CN116120291B - 吲唑类化合物及其制备方法和应用 - Google Patents
吲唑类化合物及其制备方法和应用 Download PDFInfo
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- CN116120291B CN116120291B CN202310381677.3A CN202310381677A CN116120291B CN 116120291 B CN116120291 B CN 116120291B CN 202310381677 A CN202310381677 A CN 202310381677A CN 116120291 B CN116120291 B CN 116120291B
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Abstract
本发明提供了一系列式I所示的化合物，所述化合物能够预防和/或治疗由LRRK2的通路异常引起的疾病，例如帕金森氏症或炎症性肠病。特别的是本发明化合物对炎症性肠病表现出抗炎活性。
I。
Description
技术领域
本发明属于医药技术领域，具体涉及一种吲唑类化合物及其制备方法和作为LRRK2激酶抑制剂的用途。
背景技术
富亮氨酸重复激酶2(LRRK2)由LRRK2基因编码，是一种大型的多功能蛋白，具有丝氨酸-苏氨酸激酶和GTP酶活性。LRRK2的通路异常会引发多种疾病，包括帕金森氏症(Parkinson’s disease)和炎症性肠病(inflammatory bowel disease，IBDs)等。
帕金森氏症(PD)是发生在50-60岁以上中老年人的常见神经系统变性疾病。主要病变在黑质和纹状体通路，导致静止性震颤、肌张力增高、运动迟缓。帕金森病是老年人中第四位最常见的神经变性疾病，在65岁以上人群中，1％患有此病；在40岁以上人群中为0.4％。临床治疗帕金森氏症的药物主要为复方左旋多巴制剂、多巴胺受体激动剂、单胺氧化酶抑制剂、抗胆碱能制剂和金刚烷胺等，但存在副作用大和长期应用效果下降等缺点。
炎症性肠病(IBDs)是胃肠道的慢性复发性炎症性疾病，主要包括克罗恩病(Crohn’s disease，CD)和溃疡性结肠炎(Ulcerative colitis，UC)。其中UC是一种影响结肠和直肠的慢性炎症性疾病，近年来其发病率在我国逐年上升。其主要临床症状为血性腹泻、腹痛、便血和体重减轻等，严重可累及肝脏、皮肤和视觉等器官，并且伴随肠穿孔、大出血、中毒性结肠扩张甚至癌变等并发症，严重危害群众生命健康。然而，其发病机制至今仍不清楚，通常认为由许多因素相互作用引起，包括遗传、环境和免疫等因素。
UC传统的一线治疗药物主要分为5大类：1.对氨基水杨酸类(如柳氮磺胺吡啶、美沙拉嗪)；2.皮质类固醇(如地塞米松、泼尼松)；3.免疫调节剂(如硫唑嘌呤、6-硫嘌呤和甲氨蝶呤)；4.生物制剂(英夫利昔单抗、阿达木单抗等)；5.微生态制剂，如益生菌。目前治疗UC最常用的药物如氨基水杨酸盐和免疫调节剂都有严重的副作用，如长期治疗效果较差并且影响肾功能等，而其他治疗手段仍存在分歧。
因此，迫切需要开发出新的药物，例如LRRK2激酶抑制剂来提高患有PD或IBDs病人的生活质量。
发明内容
为解决上述技术问题，本发明提供如下式I所示的化合物，其互变异构体、立体异构体，或其药学上可接受的盐：
其中，R1选自C1-6烷氧基，-O-C3-6环烷基，3-6元含O杂环基，-O-C3-6环烷基-COO-C1-6烷基，所述-O-C3-6环烷基中C3-6环烷基与O相连的碳原子上的H任选被C1-6烷基取代；
R2选自C1-6烷基；
R3选自C1-6烷基或=O。
在一些实施方案中，R1选自C1-3烷氧基，-O-C3-6环烷基，3-6元含O杂环基，-O-C3-6环烷基-COO-C1-3烷基，所述-O-C3-6环烷基中C3-6环烷基与O相连的碳原子上的H任选被C1-3烷基取代；
R2选自C1-3烷基；
R3选自C1-3烷基或=O。
在一些优选的实施方案中，R1选自如下基团：
R2选自甲基；
在一些具体的实施方案中，所述化合物选自如下：
本发明还提供如上式I所示化合物的制备方法，包括如下步骤：
其中，R1，R2，R3，
具有如上所述定义；
L选自
，/>
或/>
，X选自卤素；
化合物Ia与化合物Ib反应得到式I所示化合物。
在一个优选的实施方案中，先对化合物Ia中的NH进行保护，待与化合物Ib进行反应后，再脱去保护基，得到式I所示化合物。
本发明还提供如上式I所示化合物，其互变异构体、立体异构体，或其药学上可接受的盐在制备预防和/或治疗LRRK2的通路异常引起的疾病的药物中的用途。
根据本发明的实施方案，所述LRRK2的通路异常引起的疾病为帕金森氏症或炎症性肠病。
根据本发明的实施方案，所述炎症性肠病包括克罗恩病和溃疡性结肠炎。
本发明还提供一种药物组合物，其包括如上所述式I所示化合物，其互变异构体、立体异构体，或其药学上可接受的盐。
根据本发明的实施方案，所述药物组合物用于预防和/或治疗LRRK2的通路异常引起的疾病。
有益效果
本发明提供了一系列式I所示的化合物，所述化合物能够预防和/或治疗LRRK2的通路异常引起的疾病，例如帕金森氏症或炎症性肠病。特别地，本发明化合物对炎症性肠病表现出抗炎活性。此外，本申请的化合物制备过程简单，易于提纯，因此具有一定的应用前景。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
在本文中，术语“包括”、“包含”和/或“含有”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
在本文中，在描述一个/种、两个/种或更多个/种时，“更多个/种”应当是指大于2的情形，例如表示大于等于3的整数情形，例如3、4、5、6、7、8、9或10个/种。
在本文中，术语“任选(的/地)”表示所述特征存在或不存在这两种情形，这意味着随后所描述的事件可以但不必然发生，因此包括该事件发生或不发生的两类情形。例如，“任选被烷基取代的杂环基团”意味着该烷基可以但不必然存在，因此包括被烷基取代的杂环基团和没有被烷基取代的杂环基团的情形。
本申请通式中“R1，R2，R3”的下标数字仅为标识不同的取代基，不代表R的个数。
本申请中部分取代基的“
”处为连接位点。
本申请中基团
中的*代表环上连接的甲基为顺式结构。
在本文中，术语“卤素”表示氟、氯、溴和/或碘。
术语“C1-6烷基”应理解为表示具有1、2、3、4、5、或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子（“C1-3烷基”），例如甲基、乙基、正丙基或异丙基。
术语“C3-6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3、4、5或6个碳原子。所述C3-12环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“3-6元含O杂环基”意指饱和的一价单环，其包含1个O原子，进一步任选1个独立选自N、O和S的杂原子，其总原子个数为3、4、5或6个。
术语“3-12元含N杂环基”意指饱和的一价单环或双环烃环，其包含1个N原子，进一步任选1-3个选自N、O和S的杂原子。其总原子个数为3、4、5、6、7、8、9、10、11或12个。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，或者它可以是苯并稠合的。
术语“-C1-6烷氧基”表示“-O-C1-6烷基”，其中C1-6烷基具有如上所述定义。
在本文中，“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
附图说明
图1为测试例3在酵母聚糖耗竭诱导的骨髓衍生树突状细胞的炎症模型中化合物4，7和MLi-2的剂量对细胞炎症的抑制效果之间的关系图。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
以下实施例中化学式或英文字母缩写代表的试剂中文名称如下：
DMF: N,N-二甲基甲酰胺；
DMSO: 二甲基亚砜；
[Ir(OMe)(1,5-cod)]2：甲氧基(环辛二烯)合铱二聚体；
PdCl2(dppf)：1,1’-二茂铁二基-双(二苯基膦)二氯化钯；
NIS：N-碘代丁二酰亚胺
实施例 1: 4-(6-(5-异丙氧基-6-甲基-1H-吲唑-3-基)-2-甲基嘧啶-4-基)吗啉
步骤1：在6-甲基-1H-吲唑-5-醇 (2 g, 13.50 mmol) 的DMF(20 mL）溶液中加入2-碘丙烷 (2.52 g, 14.85 mmol) 和碳酸铯 (8.80 g, 27.00 mmol)，室温搅拌4个小时。将溶剂蒸干后，柱层析纯化得到化合物1-1 (1.20 g, 收率47% )。 1H NMR (DMSO-d6, 400MHz): δ (ppm) 1.24 (d, J=6.0 Hz, 6H), 2.17 (s, 3H), 4.46 - 4.59 (m, 1H), 7.08(s, 1H), 7.22 - 7.28 (q, J=1.0 Hz, 1H), 7.80 (t, J=1.3 Hz, 1H), 12.60 (s,1H)。
步骤2：室温下往化合物1-1 (1.2 g, 6.31 mmol) 的DMF (20 mL) 溶液中加入NIS (1.70 g, 7.57 mmol)，搅拌2个小时。加入20 mL亚硫酸氢钠饱和溶液淬灭反应，用乙酸乙酯萃取水相。有机相合并后，用饱和食盐水洗，干燥浓缩，硅胶柱层析纯化得到化合物1-2 (1.25 g, 收率63% )。
LCMS: 317.0 [M+H]+。
步骤3：室温下往化合物1-2 (1.2 g, 3.80 mmol) 的二氯甲烷 (20 mL) 溶液中加入4-二甲氨基吡啶 (46.37 mg, 379.58 μmol)、二碳酸二叔丁酯 (1.24 g, 5.69 mmol)和三乙胺 (768.19 mg, 7.59 mmol)，室温搅拌16个小时。反应结束加入20 mL的饱和氯化铵溶液，用乙酸乙酯萃取水相。有机相合并后水洗干燥浓缩，所得粗产品经硅胶柱层析纯化得到化合物1-3 (890 mg, 收率56%)。LCMS: 361.0 [M+H-56]+。1H NMR (氘代氯仿，400MHz): δ (ppm) 1.37 (s, 3H), 1.40 (s, 3H), 1.70 (s, 9H), 2.35 (d, J = 0.9 Hz,3H), 4.57 - 4.68 (m, 1H), 6.73 (s, 1H), 7.90 (s, 1H)。
步骤4：往化合物1-3 (100 mg, 240.24 μmol) 和六正丁基二锡 (418.09 mg,720.72 μmol)的二甲苯 (2 mL) 溶液中加入四三苯基膦钯 (83.28 mg, 72.07 μmol)，加热到120℃反应16个小时。 纯化得到化合物1-4 (65.00 mg, 收率47%)。 1H NMR (400MHz, 氘代氯仿)： δ (ppm)7.90 (s, 1H), 6.98 (s, 1H), 4.56 - 4.48 (m, 1H), 2.34(s, 3H), 1.75 - 1.68 (m, 9H), 1.56 - 1.50 (m, 6H), 1,44 - 1.38 (m, 13H), 1,30- 1.2 (m, 5H), 0.92 - 0.85 (m, 9H)。
步骤5：往化合物1-4 (65 mg, 112.18 μmol) 和4-(6-碘-2-甲基-嘧啶-4-基)吗啉 (68.46 mg, 224.37 μmol) 的DMF (2 mL) 溶液中加入四三苯基膦钯 (12.96 mg,11.22 μmol) 和碘化亚铜 (2.14 mg, 11.22 μmol)。 加热到90℃反应16个小时。反应液冷却至室温后浓缩得到粗产品。粗产品经柱层析纯化得到化合物1-5 (25 mg, 收率46%)。LCMS: 368.2 [M+H-100]+。
步骤6：往化合物1-5 (25 mg, 0.053 mmol) 的二氯甲烷 (5 mL) 溶液中加入盐酸 (1N, 1 mL)，室温搅拌1个小时。反应结束后把反应液倒入乙醚中，过滤得到化合物1(11.46 mg, 收率58%)。LCMS: 368.2 [M+H]+。 1H NMR (DMSO-d6, 400 MHz): δ (ppm)8.30 (s, 1H), 8.01(s, 1H), 7.33(s, 1H), 7.17(s, 1H), 4.54 - 4.57 (m, 1H),3.68 - 3.66 (m, 4H), 3.62 - 3.59 (m, 4H), 2.49 (s, 3H), 2.25 (s, 3H), 1.35(s,3H), 1.33(s, 3H)。
实施例2：4-(6-(5-异丙氧基-6-甲基-1H-吲唑-3-基)-2-甲氧基嘧啶-4-基)吗啉
步骤1：在化合物1-4 (98 mg, 169.14 μmol) 和4-(6-氯-2-甲氧基-嘧啶-4-基)吗啉 (50.50 mg, 219.88 μmol) 的二甲苯 (4 mL) 溶液中加入四三苯基膦钯 (58.64mg, 50.74 μmol)。加热到125℃ 反应16个小时。反应液冷却浓缩后经柱层析纯化得到化合物2-1 (38.00 mg, 收率45.07%)。LCMS: 484.1[M+H]+。
步骤2：往化合物2-1 (38 mg, 78.58 μmol) 的甲醇 (2 mL) 溶液中加入2M的盐酸甲醇溶液 (2 mL)。加热到50℃ 反应30分钟。反应完全后把反应液倒入水中，用乙酸乙酯萃取水相。合并的有机相干燥浓缩，纯化得到化合物2 (19.80 mg, 收率63.71%)。LCMS:384.2[M+H]+。1H NMR (400 MHz, DMSO-d6): δ (ppm)13.23 (s, 1H), 7.94 (s, 1H),7.34 (s, 1H), 7.05 (s, 1H), 4.55 - 4.52 (m, 1H), 3.95 (s, 3H), 3.65 - 3.59(m, 8H), 2.24 (s, 3H), 1.25 (d, J = 4.0 Hz, 6H)。
实施例 3: 对映异构体混合物顺式-4-(2-甲氧基-6-(6-甲基-5-(1-甲基环丙氧基)-1H-吲唑-3-基)嘧啶-4-基)-2,6-二甲基吗啉
步骤1：往6-甲基-1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-醇 (200 mg, 0.861mmol) 的 DMF (10 mL) 溶液中加入 2,4-二溴丁酸甲酯 (335.71 mg, 1.29 mmol) 和碳酸铯 (701.35 mg, 2.15 mmol)，室温下反应3个小时。过滤后，把滤液浓缩纯化得到化合物3-1 (250 mg，收率71%)。LCMS: 411.1 [M+H]+。
步骤2：往化合物 3-1 (180 mg, 0.438 mmol) 的四氢呋喃 (5 mL) 溶液中加入叔丁醇钾 (8.17 mg, 0.073 mmol)，室温反应3个小时。反应完全后加入饱和氯化铵 (5mL)，用乙酸乙酯萃取水相。合并的有机相经干燥浓缩得到粗产物化合物 3-2 (133 mg)。LCMS: 331.2 [M+H]+。
步骤3：0℃下往化合物3-2 (250 mg, 0.757 mmol) 的四氢呋喃 (10 mL) 溶液中加入氢化铝锂 (1.135 mL, 1.135 mmol)，反应2个小时。淬灭后用乙酸乙酯萃取，有机相干燥浓缩得到粗产物。粗产物用硅胶柱层析纯化得到化合物3-3 (200 mg, 收率87%)。 LCMS:303.1[M+H]+。 1H NMR (氘代氯仿, 400 MHz): δ (ppm) 7.86 (s, 1H), 7.32 (s, 1H),7.28 (s, 1H), 5.57 (s, 1H), 3.96 (d, J = 11.7 Hz, 1H), 3.95 - 3.84 (m, 2H),3.77 - 3.68 (m, 1H), 2.64 - 2.47 (m, 1H), 2.35 - 2.29 (m, 3H), 2.22 - 2.10(m, 1H), 2.08 - 2.00 (m, 1H), 1.81 - 1.73 (m, 2H), 1.68 - 1.58 (m, 2H), 1.12- 1.05 (m, 2H), 0.97 - 0.92 (m, 2H)。
步骤4：0℃下往三苯基膦 (52.05 mg, 0.198 mmol) 的二氯甲烷 (1 mL) 溶液中加入咪唑 (13.51 mg, 0.198 mmol) 和碘单质 (50.36 mg, 0.198 mmol)。溶解后把该溶液加入到化合物3-3 (50 mg, 0.165 mmol) 的二氯甲烷 (1 mL) 溶液中，0℃ 下反应3个小时。反应结束后浓缩反应液，柱层析纯化得到化合物3-4 (50 mg, 收率73%)。 LCMS:413.1[M+H]+。 1H NMR (氘代氯仿, 400 MHz): δ (ppm) 7.87 (s, 1H), 7.36 (s, 1H),7.23 (s, 1H), 5.70 - 5.60 (m, 1H), 4.06 - 3.98 (m, 1H), 3.82 - 3.70 (m, 1H),3.60 - 3.58 (m, 2H), 2.62 - 2.50 (m, 1H), 2.37 (s, 3H), 2.21 - 2.10 (m, 1H),2.10 - 2.02 (m, 1H), 1.82 - 1.70 (m, 2H), 1.69 - 1.59 (m, 1H), 1.50 - 1.42(m, 2H), 1.08 - 1.00 (m, 2H) 。
步骤5：往化合物 3-4 (230 mg, 0.558 mmol) 的 DMSO (1 mL) 溶液中加入硼氢化钠 (21.1 mg, 0.558 mmol)。90℃ 下反应1个小时。加入水 (10 mL) 淬灭反应，用乙酸乙酯萃取。有机相水洗干燥，浓缩后得到化合物 3-5 (130 mg, 收率81%)。LCMS: 287.3 [M+H]+。
步骤6：往化合物 3-5 (150 mg, 0.524 mmol) 的甲基叔丁基醚 (5 mL) 溶液中加入[Ir(OMe)(1,5-cod)]2 (17.15 mg, 0.026 mmol)、4,4-二-叔-丁基-2,2-联吡啶(14.06 mg, 0.052 mmol) 和双联频哪醇硼酸酯 (159.61 mg, 0.629 mmol)。加热到90℃反应18个小时。浓缩后硅胶柱层析纯化得到化合物 3-6 (180 mg, 收率83%)。LCMS: 339.1[M+H]+。
步骤7：往化合物3-6 (100 mg, 0.252 mmol) 的1,4-二氧六环 (4 mL) 和水 (1mL) 溶液中加入顺式-4-(6-氯-2-甲氧基嘧啶-4-基)-2,6-二甲基吗啉 (78.03 mg, 0.303mmol)、碳酸钾 (104.61 mg, 0.757 mmol) 和PdCl2(dppf) (18.46 mg, 0.025 mmol)。加热到90℃反应18个小时。加入乙酸乙酯和饱和氯化铵萃取，有机相经水洗浓缩，用硅胶柱层析纯化得到化合物3-7 (30 mg, 收率24%)。LCMS: 508.4 [M+H]+。
步骤8：往化合物3-7 (20 mg, 0.04 mmol) 的甲醇 (4 mL) 溶液中加入盐酸 (1mL, 4.0 mmol)。加热到50℃反应4个小时。浓缩后用制备HPLC纯化得到化合物3 (9.73mg)。 LCMS: 424.2[M+H]+。1H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.35 - 13.17 (s,1H), 8.18 (s, 1H), 7.31 (s, 1H), 7.09 (s, 1H), 4.34 - 4.18 (m, 2H), 3.96 (s,3H), 3.62 - 3.50 (m, 2H), 2.59 - 2.48 (m, 2H), 2.16 (s, 3H), 1.53 (s, 3H),1.17 - 1.12 (d, J = 6.1 Hz, 6H), 0.94 - 0.88 (m, 2H), 0.75 - 0.66 (m, 2H)。
实施例 4: 7-(2-甲氧基-6-(6-甲基-5-(1-甲基环丙氧基)-1H-吲唑-3-基)嘧啶-4-基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪
步骤1：往1,5,6,7,8,8a-六氢咪唑并[1,5-a]吡嗪 (244 mg, 1.95 mmol) 的乙醇(15 mL) 溶液中加入4,6-二氯-2-甲氧基嘧啶 (418.72 mg, 2.339 mmol) 和碳酸钾(808.20 mg, 5.85 mmol)。加热到60℃反应18个小时。反应完全后加入水和乙酸乙酯萃取，有机相水洗干燥，浓缩后用柱层析纯化得到化合物4-1 (330 mg, 收率63%)。
步骤2：往化合物3-6 (100 mg, 0.252 mmol) 的1,4-二氧六环 (4 mL) 和水 (1mL) 溶液中加入化合物4-1 (80.45 mg, 0.303 mmol)、碳酸钾(104.61 mg, 0.757 mmol)和PdCl2(dppf) (18.46 mg, 0.025 mmol)。加热到90℃反应18个小时。反应完全后，冷却到室温，加入乙酸乙酯和饱和氯化铵溶液。有机相水洗干燥浓缩，柱层析纯化得到化合物4-2(33 mg, 收率26%)。LCMS: 516.3 [M+H]+。
步骤3：往化合物4-2 (23 mg, 0.045 mmol) 的甲醇 (2 mL) 溶液中加入盐酸(0.5 mL)，加热到50℃反应4个小时。浓缩后用制备HPLC纯化得到化合物4 (8.74 mg, 收率45%)。LCMS: 508.2[M+H]+。 1H NMR(DMSO-d6, 400 MHz): δ (ppm) 13.37 - 13.22 (s,1H), 8.15 (s, 1H), 7.54 (s, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 6.72 (s, 1H),4.89 - 4.80 (m, 2H), 4.22 - 4.12 (m, 2H), 4.05 - 3.98 (m, 6H), 2.22 - 2.13(m, 3H), 1.49 (s, 3H), 0.97 - 0.88 (m, 2H), 0.75 - 0.66 (m, 2H)。
实施例 5: 5-(2-甲氧基-6-(6-甲基-5-(1-甲基环丙氧基)-1H-吲唑-3-基)嘧啶-4-基)-2-甲基-4,5,6,7-四氢恶唑并[4,5-c]吡啶
使用化合物4相同的方法，用2-甲基-4,5,6,7-四氢[1,3]恶唑并[4,5-c]吡啶作原料合成化合物5。LCMS: 447.1 [M+H]+。1H NMR (DMSO-d6, 400 MHz): δ (ppm) 13.20 (s,1H), 8.18 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 4.59 - 4.46 (m, 2H), 4.06 -3.96 (m, 5H), 2.82 - 2.72 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.47 (s, 3H),0.95 - 0.88 (m, 2H), 0.74 - 0.68 (m, 2H)。
实施例 6: 3-[2-甲氧基-6-(4-甲基-4-氧亚基-4λ5-1,4-氮杂磷杂环己-1-基)嘧啶-4-基]-6-甲基-5-[(甲基环丙基)氧基]-1H-吲唑
使用化合物4相同的方法，用4-甲基-1,4-氮杂膦烷4-氧化物盐酸盐作原料合成化合物6。LCMS: 441.9 [M+H]+。1H NMR (400 MHz, 氘代甲醇): δ (ppm) 8.24 (s, 1H),7.31 (s, 1H), 7.26 (s, 1H), 4.29 - 4.16 (m, 2H), 4.13 (s, 3H), 4.09 - 3.98(m, 2H), 2.26 (s, 3H), 2.10 - 1.99 (m, 4H), 1.66 (d, J = 13.4Hz, 3H) 1.62 (s,3H), 1.03 - 1.00(m, 2H), 0.77-0.74 (m, 2H)。
实施例 7: 对映异构体混合物顺式-4-(2-甲氧基-6-(6-甲基-5-(四氢-2H-吡喃-4-基)-1H-吲唑-3-基)嘧啶-4-基) -2,6-二甲基吗啉
步骤1：往5-溴-6-甲基-1-(3,4,5,6-四氢-2H-吡喃-2-基)吲唑 (2 g, 6.77mmol) 的1,4-二氧六环(15 mL) 和水 (5 mL) 溶液中加入2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧硼烷 (1.42 g, 6.77 mmol)、碳酸钾 (2.81 g, 20.32 mmol)和PdCl2(dppf) (495 mg, 0.68 mmol)。加热到90℃反应16个小时。加入乙酸乙酯和饱和氯化铵，有机相水洗干燥，浓缩纯化得到化合物7-1 (1.2 g, 收率50%)。LCMS: 299.2 [M+H]+。
步骤2：往化合物7-1 (1.2 g, 4.02 mmol) 的甲醇溶液中加入氢氧化钯 (112.95mg, 0.80 mmol)。通入氢气室温反应16个小时。过滤后，滤饼用甲醇 (20 mL) 冲洗，把滤液浓缩得到化合物7-2 (1.1 g, 收率82%)。LCMS: 301.3[M+H]+。
步骤3：往化合物7-2 (300 mg, 1.00 mmol) 的甲基叔丁基醚 (5 mL)溶液中加入[Ir(OMe)(1,5-cod)]2 (26.17 mg, 0.04 mmol)、4,4-二-叔-丁基-2,2-联吡啶 (26.80mg, 0.10 mmol) 和双联频哪醇硼酸酯 (253.60 mg, 1.00 mmol)。加热到80℃反应16个小时。浓缩后硅胶柱层析纯化得到化合物7-3 (320 mg)。 LCMS: 345.2 [M+H]+。
步骤4：往化合物7-3 (200 mg, 0.47 mmol) 的1,4-二氧六环 (6 mL) 和水 (1mL) 溶液中加入6-氯-4-[顺式-2,6-二甲基-1,4-恶嗪-4-基]-2-甲氧基嘧啶 (132.98 mg,0.52 mmol)、碳酸钾(194.48 mg, 1.41 mmol) 和PdCl2(dppf) (34.32 mg, 0.047 mmol)。加热到105℃反应18个小时。加入乙酸乙酯和饱和氯化铵，有机相水洗浓缩，用硅胶柱层析纯化得到化合物7-4 (120 mg, 收率39%)。LCMS: 522.4[M+H]+。
步骤5：往化合物7-4 (120 mg, 0.230 mmol) 的甲醇 (5 mL) 溶液中加入4M的盐酸甲醇 (420.09 mg, 2.30 mmol)。加热到50℃反应18个小时。浓缩后用制备HPLC纯化得到化合物7 (53.11 mg, 收率50%)。 LCMS: 438.3 [M+H]+。 1H NMR (400 MHz, DMSO-d6): δ(ppm) 13.28 (s, 1H), 8.44 (s, 1H), 7.38 (s, 1H), 7.13 (s, 1H), 4.29 (s, 2H),4.02 (s, 3H), 3.99 - 3.97 (m, 2H), 3.62 - 3.48 (m, 4H), 3.06 - 3.01 (m, 1H),2.59 - 2.57 (m, 2H), 2.47 (s, 3H), 1.76 - 1.65 (m, 4H), 1.18 (s, 3H), 1.17(s, 3H)。
测试例1、应用ADP-Glo实验法测定本发明化合物对LRRK2酶的抑制活性
采用Promega的ADP-Glo试剂（V9102）监测在LRRK2激酶反应期间二磷酸腺苷(ADP) 的形成。完成后，停止测定，测量ADP转化为ATP产生的发光信号。具体筛选方案如下：
1、在100% DMSO中将10 mM化合物原液稀释至最大浓度9.99 μM，然后在 DMSO 中连续稀释九次进行制备。
2、 使用Echo 550将化合物稀释液转移到384孔测定板孔中，并在密封板中以1000g 离心1分钟。
3、将2 ng/μL的LRRK2酶 (Invitrogen，PR8604B)加入到1x激酶缓冲液中后，取2.5μl添加到测定板的每个孔中。将测定板在室温下孵育 10 分钟。
4、孵育后加入2.5μl的2x底物（Invitrogen，LRRK2多肽底物）和ATP（Promega，V910B）混合物启动反应。
5、室温孵育2小时后，在测试孔中加入4 μL ADP-Glo 试剂。
6、室温孵育40分钟后加入8 μL激酶检测试剂。
7、室温孵育40分钟后，在Envision 2104读板器上读取发光信号，使用GraphPad6.0分析结果。测定数据基于多个测试结果的平均IC50值，并且可能有合理的偏差，具体取决于所用的特定条件和试剂。
表1汇总了化合物的LRRK2激酶活性的抑制效应(IC50)。
表1
| 化合物编号 | IC50(nM) |
| 化合物 1 | 2.46 |
| 化合物 2 | 0.88 |
| 化合物 3 | 1.27 |
| 化合物 4 | 0.86 |
| 化合物 5 | 1.26 |
| 化合物 6 | 1.11 |
| 化合物 7 | 1.66 |
。
测试例2、应用HTRF实验法测定本发明化合物在野生型和G2019S重组细胞中对LRRK2激酶活性的抑制作用
一、G2019S质粒瞬时转染
1、将DMEM介质、FBS、PBS、Trans-IT、OPTI-MEM加热至室温。
2、HEK293T 细胞在DMEM + 10% FBS完全培养基中培养，直至转染前约 80% 汇合。
3、用10 mL PBS洗涤细胞并用3 mL 0.25% 胰蛋白酶分离。
4、将30×10^6 HEK293T细胞接种在15厘米培养皿中的DMEM + 10% FBS 完全培养基中。
5、制备 DNA:Trans IT-LT1:OPTI-MEM复合物 (20μg:60μL:2000μL)。
6、将2000 μL OPTI-MEM 添加到15 mL锥形管中，然后将20 μg质粒添加到OPTI-MEM中并混合，然后将60 μL TransIT-LT1添加到质粒OPTI-MEM混合物中，混合后孵育15分钟。
7、将上述质粒、DNA 和OPTI-MEM混合物滴加到15 cm 培养皿中。轻轻地来回摇晃培养皿，从左到右均匀分布复合物。
8、将转染的培养皿在37 ℃和5% CO2条件下孵育24小时。
二、测试化合物活性
1、将G2019S转染的HEK293或未转染HEK293细胞分别转移到培养皿接种，细胞悬液浓度为2×10^5个/ml。
2、用Tecan将化合物稀释液转移到384孔测定板孔中，以1000 rpm转速旋转板 1分钟。
3、37ºC、5% CO2条件下孵育2小时后，移除培养基。
4、向反应孔中加入16 μL补充裂解缓冲液（裂解缓冲液+水+储备封闭试剂），并在室温下振荡孵育30分钟（800 rpm/min）。
5、向反应孔中加入4 μL抗体工作液（检测缓冲液+ d2-抗体原液+Cryptate-抗体原液），盖上封口，23℃ 培养箱孵育过夜。
6、在Envision 2104读板器上读取665 nm和615 nm波长下的发光信号，使用XLfit分析结果。
表2汇总了化合物的细胞活性的抑制效应(IC50)。
表2
| 化合物编号 | G2019S IC50(nM) | 野生型IC50(nM) |
| 化合物 1 | 10.6 | 9.0 |
| 化合物 2 | 2.2 | 1.5 |
| 化合物 3 | <1.5 | <1.5 |
| 化合物 4 | <1.5 | 1.6 |
| 化合物 5 | 2.6 | 3.6 |
| 化合物 6 | 1.9 | 2.8 |
| 化合物 7 | 3.7 | 3.5 |
。
测试例3、应用酵母聚糖耗竭诱导骨髓衍生树突状细胞的炎症模型评估化合物对细胞炎症的抑制作用
参照文献An increase in LRRK2 suppresses autophagy and enhancesDectin-1-induced immunity in a mouse model of colitis中的方法，用23G针头和IMDM培养基(Invitrogen, 12440053)冲洗小鼠股骨和胫骨后，采集小鼠骨髓衍生树突状细胞。将获得的细胞(1×10^6/mL)在培养液(IMDM培养基+10% FBS (Corning, 315-018-CV)+青霉素/链霉素(Hyclone, SV30010)+12.5 ng/mL 重组小鼠GM-CSF蛋白(R&D, 404-ML)+10ng/mL 重组小鼠IL-4蛋白(R&D, 415-ml))中孵育2天。第三天更换一半的新鲜培养液。第五天加入2 mL新鲜配制的培养液。孵育第六天，收集细胞，用PBS清洗两次后，用IMDM+10%FBS溶液调整细胞数至2×10^6/mL。将50 μL上述细胞液与50 μL待测化合物培养30分钟，随后加入50 μL 400 μg/mL的ZymD和50 μL待测化合物。孵育24小时后，取100 μL上清液用酶联免疫吸附法测定TNFα的浓度。化合物4和7展示了剂量依赖的抗炎效果，测试结果如图1所示。可见本发明所述化合物对细胞炎症具有抑制效果。
图1中MLi-2为文献J Med Chem, 2017, 60 (7): 2983-2992中公开的化合物，其结构式如下所示：
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.式I所示的化合物，或其药学上可接受的盐：
其中，
R2选自C1-6烷基；
为/>
时，R1为3-6元含O杂环基；
当
时，R1选自-O-C3-6环烷基，所述-O-C3-6环烷基中C3-6环烷基与O相连的碳原子上的H任选被C1-6烷基取代。
2.根据权利要求1所述的化合物，其特征在于，R2选自C1-3烷基；
当
时，R1选自-O-C3-6环烷基，所述-O-C3-6环烷基中C3-6环烷基与O相连的碳原子上的H任选被C1-3烷基取代。
3.根据权利要求1或2所述的化合物，其特征在于，所述化合物选自如下：
4.权利要求1-3任一项所述式I所示化合物，或其药学上可接受的盐在制备预防和/或治疗LRRK2的通路异常引起的疾病的药物中的用途。
5.根据权利要求4所述的用途，其特征在于，所述LRRK2的通路异常引起的疾病为帕金森氏症或炎症性肠病。
6.根据权利要求5所述的用途，其特征在于，所述炎症性肠病包括克罗恩病和溃疡性结肠炎。
7.一种药物组合物，其包括权利要求1-3任一项所述式I所示化合物，或其药学上可接受的盐。
8.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物用于预防和/或治疗LRRK2的通路异常引起的疾病。
9.根据权利要求8所述的药物组合物，其特征在于，所述LRRK2的通路异常引起的疾病为帕金森氏症或炎症性肠病。
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