱:蛋白结合的紫杉醇(以商品名销售)、长春碱 (也称作硫酸长春碱、长春碱和VLB,以商品名和销售)、长春新碱(也称作硫酸长春新碱、LCR和VCR,以商品名和Vincasar销售)、长春瑞滨(以商品名销售)、紫杉醇(以商品名Taxol和OnxalTM销售);
类视黄醇:阿利维A酸(以商品名销售)、维a酸(全反式维甲酸,也称作ATRA,以商品名销售)、异维a酸(13-顺式维生素A 酸,以商品名 和销售)、贝沙罗汀(以商品名销售);
糖皮质激素:氢化可的松(也称作可的松、氢化可的松琥珀酸钠、氢化可的松磷酸酯钠且以商品名磷酸氢化可的松、Hydrocort和销售)、地塞米松 (dexamethazone)((8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羟基 -17-(2-羟基乙酰基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢 -3H-环戊二烯并[a]菲-3-酮)、泼尼松龙(以商品名 和销售)、泼尼松(以商品名Liquid和销售)、甲泼尼龙(也称作6-甲基泼尼松龙、醋酸甲基氢化泼尼松、琥珀酸钠甲基强的松龙,以商品名和销售);
细胞因子:白细胞介素-2(也称作阿地白介素和IL-2,以商品名销售)、白细胞介素-11(也称作oprevelkin,以商品名销售)、α干扰素α(也称作IFN-α,以商品名A和销售);
雌激素受体下调剂:氟维司群(商品名为出售);
抗雌激素:他莫昔芬(商品名为出售);
托瑞米芬(商品名为出售);
选择性雌激素受体调节剂(SERMs):雷洛昔芬(以商品名出售);
促黄体生成激素释放激素(LHRH)激动剂:戈舍瑞林(以商品名销售);
孕酮:甲地孕酮(也称作醋酸甲地孕酮,以商品名销售);
混合细胞毒性剂:三氧化二砷(以商品名销售)、天冬酰胺酶 (也称作L-天冬酰胺酶、欧文氏菌属(Erwinia)L-天冬酰胺酶,以商品名和销售);
式(I)的化合物还可以与如下辅助疗法联用:
止恶心药:NK-1受体拮抗剂:卡索匹坦(Casopitant)(以商品名和由GlaxoSmithKline销售);和
细胞保护剂:氨磷汀(以商品名销售)、甲酰四氢叶酸(也称作亚叶酸钙、噬橙菌因子(citrovorum factor)和亚叶酸)。
免疫检查点抑制剂:在一个实施方案中,本文所公开的组合治疗包括免疫检查点分子的抑制分子的抑制剂。术语“免疫检查点”是指CD4和 CD8T细胞的细胞表面上的一组分子。这些分子可有效地作为“刹车”,以向下调制或抑制抗肿瘤免疫应答。免疫检查点分子包括但不限于程序性死亡-1(PD-1)、细胞毒性T淋巴细胞抗原4(CTLA-4)、B7H1、B7H4、OX-40、CD137、CD40和LAG3,其直接抑制免疫细胞,可以充当在本发明方法中有用的免疫检查点抑制剂的免疫治疗剂包括但不限于PD-L1、PD-L2、 CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4 和/或TGFRβ的抑制剂。抑制分子的抑制可通过在DNA、RNA或蛋白质水平的抑制来进行。在一些实施方案中,抑制性核酸(例如,dsRNA、siRNA 或shRNA)可用于抑制抑制分子的表达。在其他实施方案中,抑制信号的抑制剂是与抑制分子结合的多肽例如可溶性配体、或抗体或其抗原结合片段。
在某些实施方案中,本文描述的抗-PD-1分子与一种或多种在本领域中公知的其它PD-1、PD-L1和/或PD-L2的抑制剂组合施用。该拮抗剂可以是抗体、其抗原结合片段、免疫粘附素、融合蛋白或寡肽。
在某些实施方案中,本文所公开的组合治疗包括共刺激分子或抑制分子的调节剂例如共抑制配体或受体。
在一个实施方案中,共刺激分子的共刺激调节剂例如激动剂选自 OX40、CD2、CD27、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS (CD278)、4-1BB(CD137)、GITR、CD30、CD40、BAFFR、HVEM、 CD7、LIGHT、NKG2C、SLAMF7、NKp80、CD160、B7-H3或CD83配体的激动剂(例如,激动性抗体或其抗原结合片段或可溶性融合体)。
在另一个实施方案中,本文所公开的组合治疗包括共刺激分子,例如,与包括CD28、CD27、ICOS和GITR的共刺激结构域的正信号相关的激动剂。
在一个实施方案中,在有或无BRAF抑制剂(如,vemurafenib或dabrafenib)的情况下用抗-CTLA4抗体(例如,Ipilimumab)治疗后,例如治疗黑色素瘤后,施用抗-PD-1抗体分子。可以使用的例示性剂量包括约1 至10mg/kg例如3mg/kg的抗-PD-1抗体分子的剂量和约3mg/kg的抗 -CTLA-4抗体例如Ipilimumab的剂量。
在另一个实施方案中,抗-PD-1或PD-L1抗体分子与抗-LAG-3抗体或其抗原结合片段组合施用。在另一实施方案中,抗-PD-1或PD-L1抗体分子与抗-TIM-3抗体或其抗原结合片段组合施用。在另外一实施方案中,抗 -PD-1或PD-L1抗体分子与抗-LAG-3抗体和抗-TIM-3抗体或其抗原结合片段组合施用。本文中列举的抗体的组合可以分别地施用,例如作为分开的抗体,或连接施用,例如作为双特异性或三特异性抗体分子。在一个实施方案中,施用包含抗-PD-1或PD-L1抗体分子和抗-TIM-3或抗-LAG-3 抗体或其抗原结合片段的双特异性抗体。在某些实施方案中,本文列举的抗体的组合被用于治疗癌症例如本文描述的癌症(例如,实体瘤)。前述组合的效力可以在本领域中已知的动物模型中进行测试。例如,测试抗-PD-1 和抗-LAG-3的协同作用的动物模型描述在例如Woo等人(2012)Cancer Res. 72(4):917-27)中。
在一些实施方案中,本文所公开的组合治疗(例如,抗-PD-1或PD-L1 抗体分子,单独或与另外的免疫调节剂(例如,抗-LAG-3或抗-TIM-3抗体分子)组合。在一个实施方案中,抗-PD-1或PD-L1抗体分子与抗-LAG-3 抗体或其抗原结合片段组合施用。在另一个实施方案中,抗-PD-1或PD-L1 抗体分子与抗-TIM-3抗体或其抗原结合片段组合施用。在另一实施方案中,抗-PD-1或PD-L1抗体分子与抗-LAG-3抗体和抗-TIM-3抗体或其抗原结合片段组合施用。本文中列举的抗体的组合可以分别施用,例如作为分开的抗体,或相连施用,例如作为双特异性或三特异性抗体分子。在一个实施方案中,施用包括抗-PD-1或PD-L1抗体分子和抗-TIM-3或抗-LAG-3 抗体或其抗原结合片段的双特异性抗体。在某些实施方案中,本文列举的抗体的组合被用于治疗癌症例如本文描述的癌症(例如,实体瘤)。前述组合的效力可以在本领域中已知的动物模型中进行测试。例如,测试抗-PD-1 和抗-LAG-3的协同作用的动物模型描述在例如Woo等人(2012)Cancer Res. 72(4):917-27).24中
在某些实施方案中,所述抗体分子是双特异性或多特异性抗体分子形式的。在一个实施方案中,双特异性抗体分子具有与PD-1或PD-L1的第一结合特异性和第二结合特异性(例如与TIM-3、LAG-3或PD-L2的第二结合特异性)。在一个实施方案中,双特异性抗体分子与PD-1或PD-L1和 TIM-3结合。在另一个实施方案中,双特异性抗体分子与PD-1或PD-L1和LAG-3结合。在另一个实施方案中,双特异性抗体分子与PD-1或PD-L1 结合。在又一个实施方案中,双特异性抗体分子与PD-1和PD-L2结合。在另一个实施方案中,双特异性抗体分子与TIM-3和LAG-3结合。前述分子的任何组合可以制备在一个多特异性抗体分子中,例如,包括与PD-1 或PD-1的第一结合特异性,和与TIM-3、LAG-3或PD-L2中的两种或更多种的第二和第三结合特异性的三特异性抗体。
本公开文本内引证的参考文献中的任何一个都不应理解为承认所引述的参考文献是可能对本发明的专利性产生负面影响的现有技术。
制备本发明化合物的方法
本发明还包括用于制备本发明化合物的方法。在所述的反应中,当终产物中需要时,可能有必要保护反应官能团,例如羟基、氨基、亚氨基、硫代基团或羧基,以避免其参与不需要的反应。可根据标准实践使用常用保护基,例如参见T.W.Greene和P.G.M.Wuts“Protective Groups in Organic Chemistry”,John Wiley和Sons,1991。
可以通过如下反应流程I中的方法制备式I化合物:
反应流程I:
其中p、q、Y1、Y2、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R7和 R8如在发明内容中对式I所定义,Q是卤素(如溴)或硫醇、与化合物5上的卤素反应的硼酸酯/盐或锡酸酯/盐,且X是与Q反应的反应性基团(例如硼酸酯/盐、锡烷、醇、硫醇、卤素等)。化合物4可以通过在环境温度下或在加热或微波条件下、在存在或不存在过渡金属的情况下在适当的酸或碱条件下使化合物2与化合物3反应来制备。或者,化合物2的卤素可以被其它卤素或适当的活化基团例如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯、全氟丁基磺酸酯(nonaflates)、硼酸酯/盐、有机锡烷、有机硅烷基、有机锌、锂、镁等替换。
取决于X,式I化合物可以通过使化合物4与适当的偶联搭档(例如化合物5)反应来制备。例如,在反应流程I中显示的化合物5为通过X连接的取代的苯基基团。或者,化合物5可以是芳基-醇、芳基-硫、芳基-硼酸酯/盐、芳基-锡酸酯/盐、杂芳基-醇、芳基-硫醇、杂芳基-硫醇、芳基-硼酸酯/盐、芳基-锡烷、烯烃或其它芳基-金属或杂芳基-金属等。所述的偶联搭档还可以被取代。该反应可以在环境温度或加热或微波条件下、在存在或不存在过渡金属例如钯的条件下、在适当的酸或碱条件下进行。对于这些转化,其它卤素或适当的活性基团(例如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯和全氟丁基磺酸酯)可以用于替换Br。
或者,偶联搭档可以被反转,化合物2可以被衍生为锡烷、硼酸酯/盐、有机-锌、有机-锂、有机-镁、有机-硅、有机-铜酸酯/盐,并与适当的芳基- 卤、杂芳基-卤、烯烃或适当的反应性官能团(例如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯和全氟丁基磺酸酯)等偶联。
这些反应可以以所述的顺序或相反的顺序、在各种溶剂、温度、压力条件下和在适当的气氛中进行。反应可以在酸、碱和或过渡金属条件下进行。
合成式I化合物的详细实例可见于下面的实施例。
制备本发明化合物的其它方法
可以通过使本发明化合物的游离碱形式与药学上可接受的无机酸或有机酸反应将本发明的化合物制备成药学上可接受的酸加成盐。或者,可以通过使本发明化合物的游离酸形式与药学上可接受的无机碱或有机碱反应制备本发明化合物的药学上可接受的碱加成盐。
还可以通过附加官能团以增强选择性生物特性来修饰式I化合物。这种类型的修饰是本领域公知的且包括增加透入指定生物系统(例如血液、淋巴系统、中枢神经系统、睾丸)、增加生物利用度、增加允许胃肠外施用(例如注射、输注)的溶解度、改变代谢和/或改变分泌速率的那些。这种类型的修饰的实例包括但不限于酯化,例如使用聚乙二醇;使用新戊酰氧基或脂肪酸取代基衍生化;转化成氨基甲酸酯类;芳族环的羟基化;和芳族环上的杂原子取代。无论何时提及式I化合物和/或其N-氧化物、互变异构体和 /或(优选药学上可接受的)盐,它均包含此类修饰通式,而优选是指式I的分子、其N-氧化物、其互变异构体和/或其盐。
或者,可以使用原料或中间体的盐制备本发明化合物的盐形式。鉴于游离形式的式I新化合物与其盐形式、包括例如在新化合物纯化或鉴定过程中可以用作中间体的那些盐之间的紧密相关性,所以上文和下文任意提及的式I化合物应理解为酌情是指游离形式的化合物和/或还可以指其一种或多种盐,以及一种或多种溶剂合物,例如水合物。
例如,盐优选使用有机酸或无机酸由式I化合物与碱性氮原子形成为酸加成盐,尤其是药学上可接受的盐。适合的无机酸是例如氢卤酸如盐酸、硫酸或磷酸。适合的有机酸是例如羧酸、膦酸、磺酸或氨基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、乙醇酸、乳酸、富马酸、琥珀酸、丙二酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸如谷氨酸或天冬氨酸、马来酸、羟基马来酸、甲基马来酸、环己烷羧酸、金刚烷羧酸、苯甲酸、水杨酸、4-氨基水杨酸、苯二甲酸、苯乙酸、扁桃酸、肉桂酸、甲磺酸或乙磺酸、2-羟基乙磺酸、乙-1,2-二磺酸、苯磺酸、4-甲苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-或3-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨基磺酸、N-甲基-,N-乙基-或N-丙基-氨基磺酸或其它有机质子酸,例如抗坏血酸。
为了分离或纯化目的,还可使用药学上不可接受的盐,如苦味酸盐或高氯酸盐。为了治疗用途,仅使用药学上可接受的盐或游离化合物(当以药物制剂形式使用是)且由此优选它们。
可以分别由相应的碱加成盐或酸加成盐制备本发明化合物的游离酸或游离碱形式。例如,可以通过用适合的碱(例如氢氧化铵溶液、氢氧化钠等) 处理将酸加成盐形式的本发明化合物转化成相应的游离碱。可以通过用适合的酸(例如盐酸等)处理将碱加成盐形式的本发明化合物转化成相应的游离酸。
可以通过用还原剂(例如硫、二氧化硫、三苯膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化膦等)在适合的惰性有机溶剂(例如乙腈、乙醇、含水二氧六环等)在0-80℃处理,由本发明化合物的N-氧化物制备未氧化形式的本发明化合物。
可以通过本领域技术人员公知的方法制备本发明化合物的前药衍生物 (例如进一步的详细描述参见Saulnier等人(1994),Bioorganic and Medicinal ChemistryLetters,第4卷,p.1985)。例如,适当的前药可以通过使非衍生化的本发明的化合物与适当的氨基甲酰化剂(例如1,1-酰基氧基烷基羰基氯 (carbanochloridate),对-硝基苯基碳酸酯等)反应来制备。
可以通过本领域技术人员公知的方式制备本发明化合物的被保护的衍生物。适用于生成保护基及其除去的技术的详细描述可以在T.W.Greene, “Protecting Groups inOrganic Chemistry”,第3版,John Wiley和Sons, Inc.,1999中找到。
可以便利地将本发明化合物制备成溶剂合物(例如水合物)或在本发明方法过程中形成溶剂合物(例如水合物)。本发明化合物的水合物可以便利地通过使用有机溶剂如二噁英、四氢呋喃或甲醇从水/有机溶剂混合物中重结晶制备。
可以通过使化合物的外消旋混合物与旋光拆分试剂反应形成一对非对映体化合物、分离非对映体且回收光学纯对映体,将本发明的化合物制备成其单独的立体异构体。尽管可以使用本发明化合物的共价非对映体衍生物拆分对映体,但是优选可离解的复合物(例如结晶非对映体盐)。非对映体具有不同的物理特性(例如熔点、沸点、溶解度、反应性等)且易于通过利用这些不同性分离。可以通过色谱法或优选通过基于溶解度差异的分离/拆分技术分离这些非对映体。然后可以通过不会导致外消旋化的任意实施方式回收光学纯对映体与拆分试剂。适用于将化合物立体异构体从其外消旋混合物中拆分的技术的更详细描述可以在Jean Jacques,Andre Collet, Samuel H.Wilen,“Enantiomers,Racematesand Resolutions”,John Wiley and Sons,Inc.,1981中找到。
概括地,可以通过一种方法制备式I化合物,该方法包括:
(a)反应流程I的方法;和
(b)任选地将本发明的化合物转化成药学上可接受的盐;
(c)任选地将本发明化合物的盐形式转化成非盐形式;
(d)任选地将本发明化合物的未氧化形式转化成药学上可接受的N- 氧化物;
(e)任选地将本发明化合物的N-氧化物形式转化成其未氧化形式;
(f)任选地将本发明化合物的单独异构体从异构体混合物中拆分;
(g)任选地将非衍生的本发明的化合物转化成药学上可接受的前药衍生物;和
(h)任选地将本发明化合物的前药衍生物转化成其非衍生形式。
就原料的生产而言没有特别描述,所述化合物是已知的或可以按照与本领域公知方法类似的方法或如下文实施例中公开的那样制备。
本领域技术人员可以理解,上述转化仅是制备本发明化合物的方法的代表,且可以类似地使用其它众所周知的方法。
实施例
如下实施例和中间体用于举例说明本发明,但不限定其范围。实施例中所用的一些缩写如下:乙酸(AcOH);三乙胺(TEA);四氢呋喃(THF);含水的(aq.);大气压(atm.);2,2'-双-二苯基膦烷基-[1,1']联萘(BINAP);4-二甲基氨基吡啶(DMAP);叔丁氧基羰基(Boc);1,1-羰基二咪唑(CDI);二碳酸二叔丁酯(BOC2O);苯并三唑-1-基-氧基-三-(二甲基氨基)-六氟磷酸盐 (BOP);二氯甲烷(DCM);乙醚(Et2O);p-甲苯磺酸(PTSA);乙酸乙酯(EtOAc);乙醇(EtOH);双(三甲基硅烷基)氨基锂(LHMDS);偶氮二甲酸二异丙酯 (DIAD);N,N-二异丙基-乙胺(DIEA或DIPEA);N,N-二甲基甲酰胺(DMF);二甲基亚砜(DMSO);二苯基磷酰基叠氮化物(DPPA);小时(h);2-(1H-7- 氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HATU);高效液相色谱法(HPLC);氢化铝锂(LAH);与质谱法偶联的液相色谱(LCMS);二异丙基氨基锂(LDA);甲醇(MeOH);毫升(mL);分钟(min);微波(MW);正丁基锂(n-BuLi);1,1-双(二苯基膦基)-二茂铁二氯化钯(II)(PdCl2(dppf));三 (二亚苄基丙酮)二钯(0)(Pd2(dba)3);二氯双(三苯基膦)钯(II) (PdCl2(PPh3)2);室温(RT);三氟乙酸(TFA);四氢呋喃(THF);薄层色谱法 (TLC);保留时间(tR);&4,5-双(二苯基膦基)-9,9-二甲基呫吨(Xantophos)。
中间体1
6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺
步骤a:向3-溴-2-(三氟甲基)吡啶(1.0g,4.42mmol)、XantPhos(256mg,0.442mmol)、Pd2(dba)3(203mg,0.221mmol)的二氧六环(12mL)溶液中加入 (在RT和在N2下)3-巯基丙酸2-乙基己基酯(1.1mL,4.87mmol),随后加入 DIPEA(1.55mL,8.85mmol)。将得到的溶液在微波反应器中在110℃搅拌1h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(25mL) 洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2-乙基己基酯(1.41g,3.88mmol)。MS m/z 364.0(M+H)+.
步骤b:在-78℃和N2下,向3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2- 乙基己基酯(1.0g,2.75mmol)的THF(8mL)溶液中加入叔丁醇钾(1M在 THF中,8.25mL,8.25mmol)。在-78℃剧烈搅拌20min后,将反应用K2CO3水溶液(2M,500μL)淬灭并在减压下除去挥发物。将得到的残留物倒入含有K2CO3水溶液(2M,30mL)的分离漏斗中,将其用Et2O(2x20mL)萃取。将水相用6M HCl酸化直到pH 4,并将得到的混浊混悬液用CHCl3:IPA (9:1;3x20mL)萃取,得到2-(三氟甲基)吡啶-3-硫醇(380mg,2.12mmol)。 MS m/z 180.0(M+H)+.
步骤c:向2-(三氟甲基)吡啶-3-硫醇(285mg,1.591mmol)、3-溴-6-氯吡嗪-2-胺(414mg,1.988mmol)、XantPhos(101mg,0.175mmol)和 Pd2(dba)3(72.8mg,0.08mmol)的二氧六环(2mL)溶液中加入(在RT和在N2下)DIPEA(556μL,3.18mmol)。将得到的溶液在微波反应器中在130℃搅拌1.5h。冷却至RT后,将反应物用EtOAc稀释,并将其通过硅藻土过滤,随后用EtOAc(25mL)洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(1.41g,3.88mmol)。1H NMR(400MHz,氯仿-d)δppm 8.64(dd,J=4.55,1.26Hz,1H),7.90(s,1H),7.82(dd,J=8.08, 0.76Hz,1H),7.46(dd,J=8.08,4.80Hz,1H);19F NMR(376MHz,氯仿-d)δppm-64.34(s,1F).MS m/z 307.1(M+H)+.
中间体2
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺
将3-溴-6-氯吡嗪-2-胺(1.2g,5.76mmol)、(2,3-二氯苯基)硼酸(1.1g,5.76mmol)、磷酸钾(3.67g,17.27mmol)和PdCl2(dppf)·DCM加合物(235mg, 0.288mmol)的MeCN:H2O(9:1,15mL,脱气的)混悬液在微波反应器中在 120℃搅拌4h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用 EtOAc(25mL)洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到6-(4-氨基-4-甲基哌啶-1- 基)-3-(2,3-二氯苯基)吡嗪-2-胺(633mg,2.306mmol)。MS m/z 276.4 (M+H)+.
中间体3
6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺
将3-溴-6-氯吡嗪-2-胺(5.0g,23.99mmol)、2,3-二氯苯硫醇(6.44g, 36.0mmol)、碘化亚铜(I)(914mg,4.80mmol)、磷酸钾(10.18g,48.0mmol) 和1,10-菲咯啉(1.73mg,9.59mmol)的二氧六环(50mL,脱气的)混合物在 85℃搅拌16h。冷却至RT后,将反应物用EtOAc稀释,并将其通过硅藻土过滤,随后用EtOAc(50mL)洗涤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至25%梯度的DCM/甲苯),得到6-氯-3-((2,3- 二氯苯基)硫基)吡嗪-2-胺(3.7g,12.07mmol)。MS m/z 306.0(M+H)+.
中间体4
(R)和(S)-2-(7-氮杂螺[3.5]壬-1-基)异吲哚啉-1,3-二酮
步骤a:将1-氨基-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(250mg,1.04 mmol)、邻苯二甲酸酐(193mg,1.3mmol)、活化的分子筛(3埃,250mg)和 DIPEA(545μL,3.12mmol)的甲苯(4mL)混悬液在105℃搅拌16h。冷却至RT后,将混合物通过硅藻土垫层过滤,随后用EtOAc(10mL)洗涤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(5-40%梯度的EtOAc/庚烷),得到1-(1,3-二氧代异吲哚啉-2-基)-7-氮杂螺[3.5]壬烷-7- 甲酸叔丁酯(233mg,0.629mmol)。MS m/z 370.4(M+H)+.
步骤b:将1-(1,3-二氧代异吲哚啉-2-基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(233mg,0.629mmol)和HCl(4M在二氧六环中,800μL,3.21mmol)的二氧六环(5mL)溶液在RT搅拌16h。在旋转蒸发仪上除去挥发物,得到标题化合物的HCl盐(195mg,0.636mmol)。MS m/z 270.3(M+H)+.
步骤c:在下面的条件下进行手性SFC纯化;柱:Cellulose LUX-2 21x250mm,流速:75g/分钟,流动相:50%MeOH和10mM NH4OH在CO2中,检测:220nm UV,获得两个峰Rt(P1)=3.6min(对映体R);Rt(P2)= 7.4min(对映体S).
中间体5
2-(1,1-二氧代-1-硫杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮
步骤a:将8-(叔丁氧基羰基)-1-硫杂-8-氮杂螺[4.5]癸烷-4-甲酸1,1-二氧化物(如Carreira等人,Org Lett.,2011,13,6134-6136所述以4步由4-氧代哌啶-1-甲酸叔丁酯制备;2.00g,6.00mmol)、叠氮磷酸二苯酯(2.0g,7.26 mmol)和Et3N(1.0mL,7.26mmol)的甲苯(37mL)溶液在115℃搅拌1.5h。加入苄醇(1.50mL,14.52mmol),并将得到的混合物在100℃搅拌16h。冷却至RT后,将反应混合物倒入含有NaHCO3饱和水溶液(30mL)的分离漏斗中,将其用EtOAc(3x20mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(10至 90%梯度的EtOAc/庚烷),得到4-(((苄氧基)羰基)氨基)-1-硫杂-8-氮杂螺 [4.5]癸烷-8-甲酸叔丁酯1,1-二氧化物(1.57g.3.58mmol),为白色固体。MS m/z 339.4(M+H)+.
步骤b:将4-(((苄氧基)羰基)氨基)-1-硫杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯1,1-二氧化物(570mg.1.30mmol)和Pd/C(10%在炭上,138mg)的THF (8mL)混悬液在H2气氛下剧烈搅拌16h。将反应物通过硅藻土塞过滤,随后用EtOAc(20mL)洗涤。在减压下除去挥发物,得到4-氨基-1-硫杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯1,1-二氧化物,其没有进一步纯化即用于下一步骤。
步骤c:将4-氨基-1-硫杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯1,1-二氧化物(415mg,1.363mmol)、邻苯二甲酸酐(252mg,1.704mmol)和活化的分子筛(3埃,500mg)的甲苯(7mL)混悬液在115℃剧烈搅拌16h。冷却至RT 后,将混合物通过硅藻土垫层过滤,随后用EtOAc(10mL)洗涤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至10%梯度的 MeOH/DCM),得到4-(1,3-二氧代异吲哚啉-2-基)-1-硫杂-8-氮杂螺[4.5]癸烷 -8-甲酸叔丁酯1,1-二氧化物(385mg,0.886mmol),为白色泡沫状物。MS m/z 433.1(M-H)-.
步骤d:将4-(1,3-二氧代异吲哚啉-2-基)-1-硫杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯1,1-二氧化物(385mg,0.886mmol)和HCl(4M在二氧六环中, 2.22mL,8.86mmol)的二氧六环(4mL)溶液在RT搅拌16h。将混合物用二氧六环(20mL)稀释并过滤,得到2-(1,1-二氧代-1-硫杂-8-氮杂螺[4.5]癸-4- 基)异吲哚啉-1,3-二酮(HCl盐,328mg,0.884mmol),为白色固体。MS m/z 335.4(M+H)+.
中间体6
(R)-2-甲基-N-((S)-7-氮杂螺[3.5]壬-1-基)丙烷-2-亚磺酰胺
步骤a:将1-氧代-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(5.24g,21.9 mmol)、异丙醇(IV)钛(16.2mL,54.7mmol)和(R)-2-甲基丙烷-2-亚磺酰胺 (3.45g,28.5mmol)的THF(99mL)溶液在65℃搅拌12h。冷却至-78℃后,加入MeOH(9.9mL)随后加入硼氢化锂(1.43g,65.7mmol)。将得到的混合物在-78℃搅拌3h,并在RT搅拌1h。将MeOH缓慢加入以淬灭过量的硼氢化物,随后加入盐水。将得到的混合物搅拌15min然后通过硅藻土过滤。将含水的混合物用EtOAc(3x20mL)萃取。将有机相用MgSO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷,得到(S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-7-氮杂螺[3.5]壬烷-7-甲酸叔丁酯(4.79g.13.90mmol),为白色固体。 MSm/z 345.3(M+H)+.
步骤b:将(S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-7-氮杂螺[3.5]壬烷-7- 甲酸叔丁酯(0.4g,1.16mmol)和TFA(450μL,5.81mmol)的DCM(3.5mL) 溶液在40℃搅拌30min。加入Na2CO3饱和水溶液直到pH 11,并将含水的混合物用DCM(3x15mL)萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下除去挥发物,得到(R)-2-甲基-N-((S)-7-氮杂螺[3.5] 壬-1-基)丙烷-2-亚磺酰胺(237mg,0.97mmol),为白色固体。MS m/z 245.5(M+H)+.
中间体7
N-(4-甲氧基苄基)-8-氮杂螺[4.5]癸-1-胺
步骤a:向1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.8g,7.11mmol) 和(4-甲氧基苯基)甲胺(1.07g,7.82mmol)的DCE(7mL)溶液中分份加入氰基硼氢化钠(2.23g,35.5mmol)并在RT搅拌65h。将混合物用饱和的碳酸氢钠水溶液(10mL)稀释,并用EtOAc(3x20mL)萃取。将合并的有机相用盐水洗涤并浓缩。将得到的残留物通过硅胶色谱法纯化(0至2%梯度的 MeOH/DCM,0.25%Et3N改性的,随后是0至50%梯度的EtOAc/庚烷),得到1-((4-甲氧基苄基)氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.1g,2.94 mmol),为无色蜡状物。MS m/z 375.3(M+H)+.
步骤b:将1-((4-甲氧基苄基)氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯 (1.1g,2.94mmol)和TFA(2mL)的DCM(2mL)溶液在0℃搅拌15min。在减压下除去挥发物。将得到的残留物用NaHCO3水溶液(10mL)稀释,并用EtOAc(4x10mL)萃取,得到N-(4-甲氧基苄基)-8-氮杂螺[4.5]癸-1-胺 (0.8g,2.92mmol),为无色油状物.MS m/z 275.2(M+H)+.
按照上面的方法,由7-氧代-3-氮杂螺[5.5]十一烷-3-甲酸叔丁酯起始,获得N-(4-甲氧基苄基)-3-氮杂螺[5.5]十一-7-胺。
中间体8
N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺
步骤a:向1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(1.15g,4.54mmol) 和(R)-1-(4-甲氧基苯基)乙胺(961mg,6.36mmol)的DCE(3mL)溶液中分份加入氰基硼氢化钠,并在RT搅拌16h。将混合物用饱和的碳酸氢钠水溶液(5mL)稀释,并用EtOAc(3x10mL)萃取。将合并的有机相用盐水洗涤并浓缩。将得到的含有9:1的非对映体混合物的残留物通过硅胶色谱法纯化(0至20%梯度的EtOAc/庚烷),得到纯的1-(((R)-1-(4-甲氧基苯基) 乙基)氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(主要的非对映体;431mg, 1.11mmol)。1H NMR(400MHz,DMSO-d6)δppm 7.18-7.24(m,2H), 6.81-6.86(m,2H),3.76(d,J=13.64Hz,1H),3.72(s,3H),3.64-3.70(m,2H), 2.65-2.92(m,2H),2.05-2.14(m,1H),1.80-1.91(m,1H),1.65-1.75(m,1H), 1.42-1.60(m,4H),1.40(s,9H),1.28-1.35(m,1H),1.20(d,J=6.57Hz,3H), 1.09-1.17(m,2H),0.80(d,J=11.37Hz,1H).MS m/z 389.6(M+H)+.
步骤b:向1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(主要的非对映体;431mg,1.11mmol)的DCM(2mL)溶液中加入TFA(2mL),并在RT搅拌10min。将反应物浓缩,再加入DCM,然后用饱和的NaHCO3水溶液稀释,并用DCM(3x20mL)萃取。用盐水洗涤有机物,用Na2SO4干燥,过滤并浓缩,得到N-((R)-1-(4-甲氧基苯基)乙基)-8- 氮杂螺[4.5]癸-1-胺。1H NMR(400MHz,甲醇-d4)δ7.25(d,J=8.6Hz,2H), 6.87(d,J=8.7Hz,2H),3.85-3.78(m,1H),3.78(s,3H),3.35(m,1H),3.28 (m,1H),3.03(m,2H),2.63(dd,J=9.6,7.3Hz,1H),2.06-1.85(m,2H), 1.83-1.69(m,2H),1.62(m,1H),1.54-1.38(m,4H),1.33(d,J=6.6Hz,3H), 1.31-1.23(m,1H).MS m/z 289.5(M+H)+.
中间体9
N-((R)-1-(4-甲氧基苯基)乙基)-1-氧杂-8-氮杂螺[4.5]癸-4-胺
步骤a:向4-氧代-1-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(如Carreira 等人,Org Lett.,2013,15,4766-4769中所述以3步由4-氧代哌啶-1-甲酸叔丁酯制备的;200mg,0.78mmol)和(R)-1-(4-甲氧基苯基)乙胺(474mg,3.13 mmol)的DCE(1mL)溶液中分份加入氰基硼氢化钠(393mg,3.13mmol)。将得到的反应物在RT搅拌16h。加入硼氢化锂(34mg,1.6mmol),并将混合物在RT搅拌30min。将混合物用MeOH(2mL)稀释并在减压下除去挥发物(两次)。加入NaHCO3饱和水溶液(5mL),并将混合物用DCM(3x 20mL)萃取。将合并的有机相用Na2SO4干燥,过滤,并在减压下除去挥发物。将得到的9:1的非对映体混合物通过硅胶色谱法纯化(0至40%梯度的 EtOAc/庚烷),得到非对映体纯的4-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(65mg,0.17mmol).主要的非对映体:1H NMR(400MHz,CDCl3)δppm 7.15(d,J=8.6Hz,2H),6.79(d,J=8.6Hz, 2H),3.96-3.76(m,2H),3.77-3.66(m,5H),3.60(t,J=8.1Hz,1H),2.98(m,2 H),2.76(t,J=7.8Hz,1H),1.95(m,1H),1.67-1.41(m,4H),1.40(s,9H), 1.33(d,J=3.1Hz,1H),1.21(d,J=6.5Hz,3H),1.08-0.92(m,1H).MS m/z 391.6(M+H)+.
步骤b:将4-(((R)-1-(4-甲氧基苯基)乙基)氨基)-1-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(主要的非对映体,65mg,0.17mmol)和TFA(2mL)的 DCM(2mL)溶液在RT搅拌10min。在减压下除去挥发物,用NaHCO3饱和水溶液(5mL)稀释,并用DCM(3x20mL)萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤并在减压下除去挥发物,得到N-((R)-1-(4-甲氧基苯基)乙基)-1-氧杂-8-氮杂螺[4.5]癸-4-胺(40mg,0.13mmol),其没有进一步纯化即使用。MS m/z 291.5(M+H)+.
中间体10
3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺
步骤a:通过Marie等人,Molecules,2012,17,10683-10707中描述的程序a,将商业可获得的2,3-二氯-4-碘吡啶转化为3-氯-4-碘吡啶-2-胺。
步骤b:向3-氨基-5-氯吡嗪-2-硫醇(100mg,0.619mmol)、3-氯-4-碘吡啶-2-胺(315mg,1.238mmol)、XantPhos(35.8mg,0.062mmol)和 Pd2(dba)3(28.3mg,0.03mmol)的二氧六环(3mL)溶液中加入(在RT和在N2下)DIPEA(324μL,1.856mmol)。将得到的溶液在微波反应器中在100℃搅拌2.5h。冷却至RT后,将反应物用EtOAc稀释,并将其通过硅藻土垫过滤,随后用EtOAc(10mL)洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(1.41g,3.88mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.88(s,1H),7.68(d,J=5.56Hz,1H),6.06(d,J=5.56Hz,1H), 1.35-1.43(m,2H).MS m/z 288.2(M+H)+.
中间体11
3-氨基-5-氯吡嗪-2-硫醇
步骤a:将3-溴-6-氯吡嗪-2-胺(4.95g,23.74mmol)的二氧六环(119mL) 溶液鼓入氮气10min。然后加入3-巯基丙酸2-乙基己基酯(3.79mL,24.92 mmol)、Xantphos(1.37g,2.37mmol)、Pd2(dba)3(1.08g,1.19mmol)和DIPEA (8.29mL,47.5mmol)。将得到的混合物在105℃搅拌24h,并将反应混合物通过硅藻土过滤并浓缩。将粗品通过硅胶色谱法纯化(0-40%梯度的 EtOAc/庚烷),得到3-((3-氨基-5-氯吡嗪-2-基)硫基)丙酸2-乙基己基酯(6.24 g,18.04mmol),为黄色油状物。1H NMR(400MHz,氯仿-d)δppm 7.82(s, 1H),4.93(br.s.,2H),4.14-3.96(m,2H),3.47(t,J=6.9Hz,2H),2.78(t, J=6.9Hz,2H),1.67-1.51(m,1H),1.44-1.20(m,8H),0.90(t,J=7.4Hz,6H). MS m/z 346.0(M+H)+.
步骤b:在-78℃向3-((3-氨基-5-氯吡嗪-2-基)硫基)丙酸2-乙基己基酯 (2.3g,6.65mmol)的THF(33mL)溶液中,加入叔丁醇钾(1M在THF中, 19.95mL,19.95mmol),并将得到的混合物在-78℃搅拌1h。加入MeOH (20mL)并将得到的混合物浓缩。将粗品溶解在MeOH中,过滤,并通过 HPLC纯化(梯度洗脱5-20%,乙腈水溶液,0.1%TFA改性剂),得到3-氨基-5-氯吡嗪-2-硫醇(TFA盐:1.3g,4.72mmol),为黄色固体。MS m/z 162.0(M+H)+.
中间体12
6-氯-3-((3-氯吡啶-4-基)硫基)吡嗪-2-胺
向3-氨基-5-氯吡嗪-2-硫醇(TFA盐:0.158g,0.978mmol)的二氧六环 (4.9mL)溶液鼓入氮气10min。然后加入3-氯-4-碘吡啶(0.468g,1.955 mmol)、Xantphos(0.057g,0.098mmol)、Pd2(dba)3(0.045g,0.049mmol)和 DIPEA(0.512mL,2.93mmol)。将得到的混合物在105℃搅拌10h,通过硅藻土过滤并浓缩。将粗品通过硅胶色谱法纯化(0-40%梯度的EtOAc/庚烷;庚烷含有2%的Et3N),得到6-氯-3-((3-氯吡啶-4-基)硫基)吡嗪-2-胺(75mg,0.274mmol),为白色固体。1H NMR(400MHz,氯仿-d)δppm 8.46(s, 1H),8.22(d,J=5.3Hz,1H),7.96(s,1H),6.68(d,J=5.3Hz,1H),5.17(br.s., 2H).MS m/z 273.0(M+H)+.
中间体13
6-氯-3-((2-氯吡啶-3-基)硫基)吡嗪-2-胺
向3-氨基-5-氯吡嗪-2-硫醇(TFA盐:0.2g,1.238mmol)的二氧六环(6.2 mL)溶液鼓入氮气10min。然后加入2-氯-3-碘吡啶(0.593g,2.475 mmol)、Xantphos(0.072g,0.124mmol)、Pd2(dba)3(0.057g,0.062mmol)和 DIPEA(0.65mL,3.71mmol)。将得到的混合物在105℃搅拌10h,通过硅藻土过滤并浓缩。将粗品通过硅胶色谱法纯化(0-40%梯度的EtOAc/庚烷, 含有2%的Et3N),得到6-氯-3-((2-氯吡啶-3-基)硫基)吡嗪-2-胺(95mg,0.348 mmol),为白色固体。1H NMR(400MHz,氯仿-d)δppm 8.28-8.38(m,1H), 7.91(s,1H),7.51-7.59(m,1H),7.22(dd,J=7.9,4.6Hz,1H),5.25(br.s.,2 H).MS m/z 273.0(M+H)+.
中间体14
6-氯-3-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-胺
将3-氨基-5-氯吡嗪-2-硫醇(TFA盐:0.50g,1.814mmol)的二氧六环(90 mL)溶液用氮气脱气10min。然后加入2,3-二氯-4-碘吡啶(0.0.99g,3.63 mmol)、Xantphos(0.105g,0.181mmol)、Pd2(dba)3(0.083g,0.091mmol)和 DIPEA(0.95mL,5.44mmol)。将得到的混合物在105℃搅拌10h,通过硅藻土过滤并浓缩。将粗品通过硅胶色谱法纯化(0-10%梯度的EtOAc/DCM)。1H NMR(400MHz,DMSO-d6)δppm 8.13(d,J=5.3Hz,1H), 7.95(s,1H),7.30(br.s,2H),6.83(d,J=5.3Hz,1H).MS m/z 306.9 (M+H)+.
中间体15
6-氯-3-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-胺
向3-氨基-5-氯吡嗪-2-硫醇(TFA盐:50mg,0.181mmol)的二氧六环 (1.8mL)溶液鼓入氮气10min。然后加入3-氯-2-氟-4-碘吡啶(0.140g,0.544 mmol)、Xantphos(11mg,0.018mmol)、Pd2(dba)3(8mg,0.009mmol)和 DIPEA(95μL,0.544mmol)。将得到的混合物在100℃搅拌10h,通过硅藻土过滤,并浓缩。将粗品通过硅胶色谱法纯化(0至40%梯度的EtOAc/ 庚烷;庚烷含有2%Et3N),得到6-氯-3-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2- 胺(41mg,0.137mmol),为白色固体。1H NMR(400MHz,氯仿-d)δppm 8.06(s,1H),7.91(d,J=5.3Hz,1H),6.63(d,J=5.3Hz,1H),5.30(br.s,2H). MS m/z 291.0(M+H)+.
中间体17
2-(2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮
按照Dirat等人,PCT Int.Appl.,20044078750,2004年9月16日的方法, 由哌啶-1,4-二甲酸1-叔丁酯4-乙酯以4步制备4-羟基-2-氧杂-8-氮杂螺[4.5] 癸烷-8-甲酸叔丁酯。1H NMR(400MHz,氯仿-d)δ4.13(dd,J=10.1,4.6Hz, 1H),4.03(dd,J=4.6,2.0Hz,1H),3.78–3.71(m,2H),3.69(d,J=8.6Hz,1H), 3.67–3.58(m,2H),3.29(m,1H),3.16(m,1H),1.78(m,2H),1.58(m,1H), 1.50(m,2H),1.47(s,9H).MS m/z 258.1(M-H)+,然后如下以2步转化为 2-(2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮。
步骤a:向4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(306mg,1.19mmol)、邻苯二甲酰亚胺(262mg,1.78mmol)和三苯基膦(468mg, 1.78mmol)的THF(10mL)溶液中加入氮杂二甲酸二异丙酯(0.374mL,1.78 mmol)并搅拌16h。浓缩并通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/庚烷),获得外消旋的4-(1,3-二氧代异吲哚啉-2-基)-2-氧杂-8-氮杂螺[4.5] 癸烷-8-甲酸叔丁酯(190mg,0.49mmol)。1H NMR(400MHz,氯仿-d)δ 7.88(dd,J=5.4,3.0Hz,2H),7.77(dd,J=5.5,3.0Hz,2H),4.65(dd,J=8.7,5.6Hz,1H),4.40(dd,J=9.5,5.6Hz,1H),4.26(t,J=9.0Hz,1H),4.08(d,J=8.5 Hz,1H),3.98(d,J=8.5Hz,1H),3.84(m,1H),3.58(m,1H),3.20(m,1H), 2.94(m,1H),1.73(m,2H),1.56(s,9H),1.42–1.36(m,2H).
步骤b:向外消旋的4-(1,3-二氧代异吲哚啉-2-基)-2-氧杂-8-氮杂螺[4.5] 癸烷-8-甲酸叔丁酯(190mg,0.49mmol)的二氯甲烷(3mL)溶液中加入三氟乙酸(1mL)。浓缩,再加入二氯甲烷,然后加入乙腈,获得为TFA盐的2-(2- 氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮(定量的).MS m/z 287.0 (M+H)+.没有进一步鉴定即使用。
中间体18
2-氯-3-巯基苯甲酰胺
步骤a:将2-氯-3-氟苄腈(3.15g,20.25mmol)、2-甲基丙烷-2-硫醇 (2.283mL,20.25mmol)和Cs2CO3(6.598g,20.25mmol)的DMF(100mL) 混合物在22℃搅拌48h。将反应混合物用水(200mL)和EtOAc(300mL) 稀释。将EtOAc层用水(3x300mL)、盐水(3x100mL)洗涤,用Na2SO4干燥,过滤并浓缩。将得到的残留物通过HPLC纯化(梯度洗脱:45至70%乙腈水溶液,5mM NH4OH改性剂),得到3-(叔丁基硫基)-2-氯苄腈(1.33g, 5.89mmol)。MS m/z 226.1(M+H)+.
步骤b:将3-(叔丁基硫基)-2-氯苄腈(217mg,0.961mmol)和NaOH (1N,2.88mL,2.88mmol)的MeOH(11mL)混合物在微波反应器中在90 ℃辐射35min。冷却至RT后,将反应物浓缩,并溶解在MeOH中。将固体滤除,并将滤液浓缩至几乎干燥,并通过HPLC纯化(梯度洗脱:25至 50%乙腈水溶液,5mM NH4OH改性剂),得到3-(叔丁基硫基)-2-氯苯甲酰胺(93.6mg,0.384mmol)。MS m/z 244(M+H)+.
步骤c:将3-(叔丁基硫基)-2-氯苯甲酰胺(190mg,0.779mmol)和浓 HCl(2.36mL,78mmol)的混合物在85℃搅拌45min。冷却至RT后,将反应物浓缩至干,得到粗的2-氯-3-巯基苯甲酰胺(HCl盐:156mg,0.651 mmol)。MS m/z 188(M+H)+.
中间体19
2-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-8-氮杂
螺[4.5]癸-4-基)异吲哚啉-1,3-二酮
采用上面所述的标准方法,将2-(2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮TFA盐与6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(151 mg,0.492mmol)偶联。用DCM稀释并通过硅胶色谱法纯化(0至60%梯度的乙酸乙酯/庚烷),获得2-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪 -2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮(0.140g,0.178 mmol)。MS m/z 557.1(M+H)+.如下进行手性SFC纯化;柱:OJ-H 21x250mm,流速:80g/分钟,流动相:45%MeOH和5mM NH4OH在CO2中,检测:触发的质量,获得单一的对映体峰1(P1),Rt:2.77min.MS m/z 557.1(M+H)+,和峰2(P2),Rt:3.91min.MSm/z 557.2(M+H)+.分别对各对映体进行邻苯二甲酰亚胺脱保护,没有进一步鉴定。
中间体20
3-氯-4-碘-N,N-二甲基吡啶-2-胺
将3-氯-2-氟-4-碘吡啶(0.26g,1.01mmol)和二甲胺(2M在THF中,1.5 ml,3.03mmol)的DMSO(3.4mL)溶液在70℃搅拌2h。冷却至RT后,加入水,并将含水的混合物用EtOAc萃取。将合并的有机相用水、盐水洗涤,用Na2SO4干燥,过滤并在减压下浓缩,得到3-氯-4-碘-N,N-二甲基吡啶-2- 胺(0.26g,0.922mmol),为无色油状物。1H NMR(400MHz,氯仿-d)δppm 7.75(d,J=5.3Hz,1H),7.33(d,J=5.0Hz,1H),3.00(s,6H).MS m/z 282.9 (M+H)+.
中间体21
3-氯-4-碘-2-甲氧基吡啶
将3-氯-2-氟-4-碘吡啶(150mg,0.571mmol)和NaOMe(0.5M在MeOH 中,3.4ml,1.71mmol)的DMSO(1.9mL)溶液在70℃搅拌1h。冷却至RT 后,加入水,并将含水的混合物用EtOAc萃取。将合并的有机相用水、盐水洗涤,用Na2SO4干燥,过滤,并在减压下浓缩,得到3-氯-4-碘-2-甲氧基吡啶(123mg,0.456mmol),为无色油状物。1H NMR(400MHz,DMSO-d6) δppm7.81(d,J=5.3Hz,1H),7.55(d,J=5.3Hz,1H),3.92(s,3H).MS m/z 269.9(M+H)+.
中间体22
6-氯-3-((3-(三氟甲基)吡啶-4-基)硫基)吡嗪-2-胺
将3-氨基-5-氯吡嗪-2-硫醇(750mg,4.09mmol)、4-溴-3-(三氟甲基)吡啶(1.63g,5.31mmol)、Xantphos(236mg,0.409mmol)、Pd2(dba)3(187mg, 0.204mmol)和DIPEA(2.14mL,12.26mmol)的二氧六环(脱气的,50mL) 混合物在100℃搅拌16h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(25mL)洗涤。将合并的滤液在减压下浓缩,并将得到的残留物通过硅胶色谱法纯化(0至40%梯度的EtOAc/DCM),得到6-氯-3-((3-(三氟甲基)吡啶-4-基)硫基)吡嗪-2-胺(722mg,2.35mmol),为浅黄色固体。 MS m/z 307.0(M+H)+.
采用上面的方法或对上面的方法进行修改,利用相应的碘-或溴-吡啶基和硫醇盐来合成下面的化合物。
表1
中间体23
6-氯-3-((3-氯哒嗪-4-基)硫基)吡嗪-2-胺
将3-氨基-5-氯吡嗪-2-硫醇(100mg,0.545mmol)、3,4-二氯哒嗪(81 mg,0.545mmol)和DIPEA(0.142mL,0.817mmol)的MeCN(5.5mL)混合物在50℃搅拌12h。冷却至RT后,通过真空过滤收集沉淀物,得到6-氯 -3-((3-氯哒嗪-4-基)硫基)吡嗪-2-胺(101mg,0.368mmol),为棕色固体。1H NMR(400MHz,DMSO-d6)δppm 8.90(d,J=5.4Hz,1H),7.95(s,1H),7.31 (s,2H),7.15(d,J=5.3Hz,1H).MS m/z 274.1(M+H)+.
中间体24
1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯
步骤a:将4-甲酰基哌啶-1-甲酸叔丁酯(35.0g,164mmol)、叔丁醇锂 (15.77g,197mmol)和烯丙基溴(11.54mL,189mmol)的DMF(328mL)混合物在0℃搅拌1h。将混合物倒入含有饱和NH4Cl水溶液:H2O(1:1,500mL) 的分离漏斗中,将其用Et2O(5x50mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁酯(24g,95mmol),为无色油状物。1H NMR(400MHz,氯仿-d)δppm 9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80(br.s.,2H),2.97(t, J=11.49Hz,2H),2.26(d,J=7.33Hz,2H),1.95(dt,J=13.71,3.13Hz,2H), 1.38-1.58(m,11H).
步骤b:向4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁酯(24g,95mmol)的 THF(300mL)溶液中加入(在-78℃和N2下)乙烯基溴化镁(1M在THF 中,118mL,118mmol)。在1h内,使得到的溶液缓慢升温至RT。将混合物倒入含有饱和NH4Cl水溶液(250mL)的分离漏斗中,将其用EtOAc(4x 50mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物,得到4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁酯(26.7g,95mmol),为无色油状物。1H NMR(400MHz,氯仿-d)δppm 9.52(s,1H),5.56-5.75(m,1 H),5.05-5.18(m,2H),3.80(br.s.,2H),2.97(t,J=11.49Hz,2H),2.26(d, J=7.33Hz,2H),1.96(dt,J=13.83,3.06Hz,2H),1.49-1.60(m,2H), 1.41-1.49(m,9H).没有进一步纯化即将该化合物用于下一步骤中。
步骤c:将4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁酯(26.7g,95 mmol)和戴斯-马丁氧化剂(Dess-Martin periodinane)(44.3g,105mmol)的 DCM(380mL)混合物在RT搅拌1h。将混合物倒入含有NaHCO3:Na2SO3饱和水溶液(1:1,300mL)的分离漏斗中,将其用DCM(4x50mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物,提供白色固体。将固体混悬在庚烷(250mL)并超声5min。将白色混悬液通过硅藻土垫层过滤并在减压下除去挥发物,得到4-烯丙酰基-4-烯丙基哌啶-1-甲酸叔丁酯(26.5g,95mmol),为黄色油状物。1H NMR(400MHz,氯仿-d)δppm 6.81(dd,J=16.93,10.36Hz,1H),6.40(dd,J=16.80,1.89Hz,1H),5.71(dd, J=10.36,2.02Hz,1H),5.46-5.66(m,1H),4.91-5.14(m,2H),3.78(br.s.,2 H),2.96(br.s.,2H),2.25-2.39(m,2H),1.97-2.15(m,2H),1.37-1.57(m,11 H).没有进一步纯化即将该化合物用于下一步骤中。
步骤d:向4-烯丙酰基-4-烯丙基哌啶-1-甲酸叔丁酯(26.5g,95mmol) 的甲苯(脱气的,850mL)溶液中加入Grubbs II催化剂(2.02g,2.38mmol)的甲苯(脱气的,100mL)溶液。将得到的混合物在85℃搅拌45min。在减压下除去溶剂,并将得到的残留物通过硅胶色谱法纯化(0至40%梯度的 EtOAc/庚烷),得到1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯(20.76g,83 mmol),为棕色固体。将该化合物和DDQ(565mg,2.49mmol)的甲苯(540 mL)溶液在RT搅拌15min。将得到的亮红色溶液通过硅藻土垫层过滤。加入炭(200g),并将得到的混悬液在RT搅拌2h。将混合物通过硅藻土垫层过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至 40%梯度的EtOAc/庚烷),得到1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯 (15.6g,62.3mmol),为白色固体。1H NMR(400MHz,氯仿-d)δppm 7.63-7.74(m,1H),6.20(dt,J=5.81,2.15Hz,1H),3.99-4.25(m,2H),2.92(t, J=11.62Hz,2H),2.63(s,2H),1.72-1.86(m,2H),1.49(s,9H),1.29(d, J=12.88Hz,2H).
中间体25
1-(1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
步骤a:向1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯(4.2g,16.71 mmol)和CuI(6.37g,33.4mmol)的Et2O(100mL)混悬液中加入(在0℃和 N2下)MeLi(1.6M在THF中,31.3mL,50.1mmol)。在0℃搅拌90分钟后,将混合物倒入含有饱和NH4Cl水溶液的分离漏斗中,将其用EtOAc(3 x15mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到3-甲基-1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯(4.23g,15.82 mmol),为无色油状物。1H NMR(400MHz,氯仿-d)δppm 3.89-4.00(m,1H), 3.83(d,J=13.39Hz,1H),3.11(ddd,J=13.64,10.36,3.28Hz,1H),2.99(ddd, J=13.58,10.42,3.54Hz,1H),2.47-2.59(m,1H),2.19-2.36(m,2H), 1.74-1.97(m,2H),1.50-1.65(m,2H),1.48(s,9H),1.33-1.44(m,2H),1.17(d,J=6.32Hz,3H).
步骤b:将3-甲基-1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯(502mg,1.878mmol)、乙醇钛(IV)(1.57mL,7.51mmol)和2-甲基丙烷-2-亚磺酰胺 (455mg,3.76mmol)的THF(12.5mL)溶液在65℃搅拌16h。冷却至0℃后,加入MeOH(3mL),随后加入硼氢化锂(123mg,5.63mmol)。将得到的混合物在0℃搅拌1h。缓慢地加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物,随后加入EtOAc(30mL)。将得到的混合物剧烈搅拌15min,然后通过硅藻土垫层过滤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至75%梯度的EtOAc/庚烷),得到1-(1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(463mg,1.243mmol),为白色固体。
中间体26a/b
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-
甲酸苄酯&(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-
甲酸苄酯
步骤a:将3-甲基-1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯(4.23g,15.82mmol)和TFA(17mL)的DCM(80mL)混合物在RT搅拌30min。在减压下除去挥发物。将得到的残留物、DIPEA(13.82mL,79mmol)和氯甲酸苄酯(3.39mL,23.73mmol)的DCM(80mL)混合物在RT搅拌16h。将混合物倒入含有饱和NH4Cl水溶液的分离漏斗中,将其用DCM(3x25mL) 萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到3- 甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(4.58g,15.20mmol),为浅黄色油状物。MS m/z 302.2(M+H)+.
步骤b:将3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(4.58g,15.20 mmol)通过如下的手性SFC进一步纯化:柱:IA 21x250mm,流速:70g/分钟,流动相:45%(9:1EtOH:MeCN)在CO2中,检测:220nm UV,得到(R)-3- 甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(2.02g,6.70mmol),Rt:2.0 min;和(S)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(2.11g,7.0 mmol),Rt:3.6min.
步骤c:将(R)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(2.02g,6.70mmol)、乙醇钛(IV)(5.62mL,26.8mmol)和(R)-2-甲基丙烷-2-亚磺酰胺 (1.625g,13.4mmol)的THF(67mL)溶液在65℃搅拌16h。冷却至-78℃后,加入MeOH(12mL),随后加入硼氢化锂(0.438g,20.11mmol)。将得到的混合物在-78℃至RT搅拌16h。缓慢地加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物,随后加入EtOAc(100mL)。将得到的混合物剧烈搅拌15min,然后通过硅藻土垫层过滤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(5至90%梯度的EtOAc/庚烷),得到(1R,3R)- 1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄酯 (1.94g,4.77mmol),为白色固体。MS m/z407.3(M+H)+.
步骤c(来自对映体):按照相同的方法,由(S)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯开始,得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄酯。
中间体27
(1R,3R)-3-((叔丁基二甲基硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨
基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯)
步骤a:将CuCl(142mg,1.432mmol)、(S)-TolBINAP(972mg,1.432 mmol)和叔丁醇钠(138mg,1.432mmol)的THF(60mL)混合物在RT搅拌 30min。加入B2pin2(13.34g,52.5mmol)的THF(20mL)溶液,并将得到的混合物在RT搅拌10min。加入1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁酯 (12.0g,47.7mmol)的THF(50mL)溶液,随后加入MeOH(3.9mL,95 mmol)。将得到的混合物在RT搅拌16h。加入H2O(150mL),随后加入过硼酸钠(36.7g,239mmol),并将得到的混合物在RT剧烈搅拌1h。将得到的绿色混悬液通过硅藻土垫层过滤,倒入含有NaHCO3饱和水溶液:Na2SO3饱和水溶液(1:1,300mL)的分离漏斗,并用EtOAc(4x40mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物,得到(R)-3-羟基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯粗品。该混合物的对映体测定显示90%ee(Rt(S):1.59min,Rt(R):1.80min;手性SFC;柱:IA 4.6x100mm, 流速:70g/分钟,流动相:5-55%MeOH在CO2中,检测:220nm UV).
将(R)-3-羟基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯粗品(theor47.7mmol)、咪唑(4.87g,71.6mmol)和TBSCl(8.99g,59.6mmol)的DMF (120mL)混合物在RT搅拌16h。将反应混合物倒入含有饱和NH4Cl水溶液:H2O(1:1,250mL)的分离漏斗中,将其用Et2O(5x50mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到(R)-3-((叔丁基二甲基硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(13.115g,34.2 mmol),为一旦静置固化的无色油状物。
步骤b:将(R)-3-((叔丁基二甲基硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(8g,20.86mmol)、乙醇钛(IV)(17.49mL,83.0mmol)和 (R)-2-甲基丙烷-2-亚磺酰胺(5.06g,41.7mmol)的THF(100mL)溶液在 65℃搅拌16h。冷却至-78℃后,加入MeOH(15mL),随后加入硼氢化锂(1.363g,62.6mmol)。将得到的混合物在-78℃搅拌16h。缓慢加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物,随后加入EtOAc(100mL)。将得到的混合物剧烈搅拌15min,然后通过硅藻土垫层过滤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/ 庚烷),得到(1R,3R)-3-((叔丁基二甲基硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(5.3g,10.84mmol),为白色固体。MS m/z 489.3(M+H)+.
中间体28
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷 b8-甲酸叔丁酯)
步骤a:将(1R,3R)-3-((叔丁基二甲基硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(3.84g,7.86mmol)和 TBAF(1M在THF中;8.64mL,8.64mmol)的THF(40mL)混合物在RT搅拌30min。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化 (0至10%梯度的MeOH/DCM),得到(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(2.94g,7.86mmol)。 MSm/z 375.3(M+H)+.
步骤b:向(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(3.0g,8.01mmol)、三苯基膦(4.2g,16.02 mmol)和异喹啉-1-甲酸(4.16g,24.03mmol)的THF(80mL)溶液中加入 DIAD(3.1mL,16.02mmol)。将得到的混合物在RT搅拌1h。将反应物用 EtOAc(50mL)稀释,通过硅藻土垫层过滤,倒入含有NaHCO3饱和水溶液的分离漏斗,并用EtOAc(3x25mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至4%梯度的MeOH/DCM),得到异喹啉-1-甲酸(2S,4R)-8-(叔丁氧基羰基)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸-2-基酯(3.65g, 6.89mmol),为橙色固体。MS m/z 530.3(M+H)+.
步骤c:将异喹啉-1-甲酸(2S,4R)-8-(叔丁氧基羰基)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸-2-基酯(3.65g,6.89mmol)和氢氧化锂 (2.95g,68.9mmol)的THF:H2O(1:1,70mL)混合物在RT搅拌2h。将混合物倒入含有饱和NH4Cl水溶液的分离漏斗中,将其用EtOAc(3x15mL) 萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到 (1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(2.35g,6.27mmol),为白色固体.MS m/z 275.2(M+H-Boc)+.
中间体29
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-(异丁酰氧基)-8-氮杂螺[4.5]
癸烷-8-甲酸叔丁酯)
向(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(200mg,0.534mmol)、三苯基膦(280mg,1.068mmol) 和异丁酸(146μL,1.602mmol)的THF(5mL)溶液中加入DIAD(208μL, 1.068mmol)。将得到的混合物在RT搅拌16h。将反应物用EtOAc(50mL) 稀释,通过硅藻土垫层过滤,倒入含有饱和NaHCO3水溶液的分离漏斗,并用EtOAc(3x10mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至7%梯度的 MeOH/DCM),得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-(异丁酰氧基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯)(237mg,0.534mmol)。MS m/z 345.3(M+H-Boc)+.
中间体30a/b/c
(1R,3R)-1-((R)-N,2-二甲基丙-2-基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-
8-甲酸叔丁酯、(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]
癸烷-8-甲酸叔丁酯&(1R,3R)-1-((R)-N,2-二甲基丙-2-基亚磺酰氨基)-3-甲氧基-8-氮杂
螺[4.5]癸烷-8-甲酸叔丁酯
将(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(142mg,0.378mmol)和NaH(60%分散体在矿物油中,19 mg,0.473mmol)的THF混合物在0℃搅拌20min。加入碘甲烷(47μL,0.756 mmol),并将得到的混合物在RT搅拌4h。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5mMNH4OH改性剂),得到(1R,3R)-1-((R)-N,2-二甲基丙-2-基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(15.0mg,0.039mmol)。MS m/z 289.2 (M+H-Boc)+;(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯。MS m/z289.2(M+H-Boc)+;和(1R,3R)- 1-((R)-N,2-二甲基丙-2-基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯。MS m/z 303.2(M+H-Boc)+.
中间体31
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯
将(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(500mg,1.335mmol)、氧化银(I)(340mg,1.468mmol)和碘甲烷(250μL,4.0mmol)的DCM(5mL)混合物在RT搅拌(避光保护)24h,在45℃搅拌24h。冷却至RT后,将混合物通过硅藻土垫层过滤,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至5%梯度的 MeOH/DCM),得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8- 氮杂螺[4.5]癸烷-8-甲酸叔丁酯(248mg,0.638mmol)。MS m/z 289.2 (M+H-Boc)+.
中间体32
外消旋的1-((叔丁氧基羰基)氨基)-3,3-二氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁
酯
步骤a:将3-((叔丁基二甲基硅烷基)氧基)-1-(1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(365mg,0.746mmol)和HCl(4M在二氧六环中,1.86mL,7.46mmol)的MeOH(4mL)混合物在40℃搅拌1h。冷却至RT后,在减压下除去挥发物,得到白色固体。MS m/z 171.1(M+H)+. 将该残留物、DIPEA(2.6mL,14.92mmol)和Boc2O(407mg,1.865mmol)的 THF(15mL)混合物在RT搅拌16h。将混合物倒入含有饱和NH4Cl水溶液的分离漏斗中,将其用Et2O(5x10mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化 (10至80%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3-羟基-8- 氮杂螺[4.5]癸烷-8-甲酸叔丁酯(275mg,0.742mmol)。MS m/z271.3 (M+H-Boc)+.
步骤b:将1-((叔丁氧基羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(275mg,0.742mmol)和戴斯-马丁氧化剂(472mg,1.113mmol)的 DCM(7.5mL)混合物在0℃搅拌2h。将混合物倒入含有饱和NaHCO3水溶液的分离漏斗中,将其用DCM(3x10mL)萃取。将合并的有机相用 MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(5至75%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(135mg,0.366mmol)。1H NMR(400 MHz,氯仿-d)δppm 4.57(d,J=9.09Hz,1H),4.16(d,J=8.08Hz,1H), 3.89-4.08(m,2H),2.77-2.93(m,2H),2.71(dd,J=18.95,8.08Hz,1H),2.50 (d,J=18.19Hz,1H),2.07-2.24(m,2H),1.76(td,J=12.82,4.67Hz,1H), 1.58-1.70(m,1H),1.42-1.53(m,18H),1.25-1.38(m,1H).
步骤c:将1-((叔丁氧基羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(95mg,0.258mmol)和DeoxoFluor(190μL,1.031mmol)的DCM(1 mL)混合物在50℃搅拌48h。将混合物倒入含有饱和NaHCO3水溶液/冰的分离漏斗中,将其用EtOAc(3x5mL)萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3,3-二氟-8- 氮杂螺[4.5]癸烷-8-甲酸叔丁酯(52mg,0.133mmol)。1H NMR(400MHz, 氯仿-d)δppm 4.55(d,J=9.35Hz,1H),3.78-4.02(m,3H),2.64-2.86(m,2H), 2.38-2.59(m,1H),2.10-2.32(m,1H),1.79-2.10(m,2H),1.58(qd,J=12.72, 3.79Hz,1H),1.27-1.52(m,21H).
采用上面的方法或对上面的方法进行修改,利用手性纯的(1R,3R)- 3-((叔丁基二甲基硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯作为起始原料,来合成下面的化合物。
表2
中间体33
1-氨基-2,8-二氮杂螺[4.5]癸-1-烯-3-酮
步骤a:将二异丙胺(0.320mL,2.245mmol)的THF(4mL)溶液冷却至 -78℃,并用正丁基锂(1.3mL,2.080mmol)处理,然后在-78℃搅拌5min,并升温至0℃,得到待随后使用的LDA溶液。向-78℃的4-氰基哌啶-1- 甲酸叔丁酯(153mg,0.728mmol)的THF(10mL)溶液滴加加入制备的 LDA(2.8mL)溶液,并将得到的混合物在-78℃搅拌10min,然后在-10℃搅拌10min。将反应再冷却至-78℃,并滴加加入烯丙基-Br(80μL,0.924 mmol)的THF(2mL)溶液。将得到的反应物混合物在RT搅拌1h,并在减压下除去挥发物。将水层用EtOAc萃取,将合并的有机相用水、盐水洗涤,用Na2SO4干燥,过滤并在减压下浓缩。将残留物通过硅胶色谱法纯化(0 至50%梯度的EtOAc/庚烷),得到4-烯丙基-4-氰基哌啶-1-甲酸叔丁酯(40 mg,0.16mmol),为无色油状物。1H NMR(400MHz,DMSO-d6)δppm 5.99-5.70(m,1H),5.23(q,J=1.1Hz,1H),5.20(dtd,J=3.3,2.1,1.1Hz,1H), 3.96(d,J=13.7Hz,2H),2.86(s,2H),2.36(dt,J=7.5,1.3Hz,2H),1.84(dq, J=13.7,2.6Hz,2H),1.40(s,11H).
步骤b:在-78℃将4-烯丙基-4-氰基哌啶-1-甲酸叔丁酯(22mg,0.088 mmol)的DCM(1.5mL)溶液和NaOH(2.5M在MeOH中,0.176mL,0.439 mmol)用臭氧充气(扩散充气器)30分钟。将反应用氧气清洗,然后在水和 DCM间分配。分离各相,收集有机相并用DCM(2x5mL)萃取水相。将合并的有机相在减压下浓缩。将得到的残留物溶取在MeOH中,并在65℃搅拌24h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至70%梯度的EtOAc/庚烷),得到4-氰基-4-(2-甲氧基-2- 氧代乙基)哌啶-1-甲酸叔丁酯(21mg,0.074mmol),为无色油状物。1H NMR(400MHz,氯仿-d)δppm 4.14(s,2H),3.75(s,3H),3.08(t,J=12.9Hz, 2H),2.62(s,2H),2.15-2.02(m,2H),1.59-1.48(m,2H),1.46(s,9H).TLC(50%EtOAc/庚烷(w/KMnO4染色),Rf=0.5).
步骤c:在密封管中将4-氰基-4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(287mg,1.017mmol)和NH3(7N在MeOH中,3.0mL,21.00mmol)的 MeOH(5mL)溶液在120℃搅拌48h。冷却至RT后,在减压下除去挥发物,得到白色固体。将该固体与EtOAc研磨并过滤,得到1-氨基-3-氧代-2,8- 二氮杂螺[4.5]癸-1-烯-8-甲酸叔丁酯(157mg,0.587mmol),为白色固体。1H NMR(400MHz,DMSO-d6)δppm 8.44(s,1H),8.02(s,1H),3.98(d,J=13.3 Hz,2H),2.71(s,2H),2.34(s,2H),1.81(td,J=12.9,4.6Hz,2H),1.49-1.30 (m,11H).MS m/z 268(M+H)+.
中间体34a/b
外消旋的2-氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯&2,2-二氟-1-氧代-8-
氮杂螺[4.5]癸烷-8-甲酸叔丁酯
向-78℃的NaHMDS溶液(1M在THF中,8.68mL,8.68mmol)中加入 1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(2.0g,7.89mmol)的THF(5mL) 溶液。在该温度搅拌30min后,加入N-氟苯磺酰胺(2.49g,7.89mmol)的 THF(10mL)溶液。在-78℃搅拌3h后,将其用NaHCO3饱和水溶液(100mL) 稀释,并用DCM(3x100mL)萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至 25%梯度的EtOAc/庚烷),得到外消旋的2-氟-1-氧代-8-氮杂螺[4.5]癸烷-8- 甲酸叔丁酯(351mg,1.29mmol)。MS m/z 272.1(M+H)+和与原料共洗脱的二氟酮。将合并的二氟酮/原料共洗脱级分通过硅胶色谱法(0至5%梯度的MeOH/DCM)再纯化,得到2,2-二氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(573mg,1.98mmol)。MS m/z 290.1(M+H)+.
中间体35
(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸
叔丁酯
步骤a:将4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(544mg, 2.11mmol)和戴斯-马丁氧化剂(1.39g,3.17mmol)的DCM(10mL)溶液在 0℃搅拌2h。加入NaHCO3饱和水溶液:Na2S2O3饱和水溶液(1:1,10mL),分离有机相并将水相用DCM(3x10mL)萃取。将合并的有机相用Na2SO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8- 甲酸叔丁酯(470mg,1.84mmol),为一旦静置结晶的无色油状物。1H NMR (400MHz,氯仿-d)δppm 4.08(s,2H),4.05(s,2H),3.88(dt,J=13.7,4.9 Hz,2H),3.12(ddd,J=13.6,9.8,3.6Hz,2H),1.75(ddd,J=13.9,9.7,4.2Hz, 2H),1.58-1.51(m,2H),1.48(s,9H).MS m/z 256.2(M+H)+.
步骤b:将4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(220mg,0.86mmol)、乙醇钛(IV)(725μL,3.45mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(209mg,1.72mmol)的THF(4mL)溶液在90℃搅拌1h。冷却至0℃后,加入硼氢化锂(23mg,1.06mmol)。搅拌30min后,将反应混合物通过加入MeOH淬灭。在减压下除去挥发物。将得到的残留物用盐水稀释,将其用EtOAc(4x10mL)萃取。将合并的有机相用Na2SO4干燥,过滤,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的 EtOAc/庚烷),得到(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺 [4.5]癸烷-8-甲酸叔丁酯(170mg,0.47mmol)。MS m/z 361.1(M+H)+.
采用上面的方法或对上面的方法进行修改,利用相应的酮和磺酰胺来合成下面的化合物。
表3
中间体36
(1R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-甲基-8-氮杂螺[4.5]癸烷-8-甲酸
叔丁酯
步骤a:在0-5℃向1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(2.2g, 8.68mmol)的THF(24mL)溶液中加入LiHMDS(1M在THF中,8.68mL, 8.68mmol)。在该温度将混合物搅拌30min后,加入碘甲烷(0.543mL,8.68 mmol)。使得到的混合物升温至RT,并搅拌2h。将反应混合物用EtOAc 稀释并用NaHCO3饱和水溶液淬灭。将有机相用盐水洗涤,用Na2SO4干燥,过滤并在减压下浓缩。将得到的棕色油状物通过硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到2-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯 (1.3g,4.86mmol)。MS m/z268.1.(M+H)+.
步骤b:将2-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(267mg,0.999mmol)、乙醇钛(IV)(837μL,3.99mmol)和(R)-2-甲基丙烷-2-亚磺酰胺 (242mg,1.997mmol)的THF(10mL)溶液在85℃搅拌24h。冷却至-78℃后,加入MeOH(12mL),随后加入硼氢化锂(65.3mg,3.00mmol)。将得到的混合物在-78℃至RT搅拌16h。缓慢加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物,随后加入EtOAc(100mL)。将得到的混合物剧烈搅拌15min,然后通过硅藻土垫层过滤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至60%梯度的EtOAc/庚烷(含有0.25%的 Et3N)),得到(1R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-甲基-8-氮杂螺[4.5] 癸烷-8-甲酸叔丁酯(92mg,0.247mmol)。MS m/z373.1(M+H)+.
中间体37a/b
(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]
癸烷-8-甲酸叔丁酯&(3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮
杂螺[4.5]癸烷-8-甲酸叔丁酯
步骤a:在-78℃向叔丁基4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-(2.47 g,9.67mmol)的THF(24mL)溶液中加入LiHMDS(1M在THF中,9.67mL, 9.67mmol)。在该温度将混合物搅拌30min后,加入碘甲烷(0.605mL,9.67 mmol)的THF(10mL)溶液。将得到的混合物升温至RT,并搅拌1h。将反应混合物用EtOAc稀释并用饱和NaHCO3水溶液淬灭。将有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下浓缩。将得到的棕色油状物通过硅胶色谱法纯化(0至20%梯度的EtOAc/庚烷),得到3-甲基-4-氧代-2-氧杂-8- 氮杂螺[4.5]癸烷-8-甲酸叔丁酯(318mg,1.181mmol)。MS m/z 270.2. (M+H)+.
步骤b:将3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(318 mg,1.181mmol)、乙醇钛(IV)(990μL,4.72mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(286mg,2.361mmol)的THF(4mL)溶液在90℃搅拌90min。冷却至 0℃后,一次性加入硼氢化锂(65.3mg,3.00mmol),并将得到的混合物在 RT搅拌16h。缓慢加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物,随后加入EtOAc(25mL)。将得到的混合物剧烈搅拌15min,然后通过硅藻土垫层过滤。将有机相用饱和NaHCO3水溶液、盐水洗涤,用Na2SO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至 100%梯度的EtOAc/庚烷),得到(4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3- 甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(88mg,0.235mmol)。MS m/z 375.2(M+H)+.
步骤c:通过如下的手性SFC分离非对映体:柱:LUXC4 30x250mm, 流速:80g/分钟,流动相:20%MeOH在CO2中,检测:210nm,得到 (3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,Rt=4.0min;和(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,Rt=4.55min.
中间体38
(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]
癸烷-8-甲酸叔丁酯
步骤a:向-10℃的二异丙胺(23.4mL,166mmol)的THF(220mL)溶液中滴加加入nBuLi(2.5M在己烷中,64.1mL,160mmol)。在该温度搅拌 30min后,滴加加入哌啶-1,4-二甲酸1-叔丁酯4-乙酯(27.5g,107mmol)的 THF(50mL)溶液,并将得到的混合物在0℃搅拌30min。加入(S)-2-((叔丁基二甲基硅烷基)氧基)丙醛(20.47mL,102mmol),并将混合物在0℃搅拌1h,在RT搅拌1h。将反应物用饱和NaHCO3水溶液:H2O(1:4,125mL) 稀释,加入EtOAc(50mL),并分离各相。将水相进一步用EtOAc(3x100 mL)萃取。将合并的有机相用Na2SO4干燥,过滤,并在减压下除去溶剂。将得到的残留物没有进一步纯化即用于下一步骤。MS m/z346.4 (M+H-Boc)+.
步骤b:向粗的4-((2S)-2-((叔丁基二甲基硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-叔丁酯4-乙酯(95g,214mmol)的THF(600mL)溶液中分次加入LiBH4(7.0g,321mmol),并将得到的混合物在RT搅拌16h。冷却至 0℃后,加入饱和NaHCO3水溶液:H2O(1:2,150mL),并将得到的混合物剧烈搅拌,直到观察到没有气泡形成。加入EtOAc(100mL),将混合物过滤,分离各相,并将水相进一步用EtOAc(3x50mL)萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下除去挥发物,得到 4-((2S)-2-((叔丁基二甲基硅烷基)氧基)-1-羟基丙基)-4-(2-羟基乙基)哌啶-1- 甲酸叔丁酯(64.8g,161mmol),其没有进一步纯化即用于下一步骤。
步骤c:将4-((2S)-2-((叔丁基二甲基硅烷基)氧基)-1-羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(64.8g,161mmol)和TBAF(1M在THF中,242 mL,242mmol)的THF(500mL)溶液在RT搅拌2h。加入饱和NaHCO3水溶液:H2O(1:2,150mL),分离各相,并将水相进一步用EtOAc(3x100mL) 萃取。将合并的有机相用盐水洗涤,用Na2SO4干燥,过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(20至100%梯度的EtOAc/ 庚烷),得到4-((2S)-1,2-二羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁酯 (39.25g,136mmol),为半固体无色油状物。
步骤d:向0℃的NaH(10.60g,424mmol)的THF(600mL)混悬液中滴加加入4-((2S)-1,2-二羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(35.06 g,121mmol)和TsCl(23.10g,121mmol)的THF(200mL)溶液。将得到的混合物在0℃搅拌1h。在-20℃,缓慢加入饱和NH4Cl水溶液(~5mL),并将反应剧烈搅拌直到观察到没有气泡形成。此时,加入饱和NH4Cl水溶液(100mL),随后加入盐水(100mL),并将混合物用EtOAc(3x100mL) 萃取。将合并的有机相用Na2SO4干燥,过滤,并在减压下除去溶剂,得到 (3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(32.19g,119 mmol),其没有进一步纯化即用于下一步骤。MSm/z 171.1(M-Boc)-.
步骤e:将(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(32.19g,119mmol)和戴斯-马丁氧化剂(67.4g,154mmol)的DCM(300mL) 溶液在0℃搅拌2h。升至RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(S)-3-甲基-4- 氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(27.68g,92mmol),为淡黄色油状物。1H NMR(400MHz,氯仿-d)δppm 4.09(d,J=9.60Hz,1H), 3.66-3.86(m,4H),3.03(ddd,J=13.77,9.73,3.79Hz,1H),2.90(ddd,J=13.64,10.23,3.41Hz,1H),1.68(ddd,J=13.83,9.92,4.29Hz,1H),1.41-1.59(m,2 H),1.30-1.40(m,10H),1.20-1.25(m,3H).
步骤f:将(3S)-3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(22.52g mg,84mmol)、乙醇钛(IV)(70.1mL,334mmol)和(R)-2-甲基丙烷 -2-亚磺酰胺(21g,173mmol)的THF(300mL)溶液在90℃搅拌21h。冷却至-4℃后,加入MeOH(30mL),随后滴加加入(保持反应温度低于2℃) 硼氢化锂(1.82g,84mmol),并将得到的混合物在-4℃搅拌1h。缓慢加入饱和NH4Cl水溶液,以淬灭过量的硼氢化物(明胶型物形成),随后加入 EtOAc(500mL)。将得到的混合物在RT剧烈搅拌15min,然后通过硅藻土垫层过滤,随后用EtOAc(500mL)洗涤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到 (3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,为95:5非对映体混合物(次要的非对映体(3R,4S)- 4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯).
步骤g:通过如下的手性SFC分离非对映体:柱:LC-4 30x250mm,流速:100g/分钟,流动相:30%MeOH在CO2中,检测:225nm,Rt:0.95min (次要的非对映体Rt:0.55min),得到(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(19g,50.68 mmol)。MS m/z 375.2.
中间体39
(4R)-4-氨基-2-甲基-8-氮杂螺[4.5]癸-2-醇
步骤a:将(2R,4R)-4-氨基-8-氮杂螺[4.5]癸-2-醇二盐酸盐(623mg,2.56 mmol)、Na2CO3(1357mg,12.80mmol)和CbzCl(1048mg,6.14mmol)的 H2O(5mL)混合物在RT剧烈搅拌30min。加入THF(0.5mL),并将得到的混合物在RT搅拌18h。将混合物用水和DCM稀释。将分离的水相用DCM (2x10mL)萃取。将合并的有机相用Na2SO4干燥,过滤,并在减压下浓缩,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(1R,3R)-1-(((苄氧基)羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸苄酯 (940mg,2.14mmol),为白色泡沫状物。MS m/z 439.3(M+H)+.
步骤b:将(1R,3R)-1-(((苄氧基)羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷 -8-甲酸苄酯(440mg,1.003mmol)和戴斯-马丁氧化剂(638mg,1.505 mmol)的DCM(6mL)混合物在0℃搅拌1h并在RT搅拌18h。将反应混合物用饱和NaHCO3水溶液:饱和Na2S2O3水溶液(1:1,25mL)稀释。将分离的水相用DCM(3x15mL)萃取。将合并的有机相用盐水洗涤,用MgSO4干燥,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至70%梯度的EtOAc/庚烷),得到(R)-1-(((苄氧基)羰基)氨基)-3-氧代-8-氮杂螺[4.5] 癸烷-8-甲酸苄酯(415mg,0.951mmol),为白色泡沫状物。MS m/z 437.2 (M+H)+.
步骤c:在-30至-40℃,向MeLi(1.2M在THF中,2.61mL,3.13mmol) 的THF(15mL)溶液中滴加加入(R)-1-(((苄氧基)羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(415mg,0.951mmol)的THF(5mL)溶液。将得到的混合物在-30至-40℃搅拌20min。将混合物用NaHSO4(10%的H2O溶液)稀释,用EtOAc稀释,并在剧烈搅拌下升温至RT。将混合物用饱和NaHCO3水溶液稀释,并将分离的水相用EtOAc(1x15mL)萃取。将合并的有机相用Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物(313 mg)、Na2CO3(498mg,4.70mmol)和CbzCl(295mg,1.729mmol)的水(10 mL)和THF(1mL)溶液在RT剧烈搅拌3天。将混合物用EtOAc稀释,并将分离的水相用EtOAc(3x15mL)萃取。将合并的有机相在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到两种非对映体:非对映体A(112mg,0.25mmol),为无色半固体,MS m/z 453.3(M+H)+和非对映体B(45mg,0.010mmol),为白色泡沫状物/固体, MS m/z 453.3(M+H)+.
步骤d:将非对映体A(50mg,0.11mmol)和Pd/C(10wt.%;12mg, 0.011mmol)的MeOH(8mL)混合物在氢气气氛下剧烈搅拌2h。加入硅藻土并将混合物通过硅藻土垫层过滤,随后用DCM洗涤。将滤液在减压下浓缩,得到(4R)-4-氨基-2-甲基-8-氮杂螺[4.5]癸-2-醇,为无色固体,其没有进一步纯化即使用。MS m/z 185.2(M+H)+.
中间体40
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲
酸叔丁酯
将(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(400mg,1.068mmol)和DAST(1M在DCM中,1.87mL, 1.87mmol)的DCM(8.5mL)混合物在0℃搅拌90min。通过加入饱和 NaHCO3水溶液(5mL)将反应混合物淬灭。在0℃搅拌10min后,分离各相,将水相用DCM(2x5mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物,得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3- 氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,其没有进一步纯化即用于下一步骤。 MS m/z 277.2(M+H-Boc)+.
中间体41
(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲
酸叔丁酯
将(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(200mg,0.534mmol)和DAST(1M在DCM中,934μL, 0.934mmol)的DCM(5mL)混合物在0℃搅拌90min。通过加入饱和 NaHCO3水溶液(5mL)将反应混合物淬灭。在RT搅拌10min后,分离各相并将水相用DCM(2x5mL)萃取。将合并的有机相用MgSO4干燥,过滤,并在减压下除去挥发物,得到(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3- 氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,其没有进一步纯化即用于下一步骤。 MS m/z 277.2(M+H-Boc)+.
中间体42
3-((6-氨基-2,3-二氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺
步骤a:在0℃,向5,6-二氯吡啶-2-胺(590mg,3.62mmol)的THF(5 mL)溶液中加入LiHMDS(1M在THF中,7.96mL,7.96mmol)。将反应在0 ℃搅拌10min,然后将Boc2O(869mg,3.98mmol)的THF(5mL)溶液加入反应混合物中。将得到的溶液在0℃搅拌15min,然后通过加入1M HCl 调到pH 4。将溶液用EtOAc稀释,用饱和NaHCO3水溶液、盐水洗涤,用 Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(790mg,3.00mmol)。1H NMR(400MHz,氯仿-d)δppm 7.86(d,J=8.7Hz, 1H),7.70(d,J=8.7Hz,1H),7.20(br s,1H),1.51(s,9H).MSm/z 232.9 (M+H-tBu)+.
步骤b:在-78℃,向二异丙胺(1mL,7.07mmol)的THF(5mL)溶液中加入n-BuLi(2.5M在己烷中,2.83mL,7.07mmol),并将得到的溶液在该温度下搅拌1h。在-78℃,加入(5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(930 mg,3.53mmol)的THF(5mL)溶液。在该温度下搅拌2h后,加入碘(987mg, 3.89mmol)的THF(5mL)溶液,将得到的混合物在-78℃搅拌30min。升温至RT后,将反应混合物用水稀释,并用EtOAc(2x50mL)萃取。将合并的有机相用饱和Na2S2O3水溶液、盐水洗涤,用Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至40%梯度的 EtOAc/庚烷),得到(5,6-二氯-4-碘吡啶-2-基)氨基甲酸叔丁酯(813mg,2.09 mmol)。1H NMR(400MHz,氯仿-d)δppm 8.45(s,1H),7.12(s,1H),1.52(s, 9H).MS m/z332.9(M+H-tBu)+.
步骤c:将(5,6-二氯-4-碘吡啶-2-基)氨基甲酸叔丁酯(610mg,1.57 mmol)、3-氨基-5-氯吡嗪-2-硫醇钠(302mg,1.65mmol)、Pd2(dba)3(72mg, 0.08mmol)、Xantphos(91mg,0.16mmol)和DIPEA(0.55mL,3.14mmol)的二氧六环(7.8mL)混合物在110℃搅拌8h。冷却至RT后,将反应混合物通过硅藻土垫层过滤,并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(4-((3-氨基-5-氯吡嗪-2- 基)硫基)-5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(470mg,1.11mmol)。1H NMR (400MHz,DMSO)δppm 10.24(s,1H),7.96(s,1H),7.31(br s,2H),7.16(s, 1H),1.38(s,9H).MS m/z 321.9(M+H-Boc)+.
步骤d:将(4-((3-氨基-5-氯吡嗪-2-基)硫基)-5,6-二氯吡啶-2-基)氨基甲酸叔丁酯(470mg,1.11mmol)和HCl(4M在二氧六环中,5.56mL,22.24 mmol)混合物在RT搅拌1h。在减压下除去挥发物,得到3-((6-氨基-2,3- 二氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺二盐酸(411mg,1.04mmol),其没有进一步纯化即使用。MS m/z 324.0(M+H)+.
实施例1
(S)和(R)8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-8-氮杂螺
[4.5]癸-1-胺
步骤a:将6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(200mg,0.652mmol)和N-(4-甲氧基苄基)-8-氮杂螺[4.5]癸-1-胺(358mg,1.304 mmol)的DIPEA(3mL)溶液在130℃搅拌60h。冷却至RT后,在减压下除去挥发物。将得到的残留物溶解在TFA(3mL)中并将该溶液在微波反应器中在160℃搅拌1h,并在180℃搅拌15min。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5mM NH4OH改性剂),得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2- 基)-8-氮杂螺[4.5]癸-1-胺(73mg,0.482mmol;83%纯度,基于HRMS)。将19mg该化合物通过HPLC进一步纯化(梯度洗脱25-50%乙腈水溶液, 0.1%TFA改性剂),得到纯的标题化合物(9.5mg).1H NMR(400MHz,甲醇-d4)δppm 8.29(dd,J=4.42,1.39Hz,1H),7.48(s,1H),7.19-7.41(m,2H),4.06-4.26(m,2H),2.89-3.14(m,2H),2.71(t,J=7.33Hz,1H),1.86-2.00(m, 1H),1.73-1.84(m,1H),1.43-1.72(m,5H),1.27-1.42(m,2H),1.17-1.27(m, 1H).19F NMR(376MHz,甲醇-d4)δppm-66.45(s).C19H24N6F3S(M+H)+的 HRMS计算值425.1735,实测值425.1753.IC50是0.023μM。
步骤b:上面标题化合物的手性SFC纯化如下进行;柱:ID 21x250mm, 流速:75g/分钟,流动相:35%MeOH和10mM NH4OH在CO2中,检测: 270nm UV,获得单一的对映体Rt(P1)=4.9min;IC50是0.011μM和Rt (P2)=6.4min;IC50是0.167μM。
采用上面的方法或对上面方法进行修改,利用相应的硫吡嗪-2-胺衍生物和保护的胺,制备如表4中所示的下面的式I化合物。
表4
实施例8
(R)和(S)-2-(6-氨基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-2-氮杂螺[3.3]庚-
5-胺
步骤a:将6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺(140mg,0.457mmol) 和2-氮杂螺[3.3]庚-5-基氨基甲酸叔丁酯(HCl盐,125mg,0.502mmol)的 DIPEA(1mL)溶液在130℃搅拌24h。冷却至RT后,在减压下除去挥发物。将得到的残留物溶解在DCM(5mL)中,加入TFA(0.5mL),并将得到的混合物在RT搅拌30min。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5mM NH4OH改性剂),得到2-(6-氨基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-2-氮杂螺[3.3]庚-5-胺(75 mg,0.186mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.31(dd,J=8.03,1.51 Hz,1H),7.18(s,1H),7.11(t,J=8.03Hz,1H),6.60(dd,J=8.03,1.51Hz,1 H),4.45(d,J=8.78Hz,1H),4.03(d,J=9.03Hz,1H),3.96(d,J=9.03Hz,1H), 3.90(d,J=8.78Hz,1H),3.34-3.39(与溶剂部分重叠,m,1H),2.12-2.25(m,1H),1.90-2.11(m,2H),1.52-1.67(m,1H).C16H18Cl2N5S(M+H)+的HRMS计算值382.0660,实测值382.0585.IC50是5.36μM。
步骤b:将2-(6-氨基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-2-氮杂螺[3.3] 庚-5-胺(53.9mg,0.141mmol)通过手性SFC进一步纯化;柱:OJ-H 21x250mm,流速:80g/分钟,流动相:26%MeOH和10mM NH4OH在CO2中,检测:269nm UV,获得单一的对映体Rt(P1)=3.7min;IC50是17.49 μM和Rt(P2)=4.7min.;IC50是3.31μM。
采用上面的方法或对上面方法进行修改,利用相应的吡嗪-2-胺衍生物和保护的胺,制备如表5中所示的下面的式I化合物。
表5
实施例14
7-(6-氨基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-1-胺
将6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺(140mg,0.457mmol)和2-(7- 氮杂螺[3.5]壬-1-基)异吲哚啉-1,3-二酮(HCl盐,154mg,0.502mmol)的 DIPEA(1mL)溶液在130℃搅拌16h。冷却至RT后,在减压下除去挥发物。将得到的残留物和水合肼(29μL,0.602mmol)的THF:MeOH(1:1,1mL) 溶液在55℃搅拌16h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱35-60%乙腈水溶液,5mM NH4OH改性剂),得到标题化合物(78mg,0.502mmol)。1H NMR(400MHz,甲醇-d4) δppm 7.59(s,1H),7.31(dd,J=8.03,1.51Hz,1H),7.12(t,J=8.03Hz,1H), 6.62(dd,J=8.03,1.51Hz,1H),4.37(d,J=13.55Hz,1H),4.26(d,J=13.55Hz, 1H),3.24-3.30(与溶剂部分重叠,m,1H),3.07-3.20(m,1H),2.92 3.06(m,1 H),2.26-2.39(m,1H),1.87-2.07(m,2H),1.57-1.87(m,4H),1.34-1.42(m,1 H).C18H22Cl2N5S(M+H)+的HRMS计算值410.0973,实测值410.1018;(外消旋的).IC50是0.056μM。
如下进行上述标题化合物的手性SFC纯化;柱:AD-H 21x250mm,流速:80g/分钟,流动相:46%MeOH和10mM NH4OH在CO2中,检测:274 nm UV,获得单一的对映体Rt(P1)=4.0min和Rt(P2)=5.5min.(P1(S-对映体(通过X-射线测定));IC50是0.019μM;(P2(R-对映体));IC50是0.414 μM。
采用上面的方法或对上面方法进行修改,利用相应的吡嗪-2-胺衍生物和邻苯二甲酰胺-保护的胺,制备如表6中所示的下面的式I化合物。
表6
实施例20
(S)-7-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]
壬-1-胺
步骤a:将6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(230mg,0.750mmol)和(R)-2-甲基-N-((S)-7-氮杂螺[3.5]壬-1-基)丙烷-2-亚磺酰胺 (238mg,0.975mmol)的DIPEA(3.7mL)混合物在105℃搅拌10h。冷却至 RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(5 至70%梯度的EtOAc/庚烷),得到(R)-N-((S)-7-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-1-基)-2-甲基丙烷-2-亚磺酰胺 (172mg,0.334mmol),为白色固体。MS m/z 515.2(M+H)+.
步骤b:将(R)-N-((S)-7-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-1-基)-2-甲基丙烷-2-亚磺酰胺(142mg,0.376mmol)和 HCl(4M在二氧六环中,414μL,1.66mmol)的DCM(1.4mL)溶液在40℃搅拌20min。冷却至RT后,加入HCl(1M在H2O中),并将得到的含水混合物用DCM萃取。将水相用NH4OH(28%的H2O溶液)碱化,直到pH12,将其用DCM(3x20mL)萃取。将合并的有机层用盐水洗涤,用MgSO4干燥,过滤并在减压下除去挥发物,得到(S)-7-(6-氨基-5-((2-(三氟甲基)吡啶 -3-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-1-胺(93mg,0.227mmol)。1H NMR(400MHz,DMSO-d6)δppm 8.40-8.53(m,1H),7.61-7.69(m,1H), 7.55(dd,J=8.0,4.5Hz,1H),7.29(d,J=8.0Hz,1H),6.19(s,2H),4.11-4.24 (m,1H),3.99-4.06(m,1H),3.06-3.20(m,2H),2.90-3.06(m,2H),1.50-1.74(m,4H),1.33-1.49(m,2H).C18H21F3N6S(M+H)+的HRMS计算值411.1566, 实测值411.1579.IC50是0.038μM。
实施例21
(S)-5-氨基-3-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)
硫基)吡嗪-2-甲酰胺
步骤a:在0℃向6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(1.2 g,2.119mmol)的DCM(30mL)溶液中一次性加入NBS(745mg,4.19 mmol)。将得到的混合物在0℃剧烈搅拌30min,并在RT搅拌1h。将澄清的溶液用水淬灭,并用DCM萃取。将合并的有机层随后用水、盐水洗涤,用Na2SO4干燥,过滤并浓缩。将得到的残留物通过硅胶色谱法纯化(0 至50%梯度的EtOAc/庚烷),得到5-溴-6-氯-3-((2-(三氟甲基)吡啶-3-基) 硫基)吡嗪-2-胺(938mg,2.51mmol)。MS m/z 387.2(M+H)+.
步骤b:将5-溴-6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(750 mg,1.945mmol)和氰化亚铜(I)(348mg,3.89mmol)的DMF(7mL)混合物在 120℃搅拌14h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用 MeOH(50mL)洗涤。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到5-氨基-3-氯-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-腈(301mg,0.907mmol)。MS m/z 332.3 (M+H)+.
步骤c:将5-氨基-3-氯-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-腈(52 mg,0.157mmol)和(S)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺 (90mg,0.314mmol)的DIPEA(0.246mL)混合物在135℃搅拌1h。冷却至 RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0 至100%梯度的EtOAc/庚烷),得到5-氨基-3-((S)-1-(((R)-1-(4-甲氧基苯基) 乙基)氨基)-8-氮杂螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2- 腈(77mg,0.132mmol)。MS m/z 584.5(M+H)+.
步骤d:将5-氨基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-腈(77mg,0.132mmol) 和NaOH(1M的H2O溶液,1.451mL,1.451mmol)的MeOH(3.5mL)混合物在微波反应器中在110℃搅拌35min。冷却至RT后,在减压下除去挥发物,得到5-氨基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸 -8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲酰胺(79mg,0.132 mmol),其没有进一步纯化即用于下一步骤。MS m/z 602.5(M+H)+.
步骤e:将5-氨基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲酰胺(79mg,0.132 mmol)的TFA(1.2mL,15.76mmol)溶液在微波反应器中在100℃搅拌直到没有原料剩下(3h,通过LCMS监测)。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5mM NH4OH改性剂),得到(S)-5-氨基-3-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶 -3-基)硫基)吡嗪-2-甲酰胺(18.8mg,0.039mmol)。1H NMR(400MHz,甲醇 -d4)δppm 8.43(dd,J=4.5,1.4Hz,1H),7.57(dd,J=8.1,1.3Hz,1H),7.46 (dd,J=8.2,4.5Hz,1H),3.92-3.88(m,2H),3.20-3.08(m,2H),2.77(t,J=7.4 Hz,1H),2.04-1.96(m,1H),1.829-1.82(m,1H),1.78-1.61(m,4H),1.53 (ddd,J=12.3,9.2,5.7Hz,1H),1.43(ddd,J=9.8,4.9,2.0Hz,1H),1.39-1.32 (m,1H),1.30-1.23(m,1H).C20H25F3N7OS(M+H)+的HRMS计算值 468.1715,实测值468.1761;IC50是0.010μM。
采用上面的方法或对上面方法进行修改,利用相应的胺和胺脱保护方法,制备如表7中所示的下面的式I化合物。
表7
实施例23
(S)-8-(5-氨基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-8-氮杂
螺[4.5]癸-1-胺
步骤a:将3-氯-1,2,4-三嗪-5-胺(70mg,0.536mmol)、(S)-N-((R)-1-(4- 甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(247mg,0.644mmol)和N-甲基吗啉(177μL,1.609mmol)的MeCN(1mL)和NMP(0.1mL)混合物在微波反应器中在90℃辐射45min。冷却至RT后,将得到的残留物直接通过硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到(S)-8-(5-氨基-1,2,4-三嗪-3- 基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺,其没有进一步纯化即用于下一步骤。MS m/z 383.5(M+H)+.
步骤b:在0℃,向(S)-8-(5-氨基-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(194mg,0.507mmol)的DCM(8mL)溶液中一次性加入NBS(97mg,0.543mmol)。在0℃搅拌20min后,将澄清溶液用数滴Na2CO3水溶液淬灭,将其用DCM萃取。将合并的有机层用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化 (0至100%梯度的EtOAc/庚烷),得到(S)-8-(5-氨基-6-溴-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(77.9mg,0.169 mmol)。MSm/z 463.4(M+H)+.
步骤c:将(S)-8-(5-氨基-6-溴-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(54.1mg,0.117mmol)、2-(三氟甲基)吡啶-3-硫醇(21mg,0.117mmol)、XantPhos(7.46mg,0.013mmol)、Pd2(dba)3(5.37 mg,0.0058mmol)和DIPEA(0.041mL,0.234mmol)的二氧六环(1mL)混合物在微波反应器中在130℃搅拌1.5h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(10mL)洗涤。在减压下除去挥发物,得到(S)-8-(5-氨基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(65mg,0.116mmol)。MS m/z 560.5(M+H)+.
步骤d:将(S)-8-(5-氨基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(65mg,0.116 mmol)的TFA(1.253mL,16.26mmol)溶液在100℃搅拌,直到没有原料剩下(1.5h,通过LC/MS监测),在减压下除去挥发物,将得到的残留物用水稀释,将其用Et2O(3x10mL)萃取。采用NH4OH(28%的水溶液),将水层碱化至pH 12,将其用DCM(3x10mL)萃取。将合并的有机层用盐水洗涤,用Na2SO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过HPLC 纯化(梯度洗脱25-50%乙腈水溶液,5mM NH4OH改性剂),得到 (S)-8-(5-氨基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-8-氮杂螺 [4.5]癸-1-胺(14.5mg,0.032mmol)。1H NMR(400MHz,甲醇-d4)δppm 8.50-8.45(m,1H),7.60-7.54(m,1H),7.53-7.46(m,1H),4.64-4.50(m,2H),3.22-3.09(m,2H),2.88(t,J=7.3Hz,1H),2.11-2.00(m,1H),1.94-1.86(m,1 H),1.84-1.74(m,1H),1.74-1.63(m,3H),1.59-1.46(m,2H),1.45-1.39(m,1 H),1.39-1.31(m,1H).C18H23F3N7S(M+H)+的HRMS计算值426.1688,实测值426.1667.IC50是0.290μM。
实施例24
(S)-8-(4-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-8-氮杂螺[4.5]
癸-1-胺
步骤a:将2-(三氟甲基)吡啶-3-硫醇(150mg,0.837mmol)、2-氯-5-碘嘧啶-4-胺(267mg,1.047mmol)、XantPhos(53.3mg,0.092mmol)、Pd2(dba)3 (38.3mg,0.042mmol)和DIPEA(0.292mL,1.674mmol)的二氧六环(1mL) 混合物在微波反应器中在130℃搅拌1.5h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(10mL)洗涤。在减压下除去挥发物,得到 2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4-胺(141mg,0.460mmol)。 MS m/z 307.4(M+H)+.
步骤b:将2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4-胺(70mg,0.228mmol)和(S)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(105 mg,0.274mmol)的DIPEA(0.359mL)混合物在微波反应器中在135℃搅拌 1.5h。冷却至RT后,在减压下除去挥发物,得到(S)-8-(4-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺 [4.5]癸-1-胺(128mg,0.228mmol)。MS m/z559.5(M+H)+.
步骤c:将(S)-8-(4-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2- 基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(128mg,0.229 mmol)的TFA(2.471mL,32.1mmol)溶液在100℃搅拌,直到没有原料剩下(1.5h,通过LCMS监测),在减压下除去挥发物,将得到的残留物用水稀释,然后将其用Et2O(3x10mL)萃取。采用NH4OH(28%的水溶液)将水层碱化至pH 12,将其用DCM(3x10mL)萃取。将合并的有机层用盐水洗涤,用Na2SO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过HPLC 纯化(梯度洗脱35-60%乙腈水溶液,5mM NH4OH改性剂),得到 (S)-8-(4-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-8-氮杂螺[4.5]癸 -1-胺(32mg,0.072mmol)。1H NMR(400MHz,甲醇-d4)δppm 8.41-8.35 (m,1H),8.00(s,1H),7.47-7.43(m,2H),4.66-4.45(m,2H),3.18-3.06(m,2H),2.81(t,J=7.3Hz,1H),2.09-1.97(m,1H),1.94-1.86(m,1H),1.81-1.72 (m,1H),1.69-1.62(m,2H),1.59-1.53(m,2H),1.49-1.44(m,1H),1.40-1.35 (m,1H),1.33-1.25(m,1H).C19H24F3N6S(M+H)+的HRMS计算值425.1735, 实测值425.1741;IC50是2.78μM。
实施例25
(R)-5-氨基-3-(1-氨基-8-氮杂螺[4.5]癸-8-基)-6-((3-氯-2-(三氟甲基)吡啶-
4-基)硫基)吡嗪-2-甲酰胺
步骤a:将5-氨基-3-氯吡嗪-2-腈(1.55g,10.0mmol)和(R)-N-((R)-1-(4- 甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(2.88g,10.0mmol)的DIPEA(10 μL)和NMP(5mL)溶液在110℃搅拌16h。冷却至RT后,将反应混合物倒入含有NaHCO3水溶液的分离漏斗中。将其用EtOAc萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物。将得到的残留物通过硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到5-氨基 -3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)吡嗪-2-腈 (2.74g,6.74mmol)。MS m/z 407.3(M+H)+.
步骤b:(注意:该反应以4批进行,每批500mg)。将5-氨基 -3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)吡嗪-2-腈 (500mg,1.23mmol)的MeOH(8mL)和NaOH(2.5M在H2O中,5mL,12.3 mmol)溶液在微波反应器中在130℃搅拌90min。冷却至RT后,将得到的混合物通过HPLC纯化(35-60%梯度的乙腈/水,5mM NH4OH改性剂),得到5-氨基-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5] 癸-8-基)吡嗪-2-甲酰胺(160mg/反应,640mg总共,1.51mmol)。MS m/z 425.3(M+H)+.
步骤c:将5-氨基-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)吡嗪-2-甲酰胺(615mg,1.45mmol)的TFA(11mL)溶液在100 ℃搅拌1h。在减压下除去挥发物。将得到的残留物、DIPEA(1.2mL,6.89 mmol)和Boc2O(330mg,1.516mmol)的DCM(15mL)溶液在RT搅拌2h。在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(1至10%梯度的MeOH/DCM),得到(R)-(8-(6-氨基-3-氨基甲酰基吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(538mg,1.378mmol)。MS m/z 391.0 (M+H)+.
步骤d:将(R)-(8-(6-氨基-3-氨基甲酰基吡嗪-2-基)-8-氮杂螺[4.5]癸-1- 基)氨基甲酸叔丁酯(538mg,1.378mmol)和NBS(270mg,1.516mmol)的 DCM(5mL)溶液在0℃搅拌20min。将反应混合物用MeOH(2mL)淬灭,并在RT搅拌20min。将得到的混合物倒入含有NaHCO3水溶液的分离漏斗中。将其用DCM萃取。将合并的有机相用MgSO4干燥,过滤并在减压下除去挥发物,得到(R)-(8-(6-氨基-5-溴-3-氨基甲酰基吡嗪-2-基)-8-氮杂螺 [4.5]癸-1-基)氨基甲酸叔丁酯(627mg,1.336mmol)。MS m/z 471.2 (M+H)+.
步骤e:向(R)-(8-(6-氨基-5-溴-3-氨基甲酰基吡嗪-2-基)-8-氮杂螺[4.5] 癸-1-基)氨基甲酸叔丁酯(627mg,1.336mmol)、XantPhos(77mg,0.134 mmol)和Pd2(dba)3(61.2mg,0.067mmol)的二氧六环(3mL)溶液中加入(在 RT和在N2下)3-巯基丙酸2-乙基己基酯(334μL,1.469mmol),随后加入 DIPEA(467μL,2.67mmol)。将得到的溶液在微波反应器中在90℃搅拌1 h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(5mL) 洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到3-((3-氨基-5-((R)-1-((叔丁氧基羰基)氨基)-8-氮杂螺[4.5]癸-8-基)-6-氨基甲酰基吡嗪-2-基)硫基)丙酸2-乙基己基酯(574mg, 0.946mmol)。MS m/z 607.4(M+H)+.
步骤f:向3-((3-氨基-5-((R)-1-((叔丁氧基羰基)氨基)-8-氮杂螺[4.5]癸 -8-基)-6-氨基甲酰基吡嗪-2-基)硫基)丙酸2-乙基己基酯(574mg,0.946 mmol)的THF(3mL)溶液中加入(在-78℃和N2下)叔丁醇钾(1M在THF 中,2.84mL,2.84mmol)。在-78℃剧烈搅拌10min后,将反应用K2CO3水溶液(2M,500μL)淬灭并在减压下除去挥发物。将得到的残留物通过 HPLC纯化(15至40%梯度的乙腈/水,5mM NH4OH改性剂),得到(R)- (8-(6-氨基-3-氨基甲酰基-5-巯基吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(280mg,0.663mmol)。MS m/z 423.4(M+H)+.
步骤g:向(R)-(8-(6-氨基-3-氨基甲酰基-5-巯基吡嗪-2-基)-8-氮杂螺 [4.5]癸-1-基)氨基甲酸叔丁酯(88mg,0.208mmol)、3-氯-4-碘-2-(三氟甲基) 吡啶(80mg,0.260mmol)、XantPhos(12.1mg,0.021mmol)和Pd2(dba)3(9.6 mg,0.01mmol)的二氧六环(0.5mL)溶液中加入(在RT和在N2下)DIPEA (110μL,0.625mmol)。将得到的溶液在微波反应器中在90℃搅拌1h。冷却至RT后,将反应物用EtOAc稀释,并将其通过硅藻土垫层过滤,随后用EtOAc(5mL)洗涤。将合并的滤液浓缩并在真空中干燥。将得到的残留物的DCM(1mL)和TFA(400μL)溶液在RT搅拌10min。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5 mM NH4OH改性剂),得到(R)-5-氨基-3-(1-氨基-8-氮杂螺[4.5]癸-8- 基)-6-((3-氯-2-(三氟甲基)吡啶-4-基)硫基)吡嗪-2-甲酰胺(60mg,0.120mmol)。1H NMR(400MHz,甲醇-d4)δppm 8.18(d,J=5.05Hz,1H).6.85(d, J=5.31Hz,1H).3.87(t,J=13.89Hz,2H).2.98-3.14(m,2H),2.72(t,J=7.33 Hz,1H).1.86-2.02(m,1H).1.73-1.81(m,1H).1.43-1.72(m,5H).1.17-1.41 (m,3H).19F NMR(376MHz,甲醇-d4)δppm-67.22(s,1F). C20H24ClF3N7OS(M+H)+的HRMS计算值502.1404,实测值502.1398.IC50是0.058μM
实施例26
(R)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]
癸-1-胺
将3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(67mg,0.233mmol) 和(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺(120mg,0.465 mmol)的DIPEA(2mL)混合物在130℃搅拌5h。冷却至RT后,在减压下除去挥发物。将得到的残留物的二氧六环(5mL)和HCl(4M在二氧六环中, 1mL)溶液在40℃搅拌1h。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱25-50%乙腈水溶液,5mM NH4OH改性剂)。将得到的残留物通过SFC进一步纯化(Princeton DEAP 20x150mm,流速:80 g/分钟,流动相:20-40%MeOH在CO2中,5.7min内,质量触发的收集,炉温40℃,反压120bar),得到(R)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基) 吡嗪-2-基)-8-氮杂螺[4.5]癸-1-胺(23mg,0.057mmol)。1HNMR(400MHz, 甲醇-d4)δppm 7.50-7.64(m,2H),5.91(d,J=5.77Hz,1H),4.26(t,J=13.18Hz,2H),3.03-3.20(m,2H),2.79(t,J=7.53Hz,1H),1.95-2.11(m,1H), 1.83-1.95(m,1H),1.52-1.82(m,5H),1.37-1.52(m,2H),1.32(dd,J=13.30, 2.01Hz,1H).C18H25ClN7S(M+H)+的HRMS计算值406.1581,实测值 406.1576.IC50是0.014μM。
采用上面的方法或对上面的方法进行修改,利用相应的胺保护的胺来合成下面的化合物。
表8
实施例28
(R)-8-(6-氨基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-胺
步骤a:向6-氯-3-((3-氯吡啶-4-基)硫基)吡嗪-2-胺(53mg,0.194mmol) 的DIPEA(2mL)混悬液中加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷 -2-亚磺酰胺(65mg,0.252mmol)。将得到的混合物在90℃搅拌10h,然后浓缩。将粗品通过硅胶色谱法纯化(0-50%梯度的EtOAc/庚烷;EtOAc含有10%MeOH,庚烷含有2%Et3N),得到(R)-N-((R)-8-(6-氨基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(40 mg,0.081mmol),为灰白色固体。MS m/z 495.0(M+H)+.
步骤b:向(R)-N-((R)-8-(6-氨基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8- 氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(40mg,0.081mmol)的DCM (0.8mL)溶液中,加入HCl溶液(4M在二氧六环中,101μL,0.404mmol),将得到的混合物在40℃搅拌1h。加入HCl水溶液(2M,2mL),并将得到的混合物用DCM(2x)萃取。将水混合物用氢氧化铵(28%的水溶液)碱化,直到pH=12,将其用DCM(3x)萃取。合并有机层,用盐水洗涤,用Na2SO4干燥,过滤并浓缩,得到(R)-8-(6-氨基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8- 氮杂螺[4.5]癸-1-胺(24mg,0.061mmol)。1H NMR(400MHz,DMSO-d6)δ ppm 8.49(s,1H),8.25(d,J=5.3Hz,1H),7.66(s,1H),6.56(d,J=5.3Hz,1 H),6.24(s,2H),4.07-4.26(m,2H),2.98-3.13(m,2H),2.70(t,J=7.4Hz,1 H),1.11-1.94(m,10H).C18H24ClN6S(M+H)+的HRMS计算值391.1472, 实测值391.1480.IC50是0.023μM。
实施例29
(R)-8-(6-氨基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-胺
步骤a:向6-氯-3-((2-氯吡啶-3-基)硫基)吡嗪-2-胺(85mg,0.311mmol) 的DIPEA(1.6mL)混悬液中,加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基) 丙烷-2-亚磺酰胺(105mg,0.405mmol)。将得到的混合物在90℃搅拌10 h,然后浓缩。将粗品通过硅胶色谱法纯化(0-50%梯度的EtOAc/庚烷;EtOAc含有10%MeOH,庚烷含有2%Et3N),得到(R)-N-((R)-8-(6-氨基 -5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(40mg,0.081mmol),为灰白色固体。1H NMR(400MHz,氯仿-d) δppm8.15(dd,J=4.5,1.8Hz,1H),7.64(s,1H),7.01-7.18(m,2H),4.87(br. s,2H),4.24(s,2H),3.29-3.45(m,1H),3.20(d,J=5.8Hz,1H)2.98-3.13(m, 2H),1.98-2.21(m,1H),1.36-1.94(m,9H),1.22(s,9H).MS m/z 495.0 (M+H)+.
步骤b:向(R)-N-((R)-8-(6-氨基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8- 氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(66mg,0.133mmol)的DCM(2 mL)溶液中,加入HCl溶液(4M在二氧六环中,167μL,0.667mmol),并将得到的混合物在40℃搅拌1h。加入HCl水溶液(2M,2mL),并将得到的混合物用DCM(2x)萃取。将水混合物用氢氧化铵(28%的水溶液)碱化,直到pH=12,将其用DCM(3x)萃取。合并有机层,用盐水洗涤,用Na2SO4干燥,过滤并浓缩,得到(R)-8-(6-氨基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8- 氮杂螺[4.5]癸-1-胺(24mg,0.062mmol),为黄褐色固体。1H NMR(400MHz, 甲醇-d4)δppm 8.01(dd,J=4.8,1.8Hz,1H),7.43-7.52(m,1H),7.12(dd, J=7.9,4.6Hz,1H),7.00(dd,J=7.9,1.6Hz,1H),4.11-4.26(m,2H),2.96-3.10 (m,2H),2.67-2.81(m,1H),1.06-2.05(m,10H).C18H24ClN6S(M+H)+的 HRMS计算值391.1472,实测值391.1470.IC50是0.015μM。
实施例30
(R)-8-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-
1-胺
步骤a:向6-氯-3-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-胺(34mg,0.111 mmol)的DIPEA(0.55mL)混悬液中,加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5] 癸-1-基)丙烷-2-亚磺酰胺(37mg,0.144mmol)。将得到的混合物在90℃搅拌10h,然后浓缩。将粗品通过硅胶色谱法纯化(0-50%梯度的EtOAc/庚烷;EtOAc含有10%MeOH,庚烷含有2%Et3N),得到(R)-N-((R)-8-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(33mg,0.062mmol),为灰白色固体。1H NMR(400MHz,氯仿-d)δppm8.02(d,J=5.3Hz,1H),7.66(s,1H),6.60(d,J=5.3Hz,1H),4.82 (s,2H),4.21-4.34(m,2H),3.34-3.42(m,1H),3.20(d,J=5.8Hz,1H), 2.99-3.15(m,2H),2.08-2.21(m,1H),1.26-1.97(m,9H),1.23(s,9H).MS m/z 529.1(M+H)+.
步骤b:向(R)-N-((R)-8-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2- 基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(20mg,0.038mmol)的 DCM(0.38mL)溶液中,加入HCl溶液(4M在二氧六环中,47μL,0.189 mmol),并将得到的混合物在40℃搅拌1h。将反应混合物浓缩并溶解在 MeOH中。将粗品通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(R)-8-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2- 基)-8-氮杂螺[4.5]癸-1-胺(7mg,0.016mmol),为白色固体。1H NMR(400 MHz,甲醇-d4)δppm 7.91-8.04(m,1H),7.52-7.65(m,1H),6.61(d,J=5.3 Hz,1H),4.29(t,J=14.2Hz,2H),3.06-3.22(m,2H),2.88(t,J=7.4Hz,1H), 1.21-2.17(m,10H).C18H23Cl2N6S(M+H)+的HRMS计算值425.1082,实测值425.1095.IC50是0.003μM。
实施例31
(S)-7-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-
1-胺
步骤a:向6-氯-3-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-胺(54mg,0.176 mmol)的DIPEA(1.8mL)混悬液中,加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸 -1-基)丙烷-2-亚磺酰胺(86mg,0.351mmol)。将得到的混合物在90℃搅拌 10h,然后浓缩。将粗品通过硅胶色谱法纯化(0-50%梯度EtOAc/庚烷; EtOAc含有10%MeOH,庚烷含有2%Et3N),得到(R)-N-((S)-7-(6-氨基 -5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-7-氮杂螺[3.5]壬-1-基)-2-甲基丙烷 -2-亚磺酰胺(52mg,0.102mmol),为灰白色固体。MS m/z 514.9(M+H)+.
步骤b:向(R)-N-((S)-7-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2- 基)-7-氮杂螺[3.5]壬-1-基)-2-甲基丙烷-2-亚磺酰胺(20mg,0.039mmol)的 DCM(0.38mL)溶液中,加入HCl溶液(4M在二氧六环中,47μL,0.189 mmol),并将得到的混合物在40℃搅拌1h。将反应混合物浓缩并溶解在 MeOH中。将粗品通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(S)-7-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2- 基)-7-氮杂螺[3.5]壬-1-胺(7mg,0.017mmol),为白色固体。1H NMR(400 MHz,甲醇-d4)δppm 7.89(d,J=5.5Hz,1H),7.50(s,1H),6.51(d,J=5.5Hz, 1H),3.94-4.31(m,2H),2.76-3.11(m,3H),2.06-2.24(m,1H),1.36-1.82(m, 7H).C17H21Cl2N6S(M+H)+的HRMS计算值411.0925,实测值411.0938. IC50是0.028μM。
实施例32
(R)-8-(6-氨基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-
1-胺
步骤a:向3-((3-氨基-2-氯苯基)硫基)-6-氯吡嗪-2-胺(60mg,0.209 mmol)的DIPEA(1.5mL)混悬液中加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸 -1-基)丙烷-2-亚磺酰胺(70mg,0.272mmol)。将得到的混合物在90℃搅拌 10h,然后浓缩。将粗品通过硅胶色谱法纯化(0-50%梯度的EtOAc/庚烷;庚烷含有2%Et3N),得到(R)-N-((R)-8-(6-氨基-5-((3-氨基-2-氯苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(31mg,0.061 mmol),为灰白色固体。MS m/z 509.0(M+H)+.
步骤b:向(R)-N-((R)-8-(6-氨基-5-((3-氨基-2-氯苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(31mg,0.061mmol)的DCM (0.6mL)溶液中加入HCl溶液(4M在二氧六环中,76μL,0.304mmol),并将得到的混合物在40℃搅拌1h。加入HCl水溶液(2M,2mL),并将得到的混合物用DCM(2x)萃取。将水混合物用氢氧化铵(28%的水溶液)碱化,直到pH=12,将其用DCM(3x)萃取。合并有机层,用盐水洗涤,用Na2SO4干燥,过滤,并浓缩,得到(R)-8-(6-氨基-5-((3-氨基-2-氯苯基)硫基)吡嗪-2- 基)-8-氮杂螺[4.5]癸-1-胺(18mg,0.042mmol),为黄色固体。1H NMR (400MHz,甲醇-d4)δppm 7.40(s,1H),6.73(t,J=8.0Hz,1H),6.50(dd, J=8.1,1.3Hz,1H),5.90(dd,J=7.8,1.3Hz,1H),4.02-4.18(m,2H),3.21(dt, J=3.2,1.5Hz,1H),2.98(d,J=11.4Hz,2H),2.67(t,J=7.5Hz,1H),1.04-2.02 (m,10H).C19H26ClN6S(M+H)+的HRMS计算值405.1628,实测值405.1639.IC50是0.011μM。
实施例33
(R)-8-(6-氨基-5-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-
1-胺
向6-氯-3-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-胺(40mg,0.137mmol)的 DIPEA(0.7mL)混悬液中加入(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷 -2-亚磺酰胺(71mg,0.0275mmol)。将得到的混合物在90℃搅拌10h,然后浓缩。将粗品溶解在DCM(0.7mL)中,加入HCl溶液(4M在二氧六环中,34μL,0.137mmol),并将得到的混合物在40℃搅拌1h。将反应混合物浓缩并将粗品通过HPLC纯化(梯度洗脱15至40%乙腈水溶液,0.1% TFA改性剂),得到(R)-8-(6-氨基-5-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2- 基)-8-氮杂螺[4.5]癸-1-胺(TFA盐:17mg,0.042mmol)。1H NMR(400MHz, DMSO-d6)δppm 7.94(d,J=5.3Hz,1H),7.79(br.s.,3H),7.69(br.s.,1H), 6.51(d,J=5.5Hz,1H),6.34(br.s.,2H),4.12-4.32(m,2H),2.99-3.24(m,3 H),2.00-2.12(m,1H),1.30-1.90(m,9H).C18H23ClFN6S(M+H)+的HRMS计算值409.1377,实测值409.1385.IC50是0.005μM。
实施例34
步骤a:向RT的2-氧代-1,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(300mg,1.180mmol)的二氯甲烷(3mL)溶液中加入五硫化二磷(110mg,0.495 mmol),随后加入六甲基二硅氧烷(2.256mL,10.62mmol)。将反应在RT 搅拌3h,然后用EtOAc稀释并通过硅藻土过滤。将滤液在减压下浓缩。将粗产物通过硅胶色谱法纯化(0至80%梯度的EtOAc/庚烷),得到1-硫代 -2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁酯(0.290g,1.07mmol),为白色固体。1HNMR(400MHz,DMSO-d6)δ10.39(s,1H),3.66(dt,J=13.6,4.9Hz,2H), 3.09(s,2H),2.78(t,J=7.8Hz,2H),1.95(t,J=7.8Hz,2H),1.57(dd,J=6.6, 4.8Hz,4H),1.39(s,9H).MS m/z271(M+H)+.
步骤b:向1-硫代-2,8-二氮杂螺[4.5]癸烷-8-甲酸酯(100mg,0.370 mmol)的THF(3mL)溶液中滴加加入碘甲烷(0.231mL,3.70mmol)。将得到的溶液在RT搅拌16h。期间,反应混合物的颜色缓慢变得更黄,并在搅拌指定的反应时间后产生浅黄色沉淀物。将反应混合物浓缩并在真空下干燥,得到黄色固体。将黄色固体溶取在MeOH(2mL)中,并用7M氨的甲醇溶液(3mL)处理,然后在密封管中加热至100℃反应8h。将反应冷却至RT并在减压下浓缩,得到固体,将其与乙腈超声并过滤。将滤液浓缩并将残留物通过硅胶色谱法纯化(0至30%梯度的MeOH/DCM),得到1-氨基-2,8-二氮杂螺[4.5]癸-1-烯-8-甲酸叔丁酯(87mg,0.343mmol)。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.81(d,J=25.2Hz,2H),3.98(s,2 H),3.55(t,J=7.0Hz,2H),2.82(s,2H),2.12(t,J=7.1Hz,2H),1.74(td, J=12.9,4.7Hz,2H),1.57(d,J=12.7Hz,2H),1.41(s,9H).MS m/z 254 (M+H)+.
步骤c:在RT向1-氨基-2,8-二氮杂螺[4.5]癸-1-烯-8-甲酸叔丁酯(86 mg,0.339mmol)的DCM(3mL)溶液中加入HCl的二氧六环溶液(4M,0.500 mL,2.0mmol),并将反应搅拌16h。将反应混合物浓缩并将残留物从乙腈中研磨并过滤,得到2,8-二氮杂螺[4.5]癸-1-烯-1-胺(57.7mg,0.254mmol),为黄褐色固体。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),9.39-9.23(m, 1H),9.15(s,1H),9.07(s,1H),8.70(d,J=12.5Hz,1H),3.54(t,J=6.9Hz,2H),3.32(d,J=13.3Hz,2H),3.05-2.88(m,2H),2.18(t,J=6.9Hz,2H),2.01 (td,J=13.7,4.3Hz,2H),1.80(d,J=13.8Hz,2H).MS m/z 154(M+H)+.
步骤d:向6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(250mg,0.815mmol)和2,8-二氮杂螺[4.5]癸-1-烯-1-胺(210mg,1.371mmol)的N-甲基-2-吡咯烷酮(4mL)混悬液中加入DIPEA(1.4mL,8.02mmol),并将反应加热至140℃反应16h。将得到的黑色混合物冷却至RT,并用EtOAc和水稀释。分配各层并弃去有机层。将水层用20%异丙醇/氯仿混合物(2x30 mL)萃取,将合并的有机物用Na2SO4干燥,过滤并浓缩。将粗品残留物采用制备HPLC纯化(梯度洗脱,5至40%ACN的水溶液,0.1%TFA改性剂),并将收集的级分的一半冻干,得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3- 基)硫基)吡嗪-2-基)-2,8-二氮杂螺[4.5]癸-1-烯-1-胺(TFA盐:61.4mg,0.082 mmol)。将剩余的级分合并并通过与50%饱和的NaHCO3剧烈搅拌10分钟中和。将得到的溶液用20%异丙醇/氯仿混合物(3x30mL)萃取,将合并的有机物用Na2SO4干燥,过滤并浓缩,得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,8-二氮杂螺[4.5]癸-1-烯-1-胺(22mg,0.052 mmol),为游离碱。1H NMR(400MHz,DMSO-d6)δ8.46(d,J=4.4Hz,1H), 7.67(s,1H),7.55(dd,J=8.2,4.5Hz,1H),7.31(d,J=8.1Hz,1H),6.19(s,2 H),5.74(s,2H),4.40(d,J=13.4Hz,2H),3.43-3.34(m,2H),2.90(t,J=12.2 Hz,2H),1.97-1.89(m,2H),1.83(td,J=13.0,4.1Hz,2H),1.36(d,J=12.9Hz, 2H).MS m/z 424.1541(M+H)+.IC50是0.032μM
采用上面的胺和采用文中描述的标准方法偶联制备下面的化合物。
实施例36
外消旋的-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-
8-氮杂螺[4.5]癸-4-胺
在5mL锥形微波瓶中,将外消旋的-2-(8-(6-氨基-5-((2-(三氟甲基)吡啶 -3-基)硫基)吡嗪-2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮(40 mg,0.072mmol)溶解在乙醇(1mL)中,加入水合肼(0.070mL,1.44mmol),加盖并在90℃铝珠浴上加热2h。通过0.45μm PTFE膜真空过滤混悬液并用乙醇洗涤。HPLC纯化(梯度洗脱15至40%乙腈水溶液,0.1%TFA 改性剂),然后用EtOAc稀释并用饱和碳酸氢盐水溶液洗涤,然后用盐水洗涤。浓缩,用1mL DCM稀释,加入HCl(100μL,4M在二氧六环中),获得沉淀物。浓缩获得8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2- 基)-2-氧杂-8-氮杂螺[4.5]癸-4-胺(HCl盐:1mg,0.002mmol)。1H NMR (400MHz,甲醇-d4)δ8.43–8.39(m,1H),7.65(s,1H),7.46–7.39(m,2H), 4.35–4.14(m,2H),3.98(d,J=9.2Hz,1H),3.90(d,J=9.2Hz,1H),3.58(d, J=5.3Hz,1H),3.29–3.12(m,3H),1.76(m,4H).C18H22F3N6OS(M+H)+的HRMS计算值427.1528,实测值427.1537.IC50是0.07μM。
实施例37
(R)和(S)-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-
8-氮杂螺[4.5]癸-4-胺
在5mL锥形微波瓶中将单一的对映体P1,2-(8-(6-氨基-5-((2-(三氟甲基) 吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3-二酮 (49mg,0.088mmol)溶解在乙醇(1mL)中,加入水合肼(0.080mL,1.65 mmol),加盖并在90℃的铝珠浴中加热2h。通过0.45μm PTFE膜真空过滤该混悬液并用乙醇洗涤。HPLC纯化(梯度洗脱15至40%乙腈水溶液, 5mM NH4OH改性剂),分离得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基) 硫基)吡嗪-2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-胺(13mg,0.029mmol)。手性分析HPLC:LC-3 4.6x100mm,5μm,流动相:45%MeOH(含有10mM氨),5 mL/min,单一的对映体峰1(P1),Rt:0.88min,>99%单一的对映体.1H NMR(400MHz,甲醇-d4)δ8.39(dd,J=4.3,1.6Hz,1H),7.60(s,1H),7.41 (m,2H),4.21–4.07(m,3H),3.86(d,J=8.7Hz,1H),3.79(d,J=8.7Hz,1H), 3.51(dd,J=9.0,5.2Hz,1H),3.24(m,2H),3.15(m,1H),1.73(m,2H),1.59 (m,1.8Hz,2H).C18H22F3N6OS(M+H)+的HRMS计算值427.1528,实测值427.1542.IC50是0.025μM。
实施例38
(R)和(S)-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-
8-氮杂螺[4.5]癸-4-胺
在5mL锥形微波瓶中,将单一的对映体P2,2-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-基)异吲哚啉-1,3- 二酮(42mg,0.075mmol)溶解在乙醇(1mL)中,加入水合肼(0.080mL, 1.65mmol),加盖并在90℃铝珠浴上加热2h。通过0.45μm PTFE膜真空过滤该混悬液并用乙醇洗涤。HPLC纯化(梯度洗脱15至40%乙腈水溶液,5mM NH4OH改性剂),分离得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧杂-8-氮杂螺[4.5]癸-4-胺(13mg,0.029mmol)。手性分析HPLC:LC-34.6x100mm,5μm,流动相:45%MeOH(含有10mM氨),5 mL/min,单一的对映体峰2(P2),Rt:1.33min,>99%单一的对映体。1H NMR(400MHz,甲醇-d4)δ8.39(dd,J=4.3,1.6Hz,1H),7.60(s,1H),7.41 (m,2H),4.21–4.07(m,3H),3.86(d,J=8.6Hz,1H),3.79(d,J=8.8Hz,1H), 3.50(dd,J=9.0,5.2Hz,1H),3.24(m,2H),3.15(m,1H),1.80–1.67(m,2H), 1.64–1.50(m,2H).C18H22F3N6OS(M+H)+的HRMS计算值427.1528,实测值427.1536.IC50是0.983μM。
实施例39
(R)-6-氨基-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-5-((2-(三氟甲基)吡啶-3-基)
硫基)烟酰胺
步骤a:向2,6-二氯吡啶-3-甲酰胺(0.728g,3.81mmol)的1-甲基吡咯烷酮(7mL)溶液中加入N-甲基吗啉(1.14mL,10.40mmol)和(R)-N-((R)-1-(4- 甲氧基苯基)乙基)-8-氮杂螺[4.5]癸-1-胺(1g,3.47mmol)。将得到的混合物在回流条件下加热至100℃反应24h。将反应混合物用乙酸乙酯稀释,用浓碳酸氢钠处理并过滤。分离有机层,用硫酸钠干燥,过滤并在减压下浓缩。将得到的暗红色油状物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/庚烷,含有0.25%三乙胺),得到6-氯-2-((R)-1-(((R)-1-(4-甲氧基苯基) 乙基)氨基)-8-氮杂螺[4.5]癸-8-基)烟酰胺(0.998g,2.25mmol)。1H NMR (400MHz,甲醇-d4)δ7.81(d,J=7.8Hz,1H),7.26(d,J=8.6Hz,2H),6.86(m, 3H),3.82(m,1H),3.77(s,3H),3.75–3.63(m,2H),3.03(m,2H),2.59(m,1 H),2.01–1.92(m,1H),1.88–1.52(m,5H),1.51–1.36(m,3H),1.32(d,J=6.5 Hz,3H),1.25(m,2H).MS m/z 442.9(M+H)+.
步骤b:向6-氯-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺 [4.5]癸-8-基)烟酰胺(242mg,0.546mmol)的甲苯(11mL)溶液中,加入 Pd2(dba)3(97mg,0.169mmol)和(氧基双(2,1-亚苯基))双(二苯基膦)(103mg, 0.191mmol)。将反应混合物用氮气鼓泡,在氮气下加入二苯甲酮亚胺(0.11 mL,0.656mmol)和叔丁醇钾(0.710mL,1M的四氢呋喃溶液,0.710mmol)。将反应混合物加热80℃反应2h,使混合物冷却至RT,通过硅藻土垫层过滤,并用乙酸乙酯洗涤。将滤液在减压下浓缩,并将残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/庚烷),得到6-((二苯基亚甲基)氨基)-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)烟酰胺(250mg,0.425mmol)。MS m/z 588.3(M+H)+.
步骤c:向6-((二苯基亚甲基)氨基)-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)烟酰胺(130mg,0.221mmol)的THF(6mL) 混悬液中,加入HCl(2M,0.1mL,0.200mmol),并将得到的溶液在RT搅拌30分钟。将反应混合物在减压下浓缩,并将残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/庚烷,含有0.25%三乙胺),得到6-氨基 -2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)烟酰胺(43mg,0.102mmol)。MS m/z 424.1(M+H)+.
步骤d:将6-氨基-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)氨基)-8-氮杂螺[4.5]癸-8-基)烟酰胺(199mg,0.470mmol)的三氟乙酸(3mL)溶液加热至 100℃反应30min。将混合物在减压下浓缩,并没有进一步纯化将残留物用于下一步骤。(R)-6-氨基-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)烟酰胺.MS m/z 290.2(M+H)+.
步骤e:向(R)-6-氨基-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)烟酰胺的二氯甲烷(2mL)溶液中加入三乙胺(0.196mL,1.410mmol)和二碳酸二叔丁酯(113 mg,0.517mmol),并将得到的混合物在RT搅拌2h。将反应混合物在减压下浓缩,并将残留物通过硅胶色谱法纯化(0至50%梯度的乙酸乙酯/庚烷, 含有0.25%三乙胺),得到(R)-(8-(6-氨基-3-氨基甲酰基吡啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(147mg,0.377mmol)。1H NMR(400MHz, 甲醇-d4)δ7.88(d,J=8.5Hz,1H),6.19(d,J=8.5Hz,1H),3.66(t,J=7.7Hz,1H),3.27–3.15(m,2H),2.98(t,J=12.4Hz,2H),2.05–1.94(m,1H),1.86–1.46 (m,8H),1.45(s,9H),1.41(d,J=6.0Hz,1H).MS m/z 390.3(M+H)+.
步骤f:向在冰浴上冷却的(R)-(8-(6-氨基-3-氨基甲酰基吡啶-2-基)-8- 氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(136mg,0.349mmol)的二氯甲烷(5mL) 溶液中,加入N-碘琥珀酰亚胺(86mg,0.384mmol)。将得到的混合物在5℃搅拌2h。加入2mL甲醇将反应淬灭,并将混合物升温至RT。在减压下除去溶剂。将粗产物用二氯甲烷萃取,并用盐水洗涤。将有机层用硫酸钠干燥,过滤并在减压下浓缩,得到(R)-(8-(6-氨基-3-氨基甲酰基-5-碘吡啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(170mg,0.330mmol),没有进一步纯化将其用于下一步骤。MS m/z 516.1(M+H)+.
步骤g:向(R)-(8-(6-氨基-3-氨基甲酰基-5-碘吡啶-2-基)-8-氮杂螺[4.5] 癸-1-基)氨基甲酸叔丁酯(177mg,0.343mmol)的二氧六环(10mL)溶液中,加入Pd2(dba)3(31.4mg,0.034mmol)、(9,9-二甲基-9H-呫吨-4,5-二基)双(二苯基膦)(39.7mg,0.069mmol)、2-(三氟甲基)吡啶-3-硫醇(67.7mg,0.378 mmol)和N,N-二异丙基乙胺(0.120mL,0.687mmol)。将得到的混合物加热至120℃反应2h,然后冷却至RT。将反应混合物用乙酸乙酯稀释并通过短的硅藻土垫层过滤。将滤液在减压下浓缩并通过硅胶色谱法纯化(0至 50%梯度的乙酸乙酯/庚烷,含有0.25%三乙胺),得到(R)-(8-(6-氨基-3- 氨基甲酰基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡啶-2-基)-8-氮杂螺[4.5]癸-1- 基)氨基甲酸叔丁酯(115mg,0.203mmol)。MS m/z 567.2(M+H)+.
步骤h:向(R)-(8-(6-氨基-3-氨基甲酰基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡啶-2-基)-8-氮杂螺[4.5]癸-1-基)氨基甲酸叔丁酯(110mL,0.194mmol) 的二氯甲烷(2mL)溶液中加入三氟乙酸(2mL,26mmol),并将得到的混合物在RT搅拌1h。在减压下除去溶剂,并将残留物通过HPLC(梯度洗脱: 35-60%乙腈水溶液,5mM NH4OH改性剂)纯化,得到(R)-6-氨基-2-(1-氨基-8-氮杂螺[4.5]癸-8-基)-5-((2-(三氟甲基)吡啶-3-基)硫基)烟酰胺(40mg, 0.084mmol)。1H NMR(400MHz,甲醇-d4)δ8.38(dd,J=4.1,1.9Hz,1H), 7.93(s,1H),7.56-7.31(m,2H),3.77-3.55(m,2H),3.16-2.98(m,2H),2.82 (t,J=7.4Hz,1H),2.03(m,1H),1.94-1.60(m,5H),1.60-1.20(m,4H).19F NMR(376MHz,甲醇-d4)δ-66.48.C21H26F3N6OS(M+H)+的HRMS计算值467.1841,实测值467.1837.IC50是0.118μM。
实施例40
(R)-3-((3-氨基-5-(1-氨基-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯
甲酰胺
步骤a:将2-氯-3-巯基苯甲酰胺(HCl盐,145mg,0.647mmol)、3-溴 -6-氯吡嗪-2-胺(299mg,1.436mmol)、碘化亚铜(I)(49.3mg,0.259 mmol)、磷酸钾(412mg,1.941mmol)和1,10-菲咯啉(58.3mg,0.324mmol) 的二氧六环(5mL,脱气的)混合物在微波反应器中在130℃搅拌4h。冷却至RT后,将反应物通过硅藻土垫层过滤,随后用EtOAc(50mL)洗涤。将合并的滤液浓缩,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到3-((3-氨基-5-氯吡嗪-2-基)硫基)-2-氯苯甲酰胺(140 mg,0.444mmol)。MS m/z 315.0(M+H)+
步骤b:将3-((3-氨基-5-氯吡嗪-2-基)硫基)-2-氯苯甲酰胺(130mg, 0.412mmol)和(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺 (139mg,0.536mmol)的DIPEA(0.648mL)混合物在微波反应器中在95℃搅拌14h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的MeOH/DCM,含有0.25%TEA),得到 3-((3-氨基-5-((R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲酰胺(65mg,0.121mmol)。MS m/z 537.2 (M+H)+.
步骤c:将3-((3-氨基-5-((R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲酰胺(65mg,0.121mmol) 溶解在HCl/二氧六环(4M,0.121mL,0.484mmol)中并在22℃搅拌直到没有原料剩下(1h,通过LCMS监测)。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱:25至50%乙腈水溶液,5mMNH4OH改性剂),得到R)-3-((3-氨基-5-(1-氨基-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲酰胺(25.5mg,0.058mmol)。1H NMR(400MHz,DMSO-d6) δ7.90(s,1H),7.63(s,1H),7.62(br.s.,1H),7.28-7.18(m,1H),7.18-7.09 (m,1H),6.64(dd,J=1.6,7.9Hz,1H),6.08(s,2H),4.18-4.07(m,2H), 3.12-2.95(m,2H),2.74-2.64(m,1H),1.91-1.73(m,2H),1.66-1.47(m,4H), 1.39-1.14(m,4H).C20H26ClN6OS(M+H)+的HRMS计算值433.1577,实测值433.1598;IC50是0.016μM。
实施例41
(2R,4R)-4-氨基-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-
氮杂螺[4.5]癸-2-醇
步骤a:将(1R,3R)-3-((叔丁基二甲基硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(100mg,0.205mmol)和 HCl(4M在二氧六环中,510μL,2.05mmol)的MeOH(1mL)混合物在40℃搅拌1h。在减压下除去挥发物,并将得到的白色残留物在真空下干燥1h。 MS m/z 171.1(M+H)+.
步骤b:将该白色残留物和3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2- 胺(65mg,0.226mmol)的DIPEA:NMP(2:1;1.5mL)混合物在100℃剧烈搅拌40h。冷却至RT后,在减压下除去挥发物,并将得到的粗品通过HPLC 纯化(梯度洗脱7.5-20%乙腈水溶液,0.1%TFA改性剂)。在减压下除去挥发物,并将得到的残留物通过HPLC进一步纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(2R,4R)-4-氨基-8-(6-氨基-5-((2-氨基 -3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-2-醇(44mg,0.102 mmol),为白色固体。1HNMR(400MHz,甲醇-d4)δppm 7.51-7.64(m,2H), 5.92(d,J=5.56Hz,1H),4.16-4.39(m,3H),3.00-3.21(m,2H),2.80(dd, J=8.08,7.07Hz,1H),2.33(dt,J=13.45,6.79Hz,1H),1.95(dd,J=13.89,7.58 Hz,1H),1.83(dd,J=14.02,4.17Hz,1H),1.61-1.74(m,3H),1.56(ddd, J=13.39,8.08,5.81Hz,1H),1.30(d,J=13.14Hz,1H).C18H25ClN7OS (M+H)+的HRMS计算值422.1557,实测值422.1569.IC50是0.007μM。
采用上面的方法或对上面的方法进行修改,利用相应的保护的胺和氯- 吡嗪中间体,合成下面的表9化合物。
表9
实施例68
(3R,4S)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-
氧杂-8-氮杂螺[4.5]癸-4-胺
步骤a:将(3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂 -8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(53mg,0.142mmol)和HCl(4M在二氧六环中,354μL,1.415mmol)的MeOH(5mL)混合物在40℃搅拌1h。冷却至RT后,在减压下除去挥发物,得到(3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5] 癸烷-4-胺,其没有进一步纯化即用于下一步骤。MS m/z 171.1(M+H)+.
步骤b:将(3R,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺粗品、3-((2- 氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(35.5mg,0.123mmol)和DIPEA (193μL,1.11mmol)的DMSO(600μL)混合物在100℃搅拌16h。冷却至 RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(3R,4S)-8-(6-氨基 -5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸 -4-胺(13mg,0.030mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.72-7.51(m, 2H),5.92(d,J=5.5Hz,1H),4.31(m,2H),4.01-3.78(m,2H),3.58(dq,J=8.1, 6.0Hz,1H),3.04(m,2H),2.48(d,J=8.1Hz,1H),1.75(m,2H),1.61-1.47 (m,2H),1.31(d,J=6.1Hz,3H).C18H25ClN7OS(M+H)+的HRMS计算值 422.1530,实测值422.1505.IC50是0.010μM。
实施例69
(3S,4S)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-
氧杂-8-氮杂螺[4.5]癸-4-胺
步骤a:将(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8- 氮杂螺[4.5]癸烷-8-甲酸叔丁酯(51mg,0.136mmol)和HCl(4M在二氧六环中,340μL,1.362mmol)的MeOH(5mL)混合物在40℃搅拌1h。冷却至RT后,在减压下除去挥发物,得到(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺,其没有进一步纯化即用于下一步骤。MS m/z 171.1(M+H)+.
步骤b:将(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺粗品、3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(35.5mg,0.123mmol)和DIPEA (193μL,1.11mmol)的DMSO(600μL)混合物在100℃搅拌16h。冷却至 RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(3S,4S)-8-(6-氨基 -5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸 -4-胺(11mg,0.026mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.67-7.47(m, 2H),5.91(d,J=5.5Hz,1H),4.22(qd,J=6.4,4.8Hz,1H),4.03(ddt,J=13.5, 8.9,4.7Hz,2H),3.86(d,J=8.7Hz,1H),3.71(d,J=8.7Hz,1H),3.37(td, J=9.9,4.9Hz,1H),3.29-3.23(m,1H),3.00(d,J=5.0Hz,1H)1.91-1.56(m,4 H),1.21(d,J=6.4Hz,3H).C18H25ClN7OS(M+H)+的HRMS计算值 422.1530,实测值422.1514.IC50是0.010μM。
实施例70
(1R,3R)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8-
氮杂螺[4.5]癸-1-胺
步骤a:将(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(100mg,0.246mmol)和HCl(4M在二氧六环中,1.5 mL,6.5mmol)的MeOH(1.5mL)混合物在微波反应器中在140℃搅拌14 h。冷却至RT后,在减压下除去挥发物,得到(1R,3R)-3-甲基-8-氮杂螺[4.5] 癸-1-胺,其没有进一步纯化即用于下一步骤。MS m/z 169.2(M+H)+.
步骤b:将(1R,3R)-3-甲基-8-氮杂螺[4.5]癸-1-胺粗品(theor 0.246mmol) 和3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(70.9mg,0.246mmol)的 DIPEA(1mL)和DMSO(0.5mL)混合物在130℃搅拌2h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱 15-40%乙腈水溶液,5mM NH4OH改性剂),得到(1R,3R)-8-(6-氨基-5-((2- 氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8-氮杂螺[4.5]癸-1-胺(23mg, 0.055mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.51-7.64(m,2H),5.91 (d,J=5.31Hz,1H),4.18-4.37(m,2H),3.02-3.18(m,2H),2.82(dd,J=9.60, 6.32Hz,1H),2.09-2.20(m,1H),2.00-2.09(m,1H),1.91-2.00(m,1H), 1.58-1.74(m,2H),1.24-1.48(m,3H),1.09-1.20(m,1H),1.01-1.09(m,3H). C19H27ClN7S(M+H)+的HRMS计算值420.1737,实测值420.1719.IC50是 0.005μM。
实施例71
(1R,3S)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8-
氮杂螺[4.5]癸-1-胺
步骤a:将(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄酯(600mg,1.476mmol)和Pd(OH)2(104mg,0.148 mmol)的EtOAc:THF(1:2 75mL)混悬液在H2气氛下剧烈搅拌48h。将反应混合物通过硅藻土垫层过滤,随后用MeOH(50mL)洗涤。在减压下除去挥发物。将得到的残留物和HCl(4M在二氧六环中,1.0mL,4.0mmol)的溶液在45℃搅拌2h。冷却至RT后,在减压下除去挥发物。在60psi H2气氛下将得到的残留物和Pd/C(10%在炭上,200mg)的MeOH(20mL)混悬液振摇2h。将反应混合物通过硅藻土垫层过滤,随后用MeOH(50mL)洗涤。在减压下除去挥发物,得到(1R,3S)-3-甲基-8-氮杂螺[4.5]癸-1-胺,其没有进一步纯化即用于下一步骤。MS m/z 169.1(M+H)+.
步骤b:将(1R,3S)-3-甲基-8-氮杂螺[4.5]癸-1-胺粗品(0.729mmol)和 3-((2-氨基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(150mg,0.521mmol)的 DIPEA(3.2mL)和DMA(6mL)混合物在100℃搅拌14h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱 10-30%乙腈水溶液,0.1%TFA改性剂),得到粗的固体。该粗的固体通过 HPLC进一步纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(1R,3S)-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8- 氮杂螺[4.5]癸-1-胺(80mg,0.189mmol)。1H NMR(400MHz,甲醇-d4)δ ppm 7.65-7.49(m,2H),5.91(d,J=5.5Hz,1H),4.30(ddt,J=12.4,9.7,3.6Hz, 2H),3.34(s,1H),3.19-2.95(m,1H),2.92-2.80(m,1H),2.34-2.16(m,2H), 1.85-1.49(m,4H),1.41(dq,J=13.5,2.7Hz,1H),1.30(dq,J=13.5,2.6Hz,1 H),1.13-0.92(m,4H).C19H27ClN7S(M+H)+的HRMS的计算值420.1737,实测值420.1716.IC50是0.005μM。
实施例72
8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-1-氧杂-3,8-二氮杂
螺[4.5]癸-2-烯-2-胺
步骤a:将6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(70mg,0.304mmol)、((4-羟基哌啶-4-基)甲基)氨基甲酸叔丁酯(103mg,0.336 mmol)和DIPEA(2.0mL,11.45mmol)的NMP(1mL)溶液在120℃搅拌3 h。冷却至RT后,将反应物用EtOAc稀释,将有机相用水、盐水洗涤,用 Na2SO4干燥,并在减压下除去挥发物,得到棕色油状残留物。将该残留物溶取在DCM(5mL)中,并分两份加入HCl(4M在二氧六环中;760μL,3.04 mmol)(一半在反应开始时,另一半在3小时后)。将反应搅拌总共4h。在减压下除去挥发物,并将得到的残留物与MeCN研磨,得到棕色固体。混悬在5%MeOH/DCM中并加入饱和NaHCO3水溶液,将得到的粗品游离碱化。分离得到的层,并将水层再次用5%MeOH/DCM萃取。将合并的有机相在减压下浓缩,得到1-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2- 基)-4-(氨基甲基)哌啶-4-醇(65mg,0.149mmol),为灰白-黄褐色固体。1H NMR(400MHz,DMSO-d6)δppm 8.47(dd,J=4.6,1.4Hz,1H),7.68(s,1H), 7.55(dd,J=8.3,4.5Hz,1H)7.32(dd,J=8.3,1.4Hz,1H),4.04(dt,J=13.8,4.2 Hz,2H),3.38-3.28(m,2H),2.83(s,2H),1.70-1.48(m,4H).MS m/z 401.2(M+H)+.
步骤b:将1-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-4-(氨基甲基)哌啶-4-醇(65mg,0.162mmol)的EtOH(3mL)溶液用溴化氰(0.541 mL,1.623mmol)连续处理,随后加入NaHCO3(68.2mg,0.812mmol),并将得到的混合物在RT搅拌16h。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-1-氧杂-3,8-二氮杂螺[4.5]癸-2-烯-2-胺(12.5mg,0.029mmol)。1H NMR(400MHz,DMSO-d6) δppm 8.46(dd,J=4.5,1.4Hz,1H),7.68(s,1H),7.55(dd,J=8.3,4.6Hz,1H), 7.31(dd,J=8.2,1.5Hz,1H),6.22(s,2H),5.78(s,2H),3.94-3.73(m,2H), 3.64-3.45(m,2H),3.36(s,2H),1.88-1.56(m,4H).C17H19F3N7OS(M+H)+的HRMS计算值426.1318,实测值426.1296.IC50是0.193μM。
采用上面的方法或对上面的方法进行修改,利用相应的保护的胺和氯- 吡嗪中间体,合成下面的表10化合物。
表10
实施例75
(R)-8-(6-氨基-5-((3-氯-2-(二甲基氨基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂
螺[4.5]癸-1-胺
步骤a:将6-溴-3-((3-氯-2-(二甲基氨基)吡啶-4-基)硫基)吡嗪-2-胺(124 mg,0.392mmol)和(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺 (111mg,0.431mmol)的DIPEA(2.6mL)混合物在90℃搅拌10h。冷却至 RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0 至10%梯度的EtOAc(含有10%的MeOH)/庚烷(含有25的Et3N)),得到 (R)-N-((R)-8-(6-氨基-5-((3-氯-2-(二甲基氨基)吡啶-4-基)硫基)吡嗪-2-基)-8- 氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(75mg,0.139mmol)。MS m/z 538.3(M+H)+.
步骤b:将(R)-N-((R)-8-(6-氨基-5-((3-氯-2-(二甲基氨基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(75mg,0.139 mmol)和HCl(4M在二氧六环中,174μL,0.697mmol)的DCM(2mL)混合物在RT搅拌30min。在减压下除去挥发物,并将得到的残留物通过HPLC 纯化(梯度洗脱35-60%乙腈水溶液,5mM NH4OH改性剂),得到(R)-8-(6- 氨基-5-((3-氯-2-(二甲基氨基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1- 胺(28mg,0.064mmol),为白色固体。1H NMR(400MHz,DMSO-d6)δ ppm 7.85-7.92(m,1H),7.63(s,1H),6.16(br.s,2H),6.04-6.10(m,1H), 4.06-4.23(m,2H),2.97-3.15(m,2H),2.87(s,6H),2.64-2.73(m,1H), 1.11-1.97(m,10H).C20H29ClN7S(M+H)+的HRMS计算值434.1894,实测值 434.1883.IC50是0.010μM。
采用上面的方法或对上面的方法进行修改,利用相应的保护的胺和氯- 吡嗪中间体,合成下面的表11化合物。
表11
实施例81
(R)-4-((3-氨基-5-(1-氨基-8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-3-氯吡
啶-2(1H)-酮
将(S)-N-((R)-8-(6-氨基-5-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(17mg,0.033mmol)、氢氧化锂(2 mg,0.040mmol)和水(0.07mL)的DMSO(0.3mL)混合物在微波反应器中在 90℃搅拌45min。冷却至RT后,加入MeOH(0.5mL),随后加入HCl(4 M在二氧六环中,2.0mL,8.0mmol),并将得到的混合物在40℃搅拌1h。在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱15-40%乙腈水溶液,5mM NH4OH改性剂),得到(R)-4-((3-氨基-5-(1-氨基 -8-氮杂螺[4.5]癸-8-基)吡嗪-2-基)硫基)-3-氯吡啶-2(1H)酮(5mg,0.012 mmol),为白色固体。1HNMR(400MHz,甲醇-d4)δppm 7.53-7.61(m,1H), 7.19(d,J=7.1Hz,1H),5.72(d,J=7.1Hz,1H),4.26(t,J=13.1Hz,2H), 3.06-3.20(m,2H),2.81(t,J=7.5Hz,1H),1.27-2.11(m,10H).C18H24ClN6OS (M+H)+的HRMS计算值407.1448,实测值407.1433.IC50是0.020μM。
实施例82
外消旋的-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二
氟-8-氮杂螺[4.5]癸-1-胺
步骤a:将2,2-二氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(220mg,0.76mmol)、外消旋的2-甲基丙烷-2-亚磺酰胺(184mg,1.52mmol)和乙醇钛(IV)(0.640mL,3.0mmol)的THF(4mL)溶液在90℃搅拌30min。冷却至0℃后,一次性地加入硼氢化锂(33mg,1.5mmol)。搅拌30min后,通过加入MeOH将反应混合物淬灭。在减压下除去挥发物。将得到的残留物用盐水稀释,将其用EtOAc(4x10mL)萃取,将合并的有机相用Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(10 至50%梯度的EtOAc/庚烷),得到1-(1,1-二甲基乙基亚磺酰氨基)-2,2-二氟 -8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯,为白色粉末(190mg,0.48mmol)。MS m/z 395.2(M+H)+.
步骤b:将1-(1,1-二甲基乙基亚磺酰氨基)-2,2-二氟-8-氮杂螺[4.5]癸烷 -8-甲酸叔丁酯(190mg,0.48mmol)和TFA(1mL)的DCM(4mL)溶液在0 ℃搅拌20min。在减压下除去挥发物,得到N-(2,2-二氟-8-氮杂螺[4.5]癸-1- 基)-2-甲基丙烷-2-亚磺酰胺,其没有进一步纯化即用于下一步骤。
步骤c:将N-(2,2-二氟-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(theor 0.48mmol)和6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(148 mg,0.480mmol)的DIPEA(0.8mL)溶液在100℃搅拌1h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到N-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基) 吡嗪-2-基)-2,2-二氟-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(174 mg,0.28mmol),为橙色粉末。将一部分该物质进行步骤d,将剩余的物质通过手性色谱法分离(参见实施例83)。
步骤d:将N-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2- 基)-2,2-二氟-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(54mg,0.096 mmol)和HCl(4M在二氧六环中,0.239mL,0.96mmol)的DCM(1mL)溶液在40℃搅拌30min。冷却至RT后,在减压下除去挥发物。将该残留物与MeCN研磨,得到外消旋的-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基) 吡嗪-2-基)-2,2-二氟-8-氮杂螺[4.5]癸-1-胺(HCl盐,38mg,0.075mmol),为浅黄褐色粉末。1H NMR(400MHz,甲醇-d4)δppm 8.52-8.38(m,1H),7.71 (s,1H),7.50-7.43(m,2H),4.44(dd,J=21.0,14.2Hz,2H),3.67(dd,J=15.1, 11.2Hz,1H),3.23-3.08(m,2H),2.47-2.34(m,2H),2.27(dt,J=14.6,7.4Hz, 1H),2.01-1.88(m,2H),1.75-1.54(m,3H).C19H22F5N6S(M+H)+的HRMS计算值461.1547,实测值461.1540.IC50是0.380μM。
实施例83a/b
(R)和(S)-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二
氟-8-氮杂螺[4.5]癸-1-胺
步骤a:N-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2- 二氟-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺(100mg,0.177mmol) 通过如下的手性SFC进一步纯化:柱:WHO-1 21x250mm,流速:80g/分钟,流动相:45%MeOH和5mM NH4OH在CO2中,检测:触发的质量,获得单一的对映体Rt(对映体R):2.6min(44mg,0.078mmol)和Rt(对映体S): 5.8min(41mg,0.073mmol)。
步骤b:将纯对映体和HCl(4M在二氧六环中,200μL,0.8mmol)的 DCM(2mL)混合物在40℃搅拌1h。在减压下除去挥发物,并将得到的残留物与MeCN研磨,得到为HCl盐的标题化合物:
(R)-对映体:1H NMR(400MHz,甲醇-d4)δppm 8.46(dd,J=3.7,2.3Hz, 1H),7.73(s,1H),7.53-7.45(m,2H),4.52-4.36(m,2H),3.68(dd,J=15.0, 11.2Hz,1H),3.24-3.09(m,2H),2.47-2.34(m,2H),2.32-2.21(m,1H), 2.05-1.90(m,2H),1.74-1.55(m,3H).19FNMR(376MHz,甲醇-d4)δ-66.19, -98.51(d,J=234.5Hz),-101.83(d,J=234.6Hz).C19H22F5N6S(M+H)+的 HRMS计算值461.1547,实测值461.1540.IC50是0.882μM。
(S)-对映体:1H NMR(400MHz,甲醇-d4)δppm 8.50-8.41(m,1H),7.70 (s,1H),7.47(m,2H),4.52-4.35(m,2H),3.67(dd,J=15.1,11.2Hz,1H), 3.24-3.05(m,2H),2.49-2.32(m,2H),2.31-2.19(m,1H),2.02-1.88(m,2H), 1.73-1.51(m,3H).19F NMR(376MHz,甲醇-d4)δ-66.24,-98.47(d,J=234.4 Hz),-101.77(d,J=234.6Hz).C19H22F5N6S(M+H)+的HRMS计算值461.1547, 实测值461.1541.IC50是0.306μM。
实施例84
8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氟-8-氮杂螺
[4.5]癸-1-胺
步骤a:将外消旋的2-氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁酯(78 mg,0.28mmol)、乙醇钛(IV)(235μL,1.1mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(68mg,0.56mmol)的THF(1.5mL)溶液在90℃搅拌1h。冷却至0℃后,一次性加入硼氢化锂(12mg,0.56mmol)。搅拌30min后,通过加入 MeOH将反应混合物淬灭。在减压下除去挥发物。将得到的残留物用盐水稀释,将其用EtOAc(4x10mL)萃取,将合并的有机相用Na2SO4干燥,过滤,并在减压下浓缩。将得到的残留物通过硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氟-8-氮杂螺 [4.5]癸烷-8-甲酸叔丁酯(64mg,0.17mmol)。MS m/z377.3(M+H)+.
步骤b:将1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氟-8-氮杂螺[4.5]癸烷 -8-甲酸叔丁酯(64mg,0.17mmol)和TFA(1mL)的DCM(4mL)混合物在 0℃搅拌10min。在减压下除去挥发物,并将得到的残留物没有进一步纯化即用于下一步骤。
步骤c:将前面的残留物和6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪 -2-胺(51mg,0.17mmol)的DIPEA(0.3mL)混合物在100℃搅拌2h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过硅胶色谱法纯化(0 至10%梯度的MeOH/DCM(含有0.25%Et3N)),得到N-(8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氟-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷 -2-亚磺酰胺(41mg,0.075mmol)。MS m/z 547.2(M+H)+,为非对映体混合物。采用手性SFC如下进行进一步纯化:柱:ID 21x250mm,流速:80g/ 分钟,流动相:45%iPrOH和10mM NH4OH在CO2中,检测:触发的质量,得到单一的对映体Rt(P1)=2.7min(17mg,0.031mmol)和Rt(enant-P1)= 4.4min(17mg,0.031mmol)。
步骤d:将各纯的异构体和HCl(4M在二氧六环中,100μL,0.4mmol) 的DCM(0.1mL)溶液在40℃搅拌1h。冷却至RT后,在减压下除去挥发物,并将得到的残留物与MeCN研磨,得到标题化合物,为HCl盐。
表12
实施例86a/b
(1R)-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮
杂螺[4.5]癸-1-胺
步骤a:将(1R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-甲基-8-氮杂螺 [4.5]癸烷-8-甲酸叔丁酯(32mg,0.086mmol)和TFA(0.2mL,2.60mmol)的 DCM(2mL)溶液在RT搅拌30min。在减压下除去挥发物,得到(R)-2-甲基 -N-((1R)-2-甲基-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺。MS m/z 273.0 (M+H)+。将粗产物没有进一步纯化即用于下一步骤。
步骤b:将(R)-2-甲基-N-((1R)-2-甲基-8-氮杂螺[4.5]癸-1-基)丙烷-2-亚磺酰胺(23mg,0.084mmol)、6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺 (23mg,0.075mmol)和NMP(0.1mL)的DIPEA(1mL)混合物在115℃搅拌6h。冷却至RT后,在减压下除去挥发物,得到(R)-N-((1R)-8-(6-氨基 -5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮杂螺[4.5]癸-1- 基)-2-甲基丙烷-2-亚磺酰胺,为黑色油状物,没有纯化即将其用于下一步骤。
步骤c:将(R)-N-((1R)-8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪 -2-基)-2-甲基-8-氮杂螺[4.5]癸-1-基)-2-甲基丙烷-2-亚磺酰胺和HCl(4M在二氧六环中,84μL,0.338mmol)的DCM(2mL)混合物在40℃搅拌1h。冷却至RT后,在减压下除去挥发物,并将得到的残留物通过HPLC纯化(梯度洗脱35-60%乙腈水溶液,0.1%TFA改性剂),得到8-(6-氨基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮杂螺[4.5]癸-1-胺TFA盐。 C20H26F3N6S的HRMS计算值439.1892(M+H)+,实测值439.1872.IC50是 0.0010μM。
步骤d:手性分离(详情见表13)。
表13
可采用上面的方法和适当的原料制备下面表14的实施例:
表14
测定
就其选择性抑制SHP2活性的能力评估本发明的化合物。本文中所描述的本发明的化合物的抑制性质可通过下面任一测定法中的测试来证实。
SHP2变构抑制测定
SHP2通过双-酪氨酰-磷酰化的肽与其Src同源2(SH2)结构域的结合而变构活化。该在后的活化步骤导致SHP2的自动抑制界面的释放,这又使该SHP2蛋白酪氨酸磷酸酶(PTP)活化并可用于底物识别和反应催化。在迅速荧光测定版式中使用替代底物DiFMUP监测SHP2的催化活性。
更具体地,在室温下在384孔黑色聚苯乙烯板(平底、低凸缘、非结合表面)(Corning,Cat#3575)中,使用25μL的最终反应体积和以下测定缓冲液条件进行磷酸酶反应:60mM的HEPES,pH 7.2、75mM NaCl、75mM KCl、1mM EDTA、0.05%P-20、5mM DTT。
采用下述测定监测本发明化合物的SHP2的抑制(浓度从0.003–100 μM变化),在测定中用0.5μM的肽IRS1_pY1172(dPEG8)pY1222(序列: H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-酰胺)孵育0.5nM的 SHP2。在25℃孵育30-60分钟后,将替代底物DiFMUP(Invitrogen,cat# D6567)加入反应中并在25℃孵育30分钟。然后通过加入5μl的160μMbpV(Phen)溶液(Enzo Life Sciences cat#ALX-270-204)猝灭反应。采用分别使用340nm和450nm激发和发射波长的酶标仪(Envision,Perki-Elmer)监测荧光信号。采用用基于对照的标准化拟合的标准化的IC50回归曲线来分析抑制剂剂量响应曲线。本发明的化合物的IC50结果显示在上面的实施例和表4-表 13中。
p-ERK细胞测定
使用SureFireTM Phospho-ERK 1/2Kit(PerkinElmer)的 p-ERK细胞测定法:将KYSE-520细胞(30,000个细胞/孔)在96孔板培养物中生长过夜,并用浓度20、6.6、2.2、0.74、0.24、0.08、0.027μM的Shp2 抑制剂在37℃处理2小时。通过加入提供有SureFire磷酸化细胞外信号调节激酶(pERK)测定试剂盒(PerkinElmer)的30μL裂解缓冲液(PerkinElmer),终止孵育。根据制造商的指示处理样品。使用2101多标记读数器(PerkinElmer Envision)一式两份测定来自pERK的荧光信号。抑制的百分比被总ERK信号标准化并且与DMSO溶媒对照比较。
集落形成测定和细胞增殖测定
将KYSE-520细胞(1500细胞/孔)接种到24孔板上至300μL培养基(含有10%FBS的RPMI-1640,Lonza)中。对于药物治疗,在细胞接种后24小时和5天,加入各种浓度(20、10、5、2.5、1.25μM)的本发明化合物。在第11天,将集落用0.2%结晶紫(MP Biomedicals)染色,随后溶解于20%乙酸中,用于采用Spectramax读数器(Thermo Scientific)定量。在细胞增殖测定中,将细胞(1500细胞/孔)接种到96孔板上至100μL培养基(含有10% FBS的RPMI-1640,Lonza)中。在第6天,加入50μL的Celltiter-Glo试剂 (Promega),并根据供应商的指示(Promega)测定发光信号。
应当理解,文中描述的实施例和实施方案仅用于说明的目的,在其启示下,各种修改或改变将被建议给本领域的技术人员,并且被包括在本申请的精神和范围内,以及所附权利要求的范围内。
Claims (26)
1.式Ia的化合物:
其中:
n选自1、2、3和4;
p选自0和1;
q选自0和1;
Y1选自CH和N;
Y2选自CR6和N;
各Y4独立地选自N、C(O)和CR9;其中当Y4是C(O)时,仅一个Y4是C(O);
R6选自氢、卤素、甲基和氨基-羰基;
R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被1-3个独立地选自以下的基团取代:氨基、卤素、羟基、氨基-甲基和甲基-氨基;
R9选自卤素、氨基、羟基、N3、二甲基-氨基、C1-4烷基、卤素-取代的-C1-4烷基、C1-4烷氧基、-C(O)OR10和-NHC(O)R10;
R10选自氢、苯基和萘基;其中所述R10的苯基未被取代或被甲氧基取代;或其药学上可接受的盐。
2.式Ia的化合物:
其中:
n选自1、2、3和4;
p选自0和1;
q选自0和1;
Y1选自CH和N;
Y2选自CR6和N;
各Y4独立地选自N、C(O)和CR9;其中当Y4是C(O)时,仅一个Y4是C(O);
R6选自氢、卤素、甲基和氨基-羰基;
R7和R8与它们都相连的碳原子一起形成5元饱和的或部分不饱和的环,该环可任选包含1-2个独立地选自N、O、C(O)和S(O)m的杂原子或基团;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被1-3个独立地选自以下的基团取代:氨基、羟基、甲氧基、卤素、甲基、甲基-氨基和异丁酰氧基;
R9选自卤素、氨基、羟基、N3、二甲基-氨基、C1-4烷基、卤素-取代的-C1-4烷基、C1-4烷氧基、-C(O)OR10和-NHC(O)R10;
R10选自氢、苯基和萘基;其中所述R10的苯基未被取代或被甲氧基取代;
或其药学上可接受的盐。
3.化合物,或其药学上可接受的盐,所述化合物选自:
4.权利要求1的化合物,其中R7和R8与它们都相连的碳原子一起形成6元饱和的或部分不饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被氨基取代;或其药学上可接受的盐。
5.化合物,或其药学上可接受的盐,所述化合物选自:
6.权利要求1的化合物,其中R7和R8与它们都相连的碳原子一起形成4元饱和的或部分不饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被选自以下的基团取代:氨基、氨基-甲基和甲基-氨基;或其药学上可接受的盐。
7.化合物,或其药学上可接受的盐,所述化合物选自:
8.权利要求1的化合物,其中p和q都是0;或其药学上可接受的盐。
9.化合物,或其药学上可接受的盐,所述化合物选自:
10.一种化合物,或其药学上可接受的盐,所述化合物选自
11.一种化合物,或其药学上可接受的盐,所述化合物选自
12.一种化合物,或其药学上可接受的盐,所述化合物选自
13.一种化合物,或其药学上可接受的盐,所述化合物选自
14.式II的化合物:
其中:
p选自0和1;
q选自0和1;
Y1选自CH和N;
Y2选自CR6和N;
R1选自苯基、吡啶基、咪唑基、嘧啶基、噁唑基、异噁唑基、三唑基、四唑基和吡唑基;其中所述苯基、吡啶基、咪唑基、嘧啶基、噁唑基、异噁唑基、三唑基、四唑基或吡唑基被1至5个独立地选自以下的R9基团取代:卤素、氨基、羟基、N3、C1-4烷基、羟基-取代的-C1-4烷基、卤素-取代的-C1-4烷基和氨基-取代的-C1-4烷基;
R2a和R2b独立地选自氢;
R3a和R3b独立地选自卤素;
R4a和R4b独立地选自氢;
R5a和R5b独立地选自氢;
R6选自氢、卤素、C1-4烷基、C1-4烷氧基和氨基-羰基;
R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被1-3个独立地选自以下的基团取代:氨基、卤素、羟基、氨基-甲基和甲基-氨基;或其药学上可接受的盐。
15.式IIa的化合物:
其中:
n选自1、2、3和4;
p选自0和1;
q选自0和1;
Y1选自CH和N;
Y2选自CR6和N;
Y4选自N和CR9;
R6选自氢、卤素、甲基和氨基-羰基;
R7和R8与它们都相连的碳原子一起形成3至7元饱和或部分不饱和的环,该环可任选地含有选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环可以是未取代的或被选自以下的基团取代:氨基、氨基-甲基和甲基-氨基;
R9选自卤素、氨基、羟基、N3、C1-4烷基、卤素-取代的-C1-4烷基、C1-4烷氧基、-C(O)OR10和-NHC(O)R10;
R10选自氢、苯基和萘基;其中所述R10的苯基未被取代或被甲氧基取代;或其药学上可接受的盐。
16.权利要求15的化合物,其中R7和R8与它们都相连的碳原子一起形成5元饱和的或部分不饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被氨基取代;或其药学上可接受的盐。
17.化合物,或其药学上可接受的盐,所述化合物选自:
18.权利要求15的化合物,其中R7和R8与它们都相连的碳原子一起形成6元饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被氨基取代;或其药学上可接受的盐。
19.化合物,或其药学上可接受的盐,所述化合物选自:
20.权利要求15的化合物,其中R7和R8与它们都相连的碳原子一起形成4元饱和的环,该环可任选包含选自N、O和S(O)m的杂原子;其中m选自0、1和2;其中所述由R7和R8形成的饱和的环被氨基取代;或其药学上可接受的盐。
21.化合物,或其药学上可接受的盐,所述化合物选自:
22.权利要求15的化合物,其中p和q都是0;或其药学上可接受的盐。
23.化合物,或其药学上可接受的盐,所述化合物选自:
24.药物组合物,其包含权利要求1的化合物或其药学上可接受的盐以及至少一种药学上可接受的载体。
25.权利要求1的化合物或其药学上可接受的盐在制备用于预防或治疗由SHP2活性介导的疾病或病症的药物中的用途。
26.权利要求25的用途,其中由SHP2活性介导的疾病或病症选自努南综合征、豹综合征、青少年髓单核细胞白血病、成神经细胞瘤、黑色素瘤、急性髓性白血病、乳腺癌、食道癌、肺癌、结肠癌、头癌、头颈的鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。
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