CN106794176A - 色氨酸双加氧酶(ido1和tdo)的抑制剂和其在治疗中的用途 - Google Patents
色氨酸双加氧酶(ido1和tdo)的抑制剂和其在治疗中的用途 Download PDFInfo
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- CN106794176A CN106794176A CN201580055358.7A CN201580055358A CN106794176A CN 106794176 A CN106794176 A CN 106794176A CN 201580055358 A CN201580055358 A CN 201580055358A CN 106794176 A CN106794176 A CN 106794176A
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- Prior art keywords
- pyridine
- amine
- azoles simultaneously
- different azoles
- optionally substituted
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Abstract
本申请描述了包含具有IDO1和/或TDO抑制活性的式I的3‑氨基异唑并吡啶化合物的药物组合物,其中W是CR1、N或N‑氧化物;X是CR2、N或N‑氧化物;Y是CR3、N或N‑氧化物;Z是CR4、N或N‑氧化物;且至少W、X、Y和Z之一是N或N‑氧化物;且R9和R10如所定义的。还描述了使用此类化合物治疗各种疾患例如癌症的方法。
Description
技术领域
本发明涉及3-氨基异唑并吡啶类化合物、含有它们的药物组合物及其作为药物的用途,更具体地涉及它们单独或与其它活性剂如抗癌疫苗、其它类型的免疫调节治疗、放射和其他化疗剂组合在癌症治疗中的用途。
发明背景
吲哚胺2,3-双加氧酶1(IDO1)催化色氨酸转化为犬尿氨酸的第一和速率限制步骤,并且在抑制免疫系统的广泛的癌症中表达(Uyttenhove等人,J.Nat.Med.2003,9,1269)。临床肿瘤中的高IDO1表达已经显示与广泛的癌症(包括肺癌、结肠直肠癌、乳腺癌、黑色素瘤和妇科癌症)中的差的患者预后相关。鼠黑色素瘤细胞系中IDO1基因的沉默导致当植入小鼠时细胞形成肿瘤的能力降低(Zheng等人,J.Immunol.2006,177,5639),证实IDO1作为癌症干预的靶标。许多团队已经开始研究IDO1的小分子抑制剂作为在癌症患者中恢复肿瘤免疫的方法。这样的抑制剂应当具有自身或与其它标准化学疗法组合展示抗肿瘤活性的潜力。用小分子抑制剂阻断IDO1酶的下游信号传导还具有与其它免疫调节方法(例如抗癌疫苗施用、免疫检查点蛋白(例如CTLA4和PD1-4s)的调节和过继性T细胞治疗(adoptive T-cell therapies)(例如CART细胞)的应用(Mautina等人,Proceedings ofthe AACR Annual Meeting,2014,Poster 5023))协同的潜力。早期研究使用色氨酸的衍生物例如1-甲基色氨酸(1-MT)作为IDO1的竞争性抑制剂(Cady和Sono,Arch.Biochem.Biophys.1991,291,326),并为IDO1将是用于癌症的药理学干预的有吸引力的靶标的观念提供了证明(Hou等人,Cancer Res.2007,614)。从海洋无脊椎动物分离的天然产物以比色氨酸衍生物高得多的效力抑制IDO1。迄今为止已经描述的在nM浓度具有活性的最有效的IDO1抑制剂之一是从海洋海绵中分离的exiguamine(Brastianos等人,J.Am.Chem.Soc.,2006,128,16046)。从海洋水螅虫分离的两种annulin在nM浓度下表现出活性,并刺激产生具有低nM效力的一系列IDO1抑制性吡喃并萘醌化合物的药物化学项目(Pereira等人,J.Nat.Prod.2006,69,1496;Kumar等人,J.Med.Chem.2008,51,1706)。化合物库的高通量筛选导致IDO1的羟基脒抑制剂的结构类型的发现和优化(Yue等人,J.Med.Chem.2009,52,7364)。具有针对细胞中的酶的nM效力且具有口服生物利用度的优化的羟基脒候选物目前在临床试验中(Newton等人,J Clin Oncol.2012,30,(Suppl;摘要2500))。另一种有效的咪唑并异吲哚类的IDO抑制剂目前也处于早期临床试验中(Mautina等人,Proceedings of the AACR Annual Meeting,2013)。
色氨酸2,3-双加氧酶(TDO)是色氨酸降解途径中的另一种关键酶。TDO抑制剂在治疗癌症和其它疾患中也可具有广泛的治疗效力。
本发明的一个目的是提供3-氨基异唑并吡啶化合物及其在医药中例如在癌症治疗中的用途,或至少为公众提供有用的选择。
发明简述
在第一方面,本发明提供药物组合物,其包含:
式I化合物或其药学上可接受的盐,其中:
W是CR1、N或N-氧化物;
X是CR2、N或N-氧化物;
Y是CR3、N或N-氧化物;
Z是CR4、N或N-氧化物;
并且其中至少W、X、Y和Z之一是N或N-氧化物;
R1、R2、R3和R4各自独立地选自下列基团:H、卤代、R、-OH、-OR、-OC(O)H、-OC(O)R、-OC(O)NH2、-OC(O)NHR、-OC(O)NRR、-OP(O)(OH)2、-OP(O)(OR)2、-NO2、-NH2、-NHR、-NRR、-NHC(O)H、-NHC(O)R、-NRC(O)R、-NHC(O)NH2、-NHC(O)NRR、-NRC(O)NHR、-SH、-SR、-S(O)H、-S(O)R、-SO2R、-SO2NH2、-SO2NHR、-SO2NRR、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-C≡CH、-C≡CR、-CH=CHR、-CH=CRR、-CR=CHR、-CR=CRR、-CO2H、-CO2R、-CHO、-C(O)R、-C(O)NH2、-C(O)NHR、-C(O)NRR、-CONHSO2H、-CONHSO2R、-CONRSO2R、环状C3-C7烷基氨基、咪唑基、C1-C6烷基哌嗪基、吗啉基和硫代吗啉基;
或R1和R2结合在一起,或R2和R3结合在一起,或R3和R4结合在一起能够形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环任选独立地被1-4个选自R的取代基取代;
各R独立地选自下面的段落(a)和(b)中定义的任何基团:
(a)任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基基团的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR5、-OC(O)R5、-OC(O)NH2、-OC(O)NHR5、-OC(O)NR5R5、-OP(O)(OH)2、-OP(O)(OR5)2、-NO2、-NH2、-NHR5、-NR5R5、-N+(O-)R5R5、-NHC(O)H、-NHC(O)R5、-NR5C(O)R5、-NHC(O)NH2、-NHC(O)NR5R5、-NR5C(O)NHR5、-SH、-SR5、-S(O)H、-S(O)R5、-SO2R5、-SO2NH2、-SO2NHR5、-SO2NR5R5、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R5、-CHO、-C(O)R5、-C(O)NH2、-C(O)NHR5、-C(O)NR5R5、-CONHSO2H、-C(O)NHSO2R5、-C(O)NR5SO2R5、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR7、-OC(O)R7、-OC(O)NH2-OC(O)NHR7、-OC(O)NR7R7、-OP(O)(OH)2、-OP(O)(OR7)2、-NO2、-NH2、-NHR7、-NR7R7、-N+(O-)R7R7、-NHC(O)H、-NHC(O)R7、-NR7C(O)R7、-NHC(O)NH2、-NHC(O)NR7R7、-NR7C(O)NHR7、-SH、-SR7、-S(O)H、-S(O)R7、-SO2R7、-SO2NH2、-SO2NHR7、-SO2NR7R7、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R7、-CHO、-C(O)R7、-C(O)NH2、-C(O)NHR7、-C(O)NR7R7、-CONHSO2H、-C(O)NHSO2R7、-C(O)NR7SO2R7、任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;并且其中所述各芳基和杂芳基基团的一个或多个任选取代基各自独立地选自下列基团:C1-6烷基、C2-6烯基、C2-6炔基或C3-7环烷基、卤代、-OH、-OR8、-OC(O)R8、-OC(O)NH2、-OC(O)NHR8、-OC(O)NR8R8、-OP(O)(OH)2、-OP(O)(OR8)2、-NO2、-NH2、-NHR8、-NR8R8、-N+(O)R8R8、-NHC(O)H、-NHC(O)R8、-NR8C(O)R8、-NHC(O)NH2、-NHC(O)NR8R8、-NR8C(O)NHR8、-SH、-SR8、-S(O)H、-S(O)R8、-SO2R8、-SO2NH2、-SO2NHR8、-SO2NR8R8、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R8、-CHO、-C(O)R8、-C(O)NH2、-C(O)NHR8、-C(O)NR8R8、-CONHSO2H、-C(O)NHSO2R8和-C(O)NR8SO2R8;其中各R5、R7和R8独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;且其中所述一个或多个任选的取代基各自独立地选自与对于R的在上面(a)中所定义的那些相同的任选取代基;
R9和R10各自独立地选自下面段落(a)和(b)中所定义的任何基团:
(a)H、任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR11、-OC(O)R11、-OC(O)NH2、-OC(O)NHR11、-OC(O)NR11R11、-OP(O)(OH)2、-OP(O)(OR11)2、-NO2、-NH2、-NHR11、-NR11R11、-N+(O)R11R11、-NHC(O)H、-NHC(O)R11、-NR11C(O)R11、-NHC(O)NH2、-NHC(O)NR11R11、-NR11C(O)NHR11、-SH、-SR11、-S(O)H、-S(O)R11、-SO2R11、-SO2NH2、-SO2NHR11、-SO2NR11R11、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R11、-CHO、-C(O)R11、-C(O)NH2、-C(O)NHR11、-C(O)NR11R11、-CONHSO2H、-C(O)NHSO2R11、-C(O)NR11SO2R11、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中所述环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR13、-OC(O)R13、-OC(O)NH2、-OC(O)NHR13、-OC(O)NR13R13、-OP(O)(OH)2、-OP(O)(OR13)2、-NO2、-NH2、-NHR13、-NR13R13-N+(O)R13R13、-NHC(O)H、-NHC(O)R13、-NR13C(O)R13、-NHC(O)NH2、-NHC(O)NR13R13、-NR13C(O)NHR13、-SH、-SR13、-S(O)H、-S(O)R13、-SO2R13、-SO2NH2、-SO2NHR13、-SO2NR13R13、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R13、-CHO、-C(O)R13、-C(O)NH2、-C(O)NHR13、-C(O)NR13R13、-CONHSO2H、-C(O)NHSO2R13和-C(O)NR13SO2R13;其中各R11和R13独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;且其中所述各芳基和杂芳基的一个或多个任选取代基各自独立地选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基;
或
(c)R9和R10结合在一起能够形成部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环能够任选独立地被1-5个取代基取代,所述取代基选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基;
和药学上可接受的载体。
在另一个方面,本发明提供式I化合物或其药学上可接受的盐,其用作药物。
在另一个方面,本发明提供式I化合物或其药学上可接受的盐,其用于医药中。
在另一方面,本发明提供式I化合物或其药学上可接受的盐,其用作治疗活性物质。
在另一方面,本发明提供式I化合物或其药学上可接受的盐,其用于治疗温血动物包括人的癌症。
在另一方面,本发明提供式I化合物或其药学上可接受的盐在制备药物中的用途。
在另一方面,本发明提供式I化合物或其药学上可接受的盐在制备用于治疗温血动物包括人的癌症的药物中的用途。
在另一方面,本发明提供式I化合物或其药学上可接受的盐在制备用于治疗温血动物包括人的癌症的药物中的用途,其中所述治疗包括施用式I化合物和一种或多种其它活性剂,所述其它活性剂选自化疗剂、免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂、过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))和放射治疗,并且其中所述其它活性剂在式I化合物施用之前、期间或之后施用。在某些实施方案中,所述其它活性剂包括免疫调节剂。
在另一方面,本发明提供治疗温血动物包括人的癌症的方法,其包括向动物施用治疗有效量的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供治疗温血动物包括人的癌症的方法,其中所述方法包括向动物施用治疗有效量的式I化合物或其药学上可接受的盐,并且其中所述方法还包括施用一种或多种其它活性剂的步骤,所述其它活性剂选自化疗剂、免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂、过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))和放射治疗,并且其中所述其它活性剂在式I化合物施用之前、期间或之后施用。在某些实施方案中,所述其它活性剂包括免疫调节剂。
在另一方面,本发明提供在有其需要的温血动物包括人中抑制吲哚胺2,3-双加氧酶1(IDO1)的方法,其包括以有效抑制IDO1的量向动物施用具有IDO1抑制活性的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供在有其需要的温血动物包括人中抑制色氨酸2,3-双加氧酶(TDO)的方法,其包括以有效抑制TDO的量向动物施用具有TDO抑制活性的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供在有其需要的温血动物包括人中抑制IDO1和TDO的方法,其包括以有效抑制IDO1和TDO的量向动物施用具有IDO1和TDO抑制活性的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供药物组合产品或药盒,其包括
(a)式I化合物或其药学上可接受的盐,和
(b)一种或多种选自以下的其它活性剂:化疗剂和免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂和过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))。
在另一方面,本发明提供用于治疗癌症的药物组合产品或药盒,其包括
(a)式I化合物或其药学上可接受的盐,和
(b)一种或多种选自以下的其它活性剂:化疗剂和免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂和过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))。
在另一方面,本发明提供式I化合物或其药学上可接受的盐,其用于治疗选自以下的疾患或病症:炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障。
在另一方面,本发明提供式I化合物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗选自以下的疾患或病症:炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障。
在另一方面,本发明提供在温血动物包括人中治疗选自以下的疾患或病症的方法:炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障,其中所述方法包括向动物施用治疗有效量的式I化合物或其药学上可接受的盐。
可以在如上所定义的本发明的任何组合物、方法、用途和其它方面中使用的式I化合物的某些实施方案描述在下面编号的段落(1)至(30)。
(1).如上面本发明的第一方面中所定义的式I化合物或其药学上可接受的盐。
(2).式I化合物或其药学上可接受的盐,其中W、X、Y和Z都如上面本发明的第一方面中所定义,且其中:
R1、R2、R3和R4各自独立地选自下列基团:H、卤代、R、-OH、-OR、-OC(O)H、-OC(O)R、-OC(O)NH2、-OC(O)NHR、-OC(O)NRR、-OP(O)(OH)2、-OP(O)(OR)2、-NO2、-NH2、-NHR、-NRR、-NHC(O)H、-NHC(O)R、-NRC(O)R、-NHC(O)NH2、-NHC(O)NRR、-NRC(O)NHR、-SH、-SR、-S(O)H、-S(O)R、-SO2R、-SO2NH2、-SO2NHR、-SO2NRR、-CF3、-OCF3、-OCHF2、-CN、-C≡CH、-C≡CR、-CH=CHR、-CH=CRR、-CR=CHR、-CR=CRR、-CO2H、-CO2R、-CHO、-C(O)R、-C(O)NH2、-C(O)NHR、-C(O)NRR、-CONHSO2H、-CONHSO2R、-CONRSO2R、环状C3-C7烷基氨基、咪唑基、C1-C6烷基哌嗪基、吗啉基和硫代吗啉基;
或R1和R2结合在一起,或R2和R3结合在一起,或R3和R4结合在一起能够形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环任选独立地被1-4个选自R的取代基取代;
各R独立地选自下面的段落(a)和(b)中所定义的基团:
(a)任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基基团的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR5、-OC(O)R5、-OC(O)NH2、-OC(O)NHR5、-OC(O)NR5R5、-OP(O)(OH)2、-OP(O)(OR5)2、-NO2、-NH2、-NHR5、-NR5R5、-N+(O-)R5R5、-NHC(O)H、-NHC(O)R5、-NR5C(O)R5、-NHC(O)NH2、-NHC(O)NR5R5、-NR5C(O)NHR5、-SH、-SR5、-S(O)H、-S(O)R5、-SO2R5、-SO2NH2、-SO2NHR5、-SO2NR5R5、-CF3、-OCF3、-OCHF2、-CN、-CO2H、-CO2R5、-CHO、-C(O)R5、-C(O)NH2、-C(O)NHR5、-C(O)NR5R5、-CONHSO2H、-C(O)NHSO2R5、-C(O)NR5SO2R5、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR7、-OC(O)R7、-OC(O)NH2-OC(O)NHR7、-OC(O)NR7R7、-OP(O)(OH)2、-OP(O)(OR7)2、-NO2、-NH2、-NHR7、-NR7R7、-N+(O-)R7R7、-NHC(O)H、-NHC(O)R7、-NR7C(O)R7、-NHC(O)NH2、-NHC(O)NR7R7、-NR7C(O)NHR7、-SH、-SR7、-S(O)H、-S(O)R7、-SO2R7、-SO2NH2、-SO2NHR7、-SO2NR7R7、-CF3、-OCF3、-OCHF2、-CN、-CO2H、-CO2R7、-CHO、-C(O)R7、-C(O)NH2、-C(O)NHR7、-C(O)NR7R7、-CONHSO2H、-C(O)NHSO2R7、-C(O)NR7SO2R7、任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;并且其中所述各芳基和杂芳基基团的一个或多个任选取代基各自独立地选自下列基团:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR8、-OC(O)R8、-OC(O)NH2、-OC(O)NHR8、-OC(O)NR8R8、-OP(O)(OH)2、-OP(O)(OR8)2、-NO2、-NH2、-NHR8、-NR8R8、-N+(O)R8R8、-NHC(O)H、-NHC(O)R8、-NR8C(O)R8、-NHC(O)NH2、-NHC(O)NR8R8、-NR8C(O)NHR8、-SH、-SR8、-S(O)H、-S(O)R8、-SO2R8、-SO2NH2、-SO2NHR8、-SO2NR8R8、-CF3、-OCF3、-OCHF2、-CN、-CO2H、-CO2R8、-CHO、-C(O)R8、-C(O)NH2、-C(O)NHR8、-C(O)NR8R8、-CONHSO2H、-C(O)NHSO2R8和-C(O)NR8SO2R8;其中各R5、R7和R8独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;并且其中各芳基和杂芳基的一个或多个任选取代基各自独立地选自与对于R的在上面(a)中所定义的那些相同的任选取代基;
R9和R10各自独立地选自下面段落(a)和(b)中所定义的基团:
(a)H、任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR11、-OC(O)R11、-OC(O)NH2、-OC(O)NHR11、-OC(O)NR11R11、-OP(O)(OH)2、-OP(O)(OR11)2、-NO2、-NH2、-NHR11、-NR11R11、-N+(O)R11R11、-NHC(O)H、-NHC(O)R11、-NR11C(O)R11、-NHC(O)NH2、-NHC(O)NR11R11、-NR11C(O)NHR11、-SH、-SR11、-S(O)H、-S(O)R11、-SO2R11、-SO2NH2、-SO2NHR11、-SO2NR11R11、-CF3、-OCF3、-OCHF2、-CN、-CO2H、-CO2R11、-CHO、-C(O)R11、-C(O)NH2、-C(O)NHR11、-C(O)NR11R11、-CONHSO2H、-C(O)NHSO2R11、-C(O)NR11SO2R11、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中基团环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR13、-OC(O)R13、-OC(O)NH2、-OC(O)NHR13、-OC(O)NR13R13、-OP(O)(OH)2、-OP(O)(OR13)2、-NO2、-NH2、-NHR13、-NR13R13-N+(O)R13R13、-NHC(O)H、-NHC(O)R13、-NR13C(O)R13、-NHC(O)NH2、-NHC(O)NR13R13、-NR13C(O)NHR13、-SH、-SR13、-S(O)H、-S(O)R13、-SO2R13、-SO2NH2、-SO2NHR13、-SO2NR13R13、-CF3、OCF3、-OCHF2、-CN、-CO2H、-CO2R13、-CHO、-C(O)R13、-C(O)NH2、-C(O)NHR13、-C(O)NR13R13、-CONHSO2H、-C(O)NHSO2R13和-C(O)NR13SO2R13;其中各R11和R13独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;并且其中所述各芳基和杂芳基的一个或多个任选取代基各自独立地选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基;或
(c)R9和R10结合在一起能够形成部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环能够任选独立地被1-5个取代基取代,所述取代基选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基。
(3).段落(1)或(2)中定义的化合物,其中当R9和R10各自独立地选自下列基团:任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团时;则所述各烷基、烯基、炔基和环烷基的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR11、-OC(O)R11、-OC(O)NH2、-OC(O)NHR11、-OC(O)NR11R11、-OP(O)(OH)2、-OP(O)(OR11)2、-NO2、-NH2、-NHR11、-NR11R11、-N+(O)R11R11、-NHC(O)H、-NHC(O)R11、-NR11C(O)R11、-NHC(O)NH2、-NHC(O)NR11R11、-NR11C(O)NHR11、-SH、-SR11、-S(O)H、-S(O)R11、-SO2R11、-SO2NH2、-SO2NHR11、-SO2NR11R11、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R11、-CHO、-C(O)R11、-C(O)NH2、-C(O)NHR11、-C(O)NR11R11、-CONHSO2H、-C(O)NHSO2R11和-C(O)NR11SO2R11;其中各R11独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团。
(4).如段落(1)至(3)中任一段所定义的化合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3。
(5).如段落(1)至(3)中任一段所定义的化合物,其中X是N或N-氧化物例如N,W是CR1,Y是CR3且Z是CR4。
(6).如段落(1)至(3)中任一段所定义的化合物,其中X和Z都是N或N-氧化物例如N,W是CR1且Y是CR3。
(7).如段落(1)至(6)中任一段所定义的化合物,其中R1、R2、R3和R4,当存在时,各自独立地选自H、卤代、任选取代的C1-C6烷基、其中R是任选取代的C1-C6烷基的-O-R、任选取代的芳基例如取代的苯基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团。
(8).如段落(1)至(6)中任一段所定义的化合物,其中R1、R2、R3和R4,当存在时,各自独立地选自H、卤代、任选取代的C1-C6烷基、其中R选自任选取代的C1-C6烷基和任选取代的芳基(例如苯基)的-O-R、其中R是任选取代的芳基的–NHR、任选取代的芳基和具有至多12个碳原子并且在其环系统具有一个或多个各自独立地选自O、N和S的杂原子的任选取代的杂芳基基团。
(9).如在段落(8)中所定义的化合物,其中R1、R2、R3和R4,当存在时,各自独立地选自H、卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的–OR和其中R是任选取代的芳基的–NHR。
(10).如在段落(8)中所定义的化合物,其中R1、R2、R3和R4中的一个或两个,当存在时,是H,并且不是H的其它R1、R2、R3和R4独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
(11).段落(8)至(10)中任何一段中所定义的化合物,其中R3存在并且选自卤素、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
(12).在段落(4)中定义的化合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,且R3选自卤素、其中R是任选取代的芳基的-O-R和其中R是任选取代的芳基的–NHR。
(13).在段落(4)中定义的化合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,R1是H,且R2和R3中的一个或两个不是H,例如,R2和R3都不是H,或R2是H且R3不是H,或R3是H且R2不是H。
(14).在段落(13)中定义的化合物,其中不是H的R2和R3各自独立地选自卤素、任选取代的C1-C6烷基、其中R选自任选取代的C1-C6烷基和任选取代的芳基的-OR、其中R是任选取代的芳基的-NHR;任选取代的芳基例如取代的苯基和任选取代的杂芳基基团。
(15).在段落(14)中定义的化合物,其中不是H的R2和R3各自独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
(16).如段落(1)至(6)中任一段所定义的化合物,其中R1和R2结合在一起,或R2和R3结合在一起,或R3和R4结合在一起形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1-3个选自O、N或S的杂原子并且所述环任选被1-4个独立地选自R的取代基取代,R1、R2、R3和R4的不是环的部分的那些部分独立地选自:H、卤代、任选取代的C1-C6烷基、其中R是任选取代的C1-C6烷基的O-R、任选取代的芳基和具有至多12个碳原子并且在其环系统具有一个或多个各自独立地选自O、N和S的杂原子的任选取代的杂芳基基团。
(17).如段落(1)至(16)中任一段所定义的化合物,其中R9和R10独立地选自H、任选取代的C1-6烷基基团、任选取代的芳基例如取代的苯基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团。
(18).如段落(1)至(17)中任一段所定义的化合物,其中R9和R10都是H。
(19).在段落中(4)定义的化合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,且R9和R10都是H。
(20)在段落(19)中定义的化合物,其中R1、R2和R3各自独立地选自H、卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
(21).在段落(19)中定义的化合物,其中R1、R2和R3各自独立地选自H、卤素、C1-6烷基例如甲基、取代的芳基和取代的杂芳基。
(22).在段落(19)中定义的化合物,其中R1、R2和R3中的一个或两个是H,且不是H的其它R1、R2和R3独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
(23).在段落(19)中定义的化合物,其中R1是H,且R2和R3中的一个或两个不是H,其中不是H的R2和R3各自独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
(24).在段落(19)至(23)中任何一段所定义的化合物,其中R3选自卤素、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
(25).在段落(19)中定义的化合物,其中R1是H,且R2和R3形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1-3个选自O、N和S的杂原子,并且所述环任选被1-4个独立选自R的取代基取代。
(26).在段落(1)中定义的化合物,其选自:
5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)
异唑并[5,4-b]吡啶-3-胺(2)
5-氯-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(3)
4,6-二甲基异唑并[5,4-b]吡啶-3-胺(4)
4,5,6-三甲基异唑并[5,4-b]吡啶-3-胺(5)
5-溴异唑并[5,4-b]吡啶-3-胺(6)
6-甲基异唑并[5,4-b]吡啶-3-胺(7)
5-氯异唑并[5,4-b]吡啶-3-胺(8)
异唑并[5,4-b]喹啉-3-胺(9)
5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(10)
6-氯异唑并[5,4-b]吡啶-3-胺(11)
异唑并[5,4-d]嘧啶-3-胺(12)
4-苯基异唑并[5,4-b]吡啶-3-胺(13)
5-氟异唑并[5,4-b]吡啶-3-胺(14)
6-苯基异唑并[5,4-b]吡啶-3-胺(15)
5-碘异唑并[5,4-b]吡啶-3-胺(16)
异唑并[4,5-c]吡啶-3-胺(17)
N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)
N4,N4-二甲基异唑并[5,4-b]吡啶-3,4-二胺(19)
5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)
5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)
5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)
5-(2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(23)
5-苯基异唑并[5,4-b]吡啶-3-胺(24)
5-(3-氟-4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(25)
5-(吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(26)
5-(吡啶-4-基)异唑并[5,4-b]吡啶-3-胺(27)
2-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(28)
4-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(29)
5-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(30)
5-(3-氟苯基)异唑并[5,4-b]吡啶-3-胺(31)
5-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(32)
5-(3,5-二氟-2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(33)
5-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(34)
5-(2,3,4-三氯苯基)异唑并[5,4-b]吡啶-3-胺(35)
5-(4-(三氟甲基苯基)异唑并[5,4-b]吡啶-3-胺(36)
5-(3-氨基苯基)异唑并[5,4-b]吡啶-3-胺(37)
3-(3-氨基异唑并[5,4-b]吡啶-5-基)苯甲酸甲酯(38)
5-(6-氟吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(39)
5-(2-氯-4-(三氟甲基)苯基)异唑并[5,4-b]吡啶-3-胺(40)
6-甲氧基异唑并[5,4-b]吡啶-3-胺(41)
6-氯-4-甲基异唑并[5,4-b]吡啶-3-胺(42)
异唑并[5,4-b]吡啶-3,6-二胺(43)
5-甲基异唑并[5,4-b]吡啶-3-胺(44)
5,6-二甲基异唑并[5,4-b]吡啶-3-胺(45)
6-甲基-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(46)
6-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(47)
6-异丙基异唑并[5,4-b]吡啶-3-胺(48)
5-硝基异唑并[5,4-b]吡啶-3-胺(49)
3-氨基-6-(三氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(50)
4-甲氧基异唑并[5,4-b]吡啶-3-胺(51)
5-(二氟甲氧基)-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(52)
3-氨基-6-甲基异唑并[5,4-b]吡啶-5-甲酸乙酯(53)
3-氨基-6-(二氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(54)
5-氟-6-吗啉代异唑并[5,4-b]吡啶-3-胺(55)
N6-环丙基-5-氟异唑并[5,4-b]吡啶-3,6-二胺(56)
5-氟-N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(57)
6-(呋喃-2-基)异唑并[5,4-b]吡啶-3-胺(58)
6,7-二氢-5H-环戊二烯并[b]异唑并[4,5-e]吡啶-3-胺(59)
6,7,8,9-四氢-5H-环庚三烯并[b]异唑并[4,5-e]吡啶-3-胺(60)
6,6-二甲基-5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(61)
7,8-二氢-5H-异唑并[5,4-b]吡喃并[3,4-e]吡啶-3-胺(62)
6-(甲硫基)异唑并[5,4-d]嘧啶-3-胺(63)
6-甲基异唑并[5,4-d]嘧啶-3-胺(64)
4-(甲硫基)-6-苯基异唑并[5,4-d]嘧啶-3-胺(65)
6-氯-5-氟异唑并[5,4-b]吡啶-3-胺(66)
5,6-二氯异唑并[5,4-b]吡啶-3-胺(67)
6-氯-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(68)
5-(3-甲氧基丙-1-炔-1-基)异唑并[5,4-b]吡啶-3-胺(69)
6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(70)
6-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(71)
6-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(72)
6-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(73)
6-(2-噻吩基)异唑并[5,4-b]吡啶-3-胺(74)
6-(1-甲基-1H-吡唑-5-基)异唑并[5,4-b]吡啶-3-胺(75)
6-(3-(二甲基氨基)丙氧基)异唑并[5,4-b]吡啶-3-胺(76)
6-(2-(二甲基氨基)乙氧基)异唑并[5,4-b]吡啶-3-胺(77)
6-(2-吗啉代乙氧基)异唑并[5,4-b]吡啶-3-胺(78)
6-(甲硫基)异唑并[5,4-b]吡啶-3-胺(79)
6-(甲基磺酰基)异唑并[5,4-b]吡啶-3-胺(80)
3-氨基异唑并[5,4-b]吡啶-6-甲酸(81)
3-氨基异唑并[5,4-b]吡啶-6-甲酸甲酯(82)
6-苯氧基异唑并[5,4-b]吡啶-3-胺(83)
6-(2-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(84)
6-(3-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(85)
6-(4-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(86)
6-(2-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(87)
6-(3-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(88)
6-(4-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(89)
6-(2-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(90)
6-(3-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(91)
6-(4-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(92)
6-(3-(三氟甲基)苯氧基)异唑并[5,4-b]吡啶-3-胺(93)
N6-苯基异唑并[5,4-b]吡啶-3,6-二胺(94)
N6-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(95)和
N6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(96),
和其药学上可接受的盐。
(27).前面段落(1)至(26)中任何一项所定义的化合物,其中所述化合物不是5-苯基异唑并[5,4-b]吡啶-3-胺。
(28).前面段落(1)至(27)中任何一项所定义的化合物,其中所述化合物是IDO1抑制剂。
(29).前面段落(1)至(27)中任何一项所定义的化合物,其中所述化合物是TDO抑制剂。
(30).前面段落(1)至(27)中任何一项所定义的化合物,其中所述化合物是IDO1抑制剂和TDO抑制剂。
某些式I化合物是新的。因此,提供这些化合物作为本发明的另一特征。例如,本发明还提供了式I化合物,其选自:
5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)
4,5,6-三甲基异唑并[5,4-b]吡啶-3-胺(5)
5-氯异唑并[5,4-b]吡啶-3-胺(8)
4-苯基异唑并[5,4-b]吡啶-3-胺(13)
5-氟异唑并[5,4-b]吡啶-3-胺(14)
6-苯基异唑并[5,4-b]吡啶-3-胺(15)
5-碘异唑并[5,4-b]吡啶-3-胺(16)
N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)
N4,N4-二甲基异唑并[5,4-b]吡啶-3,4-二胺(19)
5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)
5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)
5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)
5-(2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(23)
5-(3-氟-4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(25)
5-(吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(26)
5-(吡啶-4-基)异唑并[5,4-b]吡啶-3-胺(27)
2-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(28)
4-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(29)
5-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(30)
5-(3-氟苯基)异唑并[5,4-b]吡啶-3-胺(31)
5-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(32)
5-(3,5-二氟-2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(33)
5-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(34)
5-(2,3,4-三氯苯基)异唑并[5,4-b]吡啶-3-胺(35)
5-(4-(三氟甲基苯基)异唑并[5,4-b]吡啶-3-胺(36)
5-(3-氨基苯基)异唑并[5,4-b]吡啶-3-胺(37)
3-(3-氨基异唑并[5,4-b]吡啶-5-基)苯甲酸甲酯(38)
5-(6-氟吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(39)
5-(2-氯-4-(三氟甲基)苯基)异唑并[5,4-b]吡啶-3-胺(40)
6-氯-4-甲基异唑并[5,4-b]吡啶-3-胺(42)
异唑并[5,4-b]吡啶-3,6-二胺(43)
5-甲基异唑并[5,4-b]吡啶-3-胺(44)
5,6-二甲基异唑并[5,4-b]吡啶-3-胺(45)
6-甲基-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(46)
6-异丙基异唑并[5,4-b]吡啶-3-胺(48)
5-硝基异唑并[5,4-b]吡啶-3-胺(49)
3-氨基-6-(三氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(50)
4-甲氧基异唑并[5,4-b]吡啶-3-胺(51)
5-(二氟甲氧基)-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(52)
3-氨基-6-甲基异唑并[5,4-b]吡啶-5-甲酸乙酯(53)
3-氨基-6-(二氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(54)
5-氟-6-吗啉代异唑并[5,4-b]吡啶-3-胺(55)
N6-环丙基-5-氟异唑并[5,4-b]吡啶-3,6-二胺(56)
5-氟-N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(57)
6-(呋喃-2-基)异唑并[5,4-b]吡啶-3-胺(58)
6,7,8,9-四氢-5H-环庚三烯并[b]异唑并[4,5-e]吡啶-3-胺(60)
6,6-二甲基-5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(61)
7,8-二氢-5H-异唑并[5,4-b]吡喃并[3,4-e]吡啶-3-胺(62)
6-(甲硫基)异唑并[5,4-d]嘧啶-3-胺(63)
4-(甲硫基)-6-苯基异唑并[5,4-d]嘧啶-3-胺(65)
6-氯-5-氟异唑并[5,4-b]吡啶-3-胺(66)
5,6-二氯异唑并[5,4-b]吡啶-3-胺(67)
6-氯-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(68)
5-(3-甲氧基丙-1-炔-1-基)异唑并[5,4-b]吡啶-3-胺(69)
6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(70)
6-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(71)
6-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(72)
6-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(73)
6-(2-噻吩基)异唑并[5,4-b]吡啶-3-胺(74)
6-(1-甲基-1H-吡唑-5-基)异唑并[5,4-b]吡啶-3-胺(75)
6-(3-(二甲基氨基)丙氧基)异唑并[5,4-b]吡啶-3-胺(76)
6-(2-(二甲基氨基)乙氧基)异唑并[5,4-b]吡啶-3-胺(77)
6-(2-吗啉代乙氧基)异唑并[5,4-b]吡啶-3-胺(78)
6-(甲硫基)异唑并[5,4-b]吡啶-3-胺(79)
6-(甲基磺酰基)异唑并[5,4-b]吡啶-3-胺(80)
3-氨基异唑并[5,4-b]吡啶-6-甲酸(81)
3-氨基异唑并[5,4-b]吡啶-6-甲酸甲酯(82)
6-苯氧基异唑并[5,4-b]吡啶-3-胺(83)
6-(2-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(84)
6-(3-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(85)
6-(4-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(86)
6-(2-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(87)
6-(3-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(88)
6-(4-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(89)
6-(2-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(90)
6-(3-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(91)
6-(4-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(92)
6-(3-(三氟甲基)苯氧基)异唑并[5,4-b]吡啶-3-胺(93)
N6-苯基异唑并[5,4-b]吡啶-3,6-二胺(94)
N6-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(95)
N6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(96),
和其药学上可接受的盐.
本发明的其它方面可以包括本文公开的实施方案的适当组合。此外,如本领域技术人员将理解的,本发明的一个方面的特征和优选实施方案也将涉及本发明的其它方面。
虽然本发明广泛地如上所定义,但是本发明不限于此,并且还包括以下描述提供示例的实施方案。现在将更详细地描述本发明。
附图说明
图1显示C57/BI小鼠处理后0至16天的肿瘤体积,所述小鼠用被转染以表达hIDO1的Lewis肺癌细胞sc接种,随后当肿瘤可触知时,用化合物3每天以75mg/kg ip或sc进行处理。每隔一天测量肿瘤直到达到人道伦理终点。肿瘤体积以mm3表示。每组N=7。*表示通过重复测量单因素Anova的显著性。
图2显示在用150mg/kg化合物3处理后0.25小时、1小时、2小时、4小时、6小时和24小时通过分析HPLC确定的具有16天皮下GL-261-hIDO1肿瘤(肿瘤大小15-20mm)的小鼠的血浆和肿瘤中的K:T比例,每个时间点n=3。DMSO处理后0.25小时、1小时、2小时、4小时、6小时和24小时从3只小鼠收集的DMSO溶媒对照组(黑色,n=21)。*和**表示与DMSO对照相比的通过单因素ANOVA和Sidak多重比较的显著性(分别为p<0.05,p<0.01)。
图3显示用以下物质处理的具有sc GL261-hIDO1肿瘤的小鼠的研究的至人道伦理终点的存活:溶媒(A);每日以75mg/kg(B)IP的化合物3,在肿瘤植入后8天开始;针对抗-PD1(上部:肿瘤移植后第8天、第11天和第14天,250μg/小鼠IP)或抗-CTLA4(底部:肿瘤植入后6天1mg/小鼠IP)的抗免疫检查点抗体(C);或化合物3加免疫检查点抗体的组合(D)。P值表示与溶媒存活曲线相比通过Log-rank分析的显着差异。彩色箭头表示给药方案。
发明的详细说明
定义
如本文所用,术语“放射治疗”是指使用来自x射线、γ射线、中子、质子和其它源的高能辐射来杀死癌细胞和收缩肿瘤。放射可以来自身体外部的机器(外部束放射治疗),或者其可以来自放置在身体中靠近癌细胞的放射性材料(内部放射治疗)。系统放射治疗使用放射性物质,例如放射性标记的单克隆抗体,其在血液中行进到整个身体的组织。术语放射和放射治疗具有相同的含义。
应当认识到,本发明的某些化合物可以以一种或多种不同的对映异构体或非对映异构体形式存在。应当理解,对映体或非对映体形式包括在本发明的上述方面中。
在整个说明书中使用的术语卤代或卤素基团被认为是指氟、氯、溴或碘基团。
应当理解,当如上定义的式I的变量任选地被一个或多个咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基基团取代时,与该相关变量的连接可以通过这些基团的可用的氮或碳环原子之一进行。
应当理解,术语“杂芳基”包括单环和双环环系统,除非上下文另有要求。
应当理解,术语“芳基”是指芳族烃,例如苯基或萘基。
应当理解,当基团为“任选取代的”时,这意味着该基团可以是(a)未取代的或(b)被所定义的取代基取代。
应当理解,在整个说明书中提及C1-C6烷基或C2-C6烯基基团时,这些基团可以是未分支的或支链的。例如,C1-C6烷基的提及旨在将包括叔丁基(Me)3C-基团。
表述“治疗癌症”和“癌症的治疗”包括产生一种或多种抗癌效果的方法,所述抗癌效果包括但不限于抗肿瘤效果、响应率、疾病进展时间和总生存率。“抗肿瘤”效果包括但不限于抑制肿瘤生长、肿瘤生长延迟、肿瘤消退、肿瘤收缩、停止治疗时肿瘤再生长的时间增加和疾病进展的减缓。
“治疗有效量”是指当施用于受试者用于治疗癌症时足以实现癌症治疗的化合物的量。“有效量”将取决于待治疗的癌症、待施用的化合物、所治疗的癌症的严重性、受试者的年龄和相对健康、施用途径和形式、治疗是单一疗法还是联合治疗、主治医师的判断和其他因素。
“药学上可接受的”是指其可用于制备药物组合物,所述药物组合物通常是安全的、无毒的,并且既不是生物学上也不是其它不期望的,并且包括其是兽医以及人类药学用途可接受的。
化合物的“药学上可接受的盐”是指如本文所定义的药学上可接受的并且具有母体化合物所需的药理活性的盐。此类盐包括:
(a)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐;或与有机酸如乙酸、甲磺酸、马来酸、酒石酸、柠檬酸等形成的酸加成盐;和
(b)当存在于母体化合物中的酸性质子被金属离子例如碱金属离子、碱土金属离子或铝离子置换时形成的盐;或与有机或无机碱配位形成的盐。可接受的有机碱包括乙醇胺、二乙醇胺、N-甲基葡糖胺、三乙醇胺等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
“温血动物”是指哺乳类的任何成员,包括但不限于人、非人灵长类动物例如黑猩猩和其他猿和猴种、农场动物例如牛、马、绵羊、山羊和猪;家养动物例如兔、狗和猫;实验室动物,包括啮齿动物例如大鼠、小鼠和豚鼠等。
本发明的化合物及其制备方法
如上所定义,广义上,本发明涉及含有通式I化合物的药物组合物,以及这些化合物在治疗、特别是癌症治疗中的用途。已经发现式I化合物是吲哚胺2,3-双加氧酶1(IDO1)和/或色氨酸2,3-双加氧酶(TDO)的抑制剂。因此,预期本发明的化合物可单独或与其它活性剂组合用于癌症治疗,所述其它活性剂例如例如抗癌疫苗、免疫检查点蛋白的调节剂、过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))、放射治疗和其他化疗剂。还预期式I化合物可用于治疗癌症以外的其它各种疾患,如下文的本发明治疗方法部分中更详细描述的。
下文参考方法1至8描述了用于制备式I化合物和化合物的药学上可接受的盐的某些方法。
合成流程
某些式I化合物可以通过在碱例如叔丁醇钾、碳酸钾或碳酸铯的存在下,使适当取代的卤代氰基吡啶与乙酰氧肟酸反应来制备(方法1)。一系列溶剂可用于该反应,包括DMF、对二氧六环和N-甲基吗啉。
方法1
具有烷基氨基取代基和/或芳基氨基取代基的化合物可以通过用胺和/或苯胺置换活化的卤素原子来制备(方法2)。
方法2
在环外氨基上含有烷基取代的化合物可以通过伯胺与原甲酸三烷基酯反应,随后用合适的还原剂如硼氢化钠还原来制备(方法3)。
方法3
这些化合物也可以通过在还原胺化方法中使伯胺与烷基醛反应,然后与还原剂如氰基硼氢化钠反应制备(方法4)。
方法4
带有悬挂的芳基或杂芳基(Het)取代基的化合物可以通过在Suzuki偶联反应中,在钯催化下,使适当取代的含卤素或三氟甲磺酸酯的底物与合适的芳基或杂芳基硼酸或酯反应(方法5)。
方法5
带有悬挂的芳基或杂芳基(Het)取代基的化合物也可以通过以下方法制备:
用适当取代的含卤素或三氟甲磺酸酯的化学中间体和合适的芳基或杂芳基硼酸或酯进行钯催化的Suzuki偶联反应,然后将所得芳基或杂芳基化产物修饰成最终产物(方法6)。
方法6
含有烷基和/或芳基醚连接的取代基的化合物可以通过在碱例如钠或氢化钠或碳酸铯的存在下用醇和/或酚置换活化的卤素原子来制备(方法7)。
方法7
含有硫烷基和/或硫芳基醚连接的取代基的化合物可以通过在碱例如钠或氢化钠或碳酸铯存在下,通过硫醇和/或苯硫酚置换活化的卤素原子来制备,或通过与硫醇或苯硫酚的金属盐直接反应制备。所得的硫烷基或苯硫酚衍生物可以用合适的氧化剂如过氧化氢、过酸、金属络合物和氧杂吖丙啶(oxaziridines)氧化成其相应的亚砜或砜衍生物(方法8)。
方法8
本领域技术人员将理解,通过使用与上述类似的方法,也可以制备式I的其它化合物。
本发明的治疗方法
本发明的式I化合物可以是IDO1或TDO的抑制剂或者IDO1和TDO两者的抑制剂。为IDO1或TDO的抑制剂的化合物和为IDO1和TDO的双重抑制剂的化合物预期可用于癌症治疗。因此,在某些实施方案中,本发明提供了通过向需要这种治疗的受试者施用治疗有效量的式I化合物或含有式I化合物的药物组合物来治疗温血动物(包括人)中的癌症的方法。
在本发明的具体方面,预期式I化合物可用于恢复癌症患者的肿瘤免疫。本发明的化合物可以单独使用,或与其它癌症疗法包括化疗剂、放射和/或免疫调节剂组合使用。
免疫调节剂包括但不限于抗癌疫苗、调节免疫检查点蛋白的活性剂(例如CTLA4和PD1-4s)和过继性T细胞疗法(例如CART)。因此,式I化合物可以单独施用或与一种或多种其它此类疗法组合施用,根据待治疗的特定疾患同时或依次施用。
在具体实施方案中,式I化合物可以与一种或多种选自易普利姆玛(Ipilimumab,一种CTLA4的抑制剂)、Nivolumab和Lambrolizumab(两者都为PD-1抑制剂)的免疫治疗组合施用。
可以与式I化合物组合施用的其它化疗剂包括但不限于在第14版的Merck Index(2006)(其通过引用并入本文)中列于癌症化疗药物方案中的化合物,例如天冬酰胺酶、博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、门冬酰胺酶(colaspase)、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、多柔比星(阿霉素)、表柔比星、依托泊苷、5-氟尿嘧啶、六甲蜜胺、羟基脲、异环磷酰胺、伊立替康、亚叶酸(leucovorin)、洛莫司汀、氮芥、6-巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托蒽醌、泼尼松龙、泼尼松、丙卡巴肼、雷洛昔芬、链佐星、他莫昔芬、硫鸟嘌呤、拓扑替康、长春碱、长春新碱和长春地辛。
可以与式I化合物组合施用的另外的抗增殖剂包括但不限于BCNU、CCNU、DTIC和放线菌素D。其它抗增殖剂包括但不限于公认的用于治疗Goodman and Gilman's ThePharmacological Basis of Therapeutics(第11版),编辑Molinoff等人,McGraw-Hill出版,第1225-1287页(2006)(将其引入文中作为参考)中的肿瘤性疾病的那些化合物,如氨鲁米特、L-天冬酰胺酶、硫唑嘌呤、5-氮杂胞苷克拉屈滨、白消安、己烯雌酚、2′,2′-二氟脱氧胞苷、多西紫杉醇、赤羟基壬基腺嘌呤(erythrohydroxynonyladenine)、乙炔基雌二醇、5-氟脱氧尿苷、5-氟脱氧尿苷一磷酸、磷酸氟达拉滨、氟甲睾酮、氟他胺、己酸羟孕酮、伊达比星、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、紫杉醇、喷司他丁、N-膦酰基乙酰基-L-天冬氨酸(PALA)、普卡霉素、司莫司汀、替尼泊苷、丙酸睾酮、噻替派、三甲基三聚氰胺、尿苷和长春瑞滨。
可以与式I化合物组合施用的另外的抗增殖剂包括但不限于其它分子靶向剂,其通过干扰癌发生和肿瘤生长所需的特定靶分子阻断癌细胞的生长。实例包括小分子蛋白和脂质激酶抑制剂、单克隆抗体、分子靶向人源化单克隆抗体和单克隆抗体药物缀合物。此类抑制剂的例子包括:利妥昔单抗、曲妥珠单抗、阿仑单抗、托西莫单抗-I131、西妥昔单抗、替伊莫单抗(Ibritumomab tiuxetan)、贝伐单抗、帕尼单抗、奥法木单抗(Ofatumumab)、易普利姆玛、Brentuximab vedotin、帕妥珠单抗(Pertuzumab)、Ado-曲妥单抗emtansine、雷莫芦单抗(Ramucirumab)、Obinutuzumab、Nivolumab、Lambrolizumab、Dinutuximab、伊马替尼、吉非替尼、厄洛替尼、索拉非尼、达沙替尼、舒尼替尼、拉帕替尼(Lapatinib)、尼洛替尼、帕唑帕尼、克里唑替尼(Crizotinib)、鲁索利替尼(Ruxolitinib)、凡德他尼(Vandetanib)、威罗非尼(Vemurafenib)、阿西替尼(Axitinib)、波舒替尼(Bosutinib)、Cabozantinib、Ponatinib、Regorafenib、Tofacitinib、阿法替尼、达拉菲尼(Dabrafenib)、依鲁替尼(Ibrutinib)和曲美替尼(Trametinib)。
多种癌症可以通过本发明的化合物治疗。可根据本发明治疗的癌症包括但不限于:结肠直肠癌、乳腺癌、黑色素瘤、生殖器官、呼吸道、脑、消化道、泌尿道、眼、肝、皮肤、头颈、甲状腺、甲状旁腺的癌症及其远处转移。那些疾病还包括淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括但不限于浸润性导管癌、浸润性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌的实例包括但不限于小细胞和非小细胞肺癌、以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括但不限于脑干和眼球下(hypophthalmic)神经胶质瘤、小脑和大脑星形细胞瘤、成神经管细胞瘤、室管膜瘤以及神经外胚层和松果体肿瘤。
雄性生殖器官的肿瘤包括但不限于前列腺癌和睾丸癌。
雌性生殖器官的肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫肉瘤。
消化道的肿瘤包括但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道的肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌和尿道癌。
眼癌包括但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌的实例包括但不限于肝细胞癌(具有或不具有纤维板层变体的肝细胞癌)、胆管癌(肝内胆管癌)和混合的肝细胞胆管癌。
皮肤癌包括但不限于鳞状细胞癌、卡波西肉瘤、恶性黑色素瘤、梅克尔(Merkel)细胞皮肤癌和非黑色素瘤皮肤癌。
头颈癌包括但不限于喉/下咽/鼻咽/口咽癌、以及唇和口腔癌。淋巴瘤包括但不限于AIDS相关淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、霍奇金病和中枢神经系统淋巴瘤。
肉瘤包括但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。白血病包括但不限于急性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、慢性骨髓性白血病和毛细胞白血病。
这些疾病在人类中已经被很好地表征,但在其他温血动物中也存在类似的病因,并且可以通过本发明的化合物治疗。
本领域技术人员将理解,特定的治疗方法将采用选择的施用途径,所述施用途径又取决于多种因素,所有这些因素在施用治疗剂时都是常规的。本领域技术人员还将理解的是,本领域技术人员使用常规处理测试可以确定最佳治疗过程,即治疗方式和在给定的天数内给予的本发明化合物的每日剂量数。
治疗剂量可能在每天1mg至30g的范围内。对于任何特定患者选择的具体剂量水平将取决于多种因素,包括所使用的具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、施用途径和排泄率、药物组合和正在进行治疗的疾患的严重性。
作为IDO1抑制剂的某些式I化合物也可抑制IDO2。为IDO1和IDO2的双重抑制剂的化合物也预期可用于癌症治疗。因此,在另一方面,本发明提供了抑制有需要的温血动物(包括人)中IDO1和IDO2的方法,其包括以有效抑制IDO1和IDO2的量向动物施用式I化合物或其药学上可接受的盐。
已经报道,为IDO(IDO1和IDO2)和/或TDO的抑制剂的化合物不仅可以在治疗癌症中具有功效,而且在治疗一系列其它疾病或疾患中具有功效,例如在PCT国际公开WO 2015/082499以及其中提及的科学文献中所讨论,所有这些文献通过引用并入本文。例如,此类化合物可用于治疗炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障。因此,本发明的式I化合物也可用于治疗此类疾病或疾患。
可以由式I化合物治疗的炎性疾患的实例包括与免疫B细胞、T细胞、树突细胞、自然杀伤细胞、巨噬细胞和/或嗜中性粒细胞调节异常有关的疾患。
可以由式I化合物治疗的感染性疾病的实例包括细菌感染、病毒感染例如肠道感染、丙型肝炎、败血症和败血症诱发的低血压。
可以由式I化合物治疗的中枢神经系统疾病或病症的实例包括肌萎缩性侧索硬化(AML)、亨廷顿病、阿尔茨海默病、疼痛、包括情感障碍如抑郁症的精神障碍、多发性硬化、帕金森氏病和HIV相关的神经认知下降。
可以由式I化合物治疗的与雌性生殖健康相关的疾病或病症的实例是子宫内膜异位症和与雌性生殖健康有关的疾患包括避孕和堕胎。
本发明的药物组合物
本发明包括包含一种或多种本发明式I化合物和药学上可接受的载体的药物组合物。
药学上可接受的赋形剂、辅助剂、载体、缓冲剂或稳定剂应当是无毒的,并且不应干扰活性成分的功效。载体或其它物质的确切性质将取决于施用途径。
化合物可以以剂量单位制剂口服、局部、胃肠外、通过吸入或喷雾或直肠施用。术语“通过注射施用”包括静脉内、肌内、皮下和肠胃外注射以及输注技术的使用。一种或多种化合物可以与一种或多种无毒的药学上可接受的载体以及如果需要的话其它活性成分联合存在。
用于口服使用的组合物可以根据本领域已知的用于制备药物组合物的任何合适的方法制备。此类组合物可以含有一种或多种选自稀释剂、甜味剂、矫味剂、着色剂和防腐剂的物质,以提供可口的制剂。片剂含有活性成分以及适合制备片剂的无毒的药学上可接受的赋形剂。这些赋形剂可以是例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒和崩解剂,例如玉米淀粉或藻酸;和粘合剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者它们可以通过已知技术包衣,以延迟在胃肠道中的崩解和吸附,从而在更长的时间内提供持续的作用。例如,可以使用时间延迟材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。这些化合物也可以制备为固体快速释放的形式。
口服使用的制剂也可以作为硬明胶胶囊存在,其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合,或作为软明胶胶囊存在,其中活性成分与水或油介质例如花生油、液体石蜡或橄榄油混合。
水性混悬剂含有活性物质以及适于制备水性混悬剂的赋形剂。此类赋形剂是助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂可以是天然存在的磷脂,例如卵磷脂,或缩合产物或具有脂肪酸的氧化烯,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂族醇的缩合产物,例如十七碳亚乙基氧基鲸蜡醇(heptadecaethylene oxycetanol),或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如聚乙烯失水山梨醇单油酸酯。水性混悬剂还可以含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂例如蔗糖或糖精。
适于通过加入水制备水性混悬剂的可分散粉末和颗粒提供与分散或润湿剂、助悬剂和一种或多种防腐剂混合的活性成分。合适的分散或润湿剂和助悬剂由上面已经提到的那些举例说明。还可以存在另外的赋形剂例如甜味剂、矫味剂和着色剂。
所述化合物还可以是非水性液体制剂的形式,例如油性混悬剂,其可以通过将活性成分悬浮在植物油(例如落花生油(arachis oil)、橄榄油、芝麻油或花生油(peanutoil))中或悬浮在矿物油如液体石蜡来配制。油性混悬剂可以含有增稠剂例如蜂蜡、硬石蜡或鲸蜡醇。可以加入甜味剂如上述的那些,以及矫味剂,以提供可口的口服制剂。这些组合物可以通过加入抗氧化剂如抗坏血酸来保存。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或落花生油,或矿物油例如液体石蜡或这些的混合物。合适的乳化剂可以是天然存在的树胶,例如阿拉伯树胶或黄蓍胶,天然存在的磷脂,例如大豆、卵磷脂,和衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨醇单油酸酯,所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨醇单油酸酯。乳剂还可以含有甜味剂和矫味剂。
糖浆和酏剂可以用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制。此类制剂还可以含有缓和剂、防腐剂和矫味剂和着色剂。
所述化合物也可以以用于直肠给药的栓剂的形式施用。这些组合物可以通过将药物与合适的非刺激性赋形剂混合来制备,所述赋形剂在常温下为固体,但在直肠温度下为液体,因此将在直肠中熔化以释放药物。这样的材料包括可可脂和聚乙二醇。
实施例
以下实施例是本发明的化合物及其制备方法的代表。然而,本发明的范围不限于这些实施例。
合成程序(procedures)
未明确描述的起始材料可商购获得,或其合成已描述于化学文献中,或所述材料可通过本领域技术人员已知的方法制备。通过1H NMR波谱、APCI电离质谱、熔点和燃烧或HRMS分析表征示例性化合物。通过HPLC分析测定示例性化合物的纯度,发现对于所有化合物,纯度>95%。
硅胶60(SiO2)(0.040-0.063mm)用于所有柱色谱。
缩写
NMR 核磁共振
ESI 电喷雾电离
APCI 大气压化学电离
HPLC 高效液相色谱
LCMS 液相色谱-质谱
HRMS 高分辨质谱
mp 熔点
DMF 二甲基甲酰胺
EtOAc 乙酸乙酯
DCM 二氯甲烷
MeOH 甲醇
THF 四氢呋喃
HOAc 乙酸
dppf 2-(二苯基膦基)二茂铁
EDCI 1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐
TEA 三乙胺
方法1.代表性实施例
5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)
在氮气气氛下,向乙酰氧肟酸(0.61g,8.13mmol)的干燥DMF(10mL)溶液中加入叔丁醇钾(0.91g,8.14mmol)。将反应混合物在20℃搅拌2hr。然后加入5-溴-2-氯-4,6-二甲基烟腈(1.00g,4.07mmol)并将得到的混合物在20℃搅拌24hr,然后用H2O(150ml)稀释并搅拌1hr。将得到的白色沉淀过滤并用水洗涤。将滤液用EtOAc(30mL x3)萃取。将合并的有机流分干燥(Na2SO4),并将溶剂在真空下蒸发,得到另外的材料。将所述分离的固体和萃取的材料合并,在SiO2上色谱分离,采用0-50%梯度的石油醚/EtOAc洗脱。将柱纯化的产物从DCM/石油醚中重结晶,得到5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)(0.68g,69%),为白色固体,mp(DCM/石油醚)208-211℃,1H NMR[(CD3)2SO]δ6.24(s,2H,NH2),2.66(6H,2xCH3),LCMS[M+H]=242和244.C8H8BrN3O的计算值:C,36.7;H,3.3;N,17.4;实测值C,36.9;H,3.2,N,17.4%.
类似地制备下述化合物:
异唑并[5,4-b]吡啶-3-胺(2)
其由2-氯烟腈在1,2-二甲氧基乙烷中以48%产率制备;
5-氯-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(3)
其由2,5-二氯-4,6-二甲基烟腈以75%产率制备;mp(DCM/石油醚)214-216℃.1HNMR[(CD3)2SO]δ6.25(bs,2H,NH2),2.64(s,3H,CH3),2.61(s,3H,CH3);LCMS[M+H]=198;HPLC99.8%;C8H8ClN3O的分析计算值:C,48.6;H,4.1;N,21.4;实测值C,48.8;H,3.9,N,21.4%.
4,6-二甲基异唑并[5,4-b]吡啶-3-胺(4)
其由2-氯-4,6-二甲基烟腈以40%产率制备;mp(DCM/石油醚)156-158℃;1H NMR[(CD3)2SO]δ6.98(s,1H),6.09(bs,2H,NH2),2.57(d,J=0.6Hz,3H,CH3),2.48(s,3H,CH3);HPLC 99.9%;C8H9N3O的分析计算值:C,58.9;H,5.6;N,25.5;实测值C,59.0;H,5.6;N,25.9%.
4,5,6-三甲基异唑并[5,4-b]吡啶-3-胺(5)
其由2-氯-4,5,6-三甲基烟腈以39%产率制备;mp(DCM/石油醚)204-207℃;1HNMR[(CD3)2SO]δ6.04(bs,2H,NH2),2.44(s,6H,2x CH3),2.14(s,3H,CH3);HPLC 99.9%;C9H11N3O的分析计算值:C,61.0;H,6.3;N,23.7;实测值C,61.0;H,6.3;N,23.7%.
5-溴异唑并[5,4-b]吡啶-3-胺(6)
其由5-溴-2-氯烟腈以60%产率制备;mp(DCM/石油醚)231-234℃;1H NMR[(CD3)2SO]δ8.63((d,J=2.3Hz,1H),8.55(d,J=2.3Hz,1H),6.71(bs,2H,NH2);HPLC 99.6%;LCMS[M+H]214和216;C6H4BrN3O的分析计算值:C,33.7;H,1.9;N,19.6;实测值C,33.9;H,1.7;N,19.5%.
6-甲基异唑并[5,4-b]吡啶-3-胺(7)
其由2-氯-6-甲基烟腈以40%产率制备;mp(DCM/石油醚)224-226℃;HPLC 100%;LCMS[M+H]=150;C7H7N3O的分析计算值:C,56.4;H,4.7;N,28.2;实测值C;56.6;H,4.5;N,28.2%.
5-氯异唑并[5,4-b]吡啶-3-胺(8)
其由2,5-二氯烟腈以79%产率制备;mp(DCM/石油醚)257-260℃;1H NMR[(CD3)2SO]δ8.57(d,J=2.4Hz,1H),8.42(d,J=2.5Hz,1H),6.72(s,2H,NH2),HPLC 99.9%;LCMS[M+H]=170;C6H4ClN3O的分析计算值;C,42.5;H,2.4;N,24.8;实测值C,42.6;H,2.2;N,24.6%.
异唑并[5,4-b]喹啉-3-胺(9)
其由2-氯喹啉-3-腈以72%产率制备;mp(DCM/石油醚)261-263℃;1H NMR[(CD3)2SO]δ8.93(s,1H),8.16(dd,J=8.3,1.0Hz,1H),7.99(d,J=8.6Hz,1H),7.87(ddd,J=8.5,6.8,1.4Hz,1H),7.59(ddd,J=8.1,6.8,1.1Hz,1H),6.89(s,2H,NH2).HPLC 99.6%;C10H7N3O的分析计算值;C,64.9;H,3.8;N,22.7;C,65.0;H,3.7;N,22.7%.
5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(10)
其由2-氯-5,6,7,8-四氢喹啉-3-腈以61%产率制备;mp(DCM/MeOH)236-239℃;1HNMR[(CD3)2SO]δ7.92(s,1H),6.46(bs,2H,NH2),2.88(t,J=6.4Hz,2H),2.83(t,J=6.2Hz,2H),1.87-1.74(m,4H);HPLC 100%;LCMS[M+H]=190;C10H11N3O的分析计算值:C,63.5;H,5.9;N,22.2;实测值C,63.6;H,5.9,N,22.2%.
6-氯异唑并[5,4-b]吡啶-3-胺(11)
其由2,6-二氯烟腈以2%产率制备;mp(DCM/MeOH)238-241℃;1H NMR[(CD3)2SO]δ8.33(d,J=8.1Hz,1H),7.48(d,J=8.1Hz,1H),6.76(bs,2H,NH2);LCMS[M+H]=170;HPLC99.9%,C6H4ClNO3的分析计算值:C,42.5;H,2.4;N,24.8;实测值C,42.7;H,2.3;N,24.7%.
异唑并[5,4-d]嘧啶-3-胺(12)
其由4-氯嘧啶-5-腈在1,4-二氧六环中以15%产率制备;mp(DCM/石油醚)>295℃;1H NMR[(CD3)2SO]δ9.29(s,1H),9.08(s,1H),7.00(bs,2H,NH2);LCMS[M+H]=137;HPLC96.0%;C5H4N4O的分析计算值;C,44.1;H,3.0;N,41.2;实测值C,44.3;H,2.9;N,40.9%.
4-苯基异唑并[5,4-b]吡啶-3-胺(13)
其由2-氯-4-苯基烟腈在1,2-二甲氧基乙烷中以26.6%产率制备;mp(DCM/石油醚)196-199℃;LCMS[M+H]=212;HPLC 99.7%;C12H9N3O的分析计算值:C,68.2;H,4.3;N,19.9;实测值C,68.4;H,4.2;N,20.0%.
5-氟异唑并[5,4-b]吡啶-3-胺(14)
其由2-氯-5-氟烟腈在1,2-二甲氧基乙烷中以45%产率制备;mp(DCM/石油醚)223-226℃;LCMS[M+H]=154;HPLC 99.8%;C6H4FN3O的分析计算值:C,47.1;H,2.6;N,27.4实测值C,47.3;H,2.5N,27.7%.
6-苯基异唑并[5,4-b]吡啶-3-胺(15)
其由2-氯-6-苯基烟腈以48%产率制备;mp(DCM/石油醚)236-238℃;LCMS[M+H]=212;1H NMR[(CD3)2SO]δ8.36(d,J=8.1Hz,1H),8.17-8.14(m,2H),7.97(d,J=8.27Hz,1H);7.56-7.48 9(m,3H),6.65(s,2H,NH2);HPLC 100%;C12H9N3O的分析计算值:C,68.2;H,4.3;N,19.9;实测值C,68.3;H,4.2;N,19.8%.
5-碘异唑并[5,4-b]吡啶-3-胺(16)
其由2-氯-5-碘烟腈以35%产率制备;mp(DCM/MeOH)243-246℃;LCMS[M+H]=262;1H NMR[(CD3)2SO]δ8.69(2xd,J=2.1Hz,2H),6.68(bs,2H,NH2);HPLC 99.9%;C6H4IN3O的分析计算值:C,27.6;H,1.5;N;16.1;实测值C,27.7;H,1.6;N,16.0%.
异唑并[4,5-c]吡啶-3-胺(17)
其由4-氯烟腈以11%产率制备;mp(DCM/MeOH)189-192℃;LCMS[M+H]=136;HPLC99.7%.HRMS(ESI+)C6H6N3O的计算值136.0505;实测值136.0502.
6-氯-4-甲基异唑并[5,4-b]吡啶-3-胺(42)
其由2,6-二氯-4-甲基烟腈制备,mp 225-228℃;1H NMR[(CD3)2SO]δ7.28(s,1H),6.33(br s,2H,NH2),2.63(s,3H,CH3);HPLC 99.3%;LCMS实测值:[M+H]=184,186.
异唑并[5,4-b]吡啶-3,6-二胺(43)
其由6-氨基-2-氯烟腈制备,mp 205-208℃;1H NMR[(CD3)2SO]δ7.71(d,J=8.8Hz,1H),6.70(br s,2H,NH2),6.31(d,J=8.8Hz,1H),6.08(br s,2H,NH2);HPLC 99.0%;LCMS实测值:[M+H]=151.
5-甲基异唑并[5,4-b]吡啶-3-胺(44)
其由5-甲基-2-氯烟酸盐制备,mp 232-234℃;1H NMR[(CD3)2SO]δ8.35(d,J=1.2Hz,1H),8.07(d,J=1.2Hz,1H),6.57(br s,2H,NH2),2.39(s,3H,CH3);HPLC 96.4%.LCMS实测值:[M+H]=150.
5,6-二甲基异唑并[5,4-b]吡啶-3-胺(45)
其由2-氯-5,6-二甲基烟腈制备,mp 263-266℃;1H NMR[(CD3)2SO]δ7.95(s,1H),6.47(br s,2H,NH2),2.49(s,3H,CH3),2.31(s,3H,CH3);HPLC 99.1%;LCMS实测值:[M+H]=164.
6-甲基-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(46)
其由2-氯-6-甲基-4-(三氟甲基)烟腈制备,mp 112-114℃;1H NMR[(CD3)2SO]δ7.70(s,1H),6.07(br s,2H,NH2),2.68(s,3H,CH3);HPLC 97.7%.LCMS实测值:[M+H]=218.
6-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(47)
其由2-氯-6-(三氟甲基)烟腈以31%产率制备,mp(DCM/MeOH)226-228℃;1H NMR[(CD3)2SO]δ8.60(d,J=7.90Hz,1H),7.90(d,J=7.90Hz,1H),6.93(brs 2H);C7H4F3N3O的分析计算值:C,41.4,H,2.0;N,20.7;实测值C,41.4,H,1.8;N,20.5%.
6-异丙基异唑并[5,4-b]吡啶-3-胺(48)
其由2-氯-6-异丙基烟腈以79%产率制备,mp(DCM/石油醚)165-168°;1H NMR[(CD3)2SO]δ8.18(d,J=8.0Hz,1H),7.26(d,J=8.0Hz,1H),6.53(brs,2H),3.11(sp,J=6.9Hz,1H),1.25(d,J=6.9Hz,6H);C9H11N3O的分析计算值:C,61.0;H,6.3N,23.7;实测值C,61.2;H,6.4;N,23.5%
5-硝基异唑并[5,4-b]吡啶-3-胺(49)
其由5-硝基-2-氯烟腈制备,mp>290℃;1H NMR[(CD3)2SO]δ9.37(d,J=2.8Hz,1H),9.27(d,J=2.8Hz,1H),7.06(br s,2H,NH2);HPLC 99.8%.LCMS实测值:[M+H]=181.
3-氨基-6-(三氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(50)
其由6-氯-5-氰基-2-(三氟甲基)烟酸乙酯制备,mp 177-180℃;1H NMR[(CD3)2SO]δ8.95(s,1H),7.08(br s,2H,NH2),4.40(q,J=8.0Hz,2H,OCH2).1.34(t,J=8.0Hz,3H,CH3);HPLC 99.1%.LCMS实测值:[M+H]=276.
4-甲氧基异唑并[5,4-b]吡啶-3-胺(51)
其由2-氯-4-甲氧基烟腈制备,mp 241-243℃;1H NMR[(CD3)2SO]δ8.35(d,J=5.9Hz,1H),6.91(d,J=5.9Hz,1H),6.17(br s,2H,NH2),3.99(s,3H);HPLC 97.6%.LCMS实测值:[M+H]=166.
5-(二氟甲氧基)-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(52)
其由2-氯-5-(二氟甲氧基)-4,6-二甲基烟腈制备,mp 151-153℃;1H NMR[(CD3)2SO]δ7.05(t,J=74Hz,1H),6.23(br s,2H,NH2),2.54(s,3H),2.51(s,3H);HPLC 99.7%.LCMS实测值:[M+H]=230.
3-氨基-6-甲基异唑并[5,4-b]吡啶-5-甲酸乙酯(53)
其由6-氯-5-氰基-2-甲基烟酸乙酯制备,mp 178-180℃;1H NMR[(CD3)2SO]δ8.86(s,1H),6.81(br s,2H,NH2),4.35(q,J=7.2Hz,2H,OCH2),2.80(s,3H,CH3),1.36(t,J=7.2Hz,3H,CH3);HPLC 99.6%.LCMS实测值:[M+H]=222.
3-氨基-6-(二氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(54)
其由6-氯-5-氰基-2-(二氟甲基)烟酸乙酯制备,mp 158-160℃;1H NMR[(CD3)2SO]δ9.05(s,1H),7.59(t,J=53Hz,1H),7.04(br s,2H,NH2),4.39(q,J=6.8Hz,2H,OCH2),1.37(t,J=6.8Hz,3H,CH3);HPLC 99.1%.LCMS实测值:[M+H]=258.
5-氟-6-吗啉代异唑并[5,4-b]吡啶-3-胺(55)
其由2-氯-5-氟-6-吗啉代烟腈制备,mp 168-170℃;1H NMR[(CD3)2SO]δ7.86(d,J=12.8Hz,1H),6.33(br s,2H,NH2),3.72(br s,4H,CH2O),3.51(br s,4H,CH2N);HPLC98.0%.LCMS实测值:[M+H]=239.
N6-环丙基-5-氟异唑并[5,4-b]吡啶-3,6-二胺(56)
其由2-氯-6-(环丙基氨基)-5-氟烟腈制备,mp 182-184℃;1H NMR[(CD3)2SO]δ7.66(d,J=12.9Hz,1H),7.63(br s,1H,NH),6.14(br,2H,NH2),2.75(m,1H,CHN),0.73(m,2H,CH2),0.56(m,2H,CH2);HPLC 99.4%.LCMS实测值:[M+H]=209.
5-氟-N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(57)
其由2-氯-6-(二甲基氨基)-5-氟烟腈制备,mp 186-189℃;1H NMR[(CD3)2SO]δ7.74(d,J=13.2Hz,1H),5.76(br,2H,NH2),3.11(s,6H,NMe2);HPLC 96.2%.LCMS实测值:[M+H]=197.
6-(呋喃-2-基)异唑并[5,4-b]吡啶-3-胺(58)
其由2-氯-6-(呋喃-2-基)烟腈制备,mp 269-272℃;1H NMR[(CD3)2SO]δ8.31(d,J=8.4Hz,1H),7.93(d,J=1.2Hz,1H),7.72(d,J=8.4Hz,1H),7.28(d,J=3.2Hz,1H),6.72(dd,J=3.2,1.2Hz,1H),6.64(br s,2H,NH2).HPLC 98.7%.LCMS实测值:[M+H]=202.
6,7-二氢-5H-环戊二烯并[b]异唑并[4,5-e]吡啶-3-胺(59)
其由2-氯-6,7-二氢-5H-环戊二烯并[b]吡啶-3-腈制备,mp 217-220℃;1H NMR[(CD3)2SO]δ7.99(s,1H),6.47(br s,2H,NH2),2.94(m,4H),2.13(m,2H);HPLC 99.4%.LCMS实测值:[M+H]=176.
6,7,8,9-四氢-5H-环庚三烯并[b]异唑并[4,5-e]吡啶-3-胺(60)
其由2-氯-6,7,8,9-四氢-5H-环庚三烯并[b]吡啶-3-腈制备,mp 210-212℃;1HNMR[(CD3)2SO]δ7.94(s,1H),6.47(br s,2H,NH2),3.02(d,J=4.0Hz,2H),2.87(d,J=4.1Hz,2H),1.83(m,2H),1.61(m,4H);HPLC 96.6%.LCMS实测值:[M+H]=204.
6,6-二甲基-5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(61)
其由2-氯-6,6-二甲基-5,6,7,8-四氢喹啉-3-腈制备,mp 203-205℃;1H NMR[(CD3)2SO]δ7.90(s,1H),6.49(br s,2H,NH2),2.62(s,2H),2.06(t,J=6.9Hz,2H),1.65(t,J=6.9Hz,2H),0.97(s,6H);HPLC 99.1%.LCMS实测值:[M+H]=218.
7,8-二氢-5H-异唑并[5,4-b]吡喃并[3,4-e]吡啶-3-胺(62)
其由2-氯-7,8-二氢-5H-吡喃并[4,3-b]吡啶-3-腈制备,mp 248-250℃;1H NMR[(CD3)2SO]δ7.94(s,1H),6.57(br s,2H,NH2),4.81(s,2H),4.00(m,2H),2.97(m,2H);HPLC97.8%.LCMS实测值:[M+H]=192.
6-(甲硫基)异唑并[5,4-d]嘧啶-3-胺(63)
其由4-氯-2-(甲硫基)嘧啶-5-腈制备,mp>310℃;1H NMR[(CD3)2SO]δ9.05(s,1H),6.92(br s,2H,NH2),2.56(s,3H,SCH3);HPLC 99.9%.LCMS实测值:[M+H]=183.
6-甲基异唑并[5,4-d]嘧啶-3-胺(64)
其由4-氯2-甲基嘧啶-5-腈制备,mp 180-182℃;1H NMR(CD3OD)δ9.10(s,1H),2.78(s,3H,CH3);HPLC 97.9%.LCMS实测值:[M+H]=151.
4-(甲硫基)-6-苯基异唑并[5,4-d]嘧啶-3-胺(65)
其由4-氯-6-(甲硫基)-2-苯基嘧啶-5-腈制备,mp 230-233℃;1H NMR[(CD3)2SO]δ8.48(m,2H),7.57(m,3H),6.37(br s,2H,NH2),2.84(s,3H,SCH3);HPLC 98.3%.LCMS实测值:[M+H]=259.
6-氯-5-氟异唑并[5,4-b]吡啶-3-胺(66)
在20℃向乙酰氧肟酸(589mg,7.85mmol)的N-甲基吗啉(10mL)溶液中加入干燥K2CO3(1.08g,7.83mmol)并将混合物在该温度搅拌1hr。将该混合物在冰中冷却,并加入2,6-二氯-5-氟烟腈(1.00g,5.24mmol),并使反应混合物缓慢升温至20℃并在该温度搅拌3天。然后将反应混合物用H2O稀释并用K2CO3碱化,萃取至EtOAc中并干燥(Na2SO4)。蒸发溶剂得到半固体,将其色谱分离(SiO2/X4/EtOAc,0-20%)。合并具有正确质量的流分,并蒸发溶剂。将得到的残留物用DCM和MeOH研磨,得到(66)(2.0mg,0.2%产率),mp 243-245℃;1H NMR[(CD3)2SO]δ8.32(d,J=7.6Hz,1H),6.77(brs,2H);HPLC 99.4%;C6H3ClFN3O.0.25MeOH的分析计算值:C,38.38,H,2.06;N,21.49;实测值C,38.32;H,1.85,N,21.54%.
5,6-二氯异唑并[5,4-b]吡啶-3-胺(67)
由2,5,6-三氯烟腈和乙酰氧肟酸在N-甲基吗啉中在室温3天,得到67(3%产率)。1H NMR[(CD3)2SO]δ8.58(s,1H),6.82(brs,2H),HPLC 96.5%,LCMS[M+H]=204/206.
6-氯-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(68)
将纯净的2,6-二氯-4-(三氟甲基)烟腈(102mg,0.42mmol)和乙酰氧肟酸(315mg4.2mmol)混合物加热至120℃反应20hr。然后将冷却的反应混合物用H2O稀释,用K2CO3碱化,萃取至EtOAc中,并将溶液干燥(Na2SO4)。蒸发溶剂并色谱分离残留物(SiO2/石油醚/EtOAc0-20%),得到68(4.0mg,4%产率),1H NMR[(CD3)2SO]δ7.95(d,J=0.6Hz,1H),6.24(brs,2H),HPLC 99.5%,LCMS[M+H]=238.
5-(3-甲氧基丙-1-炔-1-基)异唑并[5,4-b]吡啶-3-胺(69)
将2-氯-5-碘烟腈(277mg,1.05mmol)、CuI(19.8mg,0.104mmol)和PdCl2(PPh3)2(44mg,0.022mmol)的DMF(6.0ml)和Et3N(6.0ml)溶液在N2下在密封管中脱气,然后加入甲基炔丙基醚(1.1ml,910mg,13mmol),并将反应混合物在20℃搅拌2hr。然后将反应混合物用H2O稀释,萃取至EtOAc中并干燥(Na2SO4)。蒸发溶剂并用SiO2/石油醚/EtOAc(0-10%)色谱分离残留物,得到2-氯-5-(3-甲氧基丙-1-炔-1-基)烟腈(103mg,47.4%);1H NMR[(CD3)2SO]δ8.80(d,J=2.3Hz,1H),8.67(d,J=2.3Hz,1H),4.39(s,2H),3.59(s,3H),LCMS[M+H]=207.用20%石油醚/EtOAc进一步洗脱得到双加成的产物
2,5-双((3-甲氧基丙-1-炔-1-基)氧基)烟腈(100mg,40%).1H NMR[(CD3)2SO]δ8.90(d,J=2.1Hz,1H),8.56(d,J=2.1Hz,1H),4.49(s,2H),4.40(s,2H),3.39(s,3H),3.35(s,3H),LCMS[M+H]=241.
2-氯-5-(3-甲氧基丙-1-炔-1-基)烟腈在DMF中与乙酰氧肟酸和KOtBu的类似的闭环以24%产率得到69,mp(DCM/石油醚)183-186℃;1H NMR[(CD3)2SO]δ8.61(d,J=2.1Hz,1H),8.42(d,J=2.1Hz,1H),6.70(brs,2H),4.37(s,2H),3.37(s,3H);HPLC 99.9%;LCMS[M+H]=204,C9H9N3O2的分析计算值:C,59.1,H,4.5,N,20.7;实测值C,59.2,H,4.3;N,20.7%.
方法2.代表性实施例
N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)
向6-氯异唑并[5,4-b]吡啶-3-胺的THF(15ml)溶液中加入40%二甲基胺的水溶液(2mL)。将反应混合物在20℃搅拌4天。在真空下除去过量溶剂,并将得到的沉淀过滤并收集固体。用EtOAc(20mL x3)萃取滤液得到另外的材料。将合并的产物在SiO2上色谱分离,采用0-75%梯度的石油醚/EtOAc洗脱,得到N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)(81mg;77%),为白色固体;mp(DCM/石油醚)238-241℃;1H NMR[(CD3)2SO]δ7.85(d,J=8.8Hz,1H),6.57(d,J=8.8Hz,1H),1.13(s,2H,NH2);3.09[s,6H,N(CH3)2].LCMS[M+H]=179;HPLC 99.7%;C8H10N4O的分析计算值:C,53.9;H,5.7;N,31.4;实测值C,54.1;H,5.6;N,31.5%.
类似地制备以下化合物
N4,N4-二甲基异唑并[5,4-b]吡啶-3,4-二胺(19)
其由4-氯异唑并[5,4-b]吡啶-3-胺以74%产率制备,mp(DCM/MeOH)218-220℃;LCMS[M+H]=179;HPLC 99.9%.HRMS(ESI+)C7H11N4O的计算值179.0927;实测值179.0926.
方法2.其它实施例
一般实验程序
向A(1.0eq)的DMSO溶液中加入B(2.0eq)和KF(3.0eq),并将得到的混合物在微波反应器中在150℃加热2小时。将反应混合物用乙酸乙酯稀释,用水和盐水洗涤,用无水Na2SO4干燥,过滤并浓缩。将残留物通过制备TLC(CH2Cl2/MeOH=20/1)纯化,得到需要的产物。
采用上述方法制备下面的化合物:
方法3.代表性实施例
5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)
将5-氯-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(0.21mg,1.05mmol)的原甲酸三甲酯(3mL)混合物回流20hr。在真空下除去过量的原甲酸三甲酯,然后将残留物溶解在乙醇(10mL)中,并用NaBH4(284mg,7.7mmol)处理,并将混合物在20℃搅拌3hr,然后在50℃搅拌20hr。将反应混合物浓缩,并将残留物在H2O(50mL)中搅拌。将得到的沉淀过滤,并再用水洗涤。将收集的固体通过柱色谱法在SiO2上纯化,采用梯度的0-40%石油醚/EtOAc洗脱。从DCM/石油醚、然后石油醚/EtOAc、最终MeOH/H2O中重结晶,得到产物5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)(50mg,22.5%);mp 167-170℃;1H NMR[(CD3)2SO]δ6.53[(q,J=4.4Hz 1H,NH(CH3)],2.82(d,J=4.9Hz,3H,NCH3);2.62(s,3H,CH3),2.60(s,3H,CH3);LCMS[M+H]=212.5;HPLC 97.5%;C9H10ClN3O的分析计算值:C,51.1;H,4.8;N,19.8;实测值C,51.0;H,4.5;N,19.9%.
方法4.代表性实施例
5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)
向5-氯-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(0.10g,0.506mmol)的HOAc(5mL)混悬液中加入多聚甲醛(0.65g,7.2mmol)和NaBH3CN(0.45g,7.2mmol)。将反应混合物加热至100℃反应2hr,冷却并用aq K2CO3碱化。将得到的沉淀过滤,用H2O洗涤,并在SiO2上色谱分离,采用梯度的0-75%石油醚/DCM洗脱,得到5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)(45mg;39%);mp(DCM/石油醚)112-113℃;1H NMR[(CD3)2SO]δ2.90[s,6H,N(CH3)2],2.65(s,3H,CH3),2.63(s,3H,CH3);LCMS[M+H]=226.5;HPLC 98.3%;C10H12ClN3O的分析计算值:C,53.2;H,5.4;N,18.6;实测值C,53.1;H,5.3;N,18.5%.
方法5.代表性实施例
5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)
将5-溴异唑并[5,4-b]吡啶-3-胺(0.16g,0.76mmol)、(3-甲氧基苯基)硼酸(0.23g,152mmol)和2M K2HPO4(3mL)在1,4-二氧六环(6mL)中的混合物用N2脱气。加入PdCl2(dppf)(50mg,9%mol),并将反应混合物在70℃搅拌加热过夜。在真空下蒸发二氧六环,并将残留物在水和EtOAc之间分配。将合并的有机萃取物干燥(Na2SO4)并蒸发溶剂。将残留物在硅胶上色谱分离,采用0-30%的石油醚/EtOAc梯度洗脱,得到5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)(66mg,36%),mp(EtOAc/石油醚)200-202℃,1H NMR[(CD3)2SO]δ8.83(d,J=2.3Hz,1H),8.59(d,J=2.3Hz,1H),7.45(t,J=8.1Hz,1H),7.28-7.26(m,2H),7.02-7.03(m,1H),7.00-6.99(m,1H),6.68(s,2H,NH2),3.85(s,3H,OCH3),LCMS[M+H]=242,HPLC:98.2%,C13H11N3O2的分析计算值:C,64.7;H,4.6;N,17.4;实测值C,64.7;H,4.6,N,17.4%
类似地制备下述化合物:
5-(2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(23)
其由(2-甲氧基苯基)硼酸以19%产率制备;mp(DCM/石油醚)191-193℃;HPLC98.6%:HRMS(ESI+)C13H12N3O2的计算值242.0924;实测值242.0928.
5-苯基异唑并[5,4-b]吡啶-3-胺(24)
其由5-溴异唑并[5,4-b]吡啶-3-胺和苯基硼酸以13%产率制备;mp(DCM/MeOH)249-252℃;LCMS[M+H]=212;HPLC 99.3%.C7H9N3O.1/4 H2O的分析计算值;C,67.5;H,4.4;N,19.7;实测值;C,67.4;H,4.2;N,19.8%
5-(3-氟-4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(25)
其由(3-氟-4-甲氧基苯基)硼酸以18%产率制备;mp(DCM/MeOH)258-261℃;LCMS[M+H]=260;HPLC 99.6%;C13H10FN3O的分析计算值:C,60.2;H,4.0;N,16.2;实测值C,60.1;H,3.8;N,16.2%.
5-(吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(26)
其由3-吡啶基硼酸以6%产率制备;mp(MeOH)239-242℃;HPLC 98.8%;HRMS(ESI+)C11H9N4O的计算值213.0771;实测值213.0779.
5-(吡啶-4-基)异唑并[5,4-b]吡啶-3-胺(27)
其由4-吡啶基硼酸以6%产率制备;mp(DCM/MeOH)291-294℃;HPLC 98.6%;HRMS(ESI+);C11H9N4O的计算值213.0771;实测值213.0774.
2-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(28)
其由(2-羟基苯基)硼酸以4%产率制备;mp(MeOH/H2O)208-211℃;HPLC 95.7%;HRMS(ESI+)C12H10N3O2的计算值228.0768;实测值228.0771.
4-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(29)
其由(4-羟基苯基)硼酸以4%产率制备;mp(MeOH)272-275℃;HPLC 99.6%.HRMS(ESI+)C12H10N3O2的计算值228.0768;实测值228.0763.
5-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(30)
其由(4-氟苯基)硼酸以16%产率制备;mp(MeOH)235-238℃;HPLC 99.6%;C12H8FN3O的分析计算值:C,62.9;H,3.5;N,18.3;实测值C,62.3;H,3.4;N,18.3%.
5-(3-氟苯基)异唑并[5,4-b]吡啶-3-胺(31)
其由(3-氟苯基)硼酸以38%产率制备;mp(MeOH)233-236℃;HPLC 98.4%;C12H8FN3O的分析计算值:C,62.9;H,3.5;N,18.3;实测值C,62.5;H,3.5;N,18.1%.
5-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(32)
其由(2,4-二氟苯基)硼酸以18%产率制备;mp(MeOH)258-261℃;HPLC 99.5%;C12H7F2N3O的分析计算值:C,58.3;H,2.8;N,17.0;实测值C,58.2;H,2.7;N,16.9%.
5-(3,5-二氟-2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(33)
其由(3,5-二氟-2-甲氧基苯基)硼酸以5%产率制备;mp(MeOH)210-211℃;HPLC99%;HRMS(ESI+)C13H10F2N3O2的计算值278.0737;实测值278.0736.
5-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(34)
其由(2,4-二氯苯基)硼酸以5%产率制备;mp(石油醚/EtOAc)233-236℃;HPLC97%;C12H7Cl2N3O的分析计算值;C 51.4;H,2.5;N,15.0;实测值C,51.3;H,2.6;N,14.8%.
5-(2,3,4-三氯苯基)异唑并[5,4-b]吡啶-3-胺(35)
其由(2,3,4-三氯苯基)硼酸以3%产率制备;mp(DCM/MeOH)250-153℃;HPLC97.5%LCMS[M+H]314和316.HRMS(ESI+)C12H7Cl3N3O的计算值313.9648;实测值313.9649.
5-(4-(三氟甲基苯基)异唑并[5,4-b]吡啶-3-胺(36)
其由(4-三氟甲基苯基)硼酸以17%产率制备;mp(MeOH)267-270℃;HPLC 99.9%;LCMS(M+H)281;C13H8F3N3O的分析计算值:C,55.9;H,3.0;N,15.0;实测值C,55.8;H,2.8;N,15.0%.
5-(3-氨基苯基)异唑并[5,4-b]吡啶-3-胺(37)
其由(3-氨基苯基)硼酸以83%产率制备;mp(MeOH/H2O)220-221℃;HPLC 96.0%;LCMS(M+H)227;C12H10N4O的分析计算值:C,63.7;H,4.5;N,24.8;C,64,H,4.5;N,24.5%.
3-(3-氨基异唑并[5,4-b]吡啶-5-基)苯甲酸甲酯(38)
其由(3-(甲氧基羰基)苯基)硼酸以28%产率制备;mp(MeOH)221-223℃;HPLC98.2%;LCMS(M+H)270;C14H11N3O3的分析计算值:C,62.4;H,4.1;N,15.6;实测值C,62.1;H,4.1;N,15.6%.
5-(6-氟吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(39)
其由(6-氟吡啶-3-基)硼酸以37%产率制备;mp(MeOH)278-281℃;HPLC 99.4%;HRMS(ESI+)C11H8FN4O的计算值231.0677;实测值231.0680.
5-(2-氯-4-(三氟甲基)苯基)异唑并[5,4-b]吡啶-3-胺(40)
其由(2-氯-4-(三氟甲基)苯基)硼酸以8.2%产率制备;mp(MeOH)195-198℃;LCMS[M+H]=314;HPLC 98.5%;C13H7ClF3N3O的分析计算值:C,49.2;H,2.2;N,13.4;实测值C,49.7;H,2.1;N,13.3%.
方法6.代表性程序和其它实施例
6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(70)
将2,6-二氯烟酸(1.0g,5.21mmol)、4-甲氧基苯基硼酸(0.96g,1.15mmol,1.2eq)K2CO3(2.5g,3.5eq)的二甲氧基乙烷(6ml)、EtOH(6ml)和H2O(6ml)混合物用N2脱气,然后加入Pd(dppf)Cl2(180mg),并将反应混合物在N2下回流2hr。将混合物蒸发至干,并将得到的固体在EtOAc中搅拌并过滤。将收集的固体溶解在小量的水中,并将溶液小心地用2M HCl酸化。将得到的沉淀过滤,并将母液用EtOAc进一步萃取并干燥(Na2SO4)。蒸发溶剂得到另外的材料。将两份固体合并,并从MeOH/DCM中重结晶,得到2-氯-6-(4-甲氧基苯基)烟酸(196mg,16%);1H NMR[(CD3)2SO]δ13.62(br,1H,CO2H),8.25(d,J=8.1Hz,1H),8.09(d,J=8.9Hz,2H),8.03(s,J=8.1Hz,1H),7.09(d,J=8.9Hz,2H),3.84(s,3H,OCH3)。其没有进一步纯化即直接使用。
将具有微量DMF的2-氯-6-(4-甲氧基苯基)烟酸(196mg,0.74mmol)和SOCl2(10ml)的混合物回流2h。在真空下除去过量的SOCl2,并将得到的残留物溶解在干燥1,4-二氧六环中,并在冰中冷却。加入NH3水溶液(10ml),并将溶液在室温搅拌20h。在真空下除去溶剂,并将得到的沉淀过滤,用水洗涤并干燥,得到2-氯-6-(4-甲氧基苯基)烟酰胺(153mg 78%);1H NMR[(CD3)2SO]δ8.05(d,J=8.6Hz,2H),8.01(brs,1H),7.98-7.91(m,2H),7.73(brs,1H),7.07(d,J=8.6Hz,2H),3.83(s,3H)。其没有进一步纯化即直接使用。
将2-氯-6-(4-甲氧基苯基)烟酰胺(153mg,0.58mmol)在甲苯(3mL)和POCl3(0.5ml)的混合物中回流1hr。将反应混合物冷却至20℃,并小心地用aq.K2CO3碱化,并用EtOAc萃取,然后干燥(Na2SO4)。蒸发溶剂并色谱分离残留物(SiO2/0-20%石油醚/EtOAc),得到2-氯-6-(4-甲氧基苯基)烟腈(120mg,84%);1H NMR(CDCl3)δ8.03(d,J=9.0Hz,2H),7.96(d,J=8.2Hz,1H),7.70(d,J=8.2Hz,1H),7.01(d,J=9.0Hz,2H),3.89(s,3H).其没有进一步纯化即使用。
根据一般方法1采用乙酰氧肟酸和KOtBu在DMF中使2-氯-6-(4-甲氧基苯基)烟腈闭环,以57%产率得到(70),mp(DCM/MeOH)249-252℃,1H NMR[(CD3)2SO]δ8.29(d,J=8.2Hz,1H),8.12(brd,J=9.0Hz,2H),7.90(d,J=8.2Hz,1H),7.08(brd,J=9.0Hz,2H),6.60(s,2H,NH2),3.84(s,3H,OCH3);HPLC 96.4%;LCMS[M+H]=242.5;C13H11N3O2的分析计算值:C,64.7;H,4.6,N,17.4;实测值C,64.4;H,4.4;N,17.4%.
6-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(71)
2,6-二氯烟酸与(4-氟苯基)硼酸进行类似的Suzuki偶联,以49%产率得到2-氯-6-(4-氟氟苯基)烟酸;1H NMR[(CD3)2SO]δ13.72(br s,1H),8.31(d,J=8.1Hz,1H),8.19(brdd,J=9.0,5.5Hz,1H),8.10(d,J=8.1Hz,1H),7.38(t,J=8.9Hz,1H),其没有进一步纯化即直接使用。
2-氯-6-(4-氟苯基)烟酸与亚硫酰氯反应,随后与aq.NH3反应,得到2-氯-6-(4-氟苯基)烟酰胺;1H NMR[(CD3)2SO]δ8.17-8.13(m,2H),8.05-8.36(m,2H),7.98(d,J=7.9Hz,1H),7.67(br s,1H),7.38-7.34(m,2H)。将其在POCl3/甲苯中回流,经两步以83%产率得到2-氯-6-(4-氟苯基)烟腈;1H NMR[(CD3)2SO]δ8.55(d,J=8.2Hz,1H),8.26-8.21(m,3H),7.43-7.37(m,2H).
2-氯-6-(4-氟苯基)烟腈与乙酰氧肟酸和KOtBu在DMF中反应以21%产率得到(71),MP(DCM/石油醚)265-268℃;1H NMR[(CD3)2SO]δ8.35(d,J=8.2Hz,1H),8.22(dd,J=9.0,5.5Hz,2H),7.96(d,J=8.2Hz,1H),7.37(t,J=8.0Hz,2H),6.65(s,2H);HPLC 99.8%;C12H8FN3O的分析计算值;C,61.7;H,3.7;N,18.0;实测值C,61.8;H,3.6;N,18.1%.
6-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(72)
2,6-二氯烟酸与(2,4-二氯苯基)硼酸进行类似的Suzuki偶联,随后用亚硫酰氯和NH3水溶液处理,得到2-氯-6-(2,4-二氯苯基)烟酰胺。其与POCl3/甲苯在回流下反应,以15%总产率得到2-氯-6-(2,4-二氯苯基)烟腈;1H NMR[(CD3)2SOδ8.61(d,J=8.0Hz,1H),7.98(d,J=8.1Hz,1H),7.85(d,J=2.0Hz,1H),7.69(d,J=8.4Hz,1H),7.62(dd,J=8.4,2.0Hz,1H);LCMS[M+H]=279.
2-氯-6-(2,4-二氯苯基)烟腈与乙酰氧肟酸和KOtBu在DMF中反应,以41%产率得到(72),mp(DCM/石油醚)231-233℃;1H NMR[(CD3)2SOδ8.40(d,J=8.0Hz,1H),7.80(d,J=2.0Hz,1H),7.66(d,J=8.3Hz,1H),7.63(d,J=8.0Hz,1H),7.59(dd,J=8.4,2.1Hz,1H),6.73(s,2H);HPLC 99.3%;C12H7Cl2N3O的分析计算值:C,51.5;H,2.5;N,15.0;实测值:C,51.6;H,2.4;N,15.1%
6-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(73)
2,6-二氯烟酸与(2,4-二氟苯基)硼酸进行类似的Suzuki偶联,随后与亚硫酰氯/NH3水溶液反应,得到2-氯-6-(2,4-二氟苯基)烟酰胺,将该材料与POCl3/甲苯在回流下反应,以19%产率得到2-氯-6-(2,4-二氟苯基)烟腈;1H NMR[(CD3)2SO]δ8.57(d,J=8.1Hz,1H),8.08-7.99(m,2H),7.50(ddd,J=11.8,9.2,2.5Hz,1H),7.34-7.29(m,1H).
2-氯-6-(2,4-二氟苯基)烟腈与乙酰氧肟酸和KOtBu在DMF中反应,以74%产率得到(73),mp(DCM/石油醚)235-238℃;1H NMR[(CD3)2SOδ8.39(d,J=8.1Hz,1H),8.04(dt,J=8.9,6.7Hz,1H),7.76(dd,J=8.1,2.0Hz,1H),7.45(ddd,J=11.7,9.3,2.5Hz,1H),7.31-7.26(m,1H),6.71(s,2H);HPLC 97.8%.
6-(2-噻吩基)异唑并[5,4-b]吡啶-3-胺(74)
2,6-二氯烟酸与2-噻吩基硼酸进行类似的Suzuki偶联,随后如上所述修饰产物,得到(74),mp 241-244℃;1H NMR[(CD3)2SO]δ8.28(d,J=8.2Hz,1H),7.96(dd,J=3.7,1.1Hz,1H),7.90(d,J=8.2Hz,1H),7.76(dd,J=5.0,1.1Hz,1H),7.22(dd,J=5.0,3.7Hz,1H),6.6(br s,2H).HPLC 99.2%;LCMS[M+H]=218.
6-(1-甲基-1H-吡唑-5-基)异唑并[5,4-b]吡啶-3-胺(75)
2,6-二氯烟酸与(1-甲基-1H-吡唑-5-基)硼酸进行类似的Suzuki偶联,随后如上所述进行产物修饰,得到(75);1H NMR[CD3OD]δ
8.29(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),7.54(d,J=2.1Hz,1H),6.89(d,J=2.1Hz,1H),4.27(s,3H);HPLC 97%;ESI+实测值216.0872,C10H9N5O要求216.0880.
方法7.代表性实施例
在20℃,向通过将钠(129mg,5.6mmol)加至干燥MeOH(3mL)中形成的溶液中,加入6-氯异唑并[5,4-b]吡啶-3-胺(16mg,0.09mmol),并将溶液在20℃搅拌20hr。然后将反应混合物蒸发至干,并将得到的残留物在H2O(10mL)中搅拌,得到白色沉淀,将其过滤,用H2O洗涤并在100℃干燥,得到6-甲氧基异唑并[5,4-b]吡啶-3-胺(41)(7mg,46%),mp(H2O),213-215℃;1H NMR[(CD3)2SO]δ8.10(d,J=8.5Hz,1H),6.75(d,J=8.5Hz,1H),6.42(bs,2H,NH2),3.91,(s,3H,OCH3),HPLC 99.8%;HRMS(ESI+)C7H8N3O2的计算值166.0611;实测值166.0606.
方法7其它实施例
6-(3-(二甲基氨基)丙氧基)异唑并[5,4-b]吡啶-3-胺(76)
其由6-氯异唑并[5,4-b]吡啶-3-胺和N,N-二甲基氨基丙醇以33%产率类似地制备,mp(DCM/石油醚)164-166℃;1H NMR[(CD3)2SO]δ8.09(d,J=8.5Hz,1H),6.73(d,J=8.5Hz,1H),6.41(brs,2H),4.32(t,J=6.6Hz,2H),2.35(t,J=7.1Hz,2H),2.14(s,6H),1.86(p,J=6.8Hz,1H);HPLC 99.7%;HRMS(ESI+)C11H17N4O2[M+H]的计算值237.1346,实测值237.1346.
6-(2-(二甲基氨基)乙氧基)异唑并[5,4-b]吡啶-3-胺(77)
其由6-氯异唑并[5,4-b]吡啶-3-胺和N,N-二甲基氨基乙醇以43%产率类似地制备,mp DCM/石油醚)168-170℃;1H NMR[(CD3)2SO]δ8.09(d,J=8.5Hz,1H),6.73(d,J=8.5Hz,1H),6.42(brs,2H),4.38(t,J=5.8Hz,2H),2.63(t,J=5.8Hz,2H),2.20(s,6H);HPLC 99.9%;HRMS(ESI+)C10H15N4O2[M+H]的计算值223.1190,实测值223.1197.
6-(2-吗啉代乙氧基)异唑并[5,4-b]吡啶-3-胺(78)
其由6-氯异唑并[5,4-b]吡啶-3-胺和2-吗啉代乙醇以24%产率类似地制备,mp(DCM/石油醚)151-153℃;1H NMR[CD3)2SO]δ8.10(d,J=8.5Hz,1H),6.75(d,J=8.5Hz,1H),6.42(brs 2H),4.42(brm,2H),3.56(brm,4H),2.70(brm,2H),2.40(brm,4H);HPLC99.9%;HRMS(ESI+)C12H17N4O3[M+H]的计算值265.1295,实测值265.1295.
一般方法:
在0℃向B(2.0eq)的DMF溶液中加入NaH(60%在矿物油中的分散体,1.9eq),并将反应混合物在室温搅拌30min。然后加入A(1.0eq),并将得到的混合物在90℃搅拌6-16h(通过TLC监测)。将反应混合物用乙酸乙酯稀释,并用水和盐水洗涤。将有机层用无水Na2SO4干燥,过滤并浓缩,得到粗产物,将其通过柱色谱法在硅胶上纯化(石油醚/乙酸乙酯=3/1),得到希望的产物。
通过该一般方法制备下面的化合物C:
方法8.代表性程序
6-(甲硫基)异唑并[5,4-b]吡啶-3-胺(79)和6-(甲基磺酰基)异唑并[5,4-b]吡啶-3-胺(80)
使6-氯异唑并[5,4-b]吡啶-3-胺与3当量的硫甲醇钠在DMF中在室温反应18h,以68%产率得到(79),mp(DCM/MeOH)230-233℃;1H NMR[(CD3)2SO]δ8.07(d,J=8.2Hz,1H),7.24(d,J=8.2Hz,1H),6.53(brs,2H),2.56(s,CH3);HPLC 99.3%;HRMS(ESI+)C7H8N3OS[M+H]的计算值182.0383;实测值182.0380.
向(79)(18mg,0.1mmol)的THF(3.0mL)溶液中加入过乙酸(0.5mL 32%在乙酸中的溶液),并将反应混合物在20℃搅拌30hr。在20℃蒸发溶剂,并将残留物用H2O稀释,用K2CO3碱化,萃取至EtOAc中并用Na2SO4干燥。蒸发溶剂并使残留物从DCM/石油醚中结晶,得到(80)(19mg,89%产率),mp(DCM/石油醚)231-234℃;1H NMR[(CD3)2SO]δ8.65(d,J=7.9Hz,1H),8.04(d,J=7.94Hz,1H),6.96(brs,2H),3.35(s,CH3);HPLC 98.5%;LCMS实测值[M+H]=214.
3-氨基异唑并[5,4-b]吡啶-6-甲酸(81)
在0℃,将6-甲基异唑并[5,4-b]吡啶-3-胺(48mg,0.32mmol)溶解在浓H2SO4(5mL)中,然后加入CrO3(160mg,1.6mmol),并在20℃持续搅拌20hr。然后使混合物在冰中搅拌,并将得到的沉淀过滤,用H2O洗涤,然后用石油醚/DCM的1:1混合物洗涤,然后在烘箱中干燥,得到81(8.0mg,14%);1H NMR[(CD3)2SO]δ12.78(br,1H),8.45(d,J=7.9Hz,1H),8.02(d,J=7.9Hz,1H),6.81(brs,2H).HPLC 96%.LCMS实测值[M+H]=178.
3-氨基异唑并[5,4-b]吡啶-6-甲酸甲酯(82)
在0℃,将6-甲基异唑并[5,4-b]吡啶-3-胺(248mg,1.66mmol)溶解在冷却的浓H2SO4(10ml)中,然后加入CrO3(350mg,3.5mmol),并将混合物在20℃搅拌3天。冷却至0℃后,加入MeOH(1ml),并在20℃连续搅拌20hr。将混合物用水稀释,萃取至EtOAc中。将合并的萃取物干燥(Na2SO4),并蒸发溶剂,然后用HPLC分离残留物,得到82(44mg),1H NMR[(CD3)2SO]δ8.48(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),6.84(brs,2H),3.92(s,3H)C8H7N3O3的分析计算值:C,49.7;H,3.6;N,21.7;实测值C,49.8;H,3.5;N,21.8%.HPLC 99.6%.
IDO1活性的酶测定
从用pREP4和pQE9-IDO质粒转化的大肠杆菌EC538菌株的培养物中表达和纯化重组人IDO1(rhIDO1)。将反应混合物置于含有50mM磷酸盐缓冲液、10mM抗坏血酸、10μM亚甲基蓝、100μg/mL过氧化氢酶、80μM TRP、0.01%Tween 20(v/v)和rhIDO1(15μL)(终浓度为9nM)的384孔微孔板中,总体积为30μL测定培养基。将板在37℃下孵育30分钟,通过加入哌啶(200mM)终止酶促反应,并在65℃下加热20分钟。在λex400nm和λem500nm处读取荧光强度。将测试化合物溶解于100%DMSO中,并在添加rhIDO1之前在测定培养基中预稀释。IDO1抑制(%)计算为
所有实验一式三份进行,统计分析在Prism v5(Graphpad Software,Inc.,LaJolla,CA,USA)中进行。
用于IDO1抑制的基于细胞的测定
为了测定细胞IDO1活性的抑制,将转染以表达人IDO1(LLTC-hIDO1)或鼠(LLTC-mIDO1)的Lewis肺癌细胞在37℃、5%CO2下与测试化合物培养24小时。然后将来自各孔的培养物上清液转移到新鲜的平底96孔板中,与三氯乙酸(10%终浓度)混合,并在60℃下孵育20分钟。然后将板离心(在2500g下10分钟),然后将上清液转移并与4-(二甲基氨基)苯甲醛(20mg/mL,在乙酸中)在新板中1:1混合。在480nm处读取每个孔的吸光度,并计算抑制50%细胞酶活性的浓度。
使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)比色法测定相同实验中每个孔中细胞的活力。除去用于测定IDO1抑制的上清液后,将细胞与MTT(500μg/mL)一起温育直到观察到晶体形成。将板以2500g离心15分钟,然后弃去所有孔中的上清液。加入DMSO(100μL/孔)以溶解晶体,然后在570nm测量每个孔中的吸光度。每个孔中的细胞活力表示为未处理对照的百分比。除非另有说明,对于所有实验,使用一式三份培养物。
测定结果如下表所示。
化合物活性
活性IC50范围:A;<1μM,B;1-10μM,C;10-100μM,D;>100μM
用于TDO抑制的基于细胞的测定
对于细胞TDO的抑制测定,转染以过表达全长人TDO的GL261细胞在37℃、5%CO2下与测试化合物一起培养24小时。然后将来自各孔的培养物上清液转移到新鲜的平底96孔板中,并且如上对于IDO1测定所述测定犬尿氨酸含量,并计算抑制50%细胞酶活性的浓度。
使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)比色法测定相同实验中每个孔中细胞的活力。
测定结果如下表所示。
化合物活性
活性IC50范围:A;<1μM,B;1-10μM,C;10-100μM,D;>100μM
肿瘤生长抑制的测定
将肿瘤皮下植入同基因C57BI/6小鼠,当肿瘤大小达到约3×3mm时分配到不同的治疗组。将化合物溶于DMSO中,每日ip或sc注射给药体积为50ml的剂量。每隔一天测量肿瘤,并监测小鼠,直到达到人道伦理终点。
对于化合物3,研究结果显示的图1中,使用已经转染以产生人IDO1的Lewis LungTC癌细胞系。肿瘤体积以mm3表示。每组N=7。*表示重复测量单因素Anova的显著性。
犬尿氨酸与色氨酸比值(K:T)的变化的测定。
具有16天皮下GL-261-hIDO1肿瘤(肿瘤大小15-20mm)的小鼠的血浆和肿瘤中的K:T比值通过分析HPLC在用150mg/kg化合物3处理后0.25h、1h、2h、4h、6h和24h测定,每个时间点n=3。在DMSO处理后0.25h、1h、2h、4h、6h和24h,从3只小鼠收集DMSO溶媒对照组(n=21)。*和**表示与DMSO对照相比,通过单因素ANOVA和Sidak多重比较的显著性(分别为p<0.05,p<0.01)。
本研究的结果如图2所示。
与免疫检查点阻断组合的协同作用的测定。
图3显示了用下列物质处理的具有sc GL261-hIDO1肿瘤的小鼠的研究的至人道伦理终点的存活:溶媒(A);化合物3,75mg/kg(B)IP每日,肿瘤植入后8天开始;针对抗-PD1(顶部:肿瘤植入后第8、11和14天,250μg/小鼠IP)或抗CTLA4(底部:肿瘤植入后6天,1mg/小鼠IP)的抗免疫检查点抗体(C);或化合物3+免疫检查点抗体的组合(D)。P值表示与溶媒存活曲线相比,通过对数秩(Log-rank)分析的显着差异。彩色箭头表示给药方案。
本研究的结果如图3所示。
如本文所使用,“包括”与“含有”、“包含”或“特征在于”同义,并且是包容性的或开放式的,并且不排除另外的未被引用的要素或方法步骤。如本文所用,“由...组成”排除所述权利要求要素中未指定的任何要素、步骤或成分。如本文所使用的,“基本上由...组成”不排除不会实质上影响权利要求的基本和新特性的材料或步骤。在本文的各情况中,任何术语“包括”、“基本上由...组成”和“由...组成”可以用其他两个术语中的任何一个来代替。
当本文公开一组材料、组合物、组分或化合物时,应当理解,这些组的所有个体成员及其所有亚组被分别地公开。当本文使用马库什组或其他分组时,该组的所有个体成员以及组中可能的所有组合和子组合意图被单独包含在本公开中。除非另有说明,本文描述或示例的组分的每种配方或组合均可用于实施本发明。无论何时在说明书中给出范围,例如温度范围、时间范围或组成范围,所有中间范围和子范围以及包括在所给出的范围内的所有个体值意图被包括在本公开中。在本公开和权利要求中,“和/或”是附加地或替代地。而且,单数术语的任何使用也包括复数形式。
本文引用的所有参考文献以没有与本说明书的公开不一致的程度通过引用整体并入本文。本文提供的一些参考文献通过引用并入本文,以提供关于原料、其它原料、其它试剂、其它合成方法、其它分析方法、其它生物材料、其它细胞和本发明的其它用途的来源的细节。本文使用的所有标题仅为方便起见。本说明书中提到的所有专利和出版物都指示本发明所属领域技术人员的水平,并且通过引用并入本文,其程度如同每个单独的出版物、专利或专利申请被具体和单独指出而并入本文作为参考。本文引用的参考文献通过引用整体并入本文以指示其出版或提交日时的技术状态,并且如果需要,可以在本文中使用该信息来排除现有技术中的具体实施方案。
Claims (39)
1.药物组合物,其包含:
式I化合物或其药学上可接受的盐,其中:
W是CR1、N或N-氧化物;
X是CR2、N或N-氧化物;
Y是CR3、N或N-氧化物;
Z是CR4、N或N-氧化物;
并且其中至少W、X、Y和Z之一是N或N-氧化物;
R1、R2、R3和R4各自独立地选自下列基团:H、卤代、R、-OH、-OR、-OC(O)H、-OC(O)R、-OC(O)NH2、-OC(O)NHR、-OC(O)NRR、-OP(O)(OH)2、-OP(O)(OR)2、-NO2、-NH2、-NHR、-NRR、-NHC(O)H、-NHC(O)R、-NRC(O)R、-NHC(O)NH2、-NHC(O)NRR、-NRC(O)NHR、-SH、-SR、-S(O)H、-S(O)R、-SO2R、-SO2NH2、-SO2NHR、-SO2NRR、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-C≡CH、-C≡CR、-CH=CHR、-CH=CRR、-CR=CHR、-CR=CRR、-CO2H、-CO2R、-CHO、-C(O)R、-C(O)NH2、-C(O)NHR、-C(O)NRR、-CONHSO2H、-CONHSO2R、-CONRSO2R、环状C3-C7烷基氨基、咪唑基、C1-C6烷基哌嗪基、吗啉基和硫代吗啉基;
或R1和R2结合在一起,或R2和R3结合在一起,或R3和R4结合在一起能够形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环任选独立地被1-4个选自R的取代基取代;
各R独立地选自下面的段落(a)和(b)中定义的任何基团:
(a)任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基基团的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR5、-OC(O)R5、-OC(O)NH2、-OC(O)NHR5、-OC(O)NR5R5、-OP(O)(OH)2、-OP(O)(OR5)2、-NO2、-NH2、-NHR5、-NR5R5、-N+(O-)R5R5、-NHC(O)H、-NHC(O)R5、-NR5C(O)R5、-NHC(O)NH2、-NHC(O)NR5R5、-NR5C(O)NHR5、-SH、-SR5、-S(O)H、-S(O)R5、-SO2R5、-SO2NH2、-SO2NHR5、-SO2NR5R5、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R5、-CHO、-C(O)R5、-C(O)NH2、-C(O)NHR5、-C(O)NR5R5、-CONHSO2H、-C(O)NHSO2R5、-C(O)NR5SO2R5、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR7、-OC(O)R7、-OC(O)NH2-OC(O)NHR7、-OC(O)NR7R7、-OP(O)(OH)2、-OP(O)(OR7)2、-NO2、-NH2、-NHR7、-NR7R7、-N+(O-)R7R7、-NHC(O)H、-NHC(O)R7、-NR7C(O)R7、-NHC(O)NH2、-NHC(O)NR7R7、-NR7C(O)NHR7、-SH、-SR7、-S(O)H、-S(O)R7、-SO2R7、-SO2NH2、-SO2NHR7、-SO2NR7R7、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R7、-CHO、-C(O)R7、-C(O)NH2、-C(O)NHR7、-C(O)NR7R7、-CONHSO2H、-C(O)NHSO2R7、-C(O)NR7SO2R7、任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;并且其中所述各芳基和杂芳基基团的一个或多个任选取代基各自独立地选自下列基团:C1-6烷基、C2-6烯基、C2-6炔基或C3-7环烷基、卤代、-OH、-OR8、-OC(O)R8、-OC(O)NH2、-OC(O)NHR8、-OC(O)NR8R8、-OP(O)(OH)2、-OP(O)(OR8)2、-NO2、-NH2、-NHR8、-NR8R8、-N+(O)R8R8、-NHC(O)H、-NHC(O)R8、-NR8C(O)R8、-NHC(O)NH2、-NHC(O)NR8R8、-NR8C(O)NHR8、-SH、-SR8、-S(O)H、-S(O)R8、-SO2R8、-SO2NH2、-SO2NHR8、-SO2NR8R8、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R8、-CHO、-C(O)R8、-C(O)NH2、-C(O)NHR8、-C(O)NR8R8、-CONHSO2H、-C(O)NHSO2R8和-C(O)NR8SO2R8;其中各R5、R7和R8独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;且其中所述一个或多个任选的取代基各自独立地选自与对于R的在上面(a)中所定义的那些相同的任选取代基;
R9和R10各自独立地选自下面段落(a)和(b)中所定义的任何基团:
(a)H、任选取代的C1-6烷基基团、任选取代的C2-6烯基基团、任选取代的C2-6炔基基团和任选取代的C3-7环烷基基团;其中所述各烷基、烯基、炔基和环烷基的一个或多个任选取代基各自独立地选自下列基团:卤代、-OH、-OR11、-OC(O)R11、-OC(O)NH2、-OC(O)NHR11、-OC(O)NR11R11、-OP(O)(OH)2、-OP(O)(OR11)2、-NO2、-NH2、-NHR11、-NR11R11、-N+(O)R11R11、-NHC(O)H、-NHC(O)R11、-NR11C(O)R11、-NHC(O)NH2、-NHC(O)NR11R11、-NR11C(O)NHR11、-SH、-SR11、-S(O)H、-S(O)R11、-SO2R11、-SO2NH2、-SO2NHR11、-SO2NR11R11、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R11、-CHO、-C(O)R11、-C(O)NH2、-C(O)NHR11、-C(O)NR11R11、-CONHSO2H、-C(O)NHSO2R11、-C(O)NR11SO2R11、环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基;其中基团环状C3-C7烷基氨基、咪唑基、哌嗪基、吗啉基、硫代吗啉基、哌啶基、氮杂环庚烷基、吡咯烷基和氮杂环丁烷基各自任选被一个或多个下列基团取代:C1-6烷基、C2-6烯基、C2-6炔基、C3-7环烷基、卤代、-OH、-OR13、-OC(O)R13、-OC(O)NH2、-OC(O)NHR13、-OC(O)NR13R13、-OP(O)(OH)2、-OP(O)(OR13)2、-NO2、-NH2、-NHR13、-NR13R13-N+(O)R13R13、-NHC(O)H、-NHC(O)R13、-NR13C(O)R13、-NHC(O)NH2、-NHC(O)NR13R13、-NR13C(O)NHR13、-SH、-SR13、-S(O)H、-S(O)R13、-SO2R13、-SO2NH2、-SO2NHR13、-SO2NR13R13、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R13、-CHO、-C(O)R13、-C(O)NH2、-C(O)NHR13、-C(O)NR13R13、-CONHSO2H、-C(O)NHSO2R13和-C(O)NR13SO2R13;其中各R11和R13独立地选自C1-6烷基基团、C2-6烯基基团、C2-6炔基基团和C3-7环烷基基团;和
(b)任选取代的芳基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团;且其中所述各芳基和杂芳基的一个或多个任选取代基各自独立地选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基;
或
(c)R9和R10结合在一起能够形成部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1至3个选自O、N和S的杂原子,并且所述环能够任选独立地被1-5个取代基取代,所述取代基选自与对于R9和R10的在上面(a)中所定义的那些相同的任选取代基;
和药学上可接受的载体。
2.根据权利要求1所述的药物组合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3。
3.根据权利要求1所述的药物组合物,其中X是N或N-氧化物例如N,W是CR1,Y是CR3且Z是CR4。
4.根据权利要求1所述的药物组合物,其中X和Z都是N或N-氧化物例如N,W是CR1且Y是CR3。
5.根据权利要求1-4中任何一项所述的药物组合物,其中R1、R2、R3和R4,当存在时,各自独立地选自H、卤素、任选取代的C1-C6烷基、其中R选自任选取代的C1-C6烷基和任选取代的芳基(例如苯基)的-O-R、其中R是任选取代的芳基的–NHR、任选取代的芳基和具有至多12个碳原子并且在其环系统具有一个或多个各自独立地选自O、N和S的杂原子的任选取代的杂芳基基团。
6.根据权利要求5所述的药物组合物,其中R1、R2、R3和R4,当存在时,各自独立地选自H、卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的–OR和其中R是任选取代的芳基的–NHR。
7.根据权利要求5所述的药物组合物,其中R1、R2、R3和R4的一个或两个,当存在时,是H,且不是H的其它R1、R2、R3和R4独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
8.根据权利要求5-7中任何一项所述的药物组合物,其中R3存在并且选自卤素、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
9.根据权利要求2所述的药物组合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,且R3选自卤素、其中R是任选取代的芳基的-O-R和其中R是任选取代的芳基的–NHR。
10.根据权利要求2所述的药物组合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,R1是H,且R2和R3之一或两者不是H。
11.根据权利要求10所述的药物组合物,其中不是H的R2和R3各自独立地选自卤素、任选取代的C1-C6烷基、其中R选自任选取代的C1-C6烷基和任选取代的芳基的-OR、其中R是任选取代的芳基的-NHR;任选取代的芳基例如取代的苯基、和任选取代的杂芳基基团。
12.根据权利要求10所述的药物组合物,其中不是H的R2和R3各自独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
13.根据权利要求1-4中任何一项所述的药物组合物,其中R1和R2结合在一起,或R2和R3结合在一起,或R3和R4结合在一起形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1-3个选自O、N或S的杂原子并且所述环任选被1-4个独立地选自R的取代基取代,R1、R2、R3和R4的不是环的部分的那些部分独立地选自:H、卤代、任选取代的C1-C6烷基、其中R是任选取代的C1-C6烷基的O-R、任选取代的芳基和具有至多12个碳原子并且在其环系统具有一个或多个各自独立地选自O、N和S的杂原子的任选取代的杂芳基基团。
14.根据权利要求1-13中任何一项所述的药物组合物,其中R9和R10独立地选自H、任选取代的C1-6烷基基团、任选取代的芳基例如取代的苯基和具有至多12个碳原子且在其环系统中具有一个或多个各自独立选自O、N和S的杂原子的任选取代的杂芳基基团。
15.根据权利要求1-14中任何一项所述的药物组合物,其中R9和R10都是H。
16.根据权利要求2所述的药物组合物,其中Z是N或N-氧化物例如N,W是CR1,X是CR2且Y是CR3,且R9和R10都是H。
17.根据权利要求16所述的药物组合物,其中R1、R2和R3各自独立地选自H、卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
18.根据权利要求16所述的药物组合物,其中R1、R2和R3中的一个或两个是H,且不是H的其它R1、R2和R3独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
19.根据权利要求16所述的药物组合物,其中R1是H,且R2和R3中的一个或两个不是H,其中不是H的R2和R3各自独立地选自卤素、-CF3、-CHF2、-OCF3、-OCHF2、C1-6烷基例如甲基、取代的芳基、取代的杂芳基、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的-NHR。
20.根据权利要求16所述的药物组合物,其中R3选自卤素、其中R是任选取代的芳基的-OR和其中R是任选取代的芳基的–NHR。
21.根据权利要求16所述的药物组合物,其中R1是H,且R2和R3形成饱和的或部分饱和的或完全不饱和的5-或6-元碳原子环,其任选包含1-3个选自O、N和S的杂原子,并且所述环任选被1-4个独立选自R的取代基取代。
22.根据权利要求1所述的药物组合物,其中所述式I化合物选自:
5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)
异唑并[5,4-b]吡啶-3-胺(2)
5-氯-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(3)
4,6-二甲基异唑并[5,4-b]吡啶-3-胺(4)
4,5,6-三甲基异唑并[5,4-b]吡啶-3-胺(5)
5-溴异唑并[5,4-b]吡啶-3-胺(6)
6-甲基异唑并[5,4-b]吡啶-3-胺(7)
5-氯异唑并[5,4-b]吡啶-3-胺(8)
异唑并[5,4-b]喹啉-3-胺(9)
5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(10)
6-氯异唑并[5,4-b]吡啶-3-胺(11)
异唑并[5,4-d]嘧啶-3-胺(12)
4-苯基异唑并[5,4-b]吡啶-3-胺(13)
5-氟异唑并[5,4-b]吡啶-3-胺(14)
6-苯基异唑并[5,4-b]吡啶-3-胺(15)
5-碘异唑并[5,4-b]吡啶-3-胺(16)
异唑并[4,5-c]吡啶-3-胺(17)
N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)
N4,N4-二甲基异唑并[5,4-b]吡啶-3,4-二胺(19)
5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)
5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)
5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)
5-(2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(23)
5-苯基异唑并[5,4-b]吡啶-3-胺(24)
5-(3-氟-4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(25)
5-(吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(26)
5-(吡啶-4-基)异唑并[5,4-b]吡啶-3-胺(27)
2-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(28)
4-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(29)
5-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(30)
5-(3-氟苯基)异唑并[5,4-b]吡啶-3-胺(31)
5-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(32)
5-(3,5-二氟-2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(33)
5-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(34)
5-(2,3,4-三氯苯基)异唑并[5,4-b]吡啶-3-胺(35)
5-(4-(三氟甲基苯基)异唑并[5,4-b]吡啶-3-胺(36)
5-(3-氨基苯基)异唑并[5,4-b]吡啶-3-胺(37)
3-(3-氨基异唑并[5,4-b]吡啶-5-基)苯甲酸甲酯(38)
5-(6-氟吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(39)
5-(2-氯-4-(三氟甲基)苯基)异唑并[5,4-b]吡啶-3-胺(40)
6-甲氧基异唑并[5,4-b]吡啶-3-胺(41)
6-氯-4-甲基异唑并[5,4-b]吡啶-3-胺(42)
异唑并[5,4-b]吡啶-3,6-二胺(43)
5-甲基异唑并[5,4-b]吡啶-3-胺(44)
5,6-二甲基异唑并[5,4-b]吡啶-3-胺(45)
6-甲基-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(46)
6-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(47)
6-异丙基异唑并[5,4-b]吡啶-3-胺(48)
5-硝基异唑并[5,4-b]吡啶-3-胺(49)
3-氨基-6-(三氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(50)
4-甲氧基异唑并[5,4-b]吡啶-3-胺(51)
5-(二氟甲氧基)-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(52)
3-氨基-6-甲基异唑并[5,4-b]吡啶-5-甲酸乙酯(53)
3-氨基-6-(二氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(54)
5-氟-6-吗啉代异唑并[5,4-b]吡啶-3-胺(55)
N6-环丙基-5-氟异唑并[5,4-b]吡啶-3,6-二胺(56)
5-氟-N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(57)
6-(呋喃-2-基)异唑并[5,4-b]吡啶-3-胺(58)
6,7-二氢-5H-环戊二烯并[b]异唑并[4,5-e]吡啶-3-胺(59)
6,7,8,9-四氢-5H-环庚三烯并[b]异唑并[4,5-e]吡啶-3-胺(60)
6,6-二甲基-5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(61)
7,8-二氢-5H-异唑并[5,4-b]吡喃并[3,4-e]吡啶-3-胺(62)
6-(甲硫基)异唑并[5,4-d]嘧啶-3-胺(63)
6-甲基异唑并[5,4-d]嘧啶-3-胺(64)
4-(甲硫基)-6-苯基异唑并[5,4-d]嘧啶-3-胺(65)
6-氯-5-氟异唑并[5,4-b]吡啶-3-胺(66)
5,6-二氯异唑并[5,4-b]吡啶-3-胺(67)
6-氯-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(68)
5-(3-甲氧基丙-1-炔-1-基)异唑并[5,4-b]吡啶-3-胺(69)
6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(70)
6-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(71)
6-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(72)
6-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(73)
6-(2-噻吩基)异唑并[5,4-b]吡啶-3-胺(74)
6-(1-甲基-1H-吡唑-5-基)异唑并[5,4-b]吡啶-3-胺(75)
6-(3-(二甲基氨基)丙氧基)异唑并[5,4-b]吡啶-3-胺(76)
6-(2-(二甲基氨基)乙氧基)异唑并[5,4-b]吡啶-3-胺(77)
6-(2-吗啉代乙氧基)异唑并[5,4-b]吡啶-3-胺(78)
6-(甲硫基)异唑并[5,4-b]吡啶-3-胺(79)
6-(甲基磺酰基)异唑并[5,4-b]吡啶-3-胺(80)
3-氨基异唑并[5,4-b]吡啶-6-甲酸(81)
3-氨基异唑并[5,4-b]吡啶-6-甲酸甲酯(82)
6-苯氧基异唑并[5,4-b]吡啶-3-胺(83)
6-(2-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(84)
6-(3-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(85)
6-(4-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(86)
6-(2-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(87)
6-(3-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(88)
6-(4-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(89)
6-(2-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(90)
6-(3-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(91)
6-(4-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(92)
6-(3-(三氟甲基)苯氧基)异唑并[5,4-b]吡啶-3-胺(93)
N6-苯基异唑并[5,4-b]吡啶-3,6-二胺(94)
N6-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(95)和
N6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(96),
和其药学上可接受的盐。
23.根据前述权利要求中任何一项所述的药物组合物,其中所述式I化合物是IDO1抑制剂。
24.根据权利要求1-22中任何一项所述的药物组合物,其中所述式I化合物是TDO抑制剂。
25.如权利要求1-22中任何一项所定义的药物组合物,其中所述式I化合物是IDO1抑制剂和TDO抑制剂。
26.如权利要求1中所定义的式I化合物,其选自以下化合物:
5-溴-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(1)
4,5,6-三甲基异唑并[5,4-b]吡啶-3-胺(5)
5-氯异唑并[5,4-b]吡啶-3-胺(8)
4-苯基异唑并[5,4-b]吡啶-3-胺(13)
5-氟异唑并[5,4-b]吡啶-3-胺(14)
6-苯基异唑并[5,4-b]吡啶-3-胺(15)
5-碘异唑并[5,4-b]吡啶-3-胺(16)
N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(18)
N4,N4-二甲基异唑并[5,4-b]吡啶-3,4-二胺(19)
5-氯-N3,4,6-三甲基异唑并[5,4-b]吡啶-3-胺(20)
5-氯-N3,N3,4,6-四甲基异唑并[5,4-b]吡啶-3-胺(21)
5-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(22)
5-(2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(23)
5-(3-氟-4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(25)
5-(吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(26)
5-(吡啶-4-基)异唑并[5,4-b]吡啶-3-胺(27)
2-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(28)
4-(3-氨基异唑并[5,4-b]吡啶-5-基)苯酚(29)
5-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(30)
5-(3-氟苯基)异唑并[5,4-b]吡啶-3-胺(31)
5-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(32)
5-(3,5-二氟-2-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(33)
5-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(34)
5-(2,3,4-三氯苯基)异唑并[5,4-b]吡啶-3-胺(35)
5-(4-(三氟甲基苯基)异唑并[5,4-b]吡啶-3-胺(36)
5-(3-氨基苯基)异唑并[5,4-b]吡啶-3-胺(37)
3-(3-氨基异唑并[5,4-b]吡啶-5-基)苯甲酸甲酯(38)
5-(6-氟吡啶-3-基)异唑并[5,4-b]吡啶-3-胺(39)
5-(2-氯-4-(三氟甲基)苯基)异唑并[5,4-b]吡啶-3-胺(40)
6-氯-4-甲基异唑并[5,4-b]吡啶-3-胺(42)
异唑并[5,4-b]吡啶-3,6-二胺(43)
5-甲基异唑并[5,4-b]吡啶-3-胺(44)
5,6-二甲基异唑并[5,4-b]吡啶-3-胺(45)
6-甲基-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(46)
6-异丙基异唑并[5,4-b]吡啶-3-胺(48)
5-硝基异唑并[5,4-b]吡啶-3-胺(49)
3-氨基-6-(三氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(50)
4-甲氧基异唑并[5,4-b]吡啶-3-胺(51)
5-(二氟甲氧基)-4,6-二甲基异唑并[5,4-b]吡啶-3-胺(52)
3-氨基-6-甲基异唑并[5,4-b]吡啶-5-甲酸乙酯(53)
3-氨基-6-(二氟甲基)异唑并[5,4-b]吡啶-5-甲酸乙酯(54)
5-氟-6-吗啉代异唑并[5,4-b]吡啶-3-胺(55)
N6-环丙基-5-氟异唑并[5,4-b]吡啶-3,6-二胺(56)
5-氟-N6,N6-二甲基异唑并[5,4-b]吡啶-3,6-二胺(57)
6-(呋喃-2-基)异唑并[5,4-b]吡啶-3-胺(58)
6,7,8,9-四氢-5H-环庚三烯并[b]异唑并[4,5-e]吡啶-3-胺(60)
6,6-二甲基-5,6,7,8-四氢异唑并[5,4-b]喹啉-3-胺(61)
7,8-二氢-5H-异唑并[5,4-b]吡喃并[3,4-e]吡啶-3-胺(62)
6-(甲硫基)异唑并[5,4-d]嘧啶-3-胺(63)
4-(甲硫基)-6-苯基异唑并[5,4-d]嘧啶-3-胺(65)
6-氯-5-氟异唑并[5,4-b]吡啶-3-胺(66)
5,6-二氯异唑并[5,4-b]吡啶-3-胺(67)
6-氯-4-(三氟甲基)异唑并[5,4-b]吡啶-3-胺(68)
5-(3-甲氧基丙-1-炔-1-基)异唑并[5,4-b]吡啶-3-胺(69)
6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3-胺(70)
6-(4-氟苯基)异唑并[5,4-b]吡啶-3-胺(71)
6-(2,4-二氯苯基)异唑并[5,4-b]吡啶-3-胺(72)
6-(2,4-二氟苯基)异唑并[5,4-b]吡啶-3-胺(73)
6-(2-噻吩基)异唑并[5,4-b]吡啶-3-胺(74)
6-(1-甲基-1H-吡唑-5-基)异唑并[5,4-b]吡啶-3-胺(75)
6-(3-(二甲基氨基)丙氧基)异唑并[5,4-b]吡啶-3-胺(76)
6-(2-(二甲基氨基)乙氧基)异唑并[5,4-b]吡啶-3-胺(77)
6-(2-吗啉代乙氧基)异唑并[5,4-b]吡啶-3-胺(78)
6-(甲硫基)异唑并[5,4-b]吡啶-3-胺(79)
6-(甲基磺酰基)异唑并[5,4-b]吡啶-3-胺(80)
3-氨基异唑并[5,4-b]吡啶-6-甲酸(81)
3-氨基异唑并[5,4-b]吡啶-6-甲酸甲酯(82)
6-苯氧基异唑并[5,4-b]吡啶-3-胺(83)
6-(2-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(84)
6-(3-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(85)
6-(4-氯苯氧基)异唑并[5,4-b]吡啶-3-胺(86)
6-(2-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(87)
6-(3-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(88)
6-(4-(三氟甲氧基)苯氧基)异唑并[5,4-b]吡啶-3-胺(89)
6-(2-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(90)
6-(3-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(91)
6-(4-甲氧基苯氧基)异唑并[5,4-b]吡啶-3-胺(92)
6-(3-(三氟甲基)苯氧基)异唑并[5,4-b]吡啶-3-胺(93)
N6-苯基异唑并[5,4-b]吡啶-3,6-二胺(94)
N6-(3-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(95)
N6-(4-甲氧基苯基)异唑并[5,4-b]吡啶-3,6-二胺(96),
和其药学上可接受的盐。
27.如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐在制备药物中的用途。
28.如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐在制备用于治疗温血动物包括人的癌症的药物中的用途。
29.如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐在制备用于治疗温血动物包括人的癌症的药物中的用途,其中所述治疗包括施用式I化合物和一种或多种其它活性剂,所述其它活性剂选自化疗剂、免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂、过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))和放射治疗,并且其中所述其它活性剂在式I化合物施用之前、期间或之后施用。
30.根据权利要求29所述的用途,其中所述其它活性剂包括免疫调节剂。
31.治疗温血动物包括人的癌症的方法,其包括向动物施用治疗有效量的如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐。
32.治疗温血动物包括人的癌症的方法,其中所述方法包括向动物施用治疗有效量的如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐,并且其中所述方法还包括施用一种或多种其它活性剂的步骤,所述其它活性剂选自化疗剂、免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂、过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))和放射治疗,并且其中所述其它活性剂在式I化合物施用之前、期间或之后施用。
33.根据权利要求32所述的方法,其中所述其它活性剂包括免疫调节剂。
34.在有其需要的温血动物包括人中抑制吲哚胺2,3-双加氧酶1(IDO1)的方法,其包括以有效抑制IDO1的量向动物施用如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐,其中所述化合物具有IDO1抑制活性。
35.在有其需要的温血动物包括人中抑制色氨酸-2,3-双加氧酶(TDO)的方法,其包括以有效抑制TDO的量向动物施用如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐,其中所述化合物具有TDO抑制活性。
36.在有其需要的温血动物包括人中抑制IDO1和TDO的方法,其包括以有效抑制IDO1和TDO的量向动物施用如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐,其中所述化合物具有IDO1和TDO抑制活性。
37.药物组合产品或药盒,其包括
(a)如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐,和
(b)一种或多种选自以下的其它活性剂:化疗剂和免疫调节剂例如抗癌疫苗、免疫检查点蛋白的调节剂和过继性T细胞免疫治疗(例如嵌合抗原受体T细胞(CART细胞))。
38.如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐在制备用于治疗选自以下的疾患或病症的药物中的用途:炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障。
39.在温血动物包括人中治疗选自以下的疾患或病症的方法:炎性疾患、感染性疾病、中枢神经系统疾病或病症、冠心病、慢性肾衰竭、麻醉后认知功能障碍、与雌性生殖健康有关的疾患或病症和白内障,其中所述方法包括向动物施用治疗有效量的如权利要求1-26中任何一项所定义的式I化合物或其药学上可接受的盐。
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