CN110577532B - 原肌球蛋白受体激酶抑制剂及其制备方法和应用 - Google Patents
原肌球蛋白受体激酶抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及具有式(I)结构的吡唑并[1,5‑a]嘧啶衍生物、含有式(I)化合物的药物组合物及所述化合物在制备预防或治疗原肌球蛋白受体激酶相关疾病的用途，特别是用于预防或治疗与原肌球蛋白受体激酶相关的癌症的用途。其中式(I)中的各取代基与说明书中的定义相同。
Description
技术领域
本申请属于医药技术领域，具体涉及吡唑并[1,5-a]嘧啶衍生物及其用于疼痛、癌症、炎症相关疾病治疗的用途。
本申请要求中国专利CN201810597223.9(申请日2018年6月8日，发明名称原肌球蛋白受体激酶抑制剂及其制备方法和应用)的优先权。
背景技术
原肌球蛋白受体激酶(Trk)是一个可调节哺乳动物神经系统突触的强度与可塑性的受体酪氨酸激酶家族。Trk受体的激活通过多种信号通路影响神经元的存活和分化，同时也显著影响神经元的功能。Trk受体的共同配体是神经营养因子(neurotrophins)，在神经系统中起关键作用，两两之间的结合是高度特异性的(J.Mol.Biol.1999,90,149)。每种神经营养因子都有对应的不同的亲和力的Trk受体，结合造成Trk受体二聚并磷酸化激活，引起下游信号包括RAS/MAPK/ERK、PLCγ和PI3K/Akt通路等激活，调控细胞存活以及其它功能(Cancers 2018,10,105)。
已经证实Trk/神经营养因子途径的抑制剂在许多疼痛的临床前动物模式中有效。例如，拮抗神经生长因子NGF与TrkA的抗体RN-624在炎性疼痛与神经性疼痛的动物模式中显示有效(Neuroscience 1994,62,327；Eur.J.Neurosci.1999,11,837)。此外，有文献指出，在发炎后，背根神经节中的脑源性神经营养因子(BDNF)水平和TrkB信号传导增加(Brain Research 1997,749,358)。多项研究显示通过抗体抑制BDNF/TrkB途径，减少信号传导，可减缓神经过敏作用与相关疼痛(Molecular Pain 2008,4,27)。目前，已有多种Trk激酶小分子抑制剂显示可用于治疗疼痛(Expert Opin.Ther.Patents 2009,19,305)。
此外，使用NGF抗体或TrkA、B与C的小分子抑制剂阻断神经营养因子/Trk途径在炎性疾病的临床前模型中显示有效，例如，炎性肺部疾病，包括哮喘(Pharmacology&Therapeutics 2008,117,52)、间质性膀胱炎(The Journal of Urology 2005,173,1016)、炎性肠病(包括溃疡性结肠炎与克罗恩氏症(Gut 2000,46,670)、炎性皮肤疾病等(Archives of Dermatological Research 2006,298,31)、湿疹与牛皮癣(J.Investigative Dermatology 2004,122,812)等。
文献报道也显示Trk激酶的过度表达、活化、放大或突变与许多癌症密切相关，包括成神经细胞瘤、卵巢癌、胶质母细胞瘤、肺腺癌、青少年肉瘤、结直肠癌、纤维肉瘤、Spitzoid黑色素瘤、甲状腺癌、肝内胆管细胞癌、大细胞神经内分泌肿瘤、乳头状甲状腺癌、毛细胞性星形细胞瘤、头颈鳞状细胞癌、急性骨髓性白血病、先天性中胚层肾瘤、导管腺癌、胃肠道间质细胞癌、涎腺乳腺样分泌癌(Cancers 2018,10,105)等。在癌症的临床前模型中，Trk A、B与C的小分子抑制剂有效抑制肿瘤生长并阻止肿瘤转移(Cancer Letters2001,169,107；Leukemia 2007,1-10；Cancer Letters 2006,232,90；Cancer Res.2008,68,346)。
发明内容
本发明的目的是提供一种吡唑并[1,5-a]嘧啶类Trk抑制剂。
本发明的另一个目的是提供所述的Trk抑制剂在制备预防或治疗原肌球蛋白受体激酶相关疾病的药物的用途。
为实现本发明的目的，本发明的技术方案如下：
本发明所述的如下式(I)所示的化合物、其立体异构体或其药学上可接受的盐：
R1选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基、C2-C8炔基、-COR5、-SO2R5或-SOR5，任选进一步被一个或多个选自氘、卤素、羟基、氰基、硝基、-NR6R8、-NR6COR7、-COR7、-SO2R7、-SOR7、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基或C2-C8炔基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、硝基、-NR6R8、-NR6COR5、-COR5、-SO2R5、-SOR5、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R5和R7各自独立选自H、C1-C8烷基、C3-C8环烷基或-NR8；
R6和R8各自独立选自H、C1-C8烷基或C3-C8环烷基；
Y为-(CH2)n-或-O(CH2)n-；
n选自0、1、2或3；
作为选择，R1、R2和R4两两间可独立地形成C3-C8环烷基或4-10元杂环基；
R3选自H、氘、卤素、氰基、硝基、C1-C8烷基、C3-C8环烷基或C1-C8烷氧基；
X选自CH或N。
本发明实施方案，其为通式(II)所述的化合物、其立体异构体或其药学上可接受的盐：
R1选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基、C2-C8炔基、-COR5、-SO2R5或-SOR5，任选进一步被一个或多个选自氘、卤素、羟基、氰基、硝基、-NR6R8、-NR6COR7、-COR7、-SO2R7、-SOR7、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基或C2-C8炔基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、硝基、-NR6R8、-NR6COR5、-COR5、-SO2R5、-SOR5、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R5和R7各自独立选自H、C1-C8烷基、C3-C8环烷基或-NR8；
R6和R8各自独立选自H、C1-C8烷基或C3-C8环烷基；
作为选择，R1、R2和R4两两间可独立地形成C3-C8环烷基或4-10元杂环基；
R3选自H、氘、卤素、氰基、硝基、C1-C8烷基、C3-C8环烷基或C1-C8烷氧基；
X选自CH或N。
本发明实施方案，其特征在于：
R1选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基或C2-C8炔基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、-NR6R8、-NR6COR7、-COR7、-SO2R7、-SOR7、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基、C3-C8环烷基、C2-C8烯基或C2-C8炔基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、-NR6R8、-NR6COR5、-COR5、-SO2R5、-SOR5、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R5和R7各自独立选自H、C1-C8烷基、C3-C8环烷基或-NR8；
R6和R8各自独立选自H、C1-C8烷基或C3-C8环烷基；
作为选择，R1、R2和R4两两间可独立地形成C3-C8环烷基或4-10元杂环基；
R3为卤素；X选自CH或N。
本发明实施方案，其特征在于：
R1选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、-NR6R8、-NR6COR7、-COR7、-SO2R7、-SOR7、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、-NR6R8、-NR6COR5、-COR5、-SO2R5、-SOR5、C1-C8烷基、C3-C8环烷基、C1-C8烷氧基或4-10元杂环基的取代基所取代；
R5和R7各自独立选自H、C1-C8烷基、C3-C8环烷基或-NR8；
R6和R8各自独立选自H、C1-C8烷基或C3-C8环烷基；作为选择，R1、R2和R4两两间可独立地形成C3-C8环烷基或4-10元杂环基；
R3为卤素；
X选自CH或N。
本发明实施方案，其特征在于：
R1选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、-SO2R7、C1-C4烷基、C3-C6环烷基或C1-C4烷氧基的取代基所取代；
R7选自H、C1-C8烷基或C3-C8环烷基；
R2和R4各自独立选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、卤素、羟基、氰基、C1-C4烷基、C3-C6环烷基或C1-C4烷氧基的取代基所取代；
作为选择，R1、R2和R4两两间可独立地形成C3-C8环烷基或4-10元杂环基；
R3为卤素；X为CH或N。
本发明实施方案，其特征在于：
R1选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、羟基、卤素、-SO2R7或C1-C4烷氧基的取代基所取代；
R7选自H或C1-C8烷基；R2和R4各自独立选自H、C1-C8烷基或C3-C8环烷基；
作为选择，R1、R2和R4两两间可独立地形成4-10元杂环基；
R3为氟或氯；X选自CH或N。
本发明实施方案，其特征在于：
R1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或环己基，任选进一步被一个或多个选自氘、羟基、F、Cl、-SO2CH3或甲氧基的取代基所取代；
R2和R4各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或环己基；
作为选择，R1、R2和R4两两间可独立地形成吗啉基；
R3为氟或氯；X选自CH或N。
本发明优选方案，化合物、其立体异构体或其药学上可接受的盐，选自如下结构：
更优选地，选自如下结构：
本发明所述的式(I)化合物、其立体异构体或其药学上可接受的盐是新型Trk抑制剂，因而可用于制备预防或治疗与原肌球蛋白受体激酶相关疾病的药物，所述疾病包括但不限于疼痛、癌症、炎症。
本发明进一步提供了所述的式(I)化合物、其立体异构体或其药学上可接受的盐用于预防或治疗癌症的用途。
作为进一步优选的方案，所述癌症包括：成神经细胞瘤、卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病、多发性骨髓瘤、黑色素瘤或间皮瘤、青少年肉瘤、纤维肉瘤、大细胞神经内分泌肿瘤、毛细胞性星形细胞瘤、头颈鳞状细胞癌、先天性中胚层肾瘤、导管腺癌、涎腺乳腺样分泌癌、阑尾癌。
本发明另一方面提供药物组合物，其包括治疗有效剂量的前述式(I)化合物、其立体异构体或其药学上可接受的盐及可药用的载体。
本发明另一方面提供了所述药物组合物在制备预防或治疗癌症药物中的应用。
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
本发明中“C1-C8烷基”指包括1至8个碳原子的直链烷基和含支链烷基，烷基指饱和的脂族烃基团，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
本发明中“环烷基”指饱和单环烃取代基，“C3-C8环烷基”指包括3至8个碳原子的单环环烷基，例如：单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环己基、环庚基、环辛基等；“C3-C6环烷基”指包括3至6个碳原子的单环环烷基，例如：单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环己基等。
本发明中“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，“C2-C8烯基”指含有2-8个碳的直链或含支链烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
本发明中“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，“C2-C8炔基”指含有2-8个碳的直链或含支链炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
本发明中“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“4-10元杂环基”指包含4至10个环原子的环基。单环杂环基的非限制性实施例包含四氢吡喃基、二氢吡喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。本发明中“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。“C1-C8烷氧基”指含1-8个碳的烷基氧基，非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基等。
“卤素”指氟、氯、溴或碘。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明制备步骤中，所用试剂的缩写分别表示：
MTBE 甲基叔丁基醚
Sec-BuLi 仲丁基锂
THF 四氢呋喃
Pd2(dba)3 三(二亚苄基丙酮)二钯
t-Bu3P-HBF4 四氟硼酸三正丁基磷
Hexane 正己烷
EA 乙酸乙酯
DCM 二氯甲烷
DIEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
TEA 三乙胺
(Ph3P)2PdCl2 二氯二三苯基磷钯
HOBt 1-羟基苯并三唑
EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
附图说明
图1实施例1化合物的核磁共振氢谱；
图2实施例2化合物的核磁共振氢谱；
图3实施例3a化合物的核磁共振氢谱；
图4实施例3b化合物的核磁共振氢谱；
图5实施例4化合物的核磁共振氢谱；
图6实施例5化合物的核磁共振氢谱；
图7实施例6化合物的核磁共振氢谱；
图8实施例7a化合物的核磁共振氢谱；
图9实施例7b化合物的核磁共振氢谱；
图10实施例8a化合物的核磁共振氢谱；
图11实施例8b化合物的核磁共振氢谱；
图12实施例9化合物的核磁共振氢谱；
图13实施例10化合物的核磁共振氢谱。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的药材原料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1
(R,13E,14E)-6-环丙基-35-氟-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
步骤1:2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-羧酸(R)-叔丁酯的合成
室温下，向250mL三口瓶中加入吡咯烷-1-羧酸叔丁酯(2.86mL，16.03mmol)、(-)-斯巴丁(4.50g，19.20mmol)和MTBE(35.0mL)，氮气置换三次，缓慢降温至-78℃，待温度稳定后，滴加Sec-BuLi(17.01mL，21.70mmol，1.3N环己烷溶液)，-75℃下搅拌3小时，-65℃条件下缓慢滴加ZnCl2(14.68mL，14.36mmol，1N THF溶液)，降温至-78℃左右搅拌20分钟。升温至室温，氮气保护下，依次加入3-溴-5-氟-2-甲氧基吡啶(3.44g，16.70mmol)，Pd(OAc)2(0.18g，0.84mmol)，t-Bu3P-HBF4(0.28g，1.00mmol)，加毕室温反应16小时。向反应体系滴加氨水1.50mL，室温下搅拌1小时，反应液硅藻土过滤，MTBE(20mL x 3)洗涤，分液，有机相浓缩后柱层析(Hexane:EA＝20:1)，减压、浓缩后得黄色油状物2.60g，收率52.53％。1H NMR(400MHz,Chloroform-d)δ7.84(d,J＝7.2Hz,1H),7.09(dd,J＝29.5,6.1Hz,1H),4.99(dd,J＝52.8,8.0Hz,1H),3.93(s,3H),3.53(m,2H),2.28(m,1H),1.82(m,3H),1.46(s,9H)。
步骤2:(R)-5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶的合成
室温下，向100mL单口瓶中依次加入2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-羧酸(R)-叔丁酯(2.60g，8.77mmol)、三氟乙酸(7.80mL)和二氯甲烷(7.80mL)，室温下搅拌1.5小时，原料反应完全，停止反应。将反应液减压蒸干，得到3.94g黄色油状物，直接投下一步反应。
步骤3:5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯的合成
室温下，向30mL微波封管中加入(R)-5-氟-2-甲氧基-3-(吡咯烷-2-基)吡啶(1.72g，8.78mmol)、5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯(2.38g，10.54mmol)、DIEA(5.25g，40.65mmol)、DMF(19.30mL)，缓慢升温至90℃，搅拌反应15.5h。反应冷却后，加EA(100mL)溶解分散，加水(100mL)洗涤，分液，依次以饱和食盐水(100mL)、饱和碳酸氢钠水溶液(100mL)洗涤，无水硫酸钠干燥，减压蒸干，柱层析(PE:EA＝1:1)得黄色固体1.83g。MS(ESI)m/z:386[M+H]+。1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),8.15(d,J＝5.2Hz,1H),7.91(s,1H),7.04(d,J＝7.2Hz,1H),5.84(d,J＝4.5Hz,1H),5.09(m,1H),4.37(m,2H),4.18–4.11(m,1H),4.02(s,3H),3.96(m,1H),2.47(m,1H),2.04(m,2H),1.95(m,1H),1.42(m,3H)。
步骤4:5-(2-(5-氟代-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯的合成
室温下，向100mL单口瓶中加入5-(2-(5-氟-2-甲氧基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯(1.83g，4.75mmol)、HBr(18.30mL，33％AcOH溶液)，缓慢升温至90℃，搅拌反应4.5小时。加EA(100mL)溶解分散，加水(100mL)洗涤，分液，依次用NaHCO3饱和溶液(100mL)、饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压蒸干。柱层析(DCM:EtOH＝20:1)得黄色固体1.34g。MS(ESI)m/z:372[M+H]+。1H NMR(400MHz,Chloroform-d)δ12.92(br,1H),8.29(s,1H),8.21(d,J＝7.5Hz,1H),7.30(s,1H),7.17(s,1H),6.93(d,J＝4.7Hz,1H),5.13(m,1H),4.37(q,J＝8.7Hz,2H),4.16(m,1H),3.95(m,1H),2.49(m,1H),2.13–2.07(m,2H),1.95(m,1H),1.42(t,J＝8.8Hz,3H)。
步骤5:5-(2-(5-氟代-2-(三氟甲基-磺酰基氧基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯的合成
室温下，向100mL单口瓶中加入5-(2-(5-氟-2-羟基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯(1.34g，3.61mmol)、DMF(13.0mL)，超声分散至全溶。向反应体系中依次加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲基磺酰胺(1.42g，3.97mmol)、TEA(0.44g，4.33mmol)，室温下搅拌反应24小时。向反应体系中加EA(110mL)，依次以饱和NaHCO3溶液(100mL)、水(100mL)、饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压蒸干，柱层析(PE:EA＝1:1)得泡沫状白色固体1.60g。MS(ESI)m/z:504.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.78(d,J＝7.8Hz,1H),8.37(s,1H),8.17(s,1H),7.93(d,J＝8.8Hz,1H),6.69(d,J＝7.8Hz,1H),5.37(m,1H),4.08(m,1H),4.04(q,J＝7.2Hz,2H),3.65(m,1H),2.08(m,3H),1.91(m,1H),1.11(t,J＝7.2Hz,3H)。
步骤6:乙基(S)-5-(2-(5-氟-2-乙烯基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温下，向100mL单口瓶中依次加入5-(2-(5-氟代-2-(三氟甲基-磺酰基氧基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-羧酸(R)-乙酯(1.75g，3.47mmol)、三丁基乙烯基烯(1.73g，5.21mmol)、氯化锂(0.74g，17.38mmol)、(Ph3P)2PdCl2(0.24g，0.34mmol)和DMF(35.0mL)，氮气置换三次，缓慢升温至80℃，搅拌反应4小时。冷却至室温，依次以饱和NaHCO3溶液(100mL)、水(100mL)、饱和食盐水(100mL)洗涤，无水硫酸钠干燥，减压蒸干，柱层析(PE:EA＝1:1)得白色固体1.23g。MS(ESI)m/z:382.0[M+H]+。1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),8.29(s,1H),8.16(br,1H),7.05(br,2H),6.42(d,J＝16.8Hz,1H),5.81–5.53(m,2H),5.20(m,1H),4.36(m,2H),4.11(q,J＝7.2Hz,2H),2.58(m,1H),2.07(m,3H),1.26(t,J＝7.2Hz,3H)。
步骤7:乙基(S)-5-(2-(2-(2-(环丙胺基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温下，向100mL单口瓶中加入乙基(S)-5-(2-(5-氟-2-乙烯基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(1.23g，3.22mmol)、环丙胺(5.52g，96.75mmol)、冰醋酸(5.81g，96.75mmol)和乙醇(12.30mL)，氮气保护，缓慢升温至75℃，回流反应20.5小时。反应液冷却至室温，饱和碳酸钠水溶液调节pH至中性，加EA(150mL)萃取，无水硫酸钠干燥有机相，减压蒸干，柱层析(DCM:EtOH＝25:1)得黄色固体378.2mg，回收原料605.4mg。对回收原料再进行上述操作，合并得到黄色固体507.2mg。MS(ESI)m/z:439.0[M+H]+。
步骤8:乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温下，向10mL单口瓶中加入乙基(S)-5-(2-(2-(2-(环丙胺基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成(0.20g，0.45mmol)、四氢呋喃(4.0mL)，超声溶解，降温至0℃，加入N-Boc-O-对甲苯磺酰基-羟胺(131.0mg，0.45mmol)和N-甲基吗啉(22.5mg，0.23mmol)，恢复至室温搅拌反应过夜。加二氯甲烷(40mL)稀释，饱和碳酸氢钠水溶液(300mL)洗涤，二氯甲烷(40mL x3)萃取，无水Na2SO4干燥，减压蒸干，柱层析(PE:EA＝1:1)得黄色固体100.0mg。MS(ESI)m/z:554.0[M+H]+。
步骤9:(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温下，向10mL的单口瓶中加入乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(85.0mg，0.15mmol)和乙醇(3.0mL)，搅拌待全部溶解后加入一水氢氧化锂(38.6mg，0.92mmol，溶于0.5mL水中)，缓慢升温至70℃，搅拌反应15小时。将反应的溶剂在40℃条件下减压蒸干，得到黄色固体粗品产物。MS(ESI)m/z:526.0[M+H]+。
步骤10:(R,13E,14E)-6-环丙基-35-氟-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的合成
室温下，将上步粗品产物加入10mL的单口瓶中，之后加入二氯甲烷(1.0mL)、三氟乙酸(1.0mL)，超声分散，搅拌反应2小时。将反应的溶剂在40℃条件下减压蒸干，得到黄色油状物，再室温下油泵抽4小时，得到淡黄色粗品1。MS(ESI)m/z:426.0[M+H]+.
室温下，将上述粗品1放入10mL单口瓶中，再加入HOBt(103.7mg，0.77mmol)、EDCI(310.7mg，0.77mmol)和DMF(4.0mL)，超声分散，加入TEA(310.7mg，3.07mmol)，氮气保护，室温条件下反应过夜。减压蒸干，经反向柱层析纯化(0.1％甲酸水溶液/乙腈，95％～0)得白色固体11.0mg。MS(ESI)m/z:408.0[M+H]+。1H NMR(300MHz,Chloroform-d)δ9.73(br,1H),8.33(d,J＝7.7Hz,1H),8.31(d,J＝2.5Hz,1H),8.29(s,1H),7.08(dd,J＝9.4,2.8Hz,1H),6.33(d,J＝7.7Hz,1H),5.58(t,J＝7.4Hz,1H),4.01–3.65(m,6H),2.94(dd,J＝16.4,8.6Hz,1H),2.62(dt,J＝13.3,6.7Hz,1H),2.43(dt,J＝12.2,6.0Hz,1H),2.24(dt,J＝13.9,7.5Hz,1H),1.96(dt,J＝13.7,6.7Hz,1H),1.17(dd,J＝10.3,5.6Hz,1H),0.87(dd,J＝10.3,4.0Hz,1H),0.51(d,J＝6.3Hz,2H)。
实施例2
(13E,14E,22R)-6-环丙胺基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮
(13E,14E,22R)-6-环丙胺基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮的制备方法与实施例1类似。
1H NMR(300MHz,Chloroform-d)δ8.33(d,J＝9.0Hz,1H),8.31(d,J＝6.0Hz 1H),8.24(s,1H),7.21(dd,J＝9.0,3.0Hz,0.5H),7.11(dd,J＝9.0,3.0Hz,0.5H),6.33(d,J＝7.6Hz,1H),5.55(t,J＝6.0Hz,0.5H),5.48(t,J＝6.0Hz,0.5H),4.17(m,1H),3.97(m,1H),3.78(m,1H),3.64(m,1H),3.41(m,1H),2.57(ddq,J＝19.1,9.9,8.6Hz,1H),2.40(dd,J＝13.1,6.7Hz,1H),2.23(m,1H),2.01(m,1H),1.88(m,6.3Hz,1H),1.49(d,J＝6.9Hz,1.5H),1.16(m,1.5H),1.00(m,1H),0.88(m,1H),0.70(m,1H),0.43(m,1H)。MS(ESI)m/z:422.2[M+H]+。
实施例3
(13E,14E,22R,5R)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
步骤1:按实施例2方法合成(13E,14E,22R)-6-环丙胺基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮
步骤2:(13E,14E,22R,5R)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的制备
取(13E,14E,22R)-6-环丙胺基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮(200mg，0.47mmol)手性制备柱分离，得到实施例3a：(13E,14E,22R,5R或S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(28.3mg，收率28.3％)和实施例3b：(13E,14E,22R,5R或S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(35.6mg，收率35.6％)。
分离制备方法：
仪器：waters SFC200
色谱柱：ChiralPak OD,250×30mm I.D.,5μm
流动相：A为CO2；B为MEOH(0.1％NH3H20)
波长：254nm
柱温：38℃
流速：60g/min
单次进样量:5mL
单次进样浓度：10mg/mL
进样次数：4
溶剂：MeOH
背压：100bar
梯度条件：B 40％
循环时间：8min
收集条件：40℃减压浓缩
分离检测方法：
仪器：waters UPCC
色谱柱：ChiralPak OD,2.1×150mm I.D.,3μm
流动相：A为CO2；B为MEOH(0.1％DEA)
波长：254nm
柱温：40℃
流速：1mL/min
进样量:2μL
进样浓度：2mg/mL
溶剂：MeOH
背压：1500psi
梯度条件：B 5％-40％
运行时长：10min
保留时间：4.471min、4.788min
实施例3a：(13E,14E,22R,5R或S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间4.471min。MS(ESI)m/z:422.2[M+H]+.1H NMR(400MHz,CDCl3)δ8.63(br,1H),8.31(dd,J＝23.1,15.6Hz,3H),7.16–7.07(m,1H),6.33(d,J＝7.6Hz,1H),5.49(t,J＝17.1Hz,1H),4.16(t,J＝8.0Hz,1H),4.01–3.92(m,1H),3.81(m,1H),3.46(dd,J＝33.0,21.6Hz,2H),3.18(m,1H),2.60(m,1H),2.39(m,1H),2.24(m,1H),1.89(d,J＝11.6Hz,1H),1.29–1.21(d,J＝7.6Hz,3H),1.07–0.93(m,2H),0.74–0.66(m,1H),0.51–0.42(m,1H).
实施例3b：(13E,14E,22R,5R或S)-6-环丙基-35-氟-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间4.788min。MS(ESI)m/z:422.2[M+H]+.1H NMR(400MHz,CDCl3)δ9.11(br,1H),8.42–8.22(m,3H),7.20(d,J＝9.3Hz,1H),6.39–6.25(d,J＝7.6Hz,1H),5.56(t,J＝7.2Hz,1H),4.18(t,J＝8.0Hz,1H),3.98(s,1H),3.86(d,J＝24.8Hz,2H),2.80(d,J＝16.3Hz,1H),2.53(m,1H),2.42(m,1H),2.30(m,1H),2.22(m,1H),1.88(d,J＝11.6Hz,1H),1.57–1.42(d,J＝7.6Hz,3H),1.02(m,1H),0.93–0.85(m,1H),0.44(m,2H).
实施例4
(R,13E,14E)-35-氟-6-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮的合成
步骤1:乙基(S)-5-(2-(5-氟-2-(2-(甲胺基)乙基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温条件下，向100mL单口瓶中加入乙基(S,E)-5-(2-(5-氟-2-(丙-1-烯-1-基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(1.00g，2.62mmol)，30％的甲胺乙醇溶液(30mL)和冰醋酸(10mL)，抽真空，置换氮气，缓慢升温至75℃，回流反应19小时，停止反应。反应液冷却至室温，加入EA，饱和碳酸钠水溶液洗涤，水相用EA反萃，合并有机相，无水硫酸钠干燥，减压蒸干，柱层析(DCM/EtOH体系)，得黄色固体544.3mg，收率45.74％。MS(ESI)m/z:413.3[M+H]+.
步骤2:乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-甲基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温条件下，向50mL单口瓶中加入乙基(S)-5-(2-(5-氟-2-(2-(甲胺基)乙基)吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(439.0mg，1.04mmol)，四氢呋喃(9.00mL)和N-甲基吗啉(158.0mg，1.56mmol)，降温至0℃，分批加入N-Boc-O对甲苯磺酰基-羟胺(898.3mg，3.12mmol)，加毕，恢复至室温进行反应，反应19小时，停止反应，加入EA，饱和碳酸钠水溶液洗涤，水相用EA萃取，合并有机相，无水Na2SO4干燥，减压蒸干，柱层析(PE/EA体系)，得产物68.2mg。MS(ESI)m/z:528.3[M+H]+.
步骤3:(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-甲基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温条件下，向25mL的单口瓶中加入乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-甲基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(62.8mg，0.13mmol)和乙醇(2.00mL)，待全部溶解后，加入一水氢氧化锂(32.5mg，0.77mmol)的水溶液(0.5mL)，缓慢升温至70℃，搅拌反应6小时，反应完全。反应液降至室温，减压蒸干，得到黄色固体粗品产物1。MS(ESI)m/z:500.1[M+H]+。
步骤4:(R,13E,14E)-35-氟-6-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮的合成
室温条件下，将上述粗品产物1加入25mL的单口瓶中，之后加入二氯甲烷(2.00mL)和三氟乙酸(2.00mL)，超声溶解，室温下搅拌2小时，反应完全，停止反应。将反应体系减压蒸干，得到微黄色粗品2。MS(ESI)m/z:400.5[M+H]+。
室温条件下，将上述粗品2放入25mL单口瓶中，再加入HOBt(87.3mg，0.64mmol)，EDCI(123.9mg，0.64mmol)、DMF(3.00mL)和TEA(261.6mg，2.58mmol)，抽真空，置换氮气，室温条件下反应过夜，反应完全。将反应体系减压蒸干，柱层析(0.1％甲酸水溶液/乙腈体系)，得到16.5mg的产物。MS(ESI)m/z:382.4[M+H]+.1H NMR(300MHz,Chloroform-d)δ8.35(d,J＝9.4,1H),8.34(d,J＝2.8,1H),8.31(s,1H),7.10(dd,J＝9.4,2.8Hz,1H),6.34(d,J＝7.6Hz,1H),5.54(t,J＝7.5Hz,1H),4.12(dd,J＝15.0,6.2Hz,1H),3.99(dd,J＝7.9,7.2Hz,1H),3.86(dd,J＝8.7,7.8Hz,1H),3.72–3.69(m,1H),3.67–3.65(m,1H),2.87–2.79(m,1H),2.77(s,3H),2.66–2.56(m,1H),2.47–2.41(m,1H),2.30–2.23(m,1H),1.97–1.90(m,1H).
实施例5
(R,13E,14E)-6-乙基-35-氟-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮
步骤1:乙基(S)-5-(2-(2-(2-(乙胺基)乙基)-5-氟代吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温条件下，向100mL单口瓶中加入乙基(S)-5-(2-(5-氟-2-乙烯基吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(1.52g，3.98mmol)，30％的乙胺乙醇溶液(40.80mL)和冰醋酸(13.60mL)，抽真空，置换氮气，缓慢升温至75℃，回流反应。搅拌23.5小时，停止反应。将反应液冷却至室温，加入EA，饱和碳酸钠水溶液洗涤，水相用EA反萃，合并有机相，无水硫酸钠干燥，减压蒸干，柱层析(DCM/EtOH体系)，得黄色固体610mg，收率为33.66％。MS(ESI)m/z:427.5[M+H]+.
步骤2:乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-乙基肼基)乙基)-5-氟代吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯的合成
室温条件下，向50mL单口瓶中加入乙基(S)-5-(2-(2-(2-(乙胺基)乙基)-5-氟代吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(753.7mg，1.77mmol)，四氢呋喃(15mL)和N-甲基吗啉(178.8mg，1.77mmol)，降温至0℃，分批加入N-Boc-O对甲苯磺酰基-羟胺(2.54g，8.84mmol)，加毕，恢复至室温进行反应，反应17小时，停止反应，加入EA，饱和碳酸钠水溶液洗涤，水相再用EA萃取，合并有机相，无水Na2SO4干燥，减压蒸干，柱层析(PE/EA体系)，得到101.6mg产物。MS(ESI)m/z:542.6[M+H]+.
步骤3:(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-乙基肼基)乙基)-5-氟吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温条件下，向25mL的单口瓶中加入乙基(S)-5-(2-(2-(2-(2-(叔丁基羰基)-1-乙基肼基)乙基)-5-氟代吡啶-3-基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸酯(101.6mg，0.19mmol)和乙醇(4.00mL)，待全部溶解后，加入一水氢氧化锂(47.2mg，1.13mmol)的水溶液(0.8mL)，缓慢升温至70℃，搅拌5小时，反应完全。将反应体系降至室温，减压蒸干，得到黄色固体粗品产物1。MS(ESI)m/z:514.5[M+H]+。
步骤4:(R,13E,14E)-35-氟-6-乙基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮的合成
室温条件下，将上述粗品产物1加入25mL的单口瓶中，之后加入二氯甲烷(3.00mL)和三氟乙酸(3.00mL)，超声溶解，室温下搅拌1.5小时，反应完全，停止反应。将反应体系减压蒸干，得到微黄色粗品2。MS(ESI)m/z:414.4[M+H]+。
室温条件下，将上述粗品2放入25mL单口瓶中，再加入HOBt(126.7mg，0.94mmol)，EDCI(180.0mg，0.94mmol)、DMF(6.00mL)和TEA(380.0mg，3.75mmol)，抽真空，置换氮气，室温条件下反应过夜，反应完全。将反应体系减压蒸干，柱层析(0.1％甲酸水溶液/乙腈体系)，得到14.4mg的产物。MS(ESI)m/z:396.4[M+H]+.HPLC:97.87％.1H NMR(300MHz,Chloroform-d)δ9.42(br,1H),8.41–8.31(m,3H),7.10(dd,J＝8.4,2.8Hz,1H),6.36(d,J＝7.9Hz,1H),5.57(t,J＝7.5Hz,1H),4.04–3.95(m,2H),3.92–3.83(m,2H),3.78–3.70(m,1H),3.63(d,J＝17.8Hz,1H),2.98(q,J＝8.4Hz,2H),2.66–2.57(m,1H),2.29–2.18(m,2H),1.26–1.20(t,J＝6.0Hz,3H).
实施例6
(R,13E,14E)-35-氟-6-异丙基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
(R,13E,14E)-35-氟-6-异丙基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的制备方法与实施例1类似。
1H NMR(400MHz,CDCl3)δ9.41(br,1H),8.33(d,J＝8.0Hz,1H),8.32(s,2H),7.09(dd,J＝9.4,2.3Hz,1H),6.34(d,J＝7.9Hz,1H),5.56(t,J＝7.3Hz,1H),4.20–4.14(m,1H),4.00(q,J＝8.0Hz,1H),3.88–3.82(m,1H),3.65(dd,J＝15.4,4.0Hz,1H),3.56(d,J＝16.2Hz,1H),3.09(p,J＝6.2Hz,1H),2.86(dd,J＝15.1,10.1Hz,1H),2.61(dd,J＝13.4,6.8Hz,1H),2.44(dt,J＝12.7,6.3Hz,1H),2.25(dt,J＝13.7,7.3Hz,1H),1.94(dd,J＝13.5,6.8Hz,1H),1.29(d,J＝6.3Hz,3H),1.22(d,J＝6.3Hz,3H)。MS(ESI)m/z:410.2[M+H]+。
实施例7
(13E,14E,22R,5R)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
步骤1:按实施例2方法合成(13E,14E,22R)-5,6-二甲基-35-氟-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮
步骤2:(13E,14E,22R,5R)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的制备
取(13E,14E,22R)-5,6-二甲基-35-氟-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-氮杂苯-2(1,2)-吡咯烷环八烷-8-酮(260mg，0.65mmol)制备柱分离，得到实施例7a：(13E,14E,22R,5R或S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(23mg，收率17.7％)和实施例7b：(13E,14E,22R,5R或S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(56mg，收率43.1％)。
分离制备方法：
仪器：清博华LC2000型高效液相色谱
色谱柱：YMC Triart C18 250*20mm 10um
流动相：A：乙腈；流动相B：0.1％三氟乙酸水溶液
波长：230nm
柱温：35℃
流速：10ml/min
溶剂：乙腈
制备条件：0min A25B75 25min A25B75 30min A26B74 35min A28B72
收集条件：40℃减压浓缩
分离检测方法：
仪器：Agilent 1260Infinity II
色谱柱：Xtimate C18 4.6*50mm 3um
流动相：A为纯乙腈；B为0.1％三氟乙酸水
波长：230nm
柱温：35℃
流速：1mL/min
进样量:20μL
保留时间：2.371min、2.844min
溶剂：乙腈
检测条件：B 10％-76％
实施例7a：(13E,14E,22R,5R或S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间2.371min。MS(ESI)m/z:396.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.55(br,1H),8.82(d,J＝7.7Hz,1H),8.37(m,1H),8.11(s,1H),7.54(d,J＝9.8Hz,1H),6.72(d,J＝7.8Hz,1H),5.40(t,J＝6.8Hz,1H),4.20(m,1H),4.08(q,J＝7.5Hz,1H),3.84(m,1H),3.53–3.42(m,1H),3.23(dd,J＝14.5,10.6Hz,1H),3.04(s,3H),2.62(dt,J＝12.6,6.5Hz,1H),2.24(dt,J＝11.7,5.9Hz,1H),2.08(dq,J＝12.9,7.4Hz,1H),1.83–1.72(m,1H)，1.31(d,J＝6.9Hz,3H).
实施例7b：(13E,14E,22R,5R或S)-35-氟-5,6-二甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间2.844min。MS(ESI)m/z:396.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.64(br,1H),8.80(d,J＝7.7Hz,1H),8.42(d,J＝2.6Hz,1H),8.13(s,1H),7.59(d,J＝12.6Hz,1H),6.69(d,J＝7.8Hz,1H),5.61(t,J＝7.1Hz,1H),4.14(d,J＝7.2Hz,1H),3.96(s,1H),3.91(d,J＝5.0Hz,1H),3.88–3.75(m,2H),2.65(s,3H),2.59(s,1H),2.31(dq,J＝11.7,5.7,5.1Hz,1H),2.14–1.99(m,1H),1.80(dq,J＝13.5,7.1Hz,1H),1.46(d,J＝6.9Hz,3H).
实施例8
(13E,14E,22R,5R)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5R)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
步骤1:按实施例2方法合成(13E,14E,22R)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
步骤2:(13E,14E,22R,5R)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮和(13E,14E,22R,5S)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的制备
取(13E,14E,22R)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(320mg，0.78mmol)制备柱分离，得到实施例8a：(13E,14E,22R,5R或S)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(26mg，收率16.2％)和实施例8b：(13E,14E,22R,5R或S)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮(53mg，收率33.1％)。
分离制备方法：
仪器：清博华LC2000型高效液相色谱
色谱柱：YMC Triart C18 250*20mm 10um
流动相：A：乙腈；流动相B：0.05％三氟乙酸水溶液
波长：230nm
柱温：35℃
流速：10ml/min
溶剂：乙腈
制备条件：0min A33B67 25min A33B67 30min A35B65
收集条件：40℃减压浓缩
分离检测方法：
仪器：Agilent 1260Infinity II
色谱柱：Xtimate C18 4.6*50mm 3um
流动相：A为纯乙腈；B为0.1％三氟乙酸水
波长：230nm
柱温：35℃
流速：1mL/min
进样量:20μL
保留时间：1.898min,2.369min
溶剂：乙腈
检测条件：B 10％-72％
实施例8a：(13E,14E,22R,5R或S)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间1.898min。MS(ESI)m/z:410.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.55(br,1H),8.82(d,J＝7.7Hz,1H),8.37(m,1H),8.11(s,1H),7.54(d,J＝9.8Hz,1H),6.72(d,J＝7.8Hz,1H),5.40(t,J＝6.8Hz,1H),4.20(m,1H),4.08(q,J＝7.5Hz,1H),3.84(m,1H),3.53–3.42(m,1H),3.23(dd,J＝14.5,10.6Hz,1H),3.04(s,3H),2.62(dt,J＝12.6,6.5Hz,1H),2.24(dt,J＝11.7,5.9Hz,1H),2.08(dq,J＝12.9,7.4Hz,1H),1.83–1.72(m,1H)，1.04(m,6H).
实施例8b：(13E,14E,22R,5R或S)-35-氟-6-乙基-5-甲基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮，保留时间2.369min。MS(ESI)m/z:410.1[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.02(br,1H),8.76(d,J＝7.7Hz,1H),8.39(d,J＝2.5Hz,1H),8.06(s,1H),7.56(dd,J＝10.1,2.4Hz,1H),6.66(d,J＝7.8Hz,1H),5.59(s,1H),4.22–3.94(m,1H),3.90–3.73(m,2H),3.68–3.59(m,1H),2.90–2.74(m,1H),2.67(p,J＝8.3,7.5Hz,1H),2.53(m,1H),2.48–2.40(m,1H),2.30(dq,J＝12.0,6.6Hz,1H),2.07(dt,J＝13.2,7.2Hz,1H),1.77(td,J＝12.9,6.3Hz,1H),1.44(d,J＝6.9Hz,3H),0.98(t,J＝6.9Hz,3H).
实施例9
(R,13E,14E)-35-氟-6-异丁基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮
(R,13E,14E)-35-氟-6-异丁基-6,7-二氮杂卓-1(5,3)-吡唑并[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环八烷-8-酮的制备方法与实施例1类似。
1H NMR(400MHz,CDCl3)δ9.29(br,1H),8.30(dd,J＝9.5,7.2Hz,3H),7.07(dd,J＝9.4,2.8Hz,1H),6.32(d,J＝7.7Hz,1H),5.57–5.53(t,J＝7.3Hz,1H),3.99–3.91(m,2H),3.87–3.80(m,2H),3.63(dt,J＝16.0,3.5Hz,1H),2.86–2.76(m,2H),2.65(dt,J＝13.3,6.8Hz,1H),2.54(dd,J＝11.8,8.4Hz,1H),2.43(dt,J＝12.6,6.2Hz,1H),2.25(dt,J＝13.5,7.5Hz,1H),1.97-1.88(dt,J＝14.2,7.2Hz,1H),1.82(dt,J＝13.6,6.6Hz,1H),1.12(d,J＝6.5Hz,3H),0.96(d,J＝6.7Hz,3H).MS(ESI)m/z:424.2[M+H]+.
实施例10
(R,13E,14E)-6-环丙基-35-氟-6,7-二氮杂-1(5,3)-吡唑啉[1,5-a]嘧啶-3(3,2)-吡啶-2(1,2)-吡咯烷环十三烷-8-酮的合成
步骤1:2-(2-溴-4-氟苯基)乙醇
将2-(2-溴-4-氟苯基)乙酸(46.63g，200.00mmol)溶于THF 500mL中，0℃下加入硼烷四氢呋喃溶液(1.0M，300mL)，18℃下反应16h后终止。反应液用1N稀盐酸淬灭，加入EA萃取，有机相用饱和食盐水洗，无水Na2SO4干燥，过滤，浓缩得黄色油状物42.57g，收率97％。
步骤2:2-溴-4-氟-1-(2-(4-甲氧基苄氧基)乙基)苯
室温下，向四口瓶中加入NaH(4.10g，102.00mmol)和THF 200mL，0℃下加入2-(2-溴-4-氟苯基)乙醇(14.90g，102.00mmol)，0℃下反应0.5h，加入四丁基碘化铵(36.28g，96.00mmol)和对甲氧基苄氯(12.78g，82.00mmol)，50℃下反应4h后终止。反应液用1N稀盐酸淬灭，加入EA萃取，有机相用饱和食盐水洗，无水Na2SO4干燥，过滤，浓缩得无色油状物15.37g，收率67％。
步骤3:5-氟-2-(2-(4-甲氧基苄氧基)乙基)苯甲醛
室温下，将2-溴-4-氟-1-(2-(4-甲氧基苄氧基)乙基)苯(15.37g，45.50mmol)溶于THF(500mL)中，-78℃，N2保护下加入仲丁基锂(70mL)，-78℃搅拌1h后加入DMF(18.17g，230.00mmol)，控温-78℃反应0.5h终止。反应液用饱和氯化铵溶液淬灭。加入EA萃取，水洗，无水MgSO4干燥，过滤，浓缩，柱层析纯化(EA/PE体系)，得黄色油状物8.01g，收率62％。
步骤4:(R,E)-N-(5-氟-2-(4-甲氧基苄氧基)乙基)苯亚甲基)-2-叔丁基-2-磺酰亚胺
室温下，向单口瓶中依次加入5-氟-2-(2-(4-甲氧基苄氧基)乙基)苯甲醛(8.00g，28.00mmol)、R-叔丁基亚磺酰胺(3.56g，30.00mmol)、Cs2CO3(6.33g，19.00mmol)和DCM100mL，N2保护，25℃下反应16h后终止。反应液倒入水中，分液，有机相饱和食盐水洗，无水MgSO4干燥，过滤，浓缩，得黄色油状物10.88g，收率100％。
步骤5:N-((R)-3-((1,3-二恶烷-2-基)-1-(5-氟-2-(2-(4-甲氧基苄氧基)乙基)苯基)丙基)-2-叔丁基-2-磺酰亚胺
室温下，向四口瓶中依次加入Mg粉(0.87g，36.00mmol)、1-溴-3,3-二甲氧基丙烷(7.10g，36.00mmol)和THF(100mL)，抽真空置换N2，N2保护，点加热引发反应，于25℃下反应2h。冰浴下滴加(R,E)-N-(5-氟-2-(4-甲氧基苄氧基)乙基)亚甲基)-2-叔丁基-2-磺酰亚胺(10.88g，28.00mmol)的THF(40mL)溶液，滴毕升至25℃反应2h后终止，冰浴下加入饱和NH4Cl溶液淬灭反应，分层，水相用EA萃取，合并有机相，无水MgSO4干燥，过滤，浓缩，得白色固体14.20g，收率100％。
步骤6:(R)-2-(2-(3,4-二氢-2H-吡咯-2-基)-4-氟)苯乙醇
室温下，向单口瓶中依次加入(S)-N-((R)-3-((1,3-二恶烷-2-基)-1-(5-氟-2-(2-(4-甲氧基苄氧基)乙基)苯基)丙基)-2-叔丁基-2-磺酰亚胺(14.20g，28.00mmol)和H2O(25mL)，冰浴下滴加TFA(100mL)，滴毕搅拌反应20min后，升至25℃反应22h后终止。反应液直接用于下一步。
步骤7:(R)-2-(4-氟-2-(吡咯烷-2-基)苯乙醇
室温下，向单口瓶中依次加入(R)-2-(2-(3,4-二氢-2H-吡咯-2-基)-4-氟)苯乙醇(上一步反应液)，冰盐浴下分批加入三乙基硅烷(9.77g，84.00mmol)，加毕升至17℃反应1h后终止，加入2N HCl水溶液淬灭反应，调节体系pH至2-3，EA洗涤，1N NaOH水溶液调节pH至9-10，DCM萃取，无水Na2SO4干燥，过滤，浓缩，得到浅黄色油状物3.80g，两步总收率65％。
步骤8:(R)-5-(2-(5-氟-2-(2-羟乙基)苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯
室温下，向单口瓶中依次加入(R)-2-(4-氟-2-(吡咯烷-2-基)苯乙醇(3.80g，18.00mmol)、5-氯吡唑并[1,5-A]嘧啶-3-甲酸乙酯(4.10g，18.00mmol)、TEA(3.64g，36.00mmol)和EtOH(50mL)，抽真空置换N2，N2保护，24℃反应16h后终止。旋掉乙醇，加入DCM和水，搅拌分液，除去水相，有机相用饱和食盐水洗涤，饱和NaHCO3水溶液洗涤，无水Na2SO4干燥，过滤，浓缩，柱层析纯化(EA/PE体系)，得到黄色泡沫状固体3.56g，收率50％。
步骤9:(R)-5-(2-(5-氟-2-(2-甲磺酰基)乙基)苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯
室温下，向单口瓶中依次加入(R)-5-(2-(5-氟-2-(2-羟乙基)苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯(2.00g，5.02mmol)、TEA(1.52g，15.06mmol)和DCM 50mL，冰浴下加入甲磺酰氯(1.16g，10.04mmol),自然升温至26℃反应2h后终止。反应液倒入水中，搅拌，萃取，分液，有机相无水Na2SO4干燥，过滤，浓缩，得到黄色液体，粗品直接投下一步，收率100％。
步骤10:(R)-5-(2-(2-(2(环丙基氨基)乙基)-5-氟苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯
室温下，向单口瓶中依次加入(R)-5-(2-(5-氟-2-(2-甲磺酰基)乙基)苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯(上步粗品，5.02mmol)、环丙胺(0.86g，15.06mmol)和DMF(30mL)，N2保护下，80℃条件下搅拌反应3h后终止。反应液倒入水中，加入EA萃取，EA相用1N的稀盐酸洗，水相加入碳酸钠调节PH＝12，加入EA萃取，饱和食盐水洗涤，无水Na2SO4干燥，过滤，浓缩得淡黄色液体1.69g，收率77％。
步骤11:(R)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯的合成
室温下，向单口瓶中依次加入(R)-5-(2-(2-(2(环丙基氨基)乙基)-5-氟苯基)吡咯-1-基)吡唑啉[1,5-a]嘧啶-3-甲酸乙酯(1.67g，3.82mmol)、N-叔丁氧羰基-3-(4-氰苯基)哑嗪(1.25g，4.97mmol)和DMF(25mL)，21℃下反应16h后停止。加入EA，水洗，水相用EA反萃，合并有机相，无水Na2SO4干燥，过滤，浓缩，柱层析纯化(PE/EA体系)，得黄色油状固体1.02g，收率68％。
步骤12:(R)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸的合成
室温下，向单口瓶中依次加入(R)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(0.70g，1.34mmol)和乙醇(10mL)，搅拌至全溶后，加入氢氧化钠(0.32g，8.04mmol)的H2O(5mL)溶液，升温至70℃反应16h后终止，降温至室温，浓缩除去大部分乙醇，加入DCM和H2O，1N HCl调节pH至3-4，搅拌分层，水相再用DCM萃取，合并有机相，无水Na2SO4干燥，过滤，浓缩，得到白固体0.63g，收率95％。
步骤13:(R)-5-(2-(2-(2-(1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸
室温下，向单口瓶中依次加入(R)-5-(2-(2-(2-(2-(叔丁基羰基)-1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(0.63g，1.20mmol)和HCl的乙醇溶液(10mL)，搅拌至全溶，32℃下反应1h后终止，减压浓缩干，得微黄色固体0.60g，收率100％。
步骤14:(R,13E,14E)-6-环丙基-35-氟-6,7-二氮杂-1(5,3)-吡唑啉[1,5-a]嘧啶-3(3,2)-苯基-2(1,2)-吡咯烷环十三烷-8-酮
室温条件下，向四口瓶中依次加入TBTU(0.68g，2.12mmol)、DMAP(0.034g，0.30mmol)、DMF(6mL)和DCM(30mL)，抽真空，置换N2，N2保护，加入DIEA(1.09g，8.46mmol)。将(R)-5-(2-(2-(2-(1-环丙基肼基)乙基)-5-氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-甲酸(0.60g，1.41mmol)用DMF(6mL)和DCM(6mL)混合溶液溶清后平均分成五等分，32℃下平均每隔1h后加入上述溶液的一等份，加毕后32℃下反应1h后终止，减压浓缩干，柱层析纯化(DCM/CH3OH体系)，得到类白色固体0.22g，收率42％。1H NMR(400MHz,Chloroform-d)δ9.85(br,1H),8.30(d,J＝9.3Hz,2H),7.20(m,1H),6.90(t,J＝8.0Hz,1H),6.78(d,J＝10.2Hz,1H),6.33(d,J＝7.7Hz,1H),5.67(t,J＝6.6Hz,1H),3.99(dt,J＝14.0,7.9Hz,2H),3.90–3.72(m,1H),3.65–3.50(m,2H),2.94–2.88(m,1H),2.67–2.50(m,2H),2.50–2.33(m,1H),2.21(dt,J＝13.3,7.0Hz,1H),1.93(dt,J＝12.7,6.5Hz,1H),1.14(m,1H),0.90(d,J＝10.2Hz,1H),0.54(m,2H).MS(ESI)m/z:407[M+H]+.
实施例11
Trk激酶抑制活性测试
本试验采用γ-33p-ATP同位素测试法测试化合物对激酶TrkA、TrkB、TrkC的抑制作用，并得出化合物对该酶抑制活性的半数抑制浓度IC50，文献报道的Trk抑制剂LOXO-101作为阳性对照，LOXO-101购于上海赛诺克医药科技有限公司，批号：SCT0142170801。
1.基础反应缓冲液
20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
2.化合物配制
化合物采用100％DMSO溶解至特定的浓度，之后采用自动加样装置梯度稀释成不同浓度的待测样品(DMSO溶解液)。
3.反应步骤
3.1使用基础反应缓冲液稀释反应底物；
3.2将激酶加入底物溶液中，轻柔混匀；
3.3采用自动加样系统将100％DMSO稀释的不同浓度化合物加入激酶溶液中，室温下孵育20min；
3.4室温下加入33P-ATP(10μM,10μCi/μl)启动激酶反应，反应2h。
4.检测
反应液经离子交换过滤系统除去未反应的ATP及反应产生的ADP等离子后检测底物中33P同位素放射量。
5.数据处理
依据放射量计算加入不同浓度抑制剂体系中的激酶活性从而得到不同浓度化合物对激酶活性的抑制作用，采用graphpad prism拟合得化合物抑制IC50。
本发明化合物的生物化学活性通过以上的试验进行测定，测得的IC50值参见表1：
表1 Trk激酶抑制活性测试结果
注：表格中“-”代表未测试
结论：本发明化合物与阳性药相比具有更好的Trk激酶抑制活性。
实施例12
tel-NTRK1-BaF3、BaF3-LMNA-NTRK1细胞生长抑制测试
本试验采用CellTiter-Glo细胞增殖荧光检测法测试化合物对tel-NTRK1-BaF3、BaF3-LMNA-NTRK1转基因细胞的生长抑制作用，并得出化合物对该细胞的半数生长抑制浓度GI50，文献报道的Trk抑制剂LOXO-101作为阳性对照，LOXO-101购于HaoyuanChemexpressCo.,Ltd.。
1.实验仪器及耗材
I)PreceDo靶点等效基因稳定细胞系文库；
II)CellTiter-Glo细胞增殖荧光检测试剂(Promega，USA)；
III)药物筛选96孔专用板(Corning，Rochester，NY)；
IV)测试化合物。
2.化合物药板的制备
待测化合物溶于DMSO中配成10mM的母液，按照3倍稀释制备成10mM、3.333mM、1.111mM、0.370mM、0.123mM、0.041mM、0.014mM、0.005mM、0.002mM储存于0.5ml灭菌dorf管(Corning，USA)中，同时采用同等体积的DMSO溶剂作为空白对照，共10个浓度梯度，药板-20℃真空保存。
3.细胞培养条件
tel-NTRK1-BaF3、BaF3-LMNA-NTRK1细胞系采用RPMI 1640(Corning，NY，USA)+10％胎牛血清(Gibico，Invitrogen，USA)进行培养，细胞复苏后培养两代，待测试。
4.测试及数据处理
取对数生长期细胞(2000-2500个/孔)接种于12×8的96孔白色不透明细胞培养板(Corning 3570，NY，USA)，每孔体积为100μL，给细胞板加药(0.1μL/孔)，化合物最终浓度为10μM、3.3μM、1.1μM、0.37μM、0.12μM、0.04μM、0.014μM、0.005μM、0.002μM(0.4uL药液加到400ul的细胞混匀液中，然后混匀，每孔加100ul)，37℃、5％CO2培养箱中孵育72小时后，加入20μLCellTiter-Glo细胞增殖荧光检测试剂，静置10分钟，Envision Plate-Reader读数。
5.实验验证
药板中均有溶媒组(仅加DMSO)作为阴性对照。
6.结果
Envision Plate-reader读数得出对应的每孔荧光值RLU。待测化合物原始数据RLUDrug与DMSO对照组RLUDMSO进行归一化：
Cell Viability％＝(RLUDrug/RLUDMSO)*100％
采用Graph Pad Prism version 6.0.对待测化合物单个浓度对细胞抑制率数值进行非线性回归曲线拟合，得出GI50值。
7.基础反应缓冲液
20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
本发明化合物的生物化学活性通过以上的试验进行测定，测得的GI50值参见表2：
表2 Trk融合突变细胞抑制活性测试结果
注：表格中“-”代表未测试。
结论：本发明化合物与阳性药相比具有更好的Trk融合突变细胞生长抑制活性。
实施例13
化合物对人肝微粒体代谢稳定性测试
孵育体系总体积为250μL，用50mmol/L PBS缓冲液(pH＝7.4)配制其中含有蛋白浓度为0.5mg/mL的各种属肝微粒体孵育液，孵育开始前将100μmol/L待测化合物2.5μL与上述孵育液197.5μL混合，在37℃水浴中预孵育5min后加入同样经预孵育5min的还原性辅酶Ⅱ溶液(5mmol/L)50μL启动反应，(反应体系中种属肝微粒体蛋白含量为0.5g/L、待测化合物终浓度为1μmol/L)，在37℃水浴中振荡孵育，并分别于0，5，15，30，60min取出，立即加入内标为Terfenadine(正离子内标，25ng/mL)和Tolbutamide(负离子内标，50ng/mL)的正负内标混合甲醇溶液600μL以终止反应。将终止后的孵育液振荡2min、离心(4℃、16000r/min)10min后取上清液进行LC-MS/MS检测，定量分析母药的剩余量。(DMSO<0.1％)。
将孵育0min化合物的浓度作为100％，其他孵育时间点的浓度转换为百分剩余量，将各时间点的百分剩余量的自然对数对孵育时间作线性回归，求算得斜率k，根据公式，T1/2＝-0.693/k计算得到体外半衰期。肝微粒体中的清除率(CLint(μL/min/mg protein)＝Ln(2)*1000/T1/2(min)/Protein Conc(mg/ml))。
本发明化合物对人肝微粒体代谢稳定性测试数据详见表3：
表3人肝微粒体代谢稳定性测试结果
注：Trk抑制剂LOXO-195参考专利WO2011146336方法制备。
结论：与对照化合物相比，本发明化合物比照阳性对照药具有更好的人肝微粒体代谢稳定性，具有更好的成药性。
Claims (11)
1.如式(II)所述的化合物、其立体异构体或其药学上可接受的盐：
R1选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、卤素、羟基或C1-C4烷氧基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基；
R3为卤素；
X选自N。
2.根据权利要求1所述的化合物，其特征在于：
R1选自H、C1-C8烷基或C3-C8环烷基，任选进一步被一个或多个选自氘、羟基、卤素或C1-C4烷氧基的取代基所取代；
R2和R4各自独立选自H、C1-C8烷基；
R3选自氟或氯；
X选自N。
3.根据权利要求2所述的化合物，其特征在于：
R1选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、环丁基、环戊基或环己基，任选进一步被一个或多个选自氘、羟基、F、Cl或甲氧基的取代基所取代；
R2和R4各自独立选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
R3选自氟或氯；
X选自N。
4.化合物、其立体异构体或其药学上可接受的盐，其特征在于，化合物选自如下结构：
5.化合物、其立体异构体或其药学上可接受的盐，其特征在于，化合物选自如下结构：
6.一种药物组合物，其包含如权利要求1～5任一项所述的化合物、其立体异构体或其药学上可接受的盐和可药用的载体。
7.如权利要求6所述的药物组合物，其特征在于，所述药物组合物是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
8.权利要求1～5中任一项所述的化合物、其立体异构体或其药学上可接受的盐或权利要求6～7所述的药物组合物在制备预防或治疗由原肌球蛋白受体激酶活性介导疾病的药物中的应用。
9.权利要求1～5中任一项所述的化合物、其立体异构体或其药学上可接受的盐或权利要求6～7所述的药物组合物在制备预防或治疗疼痛、炎症、癌症的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述癌症选自成神经细胞瘤、卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、多发性骨髓瘤、间皮瘤、青少年肉瘤、纤维肉瘤、大细胞神经内分泌肿瘤、毛细胞性星形细胞瘤、头颈鳞状细胞癌、先天性中胚层肾瘤、导管腺癌、涎腺乳腺样分泌癌、阑尾癌。
11.根据权利要求9所述的应用，其特征在于，所述癌症选自急性髓细胞白血病。
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| CA3095955A1 (en) | 2019-12-12 |
| JP7391871B2 (ja) | 2023-12-05 |
| EP3772516A1 (en) | 2021-02-10 |
| AU2019280360A1 (en) | 2020-11-26 |
| EP3772516A4 (en) | 2021-02-24 |
| AU2019280360B2 (en) | 2024-07-04 |
| ES2937392T3 (es) | 2023-03-28 |
| US11597729B2 (en) | 2023-03-07 |
| CA3095955C (en) | 2024-05-07 |
| CN110577532A (zh) | 2019-12-17 |
| JP2021527623A (ja) | 2021-10-14 |
| KR20210019990A (ko) | 2021-02-23 |
| EP3772516B1 (en) | 2022-12-14 |
| US20210094953A1 (en) | 2021-04-01 |
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