CN101687852A - 可用作激酶抑制剂的噻唑类和吡唑类化合物 - Google Patents
可用作激酶抑制剂的噻唑类和吡唑类化合物 Download PDFInfo
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Abstract
本发明涉及可用作Aurora蛋白激酶抑制剂的化合物。本发明还提供了包含这些化合物的药学上可接受的组合物,以及使用所述化合物和组合物治疗不同疾病、病症和障碍的方法。本发明还提供了制备本发明化合物的方法。
Description
技术领域
[0000]本发明涉及可用作Aurora蛋白激酶抑制剂的化合物。本发明还涉及包含本发明化合物的药学上可接受的组合物,使用所述化合物和组合物治疗不同疾病的方法,以及制备所述化合物的方法。
背景技术
[0001]Aurora蛋白是三种相关的丝氨酸/苏氨酸激酶(称为Aurora-A、-B和-C)的家族,它们对于通过细胞周期的分裂期的进程是必需的。特别地,Aurora-A在中心体成熟和分离、有丝分裂纺锤体的形成和染色体的可靠分离中发挥决定性作用。Aurora-B是一种染色体过客蛋白,其在调节中期板上的染色体的比对、纺锤体组装检测点和胞质分裂的修正完成中发挥重要作用。
[0002]已在一系列人类癌症中观察到Aurora-A、-B或-C的过表达,所述癌症包括结直肠癌、卵巢癌、胃癌和侵袭性导管腺癌。
[0003]许多研究已证实,Aurora-A或-B在人类癌细胞系中的缺失或被siRNA、显性负相抗体或中和抗体的抑制,中断了通过具有4N DNA的细胞的蓄积的有丝分裂的进程,并且在某些情况下接着会核内复制和细胞死亡。
[0004]Aurora激酶是有吸引力的靶,因为它们与众多人类癌症以及它们在这些癌症细胞增殖中所发挥的作用有关。因此,对抑制Aurora激酶的化合物存在需求。
发明内容
[0005]本发明提供可用作Aurora蛋白激酶的抑制剂的化合物及其药学上可接受的组合物。这些化合物由式I表示:
或其药学上可接受的盐,其中各变量如本文中所定义。
[0006]这些化合物及其药学上可接受的组合物可用于体外、体内和离体抑制激酶。这些用途包括治疗或预防骨髓增殖性疾病以及增生性疾病例如黑色素瘤、骨髓瘤、白血病、淋巴瘤、成神经细胞瘤和癌症。其它用途包括研究生物学和病理学现象中的激酶;研究由此类激酶介导的细胞内信号转导途径;以及比较评价新型激酶抑制剂。
具体实施方式
[0007]本发明的一个实施方案提供了式I化合物:
或其药学上可接受的盐,其中:
X1是N或CH;
X2是N或CH;
X3是N或CRX;
条件是当X3是CRX时,X1和X2中仅一个是N;且条件是X1,X2和X3中的至少一个是N;
Ht是噻唑或吡唑,其中每个环任选和独立地被R2和R2′取代;
Q是-O-,-NR′-,-S-,-C(=O)-,或-C(R′)2-;
RX是H或F;
RY是-Z-R10;
R1是T-(环D);
环D是5-7元单环芳基或杂芳基环,其中所述杂芳基具有1-4个选自O、N或S的环杂原子;环D可以任选地与环D′稠合;
环D′是包含0-4个选自氮、氧或硫的环杂原子的5-8元芳族部分饱和或完全不饱和的环;
环D和环D′各自独立和任选地被0-4次出现的氧代或-W-R5取代;
T各自独立地是C1-4亚烷基链或不存在;
R2是H,C1-3烷基或环丙基;
R2′是H;
Z和W各自独立地不存在或是C1-10亚烷基链,其中亚烷基链中至多6个亚甲基单元任选被V替代;
V各自选自-O-,-C(=O)-,-S(O)-,-S(O)2-,-S-或-N(R4)-;
R5各自独立地是-R,-卤素,-OR,-C(=O)R,-CO2R,-COCOR,COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6脂肪族基团),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R或-OC(=O)N(R7)2;
R各自是H,C1-6脂肪族基团,C6-10芳基环,具有5-10个环原子的杂芳基环或具有4-10个环原子的杂环基环;其中所述杂芳基或杂环基环具有1-4个选自氮、氧或硫的环杂原子;R任选被0-6个R9取代;
R4各自是-R7,-COR7,-CO2R7,-CON(R7)2或-SO2R7;
R7各自独立地是H或任选被1-6个卤素或-O(C1-6烷基)取代的C1-6脂肪族基团;或在同一个氮上的两个R7与氮一起形成包含1-4个选自氮、氧或硫的杂原子的任选取代的4-8元杂环基或杂芳基环;
R9各自是-R′,-卤素,-OR′,-C(=O)R′,-CO2R′,-COCOR′,COCH2COR′,-NO2,-CN,-S(O)R′,-S(O)2R′,-SR′,-N(R′)2,-CON(R′)2,-SO2N(R′)2,-OC(=O)R′,-N(R′)COR′,-N(R′)CO2(C1-6脂肪族基团),-N(R′)N(R′)2,-N(R′)CON(R′)2,-N(R′)SO2N(R′)2,-N(R′)SO2R′,-OC(=O)N(R′)2,=NN(R′)2,=N-OR′或=O;
R10各自是包含1个选自O、N或S的杂原子的5-6元杂环;R10各自任选被0-6次出现的J取代;
J各自独立地是R,-卤素,-OR,氧代,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6脂肪族基团),-N(R4)N(R4)2,=NN(R4)2,=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R,-OC(=O)N(R7)2或-OP(=O)(OR″)2;或
相同原子或不同原子上的2个J基团与它们所连接的原子一起形成具有0-2个选自O、N或S的杂原子的3-8元饱和、部分饱和或不饱和的环;其中2个J基团形成的环上的1-4个氢原子任选被JR替代;或所述环上的两个氢原子任选被氧代或被螺-连接的C3-4环烷基替代;其中所述C3-4烷基任选被1-3个氟取代;
JR各自是F或R7′;
R7′各自独立地是C1-6脂肪族基团;-O(C1-6脂肪族基团);或包含1-4个选自O、N或S的杂原子的5-6元杂芳基;R7′各自任选被0-3个J7取代;
J7独立地是NH2,NH(C1-4脂肪族基团),N(C1-4脂肪族基团)2,卤素,C1-4脂肪族基团,OH,O(C1-4脂肪族基团),NO2,CN,CO2H,CO2(C1-4脂肪族基团),O(卤代C1-4脂肪族基团)或卤代C1-4脂肪族基团;
R′各自独立地是H或C1-6脂肪族基团;或者两个R′与它们所连接的原子一起形成3-6元碳环基或包含0-1个选自O、N或S的杂原子的3-6元杂环基;且
R″各自独立地是H或C1-2烷基。
[0008]在一些实施方案中,X1是N。在其它实施方案中,X1是CH。在一些实施方案中,X2是N。在其它实施方案中,X2是CH。在一些实施方案中,X3是CRX。在其它实施方案中,X3是N。在一些实施方案中,X1,X2和X3均是N。在其它实施方案中,X1是N,X2是CH,且X3是CRx。在其它实施方案中,X1是CH,X2是N,且X3是CRx。在一些实施方案中,X1是N,X2是CH,且X3是N。在其它实施方案中,X1是CH,X2是CH,且X3是N。
[0009]某些实施方案提供了式I-a至I-f的化合物,其中变量如本文所定义。
[0011]在一些实施方案中,Q是-S-。在其它实施方案中,Q是-O-。在其它实施方案中,Q是-C(=O)-。在一些实施方案中,Q是-C(R′)2-。
[0012]在一些实施方案中,R2是H或C1-3烷基。
[0013]在另一个实施方案中,环D是5-6元单环芳基或杂芳基环。在一些实施方案中,环D是6-元单环芳基或杂芳基环。在一些实施方案中,环D与环D′稠合。
[0014]在本发明的一个方面中,环D-D′是包含1-5个选自氮、氧或硫的杂原子的8-12元双环芳基或杂芳基。在一些实施方案中,环D-D′是6:6环系。一些实施方案中,环D-D′是喹啉。在其它实施方案中,环D-D′是6:5环系。在一些实施方案中,所述6:5环系包含2个氮原子。在一些实施方案中,环D-D′是苯并咪唑、吲唑或咪唑并吡啶环。在其它实施方案中,环D-D′是苯并咪唑环。在本发明的另一个方面中,环D是5-6元单环芳基或杂芳基环;且其中D不与D′稠合。
[0015]在一些实施方案中,环D是苯基。在一个实施方案中,环D是苯基,其中苯基独立地被1或2个选自-卤素和-N(R7)CO2(C1-6脂肪族基团)的取代基取代。在另一个实施方案中,环D是苯基,其中苯基独立地被-F和-NHCO2(C1-3脂肪族基团)取代。在另一个实施方案中,环D是苯基,其中苯基独立地被-F和-NHCO2(环丙基)取代。在一个实施方案中,环D是
[0016]在其它实施方案中,环D是吡啶基。
[0017]在一些实施方案中,R7是氟。在其它实施方案中,R7是OCH3。
[0018]在一些实施方案中,T不存在。
[0019]在一些实施方案中,RY是-Z-R10。
[0020]在其它实施方案中,Z不存在。在一些实施方案中,Z是C1-6亚烷基链,其中Z的1-2个亚甲基单元任选被O、-N(R4)-或S替代。在其它实施方案中,Z是C1-4亚烷基链。
[0021]在本发明的另一个方面中,R10是包含1个氮原子的5-6元杂环。在一些实施方案中,R10是任选取代的吡咯烷。在其它实施方案中,R10是任选取代的哌啶。在一些实施方案中,所述杂环通过氮原子与Z连接。
[0022]在一些实施方案中,R10是
其中
n是1或2;且J如本文所定义。
[0023]在一个实施方案中,RY是其中n是1或2。在一些实施方案中,J各自独立地是C1-6烷基,F,-N(R4)2,CN,或-OR;或者两个J基团与它们所连接的原子一起形成包含1-2个选自N或O的杂原子的4-7元杂环基环;其中所述环任选被0-3个JR取代。
[0024]在一些实施方案中,每个-N(R4)2基团中的至少一个R4不是H。
[0025]在其它实施方案中,R是H,C1-4烷基或C3-6环烷基;其中所述C1-4烷基或C3-6环烷基任选被1-3个氟原子取代。
[0026]在其它实施方案中,R4是H,C1-5烷基或C3-6环烷基;或者两个R4与它们所连接的氮原子一起形成包含1-2个选自0、N或S的杂原子的3-6元单环;其中所述单环任选被0-3个JR取代。
[0027]在一些实施方案中,每个-N(R4)2基团中的至少一个R4不是H。在一些实施方案中,JR是卤素,C1-3烷基或-O(C1-3烷基)。
[0028]在另一个实施方案中,RY是其中n是1或2。在一些实施方案中,J是F,-N(R4)2,CN,-OR,氧代(=O)或任选被出现1次的OH或OCH3取代的C2-6烷基。在一些实施方案中,每个-N(R4)2基团中的至少一个R4不是H。在一些实施方案中,J是F。
[0029]在一个实施方案中,
Z不存在;
n是2;且
J各自独立地是C1-6烷基,F,-N(R4)2,CN,或-OR。
[0030]在一些实施方案中,每个-N(R4)2基团中的至少一个R4不是H。
[0031]在另一个实施方案中,
Z不存在;
n是2;且
两个J基团与它们所连接的原子一起形成包含1-2个选自N或O的杂原子的4-7元杂环基环。
[0032]在一些实施方案中,所述杂环基是包含1-2个选自N或O的杂原子的4-7元螺杂环基环。在一些实施方案中,所述螺杂环基是包含1个选自N或O的杂原子的5-元螺杂环基环。在一些实施方案中,所述5-元螺杂环基环包含1个N(氮)杂原子。在一些实施方案中,所述两个J基团形成的环任选被0-3个JR取代。在一些实施方案中,所述两个J基团形成的环任选被1个JR取代。
[0035]在一些实施方案中,JR是CH3。
[0036]本发明的另一个方面提供了化合物,其中
n是1;
J是F,-N(R4)2,CN,-OR,氧代(=O)或任选被出现1次的OH或OCH3取代的C2-6烷基;且R1任选被出现1次的-NHC(O)(C1-6脂肪族基团)取代,其中所述C1-6脂肪族基团被0-6个卤素取代。
[0037]在一些实施方案中,每个-N(R4)2基团中的至少一个R4不是H。
[0038]本发明的另一个方面提供了化合物,其中
RY是
n是1;
J是F;且
R1任选被出现1次的-NHC(O)(C1-6脂肪族基团)取代,其中所述C1-6脂肪族基团被0-6个卤素取代。
[0039]在一些实施方案中,RY是
[0041]为了本发明的目的,化学元素根据CAS版本的化学物理手册(Handbook of Chemistry和Physics)第75版的元素周期表鉴定。此外,有机化学的一般原理描述于本领域技术人员已知的教科书中,包括,例如“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,以及“March′sAdvanced Organic Chemistry”,5th Ed.,Ed.:Smith,M.B.和March,J.,J ohn Wiley & Sons,New York:2001,其全部内容在此通过引用并入。
[0042]如本文所述,明确说明的原子的数目范围包括其中的任何整数。例如,具有1-4个原子的基团可具有1、2、3或4个原子。
[0043]如本文所述,本发明化合物可任选被一个或多个取代基取代,例如上文一般性描述的那些,或者由本发明的特定类、亚类、种类所示例的那些。应当理解,短语“任选取代的”可与短语“取代或未取代的”互换使用。通常,术语“取代的”,不管前面是否有“任选”,均指在给定结构中的氢原子团被所指明的取代基基团替换。除非另有说明,任选取代的基团可在该基团的每一个可取代的位置上具有取代基,并且当在任意给定结构中有多于一个位置可被多于一个选自特定基团的取代基取代时,在每一个位置上的取代基可以相同或者不同。本发明考虑的取代基的组合优选是导致形成稳定的或化学上可行的化合物的那些。
[0044]本文所用的术语“稳定的”是指当经受允许其产生、检测并优选其回收、纯化的条件和用于本文公开的一个或多个目的时基本不变化的化合物。在一些实施方案中,稳定的化合物或化学上可行的化合物是当维持于40℃或更低的温度,无水份或其它化学反应性条件至少一周时基本不变化的化合物。
[0045]本文所用的术语“脂肪族的”或“脂肪族基团”等表示未分支或支链的、直链或环状、取代或未取代的烃,其是完全饱和的或者含有一个或多个具有与分子剩余部分连接的单一点的不饱和单元。适当的脂肪族基团包括但不限于线性或分支、取代或未取代的烷基、链烯基或炔基。具体实例包括但不限于甲基、乙基、异丙基、正丙基、仲丁基、乙烯基、正丁烯基、乙炔基和叔丁基。
[0046]术语“环脂肪族基团”(或“碳环”或“碳环基”或“环烷基”等)是指单环C3-C8烃或二环C8-C12烃,其是完全饱和的或者含有一个或多个不饱和单元,但是其不是芳香族的,其具有与分子剩余部分连接的单一点,在所述分子中的所述二环环系中的任何单独环为3-7元。适当的环脂肪族基团包括但不限于环烷基和环烯基。具体实例包括但不限于环己基、环丙烯基和环丁基。
[0048]术语“环烷基”是指完全饱和并且具有与分子剩余部分连接的单一点的单环烃。适当的环烷基包括,但不限于环丙基,环丁基和环戊基。
[0049]在本发明的化合物中,环包括线性稠合环、桥环或螺环。桥接环脂肪族基团的实例包括但不限于二环[3.3.2]癸烷、二环[3.1.1]庚烷和二环[3.2.2]壬烷。
[0050]本文所用的术语“杂环”、“杂环基”或“杂环的”等表示非芳香的单环或二环,其中一个或多个环成员独立地选自杂原子。在一些实施方案中,所述“杂环”、“杂环基”或“杂环的”基团具有3-10个环成员,其中一个或多个环成员是独立地选自氧、硫、氮或磷的杂原子,并且系统中的各环含有3-7个环成员。桥接杂环的实例包括但不限于7-氮杂-二环[2.2.1]庚烷和3-氮杂-二环[3.2.2]壬烷。
[0051]适当的杂环包括但不限于3-1H-苯并咪唑-2-酮、3-(1-烷基)-苯并咪唑-2-酮、2-四氢呋喃基、3-四氢呋喃基、2-四氢噻吩基、3-四氢噻吩基、2-吗啉代、3-吗啉代、4-吗啉代、2-硫代吗啉代、3-硫代吗啉代、4-硫代吗啉代、1-吡咯烷基、2-吡咯烷基、3-吡咯烷基、1-四氢哌嗪基、2-四氢哌嗪基、3-四氢哌嗪基、1-哌啶基、2-哌啶基、3-哌啶基、1-吡唑啉基、3-吡唑啉基、4-吡唑啉基、5-吡唑啉基、1-哌啶基、2-哌啶基、3-哌啶基、4-哌啶基、2-噻唑烷基、3-噻唑烷基、4-噻唑烷基、1-咪唑烷基、2-咪唑烷基、4-咪唑烷基、5-咪唑烷基、二氢吲哚基、四氢喹啉基、四氢异喹啉基、苯并硫杂环戊烷、苯并二噻烷和1,3-二氢-咪唑-2-酮。
[0052]本文所用的术语“Ht”与“Het”和可互换。
[0053]术语“杂原子”表示一个或多个氧、硫、氮、磷或硅(包括氮、硫、磷或硅的任何氧化形式;任何碱性氮的季铵化形式;或者杂环的可取代氮,例如N(如在3,4-二氢-2H-吡咯基中)、NH(如在吡咯烷基中)或NR+(如在N-取代的吡咯烷基中))。
[0054]术语“芳基”是指具有总计5-12个环成员的单环或二环,其中在系统中的至少一个环是芳族的,并且其中系统中的各环含有3-7个环成员。术语“芳基”可与术语“芳基环”互换使用。术语“芳基”还指如下文所定义的杂芳基系统。
[0055]术语“杂芳基”是指具有总计5-12个环成员的单环或二环,其中在系统中的至少一个环是芳族的,在系统中的至少一个环含有一个或多个杂原子,并且其中系统中的各环含有3-7个环成员。术语“杂芳基”可与术语“杂芳基”或术语“杂芳族基团”互换使用。适当的杂芳基包括但不限于2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、苯并咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(例如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(例如5-四唑基)、三唑基(例如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、苯并呋喃基、苯并噻吩基、吲哚基(例如2-吲哚基)、吡唑基(例如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-噻二唑基、1,3,4-噻二唑基、1,2,5-噻二唑基、嘌呤基、吡嗪基、1,3,5-三嗪基、喹啉基(例如2-喹啉基、3-喹啉基、4-喹啉基)和异喹啉基(例如1-异喹啉基、3-异喹啉基或4-异喹啉基)。
[0056]本文所用的术语“不饱和”表示具有一个或多个不饱和单元的部分。
[0057]术语“卤素”表示F、Cl、Br或I。
[0058]本文所用的术语“保护基团”是指用于暂时阻断多官能化合物中的一个或多个希望反应位点的基团。在某些实施方案中,保护基团具有以下特征中的一个或多个,或者优选具有所有以下的特征:a)以高收率选择性反应以得到被保护的底物,其对在一个或多个其它反应位点发生的反应是稳定的;以及b)可通过不攻击再生官能团的试剂以高收率被选择性除去。示例性保护基团详细描述于Greene,T.W.,Wuts,P.G,“Protective Groups in OrganicSynthesis”,第三版,John Wiley & Sons,New York:1999和此书的其它版本中,其全部内容通过引用并入本文。本文所用的术语“氮保护基团”是指用于暂时阻断多官能化合物中的一个或多个希望的氮反应性位点的基团。优选的氮保护基团也具有上文例举的特征,并且某些示例性氮保护基团也详细描述于Greene,T.W.,Wuts,P.G,“Protective Groups in Organic Synthesis”,第三版,JohnWiley & Sons,New York:1999的第7章中,其全部内容通过引用并入本文。
[0059]除非另外指出,本文描述的结构还表示包括此结构的所有异构(例如,对映体、非对映体和几何(或构象))形式;例如,各不对称中心的R和S构型,(Z)和(E)双键异构体,以及(Z)和(E)构象异构体。因此,本发明化合物的单个立体化学异构体以及对映体混合物、非对映体混合物和几何异构体(或构象异构体)混合物在本发明的范围之内。
[0060]除非另外指出,本发明化合物的所有互变异构形式都在本发明的范围之内。正如本领域技术人员可以理解的,吡唑基可以以各种方式表示。例如,画为的结构也代表其它可能的互变异构体,例如同样,画为的结构也代表其它可能的互变异构体,例如
[0062]另外,除非另外指出,本文描述的结构还表示包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如,除了由氘或氚替换氢或由13C-或14C-富集的碳替换碳以外具有本发明结构的化合物也在本发明的范围之内。这类化合物可用作例如生物测定中的分析工具或探针。
[0063]本发明的化合物可根据本说明书使用本领域普通技术人员通常已知的步骤制备。那些化合物可通过已知的方法分析,所述方法包括但不限于LCMS(液相色谱质谱法)和NMR(核磁共振)。应当理解,下文所示的具体条件仅仅是实例,并且不表示限制可用于制备本发明化合物的条件的范围。此外,本发明还包括根据本说明书对于本领域技术人员是显而易见的用于制备本发明的化合物的条件。除非另外指出,以下方案中的所有变量都如本文中所定义。
[0064]使用下列缩写:
HPLC是高效液相色谱法
LCMS是液相色谱质谱法
1H NMR是核磁共振
方案I
[0065]上述方案I表示制备本发明化合物的一般方法,其中X1是N,X2是CH,且X3是CRx。在上述方案中,LG1是Cl或NO2;LG2是Cl或Br。
方案II
[0066]上述方案II表示制备本发明化合物的一般方法,其中X1是CH,X2是N,且X3是CRx。在上述方案中,LG1是Cl或NO2;LG2是Cl或Br。
方案III
[0067]上述方案III表示制备本发明化合物的一般方法,其中X1,X2和X3是N。
[0068]存在三种加成到三嗪起始原料中的主要基团。这些基团的加成顺序可以改变。涉及的三种主要反应是:加成吡咯烷或哌啶,加成氨基-杂芳基,和加成-Q-R1。可以按照各种不同顺序加成吡咯烷或哌啶,氨基-杂芳基和-Q-R1。例如,可以首先加成氨基-杂芳基,随后加成吡咯烷或哌啶,最后加成-Q-R1。或者首先加成-Q-R1,随后加成氨基-杂芳基,最后加成吡咯烷或哌啶。本领域技术人员可以理解如上所示的各种反应。
[0069]在上述方案中,LG2是Cl或Br。
方案IV
[0070]上述方案IV表示制备本发明化合物的一般方法,其中X1是CH,X2是N,且X3是N。
方案V
[0071]上述方案V表示制备本发明化合物的其他的一般方法,其中X1是CH,X2是N,且X3是N。在上述方案V中,最后两步的顺序可以颠倒。例如,可以先加成氨基-杂芳基,再加成HQ-R1。
[0072]另外,可以按照WO2002/057259中所示的方法制备本发明的化合物,其内容通过引用并入本文。
[0073]因此,本发明涉及用于制备本发明化合物的方法。
[0074]用于评估本发明化合物的活性的方法(例如激酶测定法)在本领域中是已知的,并且也描述于阐述的实施例中。
[0075]所述化合物作为蛋白激酶抑制剂的活性可在体外、在体内或在细胞系中测定。体外测定法包括测定活化激酶的激酶活性或ATP酶活性的抑制作用的测定法。其它的体外测定法量化抑制剂结合蛋白激酶的能力,并且可通过在结合之前放射性标记抑制剂、分离抑制剂/激酶复合物,以及测定放射性示踪标记的量,或者通过进行竞争性实验来测定,在所述竞争性实验中将新的抑制剂与结合于已知放射性配体的激酶一起孵育。
[0076]本发明的另一方面涉及抑制生物样品中的激酶活性,此方法包括使所述生物样品与式I化合物或包含所述化合物的组合物接触。本文所用的术语“生物样品”表示体外或离体样品,包括但不限于细胞培养物或其提取物;得自哺乳动物的活组织检查材料或其提取物;以及血液、唾液、尿液、粪便、精液、眼泪或其它体液或其提取物。
[0077]生物样品中激酶活性的抑制作用可用于本领域技术人员已知的各种目的。这种目的的实例包括但不限于输血、器官移植、生物样品贮存和生物测定。
[0078]生物样品中激酶活性的抑制作用也可用于研究生物学和病理学现象中的激酶;用于研究由这类激酶介导的细胞内信号转导途径;以及用于比较评价新的激酶抑制剂。
[0079]Aurora蛋白激酶抑制剂或其药学盐可制成对动物或人类施用的药物组合物。本发明的另一个实施方案是这些药物组合物,其包含有效治疗或预防Aurora-介导的病症的量的Aurora蛋白抑制剂和药学上可接受的载体。
[0080]本文所用的术语“Aurora-介导的病症”或“Aurora-介导的疾病”表示已知Aurora(Aurora A、Aurora B和Aurora C)在其中起作用的任何疾病或其它有害病症。这类病症包括但不限于癌症、增生性疾病和骨髓增殖性疾病。
[0081]骨髓增殖性疾病的实例包括但不限于真性红细胞增多症、血小板增多症、伴有骨髓纤维变性的髓样化生、慢性粒细胞白血病(CML)、慢性粒单核细胞白血病、嗜酸细胞增多综合征、幼年型粒单核细胞白血病和系统性肥大细胞病。
[0082]术语“癌症”还包括但不限于以下(部位)癌症:表皮样口腔:口腔前庭、唇、舌、口、咽;心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤),粘液瘤,横纹肌瘤,纤维瘤,脂肪瘤和畸胎瘤;肺:支气管原癌(扁平细胞或表皮样细胞、未分化的小细胞、未分化的大细胞、腺癌),肺泡(细支气管)癌,支气管腺瘤,肉瘤,淋巴瘤,软骨错构瘤,间皮瘤;胃肠:食道(鳞状细胞癌、喉、腺癌、平滑肌肉瘤、淋巴瘤),胃(癌、淋巴瘤、平滑肌肉瘤),胰腺(导管腺癌、胰岛素瘤、胰高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤),小肠或小肠(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤),大肠或大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤),结肠,结肠-直肠,结肠直肠,直肠;生殖泌尿道:肾(腺癌、Wilms瘤[肾母细胞瘤]、淋巴瘤、白血病),膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌),前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维性瘤、腺瘤样瘤、脂肪瘤);肝:肝细胞瘤(肝细胞癌),胆管上皮癌,肝胚细胞瘤,血管肉瘤,肝细胞性腺瘤,血管瘤,胆道;骨:成骨性肉瘤(骨肉瘤),纤维肉瘤,恶性纤维组织细胞瘤,软骨肉瘤,尤因肉瘤,恶性淋巴瘤(网状细胞肉瘤),多发性骨髓瘤,恶性巨细胞瘤,脊索瘤,骨软骨瘤(骨软骨外生骨疣),良性软骨瘤,软骨母细胞瘤,软骨粘液样纤维瘤,骨样骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄瘤、畸形性骨炎),脑膜(脑膜瘤、脑脊膜肉瘤、神经胶质瘤),脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤[松果体瘤]、胶质母细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤),脊髓神经纤维瘤,脑膜瘤,神经胶质瘤,肉瘤);妇科学:子宫(子宫内膜癌),宫颈(宫颈癌、肿瘤前宫颈发育不良),卵巢(卵巢癌[浆液囊腺癌、粘液囊腺癌、未分类的癌]、颗粒状荚膜细胞瘤、Sertoli-Leydig细胞瘤、无性细胞瘤、恶性畸胎瘤),阴户(扁平细胞癌、上皮内癌、腺癌、纤维肉瘤、黑素瘤),阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤(胚胎性横纹肌肉瘤),输卵管(癌),乳房;血液 学:血液(髓样白血病[急性和慢性],急性淋巴细胞白血病,慢性淋巴细胞白血病,骨髓增殖性疾病,多发性骨髓瘤,骨髓增生异常综合征),何杰金氏病,非何杰金氏淋巴瘤[恶性淋巴瘤]毛细胞;淋巴疾病;皮肤:恶性黑色素瘤,基底细胞癌,鳞状细胞癌,卡波西肉瘤,角化棘皮瘤,痣发育异常痣,脂肪瘤,血管瘤,皮肤纤维瘤,疤痕疙瘩,牛皮癣,甲状腺:乳头状甲状腺癌,滤泡性甲状腺癌;甲状腺髓样癌,未分化的甲状腺癌,2A型多发性内分泌瘤病,2B型多发性内分泌瘤病,家族性甲状腺髓样癌,嗜铬细胞瘤,神经节细胞瘤;以及肾 上腺:神经母细胞瘤。因此,本文提供的术语“癌细胞”包括患有任何一种上述病症的细胞。在一些实施方案中,所述癌症选自结直肠癌、甲状腺癌或乳腺癌。
[0083]在一些实施方案中,本发明的化合物可用于治疗癌症,如结直肠癌、甲状腺癌、乳腺癌和肺癌;以及骨髓增殖性疾病,如真性红细胞增多症、血小板增多症、伴有骨髓纤维变性的髓样化生、慢性髓性白血病、慢性粒单核细胞白血病、嗜酸细胞过多综合征、幼年型粒单核细胞白血病和系统性肥大细胞病。
[0084]在一些实施方案中,本发明的化合物可用于治疗造血障碍,尤其是急性髓性白血病(AML)、慢性髓性白血病(CML)、急性早幼粒细胞白血病(APL)和急性淋巴细胞白血病(ALL)。
[0085]除本发明的化合物外,本发明化合物的药学上可接受的衍生物或前体药物也可用于组合物中以治疗或预防上述疾病。
[0086]“药学上可接受的衍生物或前体药物”表示本发明化合物的任何药学上可接受的酯、酯的盐或其它衍生物,其对受者施用后,能够直接或间接提供本发明的化合物或其抑制性活性代谢物或残基。这类衍生物或前体药物包括当这类化合物对患者施用时增加本发明化合物生物利用度的那些化合物(例如,使得经口给予的化合物更容易被吸收进入血液),或者那些相对于母体类提高了母体化合物向生物学腔室(例如,脑部或淋巴系统)递送的化合物。
[0087]本发明化合物的药学可接受的前体药物的实例包括但不限于酯类、氨基酸酯类、磷酸酯类、金属盐类和磺酸酯类。
[0088]对于治疗,本发明的化合物可以游离形式存在,或者如果合适,以药学上可接受的盐存在。
[0089]本文所用的术语“药学上可接受的盐”是指化合物的盐,其在健康的医学判断范围之内,适于与人和低等动物的组织接触使用,而没有过度毒性、刺激、过敏反应等,并且与合理的利益/风险比例相称。
[0090]本发明化合物的药学可接受盐包括那些衍生自适当的无机和有机酸和碱的盐。这些盐可在化合物的最终分离和纯化期间原位制备。酸加成盐可通过以下制备:1)使游离碱形式的纯化化合物与适当的有机或无机酸反应,和2)分离由此形成的盐。
[0091]适当的酸式盐类的实例包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。其它酸如草酸,尽管其本身不是药学上可接受的,但是可用于制备盐,该盐可用作获得本发明化合物和其药学上可接受的酸加成盐的中间体。
[0092]碱加成盐可通过以下制备:1)使酸形式的纯化化合物与适当的有机或无机碱反应,和2)分离由此形成的盐。
[0093]衍生自合适的碱的盐包括碱金属(例如钠和钾)、碱土金属(例如镁)、铵和N+(C1-4烷基)4盐。本发明还涉及本文公开的化合物的任何碱性含氮基团的季铵化。水或油溶性或可分散的产物可通过这种季铵化获得。
[0094]碱加成盐还包括碱金属盐或碱土金属盐。代表性的碱金属盐或碱土金属盐包括钠、锂、钾、钙、镁盐等。如果合适,其它的药学可接受的盐包括无毒的铵、季铵和胺阳离子,其使用抗衡离子如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐形成。其它的酸和碱,尽管其本身不是药学上可接受的,但是可用于制备盐,该盐可用作获得本发明化合物和其药学上可接受的酸或碱加成盐的中间体。
[0095]可用于这些药物组合物中的药学可接受的载体包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲剂如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段共聚物、聚乙二醇和羊毛脂。
[0096]本发明的组合物可经口、胃肠外、通过吸入喷雾、局部、经直肠、经鼻、经颊、经阴道或通过植入型储库给予。本文所用的术语“胃肠外”包括皮下、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内、腹膜内、肝内、病变内和颅内注射或输注技术。
[0097]本发明组合物的无菌注射形式可以是水性或油状混悬液。这些混悬液可根据本领域已知的技术使用适当的分散剂或湿润剂和助悬剂制成。无菌注射制剂还可以是在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射的溶液或混悬液,例如在1,3-丁二醇中的溶液。在可接受的媒介物或溶剂中,可以使用的是水、林格氏溶液和氯化钠等渗溶液。另外,无菌不挥发性油常规用作溶剂或助悬介质。为此,可使用温和的不挥发油,包括合成的单-或二甘油酯。脂肪酸,如油酸及其甘油酯衍生物可用于制备注射剂,如同天然的药学上可接受的油如橄榄油或蓖麻油,尤其是其聚氧乙基化形式。这些油溶液或混悬液还可含有长链醇稀释剂或分散剂,如羧甲基纤维素或在药学上可接受的剂型包括乳剂和混悬液的制造中常规使用的同样的分散剂。其它常规使用的表面活性剂例如可常规用于制造药学上可接受的固体、液体或其它剂型的吐温类、司盘类和其它乳化剂或生物利用度提高剂,也可用于制剂目的。
[0098]本发明药物组合物可以以任何口服可接受的剂型经口服施用,所述剂型包括但不限于胶囊剂、片剂、水混悬剂或溶液剂。在供口服使用的片剂的情况下,常用的载体可包括乳糖和玉米淀粉。润滑剂例如硬脂酸镁也可以被加入。对于以胶囊剂型的口服施用,有用的稀释剂可包括乳糖和干玉米淀粉。当水混悬剂需要用于口服使用时,可以将活性成分与乳化剂和助悬剂组合。如果需要,某些甜味剂、调味剂或着色剂也可以被加入。
[0099]或者,本发明药物组合物可以以供直肠施用的栓剂形式施用。这些栓剂可以通过将药物与适宜的非刺激性赋形剂混合来制备,所述赋形剂在室温下是固态但在直肠温度下为液态,因此在直肠肠中熔化以释放药物。此类物质可包括可可脂、蜂蜡和聚乙二醇。
[00100]本发明药物组合物还可以局部施用,特别是当治疗靶包括通过局部施用容易到达的区域或器官时,可治疗包括眼、皮肤或下肠道的疾病。可以针对这些区域或器官的每一个制备适宜的局部剂型。
[00101]用于下肠道的局部应用可以以直肠柱剂(见上文)或以适宜的灌肠剂来完成。还可以使用局部透皮贴片。
[00102]对于局部应用,可以将药物组合物配制成适宜的含有混悬或溶解在一种或多种载体中的活性组分的软膏剂。用于局部施用本发明化合物的载体可包括但不限于矿物油、液体矿脂、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。另外,该药物组合物可以配制成适宜的含有混悬或溶解在一种或多种药学上可接受的载体中的活性组分的洗剂或乳膏剂。适宜的载体可包括但不限于矿物油、脱水山梨醇单硬脂酸酯、聚山梨酯60、十六烷基酯蜡、十六十八醇、2-辛基十二烷醇、苯甲醇和水。
[00103]对于眼用,可以将药物组合物配制成在等渗、调节pH的无菌盐水中的微粉化混悬剂,或者配制成在等渗、调节pH的无菌盐水中的溶液剂,其含有或者没有防腐剂例如苯扎氯铵。或者,对于眼用,可以将药物组合物配制在软膏例如凡士林中。
[00104]本发明药物组合物还可以通过鼻气雾剂或吸入施用。此类组合物可以制备成在盐水中的溶液剂,使用苯甲醇或其它适宜的防腐剂、增强生物利用度的吸收促进剂、氟碳化合物、和/或其它常用增溶剂或分散剂。
[00105]可以与载体物质组合以制备单一剂型的激酶抑制剂的量将根据治疗的宿主、具体施用方式和适应症而改变。在一个实施方案中,该组合物应配制成可使0.01-100mg/kg体重/天的抑制剂的剂量施用于接受这些组合物的患者。在另一个实施方案中,该组合物应配制成可使0.1-100mg/kg体重/天的抑制剂的剂量施用于接受这些组合物的患者。
[00106]还应理解,用于任何特定患者的特定剂量和治疗方案将取决于多种因素,包括所用特定化合物的活性、年龄、体重、一般健康、性别、饮食、施用时间、排泄速率、药物联合、以及治疗医生的判断和所治疗的特定疾病的严重度。抑制剂的用量还取决于在组合物中的特定化合物。
[00107]根据另一个实施方案,本发明提供用于治疗或预防癌症、增生性疾病或骨髓增殖性疾病的方法,其包含对患者施用本文所述化合物或药物组合物之一的步骤。
[00108]本文所用的术语“患者”表示动物,包括人类。
[00109]在一些实施方案中,所述方法用于治疗或预防造血障碍,如急性髓性白血病(AML)、急性早幼粒细胞白血病(APL)、慢性髓性白血病(CML)或急性淋巴细胞白血病(ALL)。
[00110]在其它实施方案中,所述方法用于治疗或预防骨髓增殖性疾病,如真性红细胞增多症、血小板增多症、伴有骨髓纤维变性的髓样化生、慢性粒细胞白血病(CML)、慢性粒单核细胞白血病、嗜酸细胞增多综合征、幼年型粒单核细胞白血病和系统性肥大细胞病。
[00111]在其它的实施方案中,所述方法用于治疗或预防癌症,如乳腺癌、结肠癌、前列腺癌、皮肤癌、胰腺癌、脑癌、生殖泌尿道癌、淋巴系统癌、胃癌、喉癌和肺癌,包括肺腺癌、小细胞肺癌和非小细胞肺癌。
[00112]另一个实施方案提供了一种治疗或预防癌症的方法,其包含对患者施用式I化合物或包含该化合物的组合物的步骤。
[00113]本发明的另一方面涉及在患者中抑制激酶活性,此方法包含对该患者施用式I化合物或包含该化合物的组合物。在一些实施方案中,所述激酶是Aurora激酶(Aurora A、Aurora B和AuroraC)、Abl、Arg、FGFR1、MELK、MLK1、MuSK、Ret或TrkA。
[00114]根据所治疗或预防的特定病症,其它药物可与本发明的化合物一起给予。在一些情况下,常规地给予这些其它药物,以治疗或预防相同的病症。例如,化学治疗剂或其它抗增生剂可与本发明的化合物组合以治疗增生性疾病。
[00115]本发明的另一个方面涉及在有此需要的受试者中治疗癌症的方法,其包含依次或共同给予本发明化合物或其药学上可接受的盐,以及另外的治疗剂。在一些实施方案中,所述另外的治疗剂选自抗癌剂、抗增生剂或化学治疗剂。
[00116]在一些实施方案中,所述另外的治疗剂选自喜树碱,MEK抑制剂:U0126,KSP(纺锤体驱动蛋白)抑制剂,阿霉素,干扰素类和铂衍生物如顺铂。
[00117]在其它实施方案中,所述另外的治疗剂选自紫杉烷类;bcr-abl抑制剂(如格列卫、达沙替尼和尼洛替尼);EGFR抑制剂(如特罗凯(Tarceva)和易瑞沙(Iressa));DNA损伤剂(如顺铂、奥沙利铂、卡铂、拓扑异构酶抑制剂和蒽环类);以及抗代谢物(如AraC和5-FU)。
[00118]在一个实施方案中,所述额外的治疗剂为达沙替尼或尼洛替尼。
[00119]在一个实施方案中,所述额外的治疗剂是达沙替尼。
[00120]在一个实施方案中,所述额外的治疗剂是尼洛替尼。
[00121]在其它实施方案中,所述另外的治疗剂选自喜树碱、多柔比星、伊达比星、顺铂、紫杉醇、泰索帝、长春新碱、特罗凯、MEK抑制剂、U0126、KSP抑制剂、伏林司他、格列卫、达沙替尼和尼洛替尼。
[00122]在另一个实施方案中,所述另外的治疗剂选自Her-2抑制剂(如赫赛汀);HDAC抑制剂(如伏林司他),VEGFR抑制剂(如阿瓦斯丁),c-KIT和FLT-3抑制剂(如舒尼替尼),BRAF抑制剂(如Bayer公司的BAY 43-9006)MEK抑制剂(如辉瑞公司的PD0325901);以及纺锤体毒剂(例如埃坡霉素和紫杉醇蛋白结合颗粒(例如)。
[00123]可以与本发明抗癌剂联合使用的其它治疗或抗癌剂包括手术、放射治疗(例如,γ辐射、中子束放射治疗、电子束放射治疗、质子疗法、短距离照射治疗和全身放射性同位素,等等)、内分泌疗法、生物反应调节剂(干扰素类、白细胞介素和肿瘤坏死因子(TNF)等等)、高温和冷冻疗法、减弱任何不良反应的药物(例如止吐药),以及其它已批准的化学治疗药,包括但不限于烷化剂(氮芥、苯丁酸氮芥、环磷酰胺、美法仑、异环磷酰胺)、抗代谢药(甲氨蝶呤)、嘌呤拮抗剂和嘧啶拮抗剂(6-巯嘌呤、5-氟尿嘧啶、阿糖胞苷、吉西他滨)、纺锤体毒剂(长春碱、长春新碱、长春瑞滨、紫杉醇)、鬼臼毒素类(依托泊苷、伊立替康、托泊替康)、抗生素(多柔比星、博来霉素、丝裂霉素)、亚硝基脲(卡莫司汀、洛莫司汀)、无机离子(顺铂、卡铂)、酶类(门冬酰胺酶)和激素类(他莫昔芬、亮丙瑞林、氟他胺和甲地孕酮)、格列卫TM、地塞米松和环磷酰胺。
[00124]本发明化合物还可以与以下治疗剂组合用于治疗癌症:阿巴瑞克(Plenaxis);阿地白介素();阿地白介素();阿仑单抗();阿利维A酸();别嘌醇();六甲蜜胺();氨磷汀();阿那曲唑();三氧化二砷();门冬酰胺酶();阿扎胞苷();贝伐珠单抗();贝沙罗汀胶囊();贝沙罗汀凝胶();博来霉素();硼替佐米();静脉用白消安();口服用白消安();卡普睾酮();卡培他滨();卡铂();卡莫司汀();卡莫司汀();卡莫司汀与聚苯丙生20植入剂(Gliadel);塞来昔布();西妥昔单抗();苯丁酸氮芥();顺铂();克拉屈滨();氯法拉滨();环磷酰胺();环磷酰胺(Cytoxan注射剂);环磷酰胺(Cytoxan片);阿糖胞苷();阿糖胞苷脂质体();达卡巴嗪();更生霉素、放线菌素D();达贝泊汀α();柔红霉素脂质体();柔红霉素、道诺霉素();柔红霉素、道诺霉素();地尼白介素2();右雷佐生();多西他赛();多柔比星(Adriamycin);多柔比星();多柔比星(Adriamycin PFS注射剂);多柔比星脂质体();丙酸屈他雄酮(屈他雄酮);丙酸屈他雄酮(屈他雄酮丙酸酯注射剂);Elliott′s B溶液(Elliott′s B);表柔比星();阿法依伯汀();厄洛替尼(特罗凯);雌莫司汀();磷酸依托泊苷();依托泊苷、VP-16();依西美坦();非格司亭();氟尿苷(动脉内用)();氟达拉滨();氟尿嘧啶、5-FU();氟维司群();吉非替尼(易瑞沙);吉西他滨();吉妥珠单抗、奥佐米星();醋酸戈舍瑞林(Zoladex植入剂);醋酸戈舍瑞林();醋酸组氨瑞林(Histrelin植入剂);羟基脲();替伊莫单抗();伊达比星();异环磷酰胺();甲磺酸伊马替尼(格列卫);干扰素α-2a(Roferon);干扰素α-2b(Intron);伊立替康();来那度胺();来曲唑();亚叶酸钙();醋酸亮丙瑞林();左旋咪唑();洛莫司汀、CCNU();氮芥(mecloreth胺)、氮芥();醋酸甲地孕酮();美法仑、L-PAM();巯嘌呤、6-MP();美司钠();美司钠(Mesnex片);甲氨蝶呤();甲氧沙林();丝裂霉素C();米托坦();米托蒽醌();苯丙酸诺龙();奈拉滨();诺非单抗();奥普瑞白介素();奥沙利铂();紫杉醇();紫杉醇(紫杉醇);紫杉醇蛋白结合颗粒();帕利夫明();帕玛二磷酸();培加酶(Adagen(腺苷脱氨酶));培门冬酶();培非司亭();培美曲塞二钠();喷司他丁();哌泊溴烷();普卡霉素、光辉霉素();卟吩姆钠();丙卡巴肼();奎纳克林();拉布立酶();利妥昔单抗();沙格司亭();沙格司亭();索拉非尼();链佐星();马来酸舒尼替尼();滑石粉(talc)();他莫昔芬();替莫唑胺();替尼泊苷、VM-26();睾内酯();硫鸟嘌呤、6-TG();塞替派();托泊替康();托瑞米芬();托西莫单抗();托西莫单抗/I-131托西莫单抗();曲妥珠单抗();维A酸、ATRA();乌拉莫司汀(Uracil Mustard);戊柔比星();长春碱();长春新碱();长春瑞滨();唑来膦酸盐()和伏林司他()。
[00125]对于最新的癌症治疗的广泛讨论参见http://www.nci.nih.gov/,FDA 批准的肿瘤药物清单http://www.fda.gov /cder /cancer/druglistframe.htm以及TheMerck Manual,第17版,1999,它们的全部内容通过引用并入于此。
[00126]另一个实施方案提供了组合制剂的同时、分别或依次应用。
[00127]这些附加的药物可以作为多剂量方案的一部分与含有激酶抑制剂的化合物或组合物分开施用。或者,这些药物可以为单个剂型的一部分,在单一组合物中与所述激酶抑制剂一起混合。
[00128]为了更充分地理解本发明,提供以下制备和测定实施例。这些实施例仅仅是为说明的目的,而不应解释为以任何方式限制本发明范围。本文引述的所有文献通过引用并入于此。
实施例
[00129]用于本文的术语“Rt(min)”是指与化合物有关的HPLC保留时间,单位为分钟。除非另有指明,用于获得报告的保留时间的HPLC方法如下:
柱:ACE C8柱,4.6x150mm
梯度:0-100%乙腈+甲醇60∶40(20mM Tris磷酸盐)
流速:1.5mL/分钟
检测:225nm。
[00130]质谱样品是在MicroMass Quattro Micro质谱仪上分析的,以单MS模式操作,采用电喷射离子化。使用色谱法将样品引入质谱仪。用于所有质谱分析研究的流动相是由10mM pH 7乙酸铵和1∶1乙腈-甲醇混合物组成的,柱梯度条件为5%-100%乙腈-甲醇,在ACE C8 3.0x75mm柱上历经3.5分钟梯度时间和5分钟运行时间。流速为1.2ml/min。
[00131]使用Bruker DPX 400仪器在400MHz下记录1H-NMR光谱。如下制备和分析下式I化合物。
[00132]实施例1
[00133](S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(5-甲基噻唑-2-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺(化合物1)
[00134](S)-2,6-二氯-4-(3-氟吡咯烷-1-基)吡啶(4a)
[00135]向(S)-(+)-3-氟吡咯烷盐酸(2.0g,15.9mmol)和DiPEA(6.1mL,35mmol)在乙醇(50mL)中的混合物中加入2,4,-三氯吡啶(2.9g,15.9mmol)。将该混合物回流1小时,然后蒸发至干。通过ISCO纯化残余物(EtOAc/庚烷;TLC:SiO2,EtOAc/庚烷=1∶4,Rf=0.5(2-取代的吡啶),Rf=0.2(4-取代的吡啶)而得到0.70g(19%)所需产物。
1H-NMR(300MHz,CDCl3):δ6.37(s,2H);5.51-5.48(m,H);5.33-5.31(m,H);3.64-3.59(m,1H);3.53-3.47(m,3H);2.51-2.39(m,1H);2.39-2.08(m,1H)ppm
[00136](S)-6-氯-4-(3-氟吡咯烷-1-基)-N-(5-甲基噻唑-2-基)吡啶-2-胺
[00137]使氮气通过(S)-2,6-二氯-4-(3-氟吡咯烷-1-基)吡啶(1.73g,7.36mmol),2-氨基-5-甲基噻唑(0.92g,8.1mmol),Pd2dba3(0.34g,0.37mmol),Xantphos(0.32g,0.55mmol),和Na2CO3(1.1g,10.3mmol)在二烷中的混合物发泡。将该混合物在微波中加热至180℃下1小时。HPLC分析显示完全转化并且通过硅藻土过滤该混合物。在用二烷冲洗硅藻土后,将合并的滤液蒸发至干。通过柱色谱法纯化残余物(SiO2(100mL),EtOAc/庚烷=1∶9-1∶0)。收集具有Rf=0.5-0.8的级分(TLC,SiO2,EtOAc)并且蒸发至干而得到1.4g所需产物,具有纯度58-71%(HPLC,Rf=8.578分钟)。
1H-NMR(300MHz,CDCl3):δ7.00(s,1H);6.11(s,1H);5.99(s,1H);5.47-5.44(m,H);5.29-5.27(m,H);3.61-3.47(m,4H);2.52-2.40(m,1H);2.38(s,3H);2.28-2.04(m,1H)ppm
[00138](S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(5-甲基噻唑-2-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺
[00139]向(S)-6-氯-4-(3-氟吡咯烷-1-基)-N-(5-甲基噻唑-2-基)吡啶-2-胺(0.5g,1.6mmol),N-(4-巯基苯基)环丙烷甲酰胺(330mg,1.7mmol),碳酸钾(500mg,3.6mmol)和四(三苯膦)钯(0)(120mg,0.1mmol)在1-甲基-2-吡咯烷酮(NMP,10mL)中的混合物充氮气15分钟。将该混合物在微波中加热至180℃下1小时。HPLC分析显示完全转化。通过硅藻土过滤该混合物。用甲醇冲洗硅藻土。在减压下蒸发合并的滤液以便除去甲醇。在搅拌下向残余物中加入水(25mL)。持续搅拌半小时,通过过滤收集形成的固体且用水洗涤。通过将其溶于甲醇而将该固体涂敷在二氧化硅上。使二氧化硅上柱,然后用CH2Cl2/4-6% 2-丙醇洗脱。收集包含级分的产物(TLC(SiO2,CH2Cl2/8% 2-丙醇)Rf=0.65)并且蒸发至干而得到200mg产物,具有66-72%纯度(HPLC)。通过制备型HPLC纯化该物质。在蒸发和冻干后得到41mg(5.5%)(S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(5-甲基噻唑-2-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺,具有纯度99+%(HPLC,Rf=8.598分钟)。
1H-NMR(300MHz,DMSO-d6):δ10.49(s,1H);10.39(s,1H);7.70(d,J=8.6Hz,2H);7.48(d,J=8.6Hz,2H);6.86(s,1H);5.89(d,J=1.8Hz,1H);5.85(d,J=1.8Hz,1H);5.50-5.32(m,1H);3.51-3.20(m,4H);2.26-2.08(m,2H);2.14(s,3H);1.91-1.78(m,1H);0.82-0.80(m,4H)ppm
[00140]实施例2
[00141](S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(3-甲基-1H-吡唑-5-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺(化合物2)
[00142](S)-6-氯-4-(3-氟吡咯烷-1-基)-N-(3-甲基-1H-吡唑-5-基)吡啶-2-胺
[00143]使氮气通过(S)-2,6-二氯-4-(3-氟吡咯烷-1-基)吡啶(600mg,2.6mmol),3-氨基-5-甲基-1H-吡唑-1-甲酸叔丁酯(510mg,2.6mmol),Pd2dba3(119mg),Xantphos(150mg)和碳酸钠(382mg,3.6mmol)在二烷(10mL)中的混合物发泡。将该混合物在微波中加热至140℃下45分钟,然后加热至170℃下15分钟。在通过硅藻土过滤并且用二烷冲洗后,在减压下除去溶剂。通过柱色谱法纯化残余物(SiO2(75mL),CH2Cl2/2.5-7% 2-丙醇;TLC:CH2Cl2/5% 2-丙醇,Rf=0.3)而得到230mg所需产物,为灰白色固体(HPLC:Rf=7.341分钟)。
[00144](S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(3-甲基-1H-吡唑-5-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺
[00145]在使氮气通过(S)-6-氯-4-(3-氟吡咯烷-1-基)-N-(3-甲基-1H-吡唑-5-基)吡啶-2-胺(230mg,0.87mmol),N-(4-巯基苯基)-环丙烷甲酰胺(194mg,0.94mmo l),四(三苯膦)-钯(0)(90mg)和K2CO3(237mg,1.7mmo )在NMP(5mL)中的混合物发泡15分钟后,将该混合物加热至190℃下1小时。将该混合物倾入水(100mL)中搅拌半小时,然后通过过滤收集固体,再用水洗涤(两次)。将该固体干燥并用柱色谱法纯化(SiO2,CH2Cl2/2-10% 2-丙醇)。收集Rf=0.1的级分(TLC:SiO2,CH2Cl2/5% 2-丙醇)并且蒸发至干而得到300mg产物,具有纯度80%(HPLC,Rf=8.08分钟)。通过制备型HPLC纯化该物质,并在蒸发和冻干后得到45mg(S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(3-甲基-1H-吡唑-5-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺,具有纯度97+%(HPLC,Rf=8.092分钟)。
1H-NMR(300MHz,DMSO-d6):δ11.54(s,1H);10.39(s,1H);8.69(s,1H);7.70(d,J=8.5Hz,2H);7.46(d,J=8.6Hz,2H);6.17(s,1H);5.66-5.60(m,2H);5.48-5.30(m,1H);3.48-3.16(m,4H);2.25-2.15(m,2H);2.06(s,3H);1.84-1.77(m,2H);0.85-80(m,2H)ppm
[00146]实施例3:Aurora-2(Aurora A)抑制作用分析
[00147]使用标准偶合酶分析法(Fox等人,Protein Sci.,(1998)7,2249)针对它们抑制Aurora-2的能力筛选化合物。分析是在100mM Hepes(pH7.5)、10mM MgCl2、lmM DTT、25mM NaCl、2.5mM磷酸烯醇丙酮酸、300μM NADH、30μg/ml丙酮酸激酶和10μg/ml乳酸脱氢酶的混合物中进行的。在该分析中的最终底物浓度为400μMATP(Sigma Chemicals)和570μM肽(Kemptide,American Peptide,Sunnyvale,CA)。分析是在30℃下并在40nM Aurora-2的存在下进行的。
[00148]制备分析贮备缓冲溶液,其含有以上所列所有试剂,除了Aurora-2和目的测试化合物。将55μl的贮备溶液置于96孔板中,接着添加2μl含有系列稀释的测试化合物(通常从7.5μM的最终浓度开始)的DMSO贮备液。在30℃下将板预孵育10分钟,再通过添加10μl的Aurora-2引发反应。用Molecular Devices SpectraMaxPlus读板器经10分钟过程测定初始反应速率。IC50和Ki数据是使用Prism软件包(GraphPad Prism,3.0cx版本,Macintosh,GraphPad Software,San Diego California,USA)由非线性回归分析计算的。发现化合物1和2分别在<0.1μM的Ki值下抑制AuroraA。
[00149]实施例4:Aurora-1(Aurora B)抑制作用分析(放射 测定法)
[00150]制备分析缓冲溶液,其组成为25mM HEPES(pH7.5)、10mM MgCl2、0.1%BSA和10%甘油。还含有1.7mM DTT和1.5mM肯普肽(Kemptide,LRRASLG)的22nM Aurora-B溶液是在分析缓冲液中制备的。向在96-孔板中的22μL的Aurora-B溶液中加入在DMSO中的2μl化合物贮备溶液,再使该混合物在25℃下平衡10分钟。通过添加在分析缓冲液中制备的16μl贮备[γ-33P]-ATP溶液(~20nCi/μL),至最终分析浓度为800μM,引发酶反应。3小时后通过添加16μL 500mM磷酸中止反应,结合到肽底物中的33P的水平是通过以下方法测定的。
[00151]将磷酸纤维素96-孔板(Millipore,Cat no.MAPHNOB50)用100μL的100mM磷酸预处理,然后添加酶反应混合物(40μL)。使溶液浸泡到该磷酸纤维素膜上达30分钟,然后将板用200μL的100mM磷酸洗涤4次。向该干燥板的每个孔中加入30μL的Optiphase‘SuperMix′液体闪烁混合物(Perkin Elmer),然后闪烁计数(1450 Microbeta Liquid Scintillation Counter,Wallac)。非酶催化的背景放射活性水平是通过向对照孔中添加16μL的500mM磷酸来测定的,该对照孔中含有所有分析组分(其起使酶变性的作用),然后添加[γ-33P]-ATP溶液。酶催化的33P结合的水平是通过由每一抑制剂浓度下测定的计数减去平均背景计数来计算的。对于每个Ki测定,通常涵盖0-10μM化合物浓度范围的8个数据点是以一式双份获得的(DMSO贮备液是从10mM的起始化合物贮备液以连续的1∶2.5系列稀释制备的)。使用Prism软件包(Prism 3.0,Graphpad Software,San Diego,CA)通过非线性回归法从初始速率数据计算Ki值。发现化合物1和2在<1.0μM的Ki值下抑制Aurora B。
实施例5:细胞增殖和存活的分析
[00152]使用得自ECACC的Colo205细胞并使用下文所示的分析方法针对化合物抑制细胞增殖的能力和对细胞存活的影响来筛选化合物。
[00153]将Colo205细胞接种于96孔板,再将连续稀释的化合物一式双份加至孔中。对照组包括未处理细胞、化合物稀释剂(仅0.1%DMSO)和无细胞的培养基。然后使细胞在37℃下在5% CO2/95%湿度的气氛中孵育72或96小时。
[00154]为了测定增殖,在试验结束前3h,将0.5μCi的3H胸苷加至各孔中。然后收集细胞,再将掺入的放射性在Wallac微量培养板β-计数器上计数。细胞存活使用Promega CellTiter 96AQ测量MTS转化来评价。使用Prism 3.0(GraphPad)或SoftMax Pro 4.3.1LS(Molecular Devices)软件计算剂量反应曲线。
[00155]虽然我们描述了本发明的许多实施方案,但是显然,可以改变我们的基本的实施例以提供使用或包含本发明化合物、方法、过程的其它实施方案。因此,可以理解,本发明范围应由所附权利要求来定义。
Claims (72)
1.式I的化合物:
或其药学上可接受的盐,其中:
X1是N或CH;
X2是N或CH;
X3是N或CRX;
条件是当X3是CRX时,X1和X2中仅一个是N;且条件是X1,X2和X3中的至少一个是N;
Ht是噻唑或吡唑,其中每个环任选和独立地被R2和R2′取代;
Q是-O-,-NR′-,-S-,-C(=O)-或-C(R′)2-;
RX是H或F;
RY是-Z-R10;
R1是T-(环D);
环D是5-7元单环芳基或杂芳基环,其中所述杂芳基具有1-4个选自O、N或S的环杂原子;环D可以任选地与环D′稠合;
环D′是包含0-4个选自氮、氧或硫的环杂原子的5-8元芳族部分饱和或完全不饱和的环;
环D和环D′各自独立和任选地被0-4次出现的氧代或-W-R5取代;
T各自独立地是C1-4亚烷基链或不存在;
R2是H,C1-3烷基或环丙基;
R2′是H;
Z和W各自独立地不存在或是C1-10亚烷基链,其中亚烷基链中至多6个亚甲基单元任选被V替代;
V各自选自-O-,-C(=O)-,-S(O)-,-S(O)2-,-S-或-N(R4)-;
R5各自独立地是-R,-卤素,-OR,-C(=O)R,-CO2R,-COCOR,COCH 2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6脂肪族基团),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO 2R或-OC(=O)N(R7)2;
R各自是H,C1-6脂肪族基团,C6-10芳基环,具有5-10个环原子的杂芳基环或具有4-10个环原子的杂环基环;其中所述杂芳基或杂环基环具有1-4个选自氮、氧或硫的环杂原子;R任选被0-6个R9取代;
R4各自是-R7,-COR7,-CO2R7,-CON(R7)2或-SO2R7;
R7各自独立地是H或任选被1-6个卤素或-O(C1-6烷基)取代的C1-6脂肪族基团;或在同一个氮上的两个R7与氮一起形成包含1-4个选自氮、氧或硫的杂原子的任选取代的4-8元杂环基或杂芳基环;
R9各自是-R′,-卤素,-OR′,-C(=O)R′,-CO2R′,-COCOR′,COCH2COR′,-NO2,-CN,-S(O)R′,-S(O)2R′,-SR′,-N(R′)2,-CON(R′)2,-SO2N(R′)2,-OC(=O)R′,-N(R′)COR′,-N(R′)CO2(C1-6脂肪族基团),-N(R′)N(R′)2,-N(R′)CON(R′)2,-N(R′)SO2N(R′)2,-N(R′)SO2R′,-OC(=O)N(R′)2,=NN(R′)2,=N-OR′或=O;
R10各自是包含1个选自O、N或S的杂原子的5-6元杂环;R10各自任选被0-6次出现的J取代;
J各自独立地是R,-卤素,-OR,氧代,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6脂肪族基团),-N(R4)N(R4)2,=NN(R4)2,=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R,-OC(=O)N(R7)2或-OP(=O)(OR″)2;或
相同原子或不同原子上的2个J基团与它们所连接的原子一起形成具有0-2个选自O、N或S的杂原子的3-8元饱和、部分饱和或不饱和的环;其中2个J基团形成的环上的1-4个氢原子任选被JR替代;或所述环上的两个氢原子任选被氧代或被螺-连接的C3-4环烷基替代;其中所述C3-4烷基任选被1-3个氟取代;
JR各自是F或R7′;
R7′各自独立地是C1-6脂肪族基团;-O(C1-6脂肪族基团);或包含1-4个选自O、N或S的杂原子的5-6元杂芳基;R7′各自任选被0-3个J7取代;
J7独立地是NH2,NH(C1-4脂肪族基团),N(C1-4脂肪族基团)2,卤素,C1-4脂肪族基团,OH,O(C1-4脂肪族基团),NO2,CN,CO2H,CO2(C1-4脂肪族基团),O(卤代C1-4脂肪族基团)或卤代C1-4脂肪族基团;
R′各自独立地是H或C1-6脂肪族基团;或者两个R′与它们所连接的原子一起形成3-6元碳环基或包含0-1个选自O、N或S的杂原子的3-6元杂环基;且
R″各自独立地是H或C1-2烷基。
2.权利要求1的化合物,其中X3是CRX。
3.权利要求1的化合物,其中X3是N。
4.权利要求2或3的化合物,其中X1是N。
5.权利要求2或3的化合物,其中X1是CH。
6.权利要求2-5中任一项的化合物,其中X2是N。
7.权利要求2-5中任一项的化合物,其中X2是CH。
8.权利要求1的化合物,选自式I-b,I-c或I-f的化合物:
9.权利要求8的化合物,选自式I-b的化合物。
11.权利要求1-10中任一项的化合物,其中Q是-S-。
12.权利要求1-10中任一项的化合物,其中Q是-O-。
13.权利要求1-12中任一项的化合物,其中R2是H或C1-3烷基。
14.
15.权利要求1-13中任一项的化合物,其中环D是5-6元单环芳基或杂芳基环;且环D与环D′稠合。
16.权利要求1-13中任一项的化合物,其中环D-D′是包含1-5个选自氮、氧或硫的杂原子的8-12元双环芳基或杂芳基。
17.权利要求16的化合物,其中环D-D′是6:6环系。
18.权利要求17的化合物,其中环D-D′是喹啉。
19.权利要求16的化合物,其中环D-D′是6:5环系。
20.权利要求19的化合物,其中所述6:5环系包含2个氮原子。
21.权利要求20的化合物,其中环D-D′是苯并咪唑、吲唑或咪唑并吡啶环。
22.权利要求21的化合物,其中环D-D′是苯并咪唑环。
23.权利要求1-13中任一项的化合物,其中环D是5-6元单环芳基或杂芳基环;且其中D不与D′稠合。
24.权利要求23的化合物,其中环D是6-元单环芳基或杂芳基环。
25.权利要求24的化合物,其中环D是苯基或吡啶基。
26.权利要求25的化合物,其中环D是苯基。
27.权利要求25的化合物,其中环D是苯基,其中苯基独立地被1或2个选自-卤素和-N(R7)CO2(C1-6脂肪族基团)的取代基取代。
28.权利要求25的化合物,其中环D是苯基,其中苯基独立地被-F和-NHCO2(C1-3脂肪族基团)取代。
29.权利要求25的化合物,其中环D是苯基,其中苯基独立地被-F和-NHCO2(环丙基)取代。
31.权利要求1-29中任一项的化合物,其中RY是-Z-R10
32.权利要求30的化合物,其中Z不存在。
33.权利要求30的化合物,其中Z是C1-6亚烷基链,其中Z的1-2个亚甲基单元任选被O、-N(R4)-或S替代。
34.权利要求30-32中任一项的化合物,其中R10是包含1个氮原子的5-6元杂环。
35.权利要求33的化合物,其中R10是吡咯烷。
36.权利要求33的化合物,其中R10是哌啶。
38.权利要求36的化合物,其中J各自独立地是C1-6烷基,F,-N(R4)2,CN或-OR,其中每个-N(R4)2基团中的至少一个R4不是H;或者两个J基团与它们所连接的原子一起形成包含1-2个选自N或O的杂原子的4-7元杂环基环;其中所述环任选被0-3个JR取代。
39.权利要求37的化合物,其中R是H,C1-4烷基或C3-6环烷基;其中所述C1-4烷基或C3-6环烷基任选被1-3个氟原子取代。
40.权利要求37的化合物,其中R4是H,C1-5烷基,或C3-6环烷基;其中每个-N(R4)2基团中的至少一个R4不是H;或者两个R4与它们所连接的氮原子一起形成包含1-2个选自O、N或S的杂原子的3-6元单环;其中所述单环任选被0-3个JR取代。
41.权利要求1-39中任一项的化合物,其中JR是卤素,C1-3烷基,或-O(C1-3烷基)。
43.权利要求41的化合物,其中J是F,-N(R4)2,CN,-OR,氧代(=O)或任选被出现1次的OH或OCH3取代的C2-6烷基;其中每个-N(R4)2基团中的至少一个R4不是H。
44.权利要求42的化合物,其中J是F。
45.权利要求36-43中任一项的化合物,其中n是1。
46.权利要求36-43中任一项的化合物,其中n是2。
47.权利要求1-29中任一项的化合物,其中,
Z不存在;
RY是
n是2;且
J各自独立地是C1-6烷基,F,-N(R4)2,CN或-OR,其中每个-N(R4)2基团中的至少一个R4不是H。
49.权利要求47的化合物,其中两个J基团与它们所连接的原子一起形成包含1-2个选自N或O的杂原子的4-7元螺杂环基环;其中所述环任选被0-3个JR取代。
50.权利要求48的化合物,其中两个J基团与它们所连接的原子一起形成包含1个选自N或O的杂原子的5-元螺杂环基环;其中所述环任选被0-3个JR取代。
51.权利要求49的化合物,其中两个J基团与它们所连接的原子一起形成包含1个N杂原子的5-元螺杂环基环;其中所述环任选被0-3个JR取代。
52.权利要求50的化合物,其中两个J基团与它们所连接的原子一起形成包含1个N杂原子的5-元螺杂环基环;其中所述环任选被1个JR取代。
53.权利要求46-51中任一项的化合物,其中JR是卤素,C1-3烷基,或-O(C1-3烷基)。
55.权利要求52的化合物,其中RY是
56.权利要求54的化合物,其中JR是CH3。
64.权利要求62的方法,其中所述增生性疾病是癌症。
65.权利要求62的方法,其中所述增生性疾病选自黑素瘤、骨髓瘤、白血病、淋巴瘤、成神经细胞瘤,或者选自以下的癌症:结肠癌、乳腺癌、胃癌、卵巢癌、宫颈癌、肺癌、中枢神经系统(CNS)癌、肾癌、前列腺癌、膀胱癌、胰腺癌、脑癌(神经胶质瘤)、头颈癌、肾癌、肝癌、黑素瘤、肉瘤或甲状腺癌。
66.权利要求63的方法,其进一步包括依次或共同给予另外的治疗剂。
67.权利要求65的方法,其中所述治疗剂选自紫杉烷类、bcr-ab1的抑制剂、EGFR的抑制剂、DNA损伤剂和抗代谢药。
68.权利要求65的方法,其中所述治疗剂选自紫杉醇、格列卫、达沙替尼、尼洛替尼、特罗凯、易瑞沙、顺铂、奥沙利铂、卡铂、蒽环类、AraC和5-FU。
69.权利要求65的方法,其中所述治疗剂选自喜树碱、多柔比星、伊达比星、顺铂、紫杉醇、泰索帝、长春新碱、特罗凯、MEK抑制剂、U0126、KSP抑制剂、伏林司他、格列卫、达沙替尼和尼洛替尼。
70.权利要求65的方法,其中所述治疗剂是达沙替尼或尼洛替尼。
71.权利要求65的方法,其中所述治疗剂是达沙替尼。
72.权利要求65的方法,其中所述治疗剂是尼洛替尼。
73.权利要求1的化合物,选自如下:
(S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(5-甲基噻唑-2-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺;和
(S)-N-(4-(4-(3-氟吡咯烷-1-基)-6-(3-甲基-1H-吡唑-5-基氨基)吡啶-2-基硫)苯基)环丙烷甲酰胺。
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2008
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- 2008-05-02 AU AU2008257044A patent/AU2008257044A1/en not_active Abandoned
- 2008-05-02 WO PCT/US2008/062331 patent/WO2008147626A2/en active Application Filing
- 2008-05-02 JP JP2010509424A patent/JP2010528021A/ja active Pending
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- 2008-05-02 EP EP08747433A patent/EP2164842A2/en not_active Withdrawn
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2009
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2014
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WO2008147626A2 (en) | 2008-12-04 |
EP2164842A2 (en) | 2010-03-24 |
WO2008147626A3 (en) | 2009-03-19 |
CA2687966A1 (en) | 2008-12-04 |
AU2008257044A1 (en) | 2008-12-04 |
JP2014141529A (ja) | 2014-08-07 |
MX2009012719A (es) | 2010-02-04 |
JP2010528021A (ja) | 2010-08-19 |
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