CN106573922A - 磷脂酰肌醇3‑激酶抑制剂 - Google Patents
磷脂酰肌醇3‑激酶抑制剂 Download PDFInfo
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- CN106573922A CN106573922A CN201580031602.6A CN201580031602A CN106573922A CN 106573922 A CN106573922 A CN 106573922A CN 201580031602 A CN201580031602 A CN 201580031602A CN 106573922 A CN106573922 A CN 106573922A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Abstract
本申请提供式(J)化合物或者其药学上可接受的盐、异构体、互变异构体或混合物,其中n、m、R1、R2、R3、R4和R5描述在本申请中。所述化合物为磷脂酰肌醇3‑激酶(PI3K)活性抑制剂,可用于治疗由一种或者多种PI3K亚型介导的病症。本申请还提供包含式(I)化合物或者其药学上可接受的盐、异构体、互变异构体或混合物的药物组合物,以及使用这些化合物和组合物治疗由一种或者多种PI3K亚型介导的病症的方法。
Description
技术领域
本申请涉及选择性抑制PI3K亚型活性的新化合物及其治疗用途。
背景技术
经由3’-磷酸化磷酸肌醇的细胞信号传导已经牵涉在多种细胞过程中,例如,恶性转化、生长因子信号传导、炎症和免疫(Rameh等人,J.Biol.Chem.,274:8347-8350,1999)。磷脂酰肌醇3-激酶(PI 3-激酶或者PI3K)负责产生这些磷酸化信号传导产物。PI3K最初被鉴定为与病毒癌蛋白和生长因子受体酪氨酸激酶相关联的蛋白质,所述生长因子受体酪氨酸激酶使磷脂酰肌醇(PI)及其在肌醇环的3’-羟基处的磷酸化衍生物磷酸化(Panayotou等人,Trends Cell Biol.,2:358-60,1992)。
三类PI 3-激酶(PI3K)基于底物特异性被提出。I类PI3K磷酸化磷脂酰肌醇(PI)、磷脂酰肌醇-4-磷酸和磷脂酰肌醇-4,5-二磷酸(PIP2)以分别产生磷脂酰肌醇-3-磷酸(PIP)、磷脂酰肌醇-3,4-二磷酸和磷脂酰肌醇-3,4,5-三磷酸。此外,II类PI3K磷酸化PI和磷脂酰肌醇-4-磷酸,以及III类PI3K磷酸化PI。
PI 3-激酶的最初纯化和分子克隆揭示,其为由p85和p110亚单位组成的异二聚体(Otsu等人,Cell,65:91-104,1991;Hiles等人,Cell,70:419-29,1992)。后来,四个不同的I类PI3K被识别并指定为PI3Kα、β、δ和γ亚型。每一亚型由不同的110kDa催化亚单位和调节亚单位组成。PI3Kα、β和δ的催化亚单位(即,分别为p110α、p110β和p110δ)分别与相同的调节亚单位p85相互作用,而PI3Kγ的催化亚单位(p110γ)与不同的调节亚单位p101相互作用。
研究还显示,每一PI3K亚型具有不同的表达模式。例如,编码PI3Kα的PIK3CA经常在人类癌症中突变(Engelman,Nat.Rev.Cancer,9:550-562,2009)。此外,PI3Kδ通常在造血细胞中表达。而且,PI3K亚型显示出与癌症、炎性或者自身免疫性疾病中的增殖或者存活信号传导相关联。由于每一PI3K亚型具有不同的生物功能,PI3K亚型是治疗癌症或者障碍的潜在靶标(美国专利6,800,620;8,435,988;8,673,906;美国专利申请公开号US2013/0274253)。
由此,需要开发抑制PI3K亚型的治疗剂以治疗由PI3K介导的疾病、障碍或者病症。
发明内容
本申请提供新化合物,其为PI3K亚型的抑制剂。本申请还提供组合物(包括药物组合物)、包含所述化合物的试剂盒以及使用和制备所述化合物的方法。本申请中提供的化合物可用于治疗由PI3K亚型介导的疾病、障碍或者病症。本申请还提供用于治疗的化合物。本申请还提供在治疗由PI3K亚型介导的疾病、障碍或者病症的方法中使用的化合物。而且,本申请提供所述化合物在制备药物中的用途,所述药物用于治疗由PI3K亚型介导的疾病、障碍或者病症。
本申请提供具有式(I)的结构的化合物:
其中:
n为1、2或者3;
m为0或者1;
每一R1独立地选自卤素、氰基、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的C1-6烷氧基、任选取代的磺酰基、任选取代的C3-8芳基、任选取代的C3-8杂芳基、任选取代的C3-8环烷基和任选取代的C3-8杂环烷基;
每一R2独立地选自卤素和任选取代的C1-6烷基;
R3为氢、任选取代的C1-6烷基、任选取代的C6-10芳基或者任选取代的C3-8环烷基;
R4为具有至少一个芳基和至少两个杂原子的6至12元杂芳基,其中所述杂原子选自N、O或者S,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、任选取代的卤代烷基、任选取代的C1-6烷基和-NH2;和
R5为氢或者任选取代的C1-6烷基,其中R5和R3与它们所连接的原子一起任选地形成4或8元杂环;
或者其药学上可接受的盐、异构体或混合物。
本申请还提供具有式(I)的结构的化合物,其中:
n为1或者2;
m为0或者1;
每一R1独立地选自卤素、C1-6烷基和C1-6卤代烷基;
每一R2独立地为C1-6烷基;
R3为氢、C1-6烷基或者C3-8环烷基;
R4为具有至少一个芳环和至少两个氮原子的6至12元杂芳基,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、-NH2、C1-6卤代烷基和C1-6烷基;和
R5为氢、甲基、乙基或者丙基,或者R5和R3与它们所连接的原子一起任选地形成五元杂环;
或者其药学上可接受的盐、异构体或混合物。
在一个方面,本申请化合物具有式(I)的结构,其中每一R1独立地选自氯、溴、氟、甲基、乙基和丙基。在一些方面,本申请化合物具有式(I)的结构,其中每一R2独立地选自甲基、乙基和丙基。在一些方面,本申请化合物具有式(I)的结构,其中R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基。在另一方面,本申请化合物具有式(I)的结构,其中R5为氢、甲基、乙基或者丙基。在一些其它方面,本申请化合物具有式(I)的结构,其中R5和R3与它们所连接的原子一起任选形成吡咯烷基。在又一方面,本申请化合物具有式(I)的结构,其中R4为具有至少两个氮原子的单环杂芳基,其中R4取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2。在一些其它方面,本申请化合物具有式(I)的结构,其中R4为嘧啶基,其取代有两个或三个选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2。
在一些实施方案中,所述PI3K抑制剂为选自表1的化合物、其药学上可接受的盐、异构体或混合物。在另外的一些实施方案中,所述化合物为(S)-对映异构体。在其它一些实施方案中,所述化合物为(R)-对映异构体。在其它一些实施方案中,所述化合物为阻转异构体。
本申请还提供药物组合物,其包含式(I)化合物、其药学上可接受的盐、异构体,或者混合物,以及至少一种药学上可接受的媒介物。药学上可接受的媒介物的实例可选自载体、辅助剂和赋形剂。
本申请还提供在有需要的人中治疗疾病、障碍或者病症的方法,其通过向所述人给药治疗有效量的式(I)化合物或者其药学上可接受的盐、异构体,或者混合物。还提供了在治疗由PI3K亚型介导的疾病、障碍或者病症的方法中使用的式(I)化合物。本申请还提供了式(I)化合物在制备药物中的用途,所述药物用于治疗由PI3K亚型介导的疾病、障碍或者病症。在一些实施方案中,所述疾病、障碍或者病症与PI3K相关或者由PI3K介导。在一些实施方案中,所述疾病、障碍或者病症为炎性障碍。在其它一些实施方案中,所述疾病、障碍或者病症为癌症。
本申请还提供抑制磷脂酰肌醇3-激酶多肽的活性的方法,其通过使所述多肽与式(I)化合物或者其药学上可接受的盐、异构体,或者混合物接触。
还提供了抑制过度或破坏性免疫反应的方法,其包括给药有效量的式(I)化合物或者其药学上可接受的盐、异构体或混合物。
还提供了抑制癌细胞的生长或增殖的方法,其包括使所述癌细胞与有效量的式(I)化合物或者其药学上可接受的盐、异构体或混合物接触。
还提供了试剂盒,其包含式(I)化合物或者其药学上可接受的盐、异构体或混合物。所述试剂盒还可包含标签和/或化合物在治疗有需要的人中的疾病、障碍或者病症中的使用说明书。在一些实施方案中,所述疾病、障碍或者病症可与PI3K活性相关或者由PI3K活性介导。
还提供了制品,其包含式(I)化合物或者其药学上可接受的盐、异构体或混合物以及容器。在一种实施方案中,所述容器可为瓶、罐、安瓿、预装载注射器或者静脉输液袋。
具体实施方式
以下描述阐述了示例性方法、参数等。该描述不意图限制本申请范围,而是作为示例性实施方案提供。
本申请使用的以下词语、短语和符号通常意图具有如在下文中阐述的含义,但上下文另外说明的情况除外。
不在两个字母或者符号之间的短划线(“-”)用于指示取代基的连接点。例如,-CONH2通过碳原子连接。在化学基团的前端或者后端的短划线为出于方便的目的;化学基团可使用或者不用一个或者多个短划线进行描述,而不失去它们的普通含义。穿过结构中的线所画的波浪线指示基团的连接点。除非在化学上或者结构上需要,否则化学基团书写或者命名的顺序不指示或者暗示方向性。
前缀“Cu-v”表明随后的基团具有u至v个碳原子。例如,“C1-6烷基”表明烷基具有1至6个碳原子。
本申请中提及的“约”值或者参数包括(和描述)涉及该值或者参数本身的实施方案。在一些实施方案中,所述术语“约”包括指出的量±10%。在其它一些实施方案中,所述术语“约”包括指出的量±5%。在一些其它实施方案中,所述术语“约”包括指出的量±1%。此外,提及的术语“约X”包括“X”的描述。此外,单数形式"一(a/an)"和"该(the)"包括复数的提及形式,除非上下文清楚地另外指出。因此,例如,提及的"该化合物"包括多个这种化合物,提及的"该测定"包括提及本领域技术人员已知的一个或者多个测定及其等同物。
“烷基”是指非支化或者支化的饱和烃链。本申请使用的烷基具有1至20个碳原子(即,C1-20烷基)、1至8个碳原子(即,C1-8烷基)、1至6个碳原子(即,C1-6烷基),或者1至4个碳原子(即,C1-4烷基)。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、异-丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基和3-甲基戊基。当具有具体碳数的烷基残基被命名时,具有该碳数的所有几何异构体可被包括;因此,例如,“丁基”包括正丁基、仲丁基、异丁基和叔丁基;“丙基”包括正丙基和异丙基。
“烯基”是指脂族基团,其含有至少一个碳-碳双键和具有2至20个碳原子(即,C2-20烯基)、2至8个碳原子(即,C2-8烯基)、2至6个碳原子(即,C2-6烯基),或者2至4个碳原子(即,C2-4烯基)。烯基的实例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基和1,3-丁二烯基)。
“炔基”是指脂族基团,其含有至少一个碳-碳三键和具有2至20个碳原子(即,C2-20炔基)、2至8个碳原子(即,C2-8炔基)、2至6个碳原子(即,C2-6炔基),或者2至4个碳原子(即,C2-4炔基)。所述术语“炔基”还包括具有一个三键和一个双键的那些基团。
“烷氧基”是指基团“烷基-O-”。烷氧基的实例包括甲氧基、乙氧基、正-丙氧基、异-丙氧基、正-丁氧基、叔-丁氧基、仲-丁氧基、正-戊氧基、正-己氧基和1,2-二甲基丁氧基。
“酰基”是指基团-C(=O)R,其中R为氢、烷基、环烷基、杂环烷基、芳基、杂烷基或者杂芳基;其各自可任选被取代,如本申请所定义。酰基的实例包括甲酰基、乙酰基、环己基羰基、环己基甲基-羰基和苯甲酰基。
“酰胺基团”是指“C-酰胺基团”(其是指基团-C(═O)NRyRz)和“N-酰胺基团”(其是指基团-NRyC(═O)Rz),其中Ry和Rz独立地选自氢、烷基、芳基、卤代烷基或者杂芳基;其各自可任选被取代。
“氨基”是指基团-NRyRz,其中Ry和Rz独立地选自氢、烷基、卤代烷基、芳基或者杂芳基;其各自可任选被取代。
“芳基”是指芳族碳环基团,其具有单环(例如,单环的)或者多环(例如,二环或者三环),包括稠合体系。本申请使用的芳基具有6至20个环碳原子(即,C6-20芳基)、6至12个碳环原子(即,C6-12芳基),或者6至10个碳环原子(即,C6-10芳基)。芳基的实例包括苯基、萘基、芴基和蒽基。然而,芳基不以任何方式包括或者重叠下面定义的杂芳基。如果一个或者多个芳基与杂芳基环稠合,则所得环系为杂芳基。
“氰基”或者“甲腈”是指基团-CN。
“环烷基”是指饱和或部分饱和的环烷基,其具有单环或多环(包括稠合、桥接和螺环体系)。所述术语“环烷基”包括环烯基(即,具有至少一个烯基的环状基团)。本申请使用的环烷基具有3至20个环碳原子(即,C3-20环烷基)、3至12个环碳原子(即,C3-12环烷基)、3至10个环碳原子(即,C3-10环烷基)、3至8个环碳原子(即,C3-8环烷基),或者3至6个环碳原子(即,C3-6环烷基)。环烷基的实例包括环丙基、环丁基、环戊基和环己基。
“卤素”或者“卤代”包括氟、氯、溴和碘。“卤代烷基”是指如上所定义的非支化或者支化的烷基,其中一个或者多个氢原子被卤素替代。例如,在残基取代有超过一个卤素的情况下,它可通过使用对应于连接的卤素部分的数目的前缀来提及。二卤代烷基和三卤代烷基是指取代有两个(“二”)或者三个(“三”)卤素(其可为,但不一定为,相同的卤素)基团的烷基。卤代烷基的实例包括二氟甲基(-CHF2)和三氟甲基(-CF3)。
“杂烷基”是指烷基,其中一个或者多个碳原子(和任何相关的氢原子)各自独立地被相同或者不同的杂原子基团替代。例如,1、2或者3个碳原子可独立地被相同或者不同的杂原子基团替代。杂原子基团包括但不限于-NR-、-O-、-S-、-S(O)-、-S(O)2-等,其中R为H、烷基、芳基、环烷基、杂烷基、杂芳基或者杂环烷基,其各自可任选被取代。杂烷基的实例包括-OCH3、-CH2OCH3、-SCH3、-CH2SCH3、-NRCH3和-CH2NRCH3,其中R为氢、烷基、芳基、芳基烷基、杂烷基或者杂芳基,其各自可任选被取代。本申请使用的杂烷基包括1至10个碳原子、1至8个碳原子或者1至4个碳原子;以及1至3个杂原子、1至2个杂原子或者1个杂原子。
“杂芳基”是指具有单环、多环或者多个稠环的芳族基团,其一个或者多个环杂原子独立地选自氮、氧和硫。本申请使用的杂芳基包含1至20个环碳原子(即,C1-20杂芳基)、3至12个环碳原子(即,C3-12杂芳基)或者3至8个碳环原子(即,C3-8杂芳基);以及1至5个杂原子、1至4个杂原子、1至3个环杂原子、1至2个环杂原子或者1个环杂原子,所述杂原子独立地选自氮、氧和硫。杂芳基的实例包括嘧啶基、嘌呤基、吡啶基、哒嗪基、苯并噻唑基和吡唑基。杂芳基不包括或者重叠如上所定义的芳基。
“杂环烷基”是指饱和的或者不饱和的环烷基,其具有一个或者多个独立地选自氮、氧和硫的环杂原子。所述术语“杂环烷基”包括杂环烯基(即,具有至少一个烯基的杂环烷基)。杂环烷基可为单环或者多环,其中所述多环可为稠合、桥接或螺环的。本申请使用的杂环烷基具有2至20个环碳原子(即,C2-20杂环烷基)、2至12个环碳原子(即,C2-12杂环烷基)、2至10个环碳原子(即,C2-10杂环烷基)、2至8个环碳原子(即,C2-8杂环烷基)、3至12个环碳原子(即,C3-12杂环烷基)、3至8个环碳原子(即,C3-8杂环烷基)或者3至6个环碳原子(即,C3-6杂环烷基);具有1至5个环杂原子、1至4个环杂原子、1至3个环杂原子、1至2个环杂原子或者1个环杂原子,所述环杂原子独立地选自氮、硫或者氧。杂环烷基的实例包括吡咯烷基、哌啶基、哌嗪基、氧杂环丁烷基、二氧戊环基、氮杂环丁烷基和吗啉基。
“羟基”是指基团-OH。
“氧代(oxo)”是指基团(=O)或者(O)。
“磺酰基”是指基团-S(O)2R,其中R为烷基、卤代烷基、环烷基、杂环烷基、杂芳基或者芳基。磺酰基的实例为甲基磺酰基、乙基磺酰基、苯基磺酰基和甲苯磺酰基。
可使用某些常用替代性化学名称。举例来说,例如二价“烷基”、二价“芳基”等二价基团也可分别称为“亚烷基(alkylene或alkylenyl)”、“亚芳基(arylene或arylenyl)”。另外,除非另有明确定义,否则基团的组合在本文中作为一个部分(例如芳基烷基)提及时,最后一个提及的基团含有所述部分连接到分子其余部分的原子。
术语“任选”或“任选地”意思是随后所述的事件或情形可发生或可不发生,且所述描述包括其中所述事件或情形发生的情况以及其中所述事件或情形不发生的情况。此外,术语“任选取代的”指的是指定原子或基团上的任何一或多个氢原子可被或可不被除氢以外的部分置换。
术语“取代”意思是指定原子或基团上的任何一或多个氢原子被除氢以外的一个或多个取代基置换,条件为不超过指定原子的正常化合价。所述一个或多个取代基包括,但不限于,烷基、烯基、炔基、烷氧基、酰基、氨基、酰胺基、脒基、芳基、叠氮基、氨基甲酰基、羧基、羧基酯、氰基、胍基、卤素、卤代烷基、杂烷基、杂芳基、杂环烷基、羟基、肼基、亚氨基、氧代、硝基、烷基亚硫酰基、磺酸基、烷基磺酰基、硫氰酸基(thiocyanate)、巯基、硫酮基或其组合。作为实例,可以存在1、2、3、4、5或6个取代基。本文预期不包括通过进一步用所附取代基无限地定义取代基得到的聚合物或类似不确定的结构(例如,具有取代的烷基的取代的芳基,该取代的烷基本身取代有取代的芳基,该取代的芳基进一步被取代的杂烷基取代,等)。除非另有所述,本文所述化合物中连续取代的最大数量为3。例如,取代的芳基被2个其它取代的芳基的连续取代被限制为((取代的芳基)取代的芳基)取代的芳基。类似的,上述定义预期不包括不允许的取代方式(例如,取代有5个氟的甲基,或具有两个相邻氧环原子的杂芳基)。这些不允许的取代方式是本领域技术人员众所周知的。当用于修饰化学基团时,术语“取代”可描述本文定义的其它化学基团。例如,术语“取代的芳基”包括但不限于,“烷基芳基”。除非另外指出,当一个基团描述为任选取代的,该基团的任何取代基本身为未取代的。
在一些实施方案中,术语“取代的烷基”是指具有一个或多个取代基的烷基,所述取代基包括羟基、卤素、烷氧基、环烷基、杂环烷基、芳基和杂芳基。在其它一些实施方案中,“取代的环烷基”是指具有一个或多个取代基的环烷基,所述取代基包括烷基、卤代烷基、杂环烷基、芳基、杂芳基、烷氧基、卤素、羟基;“取代的芳基”是指具有一个或多个取代基的芳基,所述取代基包括卤素、烷基、卤代烷基、杂环烷基、杂芳基、烷氧基和氰基,且“取代的磺酰基”是指基团-S(O)2R,其中R取代有一个或多个烷基、环烷基、杂环烷基、芳基或杂芳基取代基。在其它一些实施方案中,所述一个或多个取代基可进一步取代有卤素、烷基、卤代烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基,其各自都被取代。在其它一些实施方案中,所述取代基可进一步取代有卤素、烷基、卤代烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基,其各自都未被取代。
PI3K抑制剂化合物
本申请提供用作PI3K亚型的抑制剂的化合物。在一个方面,所述PI3K抑制剂为具有式(J)结构的化合物:
其中:
n为0、1、2、3或者4;
m为0、1或者2;
W为CH或者N;
每一R1独立地选自卤素、氰基、任选取代的烷基、任选取代的卤代烷基、任选取代的烷氧基、任选取代的磺酰基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环烷基;
每一R2独立地选自卤素、任选取代的烷基、任选取代的卤代烷基;
R3为氢、任选取代的烷基、任选取代的卤代烷基、任选取代的环烷基或者任选取代的芳基;
R4为杂芳基,其任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、任选取代的卤代烷基、任选取代的烷基和-NH2;和
R5为氢或者任选取代的烷基,其中R5和R3与它们所连接的原子一起任选地形成杂环;
或者其药学上可接受的盐、异构体或混合物。
本申请还提供具有式(I)的结构的化合物,其用作PI3K亚型的抑制剂。在一种实施方案中,所述PI3K抑制剂为具有以下结构的式(I)化合物:
其中:
n为1、2或者3;
m为0或者1;
每一R1独立地选自卤素、氰基、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的C1-6烷氧基、任选取代的磺酰基、任选取代的C3-8芳基、任选取代的C3-8杂芳基、任选取代的C3-8环烷基和任选取代的C3-8杂环烷基;
每一R2独立地选自卤素和任选取代的C1-6烷基;
R3为氢、任选取代的C1-6烷基、任选取代的C6-10芳基或者任选取代的C3-8环烷基;
R4为具有至少一个芳基和至少两个杂原子的6至12元杂芳基,其中所述杂原子选自N、O或者S,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、任选取代的卤代烷基、任选取代的C1-6烷基和-NH2;和
R5为氢或者任选取代的C1-6烷基,其中R5和R3与它们所连接的原子一起任选地形成4或8元杂环;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中
n为1或者2;
m为0或者1;
每一R1独立地选自卤素、C1-6烷基和C1-6卤代烷基;
每一R2为C1-6烷基;
R3为氢、C1-6烷基或者C3-8环烷基;
R4为具有至少一个芳环和至少两个氮原子的6至12元杂芳基,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、-NH2、C1-6卤代烷基和C1-6烷基;和
R5为氢、甲基、乙基或者丙基,或者R5和R3与它们所连接的原子一起任选地形成五元杂环;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0或者1;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
每一R2独立地选自甲基、乙基和丙基;
R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基;
R4为具有至少一个芳环和至少两个氮原子的6至12元单环杂芳基,其中所述单环杂芳基取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基;
R4为6至12元二环杂芳基,其具有至少一个芳环、至少两个氮原子和至少一个选自N、O和S的杂原子,其中所述二环杂芳基任选取代有一个或者两个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
R4为嘧啶基,其取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些另外的实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0或者1;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
每一R2独立地选自甲基、乙基和丙基;
R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基;
R4为具有至少一个芳环和至少两个氮原子的6至12元单环杂芳基,其中所述单环杂芳基取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基;
R4为6至12元二环杂芳基,其具有至少一个芳环、至少两个氮原子和至少一个选自N、O和S的杂原子,其中所述二环杂芳基任选取代有一个或者两个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
R4为嘧啶基,其取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(I)的结构,其中:
n为1或者2;
m为0;
每一R1独立地选自氯、溴、氟、甲基、乙基和丙基;
R4为取代有两个或三个成员的嘧啶基,所述成员各自独立地选自氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
此外,式(J)或者(I)的化合物可具有式(Ia)的结构:
其中
每一R1a、R1b、R1c和R1d独立地选自氢、氟、氯、溴和碘;
每一R2a和R2b独立地选自氢、甲基、乙基和丙基;
以及
R4选自
或者其药学上可接受的盐、异构体或混合物,其中R4任选取代有一个、两个或者三个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基、氰基和-NH2;和
R3和R5描述在本申请中;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(Ia)的结构,其中
每一R1a、R1b、R1c和R1d独立地选自氢、氟、氯、溴和碘;
每一R2a和R2b独立地选自氢、甲基、乙基和丙基;
以及
R3选自氢、甲基、乙基、丙基、丁基、环丙基和环丁基;
R4选自
和
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(Ia)的结构,其中
每一R1a、R1b、R1c和R1d独立地选自氢、氟、氯、溴和碘;
每一R2a和R2b独立地选自氢、甲基、乙基和丙基;
R3选自氢、甲基、乙基、丙基、丁基、环丙基和环丁基;
R4选自以及
R5为氢;
或者其药学上可接受的盐、异构体或混合物。
式(J)或者(I)的化合物也可具有式(Ib)的结构:
其中
R1a、R1b、R1c、R1d、R2a、R2b、R3和R5在本申请中限定;
p为0、1或者2;和
R4a独立地选自卤素、氰基、-NH2和C1-6烷基;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(Ib)的结构,其中
R1a、R1b、R1c、R1d、R2a、R2b、R3和R5在本申请中限定;
p为0、1或者2;和
每一R4a独立地选自卤素、氰基、-NH2、C1-6卤代烷基和C1-6烷基;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(Ib)的结构,其中
每一R1a、R1b、R1c、R1d独立地选自氢、氟、氯、溴和碘;
每一R2a和R2b独立地选自氢、甲基、乙基和丙基;
以及
R3选自氢、甲基、乙基、丙基、丁基、环丙基和环丁基;
p为1或者2;和
每一R4a独立地选自溴、氯、氟、氰基、甲基、乙基、丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;
或者其药学上可接受的盐、异构体或混合物。
在一些实施方案中,所述化合物具有式(Ib)的结构,其中
每一R1a、R1b、R1c、R1d独立地选自氢、氟、氯、溴和碘;
每一R2a和R2b独立地选自氢、甲基、乙基和丙基;
以及
R3选自氢、甲基、乙基、丙基、丁基、环丙基和环丁基;
p为1或者2;和
每一R4a独立地选自氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2;
或者其药学上可接受的盐、异构体或混合物。
在一种实施方案中,n为0。在一些实施方案中,n为1、2、3或4。在一些实施方案中,n为1、2或3。在其它一些实施方案中,n为1或2。在一些实施方案中,n为1,R1部分可位于喹唑酮环的苯基的任何位置。在另一实施方案中,n为2。两个R1取代基或者部分可相同或者不同。两个R1部分可位于喹唑酮环的苯基的任何两个位置。例如,第一R1可与第二R1相邻、相间或者相对。在又一实施方案中,n为3。所有R1取代基或部分可相同或者不同,或者两个R1可与第三R1相同和不同。三个R1部分可位于喹唑酮环的苯基的任何三个位置。例如,第一R1可与第二R1相邻,第一R1可与第三R1相对。在又一实施方案中,n为4。所有R1取代基可相同或者不同,三个R1可与第四R1相同和不同,两个R1可与第三和第四R1相同和不同。
在一些其它实施方案中,每一R1独立地为卤素、氰基、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的C1-6烷氧基、羟基、任选取代的C3-6环烷基、任选取代的C3-6杂环烷基、任选取代的C6-10芳基、任选取代的C4-8杂芳基或者任选取代的C1-6烷基磺酰基。在一些实施方案中,每一R1独立地为卤素、氰基、任选取代的C1-4烷基、任选取代的C1-4卤代烷基、任选取代的C1-4烷氧基、任选取代的C3-6环烷基或者任选取代的C1-4烷基磺酰基。在其它一些实施方案中,每一R1独立地为卤素、氰基、C1-4卤代烷基、C1-4烷基或者C1-4烷基磺酰基。在一些实施方案中,每一R1独立地选自氟、氯、碘、溴、氰基、甲基、乙基、丙基、丁基、氟代甲基、氟代乙基、二氟甲基、二氟乙基、三氟甲基、三氟乙基、甲基磺酰基、乙基磺酰基或者丙基磺酰基。在一些实施方案中,每一R1独立地为氟、氯、碘、氰基、甲基、乙基、二氟甲基(-CHF2)、三氟甲基(-CF3)、甲氧基、甲基磺酰基(-SO2CH3)、环丙基甲基或者环丙基。在一种实施方案中,每一R1独立地为氟、氯、氰基、甲基磺酰基、甲基或者三氟甲基。
在一些实施方案中,m为0。在一些实施方案中,m为0、1或2。在一些其它实施方案中,m为1或2。当m为1时,R2取代基或部分可位于吡嗪环的任何位置。当m为2时,两个R2取代基可相同或者不同。
在一些实施方案中,每一R2独立地为卤素、氰基、任选取代的C1-6烷基和任选取代的C1-6卤代烷基。在一些实施方案中,每一R2独立地为卤素、氰基、C1-4烷基和C1-4卤代烷基。在一些其它实施方案中,每一R2独立地为氟、氯、碘、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基、氟代甲基(例如,-CH2F)、二氟甲基(例如,-CHF2)、三氟甲基(例如,-CF3)、氟代乙基、二氟乙基、三氟乙基、甲基、乙基、丙基或者丁基。在一种实施方案中,每一R2独立地为氟、氯、甲基、-CHF2或者-CF3。
在一些实施方案中,R3为氢、任选取代的C1-6烷基、任选取代的C3-8环烷基或者任选取代的C6-10芳基。在一种实施方案中,R3为氢、C1-4烷基、C3-6环烷基或者C6-10芳基,其中C1-4烷基任选取代有C1-4烷氧基、C6-10芳基或者C3-6环烷基,其中C1-4烷氧基任选取代有C6-10芳基。在另外的一些实施方案中,R3为C1-4烷基、C3-6环烷基或者C6-10芳基,其中C1-4烷基任选取代有C1-4烷氧基、C6-10芳基或者C3-6环烷基,其中C1-4烷氧基任选取代有苯基、环丙基或者环丁基。在一些实施方案中,R3为氢、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基甲基、环丙基丁基、环丁基甲基、环丙基乙基、苯基、环丙基、环丁基、环戊基或者环己基,其中甲氧基和乙氧基取代有苯基、环丙基或者环丁基。在其它一些实施方案中,R3为甲基、乙基、环丙基甲基或者环丙基。
在另外的一些实施方案中,R5为氢或者任选取代的C1-6烷基。在一些实施方案中,R5为氢或者C1-4烷基。在一些实施方案中,R5为氢、甲基、乙基、丙基或者丁基。在一些其它实施方案中,R5为氢。
在其它一些实施方案中,R3和R5与它们所连接的原子(例如,分别为碳和氮)任选地形成杂环,其任选取代有卤素。在其它一些实施方案中,所述R3-R5杂环为4至7元环。在一些其它实施方案中,所述R3-R5杂环为4至7元环,其任选取代有氟、氯、溴或者碘。在一些其它实施方案中,所述R3-R5杂环为氮杂环庚烷基、氮杂环丁烷基、哌啶基和吡咯烷基。在一些其它实施方案中,所述R3-R5杂环为吡咯烷基。在一种其它实施方案中,所述R3-R5杂环为取代有卤素的5元杂环烷基。在其它一些实施方案中,所述R3-R5杂环为吡咯烷基,其取代有氟、氯、溴或者碘。
在一些实施方案中,R3为氢、任选取代的C1-6烷基、任选取代的C3-8环烷基或者任选取代的C6-10芳基。在一种实施方案中,R3为氢、C3-6环烷基、C6-10芳基或者C1-4烷基,其任选取代有羟基、C6-10芳基C1-4烷氧基或者C3-6环烷基。在一些实施方案中,R3为氢、甲基、乙基、丙基、丁基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环丙基、环丁基、环戊基、环己基、-CH2OH、-C2H4OH、-C3H6OH、苄基氧基甲基(即,)或者苯基(即,)。
在其它一些实施方案中,R3和R5与它们所连接的原子(例如,分别为碳和氮)任选地形成杂环。在其它一些实施方案中,所述R3-R5杂环为3至8元杂环烷基(即,杂环烷基具有3至8个环成员并且至少一个环成员为杂原子)。在其它一些实施方案中,所述R3-R5杂环为4至7元杂环烷基(即,杂环烷基具有4至7个环成员并且至少一个环成员为杂原子)。在一种实施方案中,所述R3-R5杂环为5元杂环烷基。在一些其它实施方案中,所述R3-R5杂环为C3-8杂环烷基。在一些其它实施方案中,所述R3-R5杂环为吡咯烷基。在一种其它实施方案中,所述R3-R5杂环为5元杂环烷基,其取代有一个或者两个卤素成员。在其它一些实施方案中,所述R3-R5杂环为吡咯烷基,其取代有氟、氯、溴或者碘的一个成员。
在一种实施方案中,R4为具有至少两个氮原子和至少一个芳环的杂芳基,其中R4杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、-NH2、C1-6烷基和C1-6卤代烷基。在一些实施方案中,R4杂芳基为6至12元杂芳基(即,杂芳基具有6至12个环成员)。在一些实施方案中,R4杂芳基为6至10元杂芳基(即,杂芳基具有6至10个环成员)。R4杂芳基可为单环或者二环杂芳基。在一些实施方案中,R4杂芳基为具有至少两个氮原子的单环杂芳基。在一些实施方案中,R4杂芳基为二环杂芳基,其具有至少一个芳环、至少两个氮原子和至少一个另外的选自N、O或者S的杂原子。在一些其它实施方案中,R4杂芳基选自嘌呤基、嘧啶基、噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基或者咪唑并三嗪基。
在任何前述化学式中,R4为杂芳基,其任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、-NH2、C1-6烷基和C1-6卤代烷基,其中所述R4杂芳基选自
在一些其它实施方案中,R4选自嘌呤基、嘧啶基、噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基和咪唑并三嗪基,其各自任选取代有一个、两个或者三个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基、氰基和-NH2。在其它一些实施方案中,R4选自嘌呤基、嘧啶基、噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基和咪唑并三嗪基,其各自任选取代有一个、两个或者三个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基、氰基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2。在一些其它实施方案中,R4选自噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基和咪唑并三嗪基,其各自任选取代有两个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基和-NH2。在其它一些实施方案中,R4选自噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基和咪唑并三嗪基,其各自任选独立取代有氯、氟、溴、碘和-NH2的一个成员。在其它一些实施方案中,R4选自噻唑并嘧啶基、吡啶并嘧啶基、噻吩并嘧啶基、吡咯并嘧啶基、呋喃并嘧啶基和咪唑并三嗪基,其各自任选取代有一个或者两个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基和-NH2。在一些其它实施方案中,R4为嘧啶基或者吡嗪基,每一嘧啶基或者吡嗪基取代有至少一个-NH2。在一些其它实施方案中,R4为嘧啶基或者吡嗪基,其各自取代有两个或者三个独立地选自以下的成员:氯、氟、溴、碘、甲基、乙基、丙基、氰基和-NH2。在一些实施方案中,R4为嘧啶基或者吡嗪基,其各自取代有至少两个或三个成员,每一成员独立地选自-NH2、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基和三氟丙基。在其它一些实施方案中,R4选自
在一种实施方案中,p为0。在一些实施方案中,p为1或者2。在p为1的实施方案中,R4a部分可位于嘧啶基环的任何位置。当p为2时,两个R4a取代基或部分可相同或者不同。在p为2的实施方案中,两个R4a取代基或部分可相同或者不同;两个R4a部分中的每个可位于嘧啶基环的任何位置。在p为3的实施方案中,所有R4a取代基可相同或者不同,或者两个R4a可与第三R4a相同和不同。
在本申请中,每一R4a独立地选自卤素、氰基、任选取代的C1-6烷基和-NH2。在一种实施方案中,每一R4a独立地为卤素、氰基、C1-4烷基和-NH2。在一些实施方案中,每一R4a独立地选自溴、氯、氟、碘、氰基、甲基、乙基、丙基和-NH2。在另外的一些实施方案中,每一R4a独立地选自溴、氯、氟、碘、氰基、甲基、乙基、丙基、氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2。在其它一些实施方案中,每一R4a独立地选自氟代甲基、二氟甲基、三氟甲基、氟代乙基、二氟乙基、三氟乙基、氟代丙基、二氟丙基、三氟丙基和-NH2。p和R4a的每一变型可与如上所述的n、m、R1、R2、R3和R5的每一变型组合。
在本申请中,R1a、R1b、R1c和R1d可相同或者不同。每一R1a、R1b、R1c和R1d独立地选自氢、氟、氯、溴和碘。此外,R2a和R2b可相同或者不同。每一R2a和R2b独立地选自氢、甲基、乙基和丙基。在一种实施方案中,R1a为氯,R1b、R1c、R1d、R2a和R2b为氢。在一种其它实施方案中,R1a和R1d为氯,R1b、R1c、R1d、R2a和R2b为氢。在一些其它实施方案中,R1b为氯,R1d为氟,R1b、R1c、R2a和R2b为氢。在另外的一些实施方案中,R2a和R2b为氢。在一些另外的实施方案中,每一R1a、R1b、R1c和R1d独立地选自氢、氯、氟、溴、碘和甲基。
在一些实施方案中,W为CH或者N。在一些其它实施方案中,W为CH。在其它一些实施方案中,W为N。W的每一变型可与如上所述的n、m、R1、R2、R3、R4和R5的每一变型组合。
本申请化合物可携带一个或者多个手性中心。携带手性中心的化合物具有相同的分子式和相同的化学名称,但具有不同的立体异构指定。例如,下面的携带一个手性中心的3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-8-氟喹唑啉-4(3H)-酮可拆分成(S)和(R)对映异构体,(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-8-氟喹唑啉-4(3H)-酮和((R)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-8-氟喹唑啉-4(3H)-酮。
本申请的代表性化合物列在下表1中。另外的代表性化合物列在下表1a中。化合物可使用化学领域公认的命名体系和符号命名,包括,例如,ChemBioDraw Ultra 12.0、Chemical Abstract Service(CAS)和International Union of Pure and AppliedChemistry(IUPAC)。例如,可将表1中的化合物2分别使用IUPAC或者ChemBioDraw Ultra12.0命名为2,4-二氨基-6-[[(1S)-1-[3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-喹唑啉-2-基]乙基]氨基]嘧啶-5-甲腈或者(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈。
表1.代表性化合物
表1a.代表性化合物
本申请提供本文所述的化合物的药学上可接受的盐、水合物、溶剂合物、异构体、互变异构体、立体异构体、对映异构体、外消旋化合物、阻转异构体、多晶形、前药、或其混合物。另外,本申请提供上述化合物,其中1到n个连接到碳原子的氢原子可替代为氘原子或D,其中n为分子中氢原子的数目。已知氘原子为氢原子的非放射性同位素。此类化合物可增加抗代谢性,且因此当向哺乳动物给予时,可适用于增加本文中所述的任何化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物的半衰期。参看例如Foster,“DeuteriumIsotope Effects in Studies of Drug Metabolism”,Trends Pharmacol.Sci.,5(12):524-527(1984)。通过本领域中熟知的手段,例如通过采用一或多个氢原子已经氘替代的起始物质来合成此类化合物。
术语“本申请的化合物”、“本文所述化合物”、“任何本文所述的式的化合物”或其变型是指具有任何式(J)、(I)、(Ia)和(Ib)的结构的化合物。在一些实施方案中,本申请的化合物为本文所述的化合物1-21。
“药学上可接受的”或“生理学上可接受的”指的是化合物、盐、组合物、剂型以及其它物质适用于制备适用于兽医学或人类医药用途的药物组合物。“药学上可接受的盐”或“生理学上可接受的盐”指的是保留基础化合物的生物有效性和特性且在生物学上或在其它方面并非不合需要的药物化合物的盐。存在酸加成盐和碱加成盐。药学上可接受的酸加成盐可以由无机酸和有机酸制备。适用于与基础化合物反应形成药学上可接受的盐(分别为酸加成盐或碱加成盐)的酸和碱为本领域技术人员已知。类似地,从基础化合物(披露时)制备药学上可接受的盐的方法为本领域的技术人员所已知且披露于例如Berge等人Journal of Pharmaceutical Science,1977年1月第66卷,第1期和其它来源中。如果本文中所述的化合物以酸加成盐形式获得,那么可通过使酸式盐溶液碱化获得游离碱。相对来说,如果产物为游离碱,那么可根据从碱化合物制备酸加成盐的常规程序,通过将所述游离碱溶解于合适的有机溶剂中且用酸处理所述溶液,产生加成盐,具体来说药学上可接受的加成盐。
“异构体”是指具有相同分子式的化合物。如本文所述,术语异构体包括双键异构体、外消旋化合物、立体异构体、对映异构体、非对映异构体和阻转异构体。单一异构体,如对映异构体或非对映异构体,可通过不对称的合成或通过拆分异构体混合物而得到。异构体混合物(例如外消旋化合物)的拆分可通过例如,常规方法实现,如在拆分剂的存在下结晶,或色谱法,使用例如手性高压液相色谱(HPLC)柱。“双键异构体”是指具有碳-碳双键的化合物的Z-和E-形式(或顺-和反-形式)。
“阻转异构体”指的是当围绕分子中的单键的旋转由于与所述分子其它部分的空间相互作用而受阻或受到极大的阻碍且在单键两端的取代基不对称,即其不需要立构中心时,产生的构象立体异构体。在围绕单键的旋转能垒足够高且构象之间的相互转化足够慢的情况下,可允许异构物质的分离和分开。阻转异构体可通过本领域众所周知的方法分离。除非另有所述,该说明书预期包括单独的阻转异构体以及混合物。此外,如本领域技术人员所理解,该阻转异构体可通过相同化学名表示,而具有不同的阻转异构体指示。
“外消旋化合物”是指对映异构体的混合物。
“立体异构体”或“立体异构形式”是指一个或多个立体中心的手性不同的化合物。立体异构体包括对映异构体和非对映异构体。如果化合物具有一个或多个不对称中心或不对称取代的双键,则其可以立体异构形式存在,因此,可制备为单独的立体异构体或混合物。除非另有所述,该说明书预期包括单独的立体异构体以及混合物。用于确定立体化学和立体异构体的分离的方法是本领域熟知的(参见,例如,Advanced Organic Chemistry第4章,第4版,J.March,JohnWiley and Sons,NewYork,1992)。
“互变异构体”或“互变异构形式”是指化合物的交替形式,其不同之处在于质子的位置,如烯醇-酮和亚胺-烯胺互变异构体,或杂芳基如吡唑、咪唑、苯并咪唑、三唑和四唑。
“溶剂合物”通过溶剂和化合物的相互作用形成。还提供了本文所述的任一通式化合物的盐的溶剂合物。还提供了所述通式化合物的水合物。
“前药”在药物领域定义为药物无生物活性的衍生物,其在给药至人体后根据一些化学或酶途径转化为有生物活性的母体药物。
在上述任一实施方案中,本文所述的化合物或其药学上可接受的盐为(S)-对映异构体。在上述任一实施方案中,本文所述的化合物或其药学上可接受的盐为(R)-对映异构体。在上述任一实施方案中,本文所述的化合物或其药学上可接受的盐为阻转异构体。
本申请还提供了组合物,其包含所述化合物或其药学上可接受的盐的对映异构体的混合物。在一种实施方案中,该混合物为外消旋混合物。在其它一些实施方案中,该组合物包含的化合物的(S)-对映异构体超过对应的化合物的(R)-对映异构体。在一些实施方案中,该组合物包含化合物的(S)-对映异构体且基本上不含其对应的(R)-对映异构体。在某些实施方案中,基本上不含(R)-对映异构体的组合物具有少于约40%、35%、30%、25%、20%、15%、10%、5%、1%、0.05%、或0.01%的(R)-对映异构体。在其它一些实施方案中,包含化合物的(S)-对映异构体或其药学上可接受的盐的组合物,相对其对应的(R)-对映异构体占优势,其摩尔比为至少或约9:1,至少或约19:1,至少或约40:1,至少或约80:1,至少或约160:1,或至少或约320:1。
包含根据本文所述通式任一个的化合物或其药学上可接受的盐的组合物也可以对映异构体过量(e.e.)包含该化合物。作为实例,具有95%(S)-异构体和5%(R)-异构体的化合物将具有90%的e.e.。在一些实施方案中,所述化合物具有的e.e.为至少约60%,75%,80%,85%,90%,95%,98%或99%。
在上述任一实施方案中,所述化合物或其药学上可接受的盐为阻转异构体。另一实施方案提供组合物,其包含所述化合物或其药学上可接受的盐的阻转异构体的混合物。作为实例,化合物具有95%一种阻转异构体和5%另一阻转异构体。在一些实施方案中,化合物分别具有约90%、80%、70%、60%、50%、40%、30%、20%、或10%的一种阻转异构体和10%、20%、30%、40%、50%、60%、70%、80%、或90%的另一阻转异构体。
本申请还提供了本文所述的化合物的游离碱形式。在某些实施方案中,本文提供了本文所述化学式的化合物的对映异构体、(R)或(S)构型。在其它一些实施方案中,本文提供了本文所述化学式的化合物的阻转异构体。
本申请还提供了包含本文所述的化合物或其药学上可接受的盐、异构体、前药或溶剂合物的组合物。所述组合物可包含外消旋混合物、含对映异构体过量的一种对映异构体的混合物或单一非对映异构体或非对映异构体混合物。这些化合物的所有这些异构形式明确地包括在本文中,好像具体且分别地列举各种和每一异构形式一样。
在某些实施方案中,本文还提供本文所述的化合物的多晶型物,如晶体和无定形形式。在一些实施方案中,还提供本文所述的化学式的化合物或其药学上可接受的盐、前药或溶剂合物的螯合物、非共价络合物以及其混合物。“螯合物”通过使化合物在两个(或两个以上)点处与金属离子配位来形成。“非共价络合物”通过化合物与另一分子的相互相用形成,其中在所述化合物与所述分子之间不形成共价键。举例来说,络合可通过范德华力相互作用、氢键以及静电相互作用(也称作离子键)发生。
化合物的治疗用途
本文所述化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物可用于治疗PI3K亚型介导的疾病和/或病症。此外,本申请提供用于治疗的化合物。此外,本文提供了抑制一种或多种PI3K亚型的方法。在一种实施方案中,提供了使用本文所述的化合物或其药学上可接受的盐、异构体、前药或溶剂合物抑制PI3Kδ活性的方法。在其它一些实施方案中,提供了使用所述化合物或其药学上可接受的盐、异构体、前药或溶剂合物抑制PI3Kδ和/或PI3Kβ活性的方法。本申请还提供用于这些方法的方法。PI3K亚型可选择性或特异性被抑制。此外,所述化合物可用于治疗性或预防性抑制PI3K活性,如PI3Kδ和/或PI3Kβ。
根据本申请的化合物可与一种或多种其它治疗剂组合使用。所述治疗剂可为化合物、抗体、多肽或多核苷酸的形式。所述治疗剂包括,但不限于,化学治疗剂、免疫治疗剂、放射治疗剂、抗肿瘤剂、抗癌剂、抗增殖剂、抗纤维化剂、抗血管形成剂、治疗性抗体,或其任意组合。在一种实施方案中,本申请提供包含本文所述的化合物和其它治疗剂的产品,其作为组合制剂以用于同时、分开或相继用于治疗,例如治疗PI3K亚型介导的疾病、障碍或病症的方法。
此外,所述治疗剂可为抑制或调节以下激酶活性的那些:布鲁顿酪氨酸激酶、脾酪氨酸激酶、凋亡信号调节激酶、Janus激酶、赖氨酰氧化酶、赖氨酰氧化酶-样蛋白、基质金属肽酶、含溴结构域蛋白、腺苷A2B受体、异柠檬酸脱氢酶、丝氨酸/苏氨酸激酶TPL2、盘状结构域受体(discoidin domain receptor)、丝氨酸/苏氨酸-蛋白激酶、IKK、MEK、EGFR、组蛋白脱乙酰基酶、蛋白激酶C,或其任意组合。在某些实施方案中,所述治疗剂可选自PI3K(包括PI3Kγ,PI3Kδ,PI3Kβ,PI3Kα和/或泛-PI3K)抑制剂、JAK(Janus激酶,包括JAK1,JAK2和/或JAK3)抑制剂、SYK(脾酪氨酸激酶)抑制剂、BTK(布鲁顿酪氨酸激酶)抑制剂、A2B(腺苷A2B受体)抑制剂、ACK(活化的CDC激酶,包括ACK1)抑制剂、ASK(凋亡信号调节激酶,包括ASK1)抑制剂,Auroa激酶、BRD(含溴结构域蛋白,包括BRD4)抑制剂、Bcl(B-细胞CLL/淋巴瘤,包括Bcl-1和/或Bcl-2)抑制剂、CAK(CDK-活化激酶)抑制剂、CaMK(钙调蛋白-依赖性蛋白激酶)抑制剂、CDK(细胞周期蛋白依赖性激酶,包括CDK1、2、3、4和/或6)抑制剂、CK(酪蛋白激酶,包括CK1和/或CK2)抑制剂、DDR(盘状结构域受体,包括DDR1和/或DDR2)抑制剂、EGFR抑制剂、FXR(法尼醇x受体)抑制剂、FAK(粘着斑激酶)抑制剂、GSK(糖原合酶激酶)抑制剂、HDAC(组蛋白脱乙酰基酶)抑制剂、IDO(吲哚胺2,3-二氧化酶)抑制剂、IDH(异柠檬酸脱氢酶,包括IDH1)抑制剂、IKK(l-Kappa-B激酶)抑制剂、KDM5(赖氨酸脱甲基酶)抑制剂、LCK(淋巴细胞-特异性蛋白酪氨酸激酶)抑制剂、LOX(赖氨酰氧化酶)抑制剂、LOXL(赖氨酰氧化酶样蛋白,包括LOXL1,LOXL2,LOXL3,LOXL4和/或LOXL5)抑制剂、MTH(mut T同系物)抑制剂、MEK(促分裂原-活化的蛋白激酶激酶)抑制剂、基质金属蛋白酶(MMP,包括MMP2和/或MMP9)抑制剂、促分裂原-活化的蛋白激酶(MAPK)抑制剂、PD-1(程序性细胞死亡蛋白1)抑制剂、PD-L1(程序性死亡-配体1)抑制剂、PDGF(血小板-衍生的生长因子)抑制剂、磷酸化酶激酶(PK)抑制剂、PLK(polo样激酶,包括PLK1、2、3)抑制剂、蛋白激酶(PK,包括蛋白激酶A,B,C)抑制剂、STK(丝氨酸/苏氨酸激酶)抑制剂、STAT(信号转导和转录)抑制剂、丝氨酸/苏氨酸-蛋白激酶抑制剂、TBK(tank-结合激酶)抑制剂、TLR(toll样受体调节剂,包括TLR-1,TLR-2,TLR-3,TLR-4,TLR-5,TLR-6,TLR-7,TLR-8,TLR-9,TLR-10,TLR-11,TLR-12和/或TLR-13)抑制剂、TK(酪氨酸激酶)抑制剂、TPL2(丝氨酸/苏氨酸激酶)抑制剂、NEK9抑制剂、Abl抑制剂、p38激酶抑制剂、PYK抑制剂、c-Kit抑制剂、NPM-ALK抑制剂、Flt-3抑制剂、c-Met抑制剂、KDR抑制剂、TIE-2抑制剂、VEGFR抑制剂、SRC抑制剂、HCK抑制剂、LYN抑制剂、FYN抑制剂、YES抑制剂、化学治疗剂、免疫治疗剂、放射治疗剂、抗肿瘤剂、抗癌剂、抗增殖剂、抗纤维化剂、抗血管形成剂、治疗用抗体,或其任意组合。在一些实施方案中,所述JAK抑制剂为N-(氰基甲基)-4-[2-(4-吗啉代苯胺基)嘧啶-4-基]苯甲酰胺(通过ChemDraw命名)(也可称为CYT0387或momelotinib)且可通过美国专利号8,486,941所述的方法合成。在某实施方案中,该SyK抑制剂为6-(1H-吲唑-6-基)-N-(4-吗啉代苯基)咪唑并[1,2-a]吡嗪-8-胺(通过ChemDraw命名)(也可称为6-(1H-吲唑-6-基)-N-[4-(吗啉-4-基)苯基]咪唑并[1,2-a]吡嗪-8-胺)且可通过美国专利号8,450,321所述的方法合成。在其它一些实施方案中,BTK抑制剂为按照ChemDraw命名的(S)-6-氨基-9-(1-(丁-2-炔酰基)吡咯烷-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮(也可为6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮),且可通过美国专利8,557,803的方法合成。
化疗剂可由其作用机理分类为例如下组:抗代谢/抗癌剂,例如嘧啶类似物(氮尿苷、卡培他滨和阿糖胞苷);和嘌呤类似物、叶酸拮抗剂和相关抑制剂;抗增殖/抗有丝分裂剂,包含天然产品例如长春花生物碱(长春碱、长春新碱、和微管例如紫杉烷(紫杉醇、多西紫杉醇)、长春碱、诺考达唑、埃坡霉素(epothilone)和诺维本(navelbine)、表鬼臼毒素(epidipodophyllotoxins)(依托泊苷、替尼泊苷);DNA破坏剂(放线菌素、安吖啶、白消安、卡铂、苯丁酸氮芥、顺铂、环磷酰胺(cyclophosphamide)、环磷酰胺(Cytoxan)放线菌素D、柔红霉素、多柔比星、表柔比星、异环磷酰胺、美法仑、氮芥(merchlorehtamine)、丝裂霉素、米托蒽醌、亚硝基脲、丙卡巴肼、紫杉酚、泰索帝、替尼泊苷、依托泊苷、三亚乙基硫代磷酰胺;抗生素例如更生霉素(放线菌素D)、柔红霉素、多柔比星(阿霉素)、伊达比星、蒽环类抗生素、米托蒽醌、博来霉素、普卡霉素(光神霉素)和丝裂霉素;酶(L天门冬酰胺酶,全身性代谢L天冬酰胺和消灭没有能力合成其自身天冬酰胺的细胞);抗血小板剂;抗增殖/抗有丝分裂试烷化剂,例如氮芥环磷酰胺及类似物,美法仑、苯丁酸氮芥),和(六甲蜜胺和塞替哌)、烷基亚硝基脲(BCNU)及类似物,链佐星)、三氮烯-达卡巴嗪(DTIC);抗增殖/抗有丝分裂抗代谢剂,例如叶酸类似物(氨甲喋呤);铂配位复合物(顺铂、奥沙利铂(oxiloplatinim)、卡铂)、丙卡巴肼、羟基脲、米托坦、氨鲁米特;激素、激素类似物(雌激素、他莫昔芬、戈舍瑞林(goserelin)、比卡鲁胺(bicalutamide),尼鲁米特(nilutamide))和芳香酶抑制剂(来曲唑、阿那曲唑);抗凝剂(肝素、合成肝素盐和其他凝血酶抑制剂);纤维蛋白溶解剂(例如组织纤溶酶原激活剂、链激酶和尿激酶)、阿司匹林、双嘧达莫、噻氯匹定、氯吡格雷;抗转移剂;抑分泌剂(布雷菲德菌素(breveldin));免疫抑制剂、他克莫司、西罗莫司、硫唑嘌呤、霉酚酸酯;化合物(TNP-470、染料木黄酮)和生长因子抑制剂(血管内皮生长因子抑制剂、成纤维细胞生长因子抑制剂);血管紧张素受体阻滞剂,一氧化氮供体;反义寡核苷酸;抗体(曲妥珠单抗、利妥昔单抗);细胞周期抑制剂和分化诱导剂(维甲酸);抑制剂,拓扑异构酶抑制剂(多柔比星(阿霉素)、柔红霉素、更生霉素、替尼泊苷、表柔比星、依托泊苷、伊达比星、伊立替康和米托蒽醌、拓扑替康、伊立替康、喜树碱),皮质激素(可的松、地塞米松、氢化可的松、甲基泼尼松龙、泼尼松和泼尼松龙);生长因子信号转导激酶抑制剂;功能障碍诱导剂,毒素例如霍乱毒素、蓖麻毒素、假单胞菌外毒素、百日咳杆菌腺苷酸环化酶毒素或白喉毒素,胱天蛋白酶激活剂;以及染色质。
本文所用的术语“化疗剂”或“化疗药”(或“化疗”,在用化疗剂的治疗的情况中)指包含用于治疗癌症的任何非蛋白质的(即非肽的)化学化合物。化疗剂的实例包含烷化剂,例如塞替哌和环磷酰胺(CYTOXAN);烷基磺酸酯诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶,例如苯佐替派(benzodopa)、卡波醌、美妥替哌(meturedopa)和乌瑞替派(uredopa);乙撑亚胺(ethylenimine)和甲基氨基吖啶(memylamelamine),包含六甲蜜胺、三亚胺嗪(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫化磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯(acetogenin)(尤其是布拉它辛和布拉它辛酮);喜树碱(包含合成类似物托泊替康(topotecan));苔藓抑素(bryostatin);卡利他汀(callystatin);CC-1065(包含其阿多来新、卡折来新和比折来新合成类似物);自念珠藻环肽(cryptophycin)(特别是自念珠藻环肽1和自念珠藻环肽8);多拉司他汀;多卡霉素(duocarmycin)(包含合成类似物、KW-2189和CBI-TMI);艾榴塞洛素;水鬼蕉碱;匍枝珊瑚醇(sarcodictyin);软海绵素(spongistatin);氮芥,例如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、双氯乙基甲胺、盐酸氧氮芥、美法仑、新氮芥(novembichin)、苯芥胆甾醇、泼尼莫司汀(prednimustine)、曲磷胺、尿嘧啶氮芥(uracil mustard);亚硝基脲,例如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀(foremustine)、洛莫司丁、尼莫司汀、雷莫司汀;抗生素,例如烯二炔(enediyne)抗生素(如卡奇霉素、特别是卡奇霉素γ1I和卡奇霉素phiI1,见如Agnew,Chem.Intl.Ed.Engl.,33:183-186(1994));达内霉素(dynemicin),包含达内霉素(dynemicinA);二膦酸盐,例如氯屈膦酸(clodronate);埃斯培拉霉素(esperamicin);和新抑癌蛋白(neocarzinostatin)发色团和相关的色蛋白烯二炔抗生素发色团)、阿柔比星、放线菌素、安曲霉素、偶氮丝氨酸、博来霉素、放线菌素C、carabicin、洋红霉素、嗜癌菌素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、马赛罗霉素、丝裂霉素例如丝裂霉素C、霉酚酸、诺拉霉素、橄榄霉素、培洛霉素、甲基丝裂霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、块菌素、乌苯美司、净司他丁、佐柔比星;抗代谢剂,例如氨甲喋呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如demopterin、氨甲喋呤、蝶并蝶呤、三甲曲沙;嘌呤类似物,例如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,例如安西他宾、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他宾、氮尿苷;雄激素,例如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酪;抗肾上腺,例如氨鲁米特(aminoglutethimide)、米托坦、曲洛司坦;叶酸补充剂,例如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;二氢嘧啶脱氢酶灭活剂;安吖啶;阿莫司汀(bestrabucil);比生群;乙茎去氮氨蝶呤(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌(diaziquone);依氟鸟氨酸碱盐酸盐(elfornithine);依利醋铵;埃坡霉素(epothilone);依托格鲁;硝酸镓;羟基脲;香菇多糖(lentinan);甲酰四氢叶酸;氯尼达明;美登醇(maytansinoid),例如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;二胺硝吖啶(nitraerine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;氟嘧啶;亚叶酸;鬼臼酸;2-乙基肼;丙卡巴肼;PSK(r);雷佐生;根霉素;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯三乙胺;单端孢菌毒素(如T-2毒素、疣孢漆斑霉素A、杆孢菌素A和蛇形菌素(anguidine));乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀(mannomustine);二溴甘露醇;二溴卫矛醇;哌泊溴烷(pipobroman);gacytosine;阿糖胞苷("Ara-C");环磷酰胺;塞替派(thiopeta);紫杉烷,例如紫杉醇(TAXOL(r))和多西他赛(TAXOTERE(r));苯丁酸氮芥;吉西他滨(Gemzar(r));6-硫鸟嘌呤;巯基嘌呤;氨甲喋呤;铂类似物,例如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱(vancristine);长春瑞滨(Navelbine(r));;诺消灵(novantrone);替尼泊苷(teniposide);伊达曲杀(edatrexate);柔红霉素;氨基喋呤;希罗达(xeoloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄醇(retinoid),例如视黄酸;卡培他滨(capecitabine);FOLFIRI(氟尿嘧啶,甲酰四氢叶酸和伊立替康),和上述任何物质的药学可接受盐、酸或衍生物。在本申请中使用或包括一种或多种化学治疗剂。
“化疗剂”定义还包括用于调节或抑制激素对肿瘤作用的抗激素剂,例如抗雌激素剂和选择性雌激素受体调节剂(SERM),包括,例如他莫昔芬(包括NolvadexTM)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、雷洛昔芬(keoxifene)、LY117018、奥那司酮和托瑞米芬(Fareston(r));芳香酶抑制剂,其调节肾上腺中调节雌激素的生成,例如4(5)-咪唑类、氨鲁米特(aminoglutethimide)、乙酸甲地孕酮(Megace(r))、依西美坦、福美坦、法倔唑、伏氯唑(Rivisor(r))、来曲唑(Femara(r))和阿那曲唑(Arimidex(r));和抗雄激素药,例如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;和上述任何一个的药学上可接受盐、酸或衍生物。
抗血管生成药的示例包括但不限于,视黄酸和其衍生物、2-甲氧基雌二醇、血管他丁(r),内皮他丁(r)、舒拉明、角鲨胺、金属蛋白酶-1的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、软骨衍生的抑制剂、紫杉醇(蛋白结合型紫杉醇)、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸化壳多糖衍生物(从雪花蟹壳中制备)、硫酸化多糖肽多糖复合物(sp-pg)、星形孢菌素、基质代谢调节物,包含例如脯氨酸类似物((1-氮杂环丁烷-2-甲酸(LACA)、顺羟基脯氨酸、d,I-3,4-脱氢脯氨酸、硫杂脯氨酸(thiaproline)、α-联吡啶、β-氨基丙腈富马酸、4-丙基-5-(4-吡啶)-2(3h)-噁唑酮;氨甲喋呤、米托蒽醌、肝素、干扰素、2巨球蛋白血清、chimp-3、糜蛋白酶抑制素、β-环糊精十四硫酸酯、eponemycin;烟曲霉素、硫代苹果酸金钠、d-青霉胺(CDPT)、β-1-抗胶原酶-血清、α-2-抗纤溶酶、比生群、氯苯扎利二钠、n-2-羧基苯基-4-氯邻氨苯甲酸二钠或"CCA"、沙利度胺;血管抑制性类固醇、羧基氨基咪唑(cargboxynaminolmidazole);金属蛋白酶抑制剂如BB94。其他抗血管生成剂包含抗体,优选针对下述血管生长因子的单克隆抗体:β-FGF、α-FGF、FGF-5、VEGF同种型、VEGF-C、HGF/SF和Ang-1/Ang-2。参见Ferrara N.和Alitalo,K."Clinical application of angiogenic growth factors and their inhibitors"(1999)Nature Medicine5:1359-1364。
抗纤维化剂包括,但不限于,化合物如β-氨基丙腈(BAPN),以及以下公开的化合物:Palfreyman等人在1990年10月23日公开的名称为"Inhibitors of lysyl oxidase"的的美国专利4,965,288公开的化合物,其涉及赖氨酰氧化酶抑制剂及其在治疗与胶原异常沉积相关的疾病和病症的用途;Kagan等人在1991年3月5日公开的名称为"Anit-fibroticagents and methods for inhibiting the activity of lysyl oxidase in situ usingadjacently positioned diamine analogue substrate"的美国专利4,997,854中的化合物,其涉及抑制LOX以治疗多种病理纤维化状态的化合物,其在此引入作为参考。其它示例性抑制剂描述于Palfreyman等人在1990年7月24日公开的名称为"Inhibitors of lysyloxidase"的美国专利4,943,593中的化合物,其涉及化合物如2-异丁基-3-氟-、氯-或溴-烯丙基胺;以及例如,美国专利5,021,456;美国专利5,5059,714;美国专利5,120,764;美国专利5,182,297;美国专利5,252,608中的化合物(涉及2-(1-萘基氧基甲基)-3-氟烯丙基胺);和美国专利申请号2004/0248871,其在此引入作为参考。示例性抗纤维化剂还包括与赖氨酰氧化酶的活性位点的羰基反应的伯胺,且更具体为那些在与羰基结合后产生共振稳定的产品的伯胺,如以下伯胺:乙二胺、肼、苯基肼、以及它们的衍生物,氨基脲,和脲衍生物,氨基腈,如β-氨基丙腈(BAPN),或2-硝基乙胺,不饱和或饱和卤代胺,如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙基胺、对-卤代苄基胺,硒代高半胱氨酸内酯。此外,该抗纤维化剂为铜螯合剂,渗透或不渗透细胞。示例性化合物包括间接抑制剂,如阻断醛衍生物(源自通过赖氨酰氧化酶对赖氨酰和羟赖氨酰残基的氧化脱氨)的化合物,如硫醇胺,特别是D-青霉胺,或其类似物如2-氨基-5-疏基-5-甲基己酸,D-2-氨基-3-甲基-3-((2-乙酰氨基乙基)二硫基)丁酸,对-2-氨基-3-甲基-3-((2-氨基乙基)二硫基)丁酸,4-((对-1-二甲基-2-氨基-2-羧基乙基)二硫基)丁烷硫化钠(sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate),2-乙酰氨基乙基-2-乙酰氨基乙烷硫醇磺酸盐(sulphanate),4-疏基丁烷亚磺酸钠三水合物。
免疫治疗剂包括且不限于适用于治疗患者的治疗性抗体;诸如阿巴伏单抗(abagovomab)、阿达木单抗(adecatumumab)、阿托珠单抗(afutuzumab)、阿仑单抗(alemtuzumab)、阿妥莫单抗(altumomab)、阿玛西单抗(amatuximab)、麻安莫单抗(anatumomab)、阿西莫单抗(arcitumomab)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝伐单抗(bevacizumab)、比伐珠单抗(bivatuzumab)、布林莫单抗(blinatumomab)、贝伦妥单抗(brentuximab)、坎妥珠单抗(cantuzumab)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、西他土珠(citatuzumab)、西妥木单抗(cixutumumab)、昔瓦土单抗(clivatuzumab)、康纳木单抗(conatumumab)、达土木单抗(daratumumab)、德珠单抗(drozitumab)、杜里土单抗(duligotumab)、杜西吉土单抗(dusigitumab)、地莫单抗(detumomab)、达西珠单抗(dacetuzumab)、达洛图单抗(dalotuzumab)、依美昔单抗(ecromeximab)、埃罗妥珠单抗(elotuzumab)、恩斯土昔单抗(ensituximab)、鄂托默单抗(ertumaxomab)、埃达珠单抗(etaracizumab)、法里土珠单抗(farietuzumab)、费拉妥珠单抗(ficlatuzumab)、非吉单抗(figitumumab)、法兰土单抗(flanvotumab)、浮土西单抗(futuximab)、加尼图单抗(ganitumab)、吉妥珠单抗(gemtuzumab)、吉瑞昔单抗(girentuximab)、格雷巴土木单抗(glembatumumab)、替伊莫单抗(ibritumomab)、伊戈伏单抗(igovomab)、伊姆加土珠单抗(imgatuzumab)、因达西单抗(indatuximab)、伊诺妥珠单抗(inotuzumab)、英妥木单抗(intetumumab)、伊匹单抗(ipilimumab)、伊妥木单抗(iratumumab)、拉贝珠单抗(labetuzumab)、来沙木单抗(lexatumumab)、林妥珠单抗(lintuzumab)、洛瓦土珠单抗(lorvotuzumab)、鲁卡木单抗(lucatumumab)、马帕木单抗(mapatumumab)、马妥珠单抗(matuzumab)、米拉珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫昔土莫单抗(moxetumomab)、纳纳土单抗(narnatumab)、那莫单抗(naptumomab)、耐昔妥珠单抗(necitumumab)、尼妥珠单抗(nimotuzumab)、诺伐木单抗(nofetumomabn)、奥卡拉珠单抗(ocaratuzumab)、奥伐木单抗(ofatumumab)、奥拉单抗(olaratumab)、奥那组单抗(onartuzumab)、奥普珠单抗(oportuzumab)、奥戈伏单抗(oregovomab)、帕尼单抗(panitumumab)、帕萨珠单抗(parsatuzumab)、帕特里土单抗(patritumab)、潘妥莫单抗(pemtumomab)、帕妥珠单抗(pertuzumab)、平妥单抗(pintumomab)、普托木单抗(pritumumab)、拉克莫单抗(racotumomab)、拉德瑞单抗(radretumab)、里乐木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、沙妥莫单抗(satumomab)、西罗珠单抗(sibrotuzumab)、思图昔单抗(siltuximab)、辛图珠单抗(simtuzumab)、索利托单抗(solitomab)、他卡珠单抗(tacatuzumab)、他普莫单抗(taplitumomab)、泰纳莫单抗(tenatumomab)、泰普洛单抗(teprotumumab)、替加珠单抗(tigatuzumab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、土库珠单抗(tucotuzumab)、尤必昔单抗(ublituximab)、维托珠单抗(veltuzumab)、沃尔希珠单抗(vorsetuzumab)、伏妥莫单抗(votumumab)、扎鲁姆单抗(zalutumumab)、欧比托珠单抗(obinutuzumab)、CC49及3F8。所例示的治疗性抗体可进一步用放射性同位素粒子标记或与其组合,该放射性同位素粒子诸如铟In 111、钇Y90、碘1-131。
本申请还提供治疗正经历一种或多种标准治疗,如化学治疗、放射治疗、免疫治疗、外科手术、或其组合的受试者的方法。因此,一种或多种治疗剂或抑制剂可在给予化学治疗、放射治疗、免疫治疗、外科手术或其组合之前、之中或之后给予。
化疗治疗的其他实例(包括标准或实验的化疗)在下文中描述。此外,一些淋巴瘤的治疗见于Cheson,B.D.,Leonard,J.P.,“Monoclonal Antibody Therapy for B-CellNon-Hodgkin’s Lymphoma”The New England Journal of Medicine 2008,359(6),p.613-626和Wierda,W.G.,“Current and Investigational Therapies for Patients withCLL”Hematology 2006,p.285-294。在美国,淋巴瘤的发病模式在Morton,L.M.,et al.“Lymphoma Incidence Patterns by WHO Subtype in the United States,1992-2001”Blood 2006,107(1),p.265-276中进行分析。
免疫治疗剂的实例包括,但不限于,利妥昔单抗(如Rituxan)、阿仑单抗(如Campath、MabCampath)、抗CD19抗体、抗CD20抗体、抗MN-14抗体、抗TRAIL、抗TRAILDR4和DR5抗体、抗CD74抗体、阿泊珠单抗、贝伐单抗、CHIR-12.12、依帕珠单抗(hLL2-抗CD22人源化抗体)、加利昔单抗、ha20、替伊莫单抗、鲁昔单抗、米拉珠单抗、奥伐木单抗、PRO131921、SGN-40、WT-1类似物肽疫苗、WT1126-134肽疫苗、托西莫单抗、自体人肿瘤-衍生的HSPPC-96和维托珠单抗。其它免疫治疗剂包括使用基于个体患者肿瘤的基因构成(genetic makeup)的癌症疫苗,如淋巴瘤疫苗实例为GTOP-99
化学治疗剂的实例包括阿地白介素、alvocidib、抗瘤酮AS2-1、抗瘤酮A10、抗胸腺细胞球蛋白、氨磷汀三水合物、氨基喜树碱、三氧化二砷、βalethine、Bcl-2家族蛋白抑制剂ABT-263、ABT-199、BMS-345541、硼替佐米苔藓抑素1、白消安、卡铂、campath-1H、CC-5103、卡莫司汀、乙酸卡泊芬净、氯法拉滨、顺铂、克拉屈滨(Leustarin)、苯丁酸氮芥(Leukeran)、姜黄素、环孢菌素、环磷酰胺(Cyloxan、Endoxan、Endoxana、Cyclostin)、阿糖胞苷、地尼白介素、地塞米松、DT PACE、多西紫杉醇、多拉司他汀10、多柔比星(Adriblastine)、盐酸多柔比星、因扎托雷、阿法依伯汀、依托泊苷、依维莫司(RAD001)、芬维A胺、非格司亭、美法仑、美司钠、夫拉平度、氟达拉滨(Fludara)、格尔德霉素(17-AAG)、异环磷酰胺、盐酸伊立替康、伊沙匹隆、来那度胺(CC-5013)、淋巴因子-活化的杀伤细胞、美法仑、甲氨蝶呤、盐酸米托蒽醌、莫特沙芬钆、霉酚酸酯、奈拉滨、奥利默森(Genasense)Obatoclax(GX15-070)、奥利默森、乙酸奥曲肽、ω-3脂肪酸、奥沙利铂、紫杉醇、PD0332991、PEG化脂质体盐酸多柔比星、培非司亭、喷司他丁(Nipent)、哌立福辛、泼尼松龙、泼尼松、R-roscovitine(Selicilib、CYC202)、重组干扰素α、重组白介素-12、重组白介素-11、重组flt3配体、重组人血小板生成素、利妥昔单抗、沙格司亭、柠檬酸昔多芬、辛伐他汀、西罗莫司、苯乙烯基砜、他克莫司、坦螺旋霉素、西罗莫司脂化物(CCl-779)、沙利度胺、治疗性同种异体淋巴细胞、塞替派、替吡法尼、(硼替佐米或PS-341)、长春新碱(Oncovin)、硫酸长春新碱、长春瑞滨二酒石酸盐、伏立诺他(SAHA)、伏立诺他、和FR(氟达拉滨、利妥昔单抗)、CHOP(环磷酰胺、多柔比星、长春新碱、泼尼松)、CVP(环磷酰胺、长春新碱和泼尼松)、FCM(氟达拉滨、环磷酰胺、米托蒽醌)、FCR(氟达拉滨、环磷酰胺、利妥昔单抗)、hyperCVAD(超分割环磷酰胺、长春新碱、多柔比星、地塞米松、甲氨蝶呤、阿糖胞苷)、ICE(异环磷酰胺、卡铂和依托泊苷)、MCP(米托蒽醌、苯丁酸氮芥、和泼尼松龙)、R-CHOP(利妥昔单抗加CHOP)、R-CVP(利妥昔单抗加CVP)、R-FCM(利妥昔单抗加FCM)、R-ICE(利妥昔单抗-ICE)、和R-MCP(R-MCP)。
所述治疗可补充有任何上述用干细胞移植或处理的治疗或与其组合。一种改良的方法的实例为放射免疫治疗,其中单克隆抗体与放射性同位素粒子,如铟In 111、钇Y90、碘I-131组合。组合治疗的实例包括,但不限于,碘-131托西莫单抗钇-90替伊莫单抗与CHOP。
其它治疗过程包括外周血干细胞移植、自体造血干细胞移植、自体骨髓移植、抗体疗法、生物疗法、酶抑制剂疗法、全身照射、输注干细胞、干细胞支持的骨髓去除(干细胞支持的骨髓根除)、体外处理的外周血干细胞移植、脐带血移植、免疫酶技术、药理学研究、低-LET钴-60γ射线治疗、博来霉素、常规手术、放射疗法和非骨髓根除的同种异基因造血干细胞移植。
在一些实施方案中,所述方法包括以治疗有效量向有需要的人给药本文所述的化合物或其药学上可接受的盐、异构体、前药或溶剂合物。该方法可用于治疗患有或认为患有疾病或病症的患者,该疾病或病症的症状或病理由PI3Kβ和/或PI3Kδ的表达或活性所介导。所述患者可为哺乳动物或人。在某实施方案中,所述患者可为人。
“治疗”或“处理”是用于得到有益的或者希望的结果(包括临床结果)的方法。有益的或者希望的临床结果可包括以下中的一个或者多个:a)抑制疾病或者病症(例如,减少疾病或者病症所导致的一个或者多个症状和/或减轻疾病或者病症的程度);b)减慢或者阻止与疾病或者病症相关联的一个或者多个临床症状的发展(例如,稳定疾病或者病症,防止或者延缓疾病或者病症的恶化或者进展和/或防止或者延缓疾病或者病症的传播(例如,转移));和/或c)减轻疾病,即,导致临床症状消退(例如,改善疾病状态,提供疾病或者病症的部分或者全部缓解,增强其它药疗法的效果,延缓疾病进展,提高生命质量和/或延长存活)。
“预防”或“防止”是指疾病或病症的任何处理,其使得疾病或病症的临床症状不发展。在一些实施方案中,化合物可给药于处于疾病或病症风险或具有疾病或病症家族史的受试者(包括人)。
“受试者”或“患者”指的是动物,如哺乳动物(包括人),其已经或者将要为治疗、观察或实验的对象。本申请所述方法可用于人类治疗和兽医应用。在一些实施方案中,所述受试者为哺乳动物;在一种实施方案中,受试者为人类。“有此需要的受试者”指的是人类,其可已经患有或者被怀疑患有会从某治疗(例如用根据本申请的PI3K抑制剂化合物治疗)受益的疾病、障碍或病症。在某些实施方案中,所述受试者可为以下人类,其(i)未接受任何处理,包括化学治疗处理,(ii)用至少一种化学治疗处理基本难治的,(iii)处于用化学治疗处理后的复发中,或(i)和(ii)二者。在一些实施方案中,所述受试者是至少一种、至少两种、至少三种或至少四种化学治疗处理(包括标准或实验化学疗法)难治的。
术语“治疗有效量”或“有效量”的本申请化合物或其药学上可接受的盐、异构体、前药或溶剂合物,是指当给予受试者足以实现治疗的量,以提供治疗益处,如改善症状或减缓疾病进展。例如,治疗有效量可为足以减少对PI3Kδ和PI3Kβ活性的抑制有响应的疾病或病症的症状的量。所述治疗有效量可取决于受试者和治疗的疾病或者病症、受试者的体重和年龄、疾病或者病症的严重性和给药方式而改变,其可由本领域普通技术人员容易地确定。
除了所述治疗用途,本文所述的化合物对某些PI3K亚型具有选择性或选择性抑制。在一种实施方案中,该化合物对PI3Kβ具有选择性。在一些实施方案中,该化合物对PI3Kδ具有选择性。在其它一些实施方案中,该化合物对PI3Kβ和PI3Kδ具有选择性。对PI3K亚型的选择性可通过测量化合物在抑制某些PI3K亚型中的活性而确定,其使用以下实施例中所述的测试或常用的方法。应理解条件(例如试剂浓度或培养温度)可改变且测试结果可改变。在一些情况下,所述值可在1至3倍的范围内改变。
术语“抑制”指示生物活性或过程的基线活性的降低。术语“PI3K亚型的活性的抑制”或其变体是指相对于不存在本文所述的化合物的情况下PI3K亚型的活性,直接或间接响应于本文所述任一式的化合物存在的任何PI3K亚型(例如,α、β、γ或δ)活性的降低。“PI3Kδ和/或PI3Kβ活性的抑制”或其变体是指相对于不存在本文所述的化合物的情况下PI3Kδ和/或PI3Kβ的活性,直接或间接响应于本文所述化合物的存在的PI3Kδ和/或PI3Kβ活性的降低。在一些实施方案中,PI3K亚型活性的抑制可在治疗前的同一受试者中比较,或与其它不接受所述治疗的受试者比较。
不希望被任何理论所束缚,PI3K活性的降低可能是由于化合物与PI3K的直接相互作用,或由于本文所述的化合物与影响PI3K活性的一种或多种其它因素的相互作用。例如,化合物的存在可通过直接结合至PI3Kδ和/或PI3Kβ,通过引起(直接或间接)另一因素来降低PI3Kδ和/或PI3Kβ活性,或通过(直接或间接)降低细胞或有机体中存在的PI3Kδ和/或PI3Kβ的量来降低PI3Kδ和/或PI3Kβ的活性。
术语“PI3K抑制剂”或其变体是指抑制PI3K的活性的化合物。术语“PI3K亚型选择性抑制剂”或其变体是指抑制一种或多种PI3K亚型的活性比其它剩余PI3K亚型更有效的化合物。作为实例,术语“PI3Kβ选择性抑制剂”通常是指抑制PI3Kβ亚型的活性比PI3K家族的其它亚型更有效的化合物,且术语“PI3K δ选择性抑制剂”通常是指抑制PI3Kδ亚型的活性比PI3K家族的其它亚型更有效的化合物。术语“双重PI3Kδ/β选择性抑制剂”通常是指抑制PI3Kδ和PI3Kβ亚型二者的活性比PI3K家族的其它亚型(例如,PI3Kα或γ)更有效的化合物。
化合物作为酶活性(或其它生物活性)的抑制剂的相对功效可通过以下建立,确定各化合物抑制活性达预定程度的浓度,然后比较结果。在一种实施方案中,化合物作为一种或多种PI3K亚型的抑制剂的功效可通过在生物化学测试中抑制50%活性的化合物浓度来测量,即,50%抑制浓度或“IC50”。IC50值的测定可使用现有技术已知的常规技术实现,包括以下实施例中所述的技术。通常,IC50可通过在一系列浓度的研究化合物存在下测量给定酶的活性确定。实验获得的酶活性值然后可针对使用的化合物浓度绘图。显示50%酶活性(相比于不存在任何抑制剂的活性)的抑制剂的浓度作为IC50值。类似地,其它抑制浓度可通过活性的适当确定而定义。例如,在一些情形中可能需要建立90%抑制浓度,即,IC90。
根据本申请,PI3Kβ选择性抑制剂为以下化合物,其具有的对PI3Kβ的50%抑制浓度(IC50)为对PI3Kα或PI3Kγ或者PI3Kα和PI3Kγ二者的IC50的至多10分之一,至多20分之一,至多30分之一,至多50分之一,至多100分之一,至多200分之一,或至多500分之一。此外,PI3Kδ/β选择性抑制剂为以下化合物,其具有的对PI3Kβ和PI3Kδ的50%抑制浓度(IC50)为对PI3Kα或PI3Kγ的IC50的至多10分之一,至多20分之一,至多30分之一,至多50分之一,至多75分之一,至多100分之一,至多200分之一,和至多500分之一。双重PI3Kδ/β选择性抑制剂可对PI3Kδ和PI3Kβ二者具有相同或类似的IC50或可对PI3Kδ或PI3Kβ具有不同的IC50。如本文所述,术语“功效”、“有效的”或其变体是指该化合物具有的IC50值小于100nM。当比较两种化合物,具有较低IC50值的化合物被称为更有效的抑制剂。
本申请的化合物显示对PI3Kβ出人意料的选择性。如实施例所示,表1中某些化合物对PI3Kβ和PI3Kδ二者显示低IC50值(例如1至100nM)。表1a中某些化合物也显示这种对PI3K亚型的选择性。此外,某些式(I)化合物显示PI3Kβ的IC50值为PI3Kγ的至多10分之一至400分之一,表明相比PI3Kγ所述化合物显示对PI3Kβ有更高的选择性(即,抑制PI3Kβ亚型的活性比PI3Kγ亚型更有效,如PI3Kγ/PI3Kβ比例所示)。而且,本文所述的化合物显示对PI3Kβ和PI3Kδ二者的选择性。美国临时申请号61/745,437中所述的化合物(S)-2,4-二氨基-6-((1-(5-氯-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈,显示对PI3Kγ有较低的选择性(例如PI3Kγ/PI3Kβ比例小于1倍)。本申请的结果表明本文所述化合物为PI3Kδ和PI3Kβ的双重选择性抑制剂且显示相比PI3Kγ对PI3Kβ有更高的选择性。本申请中所述的所有专利和专利申请以其整体在此引入作为参考。
本文所述的方法可应用于体内或离体细胞群体。“体内”意指在活的个体内,如在动物或人类内。在此情况下,可在个体中在治疗学上使用本文中所述的方法。“离体”意指在活的个体外部。离体细胞群体的实例包括活体外细胞培养物及生物样品,包括自个体获得的流体或组织样品。此类样品可通过本领域熟知的方法获得。例示性生物流体样品包括血液、脑脊髓液、尿液及唾液。例示性组织样品包括肿瘤及其活检。在此情况下,该化合物可用于各种目的,包括治疗及实验目的。例如,其可离体使用来测定关于指定适应症、细胞类型、个体及其他参数,PI3K选择性抑制剂的最佳给药方案时间表及/或剂量。自此类用途搜集的信息可用于实验目的或临床中以设定体内治疗方案。本发明可适合的其他离体用途如下所述或对本领域技术人员而言应为明了的。本文所述化学式的化合物或其药学上可接受的盐、前药或溶剂合物可进一步表征以检查在人类或非人类受试者中的安全性或耐受剂量。此类性质可使用本领域技术人员通常已知的方法检查。
相比于其它PI3K亚型,PI3Kδ通常在造血细胞中表达。此外,PI3Kβ通常在某些癌细胞中失调。细胞异常增殖通常干扰正常组织功能,其可导致异常细胞响应如免疫、炎症和/或凋亡。PI3Kδ和/或PI3Kβ的选择性抑制剂可用于治疗、抑制或防止癌症和/或造血细胞的异常增殖和改善该症状和继发病症。
本文所述的化合物可用于治疗患有多种与PI3K亚型或其活性相关的疾病状态、障碍和病症(也统称为“适应症”)的受试者。如本文所述,术语“疾病”、“障碍”、“病症”可互换使用。这些适应症可包括例如,癌症,包括恶性血液病(例如白血病和淋巴瘤、骨髓增殖性疾病、骨髓增生异常综合征、浆细胞肿瘤)和实体瘤、炎症、纤维化、过敏病症(包括超敏反应)、心血管疾病、神经退行性疾病、肾疾病、病毒感染、肥胖症和自身免疫性疾病。
在其它一些实施方案中,本文所述的化合物可用于治疗由PI3K活性介导、依赖于PI3K活性或与其相关的癌症。在某些实施方案中,所述疾病或病症为自身免疫性疾病、炎性疾病或癌症。在一些实施方案中,所述疾病或病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、牛皮癣、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性呼吸道阻塞疾病、肺炎、皮炎、秃头症、肾炎、脉管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥、淋巴瘤、多发性骨髓瘤、白血病、肿瘤和实体瘤。
在其它一些实施方案中,所述疾病为实体瘤。作为实例,所述实体瘤包括但不限于胰腺癌、膀胱癌、结肠直肠癌、乳腺癌、前列腺癌、肾脏癌(renal cancer)、肝细胞癌、肺癌、卵巢癌、子宫颈癌、直肠癌、肝癌、肾癌(kidney cancer)、胃癌(stomach cancer)、皮肤癌、胃部癌症(gastric cancer)、食管癌、头颈癌、黑色素瘤、神经内分泌癌、CNS癌(例如,成神经细胞瘤),脑瘤(例如,神经胶质瘤、间变性少突胶质细胞瘤、成人多形性成胶质细胞瘤和成人间变性星形细胞瘤)、骨癌、或软组织肉瘤。在一些实施方案中,所述实体瘤为非小细胞肺癌、小细胞肺癌、结肠癌、CNS癌、黑色素瘤、卵巢癌、肾脏癌、胰腺癌、前列腺癌或乳腺癌。
本申请还提供治疗有需要的人的方法,所述人患有或疑患有对PI3Kδ和/或PI3Kβ活性的抑制有响应或认为有响应的疾病或病症,其通过向所述受试者给药本文所述的化学式化合物或其药学上可接受的盐、对映异构体、阻转异构体、互变异构体、前药或溶剂合物。
此外,本申请提供抑制PI3Kδ和/或PI3Kβ多肽的激酶活性的方法,其通过将多肽与本文所述的化学式化合物或其药学上可接受的盐、异构体、前药、溶剂合物或混合物接触。
而且,本申请提供降低细胞活力、增加细胞死亡或凋亡、增加对PI3K信号传导途径(包括AKT、S6RP、ERK磷酸化)的干扰、和/或减少趋化因子产生的方法,其通过使用有效量的本文所述任一式的的化合物或其药学上可接受的盐、异构体、前药、溶剂合物或混合物。
本申请还提供扰乱白细胞功能的方法,其包括在有需要的人中将白细胞与有效量的本文所述任一式的的化合物或其药学上可接受的盐、异构体、前药、溶剂合物或混合物接触。
还提供抑制癌细胞生长或增殖的方法,其包括将所述癌细胞与有效量的本文所述的化合物或其药学上可接受的盐、异构体、前药、溶剂合物或混合物接触。
试剂盒
本文还提供试剂盒,其包含本申请化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物以及合适的包装。在一种实施方案中,试剂盒进一步包含使用说明。在一方面,试剂盒包含本文所述的化合物或其药学上可接受的盐、异构体、前药或溶剂合物以及标签和/或说明书,用于指示该化合物在治疗适应症(包括本文所述的疾病或病症)中的使用。
本文还提供了制备的制品,其包含在合适的容器中的本申请任一化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物。该容器可为瓶、罐、安瓿、预装载注射器和静脉输液袋。
药物组合物和给药方式
本文提供的化合物通常以药物组合物形式给药。因此,本文还提供药物组合物,其包含一种或多种文中所述的任一式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物,以及一种或多种药学上可接受的选自载体、辅料和赋形剂的媒介物。合适的药学上可接受的载体可包括,例如,惰性固体稀释剂和填充剂,稀释剂(包括无菌水溶液和多种有机溶剂),渗透增强剂,增溶剂和辅料。此类组合物以药学领域公知的方式制备。参见,例如,Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelphia,Pa.17thEd.(1985);and Modern Pharmaceutics,Marcel Dekker,Inc.3rd Ed.(G.S.Banker&C.T.Rhodes,Eds.)。
药物组合物可以单一剂量或多剂量形式给药。药物组合物可通过各种方法给药,包括例如经直肠、经颊、鼻内以及经皮途径。在某些实施例中,药物组合物可藉由动脉内注射、静脉内、腹膜内、肠胃外、肌肉内、皮下、经口、局部或以吸入剂形式给药。在一些实施方案中,该药物组合物口服给药。
一种给药模式是肠胃外,例如通过注射给药。可并入本文所述的药物组合物用于通过注射给药的形式包括例如水性或油性悬浮液或乳液,其含芝麻油、玉米油、棉籽油或花生油以及酏剂、甘露糖醇、右旋糖或无菌水溶液以及类似医药媒介物。
口服给药可为用于给药本文所述的化合物的另一途径。举例来说,可通过胶囊或包覆肠溶包衣的片剂给药。在制造包括至少一种具有本文所述的任何化学式的化合物或其药学上可接受的盐、前药或溶剂合物的药物组合物中,通常通过赋形剂稀释活性成分和/或将其密封于可呈胶囊、囊袋、纸张或其它容器形式的载剂内。当赋形剂用作稀释剂时,其可以呈固体、半固体或液体材料(如上文所述)形式,其充当活性成分的媒介物、载剂或介质。因此,组合物可以呈以下形式:片剂、丸剂、粉剂、锭剂、囊袋剂、扁囊剂、酏剂、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或于液体介质中)、、含有例如高达10重量%的活性化合物的软膏、软和硬明胶胶囊、无菌可注射溶液以及无菌封装粉末。在某些实施方案中,该药物组合物为片剂形式。
合适的赋形剂的一些实例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、无菌水、糖浆及甲基纤维素。制剂可以另外包括:润滑剂,例如滑石、硬脂酸镁以及矿物油;湿润剂;乳化剂和悬浮剂;防腐剂,例如羟基苯甲酸甲酯和羟基苯甲酸丙酯;甜味剂;以及调味剂。
包括至少一种具有本文所述的任何化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物的组合物可经配制以便在通过采用本领域中已知的程序向受试者给药之后提供活性成分的快速、持续或延迟释放。用于口服给药的控制释放药物传递系统包括渗透泵系统和溶出系统,其含有聚合物涂布的贮库(reservoir)或药物-聚合物基质制剂。控制释放系统的实例在美国专利第3,845,770号、第4,326,525号、第4,902,514号以及第5,616,345号中给出。用于本发明方法中的另一种制剂采用经皮传递装置(“贴片”)。此类经皮贴片可以用于提供本文所述的化合物以控制量连续或不连续输注。用于递送药剂的经皮贴剂的构建和使用是本领域中所熟知的。参看例如美国专利第5,023,252号、第4,992,445号以及第5,001,139号。可以构建此类贴片以连续、脉冲式或按需求递送药剂。
关于制备例如片剂的固体组合物,主要活性成分可与药物赋形剂混合,以形成含有具有上述任何化学式的化合物或其药学上可接受的盐、前药或溶剂合物的均匀混合物的固体预配制组合物。当提到这些预配制组合物为均匀组合物时,活性成分可均匀分散在整个组合物中,以便组合物可以容易地再分成同等有效的单位剂型,例如片剂、丸剂和胶囊。
本文所述的化合物的片剂或丸剂可以经包衣或以其它方式混配以提供剂型,其具有作用时间延长或保护免受胃的酸性条件的作用的优势。举例来说,片剂或丸剂可以包括内部剂量和外部剂量组分,后者为在前者上的包封形式。两种成分可以由肠衣层分开,以抵抗在胃中的崩解和允许内部成分完整地进入十二指肠或使之延迟释放。许多材料可以用作该肠衣层或包衣,所述材料包括许多聚合物酸,和聚合物酸与例如虫胶、鲸腊醇和乙酸纤维素等材料的混合物。
用于吸入或吹入的组合物可包括在药学上可接受的水性或有机溶剂或其混合物中的溶液和悬浮液,以及粉剂。液体或固体组合物可以含有如上文所描述的适合的药学上可接受的赋形剂。在一些实施方案中,组合物通过经口或经鼻呼吸道途径给药,用于局部或全身作用。在其它实施方案中,药学上可接受的溶剂中的组合物可以通过使用惰性气体来雾化。雾化溶液可以直接从雾化装置吸入或所述雾化装置可以连接到面罩托上或间歇性正压呼吸机上。可以优选地以适当的方式经口或经鼻从传递调配物的装置给药溶液、悬浮液或粉剂组合物。
给药
对任何具体受试者而言,本文所述的化学式的化合物的具体剂量水平将视多种因素而定,所述因素包括在经历疗法的受试者中所采用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、给药时间、给药途径以及排泄率、药物组合以及具体疾病的严重程度。举例来说,剂量可表示为每公斤受试者体重各化学式的化合物的毫克数(mg/kg)。约0.01到200mg/kg的剂量可能适当。在一些实施例中,约0.01到150mg/kg可能适当。在其它实施例中,0.05到100mg/kg的剂量可能适当。当在体型广泛不同的受试者之间调整剂量时,例如当在儿童与成人中使用药物时或当将例如狗的非人类受试者中的有效剂量转换成适用于人类受试者的剂量时所发生,根据受试者的体重标准化尤其适用。
日剂量也可描述为每剂或每天给药的化学式化合物的总量。化合物的日剂量可为约1mg至2,000mg,约1,000至2,000mg/天,约1至1,000mg/天,约1至500mg/天,约100至150mg/天,约1至100mg/天,约约1至50mg/天,约50to 100mg/天,约100至125mg/天,约100至150mg/天,约100至175mg/天,约100至200mg/天,约100至225mg/天,约100至250mg/天,约100至350mg/天,约100至400mg/天,约100至450mg/天,或约100至500mg/天。
当口服给药时,人受试者的总日剂量可为1mg至1,000mg/天,约1至100mg/天,约1至50mg/天,约50至100mg/天,100至200mg/天,约200至300mg/天,约300至400mg/天,约400至500mg/天,约100至150mg/天,约150至200mg/天,约200至250mg/天,约75至150mg/天,或约150至300mg/天。
本申请的化合物或其组合物可使用上文所述的任何适合模式每天给药一次、两次、三次或四次。此外,根据本文所述的任何化学式的化合物的给药或用其治疗可持续多天;举例来说,针对一个治疗周期,治疗通常将持续至少7天、14天或28天。在一些治疗中,化合物或其组合物为连续给药,即每天给药。治疗周期在癌症化学疗法中为熟知的,且常常与介于周期之间的约1到28天、通常约7天或约14天的休息期交替。在其它实施例中,治疗周期也可以是连续的。
在一个具体实施方案中,所述方法包含向受试者给药约1到500mg上式化合物的初始日剂量且以一定增量增加剂量直到实现临床功效为止。可使用约1、5、10、25、50、75或100mg的增量来增加剂量。剂量可每天、每隔一天、每周两次或每周一次地增加。
化合物的合成
本发明的化合物可以利用文中公开的方法及其路线变化形式而制备,鉴于本公开以及本领域中公知的方法,所述路线变化形式将是明显的。除了本申请中教导的以外,也可以使用常规的公知的合成方法。本文所述典型的化合物的合成可如下面实施例所描述那样实现。如果市购可得,试剂可以例如自Sigma Aldrich或其他化学供应商处商业购买。通常,本文所述化合物一般在室温和室内压力是稳定的和可分离的。
通用合成
本发明化合物的典型实施方案可以利用下面描述的总的反应方案合成。鉴于本申请的描述显而易见的是,该一般合成方案可以通过用具有类似结构的其他原料替换起始原料,从而相应地得到不同的产物而进行变化。下面的合成描述给出了起始原料可如何变化得到相应产物的多个实例。在给定的取代基团限定的所需产物的情况下,必须的起始原料通常可通过检查确定。起始原料典型地自商业来源得到或利用公开的方法合成。为合成本发明实施方案的化合物,检查需要合成的化合物的结构会提供各个取代基的确定。考虑到文中所给出的实施例,通过简单的检查方法,最终产物的确定通常使得必需原料的确定变得明了。
合成反应参数
术语“溶剂”、“惰性有机溶剂”或“惰性溶剂”指的是在与其一起描述的反应条件下为惰性的溶剂(包括,例如,苯、甲苯、乙腈、四氢呋喃(“THF”)、二甲基甲酰胺(“DMF”)、氯仿、亚甲基二氯(methylene chloride)(或二氯甲烷(dichloromethane))、乙醚、甲醇等)。除非有相反指定,本发明反应中使用的溶剂为惰性有机溶剂,且反应在惰性气体(优选氮气)中进行。
式(J)化合物可使用反应方案I中指出的方法制备。式(I)化合物可使用反应方案I中指出的方法制备,其中R4为任选取代的嘧啶。
反应方案I
步骤1–式(1)化合物的制备
式(1)化合物可通过在脱水剂的存在下组合化合物(A)、(B)和(C)来制备。化合物(A)、(B)和(C)为可商购的或者可通过本领域已知的方法制备。关于化合物(A),R1如本申请中所限定。关于化合物(B),R3和R5如本申请中所限定。关于化合物(C),R2如本申请中所限定。可将化合物(A)在偶联剂如亚磷酸二苯酯的存在下在溶剂如吡啶中与化合物(B)混合。在室温和100℃之间的温度搅拌1至5小时之后,添加化合物(C)。进一步在室温和100℃之间的温度搅拌5至24小时之后,允许反应混合物冷却至室温。为萃取式(1)化合物,可添加有机溶剂如乙酸乙酯(EtOAc),然后用弱酸、水和盐水洗涤。可将有机相浓缩,得到式(1)化合物。替代地,可将残留物直接纯化而不进行水溶液后处理。式(1)化合物可通过本领域已知的任何适合的方法如硅胶色谱法来纯化。替代地,式(1)化合物可用于后续步骤而不纯化。
步骤2—式(2)化合物的制备
式(2)化合物可通过从式(1)化合物除去一个或多个保护基来制备。将式(1)化合物溶解在适合的溶剂中并用适合的酸处理。适合的溶剂可包括例如二氯甲烷、二噁烷或者其它适合的溶剂。适合的酸可包括例如三氟乙酸、盐酸或者三溴化硼(BBr3)。反应可在-78℃至室温之间的温度进行。在反应完成后,除去溶剂,得到式(2)化合物。在使用BBr3反应的情况下,在水溶液后处理之前可将反应混合物首先用MeOH处理,得到式(2)化合物。
步骤4—式(3)化合物的制备
式(3)化合物可通过以下方法制备:在适合的溶剂如二噁烷中用氢氧化铵处理5-取代的-2,4,6-三卤代嘧啶,其中所述卤代为氯代或者氟代。反应在30和80℃之间的升高的温度进行适合的时间,通常为2至8小时或者直到反应完成。在完成后,将水添加至冷却的溶液,并通过过滤收集析出物。腈可在标准条件下转换成甲酰胺。
步骤5—式(I)化合物的制备
式(Ia)化合物通常可通过以下方法制备:在适合的碱的存在下在适合的溶剂中使式(3)化合物和式(2)化合物偶联。适合的碱的实例为二异丙基乙胺。适合的溶剂的实例为N-甲基吡咯烷酮(NMP)。反应通常在50℃至150℃之间的温度进行约30分钟至24小时。替代地,反应可在微波中在100℃至150℃之间的温度进行约30分钟至24小时。在完成后可添加水以淬灭反应,可将析出物过滤,然后溶解在有机溶剂如二氯甲烷(DCM)中。产物可通过本领域已知的方法分离,例如通过在减压下除去溶剂。产物可使用本领域已知的任何适合的方法纯化,例如,在二氧化硅柱上对残留物实施色谱法。而且,式(I)化合物可通过以下方法制备:以类似的方式使式(2)化合物与通式R4-X的适当取代的杂环偶联。
在合成之后,可将化合物以游离碱或者盐(其包括但不限于盐酸盐形式或者三氟乙酸盐形式)的形式分离并通过NMR表征。因此,所得化合物和它们的NMR表征可为游离碱或者盐。母体和相应的盐的比率未测定。
实施例1.式(1)化合物的制备
A.式(1)化合物的制备,其中n为2,R1为氯和氟,m为0,R5为H,R3为甲基
将2-氨基-6-氯-3-氟苯甲酸(1.43g,7.6mmol)和Boc-L-丙氨酸(1.7g,9.1mmol)在吡啶(4.9mL,60.5mmol)中的混合物温热至45℃,直到均匀,然后允许冷却至室温,此时添加亚磷酸二苯酯(5.0mL,26mmol)。将混合物在45℃搅拌1小时,然后用单份吡嗪-2,5-二胺二HCl(1g,9.1mmol)处理。将混合物在55℃搅拌过夜。在冷却至室温之后,将混合物用甲苯(20mL)稀释并用10%盐酸水溶液洗涤三次,并在减压下浓缩至干。将残留物使用25gSiliaSep快速柱用己烷至65%乙酸乙酯洗脱进行色谱法处理。将合并的级份在减压下浓缩,得到(S)-(1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯。ES/MS 435.1(M+H+)。
B.使用实施例1A和反应方案I中所述的操作制备下面的式(1)化合物:
(S)-(1-(3-(5-氨基吡嗪-2-基)-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯;
(S)-(1-(3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯;
(S)-((3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基甲酸叔丁酯;
(S)-(1-(3-(5-氨基吡嗪-2-基)-6,8-二氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯;
(S)-(1-(3-(5-氨基吡嗪-2-基)-8-氯-6-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯;
(S)-((3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基甲酸叔丁酯;和
(S)-(1-(3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯。
实施例2.式(2)化合物的制备
A.式(2)化合物的制备,其中n为2,R1为氯和氟,m为0,R5为H,R3为甲基。
将(S)-(1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基甲酸叔丁酯(0.4g,0.92mmol)在二氯甲烷(10mL)中的溶液用三氟乙酸(0.7mL)处理。在室温搅拌2小时之后,将混合物在减压下浓缩至干,得到作为金色无定形半固体的(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-5-氯-8-氟喹唑啉-4(3H)-酮,其用于后续步骤而不经进一步纯化。ES/MS 335.1(M+H+)。
B.使用实施例2A和反应方案I中所述的操作制备下面的式(2)化合物:
(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-8-氟喹唑啉-4(3H)-酮;
(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮;
(S)-2-(氨基(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮;
(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-6,8-二氟喹唑啉-4(3H)-酮;
(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-8-氯-6-氟喹唑啉-4(3H)-酮;
(S)-2-(氨基(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5,8-二氯喹唑啉-4(3H)-酮;和
(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-5,8-二氯喹唑啉-4(3H)-酮。
实施例3.式(3)化合物的制备
A.式(3)化合物(2,4-二氨基-6-氯嘧啶-5-甲腈)的制备,其中R4为CN,X为Cl,
在室温将氢氧化铵(20mL)添加至2,4,6-三氯嘧啶-5-甲腈(5.0g,24mmol)在二噁烷(20mL)中的溶液。将溶液温热至50℃并搅拌3小时。将反应混合物冷却至10℃并添加水(50mL)。将所得固体过滤,用水洗涤,并在高真空下干燥,得到标题化合物,其为白色固体。13H NMR(100MHz,DMSO)164.8,162.6,161.9,115.8,77.6。ES/MS m/z=169.9(M+H)+。
B.使用实施例3A和反应方案I中所述的操作制备下面的式(3)化合物:
5-氯-6-氟嘧啶-2,4-二胺;
6-氯-5-(甲基磺酰基)嘧啶-2,4-二胺;
6-氯-5-(三氟甲基)嘧啶-2,4-二胺;和
2,4-二氨基-6-氯嘧啶-5-甲酰胺。
实施例4.式(I)化合物的制备
A.式(I)化合物的制备,其中n为2,R1为氯和氟,m为0,R5为H,R3为甲基,其为(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-8-氟喹唑啉-4(3H)-酮(化合物1)。
将5-氯-6-氟嘧啶-2,4-二胺(0.11g,0.69mmol)和DIEA(0.4mL,2.3mmol)添加至(S)-2-(1-氨基乙基)-3-(5-氨基吡嗪-2-基)-5-氯-8-氟喹唑啉-4(3H)-酮(0.15g,0.46mmol)在IPA中的溶液。将所得混合物在微波中加热至120℃并保持4小时,然后浓缩。残留物的HPLC纯化得到标题化合物。1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.85–7.71(m,3H),7.63(dd,J=8.7,4.5Hz,1H),7.54(s,2H),7.43(s,3H),6.86(s,2H),5.01–4.91(m,1H),1.43(d,J=6.5Hz,3H)。ES/MS 477.1(M+H+)。
B.使用实施例4A和反应方案I中所述的操作制备下面的式(I)化合物:
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物2)。1H NMR(400MHz,DMSO-d6)δ8.20–7.92(m,4H),7.92–7.73(m,3H),7.71–7.56(m,2H),7.49–7.35(m,1H),6.87(s,2H),5.01(q,J=6.8Hz,1H),1.42(d,J=6.7Hz,3H)。ES/MS 468.1(M+H)+;
(S)-4-氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物3)。1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.09–8.02(m,2H),7.94(s,1H),7.84–7.71(m,2H),7.60(dd,J=8.8,4.3Hz,1H),7.44(s,2H),6.86(s,2H),4.85–4.80(m,1H),1.42(d,J=7.4Hz,3H)。ES/MS 453.1(M+H)+;
(S)-2-(1-((3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)-3-(5-氨基吡嗪-2-基)-8-氟喹唑啉-4(3H)-酮(化合物4)。1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.41(m,3H),7.93(t,J=9.1Hz,1H),7.74–7.64(m,1H),7.53(td,J=8.3,4.7Hz,1H),7.46–7.17(m,4H),4.86–4.68(m,1H),1.66(d,J=6.8Hz,3H)。ES/MS 420.1(M+H)+;
(S)-3-(5-氨基吡嗪-2-基)-5-氯-8-氟-2-(1-(呋喃并[2,3-d]嘧啶-4-基氨基)乙基)喹唑啉-4(3H)-酮(化合物5)。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.17–8.10(m,2H),8.03(s,1H),7.91–7.67(m,3H),7.58(m,1H),7.25(m,2H),7.08(s,1H),4.78(m,1H),1.52(d,J=6.8Hz,3H)。ES/MS 453.1(M+H+);
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物6)。1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,3H),7.82(t,J=8.0Hz,2H),7.65(ddd,J=20.3,8.0,1.2Hz,2H),7.49(brs,1H),7.02–6.71(brs,3H),4.99(q,J=6.8Hz,1H),1.45–1.38(m,3H)。ES/MS 450.1(M+H)+;
(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)喹唑啉-4(3H)-酮(化合物7)。1H NMR(400MHz,DMSO-d6)δ8.02(brs,1H),7.86–7.77(m,3H),7.69(dd,J=8.1,1.2Hz,1H),7.62(dd,J=7.9,1.2Hz,1H),7.55(brs,2H),7.44(brs,2H),6.84(brs,2H),4.94(p,J=6.8Hz,1H),1.42(d,J=6.6Hz,3H)。ES/MS 459.1(M+H+);
(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(环丙基((2,6-二氨基-5-氯嘧啶-4-基)氨基)甲基)喹唑啉-4(3H)-酮(化合物8)。1H NMR(400MHz,DMSO-d6)δ7.88–7.78(m,2H),7.78–7.66(m,3H),7.63(dd,J=7.8,1.2Hz,1H),7.56(s,2H),7.41(s,2H),6.82–6.73(m,2H),4.74–4.47(m,1H),1.53(s,1H),0.57(s,1H),0.46(dp,J=12.4,7.3,6.1Hz,2H),0.16(dq,J=9.6,4.9Hz,1H)。ES/MS 485.1(M+H)+;
(S)-2,4-二氨基-6-(((3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基)嘧啶-5-甲腈(化合物9)。1H NMR(400MHz,DMSO-d6)δ8.14(d,J=19.0Hz,3H),7.90–7.78(m,2H),7.71(dd,J=8.2,1.2Hz,1H),7.63(dd,J=7.8,1.2Hz,1H),7.48(brs,1H),6.75(m,2H),5.96(brs,2H),4.69(t,J=8.3Hz,1H),1.54(s,1H),0.57(s,1H),0.51–0.39(m,2H),0.17(m,1H)。ES/MS 476.1(M+H)+;
(S)-2,4-二氨基-6-(((3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基)嘧啶-5-甲腈(化合物10)。1H NMR(400MHz,DMSO-d6)δ8.07–7.97(m,5H),7.91–7.82(m,1H),7.80(s,1H),7.63(d,J=8.5Hz,1H),7.47–7.41(m,2H),6.85(s,2H),4.82(t,J=7.9Hz,1H),0.57–0.39(m,4H),0.24–0.13(m,1H)。ES/MS 510.1(M+H+);
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物11)。1H NMR(400MHz,DMSO-d6)δ8.11–7.90(m,5H),7.83(s,2H),7.62(d,J=8.5Hz,1H),7.54–7.26(m,2H),6.90(s,2H),5.07(p,J=6.7Hz,1H),1.43(d,J=6.6Hz,3H)。ES/MS 484.1(M+H)+;
(S)-3-(5-氨基吡嗪-2-基)-5,8-二氯-2-(环丙基((2,6-二氨基-5-氯嘧啶-4-基)氨基)甲基)喹唑啉-4(3H)-酮(化合物12)。1H NMR(400MHz,DMSO-d6)δ8.52(d,J=1.5Hz,1H),8.07–8.00(m,2H),7.70(d,J=1.5Hz,1H),7.63(d,J=8.6Hz,1H),7.49(d,J=8.5Hz,1H),6.89–6.81(m,3H),6.45(s,2H),6.15(d,J=5.3Hz,1H),4.81–4.76(m,1H),1.38–1.12(m,1H),1.06–0.72(m,2H),0.66–0.39(m,2H)。ES/MS 519.1(M+H)+;
(S)-3-(5-氨基吡嗪-2-基)-5,8-二氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)喹唑啉-4(3H)-酮(化合物13)。1H NMR(400MHz,DMSO-d6)δ8.02(dd,J=8.6,0.7Hz,2H),7.84(d,J=8.1Hz,2H),7.67–7.56(m,3H),7.56–7.46(m,2H),6.95–6.87(m,3H),5.01(p,J=6.7Hz,1H),1.44(d,J=6.6Hz,3H)。ES/MS 493.0(M+H+);
(S)-2-氨基-4-((1-(3-(5-氨基吡嗪-2-基)-8-氯-6-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)-6-(二氟甲基)嘧啶-5-甲腈(化合物14)。1H NMR(400MHz,DMSO)δ8.16(dd,J=8.5,2.9Hz,1H),8.08(br s,1H),7.86–7.79(m,3H),7.54(br s,1H),7.35(br s,1H),6.87(br s,2H),6.65(t,J=53.5Hz,1H),5.10–5.00(m,1H),1.45(d,J=6.5Hz,3H).ES/MS 503.1(M+H+);
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-6,8-二氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物15).1HNMR(400MHz,DMSO-d6)δ8.00(s,3H),7.92(ddd,J=10.3,8.9,2.9Hz,1H),7.79(s,1H),7.69(ddd,J=8.2,2.9,1.3Hz,1H),6.85(s,2H),5.01(p,J=6.7Hz,1H),1.40(d,J=6.6Hz,3H)。ES/MS 468.1(M+H+);
(S)-3-(5-氨基吡嗪-2-基)-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-6,8-二氟喹唑啉-4(3H)-酮(化合物16).1H NMR(400MHz,DMSO-d6)δ7.93(ddd,J=10.4,8.9,2.9Hz,2H),7.79(d,J=7.8Hz,2H),7.69(ddd,J=8.2,2.9,1.3Hz,1H),7.50(s,2H),7.39(s,3H),6.84(s,2H),4.99(p,J=6.7Hz,1H),1.41(d,J=6.6Hz,3H).ES/MS 461.9(M+H+);
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-8-氯-6-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈(化合物17).1HNMR(400MHz,DMSO-d6)δ8.17(dd,J=8.5,2.9Hz,1H),8.02(s,2H),7.85(tt,J=7.8,3.6Hz,4H),6.90(s,2H),5.10(p,J=6.6Hz,1H),1.44(d,J=6.6Hz,3H).ES/MS 468.1(M+H+);
(S)-3-(5-氨基吡嗪-2-基)-8-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-6-氟喹唑啉-4(3H)-酮(化合物18).1H NMR(400MHz,DMSO-d6)δ8.19(dd,J=8.5,2.9Hz,1H),7.98(s,2H),7.86(dd,J=8.1、2.9Hz,2H),7.81(s,1H),7.56(s,4H),6.90(s,2H),5.23–4.91(m,1H),1.45(d,J=6.6Hz,3H).ES/MS 477.1(M+H+);
(S)-2-(1-((6-氨基-5-氯嘧啶-4-基)氨基)乙基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮(化合物19).1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.18(d,J=1.4Hz,1H),7.92(s,1H),7.89(d,J=1.5Hz,1H),7.67–7.60(m,1H),7.49(dd,J=8.2,1.2Hz,1H),7.44(dd,J=7.8,1.2Hz,1H),7.18(s,2H),4.75(s,1H),1.49(d,J=7.0Hz,3H)。ES/MS 444.1(M+H+);
(S)-2-(((6-氨基-5-氯嘧啶-4-基)氨基)(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5,8-二氯喹唑啉-4(3H)-酮(化合物20).1H NMR(400MHz,DMSO-d6)δ8.01(d,J=8.5Hz,1H),7.82(s,1H),7.71(s,1H),7.60(d,J=8.5Hz,1H),6.87(s,2H),6.62(d,J=17.2Hz,3H),4.67(s,1H),1.42(s,1H),0.51–0.27(m,4H),0.27–0.07(m,1H).ES/MS 504.1(M+H+);和
(S)-2-(((6-氨基-5-氯嘧啶-4-基)氨基)(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮(化合物21).1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.81(q,J=7.9Hz,2H),7.69(d,J=9.3Hz,3H),7.60(dd,J=7.9,1.3Hz,2H),6.81(s,3H),6.61(s,4H),4.37(d,J=12.5Hz,1H),1.49(d,J=12.0Hz,1H),0.44(s,4H),0.34(q,J=4.5Hz,1H).ES/MS 470.1(M+H+)。
生物实施例
分析式(I)化合物对PI3K亚型的酶活性的特征。使用时间分辨荧光共振能量转移(TR-FRET)分析测量活性。TR-FRET监测三磷酸3,4,5-肌醇分子的形成,该分子与经荧光标记的PIP3竞争结合至GRP-1普列克底物蛋白(pleckstrin)同源结构域蛋白。磷脂酰肌醇酯3-磷酸产物的增加导致TR-FRET信号减少,因为GRP-1蛋白结合位点的经标记的荧光团被置换。
I类PI3K亚型被表达且纯化为异二聚体重组蛋白。TR-FRET测试的所有测试试剂和缓冲剂购自Millipore。在初始速率条件,在25mM Hepes(pH 7.4)和2×Km ATP(75-500μM)、2μM PIP2、5%甘油、5mM MgCl2、50mMNaCl、0.05%(v/v)Chaps、1mM二硫苏糖醇和1%(v/v)DMSO的存在下在对各亚型的以下浓度下测试PI3K亚型:PI3Kα、PI3Kβ和PI3Kδ在25至50pM,PI3Kγ在2nM。将表1的化合物和化合物X((S)-2,4-二氨基-6-((1-(5-氯-4-氧代-3-(吡啶-3-基)-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈)和化合物Y((S)-2,4-二氨基-6-((1-(5-氯-4-氧代-3-(吡啶-3-基)-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈)添加至测试溶液且在25℃培养30分钟。该反应用10mM EDTA、10nM标记的-PIP3和35nM铕标记的GRP-1检测蛋白的终浓度终止,然后在Envision板读数器上读取TR-FRET(Ex:340nm;Em:615/665nm;100μs延迟和500μs读取视窗)。
基于阳性对照(1μM渥曼青霉素)及阴性对照(DMSO)将结果归一化,且通过将剂量-响应曲线拟合至四参数方程计算PI3Kα、β、δ和γ的IC50值。这些测试所产生的结果通常在所报导的平均值的3倍以内。
表2总结了PI3K亚型β、δ和γ的IC50(nM)值。这些结果表明本发明式(I)的化合物抑制PI3Kδ和PI3Kβ二者。而且,化合物X显示PI3KδIC50为0.2nM,PI3KβIC50为11nM,PI3KγIC50为7nM。化合物X的PI3Kγ/PI3Kβ比例为0.6。这些结果表明相比化合物X,本发明化合物对PI3Kβ(相比PI3Kγ)具有更高的选择性。使用相同测试分析表1a中的化合物,且结果总结于表2a。
表2.PI3K亚型β、δ和γ.的IC50值(nM)
化合物 | PI3Kβ | PI3Kδ | PI3Kγ |
1 | 54 | 26 | >10000 |
2 | 4.4 | 3.5 | 630 |
3 | 74 | 11 | >10000 |
4 | >10000 | 2700 | >10000 |
5 | 5800 | 2300 | >10000 |
6 | 2.0 | 2.0 | 280 |
7 | 47 | 24 | 4000 |
8 | 190 | 24 | >10000 |
9 | 4.2 | 2.7 | 900 |
10 | 3.6 | 2.4 | 3100 |
11 | 1.8 | 1.9 | 1500 |
12 | 1200 | 97 | >10000 |
13 | 170 | 31 | >10000 |
表2a.PI3K亚型β、δ和γ.的IC50值(nM)
化合物 | PI3Kβ | PI3Kδ | PI3Kγ |
14 | 200 | 340 | >10000 |
15 | 9.8 | 53 | 1500 |
16 | 530 | 780 | >10000 |
17 | 14 | 32 | 4900 |
18 | 570 | 500 | >10000 |
19 | 360 | 54 | >10000 |
20 | 1100 | 26 | >10000 |
21 | 720 | 30 | >10000 |
在本说明书中所提及的美国专利、美国专利申请公开案、美国专利申请案、外国专利、外国专利申请案及非专利公开案全都以其全文引用的方式并入本文中,并入程度不与本发明描述相互矛盾。根据以上内容应了解,虽然已出于说明的目的在本文中描述了本发明的特定实施方案,但可在不偏离本申请的精神及范畴的情况下进行各种修改。
Claims (20)
1.具有式(I)的结构的化合物或者其药学上可接受的盐、异构体或混合物:
其中:
n为1、2或者3;
m为0或者1;
每一R1独立地选自卤素、氰基、任选取代的C1-6烷基、任选取代的C1-6卤代烷基、任选取代的C1-6烷氧基、任选取代的磺酰基、任选取代的C3-8芳基、任选取代的C3-8杂芳基、任选取代的C3-8环烷基和任选取代的C3-8杂环烷基;
每一R2独立地选自卤素和任选取代的C1-6烷基;
R3为氢、任选取代的C1-6烷基、任选取代的C6-10芳基或者任选取代的C3-8环烷基;
R4为具有至少一个芳基和至少两个杂原子的6至12元杂芳基,其中所述杂原子选自N、O或者S,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、任选取代的卤代烷基、任选取代的C1-6烷基和-NH2;和
R5为氢或者任选取代的C1-6烷基,其中R5和R3与它们所连接的原子一起任选地形成4或8元杂环。
2.权利要求1的化合物或者其药学上可接受的盐、异构体或混合物,其中
n为1或者2;
m为0或者1;
每一R1独立地选自卤素、C1-6烷基和C1-6卤代烷基;
每一R2独立地选自C1-6烷基;
R3为氢、C1-6烷基或者C3-8环烷基;
R4为具有至少一个芳环和至少两个氮原子的6至12元杂芳基,其中所述杂芳基任选取代有一个、两个或者三个独立地选自以下的成员:卤素、氰基、-NH2、C1-6卤代烷基和C1-6烷基;和
R5为氢、甲基、乙基或者丙基,或者R5和R3与它们所连接的原子一起任选地形成五元杂环。
3.权利要求1-2的化合物,其中每一R1独立地选自氯、溴、氟、甲基、乙基和丙基。
4.权利要求1-3中任一项的化合物,其中每一R2独立地选自甲基、乙基和丙基。
5.权利要求1-4中任一项的化合物,其中R3为氢、甲基、乙基、丙基、丁基、环丙基或者环丁基。
6.权利要求1-5中任一项的化合物,其中R5为氢、甲基、乙基或者丙基。
7.权利要求1-6中任一项的化合物,R5和R3与它们所连接的原子一起任选形成吡咯烷基。
8.权利要求1-7中任一项的化合物,其中R4为具有至少两个氮原子的单环杂芳基,其中R4取代有两个或者三个独立地选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2。
9.权利要求1-8中任一项的化合物,其中R4为嘧啶基,其取代有两个或三个选自以下的成员:溴、氯、氟、氰基、甲基、乙基、丙基和-NH2。
10.权利要求1-19中任一项的化合物,其中所述化合物为(S)-对映异构体。
11.权利要求1-19中任一项的化合物,其中所述化合物为(R)-对映异构体。
12.权利要求1的化合物,其中所述化合物选自:
(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-8-氟喹唑啉-4(3H)-酮;
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-4-氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-8-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-2-(1-((3H-[1,2,3]三唑并[4,5-d]嘧啶-7-基)氨基)乙基)-3-(5-氨基吡嗪-2-基)-8-氟喹唑啉-4(3H)-酮;
(S)-3-(5-氨基吡嗪-2-基)-5-氯-8-氟-2-(1-(呋喃并[2,3-d]嘧啶-4-基氨基)乙基)喹唑啉-4(3H)-酮;
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)喹唑啉-4(3H)-酮;
(S)-3-(5-氨基吡嗪-2-基)-5-氯-2-(环丙基((2,6-二氨基-5-氯嘧啶-4-基)氨基)甲基)喹唑啉-4(3H)-酮;
(S)-2,4-二氨基-6-(((3-(5-氨基吡嗪-2-基)-5-氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基)嘧啶-5-甲腈;
(S)-2,4-二氨基-6-(((3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)(环丙基)甲基)氨基)嘧啶-5-甲腈;
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-5,8-二氯-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-3-(5-氨基吡嗪-2-基)-5,8-二氯-2-(环丙基((2,6-二氨基-5-氯嘧啶-4-基)氨基)甲基)喹唑啉-4(3H)-酮;
(S)-3-(5-氨基吡嗪-2-基)-5,8-二氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)喹唑啉-4(3H)-酮;
(S)-2-氨基-4-((1-(3-(5-氨基吡嗪-2-基)-8-氯-6-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)-6-(二氟甲基)嘧啶-5-甲腈;
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-6,8-二氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-3-(5-氨基吡嗪-2-基)-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-6,8-二氟喹唑啉-4(3H)-酮;
(S)-2,4-二氨基-6-((1-(3-(5-氨基吡嗪-2-基)-8-氯-6-氟-4-氧代-3,4-二氢喹唑啉-2-基)乙基)氨基)嘧啶-5-甲腈;
(S)-3-(5-氨基吡嗪-2-基)-8-氯-2-(1-((2,6-二氨基-5-氯嘧啶-4-基)氨基)乙基)-6-氟喹唑啉-4(3H)-酮;
(S)-2-(1-((6-氨基-5-氯嘧啶-4-基)氨基)乙基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮;
(S)-2-(((6-氨基-5-氯嘧啶-4-基)氨基)(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5,8-二氯喹唑啉-4(3H)-酮;和
(S)-2-(((6-氨基-5-氯嘧啶-4-基)氨基)(环丙基)甲基)-3-(5-氨基吡嗪-2-基)-5-氯喹唑啉-4(3H)-酮;
或者其药学上可接受的盐、异构体或混合物。
13.药物组合物,其包含权利要求1-12中任一项的化合物和至少一种药学上可接受的媒介物。
14.一种在有需要的人中治疗疾病或者病症的方法,其包括向所述人给药治疗有效量的权利要求1-12中任一项的化合物,其中所述疾病或者病症选自癌症、恶性血液病、白血病、淋巴瘤、骨髓增殖性疾病、骨髓增生异常综合征、浆细胞肿瘤、实体瘤、炎症、纤维化、自身免疫性障碍、过敏病症、超敏反应、心血管疾病、神经退行性疾病、肾疾病、病毒感染、肥胖症和自身免疫性疾病。
15.权利要求14的方法,其中所述疾病或者病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、牛皮癣、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性呼吸道阻塞疾病、肺炎、皮炎、秃头症、肾炎、脉管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥、淋巴瘤、多发骨髓瘤、白血病、胰腺癌、膀胱癌、结肠直肠癌、乳腺癌、前列腺癌、肾脏癌、肝细胞癌、肺癌、卵巢癌、子宫颈癌、直肠癌、肝癌、肾癌、胃癌、皮肤癌、胃部癌症、食管癌、头颈癌、黑色素瘤、神经内分泌癌、CNS癌(例如,成神经细胞瘤)、脑瘤(例如,神经胶质瘤、间变性少突胶质细胞瘤、成人多形性胶质细胞瘤和成人间变性星形细胞瘤)、骨癌,或者软组织肉瘤。一种抑制磷脂酰肌醇3-激酶多肽的活性的方法,其通过使所述多肽与权利要求1-12中的任一项的化合物接触。
16.一种抑制过度或破坏性免疫反应或者癌细胞的生长或增殖的方法,其包括给药有效量的权利要求1-12中任一项的化合物。
17.试剂盒,其包含权利要求1-12中任一项的化合物或者标签和/或使用说明书。
18.权利要求1-12中任一项的化合物、其药学上可接受的盐、异构体,或者混合物,其用于治疗。
19.权利要求1-12中任一项的化合物、其药学上可接受的盐、异构体,或者混合物,其用于权利要求14-15中任一项的治疗方法。
20.权利要求1-12中任一项的化合物、其药学上可接受的盐、异构体,或者混合物在制备用于治疗权利要求14-15中任一项的疾病或者病症的药物中的用途。
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TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
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