CN117946100A - 4H-吡咯并[3,2-c]吡啶-4-酮化合物 - Google Patents
4H-吡咯并[3,2-c]吡啶-4-酮化合物 Download PDFInfo
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- CN117946100A CN117946100A CN202311714944.0A CN202311714944A CN117946100A CN 117946100 A CN117946100 A CN 117946100A CN 202311714944 A CN202311714944 A CN 202311714944A CN 117946100 A CN117946100 A CN 117946100A
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- pyridin
- pyrrolo
- tetrahydro
- methoxy
- chloro
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
式(I)化合物、它们的制备方法和它们作为药物的用途。
Description
发明领域
本发明涉及取代的4H-吡咯并[3,2-c]吡啶-4-酮化合物、它们的制备方法及其用途。
发明背景
表皮生长因子受体(EGFR或EGF-受体)受体酪氨酸激酶家族由4个成员组成:EGFR(Erbb1、Her1)、ERBB2(Her2)、ERBB3(Her3)和ERBB4(Her4)。EGFR介导MAPK和PI3K信号通路的激活,从而调节细胞增殖、分化、迁移和存活(Pao等人,2010)。EGFR基因扩增、过表达和突变在各种癌症适应症中经常观察到,并且与不良预后相关(Gridelli等人,2015)。
在肺腺癌中,大约15%的西方患者和高达50%的东亚患者普遍存在EGFR突变(Paez等人,2004)。这些突变通常发生在EGFR激酶域中的四个外显子(外显子18-21)之一(Paez等人,2004)。EGFR中最常见的激活突变是外显子21中的点突变(用精氨酸代替亮氨酸(L858R)),以及去除了四个氨基酸的外显子19中的小框内缺失(del19/del746-750)(Pao等人,2010)。FDA批准的靶向EGFR的外显子18、19和21突变的抑制剂吉非替尼、厄洛替尼和阿法替尼对患者有效,但反应通常不持久(Mok等人,2009;Sequist等人,2013)。这些患者在获得第二个突变T790M时经常出现耐药性(Pao等人,2005)。第二代抑制剂,例如阿法替尼不可逆地靶向这种突变,但仍然是野生型EGFR的有效抑制剂,导致剂量限制性毒性并对患者缺乏疗效。第三代不可逆抑制剂奥希替尼(osimertinib)可最大限度地提高对T790M的活性,同时最大限度地降低对野生型EGFR的活性,其对T790M突变患者有效,目前是T790M阳性患者的标准治疗方法(Mok等人,2017)。奥希替尼也被批准作为EGFR外显子19或21的突变患者的一线疗法(Soria等人,2018)。
然而,患者也会对不可逆的第三代EGFR抑制剂(如奥希替尼)产生耐药性。确定的主要奥希替尼耐药机制之一是第797位半胱氨酸突变为丝氨酸,导致失去共价相互作用的半胱氨酸,并对不可逆EGFR抑制剂失去敏感性,此时进展患者目前只有有限的治疗选择(Thress等人,2015;Oxnard等人,2018)。在不存在T790M突变的情况下,当奥希替尼用作一线治疗时,也可能发生此类C797S突变(Ramalingham等人,2018a;Ramalingham等人,2018b)。一种能够专门解决EGFR-C797S获得性抗性突变的新型靶向治疗对那些患者非常有益。
相比之下,除A763_Y764insFQEA外,EGFR外显子20的小框内插入在肺癌患者可达到的剂量下对所有临床批准的EGFR抑制剂耐药,并且包含未满足的医疗需求(Yasuda等人,2013)。
具有EGFR外显子20插入(例如V769_D770insASV、D770_N771insSVD、D770_N771insNPG、N771_P772insH、H773_V774insH、H773_V774insNPH、V774_C775insHV)的患者对所有目前批准的EGFR靶向治疗表现出特别低的反应率,导致无进展生存期和总生存期显着降低(Chen等人,2016)。这已在第一代抑制剂厄洛替尼和吉非替尼以及第二代抑制剂阿法替尼中得到证实(Chen等人,2016;Yang等人,2015)。
因此,目前EGFR外显子20插入患者的标准治疗是化疗。
对于EGF受体家族的另一个成员(Arcila等人,2012)ERBB2中的外显子20插入突变(例如ERBB2A775_G776insYVMA患病率最高)和一些不常见的EGFR突变如L681Q(Chiu等人,2015)也观察到了相同的耐药性。
几种不可逆抑制剂目前正在进行临床试验,用于治疗EGFR外显子20插入患者:奥希替尼,最初批准用于治疗T790M突变NSCLC患者(Floc′h等人,2018);波齐替尼(HM-781-36B),一种未经批准的靶向EGFR、Her2/neu和Her4的泛Her抑制剂(Robichaux等人,2018);以及TAK-788(AP32788)(Doebele等人,ASCO2018)。其中,波齐替尼和TAK-788的首个临床数据已经发表。两种化合物在EGFR外显子20插入患者中均清楚地显示出临床疗效。然而,两项临床试验均报告了由抑制野生型EGFR介导的主要不良事件,并且这些不良事件可能会限制临床效用。
最近,已经发布了两种其他化合物的新临床前数据,这些化合物显示出对EGFR外显子20插入的活性:TAS6417(TCP-064)和化合物1a(Hasako等人,2018;Jang等人,2018)。这两种化合物尚无临床结果。
总之,突变EGFR是癌症治疗的有前途的药物靶点。特别地,由于EGFR外显子20插入,对批准的抗EGFR疗法具有原发性耐药的患者迄今为止只有很少的治疗选择,并且非常需要新的替代疗法和/或改进的疗法来为这些患者提供有效、耐受良好的疗法(Oxnard等人,2013)。因此,突变EGFR的有效抑制剂,尤其是具有外显子20插入突变的突变EGFR的抑制剂,与野生型EGFR相比显示出更高的选择性,其代表有价值的化合物,可以作为单一药物或与其他药物组合补充治疗选择。
发明概述
本发明提供了在存在或不存在C797S突变的情况下抑制突变EGFR(特别是包含一个或多个外显子20插入突变、L858R突变或外显子19的小框内缺失的EGFR)的化合物。此外,这些化合物对野生型-EGFR的活性降低。
现已发现,本发明的化合物具有令人惊奇且有利的特性。
特别地,已经令人惊讶地发现本发明的所述化合物有效抑制具有外显子20插入突变的突变EGFR,特别是携带D770_N771ins SVD外显子20插入的那些突变EGFR,其IC50低于5nM。此外,已经发现这些化合物在携带EGFR V769_D770insASV、D770_N771insSVD、D770_N771insNPG、N771_P772insH或H773_V774insNPH外显子20插入的BA/F3细胞系中还显示出低于1μM的细胞效力。此外,文中描述的化合物在携带D770_N771insSVD C797S的BA/F3细胞系中具有活性。此外,文中描述的化合物有效抑制携带EGFR激活突变(具有或没有C797S获得性抗性突变(EGFR E746_A750del,L858R,E746_A750del C797S,L858R C797S)、不常见的EGFR突变(EGFR L681Q)或ERBB2外显子20插入A775_G776insYVMA)的BA/F3细胞系的增殖。
令人惊讶的是,这些化合物在携带EGFR D770_N771ins SVD外显子20插入的BA/F3细胞系相对于携带野生型EGFR的BA/F3细胞的抗增殖试验中还显示出至少5倍的选择性,并且因此可以用于治疗或预防不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答的疾病,或者伴随有不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答的疾病,其中所述不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答是由具有外显子20插入突变的突变EGFR介导,和/或减少(或阻断)携带EGFR外显子20插入突变的细胞增殖,例如血液肿瘤、实体瘤和/或它们的转移瘤,例如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其他妇科肿瘤、包括肾肿瘤、膀胱肿瘤和前列腺肿瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移瘤。
发明内容
根据第一方面,本发明涉及式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,
其中:
R1代表甲基、乙基、三氟甲基、2,2-二氟乙基、氰基、氯、溴、甲氧基或二氟甲氧基;
R2代表氢、甲基、乙基、氟、氯或溴;
R3代表氢或氟;
R4代表氢或甲基;
R5在每次出现时独立地代表氢、三氟甲基或C1-C3烷基,R5与该环的任何碳原子结合;
R6在每次出现时独立地代表氢、C1-C3-烷基或C1-C3-卤代烷基;
R7代表C1-C3-烷基或C2-C3-卤代烷基;
R8代表C1-C3-烷基或C2-C3-卤代烷基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1、2或3;
n代表0或1。
在一些实施方案中,至少两个R5基团是孪位基团(geminal groups)(即,连接到相同的碳原子)。
在第二方面,本发明涉及如上文所述的式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,
其中:
R1代表甲基、乙基、氯、甲氧基或二氟甲氧基;
R2代表甲基、乙基、氟或氯;
R3代表氢或氟;
R4代表氢或甲基;
R5代表氢、甲基或三氟甲基,R5与该环的任何碳原子结合;
R6代表氢、甲基或三氟甲基;
R7代表C1-C2-烷基或C2-C3-氟代烷基;
R8代表C1-C2-烷基或C2-C3-氟代烷基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1或2;
n代表0或1。
在第三方面,本发明涉及如上文所述的式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,
其中:
R1代表甲基、乙基、氯或甲氧基;
R2代表氟或氯;
R3代表氢或氟;
R4代表氢;
R5代表氢或甲基,R5与该环的任何碳原子结合;
R6代表氢;
R7代表甲基;
R8代表甲基、2,2,2-三氟乙基或2,2-二氟乙基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1或2;
n代表0或1。
在第四方面,本发明涉及如上文所述的式(I)化合物,其选自:
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-4-(2,2-二氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[2-(4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{2-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{2-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{2-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{2-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1S)-1-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1S)-1-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1R)-1-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1R)-1-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮。
本发明的另一方面涉及式(I)化合物,其以它们的盐的形式存在。
应当理解,本发明涉及上述通式(I)的化合物的本发明的任何实施方案或方面内的任何亚组合。
再更特别地,本发明涵盖以下本文本的实施例部分中公开的通式(I)的化合物。
根据另一方面,本发明涵盖制备本发明化合物的方法,所述方法包括如本文实验部分中所述的步骤。
本发明的另一个实施方案是如权利要求部分所公开的化合物或所公开的示例化合物的类似物及其亚组合。
定义
应当理解,本文公开的实施方案并不意味着被理解为彼此不相关的单个实施方案。结合本发明的一个实施方案或方面讨论的特征意在还结合在此示出的本发明的其他实施方案或方面来公开。如果在一种情况下,特定特征未与本发明的一个实施方案或方面一起公开,但与另一实施方案或方面一起公开,则技术人员会理解,这并不一定意味着所述特征不会与本发明的所述其他实施方案或方面一起公开。本领域技术人员将理解,本申请的主旨是也针对本发明的其他实施方案或方面公开所述特征,但这只是为了清楚起见并保持本说明书的长度易于管理。例如应当理解,本文中定义的式(I)化合物的本发明的所有方面、实施方案、药物组合物、组合、用途和/或方法也涉及式(I)化合物的更具体的实施方案,例如但不限于式(Ia)的化合物,反之亦然。
还应理解,本文中引用的文件的内容通过引用以其整体并入,例如,用于启用目的,即当例如讨论了一种方法,其细节在所述文件中进行了描述。这种方法有助于使本说明书的长度易于管理。
除非另外指出,如本文所述任选取代的组分可以在任何可能的位置彼此独立地被取代一次或多次。当任何变量在任何组分中出现超过一次时,每个定义是独立的。例如,当R1、R1a、R1b、R1c、R2、R3和/或R4在任何式(I)的化合物中出现超过一次时,R1、R1a、R1b、R1c、R2、R3和R4的各自定义是独立的。
当组分由多于一个部分组成时,例如C1-C4-烷氧基-C2-C4-烷基,可能的取代基的位置可以在这些部分中的任一个的任何合适的位置。在组分开头处或末尾处的连字符标示与分子剩余部分的连接点。当环是取代的时,取代基可以在环的任何合适的位置,如果合适,还可以在环氮原子上。
当用于本说明书时,术语“包含”包括“由...组成”。
如果在描述中提到“如上所述”或“上述”、“如上”,其是指在本说明书内任何前述页面中作出的任何公开。
如果在描述中提到“如本文所述”、“本文所述的”、“本文提供的”或“如本文本所述”或“本文规定的”,其是指在本说明书内任何前述或随后页面中作出的任何公开。
本发明意义内的“合适”是指在化学上可通过技术人员知识范畴内的方法制备。
本文本中提及的术语可具有如下含义:
术语“卤素原子”、“卤代-”或“卤素-”应理解为表示氟、氯、溴或碘原子。
术语“C1-C6-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的饱和单价烃基,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1,2-二甲基丁基或它们的异构体。特别地,所述基团具有1、2、3或4个碳原子(“C1-C4-烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C1-C3-烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C1-C4-卤代烷基”应理解为表示直链或支链的饱和单价烃基,其中术语“C1-C4-烷基”定义如上,并且其中一个或多个氢原子被相同或不同的卤素原子(即一个卤素原子独立于另一个卤素原子)替代。特别地,所述卤素原子为F。所述C1-C4-卤代烷基例如为-CF3、-CHF2、-CH2F、-CF2CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CF3或-CH(CH2F)2。
术语“C2-C3-氟代烷基”应理解为表示直链或支链的饱和单价烃基,其中术语“C2-C3-烷基”如上定义,并且其中一个或多个氢原子被氟原子替代。所述C2-C3-氟代烷基例如为-CF2CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CF3或-CH(CH2F)2。
术语“C1-C4-烷氧基”应理解为表示式-O-烷基的直链或支链的饱和单价烃基,其中术语“烷基”如上所定义,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基或仲丁氧基,或它们的异构体。
除非另有定义,术语“5-至6-元杂环烷基”或“5-至6-元杂环”应理解为意指含有4或5个碳原子和一个选自O和NR的含杂原子基团的饱和单价单环烃环,其中R表示氢原子、C1-C3-烷基或C1-C3-卤代烷基,所述杂环烷基可以通过任何一个碳原子连接到分子的其余部分。
具体地,但不限于此,所述杂环烷基例如可为五元环例如四氢呋喃基、吡唑烷基,或六元环例如四氢吡喃基、哌啶基。
如本文通篇使用,例如在“C1-C6-烷基”或“C1-C6-卤代烷基”的定义的语境中使用的术语“C1-C6”应理解为表示具有1-6的有限碳原子数,即1、2、3、4、5或6个碳原子的烷基。应进一步理解所述术语“C1-C6”应解释为其中包含的任何亚范围,例如C1-C6、C2-C6、C3-C6、C1-C2、C1-C3,特别是C1-C2、C1-C3、C1-C4。
如本文通篇使用,例如在“C1-C4-烷基”、“C1-C4-卤代烷基”、“C1-C4-烷氧基”或“C1-C4-卤代烷氧基”的定义的语境中使用的术语“C1-C4”应理解为表示具有1-4的有限碳原子数,即1、2、3或4个碳原子的烷基。应进一步理解所述术语“C1-C4”应解释为其中包含的任何亚范围,例如C1-C4、C2-C4、C3-C4、C1-C2、C1-C3,特别是C1-C2、C1-C3、C1-C4,在“C1-C6-卤代烷基”或“C1-C4-卤代烷氧基”的情况下,还更特别是C1-C2。
此外,如本文所用,如本文通篇使用,例如在“C3-C6-环烷基”的定义的语境中使用的术语“C3-C6”应理解为表示具有3-6的有限碳原子数,即3、4、5或6个碳原子的环烷基。应进一步理解所述术语“C3-C6”应解释为其中包含的任何亚范围,例如C3-C6、C4-C5、C3-C5、C3-C4、C4-C6、C5-C6;特别是C3-C6。
术语“取代的”指所指定的原子的一或多个氢被从所指出的基团的选择代替,条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选取代的”指任选地被特定的基团(group)、基(radical)或部分取代。
环系统的取代基指与芳族或非芳族环系统连接的取代基,例如所述取代基代替所述环系统上可用的氢。
本文使用的术语“一或多”,例如在本发明通式化合物的取代基的定义中,应理解为表示“1、2、3、4或5等,特别是1、2、3或4,更特别地是1、2或3,甚至更特别地是1或2”。
通式(I)的化合物可以同位素变体的形式存在。本发明因此包括通式(I)的化合物的一或多种同位素变体,特别是含氘的通式(I)的化合物。
化合物或试剂的术语“同位素变体”定义为这样的化合物,其表现出非天然比例的构成该化合物的一或多种同位素。
术语“通式(I)的化合物的同位素变体”定义为这样的通式(I)的化合物,其表现出非天然比例的构成该化合物的一或多种同位素。
表述“非天然比例”应理解为表示此类同位素的比例高于其天然丰度。在该语境中适用的同位素的天然丰度描述于“Isotopic Compositions of the Elements 1997”,PureAppl.Chem.,70(1),217-235,1998。此类同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的稳定和放射性同位素,分别例如2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32p、33p、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I。
关于治疗和/或预防本文指定的病症,通式(I)的化合物的同位素变体在一个实施方案中含有氘(“含氘的通式(I)的化合物”)。其中并入一或多种放射性同位素例如3H或14C的通式(I)的化合物的同位素变体可用于例如药物和/或底物组织分布研究。这些同位素由于其易于并入和可检测性而特别优选。正电子发射同位素例如18F或11C可并入通式(I)的化合物。通式(I)的化合物的这些同位素变体可用于体内成像应用。含氘和含13C的通式(I)的化合物可用于临床前或临床研究背景下的质谱分析(H.J.Leis等人,Curr.Org.Chem.,1998,2,131)。
通式(I)的化合物的同位素变体通常可通过本领域技术人员已知的方法(例如在本文的方案和/或实施例中所述的那些)用试剂的同位素变体(在一个实施方案中为含氘的试剂)代替所述试剂来制备。根据所期望的氘化位置,在一些情况下,得自D2O的氘可直接并入所述化合物或可用于合成此类化合物的试剂(Esaki等人,Tetrahedron,2006,62,10954;Esaki等人,Chem.Eur.J.,2007,13,4052)。氘气也是用于将氘并入分子的有用试剂。烯键(H.J.Leis等人,Curr.Org.Chem.,1998,2,131;J.R.Morandi等人,J.Org.Chem.,1969,34(6),1889)和炔键(N.H.Khan,J.Am.Chem.Soc.,1952,74(12),3018;S.Chandrasekhar等人,Tetrahedron,2011,52,3865)的催化氘化是并入氘的快速途径。在氘气存在下金属催化剂(即,Pd、Pt和Rh)可用于直接将含官能团的烃中的氢置换为氘(J.G.Atkinson等人,US专利3966781)。各种各样的氘化试剂和合成构建块可商购自例如以下公司:C/D/N Isotopes,Quebec,Canada;Cambridge Isotope Laboratories Inc.,Andover,MA,USA;和CombiPhosCatalysts,Inc.,Princeton,NJ,USA。关于氘-氢交换的现有技术的其它信息在例如Hanzlik等人,J.Org.Chem.55,3992-3997,1990;R.P.Hanzlik等人,Biochem.Biophys.Res.Commun.160,844,1989;P.J.Reider等人,J.Org.Chem.52,3326-3334,1987;M.Jarman等人,Carcinogenesis 16(4),683-688,1993;J.Atzrodt等人,Angew.Chem.,Int.Ed.2007,46,7744;K.Matoishi等人,J.Chem.Soc,Chem.Commun.2000,1519-1520;K.Kassahun等人,WO2012/112363中给出。
术语“含氘的通式(I)的化合物”定义为通式(I)的化合物,其中一或多个氢原子被一或多个氘原子替代且其中通式(I)的化合物的各氘化位置处的氘的丰度高于氘的天然丰度(其为约0.015%)。特别是,在含氘的通式(I)的化合物中,通式(I)的化合物的各氘化位置处的氘的丰度高于10%、20%、30%、40%、50%、60%、70%或80%,在一个实施方案中,高于90%、95%、96%或97%,在其他实施方案中,在所述位置高于98%或99%。应理解在各氘化位置处的氘的丰度独立于在其它氘化位置处的氘的丰度。
在通式(I)的化合物中选择性并入一或多个氘原子可改变该分子的理化性质(例如酸性[A.Streitwieser等人,J.Am.Chem.Soc.,1963,85,2759;C.L.Perrin等人,J.Am.Chem.Soc.,2007,129,4490],碱性[C.L.Perrin等人,J.Am.Chem.Soc.,2003,125,15008;C.L.Perrin in Advances in Physical Organic Chemistry,44,144;C.L.Perrin等人,J.Am.Chem.Soc.,2005,127,9641],亲脂性[B.Testa等人,Int.J.Pharm.,1984,19(3),271])和/或代谢特征,并且可导致母体化合物与代谢物的比率或形成的代谢物的量的变化。这些变化可导致某些治疗益处并因此在一些情况下可能是优选的。已经报道了其中代谢物比率改变的代谢率降低和代谢转换(D.J.Kushner等人,Can.J.Physiol.Pharmacol.,1999,77,79;A.E.Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。涉及母体药物和代谢物的这些变化在含氘的通式(I)的化合物的药效动力学、耐受性和效力方面可能具有重要的影响。在一些情况下,氘取代减少或消除了不希望的或有毒的代谢物的形成并增加了所期望的代谢物的形成(例如Nevirapine:A.M.Sharma等人,Chem.Res.Toxicol.,2013,26,410;Uetrecht等人,Chemical Research inToxicology,2008,21,9,1862;Efavirenz:A.E.Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。在其它情况下,氘化的主要作用是降低系统清除率。由此,化合物的生物半衰期增加。潜在的临床益处包括维持类似的系统暴露而降低峰水平和增加谷水平的能力。这可能导致较低的副作用和增强的功效,取决于特定化合物的药代动力学/药效动力学关系。茚地普隆(A.J.Morales等人,Abstract 285,The 15th North American Meeting ofthe International Society of Xenobiotics,San Diego,CA,October 12-16,2008)、ML-337(C.J.Wenthur等人,J.Med.Chem.,2013,56,5208)和Odanacatib(K.Kassahun等人,WO2012/112363)是该氘效应的实例。还已经报道了其它例子,其中降低的代谢率导致药物暴露增加但不改变系统清除率(例如罗非昔布:F.Schneider等人,Arzneim.Forsch.Drug.Res.,2006,56,295;替拉瑞韦:F.Maltais等人,J.Med.Chem.,2009,52,7993)。显示该效应的氘代药物可能具有降低的给药要求(例如较低的给药次数或实现所需效果的较低的剂量)和/或可产生较低的代谢物负载。
通式(I)的化合物可具有代谢攻击的多个潜在位点。为了优化上述对理化性质和代谢特征的作用,可选择具有某种模式的一或多个氘-氢交换的含氘的通式(I)的化合物。特别是,含氘的通式(I)的化合物的氘原子可与碳原子连接和/或位于通式(I)的化合物的那些为代谢酶例如细胞色素P450的攻击位点的位置。
当本文中使用化合物、盐、多晶型物、水合物、溶剂化物等词的复数形式时,应理解为还表示单数的化合物、盐、多晶型物、异构体、水合物、溶剂化物等。
“稳定的化合物”或“稳定的结构”指足够强健而能够经受从反应混合物中分离到有用的纯度并配制成有效的治疗剂的化合物。
本发明的化合物可包含一或多个不对称中心,视期望的各种取代基的位置和性质而定。不对称碳原子可以(R)或(S)构型存在,在具有一个不对称中心的情况下得到外消旋混合物,并且在具有多个不对称中心的情况下得到非对映异构体混合物。在某些情况下,由于围绕特定键的旋转受阻还可能存在不对称性,例如该中心键连接特定化合物的两个被取代的芳环。
环上的取代基还可以顺式或反式形式存在。意图所有的此类构型(包括对映异构体和非对映异构体)均包括于本发明的范围内。
优选的化合物是产生更期望的生物活性的那些化合物。本发明化合物的分离的、纯净的或部分纯化的异构体和立体异构体、或者外消旋混合物或非对映异构体混合物均包括于本发明范围内。此类物质的纯化和分离可通过本领域已知的标准技术实现。
根据常规方法通过拆分外消旋混合物可获得旋光异构体,例如通过使用旋光酸或碱形成非对映异构体盐,或者通过形成共价非对映异构体。适当的酸的实例为酒石酸、二乙酰基酒石酸、二甲苯酰基酒石酸和樟脑磺酸。非对映异构体的混合物可基于它们的物理和/或化学差异,通过本领域已知的方法例如通过色谱法或分级结晶而分离成它们的单一的非对映异构体。然后,从分离的非对映异构体盐中释放旋光碱或酸。一种不同的分离旋光异构体的方法涉及在进行或不进行常规衍生化的条件下使用手性色谱法(例如手性HPLC柱),其可经过最佳选择以将对映异构体的分离最大化。适合的手性HPLC柱是由Daicel生产,例如Chiracel OD和Chiracel OJ等,所有的均可常规性选用。还可在进行或不进行衍生化的条件下使用酶法分离。同样地,可通过使用旋光原料的手性合成来获得本发明的旋光化合物。
为了将不同类型的异构体相互之间区分开来,参考了IUPAC Rules Section E(Pure Appl Chem 45,11-30,1976)。
本发明包括本发明化合物的所有可能的立体异构体,其是单一立体异构体或所述立体异构体(例如R-或S-异构体或者E-或Z-异构体)的任意比率的任意混合物的形式。可通过任意适合的现有技术方法例如色谱法特别是例如手性色谱法实现本发明化合物的单一立体异构体例如单一对映异构体或单一非对映异构体的分离。
另外,本发明化合物可以互变异构体的形式存在。例如,包含作为杂芳基的吡唑部分的任何本发明化合物例如可以1H互变异构体或2H互变异构体的形式存在或甚至以任意量的所述两种互变异构体的混合物的形式存在,或者包含三唑部分的任何本发明化合物例如可以1H互变异构体、2H互变异构体或4H互变异构体的形式存在或甚至以任意量的所述1H、2H和4H互变异构体的混合物的形式存在,即:
本发明包括本发明化合物的所有可能的互变异构体,其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。
另外,本发明的化合物可以N-氧化物的形式存在,其定义为本发明化合物中的至少一个氮被氧化。本发明包括所有此类可能的N-氧化物。
本发明还涉及如本文公开的化合物的有用形式,例如代谢物、水合物、溶剂化物、前药、盐特别是药学上可接受的盐,以及共沉淀物。
本发明的化合物可以水合物或溶剂化物的形式存在,其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂,特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。在化学计量溶剂化物例如水合物的情况下,可能分别是半(hemi-)溶剂化物或水合物、(半(semi-))溶剂化物或水合物、一溶剂化物或水合物、倍半溶剂化物或水合物、二溶剂化物或水合物、三溶剂化物或水合物、四溶剂化物或水合物、五溶剂化物或水合物等。本发明包括所有此类水合物或溶剂化物。
另外,本发明的化合物可以游离形式存在,例如以游离碱或游离酸或两性离子的形式,或者以盐的形式存在。所述盐可为任意盐,其可为有机或无机加成盐,特别是药学中常用的任意药学上可接受的有机或无机加成盐。
术语“药学上可接受的盐”指本发明化合物的相对无毒的、无机酸或有机酸加成盐。例如,参见S.M.Berge等人,“Pharmaceutical Salts,”J.Pharm.Sci.1977,66,1-19。
本发明化合物的适合的药学上可接受的盐可以是例如在链或环中携带氮原子的具有足够碱性的本发明化合物的酸加成盐,例如与如下无机酸形成的酸加成盐:例如盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸(bisulfuric acid)、磷酸或硝酸,或者与如下有机酸形成的酸加成盐:例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸(digluconic acid)、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸(hemisulfuric acid)或硫氰酸。
另外,具有足够酸性的本发明化合物的另一种适合的药学上可接受的盐是碱金属盐例如钠盐或钾盐,碱土金属盐例如钙盐或镁盐,铵盐,或与提供生理学可接受的阳离子的有机碱形成的盐,例如与如下物质形成的盐:N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、sovak碱、1-氨基-2,3,4-丁三醇。另外,碱性含氮基团可用如下试剂季铵化:低级烷基卤化物,例如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯,例如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯;长链卤化物例如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基的溴化物等。
本领域技术人员还会认识到,所要求保护的化合物的酸加成盐可通过多种已知方法中的任意一种使所述化合物与适当的无机酸或有机酸反应来制备。或者,本发明的酸性化合物的碱金属盐和碱土金属盐通过各种已知的方法使本发明的化合物与适当的碱反应来制备。
本发明包括本发明化合物的所有可能的盐,其可为单一盐或所述盐的任意比例的任意混合物。
在本文本中,特别是在实施例部分中,对于合成本发明的中间体和实施例,当化合物作为与对应的碱或酸的盐形式提及时,如各制备和/或纯化法所获得的所述盐形式的确切化学计量组成在大多数情况下是未知的。
除非另外指出,化学名称或结构式的后缀例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“x HCl”、“x CF3COOH”、“x Na+”不应理解为化学计量规格,而仅仅是盐形式。
这类似适用于其中已通过所述的制备和/或纯化方法获得具有(如果限定)未知化学计量组成的溶剂化物例如水合物形式的合成中间体或实施例化合物或其盐的情况。
所述盐包括水不溶性盐和特别是水溶性盐。
此外,本发明涵盖在生物体系中转化为式(I)化合物或其盐的式(I)化合物及其盐的衍生物(生物前体或前药)。所述生物体系是例如哺乳动物生物体,特别是人类受试者。生物前体例如通过代谢过程转化为式(I)化合物或其盐。
本文使用的术语“体内可水解的酯”应理解为表示包含羧基或羟基的本发明化合物的体内可水解的酯,例如可在人体或动物体内被水解从而产生母体酸或醇的药学上可接受的酯。对于羧基适合的药学上可接受的酯包括例如烷基酯、环烷基酯和任选取代的苯基烷基酯特别是苄基酯、C1-C6烷氧基甲基酯例如甲氧基甲基酯、C1-C6烷酰氧基甲基酯例如特戊酰氧基甲基酯、酞基酯、C3-C8环烷氧基-羰氧基-C1-C6烷基酯例如1-环己基羰氧基乙基酯;1,3-二氧杂环戊烯-2-酮基甲基酯(1,3-dioxolen-2-onylmethyl ester),例如5-甲基-1,3-二氧杂环戊烯-2-酮基甲基酯;以及C1-C6-烷氧基羰氧基乙基酯,例如1-甲氧基羰氧基乙基酯,并且所述酯可在本发明化合物的任意羧基上形成。
包含羟基的本发明化合物的体内可水解的酯包括无机酸酯(例如磷酸酯)、[α]酰氧基烷基醚和相关化合物,所述相关化合物由于所述酯的体内水解而断裂得到母体羟基。[α]酰氧基烷基醚的实例包括乙酰氧基甲基醚(acetoxymethoxy)和2,2-二甲基丙酰氧基甲基醚(2,2-dimethylpropionyloxymethoxy)。对于羟基形成体内可水解的酯的基团的选择包括烷酰基、苯甲酰基、苯基乙酰基和取代的苯甲酰基和苯基乙酰基、烷氧基羰基(以得到碳酸烷基酯)、二烷基氨基甲酰基和N-(二烷基氨基乙基)-N-烷基氨基甲酰基(以得到氨基甲酸酯)、二烷基氨基乙酰基和羧基乙酰基。本发明包括所有此类酯。
另外,本发明包括本发明化合物的所有可能的结晶形式或多晶型物,其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
在本发明的化合物的特性的上下文中,术语“药代动力学谱”表示如在合适的实验中测量的一个单一参数或其组合,包括渗透性、生物利用度、暴露,以及药效学参数如持续时间,或者药理作用的大小。具有改善的药代动力学谱的化合物可以例如以较低剂量使用以实现相同效果,可以实现较长的作用持续时间,或者可以实现两种效果的组合。
在本发明中术语“组合”如本领域技术人员已知地使用,并且可以作为固定组合、非固定组合或成套部件(kit-of-part)存在。
在本发明中“固定组合”如本领域技术人员已知地使用,并且定义为这样的组合,其中所述第一活性成分和所述第二活性成分在一个单位剂量或单一实体中一起存在。“固定组合”的一个实例是这样的药物组合物,其中所述第一活性成分和所述第二活性成分存在于混合物中用于同时给药,例如在制剂中。“固定组合”的另一实例是这样的药物组合,其中所述第一活性成分和所述第二活性成分存在于一个单元中但不在混合物中。
在本发明中非固定组合或“成套部件”如本领域技术人员已知地使用,并且定义为这样的组合,其中所述第一活性成分和所述第二活性成分存在于超过一个单元中。非固定组合或成套部件的一个实例是这样的组合,其中所述第一活性成分和所述第二活性成分分开地存在。非固定组合或成套部件的组分可以分开、依序、同时(simultaneously)、同时(concurrently)或按时间顺序交错给药。本发明的式(I)的化合物与如下所述的抗癌剂的任何此类组合是本发明的实施方案。
术语“(化疗剂)抗癌剂”涉及降低癌细胞存活或增殖的任何药剂,并且包括但不限于131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、ado-曲妥珠单抗美坦新偶联物(ado-trastuzumab emtansine)、阿法替尼、阿柏西普、阿地白介素、阿仑珠单抗、阿仑膦酸、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、氨基酮戊酸己酯、氨柔比星、安吖啶、阿那曲唑、安塞司亭、茴香脑二硫杂环戊二烯硫酮(anethole dithiolethione)、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、arglabin、三氧化二砷、天冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗、贝洛替康、苯达莫司汀、贝利司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来考昔、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、copanlisib、crisantaspase、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D、达贝泊汀α、达拉菲尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、denileukin diftitox、地舒单抗、地普奥肽、地洛瑞林、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依库珠单抗、依决洛单抗、依利醋铵、艾曲波帕、内皮抑素、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、阿法依伯汀、倍他依泊汀、泽塔依泊汀、依他铂、eribulin、厄洛替尼、埃索美拉唑、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、法倔唑、芬太尼、非格司亭、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、羧肽酶、glutoxim、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林、羟基脲、I-125种子、兰索拉唑、伊班膦酸、替伊莫单抗、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、吡地司琼、英卡膦酸、丁烯英酯(ingenol mebutate)、α干扰素、β干扰素、Y干扰素、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、兰瑞肽、拉帕替尼、lasocholine、来那度胺、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯嘌呤、关司钠、美沙酮、甲氨蝶呤、甲氧沙林、氨基酮戊酸甲酯、甲基泼尼松龙、甲睾酮、甲酪氨酸、米伐木肽、米替福新、miriplatin、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫派达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮+喷他佐辛、纳曲酮、那托司亭、奈达铂、奈拉滨、奈立膦酸、nivolumabpentetreotide、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、二胺硝吖啶、nivolumab、obinutuzumab、奥曲肽、奥法木单抗、高三尖杉酯碱(omacetaxine mepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素、奥古蛋白(orgotein)、奥立莫德、奥希替尼、奥沙利铂、羟考酮、羟甲烯龙、ozogarnicine、p53基因疗法、紫杉醇、帕利夫明、钯-103种子、帕洛诺司琼、帕米膦酸、帕尼单抗、泮托拉唑、帕唑帕尼、培门冬酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、pembrolizumab、培非司亭、聚乙二醇干扰素α-2b、培美曲塞、喷他佐辛、喷司他丁、培洛霉素、全氟正丁烷、培磷酰胺、帕妥珠单抗、溶血性链球菌制剂、匹鲁卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、波齐替尼、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、racotumomab、氯化镭-223、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫芦单抗、雷莫司汀、拉布立酶、雷佐生、refametinib、瑞格非尼(regorafenib)、利塞膦酸、铼-186依替膦酸、利妥昔单抗、罗米地新、romiplostim、罗莫肽、ronicielib、钐(153Sm)lexidronam、沙格司亭、沙妥莫单抗、促胰液素、西普鲁塞T、西佐喃、索布佐生、甘氨双唑钠(sodiumglycididazole)、索拉非尼、司坦唑醇、链佐星、舒尼替尼、他拉泊芬、他米巴罗汀、他莫昔芬、他喷他多、他索纳明、替西白介素、technetium(99mTc)nofetumomab merpentan、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、替曲膦、沙利度胺、塞替派、胸腺法新、促甲状腺素α、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲马多、曲妥珠单抗、曲妥珠单抗美坦新偶联物(trastuzumab emtansine)、曲奥舒凡(treosulfan)、维甲酸、三氟尿苷+tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星、凡德他尼、伐普肽、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉、伏林司他、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
“表皮生长因子受体(EGFR)多肽”是指与UniProt登录号P00533-1中提供的序列或其片段具有至少约95%氨基酸序列同一性的多肽。在一些实施方案中,EGFR片段结合EFGR配体和/或具有激酶活性。突变EGFR多肽包括在例如氨基酸V769和D770之间或D770和N771之间具有插入的那些。在其他实施方案中,与UniProt登录号P00533-1的氨基酸序列同一性为96、97、98、99或100%。
UniProt登录号P00533-1提供了示例性的人EGFR全长序列,以粗体表示V769、D770和N771,其复制如下:
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NCBI参考序列:NM_001346897.1中提供了编码EGFR的示例性多核苷酸,其复制如下:
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如下文所述用于合成权利要求1-4的化合物的中间体以及它们在合成权利要求1-4的化合物中的用途是本发明的另一方面。优选中间体是如下文公开的中间体实施例。
一般方法
本发明的化合物可以根据以下方案1至4来制备。
下文所述的方案和方法说明了本发明的通式(I)的化合物的合成路线,并且不意图对其限制。本领域技术人员清楚在方案中示例的转化次序可以以各种方式进行修改。因此,并不意图限制方案中示例的转化次序。此外,任何取代基R1、R2、R3、R4、R5、R6和PG的相互转化可以在所示例的转化反应之前和/或之后实现。这些修饰可以是例如保护基团的引入、保护基团的断裂、官能团的还原或氧化、卤化、金属化、取代或本领域技术人员已知的其他反应。这些转化包括引入使取代基进一步互变的官能度的那些转化。合适的保护基团以及它们的引入和断裂是本领域技术人员公知的。具体实例在随后的段落中描述。
方案1:
方案1:制备通式(I)的化合物的路线,其中R1、R2、R3、R4、R5、R6、X、Y、m和n具有通式(I)给出的含义,并且PG可以是氢或任选地合适的保护基团,例如叔丁氧基羰基(Boc)。
如本领域技术人员可理解的,式1、2和4的化合物是商购的或可按照公共领域可得的方法制备。在随后段落中描述具体实例。
在-78℃至+100℃的温度下,通式的适当取代的哌啶-2,4-二酮(式1化合物)例如哌啶-2,4-二酮可与适当取代的异硫氰酸酯(式2化合物)例如异硫氰酸3-氟苯酯在合适的溶剂系统例如乙腈中在合适的碱例如三乙胺或DBU存在下反应,在一些实施方案中,该反应在0℃或+100℃下进行以提供通式(3)的化合物。文献中己实施了类似反应(D.E.Worrall,J.Am.Chem.Soc.,1940,62,675)。
通式(3)的中间体可通过与合适的胺(通式4的化合物)例如4-(氨基甲基)吡啶在合适的溶剂系统例如乙醇和乙酸乙酯中在室温至各溶剂沸点的温度下反应来转化为通式(5)的中间体,在一些实施方案中,该反应在各溶剂的沸点下进行,由此通过本领域技术人员已知的方法例如共沸除水(Dean-Stark条件)或使用分子筛从反应中除去反应中形成的水以提供通式(5)的中间体。
使用本领域技术人员已知的标准脱保护条件,可以将其中PG表示保护基团的通式(3)的中间体和通式(5)的中间体转化为其中PG表示氢原子的中间体。当PG是保护基团例如叔丁氧基羰基(Boc)时,脱保护可以使用酸,例如盐酸和三氟乙酸,在合适的溶剂系统例如二氯甲烷和二噁烷中,在0℃至各溶剂沸点的温度下进行,在一个实施方案中,该反应在室温下进行,以提供通式(3)的化合物和通式(5)的中间体,其中PG是氢原子。
通式(5)的中间体与碱和/或氧化试剂(在一个实施方案中为氧化剂)例如过氧化氢或SIBX(稳定的碘酰基苯甲酸)在合适的溶剂系统例如甲醇中在-30℃至各溶剂的沸点温度下反应,在一个实施方案中,该反应在各溶剂的沸点下进行以提供通式(I)的中间体。任选地,这些类型的反应可以用添加剂进行,添加剂例如为酸或碱,例如乙酸或三氟乙酸(非限制性)和三乙胺或二异丙基乙胺(非限制性)。
通式(5)的中间体可以通过在合适的溶剂中在升高的温度下加热它们而转化为通式(I)的化合物,该温度可以高于所述溶剂的沸点,例如室温至+250℃。这些反应可以任选地在容器中进行,由此可以增加压力,例如在高压釜中。通式(5)的中间体也可以通过在金属催化剂(例如钯/活性炭)的存在下,在合适的溶剂例如DMF、DMA、EtOH、MeOH、NMP(非限制性)中,在升高的温度例如室温至+150℃下加热转化为通式(I)的化合物。任选地,这些类型的反应可以用添加剂进行,添加剂例如为酸或碱,例如乙酸或三氟乙酸(非限制性)和三乙胺或二异丙基乙胺(非限制性),以提供通式(I)的化合物。
方案2:
方案2:制备通式(4)的化合物的路线,其中R4、R5、R6、X、Y、m和n具有对于通式(I)给出的含义。
可以在碱性、中性、酸性、催化条件(在一个实施方案中为碱性条件)下,在合适的溶剂中或使用亲核试剂作为溶剂例如DMF、四氢呋喃(THF),在-78℃至相应溶剂沸点的温度范围内,通过用合适的亲核试剂,例如胺、醇、金属醇盐、叠氮化物、硫醇或金属硫醇盐处理,将通式(6)的化合物转化为通式(7)的化合物,在一个实施方案中,该反应在-10℃至相应溶剂的沸点下进行,以提供通式(7)的化合物。这种取代反应以前曾报道过(Clark等人,J.Med.Chem.,2008,51,6631-6634;Guo等人,Tetrahedron Letts.,2013,54,3233-3237;Watterson等人,J.Med.Chem.,2007,50,3730-3742;Bellale等人,J.Med.Chem.,2014,57,6572-6582;Klimesova等人,Eur.J.Med.Chem.,1996,31,389-395;Leroy等人,Synth.Commun.,1997,27,2905-2916;LaMattina等人,J.Org.Chem.,1981,46,4179-4182;Beugelmans等人,Tetrahedron,1983,39,4153-4162)。
通式(7)的化合物可以通过本领域技术人员已知的许多还原方法,使用许多不同的试剂和反应条件转化为通式(4)的化合物;此类方法和试剂可以使用金属氢化物例如氢化铝锂在THF中(Bullock等人,J.Am.Chem.Soc.,1956,78,490,Wang等人,J.Org.Chem.,2006,71,4021-3160),或使用锌在乙酸中(Rabe,Chem.Ber.,1913,46,1024),或使用乙硼烷(De Munno等人,Heterocycles,1996,43,1893-1900),或使用催化氢化方法,例如在酸性条件下使用氢和钯碳(Stokker等人,J.Med.Chem.,1981,24,115-117;Bertini等人,J.Med.Chem.,2005,48,664-670),在碱性条件下使用氢和镍(Walpole等人,J.Med.Chem.,1993,36,2362-2372,Kuramochi等人,Bioorg.Med.Chem.,2005,13,4022-4036)进行。
方案3:
方案3:制备通式2的化合物的路线,其中R1a代表甲基或二氟甲基,对应于通式(I)中具有甲氧基和二氟甲氧基的含义的R1。化合物9和10的合成涉及苯环的烷氧基取代。然而,含异硫氰酸酯的产物2及其合成(即,10→2或11→2)对于通式(I)的R1基团是通用的。
通式(8)的化合物可以使用本领域技术人员已知的各种方法转化为通式(9)的化合物。这种转化可以是例如用烷基化试剂烷基化酚醇,该烷基化试剂例如为烷基卤化物、烷基磺酸酯,其中这些烷基可以任选地包含氟基团、烷氧基。这些烷基化反应是本领域技术人员已知的,使用多种方法:i)K2CO3在溶剂如DMF、丙酮、DMFA中(参见Muro等人,J.Med.Chem.,2009,52,7974和WO2009/20990A1的教导);ii)KOH在EtOH中(参见Macias等人,J.Agric.Food Chem.,2006,54,9843的教导);iii)Mitsunobu反应(参见US2006/122168A1和EP2151431A1的教导),以提供通式(9)的中间体。
通式(9)的化合物可以通过还原方法转化为通式(10)的化合物,这些方法是本领域技术人员已知的。这些还原可以使用下列物质进行:i)氢气和催化剂(对于Pd/C作为催化剂,参见Chan等人,J.Am.Chem.Soc.,2011,133,2989的教导;对于铂作为催化剂,参见Niemann等人,J.Am.Chem Soc.,1941,63,2204的教导;对于兰尼镍作为催化剂,参见US2009/253767A1的教导);ii)铁和氯化铵(参见Sweeney等人,Bioorg.Med.Chem.Lett.,2008,18,4348的教导);iii)连二亚硫酸钠(参见Chong等人,J.Med.Chem.,2012,55,10601的教导);iv)锌和氯化铵(参见WO2010/42699A1的教导),以提供通式(10)的中间体。
可以通过使用试剂例如硫光气、二硫化碳、1,1”-硫代羰基二-2(1H)-吡啶酮或1,1′-硫代羰基二咪唑(在一个实施方案中为硫光气),在碱性条件下,在合适的溶剂例如二氯甲烷、氯仿、丙酮或双相混合物(例如二氯甲烷、氯仿与碱性水溶液)(在另一个实施方案中为二氯甲烷与碳酸氢钠或碳酸钠的饱和水溶液)中,在-78℃至相应溶剂沸点的温度范围内,将通式(10)的化合物转化为通式(2)的化合物,在另一个实施方案中,该反应在0℃至室温进行,以提供通式(2)的化合物。这种转化反应以前曾报道过(Harris等人,J.Med.Chem.,2005,48,1610;Degorce等人,Tetrahedron Lett.,2011,52,6719;WO2016/91845A1;Fairhurst等人,Org.Lett.,2005,7,4697;Chaskar等人,Synth.Commun.,2008,38,16940;US2004/122237A1)。
方案4:
方案4:制备通式(I)的化合物的路线,其中R1、R2、R3、R4、R5、R6、X、Y、m和n具有对于通式(I)给出的含义,并且PG代表氢或合适的保护基团,例如叔丁氧羰基(Boc)。
与通式12相似的化合物是本领域技术人员已知的,其合成方法已有文献报道(参见Voss等人,WO2015/22073A1;Hart等人,WO2016/100166 A1;Anderson等人,J.Med.Chem.,2007,50,2647;Vanotti等人,J.Med.Chem.,2008,51,487的教导)。
可以使用本领域技术人员已知的标准溴化方法(WO2016/100166 A1)将通式(12)的化合物转化为通式(13)的化合物。此类溴化可以使用溴化剂,例如N-溴琥珀酰亚胺,在合适的溶剂例如DMF中,在-78℃至所述溶剂沸点的温度范围内进行,在一个实施方案中,该温度范围为0℃至RT。
在碱如双(三甲基甲硅烷基)氨基化锂(LHMDS)的存在下,在催化剂例如合适配体(在一个实施方案中为2-(二-叔丁基膦基)-2′,4′,6′-三异丙基-3,6-二甲氧基-1,1′-联苯(tBuBrettPhos))的存在下,并且在预催化剂例如钯预催化剂(在另一个实施方案中为[2-(二环己基膦基)-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯][2-(2-氨基乙基)苯基]氯化钯(II)(BrettPhos-PreCat MTBE醚加合物))的存在下,在合适的溶剂系统例如四氢呋喃(THF)中,在0℃至200℃的温度范围下,通式(13)的中间体可以与合适的苯胺如2-二氟甲氧基苯胺反应。在一个实施方案中,该反应在80℃下进行,以提供通式(I)的化合物。已经进行并报道了类似的转化(WO2015/193339A1)。
方案5:
方案5:制备通式(I)的化合物的路线,其中R1、R2、R3、R4、R5、R6、X、Y、m和n具有对于通式(I)给出的含义,并且PG代表氢或合适的保护基团,例如叔丁氧羰基(Boc)。
在使用4-(氨基甲基)-3-羟基吡啶代替中间体(4)的情况下,可以根据方案1所述的操作制备类似于通式(14)的化合物。可以在Mitsunobu条件(Oyo Mitsunobu,Synthesis,1981,1-28或Tsunoda等人,Tetrahedron Lett.,1994,35,5081的教导)例如氧杂环丁烷-3-基甲醇下,在(三丁基膦亚基)乙腈或三苯基膦以及偶氮二甲酸二异丙酯的存在下,在合适的溶剂系统例如二噁烷或THF中,在室温和各溶剂的沸点之间的温度下,使通式(14)的中间体与合适的醇反应转化为通式(I)的化合物。
本领域技术人员已知如果在起始或中间体化合物中有许多反应中心,可能必须通过保护基团暂时封闭一个或多个反应中心以允许反应在期望的反应中心特异性地进行。
以本身已知的方式分离并纯化本发明的化合物,例如通过在真空中蒸馏去除溶剂并重结晶获自合适的溶剂的残余物,或者使其经受通常的纯化方法之一,例如在合适的支持材料上层析。此外,可应用反相制备型HPLC。具有足够碱性或酸性官能度的本发明的化合物可以导致盐的形成,例如,在足够碱性的本发明的化合物的情况下,如三氟乙酸盐或甲酸盐,或者在足够酸性的本发明的化合物的情况下,如铵盐。这种类型的盐可以通过本领域技术人员已知的各种方法分别转化为其游离碱或游离酸形式,或者作为盐用于随后的生物学测定。此外,分离本发明的化合物期间的干燥过程可以不完全去除痕量的共溶剂,特别是例如甲酸或三氟乙酸,以便得到溶剂化物或包合配合物。本领域技术人员会认识到哪种溶剂化物或包合配合物对用于随后的生物学测定是可接受的。应当理解如本文所述和分离的本发明的化合物的具体形式(例如盐、游离碱、游离酸、溶剂化物、包合配合物)不必是唯一形式,其中所述化合物可以应用于生物学测定以便定量具体生物学活性。
本发明的式(I)的化合物的盐可以通过将游离化合物溶于合适的溶剂(例如酮如丙酮、甲基乙基酮或甲基异丁基酮,醚如乙醚、四氢呋喃或二噁烷,氯化烃如二氯甲烷或氯仿,或者低分子量脂族醇如甲醇、乙醇或异丙醇)来获得,所述溶剂包含期望的酸或碱,或者然后向其添加期望的酸或碱。酸或碱可以用于盐制备,取决于是否考虑单或多元酸或碱,并且取决于期望哪种盐,以等摩尔量的比率或与其不同的比率。通过过滤、再沉淀、用盐的非溶剂沉淀或通过蒸发溶剂来获得盐。获得的盐可以转化为游离化合物,反过来,游离化合物可以转化为盐。通过这种方式,可以作为过程产物在工业规模的制备中获得的药学上不可接受的盐可以通过本领域技术人员已知的方法转化为药学上可接受的盐。特别优选盐酸盐以及实施例部分所用的方法。
本发明的化合物和盐的纯非对映异构体和纯对映异构体可以例如通过不对称合成、通过在合成中使用手性起始化合物或通过分离合成中获得的对映异构体和非对映异构体混合物来获得。
对映异构体和非对映异构体混合物可以通过本领域技术人员已知的方法分为纯对映异构体和纯非对映异构体。在一个实施方案中,通过结晶(特别是分级结晶)或色谱法分离非对映异构体混合物。对映异构体混合物可以例如通过与手性辅助剂形成非对映异构体,拆分获得的非对映异构体并去除手性辅助剂进行分离。作为手性辅助剂,例如,手性酸可以用来分离对映异构体碱,如扁桃酸,并且手性碱可以用来通过形成非对映异构体盐来分离对映异构体酸。此外,非对映异构体衍生物如非对映异构体酯可以分别利用手性酸或手性醇作为手性辅助剂分别由醇的对映异构体混合物或酸的对映异构体混合物形成。此外,非对映异构体配合物或非对映异构体包合物可以用于分离对映异构体混合物。或者,可以利用色谱法中的手性分离柱分离对映异构体混合物。分离对映异构体的另一合适的方法为酶促分离。
本发明的一优选方面是根据实施例制备权利要求1-4的化合物的方法以及用于其制备的中间体。
任选地,可以将式(I)的化合物转化为它们的盐,或者任选地,可以将式(I)的化合物的盐转化为游离化合物。相应的方法对于技术人员是常规的。
商业用途
如上文所提到的,已令人惊讶地发现本发明的化合物在与该化合物接触的细胞(例如,癌细胞)中有效抑制突变EGFR,从而诱导细胞死亡(例如凋亡),并且因此可以用于治疗或预防不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答的疾病,或者伴随有不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答的疾病,特别地,其中所述不受控制的细胞生长、增殖和/或存活,不适当的细胞免疫应答或不适当的细胞炎症应答是由突变EGFR介导的,例如良性和恶性瘤形成,更具体地,血液肿瘤、实体瘤和/或它们的转移瘤,例如白血病和骨髓增生异常综合征、恶性淋巴瘤、包括脑瘤和脑转移在内的头颈部肿瘤、包括非小细胞肺肿瘤和小细胞肺肿瘤在内的胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺肿瘤和其他妇科肿瘤、包括肾肿瘤、膀胱肿瘤和前列腺肿瘤在内的泌尿系统肿瘤、皮肤肿瘤和肉瘤、和/或它们的转移瘤,特别是血液肿瘤,实体瘤,和/或乳腺、膀胱、骨、脑、中枢和周围神经系统、宫颈、结肠、内分泌腺(例如甲状腺和肾上腺皮质)、内分泌肿瘤、子宫内膜、食道、胃肠道肿瘤、生殖细胞、肾(kidney)、肝、肺、喉和下咽、间皮瘤、卵巢、胰、前列腺、直肠、肾(renal)、小肠、软组织、胃、皮肤、睾丸、输尿管、阴道和外阴的转移以及恶性瘤形成,包括所述器官中的原发性肿瘤和远端器官中相应的继发性肿瘤(“肿瘤转移”)。血液肿瘤可以示例为白血病和淋巴瘤的侵袭性和惰性形式,即非霍奇金病、慢性和急性髓性白血病(CML/AML)、急性成淋巴细胞性白血病(ALL)、霍奇金病、多发性骨髓瘤以及T-细胞淋巴瘤。还包括骨髓增生异常综合征、浆细胞瘤形成、副肿瘤性综合征和未知原发部位的癌症以及AIDS相关的恶性肿瘤。
本发明的另一方面为式(I)的化合物在治疗肺癌,特别是携带具有外显子20插入突变的突变EGFR的肺癌,更特别是携带V769_770ins ASV和/或D770_N771ins SVD外显子20插入的肺癌,和/或其转移瘤中的用途,包括给药有效量的式(I)化合物。
本发明的另一方面是根据式(I)的化合物在治疗肺癌,特别是携带具有外显子19框内缺失(例如EGFR E746_A750del)或外显子21点突变(例如L858R)的突变EGFR的肺癌,和/或其转移瘤中的用途。
本发明的另一方面是根据式(I)的化合物在治疗肺癌,特别是携带具有D770_N771msSVD C797S、E746_A750del C797S或L858R C797S获得性抗性突变的突变EGFR的肺癌,和/或其转移瘤中的用途。
本发明的另一方面是根据式(I)的化合物在治疗肺癌,特别是携带具有外显子20插入突变的突变ERBB2(例如ERBB2A775_G776insYVMA)的肺癌,和/或其转移瘤中的用途。
根据本发明的一方面,因此本发明涉及如本文所述和定义的通式I的化合物,或者所述化合物的N-氧化物、盐、互变异构体或立体异构体,或者所述N-氧化物、互变异构体或立体异构体的盐,特别是其药学上可接受的盐,或者它们的混合物,用于治疗或预防疾病,特别是用于治疗疾病。
因此,本发明的另一具体方面为如上所述的通式I的化合物、或者其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,特别是其药学上可接受的盐,或者它们的混合物用于预防或治疗过度增殖性病症或对诱导细胞死亡例如凋亡应答的病症的用途。
“过度增殖性疾病”
是指与不适当的高水平细胞分裂、不适当的低水平细胞凋亡或两者相关的疾病,例如癌症。如本文所用,在本发明的上下文中,特别是在“不适当的细胞免疫应答或不适当的细胞炎症应答”的语境中,术语“不适当的”应理解为一般表示比正常应答更弱或更强并且与所述疾病的病理相关、引起或导致所述疾病的病理的应答。
在具体实施方案中,所述用途是用于疾病的治疗或预防,特别是治疗,其中所述疾病为血液肿瘤、实体瘤和/或它们的转移瘤。
另一方面是式(I)化合物在预防和/或治疗肺癌,特别是携带具有外显子20插入突变的突变EGFR的肺癌,更特别是携带V769_770ins ASV和/或D770_N771ins SVD外显子20插入的肺癌,和/或其转移瘤中的用途,特别优选用于其治疗。
本发明的另一方面是如本文所述的式(I)的化合物或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,特别是其药学上可接受的盐或它们的混合物在制备治疗或预防疾病的药物中的用途,其中所述疾病是过度增殖性病症或对诱导细胞死亡例如凋亡应答的病症。在一个实施方案中,所述疾病是血液肿瘤、实体瘤和/或它们的转移瘤。在另一实施方案中,所述疾病是肺癌,特别是携带具有外显子20插入突变的突变EGFR的肺癌,更特别是携带V769_770ins ASV和/或D770_N771ins SVD外显子20插入的肺癌,和/或其转移瘤。
治疗过度增殖性疾病的方法
本发明涉及一种使用本发明化合物及其组合物治疗哺乳动物的过度增殖性病症的方法。化合物可以用来抑制、阻断、降低、减少细胞增殖和/或细胞分裂,和/或引起细胞死亡例如凋亡等。这种方法包括向有需要的包括人在内的哺乳动物给药一定量的有效治疗所述病症的本发明的化合物或者其药学上可接受的盐、异构体、多晶型物、代谢物、水合物、溶剂化物或酯等。过度增殖性病症包括但不限于例如银屑病、瘢痕疙瘩和其他影响皮肤的增生、良性前列腺增生(BPH)、实体瘤如乳腺癌、呼吸道癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、眼癌、肝癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌以及它们的远端转移瘤。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。
呼吸道癌症的实例包括但不限于小细胞肺癌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下丘脑胶质瘤、小脑和大脑星形细胞瘤、髓母细胞瘤、室管膜瘤以及神经外胚层瘤和松果体瘤。
男性生殖器官肿瘤包括但不限于前列腺癌和睾丸癌。女性生殖器官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。
消化道肿瘤包括但不限于肛门癌、结肠癌、结直肠癌、食管癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道肿瘤包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、尿道癌以及人乳头状肾癌。
眼癌包括但不限于眼内黑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(伴有或不伴有纤维板层变异的肝细胞癌)、胆管癌(肝内胆管癌)和混合性肝细胞胆管癌。
皮肤癌包括但不限于鳞状细胞癌、卡波西肉瘤、恶性黑素瘤、鼻腔鼻窦内翻性乳头状瘤、鼻腔鼻窦内翻性乳头状瘤-相关的鼻腔鼻窦鳞状细胞癌、梅克尔细胞皮肤癌、以及非黑素瘤皮肤癌。
头颈癌包括但不限于喉癌、下咽癌、鼻咽癌、口咽癌、鼻腔鼻窦内翻性乳头状瘤、鼻腔鼻窦内翻性乳头状瘤-相关的鼻腔鼻窦鳞状细胞癌、唇癌和口腔癌以及鳞状细胞癌。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、伯基特淋巴瘤、霍奇金病以及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、淋巴肉瘤以及横纹肌肉瘤。
白血病包括但不限于急性髓性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞白血病、慢性髓性白血病以及毛细胞白血病。
这些病症已在人类中得到良好的表征,但是还以相似的病因学存在于其他哺乳动物中,并且可以通过给药本发明的药物组合物来治疗。
本文件通篇提及的术语“治疗(treating)”或“治疗(treatment)”的使用是常规的,例如为了抵抗、减轻、减少、缓解、改善诸如癌症的疾病或病症的情况等的目的管理或照顾个体。
本发明涉及治疗受试者癌症的方法,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
本发明涉及治疗受试者癌症的方法,其中癌症对抗EGF受体疗法具有或已经获得抗性,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
本发明涉及增强抗EGF受体疗法效力的方法,该方法包括向受试者给药与本文定义的通式(I)化合物组合的抗EGF受体疗法。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中所述癌症选自白血病、骨髓增生异常综合征、恶性淋巴瘤、头颈部肿瘤、胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿系统肿瘤、皮肤肿瘤和肉瘤,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中所述癌症选自鼻腔鼻窦内翻性乳头状瘤或与鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中胸部肿瘤是非小细胞肺癌,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中所述癌症是肺癌,特别是携带具有外显子19框内缺失(例如EGFR E746_A750del)或外显子21点突变(例如L858R)的突变EGFR的肺癌,和/或其转移瘤,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中所述癌症是肺癌,特别是携带具有D770_N771insSVD C797S、E746_A750del C797S或L858R C797S获得性抗性突变的突变EGFR的肺癌,和/或其转移瘤,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
在另一个实施方案中,本发明涉及治疗受试者癌症的方法,其中所述癌症是肺癌,特别是携带具有外显子20插入突变的突变ERBB2(例如ERBB2 A775_G776insYVMA)的肺癌,和/或其转移瘤,该方法包括向受试者给药有效量的如本文所定义的通式(I)化合物。
本公开还涉及选择用通式(I)化合物治疗癌症的患者的方法,该方法包括检测受试者生物样品中编码EGF受体的基因的外显子20中突变的存在,从而确定应该用所述化合物治疗该患者。在一些实施方案中,EGFR包含D770_N771insSVD C797S、E746_A750delC797S或L858R C797S获得性抗性突变,和/或其转移瘤。在一些实施方案中,选择用通式(I)化合物治疗癌症的患者的方法可以包括检测受试者生物样品中编码EGF受体的基因的外显子19中框内缺失或外显子21中点突变的存在,从而确定应该用所述化合物治疗该患者。例如,外显子19中框内缺失可能是EGFR E746_A750del,或者外显子21中点突变可能是L858R。在一些实施方案中,选择用通式(I)化合物治疗癌症的患者的方法可以包括检测受试者生物样品中编码ERBB2的基因的外显子20中突变的存在,从而确定应该用所述化合物治疗该患者。在一些实施方案中,ERBB2包含ERBB2 A775或_G776insYVMA插入突变,和/或其转移瘤。此外,治疗患有癌症的患者的方法可以包括向受试者给药通式(I)的化合物(例如,与抗EGF受体疗法组合),其中通过检测受试者生物样品中EGFR突变的存在来选择受试者进行治疗。检测外显子20中是否存在突变在本领域技术人员的技能范围内。
在一些实施方案中,突变的检测(例如在EGFR中或编码EGFR基因的外显子20中的突变)可以通过测序(例如Sanger,Next Generation Sequencing)或选自免疫印迹、质谱、免疫沉淀定量PCR、Northern印迹、微阵列、酶联免疫吸附测定(ELISA)、原位杂交及其组合的方法进行。
治疗激酶障碍的方法
本发明还提供用于治疗与异常的丝裂原细胞外激酶活性相关的病症的方法,所述病症包括但不限于中风、心力衰竭、肝肿大、心脏肥大、糖尿病、阿尔茨海默病、囊性纤维化、异种移植物排斥的症状、感染性休克或哮喘。
有效量的本发明的化合物可以用来治疗这类病症,包括上文背景技术部分提到的那些疾病(例如癌症)。但是,可以用本发明的化合物治疗这类癌症和其他疾病,而与作用机制和/或所述激酶与所述病症之间的关系无关。
短语“异常的激酶活性”或“异常的酪氨酸激酶活性”包括编码所述激酶的基因或其编码的多肽的任何异常表达或活性。这类异常活性的实例包括但不限于所述基因或多肽的过量表达;基因扩增;产生组成型活性的或极度活性的激酶活性的突变;基因突变、缺失、取代、添加等。
本发明还提供抑制激酶活性特别是丝裂原细胞外激酶活性的方法,所述方法包括给药有效量的本发明的化合物,包括其盐、多晶型物、代谢物、水合物、溶剂化物、前药(例如酯)及其非对映异构体形式。可以在细胞中(例如体外),或者在哺乳动物个体特别是需要治疗的人类患者的细胞中抑制激酶活性。
治疗血管生成障碍的方法
本发明还提供治疗与过度和/或异常的血管生成相关的病症和疾病的方法。
血管生成的不适当表达和异常表达对生物体可能是有害的。许多病理状况与外生(extraneous)血管的生长有关。这些包括例如糖尿病性视网膜病、缺血性视网膜静脉阻塞以及早产儿视网膜病[Aiello等人,New Engl.J.Med.1994,331,1480;Peer等人,Lab.Invest.1995,72,638]、年龄相关性黄斑变性[AMD;参见Lopez等人,Invest.Opththalmol.Vis.Sci.1996,37,855]、新生血管性青光眼、银屑病、晶状体后纤维增生症、血管纤维瘤、炎症、类风湿性关节炎(RA)、再狭窄、支架内再狭窄、血管移植再狭窄等。此外,与癌组织和肿瘤组织相关的血液供给增加促进生长,导致快速的肿瘤增大和转移。此外,肿瘤中新血管和淋巴管的生长为癌变细胞(renegade cell)提供了离开途径,促进转移并导致癌症扩散。因此,本发明的化合物可以用来治疗和/或预防任何上文提到的血管生成障碍,例如通过抑制和/或减少血管形成;通过抑制、阻断、降低、减少内皮细胞增殖或与血管生成相关的其他类型等,以及引起这类细胞的细胞死亡例如凋亡。
在多个实施方案中,所述方法中的疾病是血液肿瘤、实体瘤和/或其转移瘤。
本发明的化合物特别可用于治疗和防止(即预防)、特别是治疗肿瘤生长和转移,特别是接受或未接受所述肿瘤生长的预治疗的所有适应症和阶段的实体瘤。
本发明的化合物的药物组合物
本发明还涉及包含一种或多种本发明的化合物的药物组合物。这些组合物可以用来通过向有需要的患者给药而实现期望的药理学作用。为了本发明的目的,患者是需要治疗特定病症、障碍或疾病的包括人在内的哺乳动物。
因此,本发明包括这样的药物组合物,其包含药学上可接受的载体或助剂以及药学上有效量的本发明的化合物或其盐。
本发明的另一方面为包含药学上有效量的式(I)的化合物和药学上可接受的助剂的药物组合物,其用于治疗上文提到的疾病,特别是用于治疗血液肿瘤、实体瘤和/或其转移瘤。
药学上可接受的载体或助剂可以是这样的载体,其在与活性成分的有效活性一致的浓度下对患者无毒且无害,从而由所述载体引起的任何副作用不会破坏所述活性成分的有益作用。载体和助剂是辅助所述组合物适合给药的所有种类的添加剂。
化合物的药学上有效量可以是对正在治疗的特定病症产生结果或者产生预期影响的量。
可以使用包括即释、缓释和定时释放制剂在内的任何有效的常规剂量单位形式,将本发明的化合物与本领域公知的药学上可接受的载体或助剂一起以如下方式给药:口服、肠胃外、局部、鼻腔、眼科(ophthalmically)、眼部(optically)、舌下、直肠、阴道给药等。
对于口服给药,可以将所述化合物配制为固体或液体制剂,例如胶囊剂、丸剂、片剂、含锭剂(troche)、锭剂(lozenge)、熔胶剂(melt)、散剂、溶液剂、混悬剂或乳剂,并且可以根据本领域已知的用于制备药物组合物的方法来制备。固体单位剂型可以是胶囊剂,其可以是普通的硬壳或软壳明胶类型,包含助剂,例如表面活性剂、润滑剂和惰性填充剂如乳糖、蔗糖、磷酸钙和玉米淀粉。
在另一实施方案中,可以将本发明的化合物和常规片剂基质(例如乳糖、蔗糖和玉米淀粉)一起并与以下物质组合压制成片剂:粘合剂,例如阿拉伯胶、玉米淀粉或明胶;用于辅助给药后所述片剂分解和溶出的崩解剂,例如马铃薯淀粉、海藻酸、玉米淀粉和瓜尔胶、黄蓍树胶、阿拉伯胶;用于提高片剂制粒的流动性并防止片剂材料粘附至片剂模具和冲头的表面的润滑剂,例如滑石、硬脂酸或者硬脂酸镁、硬脂酸钙或硬脂酸锌;用于提高所述片剂的感官性质并使它们更容易被患者接受的染料、着色剂和调味剂,例如薄荷油、冬青油或樱桃香精。用于口服液体剂型的合适的赋形剂包括磷酸二钙以及稀释剂如水和醇(例如乙醇、苯甲醇和聚乙烯醇),添加或不添加药学上可接受的表面活性剂、助悬剂或乳化剂。可以存在各种其他物质作为包衣或者用于改变剂量单位的物理形式。例如可以用虫胶、糖或二者将片剂、丸剂或胶囊剂包衣。
可分散的散剂和颗粒剂适合用于制备水性混悬剂。它们提供与分散剂或润湿剂、助悬剂以及一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂以及助悬剂的实例是上文已提到的那些。还可以存在另外的赋形剂,例如上文所述的那些甜味剂、调味剂和着色剂。
本发明的药物组合物还可以为水包油乳剂的形式。油相可以为植物油如液体石蜡,或者植物油的混合物。合适的乳化剂可以为(1)天然存在的树胶,例如阿拉伯胶和黄蓍树胶,(2)天然存在的磷脂,例如大豆磷脂和卵磷脂,(3)衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯,(4)所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨糖醇酐单油酸酯。所述乳剂还可以包含甜味剂和调味剂。
可以通过将所述活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油中或者悬浮于矿物油例如液体石蜡中来配制油性混悬剂。所述油性混悬剂可以包含增稠剂,例如蜂蜡、固体石蜡或鲸蜡醇。所述混悬剂还可以包含一种或多种防腐剂,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;一种或多种调味剂;以及一种或多种甜味剂,例如蔗糖或糖精。
可以用甜味剂如甘油、丙二醇、山梨糖醇或蔗糖配制糖浆剂和酏剂。这类制剂还可以包含缓和剂和防腐剂(例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)以及调味剂和着色剂。
还可以将本发明的化合物以所述化合物的可注射剂量进行肠胃外给药,即皮下、静脉内、眼内、滑膜内、肌内或腹膜内给药,所述可注射剂量例如在具有药物载体的生理学可接受的稀释剂中,所述药物载体可以为无菌液体或液体的混合物,例如水,盐水,右旋糖水溶液和相关的糖溶液,醇如乙醇、异丙醇或十六醇,二醇如丙二醇或聚乙二醇,甘油缩酮如2,2-二甲基-1,1-二氧戊环-4-甲醇,醚如聚(乙二醇)400,油,脂肪酸,脂肪酸酯或脂肪酸甘油酯或乙酰化的脂肪酸甘油酯,添加或不添加药学上可接受的表面活性剂如肥皂或去污剂,助悬剂如果胶、卡波姆、甲基纤维素、羟丙甲基纤维素或羧甲基纤维素,或者乳化剂以及其他药学辅剂。
可以用于本发明的肠胃外制剂的油的实例是石油、动物、植物或合成来源的那些油,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、凡士林油和矿物油。合适的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。合适的脂肪酸酯是例如油酸乙酯和肉豆蔻酸异丙酯。合适的肥皂包括脂肪酸碱金属盐、铵盐和三乙醇胺盐,合适的去污剂包括阳离子去污剂,例如二甲基二烷基卤化铵、烷基卤化吡啶鎓和烷基胺醋酸盐;阴离子去污剂,例如烷基磺酸盐、芳基磺酸盐和烯烃磺酸盐,烷基硫酸盐和烷基磺基琥珀酸盐、烯烃硫酸盐和烯烃磺基琥珀酸盐、醚硫酸盐和醚磺基琥珀酸盐以及单甘油酯硫酸盐和单甘油酯磺基琥珀酸盐;非离子型去污剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺以及聚(氧乙烯-氧丙烯)或环氧乙烷共聚物或环氧丙烷共聚物;以及两性去污剂,例如烷基-β-氨基丙酸盐和2-烷基咪唑啉季铵盐,以及混合物。
本发明的肠胃外组合物通常会在溶液中包含约0.5-约25重量%的所述活性成分。还可以有利地使用防腐剂和缓冲剂。为了最小化或消除对注射部位的刺激,这类组合物可以包含非离子表面活性剂,其在一个实施方案中具有约12至约17的亲水-亲脂平衡(HLB)。这类制剂中表面活性剂的量在一个实施方案中为约5-约15重量%。所述表面活性剂可以是具有以上HLB的单一组分,或者是具有期望的HLB的两种或更多种组分的混合物。
用于肠胃外制剂的表面活性剂的实例是聚乙烯山梨糖醇酐脂肪酸酯类,例如山梨糖醇酐单油酸酯,以及环氧乙烷与疏水性基质的高分子量加合物,所述疏水性基质由环氧丙烷和丙二醇缩合形成。
所述药物组合物可以为注射用无菌水性混悬剂的形式。可以根据已知的方法使用以下物质配制这类混悬剂:合适的分散剂或润湿剂以及助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯胶;分散剂或润湿剂,其可以是天然存在的磷脂如卵磷脂,环氧烷烃与脂肪酸的缩合产物如聚氧乙烯硬脂酸酯,环氧乙烷与长链脂肪醇的缩合产物如十七乙烯氧基鲸蜡醇,环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物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如聚氧乙烯山梨糖醇酐单油酸酯。
无菌可注射制剂还可以是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液。可以使用的稀释剂和溶剂为例如水、林格氏溶液、等渗的氯化钠溶液和等渗的葡萄糖溶液。此外,无菌的不挥发性油常规用作溶剂或悬浮介质。为了这个目的,可以采用任何温和的不挥发性油,包括合成的单甘油酯或二甘油酯。此外,诸如油酸的脂肪酸可以用于制备可注射物。
还可以将本发明的组合物以用于药物的直肠给药的栓剂的形式给药。可以通过将药物与合适的无刺激性的赋形剂混合来制备这些组合物,所述赋形剂在常温下为固体但是在直肠温度下为液体且因此在直肠中熔化以释放所述药物。这类物质例如可可脂和聚乙二醇。
用于肠胃外给药的控释制剂包括本领域已知的脂质体微球、聚合物微球和聚合物凝胶制剂。
可能需要或必需通过机械递送装置将所述药物组合物递送至患者。用于递送药剂的机械递送装置的构建和使用是本领域公知的。诸如将药物直接给药至脑的直接给药技术通常涉及将药物递送导管置入患者的脑室系统以绕过血脑屏障。用于将药剂运送至身体的特定解剖学区域的一种这样的植入式递送系统描述于1991年4月30日授权的美国专利第5,011,472号。
本发明的组合物还可以必要时或视需要包含通常称为载体或稀释剂的其他常规的药学上可接受的制剂成分。可以使用将这类组合物制备为适当的剂型的常规方法。
这类成分和方法包括描述于以下参考文献中的那些,所述参考文献均通过引用并入本文:Powell,M.F.等人,″Compendium of Excipients for Parenteral Formulations″PDA Journal of Pharmaceutical Science&Technology 1998,52(5),238-311;Strickley,R.G″Parenteral Formulations of Small Molecule Therapeutics Marketedin the United States(1999)-Part-1″PDA Journal of Pharmaceutical Science&Technology 1999,53(6),324-349;和Nema,S.等人,″Excipients and Their Use inIniectable Products″PDA Journal of Pharmaceutical Science&Technology 1997,51(4),166-171。
适当时可以用于将所述组合物配制为用于其预期给药途径的常用药物成分包括:
酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸);
碱化剂(实例包括但不限于氨水、碳酸铵、二乙醇胺、单乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(triethanolamine)、三乙醇胺(trolamine));
吸附剂(实例包括但不限于粉状纤维素和活性炭);
气雾喷射剂(实例包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2和CClF3);
空气置换剂(air displacement agents)(实例包括但不限于氮气和氩气);
抗真菌防腐剂(实例包括但不限于苯甲酸、对羟基苯甲酸丁酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯甲酸钠);
抗微生物防腐剂(实例包括但不限于苯扎氯铵、苄索氯铵、苯甲醇、氯化十六烷基吡啶、三氯叔丁醇、苯酚、苯乙醇、硝酸苯汞和硫柳汞);
抗氧化剂(实例包括但不限于抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、次磷酸、硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛次硫酸氢钠、焦亚硫酸钠);
粘结材料(实例包括但不限于嵌段聚合物、天然和合成橡胶、聚丙烯酸酯、聚氨酯、硅酮、聚硅氧烷以及苯乙烯-丁二烯共聚物);
缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠和柠檬酸钠二水合物);
载体(实例包括但不限于阿拉伯胶糖浆、芳香剂糖浆、芳香剂酏剂、樱桃糖浆、可可糖浆、橙皮糖浆、糖浆、玉米油、矿物油、花生油、芝麻油、抑菌的氯化钠注射液和抑菌的注射用水);
螯合剂(实例包括但不限于依地酸二钠和依地酸);
着色剂(实例包括但不限于FD&C Red No.3、FD&C Red No.20、FD&C Yellow No.6、FD&C Blue No.2、D&C Green No.5、D&C Orange No.5、D&C Red No.8、焦糖和氧化铁红);
澄清剂(实例包括但不限于膨润土);
乳化剂(实例包括但不限于阿拉伯胶、聚西托醇、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、山梨糖醇酐单油酸酯、聚氧乙烯50单硬脂酸酯);
包囊剂(实例包括但不限于明胶和邻苯二甲酸醋酸纤维素);
香料(实例包括但不限于茴香油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);
湿润剂(实例包括但不限于甘油、丙二醇和山梨糖醇);
研磨剂(实例包括但不限于矿物油和甘油);
油(实例包括但不限于花生油(arachis oil)、矿物油、橄榄油、花生油(peanutoil)、芝麻油和植物油);
软膏基质(实例包括但不限于羊毛脂、亲水软膏、聚乙二醇软膏、凡士林油、亲水凡士林油、白色软膏、黄色软膏和玫瑰水软膏);
渗透增强剂(透皮递送)(实例包括但不限于单羟基或多羟基醇类、一价或多价醇类、饱和或不饱和脂肪醇类、饱和或不饱和脂肪酯类、饱和或不饱和二羧酸类、精油类、磷脂酰衍生物、脑磷脂、萜类、酰胺类、醚类、酮类和脲类);
增塑剂(实例包括但不限于邻苯二甲酸二乙酯和甘油);
溶剂(实例包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯化水、注射用水、无菌注射用水和无菌冲洗用水);
硬化剂(实例包括但不限于鲸蜡醇、十六烷基酯蜡、微晶蜡、石蜡、硬脂醇、白蜡和黄蜡);
栓剂基质(实例包括但不限于可可脂和聚乙二醇(混合物));
表面活性剂(实例包括但不限于苯扎氯铵、壬基酚聚醚(nonoxynol)10、辛基酚聚醚(oxtoxynol)9、聚山梨酯80、十二烷基硫酸钠和山梨糖醇酐单棕榈酸酯);
助悬剂(实例包括但不限于琼脂、膨润土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙甲基纤维素、高岭土、甲基纤维素、黄蓍胶和硅酸镁铝);
甜味剂(实例包括但不限于阿司帕坦、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨糖醇和蔗糖);
片剂抗粘附剂(实例包括但不限于硬脂酸镁和滑石);
片剂粘合剂(实例包括但不限于阿拉伯胶、海藻酸、羧甲基纤维素钠、可压糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素、非交联聚乙烯吡咯烷酮以及预胶化淀粉);
片剂和胶囊剂稀释剂(实例包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉状纤维素、沉淀碳酸钙、碳酸钠、磷酸钠、山梨糖醇和淀粉);
片剂包衣剂(实例包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素和虫胶);
片剂直接压制赋形剂(实例包括但不限于磷酸氢钙);
片剂崩解剂(实例包括但不限于海藻酸、羧甲基纤维素钙、微晶纤维素、泼拉克林钾(polacrillin potassium)、交联聚乙烯吡咯烷酮、海藻酸钠、羟基乙酸淀粉钠和淀粉);
片剂助流剂(实例包括但不限于胶体二氧化硅、玉米淀粉和滑石);
片剂润滑剂(实例包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
片剂/胶囊剂遮光剂(实例包括但不限于二氧化钛);
片剂抛光剂(实例包括但不限于巴西棕榈蜡和白蜡);
增稠剂(实例包括但不限于蜂蜡、鲸蜡醇和石蜡);
张力剂(实例包括但不限于右旋糖和氯化钠);
粘性增强剂(实例包括但不限于海藻酸、膨润土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、海藻酸钠和黄蓍胶);以及
润湿剂(实例包括但不限于十七乙烯氧基鲸蜡醇、卵磷脂、山梨糖醇单油酸酯、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯硬脂酸酯)。
本发明的药物组合物可以举例如下:
无菌i.v.溶液:可以使用无菌注射用水制备本发明的期望化合物的5mg/mL溶液,并且必要时调整pH。用无菌5%右旋糖将所述溶液稀释至1-2mg/mL用于给药,并且在约60min内以i.v.输注给药。
用于i.v.给药的冻干粉:可以用(i)100-1000mg冻干粉形式的本发明的期望化合物,(ii)32-327mg/mL柠檬酸钠,以及(iii)300-3000mg右旋糖酐40制备无菌制剂。用无菌注射用盐水或5%右旋糖将该制剂重构至10-20mg/mL的浓度,然后用盐水或5%右旋糖进一步稀释至0.2-0.4mg/mL,并且IV推注或在15-60分钟内IV输注给药。
肌内注射混悬剂:可以制备以下溶液剂或混悬剂用于肌内注射:
50mg/mL期望的水不溶性的本发明的化合物
5mg/mL羧甲基纤维素钠
4mg/mL TWEEN 80
9mg/ml氯化钠
9mg/ml苯甲醇
硬壳胶囊剂:通过各自用100mg粉状活性成分、150mg乳糖、50mg纤维素和6mg硬脂酸镁填充标准的两片式硬galantine胶囊来制备大量的单位胶囊剂。
软明胶胶囊剂:制备活性成分在可消化的油例如大豆油、棉籽油或橄榄油中的混合物,并且通过容积式泵将其注入熔化的明胶以形成包含100mg所述活性成分的软明胶胶囊。将胶囊洗涤并干燥。可以将所述活性成分溶于聚乙二醇、甘油和山梨糖醇的混合物以制备水混溶性药物混合物。
片剂:通过常规方法制备大量片剂,从而剂量单位包含100mg活性成分、0.2mg胶体二氧化硅、5mg硬脂酸镁、275mg微晶纤维素、11mg淀粉和98.8mg乳糖。适当的水性和非水性包衣可以用来增加适口性、改善外观和稳定性或者延迟吸收。
即释片剂/胶囊剂:这些是通过常规方法和新方法制备的固体口服剂型。不需用水而将这些单位口服,用于药物的即刻溶出和递送。将所述活性成分混合在包含诸如糖、明胶、果胶和甜味剂的成分的液体中。通过冷冻干燥和固态萃取技术使这些液体固化为固体片剂或囊片。可以将药物化合物与粘弹性和热弹性的糖和聚合物或泡腾组分一起压片以制备在不需要水的条件下速释的多孔基质。
剂量和给药
基于已知用来评价可用于治疗过度增殖性病症和血管生成障碍的化合物的标准实验室技术,通过标准毒性测试以及通过用于确定对哺乳动物中上文所述病症的治疗的标准药理学测定,并且通过将这些结果与用来治疗这些病症的已知药物的结果进行比较,可以容易地确定用于治疗每种期望的适应症的本发明的化合物的有效剂量。在这些病症之一的治疗中给药的活性成分的量可以根据以下考量而发生很大变化:所用的特定化合物和剂量单位、给药方式、治疗时间、受治疗的患者的年龄和性别、以及所治疗的病症的性质和程度。
待给药的活性成分的总量一般为约0.001mg/kg至约200mg/kg体重/天,并且在特定的实施方案中为约0.01mg/kg至约20mg/kg体重/天。临床上可用的剂量给药方案是每日一至三次的剂量给药至每四周一次的剂量给药。此外,“停药期”(其中在某一段时间内不给予患者药物)对于药理学效力和耐受性之间的整体平衡可能是有利的。单位剂量可以包含约0.5mg至约1500mg活性成分,并且可以每日一次或多次地给药,或者少于每日一次地给药。在其他实施方案中,通过包括静脉内、肌内、皮下和肠胃外注射在内的注射以及使用输注技术给药的平均每日剂量为0.01-200mg/kg总体重。在特定实施方案中,平均每日直肠剂量方案为0.01-200mg/kg总体重。在其他实施方案中,平均每日阴道剂量方案为0.01-200mg/kg总体重。在其他实施方案中,平均每日局部剂量方案为每日一至四次给药0.1-200mg。在其他实施方案中,透皮浓度为维持0.01-200mg/kg的每日剂量所需的浓度。在其他实施方案中,平均每日吸入剂量方案为0.01-100mg/kg总体重。
当然,每位患者的具体起始剂量和维持剂量方案会根据以下因素而变化:临床诊断医生所确定的疾病状况的性质和严重程度、所用的具体化合物的活性、所述患者的年龄和整体健康状况、给药时间、给药途径、药物的排泄速率、药物组合等。本发明的化合物或其药学上可接受的盐或酯或组合物的期望的治疗方式和剂量数量可以由本领域技术人员利用常规的治疗测试来确定。
组合疗法
可以将本发明的化合物作为唯一的药剂给药或者与一种或多种其他药剂组合给药,其中所述组合不会引起不可接受的不良作用。那些组合的药剂可以是具有抗增殖效应如治疗血液肿瘤、实体瘤和/或它们的转移瘤的其他药剂和/或治疗不期望的副作用的药剂。本发明还涉及这类组合。
适合与本发明的组合物一起使用的其他抗过度增殖剂包括但不限于Goodman andGilman′s The Pharmacological Basis of Therapeutics(Ninth Edition),Molinoff等人编辑,McGraw-Hill出版,第1225-1287页,(1996)(其通过引用并入本文)中公认用于治疗肿瘤疾病的那些化合物,特别是如上文所定义的(化疗剂)抗癌剂。视情况而定,组合可以是非固定组合或固定剂量组合。
特定药理学性质或药物性质的测试方法是本领域技术人员公知的。
本文所述的实施例测试实验用来举例说明本发明,并且本发明不限于所提供的实施例。
本领域技术人员会理解,本发明不限于本文所述的具体实施方案,而是覆盖如所附权利要求书定义的本发明的精神和范围内的所述实施方案的所有修改。
以下实施例更详细地说明本发明,但不限制它。其制备未明确描述的本发明的其他化合物可以类似的方式制备。
在实施例中提到的化合物及其盐表示本发明的优选实施方案以及覆盖如具体实施例公开的式(I)的化合物的残基的所有亚组合的权利要求。
实验部分中的术语“根据”以与所指方法“类似地”的含义使用。
实验部分
使用ACD/Labs的ACD/Name软件生成化学名称。在某些情况下,使用普遍接受的市售试剂名称代替ACD/Name生成的名称。
下表1列出本段以及实施例部分中所用的缩写,只要它们不在正文中解释。其他缩写具有本领域技术人员惯常的含义。
表1:缩写
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其他缩写具有本领域技术人员通常了解的含义。
本申请描述的发明的各个方面通过以下实施例来说明,并不意图以任何方式限制本发明。
在文中描述的实施例测试实验用于说明本发明并且本发明不限于给出的实施例。
实验部分-一般规程
实验部分未描述合成的所有试剂均为市售品,或者是已知化合物,或者可以由本领域技术人员通过已知方法由已知化合物形成。
根据本发明的方法制备的化合物和中间体可能需要纯化。有机化合物的纯化是本领域技术人员公知的,并且可以存在数种纯化相同化合物的方法。在某些情况下,可能不需要纯化。在某些情况下,所述化合物可以通过结晶来纯化。在某些情况下,可以利用合适的溶剂进行搅拌来去除杂质。在某些情况下,所述化合物可以通过色谱法,特别是快速柱色谱法进行纯化,其使用例如预填充的硅胶柱,例如Biotage SNAP柱或/>与Biotage自动净化系统(/>或Isolera/>)组合使用,以及洗脱液如己烷/乙酸乙酯或DCM/甲醇的梯度液。在快速柱色谱法中,可以使用未改性(“常规”)的硅胶以及氨基相功能化硅胶。如果在没有指定固定相的情况下在实验部分提及快速柱色谱法或快速色谱法,则使用常规硅胶。
在某些情况下,所述化合物可以通过制备型HPLC来进行纯化,其使用例如配有二极管阵列检测器和/或在线电喷雾离子质谱仪的Waters自动纯化仪与合适的预填充反相柱以及可以包含添加剂如三氟乙酸、甲酸或氨水的洗脱液如水和乙腈的梯度液的组合
在某些情况下,如上文所述的纯化方法可以提供盐形式的具有足够碱性或酸性官能度的那些本发明的化合物,例如,在足够碱性的本发明的化合物的情况下,如三氟乙酸盐或甲酸盐,或者在足够酸性的本发明的化合物的情况下,如铵盐。这种类型的盐可以通过本领域技术人员已知的各种方法分别转化为其游离碱或游离酸形式,或者作为盐用于随后的生物学测定。应当理解如本文所述分离的本发明的化合物的具体形式(例如盐、游离碱等)不必是唯一形式,其中所述化合物可以应用于生物学测定以便定量具体生物学活性。
分析LC-MS方法:
方法1:
仪器:Waters Acquity UPLCMS SingleQuad;柱:Acquity UPLC BEH C18 1.7μm,50x2.1mm;洗脱剂A:水+0.1体积%甲酸(99%),洗脱剂B:乙腈;梯度:0-1.6min.1-99%B,1.6-2.0min.99%B;流速0.8ml/min;温度:60℃;DAD扫描:210-400nm.
方法2:
仪器:Waters Acquity UPLCMS SingleQuad;柱:Acquity UPLC BEH C18 1.7μm,50x2.1mm;洗脱剂A:水+0.2体积%氨水溶液(32%),洗脱剂B:乙腈;梯度:0-1.6min.1-99%B,1.6-2.0min.99%B;流速0.8ml/min;温度:60℃;DAD扫描:210-400nm.
方法3:
仪器:Waters Acquity UPLC H-Class system;柱:Acquity CSH C18 1.7μm2.1x50mm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈,洗脱剂C:2体积%氨的水溶液(28%),洗脱剂D:2体积%甲酸的水溶液;梯度:0-1.2min 2-95%含有A的B溶液,5%D,1.2-1.4min.95%B;流速0.8ml/min;温度:40℃;PDA:215-350nm.
方法4:
仪器:Waters Acquity UPLC H-Class system;柱:XBridge BEH C18 2.5μm 2.1x 50mm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈,洗脱剂C:2体积%氨的水溶液(28%),洗脱剂D:2体积%甲酸的水溶液;梯度:0-1.2min 2-95%含有A的B溶液,5%C,1.2-1.4min95%B;流速0.8ml/min;温度:40℃;PDA:215-350nm.
方法5:
MS仪器:SHIMADZU LCMS-2020;HPLC仪器:LabSolution Version 5.72;柱:Kinetex@5um EVO C18 30 x 2.1mm;洗脱剂A:0.0375%TFA的水溶液(v/v),洗脱剂B:0.01875%TFA的乙腈溶液:梯度:0.0min 0%B→3.00min 60%B→3.50min 60%B→3.51min 0%B→4.00min 0%B;流速:0.8mL/mix;烤箱温度:50℃;UV检测:220nm&254nm.
方法6:
仪器:Agilent 1290 UPLCMS 6230 TOF;BEH C18 1.7μm,50x2.1mm;洗脱剂A:Wasser+0.05%/>(99%);洗脱剂B:乙腈+0.05%/>(99%);梯度:0-1.7 2-90%B,1.7-2.0 90%B;Fluss 1.2ml/min;温度:60℃;DAD扫描:190-400nm.
制备LC-MS方法:
方法7:
仪器:Waters Autopurification MS SingleQuad;柱:Waters XBrigde C18 5μ100x30mm;洗脱剂A:水+0.2体积%氨水溶液(32%),洗脱剂B:乙腈;梯度:0-5.5min.5-100%B;流速70ml/min;温度:25℃;DAD扫描:210-400nm
方法8:
仪器:Waters Autopurification MS SingleQuad;柱:Waters XBrigde C18 5μ50x50mm;洗脱剂A:水+0.1vol%甲酸,洗脱剂B:甲醇;梯度:0-0.50min.20%B;流速50至100ml/min,0.50-8.00min.20-60%B;流速100ml/min,温度:25℃;DAD扫描:210-400nm
方法9:
仪器:Labomatic HD-5000,泵头HDK-280,梯度模块(module)NDB-1000,级分收集器Labomatic Labocol Vario 2000,Knauer UV检测器Azura UVD 2.1S,Prepcon 5software.柱:Chromatorex C18 10μM 120x30mm;洗脱剂A:水+0.1%甲酸;洗脱剂B:乙腈;梯度:用于中间体和实施例,流速150mL/min,温度25℃.;UV 220nm
方法10:
仪器:Labomatic HD-5000,pump head HDK-280,梯度模块NDB-1000,级分收集器Labomatic Labocol Vario 2000,Knauer UV检测器Azura UVD 2.1S,Prepcon 5software.柱:Chromatorex C18 10μM 120x30mm;洗脱剂A:0.1%氨的水溶液;洗脱剂B:乙腈;梯度:用于中间体和实施例,流速:150mL/min,温度25℃.;UV 250nm
方法11:
仪器:Labomatic HD-5000,pump head HDK-280,梯度模块NDB-1000,级分收集器Labomatic Laboeol Vario 2000,Knauer UV检测器Azura UVD 2.1S,Prepcon 5software.柱:Chromatorex C18 10μM 300x50mm;洗脱剂A:0.1%氨的水溶液;洗脱剂B:乙腈;梯度:用于中间体和实施例,流速250mL/min,温度25℃.;UV 250nm
NMR波谱:
以下段落中给出的1H NMR波谱中质子信号的多重性反映了观察到的信号形式,并未考虑任何高阶信号现象。通常,化学位移数据是指相关信号的中心。在宽的多重峰的情况下,指定了一个范围。被溶剂或水隐藏的信号被暂时指定或未列出。强烈的宽信号(例如由分子部分的快速旋转或质子交换引起)也已被暂时指定(通常称为宽多重峰或宽单峰)或未显示。
所选化合物的1H-NMR数据以1H-NMR峰列表的形式列出。其中,对于每个信号峰,给出了以ppm为单位的δ值,然后信号强度报告在圆括号中。得自不同峰的δ值-信号强度对用逗号分隔。因此,峰列表用通用形式描述:δ1(强度1)、δ2(强度2)、......、δi(强度i)、......、δn(强度n)。
尖锐信号的强度与打印的NMR波谱中信号的高度(以厘米为单位)相关。与其他信号相比,该数据可以与信号强度的实际比率相关联。在宽信号的情况下,与波谱中显示的最强信号相比,显示了多个峰或信号中心及其相对强度。1H-NMR峰列表类似于经典的1H-NMR读数,因此通常包含经典NMR解释中列出的所有峰。此外,类似于经典的1H-NMR打印读数,峰列表可以显示溶剂信号、衍生自特定目标化合物的立体异构体的信号、杂质峰、13C卫星峰和/或旋转边峰(spinning sideband)。立体异构体的峰和/或杂质峰所显示的强度通常低于目标化合物(例如,纯度>90%)的峰。这种立体异构体和/或杂质对于特定的制造过程可能是典型的,因此它们的峰值可能有助于基于“副产品指纹”识别制造过程的再现。通过已知方法(MestReC、ACD模拟或使用经验评估的期望值)计算目标化合物峰的专家可以根据需要任选使用额外的强度过滤器分离目标化合物的峰。这种操作类似于经典1H-NMR解释中的拾峰法。以峰列表形式报导NMR数据的详细说明可以在出版物″Citation of NMR PeaklistData within Patent Applications″(cf.http://www.researchdisclosure.com/searching-disclosures,Research Disclosure Database Number 605005,2014,01 Aug2014)中找到。在拾峰法程序中,如Research Disclosure Database Number 605005中所述,参数“最小高度”可以在1%和4%之间进行调整。然而,根据化学结构和/或被测化合物的浓度,将参数“最小高度”设置为<1%可能是合理的。
中间体1化合物的合成
中间体1-1
3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-甲腈
将3-氯吡啶-4-甲腈(CAS 68325-15-5,1.40g,10.1mmol)和(1,4-二氧杂环己烷-2-基)甲醇(CAS 143669-41-4,1.31g,11.1mmol)溶于THF(45ml)中。加入叔丁醇钾(1.03g,9.14mmol),并将该混合物于0℃搅拌1小时。将该反应混合物用饱和的氯化铵溶液缓慢稀释,并用EtOAc(3x)萃取。将有机相用盐水洗涤,并经防水过滤器过滤,减压浓缩,并通过快速色谱法(硅胶,己烷/EtOAc梯度0-100%;EtOAc/EtOH梯度0-35%)纯化,得到1.18g的标题化合物(53%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.72(s,1H),8.23-8.46(m,1H),7.68-7.86(m,1H),4.32(d,2H),3.40-3.99(m,7H).
LC-MS(方法2):Rt=0.77min;MS(ESIpos):m/z=221[M+H]+
中间体1-2
3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-甲腈
在0℃下,向[(3S)-4-甲基吗啉-3-基]甲醇(CAS 1620510-50-0,1.00g,7.62mmol)的THF(20ml)溶液中缓慢地加入氢化钠(366mg,9.15mmol,60%纯度)。将该反应混合物在室温下搅拌3小时。加入3-氯吡啶-4-甲腈(CAS 68325-15-5,1.06g,7.62mmol)的THF(10ml)溶液,并将该混合物搅拌过夜。将该反应混合物用1N HCl淬灭直至pH=7。将悬浮液通过疏水滤纸过滤,并将滤饼用EtOAc洗涤。将滤液减压浓缩,并将残余物通过快速色谱法(碱性硅胶,己烷/EtOAc梯度0-100%)纯化,得到355mg的标题化合物(20%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.75(s,1H),8.40(d,1H),7.78(d,1H),4.44(dd,1H),4.23(dd,1H),3.87(dd,1H),3.71(dt,1H),3.50(td,1H),3.35-3.41(m,1H),2.65-2.71(m,1H),2.45-2.49(m,1H),2.29-2.35(m,3H),2.24(ddd,1H).
LC-MS(方法2):Rt=0.72min;MS(ESIpos):m/z=234.2[M+H]+
中间体1-3
3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-甲腈
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使用中间体1-1中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,764mg,5.51mmol)和[4-甲基吗啉-2-基]甲醇(CAS 40987-46-0,940mg,7.17mmol)作为起始原料;制备得到836mg(90%纯度,59%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.893(0.97),1.920(1.44),1.947(1.07),1.954(0.50),1.962(0.54),1.983(1.01),1.991(1.03),2.011(0.58),2.019(0.52),2.197(16.00),2.518(0.41),2.589(0.80),2.593(0.82),2.617(0.73),2.621(0.74),2.766(0.66),2.770(0.95),2.794(0.63),2.798(0.89),3.513(0.60),3.520(0.73),3.541(1.36),3.547(1.39),3.570(0.80),3.575(0.67),3.793(0.74),3.796(1.10),3.801(1.12),3.805(0.92),3.808(0.85),3.814(0.79),3.821(1.18),3.826(1.18),3.833(1.27),3.839(0.66),4.316(5.03),4.329(4.72),7.772(2.40),7.774(2.63),7.785(2.49),8.381(3.41),8.393(3.28),8.714(4.32).
LC-MS(方法2):Rt=0.70min;MS(ESIpos):m/z=234.2[M+H]+
中间体1-4
3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-甲腈
使用中间体1-2中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,1.00g,7.24mmol)和[(3R)-4-甲基吗啉-3-基]甲醇(1.00g,95%纯度,7.24mmol;CAS1620510-51-1)作为起始原料;制备得到823mg(99%纯度,48%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.211(0.52),2.219(0.64),2.236(0.66),2.240(0.68),2.245(0.68),2.249(0.72),2.266(0.69),2.274(0.63),2.306(16.00),2.472(0.48),2.475(0.50),2.518(1.22),2.522(0.71),2.658(0.56),2.664(1.27),2.671(0.67),2.687(0.47),2.694(0.96),2.701(0.47),3.356(1.17),3.378(1.16),3.384(1.30),3.406(1.20),3.472(0.50),3.478(0.58),3.499(0.80),3.506(0.81),3.525(0.71),3.532(0.61),3.685(0.44),3.692(0.86),3.698(0.45),3.720(0.66),3.856(0.80),3.864(0.81),3.884(0.73),3.892(0.72),4.209(1.03),4.223(1.01),4.234(1.29),4.249(1.23),4.417(1.25),4.429(1.28),4.443(1.03),4.454(0.99),7.778(2.39),7.780(2.38),7.790(2.45),7.792(2.50),8.391(3.23),8.403(3.11),8.745(3.91).
LC-MS(方法2):Rt=0.70min;MS(ESIpos):m/z=234[M+H]+
中间体1-5
(2S)-2-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯
使用中间体1-1中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,2.55g,18.4mmol)和(2S)-2-(羟基甲基)吗啉-4-甲酸叔丁酯(CAS 135065-76-8,4.00g,18.4mmol)作为起始原料;制备得到4.82g(90%纯度,74%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):6[ppm]=1.41(s,9H),2.72-3.05(m,2H),3.46(br d,1H),3.67-3.82(m,2H),3.82-3.88(m,1H),4.00(s,1H),4.37(br d,2H),7.79(d,1H),8.40(d,1H),8.73(s,1H).
LC-MS(方法2):Rt=1.06min;MS(ESIpos):m/z=320[M+H]+
中间体1-6
3-[2-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-甲腈
使用中间体1-2中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,2.10g,15.1mmol)和2-(1,4-二氧杂环己烷-2-基)乙-1-醇(CAS 151720-04-6,2.00g,15.1mmol)作为起始原料;制备得到2.89g(99%纯度,81%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.754(0.63),1.768(1.37),1.774(0.82),1.781(0.98),1.790(2.18),1.803(3.39),1.810(2.10),1.817(1.93),1.824(3.23),1.838(2.78),1.855(2.41),1.867(2.45),1.869(2.40),1.874(2.53),1.886(2.23),1.902(0.99),1.910(0.87),1.922(0.67),2.326(0.72),2.668(0.69),3.223(4.26),3.247(5.57),3.250(5.62),3.276(5.26),3.428(1.77),3.434(1.89),3.455(4.59),3.462(4.80),3.483(3.76),3.489(3.97),3.530(3.36),3.535(3.38),3.558(4.71),3.564(5.40),3.585(1.93),3.592(3.08),3.626(4.58),3.631(4.33),3.654(3.70),3.659(4.02),3.668(1.98),3.673(1.97),3.680(2.77),3.687(2.85),3.693(2.89),3.706(6.98),3.712(6.06),3.724(1.75),3.735(3.40),3.759(4.77),3.766(4.02),3.788(4.04),3.794(3.73),4.315(0.93),4.329(1.18),4.339(3.54),4.354(6.92),4.359(5.21),4.370(6.49),4.384(3.79),4.392(1.47),4.408(0.68),7.778(9.22),7.790(9.58),8.380(10.88),8.392(10.45),8.698(16.00).
LC-MS(方法6):Rt=0.64min;MS(ESIpos):m/z=235[M+H]+
中间体1-7
3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-甲腈
使用中间体1-2中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,948mg,6.84mmol)和(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲醇(1.00g,6.84mmol;CAS54321-57-2)作为起始原料;制备得到1.31g(95%纯度,73%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.014(0.69),1.048(16.00),1.172(0.55),1.200(0.51),1.263(13.01),1.987(0.92),2.518(0.62),2.523(0.43),3.313(1.67),3.340(2.27),3.342(2.21),3.542(2.95),3.570(2.39),3.604(1.50),3.627(1.97),3.734(1.24),3.760(3.08),3.781(2.25),3.787(2.73),3.791(1.58),3.796(0.77),3.802(0.63),4.356(3.63),4.365(4.41),7.780(3.42),7.792(3.63),8.387(4.49),8.399(4.29),8.715(5.54).
LC-MS(方法6):Rt=0.75min;MS(ESIpos):m/z=249[M+H]+
中间体1-8
3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-甲腈
使用中间体1-1中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,1.00g,7.22mmol)和[(2R)-1,4-二氧杂环己烷-2-基]甲醇(CAS406913-88-0,938mg,7.94mmol)作为起始原料;制备得到490mg(95%纯度,29%产率)的标题化合物。
旋光度:[α]D=-1.68°+/-0.35°(c=7mg/ml,甲醇)
1H-NMR(400MHz,DMSO-d6):δppm=3.41-3.53(m,2H),3.59-3.72(m,2H),3.75-3.81(m,1H),3.82-3.87(m,1H),3.87-3.95(m,1H),4.27-4.37(m,2H),7.77-7.80(m,1H),8.38-8.41(m,1H),8.71-8.73(m,1H).
中间体1-9
(3R)-3-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯
在0℃下,向(3S)-3-(羟基甲基)吗啉-4-甲酸叔丁酯(4.30g,19.8mmol)的THF(28ml)溶液中缓慢地加入氢化钠(1.55g,55%纯度,35.6mmol)。将该反应混合物搅拌1小时。加入3-氟吡啶-4-甲腈(CAS 113770-88-0,2.42g,19.8mmol)的THF(14ml)溶液,并将该混合物于0℃搅拌4小时。将该反应混合物用2N HCl淬灭直至pH=6-7,并用EE萃取。将有机层通过防水滤纸过滤,并减压浓缩。将残余物通过快速色谱法(硅胶,DCM/EtOH梯度0-7%)纯化,得到4g的标题化合物(70%产率)。
LC-MS(方法6):Rt=0.95min;MS(ESIpos):m/z=264[M+H]+
中间体1-10
(2R)-2-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯
使用中间体1-1中所述的类似方法,使用3-氯吡啶-4-甲腈(CAS 68325-15-5,3.25g,23.5mmol)和(2R)-2-(羟基甲基)吗啉-4-甲酸叔丁酯(CAS 135065-71-3,5.10g,23.5mmol)作为起始原料;制备得到6.92g(90%纯度,83%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.41(s,9H),2.73-3.00(m,2H),3.39-3.50(m,1H),3.75(m,2H),3.82-3.89(m,1H),3.95-4.00(m,1H),4.37(br d,2H),7.79(d,1H),8.40(d,1H),8.73(s,1H).
LC-MS(方法2):Rt=1.04min;MS(ESIpos):m/z=320[M+H]+
中间体1-11
3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-甲腈
使用中间体1-9中所述的类似方法,使用3-氟吡啶-4-甲腈(878mg,7.19mmol)和(1S)-1-[1,4-二氧杂环己烷-2-基]乙-1-醇(CAS 1372875-59-6,950mg,7.19mmol)作为起始原料;制备得到1.68g(95%纯度,95%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δppm=0.988(0.85),1.004(0.92),1.056(0.59),1.071(0.60),1.154(4.47),1.166(0.63),1.172(9.29),1.189(4.59),1.276(12.44),1.292(12.55),1.325(11.08),1.341(11.16),1.987(16.00),2.518(1.63),2.522(1.05),3.300(0.46),3.396(1.81),3.421(2.99),3.424(2.99),3.429(1.78),3.450(5.06),3.457(3.42),3.472(1.97),3.478(1.62),3.485(2.38),3.497(2.19),3.500(1.91),3.525(2.26),3.552(1.16),3.559(1.31),3.582(2.48),3.588(2.91),3.611(1.70),3.616(2.62),3.638(4.15),3.642(3.63),3.664(3.89),3.671(4.01),3.676(1.93),3.683(1.76),3.685(1.80),3.689(1.79),3.695(1.76),3.701(1.17),3.704(1.27),3.707(1.26),3.710(1.28),3.744(1.82),3.750(3.32),3.757(1.01),3.778(3.94),3.784(2.19),3.807(1.47),3.813(1.33),3.906(1.40),3.912(1.35),3.935(1.24),3.941(1.18),3.999(1.24),4.016(3.72),4.034(3.66),4.052(1.20),4.804(0.41),4.821(1.95),4.836(3.43),4.852(2.64),4.864(1.34),7.755(3.58),7.757(3.60),7.769(4.33),7.771(3.80),7.783(3.28),7.785(3.20),8.351(4.95),8.363(4.90),8.368(4.48),8.380(4.17),8.749(6.40),8.772(5.46).
LC-MS(方法6):Rt=0.64min;MS(ESIpos):m/z=235[M+H]+
中间体1-12
3-{(1R)-1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-甲腈
使用中间体1-9中所述的类似方法,使用3-氟吡啶-4-甲腈(905mg,7.42mmol)和(1R)-1-[1,4-二氧杂环己烷-2-基]乙-1-醇(CAS 1372881-98-5,980mg,7.42mmol)作为起始原料;制备得到1.39g(95%纯度,76%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δppm=1.274(0.82),1.289(0.87),1.322(16.00),1.337(15.97),1.984(0.48),2.331(0.56),2.673(0.57),3.427(2.95),3.448(3.45),3.455(3.30),3.471(3.27),3.482(2.59),3.496(3.79),3.499(3.36),3.524(3.41),3.580(1.59),3.586(1.80),3.609(2.32),3.615(2.92),3.636(5.12),3.662(3.60),3.668(3.70),3.680(2.08),3.687(1.49),3.693(1.53),3.698(1.52),3.704(1.41),3.746(3.19),3.754(1.74),3.775(2.26),3.903(2.52),3.909(2.44),3.932(2.24),3.937(2.13),4.818(0.65),4.833(2.08),4.845(2.30),4.849(2.22),4.861(2.00),4.876(0.57),7.766(5.15),7.778(5.29),8.348(0.42),8.365(6.23),8.377(6.01),8.743(0.51),8.765(9.13).
LC-MS(方法6):Rt=0.67min;MS(ESIpos):m/z=235[M+H]+
中间体1-71
3-[1-(4-甲基吗啉-2-基)乙氧基]异烟腈
使用中间体1-9中所述的类似方法,使用3-氟吡啶-4-甲腈(824mg,6.75mmol)和1-(4-甲基吗啉-2-基)乙醇(980mg,6.75mmol,CAS 1540922-49-3)作为起始原料;使用Biotage Isolera进行柱色谱法后制备得到817mg(99%纯度,48%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.285(4.44),1.300(4.47),1.318(5.38),1.333(5.31),1.848(0.57),1.874(0.94),1.901(0.63),1.927(0.93),1.933(0.66),1.953(2.04),1.961(1.23),1.981(1.32),1.990(0.60),2.188(16.00),2.518(1.33),2.522(0.90),2.572(0.89),2.600(0.79),2.718(0.54),2.746(0.52),2.839(0.64),2.867(0.60),3.485(0.78),3.488(0.66),3.491(0.85),3.516(1.00),3.522(0.92),3.544(0.48),3.550(0.42),3.562(0.44),3.568(0.54),3.573(0.73),3.578(0.77),3.587(0.81),3.593(0.83),3.598(0.85),3.604(0.71),3.772(0.51),3.777(0.56),3.781(0.78),3.786(0.61),3.789(0.59),3.794(0.56),3.800(0.46),3.805(0.46),3.809(0.64),3.814(0.50),3.817(0.45),4.818(0.60),4.833(0.97),4.848(0.79),4.858(0.65),4.862(0.67),4.874(0.57),7.746(1.41),7.760(2.88),7.772(1.71),8.341(1.93),8.355(2.69),8.368(2.12),8.745(2.34),8.766(2.68).
LC-MS(方法6):Rt=0.32min;MS(ESIpos):m/z=248[M+H]+
中间体2化合物的合成
中间体2-1
1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺
向高压反应釜中装入3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-甲腈(中间体1-1,1.17g,5.34mmol)、氨溶液(19ml,7.0M的甲醇溶液,850mmol)和兰尼镍(CAS 7440-02-0,783mg,50%湿的),并将混合物在室温下在25bar氢气气氛下搅拌22小时。将混合物通过硅藻土垫过滤,用甲醇洗脱,并将合并的滤液减压浓缩。将残余物不经进一步纯化直接用于下一步(1.13g,94%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.24(s,1H),8.17(d,1H),7.38(d,1H),4.09(d,2H),3.73-3.91(m,3H),3.59-3.73(m,4H),3.46-3.52(m,2H),3.39-3.45(m,2H).2.06(br.,2H).
LC-MS(方法2):Rt=0.54min;MS(ESIpos):m/z=225[M+H]+
中间体2-2
1-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺
使用中间体2-1中所述的类似方法,使用3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-甲腈(中间体1-2,355mg,1.52mmol)作为起始原料;制备得到350mg的标题化合物(89%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.24-8.31(m,1H),8.17(d,1H),7.39(d,1H),4.18-4.27(m,1H),4.00(dd,1H),3.86(dd,1H),3.63-3.75(m,3H),3.42-3.55(m,1H),3.36-3.41(m,1H),2.67(dq,1H),2.40-2.47(m,1H),2.19-2.31(m,4H),1.63-2.19(m,2H).
中间体2-3
1-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲胺
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使用中间体2-1中所述的类似方法,使用3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-甲腈(中间体1-3,836mg,3.58mmol)作为起始原料;制备得到860mg(90%纯度,91%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.68-1.84(br s,2H),1.85-1.94(t,1H),1.94-2.05(td,1H),2.19(s,3H),2.57-2.64(d,1H),2.73-2.83(d,1H),3.46-3.63(t,1H),3.63-3.73(s,2H),3.73-3.86(m,3H),4.10(br d,2H),7.34-7.44(d,1H),8.10-8.20(d,1H),8.21-8.30(s,1H).
LC-MS(方法2):Rt=0.56min;MS(ESIpos):m/z=238[M+H]+
中间体2-4
1-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺
使用中间体2-1中所述的类似方法,使用3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-甲腈(中间体1-4,823mg,3.53mmol)作为起始原料;制备得到798mg(90%纯度,86%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.865(0.49),2.199(0.64),2.210(1.08),2.228(0.99),2.233(0.96),2.236(0.96),2.254(0.85),2.263(0.81),2.269(0.55),2.284(16.00),2.327(0.53),2.430(0.78),2.439(0.81),2.447(0.65),2.518(2.11),2.523(1.42),2.649(0.75),2.654(1.38),2.660(0.91),2.669(0.65),2.674(0.60),2.678(0.83),2.684(1.22),2.690(0.66),3.361(1.52),3.365(1.53),3.388(1.10),3.469(0.59),3.474(0.65),3.496(1.15),3.502(1.16),3.523(0.75),3.528(0.68),3.683(2.49),3.690(2.42),3.712(0.79),3.719(1.11),3.846(1.01),3.853(1.04),3.873(0.94),3.880(0.91),3.982(0.79),3.997(0.86),4.007(1.03),4.021(0.96),4.215(1.01),4.226(1.09),4.240(0.86),4.250(0.84),7.379(0.99),7.389(1.01),8.168(1.06),8.179(1.11),8.259(1.53).
中间体2-5
(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯
使用中间体2-1中所述的类似方法,使用(2S)-2-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯(中间体1-5,5.75g,18.0mmol)作为起始原料;制备得到6.00g(95%纯度,98%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.41(s,9H),3.16(s,2H),3.39-3.49(m,2H),3.66-3.79(m,5H),3.79-3.98(m,3H),4.07-4.20(m,3H),7.39(d,1H),8.19(d,1H),8.27(s,1H).
LC-MS(方法2):Rt=0.84min;MS(ESIpos):m/z=324[M+H]+
中间体2-6
1-{3-[2-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲胺
使用中间体2-1中所述的类似方法,使用3-[2-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-甲腈(中间体1-6,2.89g,12.3mmol)作为起始原料;制备得到2.22g(90%纯度,68%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.536(0.40),1.729(1.99),1.751(3.41),1.765(5.01),1.785(6.00),1.804(5.59),1.817(5.34),1.834(4.06),1.852(2.92),1.870(2.15),2.326(1.02),2.669(1.04),3.159(0.53),3.208(5.54),3.235(8.67),3.261(7.11),3.424(3.46),3.430(3.63),3.451(7.09),3.457(7.51),3.479(5.43),3.485(5.78),3.528(4.90),3.534(5.03),3.557(6.69),3.563(7.65),3.584(3.06),3.590(4.57),3.622(8.16),3.653(8.66),3.688(14.98),3.697(16.00),3.731(13.03),3.759(6.36),4.136(7.05),4.152(13.01),4.167(8.38),7.385(5.36),7.394(5.58),8.163(5.21),8.172(5.56),8.224(7.44).
中间体2-7
1-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺
使用中间体2-1中所述的类似方法,使用3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-甲腈(中间体1-7,1.30g,5.24mmol)作为起始原料;制备得到1.26g(90%纯度,86%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.014(0.96),1.049(16.00),1.201(0.72),1.262(13.58),1.751(0.48),2.518(2.17),2.523(1.47),3.308(2.76),3.539(2.43),3.567(1.99),3.601(1.13),3.623(1.75),3.694(1.97),3.720(2.07),3.746(2.38),3.783(0.46),4.128(3.01),4.136(2.80),7.386(0.85),8.181(0.83),8.237(0.96).
中间体2-8
1-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺
使用中间体2-1中所述的类似方法,使用3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-甲腈(中间体1-8,1.24g,5.63mmol)作为起始原料;制备得到1.56g(80%纯度,99%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.232(0.52),1.845(1.06),2.518(2.37),2.523(1.54),3.159(14.24),3.171(14.33),3.376(0.69),3.379(0.65),3.404(2.41),3.419(0.41),3.428(3.79),3.431(3.86),3.439(0.59),3.447(0.69),3.455(2.71),3.465(1.97),3.474(0.57),3.486(2.71),3.493(2.97),3.508(1.01),3.520(2.61),3.592(0.45),3.601(1.92),3.608(2.10),3.630(2.77),3.636(3.65),3.659(5.73),3.661(5.45),3.683(16.00),3.700(1.95),3.754(3.49),3.762(2.18),3.784(2.51),3.794(0.57),3.812(0.61),3.823(2.48),3.829(3.16),3.842(0.81),3.849(2.07),3.856(6.45),3.868(1.93),3.874(1.37),3.880(1.69),3.887(1.30),3.892(1.13),3.899(0.89),4.087(11.44),4.099(10.46),4.111(2.62),4.125(1.15),7.380(4.02),7.391(4.11),7.411(0.67),7.423(0.67),8.168(6.28),8.179(6.26),8.184(1.58),8.196(1.02),8.230(10.21),8.274(1.76).
中间体2-9
(3R)-3-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯
使用中间体2-1中所述的类似方法,使用(3R)-3-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯(中间体1-9,4.00g,12.5mmol)作为起始原料;制备得到3.65g的标题化合物(86%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.038(0.41),1.055(0.77),1.073(0.44),1.363(10.92),1.754(6.47),2.200(1.02),2.325(1.05),2.330(1.42),2.334(1.05),2.521(5.72),2.526(3.72),2.667(0.88),2.672(1.22),2.676(0.89),3.057(1.02),3.068(1.10),3.087(1.65),3.090(1.62),3.097(1.89),3.101(1.73),3.120(2.21),3.130(2.39),3.168(16.00),3.210(1.86),3.235(0.59),3.240(1.07),3.258(1.25),3.265(1.40),3.286(1.75),3.294(2.07),3.316(3.15),3.365(3.67),3.372(3.73),3.395(1.88),3.402(1.68),3.462(1.41),3.470(1.43),3.503(3.53),3.534(2.78),3.682(7.14),3.764(1.68),3.774(1.81),3.792(3.17),3.802(2.81),3.820(1.93),3.855(0.89),3.859(1.19),3.865(1.80),3.869(2.32),3.873(3.62),3.882(2.64),3.886(3.02),3.889(2.79),3.893(4.31),3.899(3.39),3.902(2.87),3.927(2.09),4.111(1.76),4.227(3.64),4.303(0.96),4.315(1.37),4.329(3.71),4.331(3.43),4.338(1.95),4.345(2.50),7.401(2.60),8.192(2.81),8.337(2.91).
LC-MS(方法1):Rt=0.49min;MS(ESIpos):m/z=324[M+H]+
中间体2-10
(2R)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯
使用中间体2-1中所述的类似方法,使用(2R)-2-{[(4-氰基吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯(中间体1-10,6.92g,21.7mmol)作为起始原料;制备得到6.95g的标题化合物(90%纯度,89%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.41(s,9H),2.70-3.01(m,2H),3.17(d,3H),3.41-3.52(m,1H),3.63-3.70(m,2H),3.70-3.81(m,2H),3.82-4.00(m,2H),4.08-4.18(m,3H),7.39(d,1H),8.18(d,1H),8.25(s,1H).
LC-MS(方法2):Rt=0.84min;MS(ESIpos):m/z=324[M+H]+
中间体2-11
1-{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲胺
使用中间体2-1中所述的类似方法,使用3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-甲腈(中间体1-11,1.68g,7.17mmol)作为起始原料;制备得到1.49g(90%纯度,78%产率)的标题化合物。
LC-MS(方法6):Rt=0.2min;MS(ESIpos):m/z=239[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.990(0.87),1.006(0.89),1.058(0.73),1.073(0.73),1.165(0.76),1.216(15.68),1.232(16.00),1.256(14.15),1.272(13.96),1.755(9.46),1.917(0.88),3.240(0.43),3.265(0.46),3.276(0.41),3.293(0.54),3.302(0.81),3.325(0.68),3.338(0.50),3.350(0.56),3.371(0.56),3.378(0.58),3.400(2.78),3.412(2.79),3.426(5.84),3.438(5.24),3.453(6.52),3.459(6.28),3.466(5.96),3.479(2.46),3.486(3.26),3.493(2.78),3.521(0.49),3.529(0.67),3.535(0.58),3.564(2.05),3.572(2.72),3.580(2.41),3.600(6.11),3.609(5.52),3.617(4.09),3.634(11.25),3.637(11.05),3.756(8.08),3.785(6.75),3.889(2.49),3.894(2.48),3.917(2.26),3.922(2.16),4.540(1.04),4.555(3.05),4.569(4.27),4.580(2.83),4.584(2.84),7.369(3.21),7.379(4.91),8.135(3.33),8.146(5.23),8.157(3.20),8.261(4.69),8.275(4.23).
中间体2-12
1-{3-[(1R)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲胺
使用中间体2-1中所述的类似方法,使用3-{(1R)-1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-甲腈(中间体1-12,1.39g,5.93mmol)作为起始原料;制备得到1.36g(95%纯度,91%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.216(0.81),1.232(0.99),1.255(15.91),1.271(16.00),1.753(0.71),3.290(0.44),3.399(0.54),3.412(2.42),3.424(0.71),3.437(3.81),3.440(3.42),3.453(0.77),3.459(2.72),3.465(5.00),3.485(1.48),3.494(2.02),3.573(1.45),3.580(1.70),3.598(2.00),3.603(3.43),3.609(3.84),3.616(2.24),3.622(2.04),3.628(1.97),3.634(4.41),3.638(4.68),3.645(2.04),3.662(5.32),3.672(6.05),3.713(0.63),3.757(2.28),3.764(2.39),3.787(1.75),3.790(1.84),3.887(2.14),3.894(2.12),3.916(1.94),3.922(1.85),4.535(0.53),4.550(1.85),4.564(2.15),4.566(2.17),4.579(1.80),4.595(0.50),7.381(3.18),7.393(3.14),8.144(4.36),8.156(4.13),8.257(0.50),8.272(6.58).
LC-MS(方法6):Rt=0.21min;MS(ESIpos):m/z=239[M+H]+
中间体2-71
1-{3-[1-(4-甲基吗啉-2-基)乙氧基]吡啶-4-基}甲胺
使用中间体2-1中所述的类似方法,使用3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-甲腈(中间体1-71,815mg,3.30mmol)作为起始原料;制备得到810mg(99%纯度,97%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.227(3.82),1.242(3.97),1.254(4.80),1.270(4.60),1.850(1.08),1.862(1.12),1.876(1.43),1.888(1.42),1.903(0.90),1.915(1.07),1.928(0.67),1.937(0.65),1.945(0.81),1.957(1.14),1.965(0.95),1.973(0.53),1.985(0.64),1.993(0.48),2.152(0.51),2.183(16.00),2.332(0.45),2.518(2.14),2.522(1.29),2.575(1.38),2.602(1.24),2.673(0.44),2.692(0.68),2.720(0.63),2.834(0.79),2.862(0.75),3.475(0.48),3.480(0.56),3.487(0.60),3.504(1.27),3.508(1.56),3.514(1.44),3.536(1.04),3.542(1.01),3.563(0.49),3.568(0.50),3.575(0.48),3.588(0.47),3.667(1.61),3.793(1.27),3.821(1.05),4.561(0.97),7.374(1.24),8.138(1.27),8.267(1.31).
LC-MS(方法6):Rt=0.11min;MS(ESIpos):m/z=252[M+H]+
中间体3化合物的合成
中间体3-1
1-氯-3-异硫氰基-2-甲氧基苯
将3-氯-2-甲氧基苯胺(CAS 51114-68-2,8.4ml,63mmol)溶于DCM(100ml)中,并加入饱和的碳酸氢钠溶液(100ml)。向冰冷的混合物中缓慢地加入硫光气(5.4ml,70mmol)。将该反应在0℃下搅拌2小时。在室温下,将DCM层分离,并用饱和的碳酸氢钠溶液洗涤,通过疏水过滤器过滤,并减压浓缩,得到标题化合物(12.97g,100%产率),将其直接用于下一步。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=7.51(dd,1H),7.35(dd,1H),7.20(t,1H),3.85-3.91(m,3H).
中间体3-4
1-氟-3-异硫氰基-2-甲氧基苯
使用中间体3-1中所述的类似方法,使用3-氟-2-甲氧基苯胺(CAS 437-83-2,5.00g,35.4mmol)作为起始原料;制备得到6.24g的标题化合物(96%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=7.32(m,1H),7.10-7.19(m,2H),3.96(d,3H).
中间体3-18
1-氯-5-氟-3-异硫氰基-2-甲氧基苯
使用中间体3-1中所述的类似方法,使用3-氯-5-氟-2-甲氧基苯胺(1.00g,5.70mmol)作为起始原料;制备得到1.17g的标题化合物(95%纯度,90%产率)。
1H NMR(400MHz,DMSO-d6):δ[ppm]=3.86(s,3H)7.38(dd,1H)7.58(dd,1H).
中间体3-29
1-氯-2-乙基-3-异硫氰基苯
使用中间体3-1中所述的类似方法,使用3-氯-2-乙基苯胺(5.00g,85%纯度,27.3mmol)作为起始原料,制备得到标题化合物6.29g(85%纯度,99%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.009(7.50),1.027(16.00),1.046(7.55),1.090(0.44),1.109(0.89),1.128(0.44),2.590(2.26),2.608(6.71),2.627(6.58),2.646(2.00),5.199(6.39),6.533(4.44),6.539(4.27),6.553(5.20),6.559(4.97),6.821(3.47),6.841(5.70),6.861(2.75),7.056(0.43),7.060(0.52).
中间体3-65
2-乙基-1-氟-3-异硫氰基苯
使用中间体3-1中所述的类似方法,使用2-乙基-3-氟苯胺(2.50g,18.0mmol,CAS1139437-61-8)作为起始原料,制备得到标题化合物3.0g(90%纯度,83%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.108(7.13),1.127(16.00),1.146(7.13),2.462(0.95),2.483(1.27),2.517(0.79),2.522(0.48),2.637(0.95),2.641(1.11),2.655(3.17),2.659(3.17),2.674(3.17),2.678(3.17),2.693(0.95),2.697(0.95),3.461(0.48),3.477(0.63),3.484(0.63),3.506(1.11),3.528(2.06),3.537(2.69),3.625(3.01),3.648(1.11),3.663(0.63),3.669(0.63),7.185(1.11),7.189(1.11),7.205(1.58),7.209(2.53),7.212(1.27),7.229(1.43),7.233(1.74),7.243(1.27),7.246(1.43),7.263(3.80),7.266(2.38),7.282(2.53),7.296(2.38),7.301(2.38),7.317(2.53),7.322(0.79),7.337(0.79).
中间体4化合物的合成
中间体4-1
5-[(3-氯-2-甲氧基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
向冰冷的1-氯-3-异硫氰基-2-甲氧基苯(中间体3-1,4.00g,20.0mmol)和2,4-二氧代哌啶-1-甲酸叔丁酯(CAS 845267-78-9,4.27g,20.0mmol)的乙腈(92ml)溶液中滴加DBU(4.5ml,30mmol)。将该反应在室温下搅拌过夜。向该反应混合物中加入冰水(200mL)和浓HCl(2mL)。将该混合物搅拌20分钟,并用DCM萃取。将有机相经防水过滤器过滤,减压浓缩,并通过快速色谱法(硅胶,己烷/EtOAc梯度0-50%)纯化,得到6.54g的标题化合物(71%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=13.36(br s,1H),7.73(d,1H),7.47(dd,1H),7.22(t,1H),3.76-3.82(m,5H),2.88(t,2H),1.48(s,9H).
LC-MS(方法1):Rt=1.49min;MS(ESIpos):m/z=413.1[M+H]+
中间体4-4
5-[(3-氟-2-甲氧基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,7.26g,34.1mmol)和1-氟-3-异硫氰基-2-甲氧基苯(中间体3-4,6.24g,34.1mmol)作为起始原料;在MeOH中搅拌该产物,过滤并真空干燥该沉淀物后,制备得到9.49g的标题化合物(67%产率)。
1H-NMR(400MHz DMSO-d6):δ[ppm]=13.37(br s,1H),7.58(br d,1H),7.23-7.30(m,1H),7.09-7.21(m,1H),4.10(br s,1H),3.78(t,2H),3.17(s,3H),2.88(brt,2H),1.48(s,9H).
LC-MS(方法2):Rt=0.66min;MS(ESIpos):m/z=397.3[M+H]+
中间体4-7
5-[(2,3-二氯苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
将1,2-二氯-3-异硫氰基苯(CAS 6590-97-2,5.00g,24.5mmol)和2,4-二氧代哌啶-1-甲酸叔丁酯(CAS 845267-78-9,5.22g,24.5mmol)溶于乙腈(55ml)中,在氩气气氛下在0℃下小心地加入DBU(5.5ml,37mmol),并将该混合物在室温下搅拌过夜。将该反应混合物用HCl(200ml,1N的水溶液)稀释,并在室温下搅拌30分钟。滤出所得固体,将滤饼用水洗涤,用水洗涤并在真空烘箱中于50℃干燥过夜得到9.40g的标题化合物(92%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.467(16.00),1.484(0.56),1.622(0.34),1.644(0.25),1.661(0.20),1.674(0.17),1.898(0.19),1.913(0.31),1.927(0.19),2.075(0.20),2.327(0.18),2.518(0.60),2.523(0.39),2.621(0.30),2.647(0.32),2.665(0.24),2.669(0.29),2.673(0.25),3.249(0.25),3.459(0.23),3.473(0.39),3.487(0.22),3.538(0.28),3.561(0.29),3.727(0.50),7.357(0.17),7.377(0.36),7.383(0.28),7.397(0.28),7.544(0.27),7.547(0.33),7.560(0.29),7.564(0.31),7.568(0.25),7.580(0.18).
LC-MS(方法2):Rt=0.70min;MS(ESIpos):m/z=416[M-H]-
中间体4-10
5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
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根据中间体4-1中所述的方法;使用1-氯-3-异硫氰基-2-甲基苯(CAS 19241-35-1;2.50g,13.6mmol)和2,4-二氧代哌啶-1-甲酸叔丁酯(CAS 845267-78-9,2.9g,13.6mmol)作为起始原料;加入HCl,过滤,真空干燥该沉淀物后,制备得到4.68g的标题化合物(78%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=15.73(s,1H),12.77(br s,1H),7.45(d,1H),7.30(t,1H),7.19(d,1H),3.78(t,2H),2.85(t,2H),2.20(s,3H),1.48(s,9H).
LC-MS(方法2):Rt=0.72min;MS(ESIpos):m/z=397.3[M+H]+
中间体4-18
5-[(3-氯-5-氟-2-甲氧基苯基)硫代氨基甲酰基]4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,1.15g,5.38mmol)和1-氯-5-氟-3-异硫氰基-2-甲氧基苯(中间体3-18,1.17g,5.38mmol)作为起始原料;制备得到1.42g的标题化合物(75%纯度,46%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.154(0.88),1.172(1.70),1.189(0.80),1.484(16.00),1.987(3.28),2.518(0.89),2.522(0.61),2.883(0.73),2.899(0.40),3.359(0.69),3.644(4.46),3.760(7.94),3.774(0.44),3.782(1.03),3.798(0.53),4.017(0.69),4.035(0.69),6.400(0.60),6.405(0.53),6.427(1.00),7.498(0.41).
LC-MS(方法2):Rt=0.73min;MS(ESIpos):m/z=431[M+H]+
中间体4-29
5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,5.77g,27.0mmol)和2-氯-1-乙基-3-异硫氰基苯(中间体3-29,6.29g,85%纯度,27.0mmol)作为起始原料;制备得到6.35g的标题化合物(85%纯度,49%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.063(0.89),1.082(2.14),1.100(0.95),1.362(0.65),1.478(16.00),1.486(1.29),2.518(0.64),2.523(0.44),2.631(0.70),2.650(0.69),2.850(0.41),2.866(0.78),2.883(0.43),3.775(0.51),3.791(0.90),3.807(0.46),7.212(0.46),7.214(0.44),7.232(0.62),7.234(0.61),7.293(0.62),7.313(1.08),7.332(0.53),7.440(0.61),7.443(0.62),7.460(0.49),7.463(0.45).
中间体4-38
5-[(3-氟-2-甲基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,8.19g,38.4mmol)和1-氟-3-异硫氰基-2-甲基苯(CAS 363179-58-2,6.42g,38.4mmol)作为起始原料;在MeOH中搅拌该产物,过滤并真空干燥该沉淀物后,制备得到11.1g的标题化合物(95%纯度,72%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.479(16.00),2.084(2.80),2.088(2.74),2.834(0.58),2.850(1.12),2.866(0.61),3.768(0.64),3.784(1.16),3.800(0.59),7.073(0.61),7.093(0.71),7.186(0.59),7.299(0.45),7.316(0.42).
中间体4-40
5-{[2-(2,2-二氟乙基)-3-氟苯基]硫代氨基甲酰基}-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,7.85g,36.8mmol)和2-(2,2-二氟乙基)-1-氟-3-异硫氰基苯(CAS 2311902-79-9,8.00g,36.8mmol)作为起始原料;制备得到12.1g的标题化合物(95%纯度,72%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.471(16.00),2.518(0.65),2.523(0.43),2.788(0.47),2.804(0.87),2.820(0.50),3.166(3.72),3.754(0.60),3.770(1.08),3.786(0.57),7.149(0.62),7.169(0.70),7.271(0.58),7.446(0.46),7.462(0.43).
中间体4-65
5-[(2-乙基-3-氟苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
使用中间体4-1中所述的类似方法,使用2,4-二氧代哌啶-1-甲酸叔丁酯(CAS845267-78-9,7.85g,36.8mmol)和2-乙基-1-氟-3-异硫氰基苯(中间体3-65,3.00g,16.6mmol)作为起始原料;制备得到5.46g的标题化合物(95%纯度,79%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.066(1.02),1.085(2.41),1.104(1.06),1.477(16.00),1.486(1.04),2.074(0.65),2.518(1.12),2.522(0.92),2.538(0.61),2.858(0.69),3.771(0.55),3.787(0.98),3.803(0.50),7.092(0.50),7.112(0.55),7.186(0.45),7.311(0.44),7.327(0.41).LC-MS(方法2):Rt=0.72min;MS(ESIpos):m/z=395[M+H]+
中间体5化合物的合成
中间体5-1
N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
向5-[(3-氯-2-甲氧基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-1,6.54g,15.8mmol)的二氯甲烷(94ml)溶液中加入TFA(12ml,160mmol),并将混合物在室温下搅拌1.5小时。将该反应混合物减压浓缩,并将残余物溶于EtOAc中,并用饱和的碳酸氢钠溶液和盐水洗涤。将有机层通过疏水过滤器过滤,并将滤液干燥至干。将残余物通过快速色谱法(硅胶,己烷/EtOAc梯度20-100%)纯化,得到4.06g的标题化合物(78%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=16.45(d,1H),14.69(s,1H),14.33(s,1H),9.37(br s,1H),8.18(br s,1H),7.76-7.87(m,1H),7.37-7.45(m,1H),7.15-7.23(m,1H),3.73-3.76(m,3H),3.43(td,1H),3.27-3.32(m,1H),2.79(t,1H),2.59-2.69(m,1H).
LC-MS(方法1):Rt=1.19min;MS(ESIpos):m/z=313[M+H]+
中间体5-4
N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(3-氟-2-甲氧基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-4,9.49g,23.9mmol)作为起始原料,搅拌15分钟后制备得到6.98g的标题化合物(89%产率),并且无需进一步纯化即可用于下一步。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=16.48(d,1H),14.63(s,0.5H),14.28(s,0.5H),9.34(br s,0.5H),8.16(br s,0.5H),7.65(t,1H),6.97-7.37(m,2H),3.79-3.85(m,3H),3.35-3.46(m,1H),3.26-3.32(m,1H),2.78(t,1H),2.63(t,1H).
LC-MS(方法2):Rt=0.46min;MS(ESIpos):m/z=297.1[M+H]+
中间体5-7
N-(2,3-二氯苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
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使用中间体5-1中所述的类似方法,使用5-[(2,3-二氯苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-7,9.40g,22.5mmol)作为起始原料;搅拌过夜后制备得到5.71g的标题化合物(62%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.018(1.18),1.050(1.33),1.072(0.81),1.102(0.59),1.132(0.81),1.154(1.84),1.172(3.17),1.189(1.84),1.199(0.88),1.231(1.92),1.259(1.40),1.486(0.66),1.593(1.33),1.626(1.18),1.695(1.25),1.727(1.18),1.907(2.14),1.987(5.97),2.322(3.17),2.326(4.28),2.331(3.17),2.518(15.85),2.522(9.44),2.638(11.06),2.664(7.82),2.669(7.52),2.673(5.53),2.798(8.11),3.436(9.81),4.017(1.18),4.035(1.11),5.560(1.33),5.579(1.25),7.392(4.42),7.410(10.03),7.430(9.22),7.565(12.24),7.585(16.00),7.605(9.51),8.134(0.74),8.197(4.35),9.418(3.91),14.273(6.93),14.665(6.64),16.114(1.03),16.295(9.95),16.352(5.82),16.503(1.11).
LC-MS(方法2):Rt=0.55min;MS(ESIpos):m/z=316[M-H]-.
中间体5-10
N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-10,4.67g,11.8mmol)作为起始原料,3小时后,制备得到3.54g的标题化合物(91%产率),并且无需进一步纯化即可用于下一步。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=16.42(d,1H),14.01-14.37(m,1H),8.14-9.40(m,1H),7.43(br t,1H),7.16-7.32(m,2H),3.42-3.48(m,1H),3.26-3.34(m,1H),2.78(t,1H),2.60-2.68(m,1H),2.12-2.21(m,3H).
LC-MS(方法2):Rt=0.60min;MS(ESIpos):m/z=297.4[M+H]+.
中间体5-18
N-(3-氯-5-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(3-氯-5-氟-2-甲氧基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-18,1.42g,3.30mmol)作为起始原料;制备得到690mg的标题化合物(95%纯度,60%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.61-2.70(m,1H),2.80(m,1H),3.25-3.32(m,1H),3.38-3.47(m,1H),3.74(s,3H),7.39-7.62(m,1H),7.83-8.02(m,1H),8.20-8.33(s,0,5H),9.33-9.57(s,0,5H),14.53(s,0,5H),14.93(s,0,5H),16.29(s,0,5H),16.36(s,0,5H).
LC-MS(方法2):Rt=0.57min;MS(ESIneg):m/z=329[M-H]-.
中间体5-29
N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-29,2.35g,75%纯度,4.29mmol)作为起始原料;制备得到1.22g的标题化合物(95%纯度,87%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.048(7.06),1.067(16.00),1.086(7.43),1.107(1.58),1.124(1.32),1.143(0.50),1.154(1.34),1.172(2.43),1.190(1.24),1.232(0.50),1.988(4.56),2.318(0.47),2.323(1.05),2.327(1.56),2.332(1.11),2.336(0.47),2.518(5.61),2.523(4.03),2.581(2.03),2.600(6.41),2.619(6.62),2.642(4.59),2.661(2.69),2.669(1.90),2.673(1.27),2.678(0.58),2.771(2.35),2.789(4.82),2.807(2.58),3.287(1.61),3.294(1.79),3.305(3.11),3.312(3.14),3.323(2.06),3.330(2.35),3.415(1.53),3.422(1.66),3.433(2.56),3.441(2.45),3.452(1.40),3.459(1.24),4.017(1.03),4.035(1.00),7.166(0.95),7.176(0.58),7.179(0.58),7.248(0.71),7.259(6.30),7.268(3.58),7.275(4.43),7.287(7.20),7.294(3.90),7.303(3.56),7.324(0.87),7.392(1.85),7.400(1.37),7.407(1.85),7.415(1.74),7.419(2.40),7.426(1.77),7.436(1.77),7.443(1.45),8.174(1.77),9.335(1.42),14.111(2.98),14.452(2.74),16.428(7.88),16.441(7.38).
LC-MS(方法6):Rt=1.28min;MS(ESIpos):m/z=311[M+H]+.
中间体5-38
N-(3-氟-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(3-氟-2-甲基苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-38,11.1g,29.1mmol)作为起始原料,搅拌15分钟后制备得到7.25g的标题化合物(84%产率),并且无需进一步纯化即可用于下一步。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.172(0.55),1.987(1.05),2.063(16.00),2.518(1.49),2.523(1.01),2.612(1.94),2.631(3.67),2.649(2.11),2.761(1.99),2.779(4.22),2.798(2.26),3.280(1.36),3.287(1.47),3.298(2.58),3.305(2.57),3.315(1.39),3.322(1.33),3.410(1.40),3.417(1.48),3.428(2.27),3.435(2.22),3.446(1.27),3.454(1.15),7.112(1.56),7.119(0.96),7.132(2.25),7.141(3.30),7.161(2.66),7.168(2.15),7.192(1.12),7.243(0.73),7.262(1.15),7.272(0.99),7.279(1.25),7.292(1.27),7.308(1.21),7.328(0.45),8.150(1.43),9.317(1.16),14.003(2.32),14.321(2.05),16.439(5.35),16.468(4.62).
LC-MS(方法2):Rt=0.47min;MS(ESIpos):m/z=281[M+H]+.
中间体5-40
N-[2-(2,2-二氟乙基)-3-氟苯基]-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-{[2-(2,2-二氟乙基)-3-氟苯基]硫代氨基甲酰基}-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-40,12.1g,28.0mmol)作为起始原料;制备得到8.81g的标题化合物(95%纯度,90%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.145(0.50),1.154(1.98),1.172(3.87),1.190(1.88),1.441(0.60),1.987(7.01),2.323(1.39),2.327(1.98),2.332(1.39),2.518(8.20),2.523(5.52),2.617(6.21),2.635(11.74),2.653(7.04),2.665(3.21),2.669(3.14),2.673(2.21),2.769(5.92),2.786(10.81),2.803(6.18),3.059(7.57),3.067(7.93),3.104(15.40),3.111(15.40),3.148(7.93),3.307(9.36),3.434(8.96),4.000(0.56),4.017(1.65),4.035(1.65),4.053(0.53),6.057(3.27),6.067(6.55),6.077(2.98),6.198(6.18),6.208(13.09),6.217(6.12),6.339(2.81),6.348(6.12),6.358(3.01),7.165(5.62),7.185(7.24),7.207(6.64),7.227(8.53),7.242(9.39),7.265(9.26),7.288(3.31),7.393(2.38),7.413(5.55),7.430(6.51),7.459(4.53),7.479(1.45),8.152(5.29),9.352(4.96),14.013(9.02),14.389(7.90),16.346(15.47),16.353(16.00).
LC-MS(方法2):Rt=0.48min;MS(ESIpos):m/z=331.1[M+H]+.
中间体5-65
N-(2-乙基-3-氟苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体5-1中所述的类似方法,使用5-[(2-乙基-3-氟苯基)硫代氨基甲酰基]-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(中间体4-65,5.46g,71%纯度,9.83mmol)作为起始原料;制备得到4.0g的标题化合物(70%纯度,97%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.052(6.61),1.071(16.00),1.089(6.75),1.116(0.56),1.224(4.60),1.734(1.58),2.326(0.43),2.472(1.56),2.518(2.10),2.523(1.69),2.647(0.85),2.659(0.85),2.664(0.98),2.668(1.03),2.673(0.80),2.782(0.89),3.423(0.82),4.037(0.62),7.160(2.35),7.288(0.98),8.170(0.48),14.073(0.46),14.414(0.52).
LC-MS(方法6):Rt=1.18min;MS(ESIpos):m/z=295[M+H]+.
中间体6化合物的合成
中间体6-1
N-(3-氯-2-甲氧基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
将N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,498mg,1.59mmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,0.5g,2.23mmol)的混合物在120℃下搅拌4小时。将该反应混合物通过快速色谱法(硅胶,DCM/EtOH梯度0-30%)纯化,得到325mg的标题化合物(39%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.79(s,1H),13.69(t,1H),8.39(s,1H),8.24(d,1H),7.81(dd,1H),7.73(s,1H),7.26-7.33(m,2H),7.11(t,1H),4.67(d,2H),4.16(t,2H),3.84-3.95(m,2H),3.74-3.79(m,1H),3.71(s,3H),3.59-3.70(m,2H),3.45-3.54(m,2H),3.11-3.20(m,2H),2.78(t,2H).
LC-MS(方法2):Rt=1.07min;MS(ESIpos):m/z=519.2[M+H]+.
中间体6-2
N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
将N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,866mg,2.77mmol)和1-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-8,776mg,80%纯度,2.77mmol)在ACN(22ml)中的混合物用N,O-双(三甲基甲硅烷基)乙酰胺(2.05ml,8.6mmol,CAS 10416-59-8)处理,并于80℃搅拌4小时。将该反应混合物减压浓缩,并通过快速色谱法(硅胶,DCM/EtOH梯度0-20%)纯化,得到1.23g(95%纯度,81%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.78(t,2H),3.16(td,2H),3.40-3.54(m,3H),3.59-3.69(m,2H),3.71(s,3H),3.73-3.79(m,1H),3.83-3.95(m,2H),4.16(t,2H),4.67(d,2H),7.11(t,1H),7.27-7.33(m,2H),7.73(br s,1H),7.81(dd,1H),8.24(d,1H),8.39(s,1H),13.69(s,1H),14.79(s,1H).
LC-MS(方法2):Rt=1.09min;MS(ESIpos):m/z=519[M+H]+
中间体6-4
4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,179mg,604μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,190mg,845μmol)作为起始原料;加热2小时,并通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到120mg的标题化合物(34%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.74(s,1H),13.70(br t,1H),8.39(s,1H),8.24(d,1H),7.64-7.73(m,2H),7.30(d,1H),7.02-7.14(m,2H),4.67(d,2H),4.13-4.21(m,2H),3.84-3.95(m,2H),3.59-3.77(m,4H),3.40-3.53(m,2H),3.13-3.22(m,2H),2.68-2.80(m,2H),1.59(br s,1H),0.93-1.39(m,1H).
LC-MS(方法2):Rt=1.01min;MS(ESIpos):m/z=503[M+H]+.
中间体6-7
N-(2,3-二氯苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基)]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(2,3-二氯苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-7,160mg,504μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,158mg,706μmol)作为起始原料;加热2小时,并通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到110mg的标题化合物(35%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.90(s,1H),13.66(t,1H),8.39(s,1H),8.24(d,1H),7.75(br s,1H),7.55(dd,1H),7.51(dd,1H),7.28-7.38(m,3H),4.68(d,3H),4.14-4.21(m,2H),3.87-3.90(m,1H),3.72-3.76(m,1H),3.64-3.67(m,1H),3.58-3.63(m,1H),3.35-3.53(m,3H),2.79(t,2H).
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=523[M+H]+.
中间体6-10
N-(3-氯-2-甲基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-10,189mg,637μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,200mg,892μmol)作为起始原料;加热2小时,并通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到180mg的标题化合物(56%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.54(s,1H),13.64(br t,1H),8.38(s,1H),8.24(d,1H),7.69(br s,1H),7.28-7.37(m,2H),7.13-7.26(m,2H),4.65(d,2H),4.14-4.20(m,2H),3.74-3.88(m,3H),3.63-3.71(m,2H),3.42-3.53(m,2H),3.14-3.31(m,2H),2.77(t,2H),2.16(s,3H).
LC-MS(方法2):Rt=1.09min;MS(ESIpos):m/z=501[M+H]+.
中间体6-11
N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,142mg,407μmol)和1-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺(中间体2-2,116mg,489μmol)作为起始原料;加热3小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)纯化后,制备得到85.6mg的标题化合物(36%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.79(s,1H),13.67(br t,1H),8.41(s,1H),8.24(d,1H),7.81(dd,1H),7.73(br s,1H),7.28-7.33(m,2H),7.11(t,1H),4.67(br d,2H),4.31(dd,1H),4.05(dd,1H),3.90(dd,1H),3.67-3.73(m,4H),3.50(td,1H),3.34-3.40(m,1H),3.13-3.21(m,2H),2.79(t,2H),2.63-2.70(m,1H),2.19-2.33(m,4H),1.46-1.76(m,1H).
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=532.5[M+H]+
中间体6-12
N-(3-氟-2-甲氧基苯基)-4-(((3-羟基吡啶-4-基)甲基)氨基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
在氮气气氛下,将4-(氨基甲基)吡啶-3-醇(CAS 20485-35-2,75g,0.604mol)和N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,150g,0.506mol)在DMA(1.2L)中的混合物于120℃搅拌2.5小时。将混合物真空浓缩以除去大部分溶剂。在搅拌下将深褐色溶液缓慢地加入到EtOAc(8L)中。将生成的混合物用水(2.5L)和盐水(2.5L x 2)洗涤。将有机相经硫酸钠干燥,过滤并真空浓缩。将残余物用EtOAc(300mL)浆化并过滤。将滤饼真空干燥,得到标题化合物(87g,47%产率),为黄色固体。
1H NMR(400MHz,DMSO-d6):δ[ppm]=14.73(s,1H),13.69(t,1H),10.28(s,1H),8.21-8.13(m,2H),7.67-7.66(m,2H),7.10(br.s,1H),7.09-7.04(m,2H),4.61(d,2H),3.79(s,3H),3.16(t,2H),2.77(t,2H).
中间体6-15
N-(3-氯-2-甲氧基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,100mg,320μmol)和1-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-3,114mg,480μmol)作为起始原料;加热4小时,并通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到74.3mg(80%纯度,35%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.880(0.45),2.176(4.07),2.186(0.73),2.191(0.45),2.518(1.66),2.523(1.13),2.787(0.65),2.799(0.61),3.162(0.56),3.169(0.54),3.533(0.46),3.539(0.45),3.711(9.24),3.819(0.47),3.823(0.40),4.149(0.65),4.161(1.12),4.176(0.61),4.655(0.80),4.670(0.82),5.759(16.00),7.086(0.63),7.107(1.27),7.127(0.73),7.283(0.77),7.287(0.81),7.302(0.77),7.306(1.39),7.318(0.80),7.723(0.53),7.803(0.59),7.806(0.60),7.823(0.57),7.827(0.53),8.234(1.27),8.246(1.26),8.392(1.87),14.791(1.01).
LC-MS(方法2):Rt=0.84min;MS(ESIpos):m/z=532[M+H]+
中间体6-18
N-(3-氯-5-氟-2-甲氧基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-5-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-18,100mg,302μmol)和1-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-3,108mg,453μmol)作为起始原料;通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到166mg(70%纯度,70%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.881(0.59),1.908(0.51),1.984(0.51),1.991(0.55),2.174(5.75),2.185(0.88),2.191(2.53),2.518(2.46),2.523(1.65),2.581(0.55),2.609(0.49),2.785(0.52),2.798(0.96),2.815(0.60),3.096(0.44),3.161(0.55),3.168(0.51),3.387(0.97),3.535(0.57),3.542(0.68),3.700(7.75),3.786(0.69),3.791(0.73),3.795(0.71),3.810(0.63),3.815(0.70),3.823(0.75),4.115(0.52),4.119(0.55),4.128(0.53),4.154(0.77),4.166(0.94),4.181(0.60),4.672(0.76),4.687(0.77),5.759(16.00),7.267(0.58),7.275(0.65),7.287(0.58),7.295(0.63),7.313(0.77),7.325(0.74),7.792(0.49),8.046(0.50),8.053(0.50),8.073(0.47),8.080(0.47),8.238(1.20),8.250(1.12),8.267(0.55),8.279(0.66),8.399(1.72),15.080(0.94).
LC-MS(方法2):Rt=1.11min;MS(ESIpos):m/z=550[M+H]+
中间体6-19
N-(3-氯-5-氟-2-甲氧基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-5-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-18,100mg,302μmol)和1-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-1,94.9mg,423μmol)作为起始原料,通过快速色谱法(硅胶,DCM/EtOH梯度0-30%)纯化后,制备得到160mg(90%纯度,89%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.821(0.41),0.904(0.45),1.035(8.84),1.052(16.00),1.070(9.56),1.154(1.90),1.172(3.66),1.189(1.72),1.987(6.85),2.518(1.36),2.522(0.92),2.790(0.61),3.157(0.42),3.404(1.39),3.417(1.49),3.421(4.01),3.434(4.35),3.439(4.40),3.452(4.43),3.457(1.21),3.461(0.53),3.469(1.28),3.501(0.40),3.652(0.66),3.655(0.65),3.702(7.42),3.750(0.43),3.785(0.67),3.788(0.43),3.890(0.58),3.999(0.46),4.017(1.36),4.035(1.39),4.053(0.47),4.156(0.56),4.165(0.77),4.179(0.54),4.343(2.52),4.356(4.91),4.368(2.35),4.683(0.68),4.697(0.68),7.272(0.48),7.280(0.60),7.293(0.51),7.300(0.64),7.305(0.63),7.317(0.62),7.800(0.42),8.032(0.40),8.040(0.42),8.059(0.41),8.066(0.40),8.242(0.98),8.254(0.94),8.394(1.43),15.078(0.82).
LC-MS(方法2):Rt=1.14min;MS(ESIpos):m/z=537[M+H]+
中间体6-20
N-(3-氟-2-甲氧基苯基)-4-{[(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,200mg,675μmol)和1-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺(中间体2-4,208mg,877μmol)作为起始原料,加热3小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到105mg(99%纯度,30%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.195(0.50),2.203(0.62),2.221(0.73),2.224(0.80),2.229(0.79),2.232(0.77),2.250(0.69),2.258(0.63),2.287(16.00),2.322(0.48),2.326(0.65),2.331(0.46),2.518(2.86),2.522(1.80),2.645(0.60),2.651(1.24),2.658(0.75),2.664(0.58),2.668(0.75),2.673(0.96),2.680(1.16),2.687(0.56),2.760(1.14),2.776(2.31),2.793(1.34),3.134(0.86),3.142(0.98),3.152(1.59),3.158(1.51),3.167(0.87),3.175(0.73),3.347(1.31),3.371(1.26),3.375(1.37),3.398(1.19),3.473(0.50),3.480(0.60),3.501(0.98),3.507(0.98),3.527(0.72),3.533(0.60),3.677(0.56),3.683(1.07),3.690(0.58),3.704(0.46),3.711(0.82),3.718(0.41),3.780(13.85),3.783(13.72),3.884(0.99),3.892(0.99),3.912(0.89),3.920(0.88),4.029(0.98),4.044(1.01),4.054(1.17),4.070(1.12),4.291(1.18),4.302(1.21),4.317(1.03),4.327(0.97),4.658(1.87),4.674(1.89),7.044(0.58),7.049(1.31),7.065(1.59),7.069(2.63),7.075(1.64),7.085(1.41),7.090(0.58),7.096(1.44),7.101(1.44),7.117(0.56),7.122(0.41),7.296(2.20),7.308(2.24),7.653(1.44),7.658(0.89),7.670(1.15),7.676(0.86),7.704(1.58),8.236(3.27),8.247(3.17),8.411(4.92),13.661(0.56),13.676(1.10),13.690(0.53),14.736(2.92).
LC-MS(方法6):Rt=0.62min;MS(ESIpos):m/z=516[M+H]+
中间体6-21
N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,200mg,639μmol)和1-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺(中间体2-4,197mg,831μmol)作为起始原料,于120℃加热3小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到102mg(99%纯度,30%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:2.288(3.78),2.327(0.47),2.518(1.87),2.523(1.27),2.651(0.43),2.665(0.45),2.669(0.59),2.673(0.55),2.679(0.47),2.769(0.69),2.786(1.40),2.803(0.81),3.141(0.53),3.148(0.61),3.157(0.97),3.164(0.93),3.174(0.53),3.181(0.44),3.346(0.55),3.372(0.52),3.506(0.45),3.684(0.50),3.712(16.00),3.883(0.44),3.891(0.53),3.912(0.42),4.293(0.54),4.304(0.56),4.319(0.47),4.329(0.44),4.663(1.08),4.679(1.10),7.088(1.04),7.108(2.24),7.128(1.28),7.285(1.42),7.289(1.49),7.301(1.47),7.305(1.46),7.309(1.44),7.312(1.47),7.726(0.92),7.794(1.07),7.797(1.08),7.814(1.02),7.818(0.96),8.238(1.81),8.250(1.65),8.413(3.11),13.667(0.68),14.787(1.82).
LC-MS(方法6):Rt=0.68min;MS(ESIpos):m/z=532[M+H]+
中间体6-22
(2S)-2-[({4-[({5-[(3-氟-2-甲氧基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,1.00g,3.37mmol)和(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-5,1.53g,4.72mmol)作为起始原料;加热6小时,并通过快速色谱法(硅胶,DCM/EtOH梯度0-20%)纯化后,制备得到1.43g(70%纯度,49%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.035(6.69),1.052(16.00),1.070(7.70),1.394(4.63),1.401(2.39),1.405(3.46),2.331(0.41),2.518(1.92),2.523(1.41),2.673(0.42),3.404(1.10),3.417(1.21),3.422(3.66),3.435(3.78),3.440(3.26),3.452(3.33),3.457(1.19),3.469(1.18),3.780(2.11),3.782(2.08),3.797(0.42),3.857(0.84),3.860(0.83),4.219(0.41),4.231(0.42),4.344(2.52),4.356(4.87),4.369(2.35),8.241(0.54),8.253(0.53),8.402(0.81),14.735(0.40).
LC-MS(方法2):Rt=1.19min;MS(ESIpos):m/z=602[M+H]+
中间体6-24
N-(3-氯-2-甲氧基苯基)-4-[({3-[2-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,200mg,639μmol)和1-(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲胺(中间体2-6,198mg,831μmol)作为起始原料,于130℃加热3小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min15-55%B)纯化后,制备得到110mg(96%纯度,31%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.792(0.45),1.812(0.43),1.838(0.40),1.850(0.42),2.518(1.13),2.523(0.78),2.763(0.87),2.771(0.86),2.780(0.52),2.786(0.47),3.140(0.51),3.148(0.57),3.156(0.97),3.164(0.96),3.173(0.50),3.181(0.43),3.197(0.60),3.224(0.94),3.227(0.95),3.253(0.64),3.445(0.75),3.452(0.83),3.471(0.48),3.480(0.60),3.545(0.45),3.551(0.53),3.573(0.70),3.580(0.81),3.605(0.86),3.611(1.14),3.617(0.53),3.638(0.55),3.644(0.47),3.689(0.92),3.697(1.10),3.712(16.00),3.718(2.12),3.744(0.88),3.749(0.65),4.203(0.84),4.219(1.35),4.232(0.58),4.238(0.56),4.656(1.44),4.670(1.43),7.089(1.01),7.110(2.16),7.130(1.25),7.286(1.37),7.289(1.46),7.306(2.13),7.310(1.42),7.317(1.10),7.726(0.93),7.802(1.03),7.806(1.05),7.823(0.99),7.826(0.93),8.225(1.23),8.237(1.18),8.373(1.98),13.695(0.65),14.792(1.75).
LC-MS(方法6):Rt=0.90min;MS(ESIpos):m/z=533[M+H]+
中间体6-27
(2S)-2-[({4-[({5-[(3-氯-5-氟-2-甲氧基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-1中所述的类似方法,使用N-(3-氯-5-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-18,225mg,680μmol)和(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-5,308mg,952μmol)作为起始原料;加热6小时,并通过快速色谱法(硅胶,DCM/EtOH梯度0-20%)纯化后,制备得到150mg(80%纯度,28%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.035(2.70),1.052(5.86),1.070(3.02),1.232(0.46),1.389(16.00),1.405(6.16),1.419(1.21),2.331(0.75),2.430(0.47),2.447(0.51),2.518(3.46),2.523(2.53),2.673(0.75),2.772(0.61),2.789(1.14),2.805(0.74),3.137(0.46),3.145(0.53),3.154(0.79),3.161(0.75),3.405(0.58),3.417(0.72),3.422(1.54),3.435(1.70),3.440(1.70),3.445(0.63),3.452(1.56),3.457(0.61),3.469(0.63),3.655(0.79),3.699(12.68),3.719(0.53),3.732(0.75),3.738(0.84),3.757(0.49),3.764(0.44),3.787(2.07),3.821(0.49),3.842(0.93),3.870(0.40),4.225(1.58),4.237(1.60),4.344(0.84),4.357(1.63),4.370(0.82),4.681(1.14),4.696(1.11),5.759(0.75),7.267(0.93),7.275(1.12),7.287(0.96),7.295(1.05),7.311(0.79),7.323(0.79),7.799(0.77),8.031(0.67),8.038(0.68),8.057(0.67),8.065(0.63),8.245(1.81),8.257(1.63),8.290(0.54),8.410(2.60),13.671(0.58),15.074(1.58).
LC-MS(方法2):Rt=1.30min;MS(ESIpos):m/z=636[M+H]+
中间体6-29
N-(3-氯-2-乙基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-29,300mg,965μmol)和1-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-3,321mg,1.35mmol)作为起始原料;加热6小时,并通过快速色谱法(硅胶,DCM/EtOH梯度0-20%)纯化后,制备得到300mg(80%纯度,47%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.798(0.84),0.814(0.93),0.821(0.93),0.840(0.43),0.886(0.53),0.904(1.07),0.922(0.50),1.035(9.51),1.052(16.00),1.066(1.09),1.070(9.08),1.073(1.50),1.232(0.45),1.874(0.59),1.901(0.47),1.907(0.59),1.983(0.41),1.990(0.52),2.178(5.56),2.195(1.38),2.202(0.47),2.331(0.74),2.518(3.86),2.522(2.50),2.580(0.57),2.591(1.05),2.610(1.21),2.673(0.95),2.784(0.95),2.817(0.50),3.162(0.41),3.172(0.69),3.179(0.65),3.404(1.33),3.417(1.38),3.421(3.41),3.434(3.43),3.439(3.91),3.452(4.01),3.457(1.15),3.469(1.19),3.529(0.57),3.535(0.57),3.735(0.55),3.784(0.47),3.788(0.47),3.792(0.47),3.812(0.64),3.816(0.62),4.111(0.41),4.123(0.48),4.138(0.83),4.149(0.83),4.154(0.88),4.168(0.74),4.343(2.64),4.356(5.06),4.368(2.39),4.636(0.93),4.651(0.93),7.205(1.50),7.208(1.38),7.218(2.69),7.296(1.02),7.305(1.02),7.308(1.05),7.315(1.17),7.327(0.55),7.701(0.64),8.228(1.50),8.240(1.38),8.282(0.47),8.385(2.07),13.654(0.43),14.636(1.17).
LC-MS(方法2):Rt=1.14min;MS(ESIpos):m/z=530[M+H]+
中间体6-30
N-(3-氯-2-甲氧基苯基)-4-[({3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,200mg,639μmol)和1-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-7,210mg,831μmol)作为起始原料;于130℃加热3小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到55.0mg(98%纯度,15%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.042(9.29),1.249(8.31),2.518(2.85),2.523(1.83),2.752(0.79),2.768(1.57),2.785(0.95),3.147(0.74),3.156(1.18),3.164(1.13),3.299(1.11),3.533(1.90),3.562(1.50),3.628(0.50),3.648(1.21),3.658(1.28),3.667(1.26),3.691(1.55),3.713(16.00),3.720(1.14),3.795(0.51),3.806(0.64),3.817(0.52),4.154(0.42),4.164(0.43),4.180(1.25),4.191(1.23),4.198(1.31),4.212(1.18),4.225(0.43),4.663(1.86),4.678(1.86),7.088(1.13),7.108(2.42),7.128(1.39),7.286(1.58),7.290(1.68),7.305(2.17),7.310(1.58),7.316(1.59),7.729(1.16),7.799(1.26),7.803(1.27),7.819(1.18),7.823(1.14),8.241(1.91),8.253(1.81),8.397(3.02),13.669(0.43),13.683(0.81),14.792(2.17).
LC-MS(方法6):Rt=1.04min;MS(ESIpos):m/z=547[M+H]+
中间体6-33
4-[({3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,200mg,675μmol)和1-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-7,221mg,877μmol)作为起始原料,于130℃加热2小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到130mg(96%纯度,35%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.043(15.59),1.251(13.74),2.518(2.60),2.523(1.78),2.742(1.25),2.759(2.52),2.775(1.52),3.134(1.00),3.142(1.15),3.152(1.86),3.158(1.79),3.167(1.02),3.175(0.86),3.300(1.91),3.535(3.14),3.563(2.56),3.622(0.60),3.630(0.81),3.650(1.97),3.659(2.07),3.668(2.14),3.692(2.45),3.722(1.19),3.782(15.81),3.785(16.00),3.796(0.91),3.808(1.03),3.819(0.82),3.832(0.62),4.155(0.57),4.165(0.61),4.181(1.80),4.192(1.83),4.198(1.91),4.212(1.68),4.225(0.61),4.238(0.55),4.658(2.20),4.672(2.17),7.029(0.54),7.045(0.69),7.050(1.65),7.065(1.84),7.069(2.29),7.071(2.14),7.077(2.06),7.085(1.65),7.093(0.69),7.098(1.72),7.103(1.74),7.119(0.69),7.124(0.54),7.307(0.94),7.317(0.99),7.657(1.74),7.662(1.08),7.676(1.36),7.681(1.03),7.708(1.84),8.254(0.72),8.404(0.81),13.678(0.65),13.693(1.25),13.707(0.60),14.741(3.47).
LC-MS(方法6):Rt=0.94min;MS(ESIpos):m/z=531[M+H]+
中间体6-35
4-{[(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲基]氨基}-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,200mg,675μmol)和1-(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲胺(中间体2-6,209mg,877μmol)作为起始原料,制备得到137mg(96%纯度,38%产率)的标题化合物。
LC-MS(方法6):Rt=0.83min;MS(ESIpos):m/z=517[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.757(0.42),1.778(0.61),1.793(0.89),1.813(0.86),1.822(0.55),1.826(0.49),1.833(0.54),1.840(0.80),1.852(0.85),1.857(0.64),1.868(0.60),2.518(2.52),2.523(1.61),2.674(0.45),2.735(0.74),2.752(1.68),2.761(1.69),2.769(1.02),2.777(0.89),3.134(1.00),3.142(1.11),3.151(1.92),3.159(1.89),3.168(0.98),3.175(0.85),3.198(1.19),3.224(1.91),3.228(1.91),3.254(1.24),3.421(0.47),3.425(0.68),3.446(1.52),3.453(1.67),3.472(0.99),3.481(1.19),3.545(0.92),3.552(1.09),3.574(1.39),3.580(1.60),3.606(1.73),3.612(2.26),3.618(1.04),3.639(1.07),3.645(0.93),3.690(1.77),3.697(2.11),3.709(0.79),3.719(3.54),3.728(1.41),3.735(0.73),3.744(1.71),3.751(1.33),3.782(15.79),3.784(16.00),4.203(1.78),4.219(2.73),4.232(1.20),4.237(1.18),4.653(2.89),4.667(2.88),7.030(0.49),7.046(0.68),7.051(1.63),7.067(1.82),7.070(3.31),7.077(2.11),7.086(1.65),7.092(0.71),7.098(1.72),7.103(1.73),7.119(0.68),7.124(0.52),7.303(1.99),7.314(2.03),7.660(1.68),7.665(1.06),7.677(1.35),7.683(1.07),7.703(1.84),8.226(1.84),8.237(1.79),8.373(2.98),13.689(0.64),13.704(1.28),13.718(0.60),14.740(3.42).
中间体6-37
N-(3-氟-2-甲氧基苯基)-4-{[(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-4,200mg,675μmol)和1-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲胺(中间体2-2,224mg,945μmol)作为起始原料;于124℃加热1小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到134mg的标题化合物(38%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.205(0.86),2.226(1.57),2.254(1.23),2.290(15.27),2.327(1.28),2.654(2.07),2.681(1.95),2.762(2.11),2.779(3.81),2.795(2.41),3.155(3.13),3.374(3.80),3.401(2.16),3.482(0.97),3.504(1.80),3.531(1.16),3.686(1.75),3.714(1.51),3.784(16.00),3.888(1.65),3.916(1.59),4.031(1.27),4.047(1.48),4.057(1.61),4.073(1.47),4.294(1.53),4.304(1.57),4.320(1.45),4.328(1.29),4.661(3.52),4.675(3.54),7.031(0.48),7.052(1.50),7.070(3.26),7.087(1.82),7.099(1.95),7.122(0.79),7.299(2.83),7.311(2.84),7.655(2.12),7.672(2.11),7.706(2.52),8.239(3.08),8.250(2.98),8.414(5.21),13.678(1.85),14.738(3.80).
LC-MS(方法6):Rt=0.64min;MS(ESIpos):m/z=516[M+H]+
中间体6-38
4-[[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]甲基氨基]-N-(3-氟-2-甲基-苯基)-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-(3-氟-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-38,350mg,1.25mmol)和1-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-7,315mg,1.25mmol)作为起始原料;于120℃加热3小时,并通过制备型HPLC(方法11,梯度:0.00-2.00min 30%B,2.00-14.00min 30-70%B)纯化后,制备得到192mg的标题化合物(27%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.046(16.00),1.253(14.02),2.045(8.35),2.050(8.21),2.063(1.09),2.521(2.37),2.525(1.62),2.741(1.29),2.757(2.61),2.774(1.60),3.145(1.01),3.152(1.15),3.161(1.90),3.168(1.80),3.178(0.99),3.185(0.85),3.298(1.92),3.534(3.17),3.562(2.60),3.617(0.65),3.626(0.83),3.647(2.00),3.656(2.10),3.666(2.13),3.690(2.57),3.719(1.29),3.780(0.43),3.793(0.82),3.803(1.04),3.814(0.83),3.828(0.60),4.148(0.72),4.159(0.78),4.174(2.17),4.186(2.01),4.194(2.14),4.208(2.03),4.220(0.76),4.234(0.69),4.647(3.08),4.662(3.06),7.040(0.87),7.061(1.78),7.074(1.74),7.085(1.37),7.094(2.40),7.189(0.89),7.208(1.38),7.225(1.30),7.244(0.54),7.295(2.49),7.307(2.52),7.686(1.77),8.237(2.54),8.249(2.42),8.393(3.97),13.662(1.07),14.520(2.54).
LC-MS(方法6):Rt=0.98min;MS(ESIpos):m/z=515[M+H]+
中间体6-40
N-[2-(2,2-二氟乙基)-3-氟-苯基]-4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-1中所述的类似方法,使用N-[2-(2,2-二氟乙基)-3-氟苯基]-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-40,100mg,303μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,95.0mg,424μmol)作为起始原料;通过快速色谱法(硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到19.5mg的标题化合物(10%产率)。
LC-MS(方法2):Rt=1.07min;MS(ESIpos):m/z=537[M+H]+
中间体6-41
(2S)-2-{[(4-{[(5-{[2-(2,2-二氟乙基)-3-氟苯基]硫代氨基甲酰基}-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基]甲基}吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯
将N-[2-(2,2-二氟乙基)-3-氟苯基]-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-40,200mg,605μmol)和(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-5,274mg,848μmol)在ACN(2-5ml)中的混合物用N,O-双-(三甲基甲硅烷基)乙酰胺(111μl,0.6mmol,CAS 10416-59-8)处理,并于80℃搅拌5小时。将该反应用另一等量的(111μl,0.6mmol)N,O-双-(三甲基甲硅烷基)乙酰胺处理,并于80℃搅拌过夜。将该反应混合物在DCM中稀释,并通过快速色谱法(硅胶,DCM/EtOH梯度0-20%)纯化,得到255mg(45%产率)的标题化合物。
LC-MS(方法2):Rt=1.25min;MS(ESIpos):m/z=636[M+H]+
中间体6-42
(2S)-2-[({4-[({5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-10,350mg,1.18mmol)和(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-5,381mg,1.18mmol)作为起始原料;加热3小时,并通过制备型HPLC(方法11,0.00-1.00min 30%B,1.00-12.74min 30-68.9%B,12.74-14.19min 68.9B,14.19-14.45min 68.9-70%B)纯化后,制备得到208mg的标题化合物(99%纯度,29%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.396(16.00),2.077(0.96),2.158(7.73),2.520(2.53),2.525(1.63),2.542(0.50),2.747(0.68),2.763(1.35),2.780(0.85),3.146(0.53),3.153(0.62),3.162(0.99),3.169(0.96),3.434(0.57),3.441(0.60),3.710(0.46),3.723(0.54),3.730(0.70),3.737(0.68),3.749(0.56),3.756(0.45),3.837(0.42),4.213(1.89),4.225(1.86),4.648(1.39),4.663(1.40),7.153(0.57),7.170(1.15),7.196(0.92),7.216(1.36),7.236(0.59),7.294(0.89),7.306(0.92),7.326(1.13),7.329(1.10),7.346(0.85),7.349(0.79),7.691(0.91),8.237(2.11),8.249(1.94),8.399(3.05),13.653(0.59),14.540(1.38).
LC-MS(方法6):Rt=1.17min;MS(ESIpos):m/z=602[M+H]+
中间体6-43
(3R)-3-[({4-[({5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-1中所述的类似方法,使用N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-10,350mg,1.18mmol)和(3R)-3-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-9,381mg,1.18mmol)作为起始原料;加热3小时,并通过制备型HPLC(方法11,0.00-1.00min 30%B,1.00-12.74min 30-68.9%B,12.74-14.19min 68.9B,14.19-14.45min 68.9-70%B)纯化后,制备得到184mg的标题化合物(99%纯度,26%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.339(2.92),2.087(1.31),2.161(16.00),2.521(1.63),2.525(1.08),2.676(0.52),2.708(0.66),2.725(1.74),2.742(1.82),2.757(0.75),3.140(1.42),3.147(1.59),3.156(2.44),3.163(2.41),3.319(0.58),3.365(1.06),3.372(1.25),3.395(0.56),3.402(0.54),3.478(0.92),3.507(1.00),3.651(0.51),3.797(0.72),3.821(0.64),3.957(0.67),3.985(0.59),4.236(1.53),4.415(0.46),4.441(0.83),4.625(2.12),4.639(2.15),7.160(1.07),7.178(2.26),7.200(2.08),7.220(3.03),7.239(1.27),7.291(1.19),7.301(1.19),7.329(2.50),7.332(2.34),7.349(1.83),7.352(1.71),7.691(1.99),8.240(3.22),8.252(3.11),8.489(2.72),13.669(0.94),14.536(3.05).
LC-MS(方法6):Rt=1.17min;MS(ESIpos):m/z=602[M+H]+
中间体6-44
N-(3-氯-2-甲基-苯基)-4-[[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-10,200mg,674μmol)和1-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-7,200mg,85%纯度,674μmol)作为起始原料;制备得到328mg的标题化合物(97%纯度,89%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.047(14.25),1.253(12.85),2.077(16.00),2.162(14.45),2.520(1.87),2.525(1.19),2.742(1.21),2.759(2.44),2.775(1.45),3.147(0.98),3.154(1.11),3.163(1.80),3.170(1.74),3.180(0.98),3.186(0.82),3.297(1.66),3.327(2.92),3.533(2.87),3.561(2.30),3.617(0.55),3.626(0.77),3.646(1.84),3.655(1.96),3.664(1.91),3.689(2.20),3.718(1.12),3.791(0.79),3.802(0.97),3.812(0.78),3.826(0.56),4.147(0.62),4.158(0.66),4.173(1.85),4.184(1.77),4.193(1.88),4.206(1.73),4.220(0.66),4.233(0.60),4.644(2.79),4.659(2.74),7.158(1.13),7.175(2.37),7.200(1.72),7.220(2.58),7.239(1.09),7.298(1.31),7.310(1.39),7.328(2.08),7.332(2.01),7.348(1.56),7.351(1.42),7.689(1.69),8.245(0.80),8.399(1.03),13.621(0.57),13.635(1.07),14.542(2.54).
LC-MS(方法6):Rt=1.06min;MS(ESIpos):m/z=531[M+H]+
中间体6-47
4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-N-(3-氟-2-甲基-苯基)-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氟-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-38,300mg,1.07mmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,240mg,1.07mmol)作为起始原料;制备得到156.3mg的标题化合物(93%纯度,71%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.000(0.70),1.998(0.55),2.033(16.00),2.038(15.45),2.064(3.23),2.508(3.78),2.513(2.36),2.737(2.61),2.754(5.23),2.771(2.96),3.142(2.39),3.151(3.71),3.158(3.53),3.168(2.07),3.393(2.34),3.418(3.51),3.421(3.41),3.446(3.16),3.461(1.34),3.482(2.56),3.488(2.76),3.506(1.42),3.516(2.71),3.579(1.64),3.585(1.94),3.608(2.49),3.614(2.79),3.641(5.03),3.670(1.97),3.735(2.71),3.744(2.66),3.769(2.09),3.837(2.39),3.844(2.81),3.871(4.35),3.883(1.72),3.890(1.32),3.895(1.57),3.902(1.32),3.907(1.44),3.914(1.14),3.926(0.62),4.108(0.85),4.120(0.95),4.134(3.73),4.145(6.69),4.158(3.48),4.171(0.87),4.184(0.75),4.624(4.75),4.639(4.68),7.028(1.64),7.050(3.46),7.062(3.48),7.073(2.79),7.081(4.60),7.179(1.62),7.198(2.71),7.215(2.51),7.235(1.00),7.333(1.12),7.676(3.41),8.321(0.42),13.651(2.04),14.509(4.80).
LC-MS(方法6):Rt=0.85min;MS(ESIpos):m/z=487[M+H]+
中间体6-50
N-(3-氯-2-甲基-苯基)-4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-10,200mg,674μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,151mg,674μmol)作为起始原料;制备得到150.0mg的标题化合物(96%纯度,42%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.077(1.64),2.162(16.00),2.520(2.60),2.525(1.64),2.751(1.41),2.768(2.82),2.784(1.63),3.156(1.22),3.165(1.94),3.172(1.87),3.404(1.32),3.429(1.94),3.432(1.93),3.457(1.81),3.472(0.72),3.493(1.40),3.500(1.50),3.518(0.79),3.528(1.45),3.591(0.91),3.597(1.05),3.619(1.35),3.626(1.54),3.650(2.14),3.653(2.65),3.660(0.95),3.682(1.04),3.748(1.44),3.756(1.54),3.781(1.16),3.849(1.30),3.855(1.59),3.883(2.54),3.894(0.99),3.901(0.68),3.906(0.89),3.913(0.76),3.918(0.79),3.925(0.62),3.930(0.51),4.118(0.55),4.129(0.59),4.144(2.26),4.155(4.42),4.168(2.30),4.181(0.52),4.194(0.48),4.648(3.19),4.663(3.19),7.159(1.24),7.176(2.55),7.203(1.84),7.222(2.83),7.242(1.22),7.290(2.72),7.302(2.78),7.330(2.22),7.333(2.19),7.349(1.69),7.353(1.54),7.691(1.83),8.233(4.07),8.245(3.96),8.383(6.40),13.623(0.61),13.637(1.14),14.544(2.74).
LC-MS(方法6):Rt=0.94min;MS(ESIpos):m/z=503[M+H]+
中间体6-52
N-(3-氯-2-乙基-苯基)-4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-29,150mg,483μmol)和1-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲胺(中间体2-1,108mg,483μmol)作为起始原料;通过使用快速色谱法(硅胶,DCM/EtOH梯度1-13%)纯化,制备得到150.0mg的标题化合物(90%纯度,54%产率)。
1H-NMR(400MHz,DMSO-d6):δppm=1.01-1.11(m,4H),2.56-2.65(m,2H),2.73-2.81(m,2H),3.12-3.22(m,2H),3.39-3.54(m,3H),3.58-3.69(m,2H),3.73-3.80(m,1H),3.88(s,2H),4.09-4.23(m,2H),4.11-4.15(m,1H),4.57-4.71(m,2H),7.16-7.25(m,2H),7.28-7.36(m,2H),7.32(s,1H),7.66-7.75(m,1H),8.07-8.11(m,1H),8.21-8.26(m,1H),8.33-8.43(m,1H),13.60-13.70(m,1H),14.59-14.67(m,1H).
LC-MS(方法2):Rt=1.15min;MS(ESIpos):m/z=517[M+H]+
中间体6-53
N-(3-氯-2-乙基苯基)-4-{[(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-29,210mg,676μmol)和1-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-8,185mg,90%纯度,743μmol)作为起始原料;通过使用快速色谱法(硅胶,DCM/EtOH梯度1-15%)纯化,制备得到320.0mg的标题化合物(86%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.036(8.39),1.040(4.03),1.053(16.00),1.059(9.01),1.071(8.71),1.078(3.84),2.066(0.41),2.518(1.19),2.523(0.81),2.577(0.95),2.596(2.98),2.614(2.87),2.632(0.86),2.757(1.69),2.774(3.38),2.790(1.92),3.152(1.31),3.159(1.49),3.169(2.36),3.174(2.23),3.185(1.26),3.403(1.67),3.405(1.77),3.418(1.45),3.423(4.19),3.427(2.48),3.430(2.54),3.435(4.26),3.440(3.60),3.453(4.76),3.457(2.12),3.470(1.96),3.492(1.59),3.498(1.73),3.516(0.85),3.526(1.70),3.589(1.03),3.594(1.21),3.617(1.57),3.623(1.85),3.651(3.24),3.679(1.31),3.745(1.75),3.754(1.70),3.779(2.03),3.847(1.59),3.853(1.84),3.880(2.81),3.893(1.13),3.900(0.84),3.905(1.04),3.912(0.89),3.917(0.95),3.924(0.75),3.929(0.59),3.936(0.44),4.116(0.64),4.127(0.69),4.142(2.65),4.154(5.01),4.167(2.53),4.180(0.60),4.193(0.55),4.343(2.64),4.356(5.10),4.369(2.52),4.647(3.70),4.662(3.66),7.209(5.05),7.211(4.85),7.222(8.23),7.231(0.55),7.293(2.86),7.307(4.24),7.319(3.43),7.331(1.67),7.706(2.31),8.234(3.16),8.246(3.01),8.383(5.19),13.642(0.84),13.657(1.55),13.672(0.72),14.639(4.11).
LC-MS(方法2):Rt=1.17min;MS(ESIpos):m/z=517[M+H]+
中间体6-55
(2R)-2-[({4-[({5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-29,300mg,965μmol)和(2R)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-10,312mg,965μmol)作为起始原料;通过使用快速色谱法(硅胶,DCM/EtOH梯度1-10%)纯化,制备得到476.0mg的标题化合物(95%纯度,76%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.036(1.51),1.055(3.57),1.073(1.55),1.393(16.00),2.518(1.71),2.523(1.10),2.590(1.19),2.609(1.16),2.751(0.68),2.769(1.33),2.785(0.84),3.165(0.96),3.171(0.92),3.431(0.55),3.438(0.59),3.729(0.71),3.749(0.48),3.756(0.41),3.835(0.41),4.210(1.81),4.222(1.76),4.646(1.35),4.662(1.35),5.758(7.84),7.202(2.06),7.214(2.99),7.296(1.00),7.304(1.58),7.316(1.60),7.328(0.75),7.703(0.94),8.236(1.90),8.248(1.81),8.398(2.84),13.671(0.64),14.632(1.67).
LC-MS(方法2):Rt=1.32min;MS(ESIpos):m/z=616[M+H]+
中间体6-56
(2S)-2-[({4-[({5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-29,300mg,965μmol)和(2S)-2-({[4-(氨基甲基)吡啶-3-基]氧基}甲基)吗啉-4-甲酸叔丁酯(中间体2-5,312mg,965μmol)作为起始原料;通过快速色谱法(硅胶,DCM/EtOH梯度1-10%)纯化后,制备得到479.0mg的标题化合物(95%纯度,77%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=14.55-14.67(m,1H),13.60-13.72(m,1H),8.40(s,1H),8.24(d,1H),7.70(br s,1H),7.16-7.36(m,4H),5.70-5.80(m,1H),5.66-5.81(m,1H),4.59-4.73(m,2H),4.12-4.27(m,2H),3.80-3.99(m,2H),3.65-3.78(m,2H),3.37-3.50(m,1H),3.10-3.22(m,2H),2.70-2.99(m,4H),2.55-2.64(m,2H),1.30-1.46(m,9H),1.01-1.12(m,3H).
LC-MS(方法2):Rt=1.32min;MS(ESIpos):m/z=616[M+H]+
中间体6-57
N-(3-氯-2-甲氧基苯基)-4-([{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,300mg,959μmol)和1-{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲胺(中间体2-11,251mg,1.06mmol)作为起始原料;制备得到384mg的标题化合物(99%纯度,74%产率),为非对映异构体的混合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.064(0.95),1.239(2.82),1.255(2.83),1.279(2.06),1.295(2.09),2.518(1.11),2.523(0.82),2.761(0.76),2.777(0.86),3.141(0.52),3.148(0.60),3.157(1.00),3.164(0.99),3.181(0.43),3.417(0.87),3.443(0.88),3.455(0.44),3.462(0.47),3.470(0.68),3.476(0.41),3.591(0.40),3.597(0.65),3.620(0.88),3.632(0.76),3.639(0.41),3.647(0.54),3.653(0.56),3.672(0.40),3.678(0.44),3.711(16.00),3.732(0.56),3.766(0.89),3.772(0.52),3.794(0.57),4.651(1.27),4.665(1.31),4.682(0.58),7.090(0.70),7.110(1.53),7.131(0.88),7.287(1.67),7.289(1.87),7.300(1.26),7.305(1.12),7.309(1.02),7.314(0.67),7.726(0.98),7.791(0.95),7.794(0.96),7.811(0.90),7.815(0.85),8.198(1.34),8.211(1.99),8.223(0.91),8.416(1.88),8.432(1.35),13.666(0.43),13.675(0.50),14.790(1.61).
LC-MS(方法6):Rt=0.96min和Rt=0.98min;MS(ESIpos):m/z=533.2[M+H]+
中间体6-60
N-(3-氯-2-甲氧基苯基)-4-{[(3-{(1R)-1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,300mg,959μmol)和1-{3-[(1R)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲胺(中间体2-12,251mg,1.06mmol)作为起始原料;制备得到346mg(99%纯度,67%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.278(5.25),1.294(5.21),2.073(0.98),2.331(0.40),2.518(2.02),2.522(1.36),2.673(0.42),2.749(0.74),2.765(0.56),2.775(0.83),2.792(0.42),3.140(0.62),3.147(0.73),3.156(1.17),3.164(1.16),3.417(0.81),3.441(1.16),3.445(1.15),3.469(1.68),3.475(0.85),3.503(0.74),3.570(0.47),3.576(0.55),3.598(0.72),3.604(0.82),3.631(1.87),3.638(0.97),3.646(0.63),3.652(0.78),3.657(1.02),3.663(0.93),3.670(0.52),3.677(0.47),3.710(16.00),3.758(0.87),3.767(0.74),3.790(0.67),3.920(0.78),3.926(0.76),3.949(0.72),3.955(0.66),4.646(1.57),4.653(1.48),4.662(1.63),4.682(0.73),7.092(1.08),7.112(2.33),7.133(1.33),7.287(1.60),7.290(1.60),7.302(1.73),7.306(1.61),7.310(1.69),7.314(1.68),7.725(1.16),7.791(1.23),7.794(1.22),7.811(1.17),7.814(1.08),8.210(2.42),8.222(2.24),8.430(3.36),13.651(0.41),13.665(0.79),14.786(2.12).
LC-MS(方法6):Rt=0.96min;MS(ESIpos):m/z=533[M+H]+
中间体6-62
N-(3-氟-2-甲基苯基)-4-{[(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氟-2-甲基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-38,197mg,704μmol)和1-(3-{[-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-3,167mg,704μmol)作为起始原料;通过反相HPLC(碱性的)纯化后,制备得到170mg的标题化合物(93%纯度,45%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.035(0.65),1.053(1.08),1.070(0.68),1.848(1.00),1.876(1.47),1.901(1.11),1.953(0.45),1.962(0.59),1.982(1.04),1.990(1.08),2.010(0.69),2.019(0.57),2.040(7.36),2.044(6.91),2.177(16.00),2.518(1.64),2.522(1.10),2.578(0.88),2.607(0.81),2.756(0.84),2.770(1.72),2.789(2.10),2.817(1.02),3.149(0.83),3.156(0.97),3.166(1.67),3.173(1.63),3.182(0.94),3.318(0.50),3.501(0.55),3.507(0.70),3.529(1.25),3.535(1.29),3.557(0.76),3.563(0.62),3.784(0.93),3.788(0.90),3.791(0.76),3.812(1.29),3.815(1.26),3.829(0.63),3.837(0.57),4.112(0.53),4.124(0.56),4.138(1.82),4.150(1.97),4.154(2.08),4.168(1.68),4.180(0.56),4.194(0.52),4.636(2.30),4.651(2.34),7.034(0.71),7.055(1.49),7.070(1.47),7.079(1.12),7.089(1.98),7.185(0.72),7.204(1.19),7.221(1.13),7.241(0.44),7.295(2.26),7.306(2.30),7.679(1.46),8.227(3.76),8.239(3.55),8.383(5.45),13.662(0.88),14.516(2.06).
LC-MS(方法6):Rt=0.62min;MS(ESIpos):m/z=500[M+H]+
中间体6-65
4-{[(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-N-(2-乙基-3-氟苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(2-乙基-3-氟苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(300mg,1.02mmol)和1-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(229mg,1.02mmol)作为起始原料;蒸发溶剂,过滤并用ACN洗涤该固体后,制备得到218mg的标题化合物(90%纯度,38%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.057(1.12),1.042(7.32),1.061(16.00),1.080(7.29),1.231(0.88),1.751(0.58),2.074(6.86),2.522(5.66),2.753(3.09),2.770(6.11),2.787(3.52),3.156(2.86),3.166(4.42),3.172(4.30),3.181(2.51),3.402(2.65),3.427(3.92),3.430(3.92),3.455(3.70),3.471(1.62),3.491(2.84),3.498(3.08),3.516(1.51),3.526(2.87),3.589(1.80),3.594(1.99),3.617(2.79),3.623(3.19),3.650(5.74),3.679(2.35),3.745(3.17),3.754(3.06),3.778(2.46),3.846(2.80),3.853(3.24),3.881(4.78),3.893(1.98),3.900(1.58),3.905(1.80),3.911(1.59),3.918(1.69),3.925(1.36),3.936(0.73),4.117(1.01),4.129(1.14),4.143(4.20),4.155(7.71),4.168(3.95),4.181(1.08),4.194(0.91),4.632(5.48),4.646(5.40),7.029(2.23),7.051(3.97),7.074(2.84),7.091(3.92),7.110(5.33),7.191(2.31),7.207(2.86),7.211(3.55),7.228(3.42),7.248(1.35),7.351(1.30),7.701(4.14),8.329(0.48),8.476(0.42),13.662(1.51),13.676(2.76),13.691(1.37),14.588(6.37).
LC-MS(方法6):Rt=0.92min;MS(ESIpos):m/z=501[M+H]+
中间体6-68
4-{[(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-N-(2-乙基-3-氟苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(2-乙基-3-氟苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(300mg,1.02mmol)和1-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(257mg,1.02mmol)作为起始原料;通过柱色谱法纯化后,制备得到360mg的标题化合物(93%纯度,62%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.014(0.69),1.044(16.00),1.061(7.08),1.080(3.30),1.172(0.52),1.200(0.60),1.251(13.22),1.987(0.87),2.745(1.36),2.761(2.65),2.779(1.61),3.164(2.11),3.170(2.09),3.295(1.79),3.532(2.73),3.560(2.19),3.615(0.59),3.624(0.79),3.644(1.91),3.653(2.05),3.664(1.79),3.688(2.07),3.718(1.01),3.778(0.45),3.789(0.91),3.801(1.07),3.812(0.86),3.824(0.63),4.145(0.65),4.156(0.71),4.172(1.96),4.182(1.95),4.191(2.02),4.205(1.76),4.218(0.69),4.231(0.59),4.644(3.11),4.658(3.10),7.029(0.86),7.050(1.63),7.074(1.12),7.091(1.71),7.111(2.37),7.189(0.89),7.208(1.52),7.225(1.39),7.245(0.52),7.295(2.40),7.306(2.41),7.700(1.92),8.235(3.11),8.247(2.98),8.389(5.24),13.661(0.71),13.675(1.32),13.688(0.68),14.587(3.04).
LC-MS(方法6):Rt=1.03min;MS(ESIpos):m/z=529[M+H]+
中间体6-71
N-(3-氯-2-甲氧基苯基)-4-({[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]甲基}氨基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺
使用中间体6-41中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体5-1,300mg,959μmol)和1-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]甲胺(中间体2-71,265mg,1.06mmol)作为起始原料;通过柱色谱法纯化后,制备得到360mg的标题化合物(93%纯度,62%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.014(0.69),1.044(16.00),1.061(7.08),1.080(3.30),1.172(0.52),1.200(0.60),1.251(13.22),1.987(0.87),2.745(1.36),2.761(2.65),2.779(1.61),3.164(2.11),3.170(2.09),3.295(1.79),3.532(2.73),3.560(2.19),3.615(0.59),3.624(0.79),3.644(1.91),3.653(2.05),3.664(1.79),3.688(2.07),3.718(1.01),3.778(0.45),3.789(0.91),3.801(1.07),3.812(0.86),3.824(0.63),4.145(0.65),4.156(0.71),4.172(1.96),4.182(1.95),4.191(2.02),4.205(1.76),4.218(0.69),4.231(0.59),4.644(3.11),4.658(3.10),7.029(0.86),7.050(1.63),7.074(1.12),7.091(1.71),7.111(2.37),7.189(0.89),7.208(1.52),7.225(1.39),7.245(0.52),7.295(2.40),7.306(2.41),7.700(1.92),8.235(3.11),8.247(2.98),8.389(5.24),13.661(0.71),13.675(1.32),13.688(0.68),14.587(3.04).
LC-MS(方法6):Rt=1.03min;MS(ESIpos):m/z=529[M+H]+
中间体12
3-((3-氟-2-甲氧基苯基)氨基)-2-(3-羟基吡啶-4-基)-6,7-二氢-1H-吡咯并[3,2-c]吡啶-4(5H)-酮
向N-(3-氟-2-甲氧基苯基)-4-(((3-羟基吡啶-4-基)甲基)氨基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-12,41g,101.88mmol)的MeOH(410mL)悬浮液中加入TFA(0.75mL,10.13mmol),随后加入过氧化氢(18mL,30%的水溶液)。将混合物加热至60℃,并搅拌16小时。加入另外的TFA(6.8mL,91.84mmol)和过氧化氢(1.5mL,30%的水溶液)。将悬浮液于60℃再搅拌3小时。将混合物冷却至室温并放置过夜。将悬浮液与同样生成的第二批混合。将合并的悬浮液过滤,并将该滤饼用水(250mL)和MeOH(150mL)洗涤,并然后在MeOH(150mL)中浆化。将悬浮液过滤。将该滤饼用MeOH(75mL)洗涤并真空干燥,得到标题化合物(25.4g,33.8%产率),为黄色固体。
1H NMR(400MHz,DMSO-d6):δ=11.45(s,1H),8.18(s,1H),7.98(d,1H),7.39(d,1H),7.18(s,1H),6.67(t,1H),6.54(t,1H),6.04(d,1H),3.92(s,3H),3.40(t,2H),2.90(t,2H).
LC-MS(方法5):Rt=1.851min;m/z=369.0(M+H)+
中间体22-1
(2S)-2-[({4-[3-(3-氟-2-甲氧基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用实施例1中所述的类似方法,使用(2S)-2-[({4-[({5-[(3-氟-2-甲氧基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体6-22,1.43g,2.38mmol)作为起始原料;通过快速色谱法(硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到572mg(80%纯度,34%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.035(0.86),1.053(1.99),1.071(0.88),1.380(0.83),1.401(6.79),1.409(16.00),2.518(1.63),2.523(1.18),2.842(0.65),2.859(1.16),2.877(0.76),3.178(0.95),3.301(0.60),3.398(0.50),3.404(0.61),3.415(0.94),3.418(0.82),3.422(1.10),3.435(0.77),3.440(0.72),3.452(0.50),3.553(0.42),3.560(0.43),3.750(0.64),3.760(0.40),3.851(0.50),3.858(0.40),3.873(0.46),3.906(6.63),3.936(0.57),3.939(0.59),3.950(0.46),4.343(0.56),4.356(0.65),5.759(1.09),5.993(0.75),6.013(0.76),6.485(0.50),6.489(0.49),6.492(0.42),6.513(0.45),6.516(0.42),6.627(0.54),6.642(0.52),7.147(0.86),7.280(1.09),7.293(1.13),7.509(0.98),8.025(1.38),8.038(1.27),8.401(2.10),11.020(0.61).
LC-MS(方法2):Rt=1.12min;MS(ESIpos):m/z=568[M+H]+
中间体22-2
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将(2S)-2-[({4-[3-(3-氟-2-甲氧基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体22-1,572mg,1.01mmol)溶于二氯甲烷(7.2ml)中,并加入TFA(780μl,10mmol)。将该混合物在室温下搅拌2小时。将混合物蒸发,并通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-20%)纯化,得到352mg(95%纯度,71%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.53-2.78(m,4H),2.80-2.90(m,3H),3.38-3.47(m,3H),3.55-3.66(m,1H),3.83-3.90(m,1H),3.91-3.95(s,3H),4.07-4.16(m,1H),4.29-4.39(m,1H),6.01(d,1H),6.44-6.56(m,1H),6.65(dt,1H),7.17(s,1H),7.29(d,1H),7.53(s,1H),8.01(d,1H),8.39(s,1H),11.10(s,1H).
LC-MS(方法2):Rt=0.84min;MS(ESIpos):m/z=468[M+H]+
中间体27-1
(2S)-2-[({4-[3-(3-氯-5-氟-2-甲氧基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
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使用实施例1中所述的类似方法,使用(2S)-2-[({4-[({5-[(3-氯-5-氟-2-甲氧基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体6-27,150mg,236μmol)作为起始原料,制备得到73.5mg(90%纯度,47%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.40(s,9H),2.52-2.53(m,2H),2.70-3.03(m,1H),2.87(br t,2H),3.42(td,2H),3.46-3.61(m,1H),3.71-3.79(m,1H),3.82(s,4H),3.93(br d,1H),4.20(m,1H),4.27-4.33(dd,1H),5.85(dd,1H),6.55(dd,1H),7.11(s,1H),7.32(d,1H),7.60(s,1H),8.10(d,1H),8.44(s,1H),11.17(s,1H).
LC-MS(方法2):Rt=1.19min;MS(ESIpos):m/z=602[M+H]+
中间体27-2
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(2S)-2-[({4-[3-(3-氯-5-氟-2-甲氧基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体27-1,73.0mg,121μmol)作为起始原料;通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-15%)纯化后,制备得到56.3mg(95%纯度,88%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.51-2.58(m,2H),2.61-2.75(m,2H),2.77-2.94(m,3H),3.38-3.48(m,1H),3.56(td,1H),3.76-3.92(m,2H),3.84(s,3H),4.10(dd,1H),4.29(dd,1H),5.85(dd,1H),6.57(dd,1H),7.13(s,1H),7.32(d,1H),7.64(d,1H),8.09(d,1H),8.43(s,1H),11.22(s,1H).
LC-MS(方法2):Rt=0.93min;MS(ESIpos):m/z=502[M+H]+.
中间体41-1
(2S)-2-{[(4-{3-[2-(2,2-二氟乙基)-3-氟苯胺基]-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基}吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯
使用实施例1中所述的类似方法,使用(2S)-2-{[(4-{[(5-{[2-(2,2-二氟乙基)-3-氟苯基]硫代氨基甲酰基}-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基]甲基}吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯(中间体6-41,266mg,418μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)纯化后,制备得到33.0mg(65%纯度,9%产率)的标题化合物。
LC-MS(方法2):Rt=1.16min;MS(ESIneg):m/z=600[M-H]-
中间体41-2
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(2S)-2-{[(4-{3-[2-(2,2-二氟乙基)-3-氟苯胺基]-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基}吡啶-3-基)氧基]甲基}吗啉-4-甲酸叔丁酯(中间体41-1,33.0mg,54.9μmol)作为起始原料;通过快速色谱法(氨基相硅胶,DCM/EtOH梯度0-10%)纯化后,制备得到22.0mg(65%纯度,52%产率)的标题化合物。
LC-MS(方法2):Rt=0.92min;MS(ESIneg):m/z=500[M-H]-
中间体42-1
(2S)-2-[({4-[3-(3-氯-2-甲基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用实施例1中所述的类似方法,使用(2S)-2-[({4-[({5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体6-42,207mg,344μmol)作为起始原料;通过制备型HPLC(方法9,梯度:0.00-0.50min 15%B,0.50-4.65min 15-44.9%B,4.65-5.94min 44.9%B,5.94-7.29min 44.9-55%B)纯化后,制备得到27.8mg(90%纯度,13%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.414(16.00),2.349(5.99),2.520(0.82),2.525(0.50),2.853(0.68),2.870(1.29),2.887(0.75),3.405(0.49),3.410(0.53),3.422(0.95),3.428(0.93),3.439(0.48),3.445(0.43),3.554(0.43),3.560(0.45),4.294(0.43),4.304(0.45),6.191(0.69),6.195(0.66),6.211(0.71),6.214(0.69),6.719(0.48),6.735(1.31),6.738(1.11),6.747(0.85),6.767(0.82),7.175(0.83),7.232(0.92),7.245(0.92),7.351(0.48),7.998(1.24),8.010(1.16),8.378(1.84),11.016(0.78).
LC-MS(方法6):Rt=0.92min;MS(ESIpos):m/z=568[M+H]+
中间体42-2
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(2S)-2-[({4-[3-(3-氯-2-甲基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体42-1,30.0mg,52.8μmol)作为起始原料,通过SCX-2柱(MeOH洗涤,然后用1M氨的MeOH溶液洗脱)过滤后,制备得到19.0mg(92%纯度,71%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.235(1.09),2.334(1.58),2.338(0.84),2.362(16.00),2.520(7.24),2.525(4.55),2.545(1.21),2.570(1.33),2.575(1.40),2.601(1.20),2.676(1.83),2.680(1.06),2.705(1.02),2.713(0.99),2.732(1.01),2.740(0.93),2.758(1.50),2.787(0.62),2.846(1.74),2.863(4.52),2.880(2.07),2.894(1.12),3.300(4.30),3.410(1.44),3.416(1.55),3.427(2.54),3.433(2.52),3.445(1.29),3.585(0.65),3.593(0.77),3.612(1.20),3.620(1.22),3.640(0.69),3.646(0.62),3.851(0.59),3.868(0.92),3.875(0.91),3.902(1.40),3.930(1.00),4.073(1.20),4.090(1.18),4.098(1.63),4.116(1.39),4.274(1.41),4.282(1.45),4.299(1.18),4.307(1.08),5.528(0.41),6.196(1.85),6.200(1.81),6.215(2.00),6.219(1.86),6.726(1.04),6.730(1.33),6.746(3.44),6.750(2.92),6.761(2.53),6.780(2.58),6.800(0.88),7.192(2.31),7.231(3.82),7.244(3.92),7.364(4.42),7.980(4.81),7.993(4.51),8.370(6.73),8.397(0.45),11.102(2.40).
LC-MS(方法6):Rt=0.52min;MS(ESIpos):m/z=468[M+H]+
中间体43-1
(3R)-3-[({4-[3-(3-氯-2-甲基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
使用实施例1中所述的类似方法,使用(3R)-3-[({4-[({5-[(3-氯-2-甲基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(180mg,299μmol)作为起始原料;通过制备型HPLC(方法9,梯度:0.00-0.50min 15%B,0.50-4.23min 15-41.9%B,4.23-5.60min 41.9%B,5.60-7.37min 41.9-55%B)纯化后,制备得到35.1mg(90%纯度,19%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.344(16.00),2.357(14.22),2.520(2.49),2.525(1.70),2.891(0.42),2.923(1.43),3.384(1.03),3.405(2.12),3.412(2.73),3.417(2.74),3.435(1.48),3.555(0.76),3.577(0.85),3.680(1.24),3.709(1.06),3.840(1.02),3.860(0.92),3.952(1.42),3.982(1.23),4.301(0.62),6.161(1.64),6.165(1.44),6.179(1.77),6.184(1.67),6.725(0.94),6.740(3.11),6.745(3.77),6.765(1.40),6.785(0.46),7.187(1.94),7.309(2.75),7.322(2.75),7.351(4.78),7.971(1.97),7.983(1.88),8.445(5.01),11.063(1.60).
LC-MS(方法6):Rt=0.92min;MS(ESIpos):m/z=568[M+H]+
中间体43-2
3-(3-氯-2-甲基苯胺基)-2-(3-{[(3R)-吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(3R)-3-[({4-[3-(3-氯-2-甲基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体43-1,30.0mg,52.8μmol)作为起始原料,通过SCX-2柱(MeOH洗涤,然后用1M氨的MeOH溶液洗脱)过滤后,制备得到25.3mg(97%纯度,99%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.235(0.47),2.334(1.10),2.338(0.53),2.367(16.00),2.383(0.45),2.520(5.15),2.525(3.36),2.676(1.09),2.680(0.50),2.825(1.81),2.842(3.79),2.860(2.41),2.888(0.56),2.945(0.90),2.976(0.54),3.155(0.67),3.371(1.08),3.398(1.36),3.416(2.04),3.426(3.16),3.433(2.75),3.444(2.06),3.450(1.95),3.471(0.57),3.720(1.01),3.747(0.86),3.794(1.03),3.816(0.90),4.192(0.59),4.208(0.66),4.218(1.25),4.232(1.21),4.252(1.38),4.261(1.46),4.277(0.69),4.286(0.59),6.222(1.82),6.225(1.83),6.241(1.98),6.245(1.89),6.731(1.15),6.735(1.43),6.751(3.26),6.754(2.74),6.769(2.24),6.790(2.51),6.809(0.87),7.172(2.36),7.217(2.75),7.230(2.77),7.391(4.55),7.941(1.75),7.953(1.66),8.359(2.93),12.612(0.40).
LC-MS(方法6):Rt=0.53min;MS(ESIpos):m/z=468[M+H]+
中间体55-1
(2R)-2-[({4-[3-(3-氯-2-乙基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
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使用实施例1中所述的类似方法,使用(2R)-2-[({4-[({5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体6-55,473mg,768μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 10%B,0.50-11.05min 10-34.4%B,11.05-12.46min 34.4%B,12.46-24.12min 34.4-60%B)纯化,随后通过快速色谱法(硅胶,DCM/EtOH梯度0-12%)纯化后,制备得到57.0mg(95%纯度,12%产率)的标题化合物。
LC-MS(方法2):Rt=1.26min;MS(ESIpos):m/z=582[M+H]+
中间体55-2
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(2R)-2-[({4-[3-(3-氯-2-乙基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体55-1,70.4mg,121μmol)作为起始原料;通过快速色谱法(硅胶,DCM/EtOH+三乙胺梯度1-40%)纯化后,制备得到58.0mg(95%纯度,95%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=10.96-11.17(m,1H),8.36(s,1H),7.69-8.02(m,1H),7.37-7.51(m,1H),7.19(s,2H),6.65-6.86(m,2H),6.15-6.24(m,1H),6.12-6.31(m,1H),4.26-4.36(m,1H),4.06-4.14(m,1H),3.85-3.96(m,2H),3.58-3.67(m,1H),3.40-3.46(m,2H),3.35-3.39(m,1H),2.69-2.96(m,7H),2.56-2.64(m,1H),1.19-1.27(m,6H).
LC-MS(方法2):Rt=0.99min;MS(ESIneg):m/z=480[M-H]-
中间体56-1
(2S)-2-[({4-[3-(3-氯-2-乙基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯
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使用实施例1中所述的类似方法,使用(2S)-2-[({4-[({5-[(3-氯-2-乙基苯基)硫代氨基甲酰基]-6-氧代-1,2,3,6-四氢吡啶-4-基}氨基)甲基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体6-56,476mg,772μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 20%B,0.50-12.99min 20-40%B,12.99-15.46min 40%B,15.46-24.12min 40-55%B)纯化,随后通过快速色谱法(硅胶,DCM/EtOH梯度0-12%)纯化后,制备得到68.0mg(95%纯度,14%产率)的标题化合物。
LC-MS(方法2):Rt=1.26min;MS(ESIpos):m/z=582[M+H]+
中间体56-2
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用中间体22-2中所述的类似方法,使用(2S)-2-[({4-[3-(3-氯-2-乙基苯胺基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基]吡啶-3-基}氧基)甲基]吗啉-4-甲酸叔丁酯(中间体56-1,70.4mg,121μmol)作为起始原料;通过快速色谱法(氨基相硅胶,DCM/EtOH梯度1-35%)纯化后,制备得到46.9mg(95%纯度,78%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.09(s,1H),8.36(s,1H),7.96(d,1H),7.46(s,1H),7.19(d,2H),6.68-6.84(m,2H),6.23(dd,1H),4.24-4.34(m,1H),4.03-4.16(m,1H),3.82-3.96(m,2H),3.57-3.65(m,1H),3.39-3.48(m,2H),2.82-2.94(m,5H),2.64-2.79(m,2H),2.54-2.60(m,1H),1.23(t,3H).
LC-MS(方法2):Rt=0.99min;MS(ESIneg):m/z=480[M-H]-
实施例
实施例1
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
向N-(3-氯-2-甲氧基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-1,140mg,240μmol)的MeOH(2.7ml)悬浮液中加入TFA(42μl,540μmol),随后加入过氧化氢水溶液(94μl,35%纯度,1.08mmol),并将混合物于50℃加热17小时。将该反应混合物冷却至室温,并减压浓缩。将残余物通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化,得到70mg的标题化合物(51%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(t,2H),3.37-3.57(m,4H),3.70-3.90(m,4H),3.88(s,3H),3.92-4.08(m,1H),4.10-4.20(m,1H),4.28(dd,1H),6.15(t,1H),6.68(d,2H),7.16(br s,1H),7.28(d,1H),7.52(s,1H),8.04(d,1H),8.39(s,1H),11.07(s,1H).
LC-MS(方法2):Rt=0.98min;MS(ESIpos):m/z=485[M+H]+
实施例2
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例1中的标题化合物(140mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,27mg,在Rt=14.0-17.0min时)和对映异构体2(25mg,在Rt=20.0-24.8min时,参见实施例3)。
制备型手性HPLC方法:
仪器:Labomatic HD5000,Labocord-5000;Gilson GX-241,Labcol Vario 4000;柱:Cellulose SB 5μ,250x30mm;洗脱剂A:己烷+0.1体积%二乙胺(99%);洗脱剂B:2-丙醇;恒溶剂(isocratic):50%A+50%B;流速50ml/min;UV:254nm.
分析型手性HPLC方法:
仪器:Agilent HPLC1260;柱:Cellulose SB 3μ,100x4.6mm;洗脱剂A:己烷+0.1体积%二乙胺(99%);洗脱剂B:2-丙醇;恒溶剂:50%A+50%B,流速1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=4.49min.
旋光度:[α]D=1.7°+/-0.98°(c=3.6mg/2ml,甲醇)
对映体选择性合成确认该标题化合物为3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮。按照类似于实施例1,使用N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-2,1.23g,2.36mmol)作为起始原料,随后通过使用制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min15-55%B)纯化,制备得到872mg(95%纯度,72%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(t,2H),3.38-3.47(m,3H),3.53(td,1H),3.69-3.78(m,2H),3.83(dd,1H),3.88(s,3H),3.90(m,1H),3.98-4.08(m,1H),4.12-4.18(m,1H),4.28(dd,1H),6.12-6.17(quin,1H),6.66-6.71(m,2H),7.16(s,1H),7.28(d,1H),7.52(s,1H),8.04(d,1H),8.39(s,1H),11.07(s,1H).
分析型手性HPLC:Rt=4.46min.
旋光度:[α]D=-12.5°+/-0.52°(c=5.6mg/ml,氯仿)
实施例3
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例1。通过制备型手性HPLC分离对映异构体(方法参见实施例2),得到25mg的标题化合物(在Rt=20.0-24.8min时)。
分析型手性HPLC(方法参见实施例2):Rt=6.56min.
旋光度:[α]D=-3.0°+/-1.03°(c=3.2mg/2ml,甲醇)
旋光度:[α]D=22.8°+/-6.1°(c=6.3mg/ml,氯仿)
实施例4
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-4,120mg,239μmol),加热25小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min15%B,0.50-6.00min 15-55%B)纯化后,制备得到25.7mg的标题化合物(21%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(t,2H),3.37-3.57(m,4H),3.66-3.89(m,4H),3.91(s,3H),3.98-4.09(m,1H),4.09-4.20(m,1H),4.28(dd,1H),6.00(d,1H),6.45-6.54(m,1H),6.64(m,1H),7.16(br s,1H),7.29(d,1H),7.53(s,1H),8.04(d,1H),8.39(s,1H),11.05(s,1H).
LC-MS(方法2):Rt=0.92min;MS(ESIpos):m/z=469[M+H]+
实施例5
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例4中的标题化合物(26mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,11mg,在Rt=8.2-9.1min时,10%产率)和对映异构体2(12mg,在Rt=9.7-10.7min时,参见实施例6)。
制备型手性HPLC方法:
仪器:Labomatic HD5000,Labocord-5000;Gilson GX-241,Labcol Vario 4000;柱:Cellulose SB 5μ,250x30mm;洗脱剂A:MTBE+0.1体积%二乙胺(99%);洗脱剂B:乙腈;梯度:2-60%B,20min;流速50ml/min;UV:280nm
分析型手性HPLC方法:
仪器:Agilent HPLC1260;柱:Cellulose SB 3μ,100x4.6mm;洗脱剂A:MTBE+0.1体积%二乙胺(99%);洗脱剂B:乙腈;梯度:2-60%B,7min,流速1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=4.34min.
旋光度:[α]D=-0.5°+/-0.87°(c=7.5mg/2ml,甲醇)
实施例6
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例4。通过制备型手性HPLC分离对映异构体(方法参见实施例5),得到12mg的标题化合物(在Rt=9.7-10.7min时,11%产率)。
分析型手性HPLC(方法参见实施例5):Rt=5.11min.
旋光度:[α]D=-0.1°+/-0.89°(c=6.3mg/3ml,甲醇)
实施例7
3-(2,3-二氯苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(2,3-二氯苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-7,110mg,210μmol),加热25小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到34.6mg的标题化合物(32%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(br t,2H),3.35-3.45(m,3H),3.47-3.56(m,1H),3.65-3.75(m,2H),3.75-3.88(m,2H),3.93-4.04(m,1H),4.06-4.20(m,2H),6.27(dd,1H),6.83-6.91(m,2H),7.17(br s,1H),7.26(d,1H),7.66(s,1H),8.08(d,1H),8.38(s,1H),11.21(s,1H).
LC-MS(方法2):Rt=1.01min;MS(ESIpos):m/z=489[M+H]+
实施例8
3-(2,3-二氯苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例7中的标题化合物(27mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,10mg)和对映异构体2(12mg,参见实施例9)。
制备型手性HPLC方法:
仪器:Labomatic HD5000,Labocord-5000;Gilson GX-241,Labcol Vario 4000;柱:Cellulose SB 5μ,250x30mm;洗脱剂A:MTBE+0.1体积%二乙胺(99%);洗脱剂B:乙腈;梯度:2-60%B,20min;流速50ml/min;UV:280nm
分析型手性HPLC方法:
仪器:AgilentHPLC1260;柱:Cellulose SB 3μ,100x4.6mm;洗脱剂A:MTBE+0.1体积%二乙胺(99%);洗脱剂B:乙腈;梯度:2-60%B,7min,流速1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=5.11min.
旋光度:[α]D=1.4°+/-0.69°(c=5.8mg/2ml,甲醇)
实施例9
3-(2,3-二氯苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例7。通过制备型手性HPLC分离对映异构体(方法参见实施例8),得到12mg的标题化合物。
分析型手性HPLC(方法参见实施例8):Rt=6.74min.
旋光度:[α]D=-14.9°+/-3.16°(c=5.6mg/ml,甲醇)
实施例10
3-(3-氯-2-甲基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(3-氯-2-甲基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-10,180mg,358μmol),加热25小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到12.1mg的标题化合物(7%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.35(s,3H),2.86(br t,2H),3.37-3.47(m,3H),3.55(br dd,1H),3.67-3.85(m,3H),3.89(br d,1H),4.01(br dd,1H),4.08-4.18(m,1H),4.24(dd,1H),6.20(d,1H),6.71-6.80(m,2H),7.19(br s,1H),7.24(d,1H),7.37(s,1H),8.01(d,1H),8.37(s,1H),11.05(s,1H).
LC-MS(方法2):Rt=1.02min;MS(ESIpos):m/z=469[M+H]+
实施例11
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-11,82mg,139μmol),加热17小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到11mg的标题化合物(15%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.51-12.57(m,1H),8.40(br s,1H),8.04(brs,1H),7.62(br s,1H),7.32(d,1H),7.19(br s,1H),6.71(br d,2H),6.15(dd,1H),4.40(br s,2H),3.90(s,4H),3.85(br s,1H),3.60(br d,3H),3.40-3.51(m,3H),3.01(br s,1H),2.74-2.96(m,3H),2.22-2.43(m,2H).
LC-MS(方法6):Rt=0.55min;MS(ESIpos):m/z=498.2[M+H]+
旋光度:[α]D=-82.0°+/-0.41°(c=5.8mg/ml,甲醇)
实施例12
3-(3-氟-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将3-(3-氟-2-甲氧基苯胺基)-2-(3-羟基吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体12,150mg,407μmol)溶于二噁烷(4.8ml)中。将该反应混合物用氩气脱气。然后加入(三丁基亚正膦基(tributylphosphanylidene))乙腈(384μl,1.5mmol,CAS 157141-27-0)和(4-甲基吗啉-2-基)甲醇(CAS40987-46-0,80.0mg,610μmol),并将混合物于50℃搅拌30小时。将混合物减压浓缩,并加入饱和的碳酸氢钠溶液。将混合物用DCM萃取。将有机相经防水过滤器过滤,减压浓缩,并通过制备型HPLC(方法10,梯度:0.00-0.50min 1%B,0.50-27.40min 1-50%B)纯化,得到16.2mg的标题化合物(8%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.05(s,1H),8.40(s,1H),8.02(d,1H),7.52(s,1H),7.29(d,1H),7.16(s,1H),6.64(td,1H),6.50(ddd,1H),6.01(d,1H),4.34(dd,1H),4.15(dd,1H),3.88-4.00(m,5H),3.67(td,1H),3.37-3.47(m,2H),2.85(t,2H),2.77(br d,1H),2.66-2.70(m,1H),2.20(s,3H),2.04(td,1H),1.91(t,1H).
LC-MS(方法2):Rt=0.92min;MS(ESIpos):m/z=482.3[M+H]+
实施例13
3-(3-氟-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例12中的标题化合物(19mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,6mg,在Rt=6.7-8.7min时,3%产率)和对映异构体2(7mg,在Rt=8.9-11.9min时,参见实施例14)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:Chiralcel OD-H 5μ,250x20;洗脱剂A:乙腈+0.1体积%二乙胺(99%);洗脱剂B:乙醇;恒溶剂:93%A+7%B;流速20ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:Chiralcel OD-H 5μ,100x4.6;洗脱剂A:乙醇+0.1体积%二乙胺(99%);洗脱剂B:乙醇;恒溶剂:90%A+10%B,流速1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=2.91min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.05(s,1H),8.40(s,1H),8.02(d,1H),7.53(s,1H),7.29(d,1H),7.16(s,1H),6.64(td,1H),6.50(t,1H),6.01(d,1H),4.34(dd,1H),4.15(dd,1H),3.89-3.99(m,5H),3.67(td,1H),3.38-3.46(m,2H),2.85(t,2H),2.77(br d,1H),2.61-2.71(m,1H),2.20(s,3H),1.98-2.16(m,1H),1.91(t,1H).
实施例14
3-(3-氟-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例12。通过制备型手性HPLC分离对映异构体(方法参见实施例13),得到7mg的标题化合物(在Rt=8.9-11.9min时,3%产率)。
分析型手性HPLC(方法参见实施例13):Rt=3.70min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.05(s,1H),8.40(s,1H),8.02(br d,1H),7.53(s,1H),7.29(d,1H),7.16(br s,1H),6.59-6.70(m,1H),6.50(br t,1H),6.01(br d,1H),4.34(br dd,1H),4.15(br dd,1H),3.86-4.00(m,5H),3.60-3.74(m,1H),3.40-3.48(m,2H),2.85(brt,2H),2.77(br d,1H),2.63-2.70(m,1H),2.20(s,3H),1.99-2.09(m,1H),1.91(brt,1H).
实施例15
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(3-氯-2-甲氧基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-15,74.0mg,139μmol),加热18小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到24.1mg(90%纯度,31%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.86-1.95(t,1H),2.00-2.09(td,1H),2.20(s,3H),2.66(br d,1H),2.73-2.81(br d,1H),2.86(t,2H),3.42(td,2H),3.61-3.73(td,1H),3.88(s,3H),3.91-4.02(m,2H),4.16(dd,1H),4.33(dd,1H),6.15(t,1H),6.69(d,2H),7.16(s,1H),7.28(d,1H),7.53(s,1H),8.03(d,1H),8.40(s,1H),11.07(s,1H).
LC-MS(方法2):Rt=0.97min;MS(ESIpos):m/z=498[M+H]+
实施例16
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例15中的标题化合物(24.1mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,8mg,在Rt=17.4-21.8时,11%产率)和对映异构体2(7mg,在Rt=12.5-14.5min时,参见实施例17)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:Chiralpak IF 5μ,250x30;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;恒溶剂:50%A+50%B;流速:40ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:Chiralpak IF 3μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:50%A+50%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=4.55min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.232(1.95),1.259(0.49),1.888(0.59),1.914(1.04),1.941(0.65),2.016(0.40),2.037(0.73),2.045(0.70),2.065(0.49),2.206(9.36),2.327(0.42),2.518(1.60),2.523(1.15),2.540(16.00),2.646(0.75),2.670(0.96),2.673(0.98),2.758(0.81),2.787(0.77),2.841(1.13),2.858(2.36),2.876(1.27),3.405(0.89),3.410(0.98),3.422(1.69),3.428(1.67),3.439(0.85),3.445(0.77),3.638(0.41),3.644(0.49),3.666(0.89),3.672(0.89),3.694(0.54),3.700(0.52),3.883(15.90),3.933(0.86),3.952(0.89),3.960(1.15),3.976(0.47),3.983(0.40),4.137(0.82),4.154(0.74),4.163(1.02),4.179(0.84),4.315(0.97),4.324(1.01),4.341(0.80),4.349(0.72),6.139(1.35),6.151(2.23),6.163(1.38),6.681(4.49),6.692(3.40),6.694(3.35),7.163(1.58),7.274(1.81),7.287(1.83),7.533(3.41),8.021(1.20),8.034(1.14),8.402(1.87),11.066(1.70).
实施例17
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例15。通过制备型手性HPLC分离对映异构体(方法参见实施例16),得到7mg的标题化合物(在Rt=12.5-14.5min时)。
分析型手性HPLC(方法参见实施例16):Rt=2.93min.
实施例18
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-5-氟-2-甲氧基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-18,166mg,302μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到13.0mg(95%纯度,8%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.88(t,1H),1.93-2.05(dt,1H),2.19(s,3H),2.60-2.66(d,1H),2.70-2.77(d,1H),2.86(t,2H),3.37-3.48(m,2H),3.56-3.68(m,1H),3.83(s,3H),3.90(br d,2H),4.15(m,1H),4.27(dd,1H),5.85(dd,1H),6.56(dd,1H),7.13(s,1H),7.33(d,1H),7.64(s,1H),8.10(d,1H),8.43(s,1H),11.18(s,1H).
LC-MS(方法2):Rt=1.00min;MS(ESIpos):m/z=516[M+H]+
实施例19
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-5-氟-2-甲氧基苯基)-4-[({3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-19,160mg,298μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到3.90mg(90%纯度,2%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(t,2H),3.37-3.45(m,3H),3.47-3.61(m,1H),3.62-3.77(m,3H),3.77-3.87(m,6H),3.94-4.01(m,1H),4.07-4.20(m,1H),4.24(dd,1H),5.85(dd,1H),6.56(dd,1H),7.13(s,1H),7.33(d,1H),7.60-7.66(d,1H),8.11(br d,1H),8.42(s,1H),11.19(s,1H).
LC-MS(方法2):Rt=1.01min;MS(ESIpos):m/z=503[M+H]+
实施例20
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-{[(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-20,102mg,197μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 10%B,0.50-6.00min 10-50%B)纯化后,制备得到27.9mg(90%纯度,26%产率)的标题化合物。
LC-MS(方法6):Rt=0.51min;MS(ESIpos):m/z=482[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:2.274(13.29),2.304(1.76),2.318(0.55),2.404(0.46),2.426(0.88),2.434(0.91),2.449(0.43),2.454(0.88),2.458(1.03),2.463(1.43),2.468(1.37),2.473(1.55),2.518(5.99),2.523(4.32),2.775(0.40),2.798(0.70),2.815(1.49),2.822(0.88),2.832(0.91),2.841(1.16),2.858(0.79),2.908(1.13),2.938(1.00),3.294(0.43),3.406(0.64),3.423(1.46),3.429(1.19),3.438(1.37),3.453(0.58),3.459(0.55),3.546(1.13),3.573(1.76),3.589(1.13),3.594(1.22),3.600(1.28),3.618(0.61),3.816(0.94),3.840(1.83),3.847(1.95),3.868(1.06),3.875(0.97),3.938(16.00),3.951(2.07),4.374(1.67),4.386(2.71),4.414(0.46),6.011(1.89),6.031(1.89),6.514(1.03),6.518(0.97),6.535(1.28),6.539(1.34),6.541(1.19),6.545(0.94),6.562(1.19),6.565(1.06),6.655(0.97),6.670(1.03),6.675(1.70),6.691(1.55),6.696(0.82),6.711(0.67),7.176(2.07),7.310(3.71),7.323(3.68),7.514(0.43),7.527(0.52),7.533(0.58),7.601(4.56),7.977(5.29),7.990(4.50),8.067(0.61),8.080(0.55),8.358(6.27),8.439(0.73),12.011(2.13).
实施例21
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-{[(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-21,99.5mg,187μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 10%B,0.50-6.00min 10-50%B)纯化后,制备得到4.70mg(98%纯度,5%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.232(0.45),2.276(9.36),2.426(0.63),2.434(0.67),2.456(0.51),2.464(0.76),2.472(0.79),2.518(1.95),2.523(1.26),2.539(9.95),2.806(0.54),2.823(1.37),2.841(1.19),2.860(0.60),2.910(0.85),2.940(0.76),3.408(0.49),3.425(1.12),3.431(0.95),3.441(1.04),3.454(0.49),3.460(0.44),3.544(0.71),3.572(1.31),3.588(0.84),3.594(0.92),3.599(0.96),3.617(0.47),3.817(0.72),3.841(1.23),3.847(1.34),3.868(0.69),3.875(0.63),3.912(16.00),3.924(0.49),4.376(1.24),4.387(2.11),6.151(1.35),6.162(2.22),6.175(1.39),6.718(3.50),6.720(3.93),6.731(4.23),7.179(1.54),7.299(2.18),7.312(2.21),7.614(3.34),7.983(1.76),7.995(1.68),8.362(2.68),12.027(1.61).
LC-MS(方法6):Rt=0.54min;MS(ESIpos):m/z=498[M+H]+
实施例22
2-(3-{[(2S)-4-(2,2-二氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体22,50.0mg,107μmol)溶于DMF(1.6ml)中,加入三乙胺(89μl,640μmol)和三氟甲磺酸2,2-二氟乙基酯(64μl,480μmol),并将该混合物在室温下搅拌1小时。将混合物通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化,得到11.3mg(90%纯度,18%产率)的目标化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.24(t,1H),2.34-2.40(dd,1H),2.78(m,1H),2.78-2.81(m,1H),2.83(m,1H),2.85-2.90(t,2H),2.90-2.97(d,1H),3.38-3.47(m,2H),3.68(dt,1H),3.89-3.92(s,3H),3.92-4.03(m,2H),4.17(dd,1H),4.29(dd,1H),5.97-6.02(d,1H),6.02-6.34(tt,1H),6.47-6.54(m,1H),6.64(td,1H),7.16(s,1H),7.29(d,1H),7.54(s,1H),8.02(d,1H),8.40(s,1H),11.03(s,1H).
LC-MS(方法2):Rt=1.04min;MS(ESIpos):m/z=532[M+H]+
实施例23
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例22中所述的类似方法,使用3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体22,35.0mg,74.9μmol)和三氟甲磺酸2,2,2-三氟乙基酯(CAS 6226-25-1,16μl,110μmol)作为起始原料;经制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)后,制备得到11.9mg(95%纯度,27%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.231(0.47),1.264(0.47),2.326(2.22),2.331(1.58),2.359(0.93),2.387(1.69),2.414(1.15),2.518(7.61),2.522(5.31),2.668(2.30),2.673(1.58),2.805(1.18),2.836(2.55),2.853(3.44),2.870(1.79),2.936(1.26),2.964(1.11),3.196(0.54),3.205(0.61),3.221(1.54),3.230(1.58),3.247(1.51),3.255(1.47),3.271(0.61),3.281(0.54),3.400(1.26),3.406(1.33),3.417(2.37),3.423(2.26),3.434(1.15),3.440(1.08),3.654(0.54),3.660(0.65),3.674(0.72),3.683(1.18),3.688(1.15),3.711(0.68),3.912(16.00),3.934(1.11),3.966(1.11),3.983(0.72),3.999(0.75),4.008(0.65),4.157(1.04),4.174(1.00),4.183(1.51),4.199(1.22),4.277(1.40),4.286(1.36),4.303(1.04),4.312(0.86),5.989(1.94),6.010(1.97),6.472(0.86),6.475(0.86),6.493(1.26),6.497(1.26),6.502(0.93),6.520(1.18),6.523(1.04),6.611(0.90),6.626(1.04),6.632(1.54),6.647(1.51),6.652(0.75),6.668(0.65),7.161(2.22),7.278(3.52),7.291(3.55),7.535(4.77),8.018(4.38),8.030(4.02),8.391(6.17),11.018(2.48).
LC-MS(方法2):Rt=1.09min;MS(ESIpos):m/z=550[M+H]+
实施例24
3-(3-氯-2-甲氧基苯胺基)-2-{3-[2-(4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-[({3-[2-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-24,105mg,197μmol)作为起始原料;经制备型HPLC(方法7)后,制备得到43.5mg(95%纯度,42%产率)的标题化合物。
1H-NMR(400MHz9DMSO-d6):δ[ppm]=1.817(0.39),1.834(1.18),1.849(1.57),1.861(1.08),1.876(0.49),2.518(3.04),2.522(2.06),2.673(0.59),2.833(0.88),2.846(1.87),2.863(0.98),3.204(0.88),3.231(1.47),3.260(1.08),3.312(1.28),3.396(1.67),3.408(2.16),3.413(2.16),3.426(1.28),3.456(1.18),3.462(1.08),3.484(0.98),3.490(0.98),3.521(0.79),3.525(0.88),3.549(1.08),3.554(1.18),3.582(0.69),3.625(1.28),3.648(1.37),3.668(2.45),3.678(0.98),3.693(1.37),3.716(1.28),3.745(0.98),3.858(16.00),4.226(1.37),4.241(2.94),4.257(1.37),6.103(1.47),6.115(2.06),6.127(1.47),6.640(5.60),6.650(3.63),7.108(1.77),7.287(2.65),7.299(2.75),7.458(3.93),8.020(3.04),8.033(2.85),8.350(4.32),11.191(1.96).
LC-MS(方法6):Rt=0.68min;MS(ESIpos):m/z=499[M+H]+
实施例25
3-(3-氯-2-甲氧基苯胺基)-2-{3-[2-(4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例24中的标题化合物(40mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,18.0mg,在Rt=18.8-21.3min时,96%纯度)和对映异构体2(17mg,在Rt=21.7-24.5min时,参见实施例26)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈+0.1体积%二乙胺;梯度:0-20min 2-60%B;流速:40ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;梯度:0-7min 2-60%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=4.94min.
旋光度:[α]D=-1.6°+/-1.63°(c=2,8mg/ml在甲醇中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]=1.835(1.01),1.851(1.31),1.862(0.93),1.877(0.41),2.518(1.52),2.522(0.99),2.834(0.77),2.846(1.61),2.852(1.47),2.864(0.82),2.869(0.80),3.205(0.76),3.231(1.30),3.235(1.27),3.261(0.85),3.391(0.83),3.397(0.91),3.408(1.57),3.415(1.62),3.430(0.98),3.457(0.99),3.463(1.01),3.485(0.84),3.491(0.79),3.522(0.72),3.527(0.76),3.551(0.96),3.556(1.07),3.584(0.57),3.624(1.00),3.649(1.11),3.654(1.11),3.671(1.96),3.680(0.81),3.687(0.53),3.695(1.23),3.718(1.09),3.723(1.01),3.747(0.79),3.859(16.00),4.227(1.22),4.242(2.58),4.258(1.21),6.105(1.40),6.118(1.81),6.129(1.46),6.641(5.45),6.651(3.33),6.654(3.12),7.110(1.60),7.288(2.35),7.300(2.36),7.306(0.49),7.462(3.57),8.023(2.38),8.035(2.27),8.353(3.43),11.186(1.77).
实施例26
3-(3-氯-2-甲氧基苯胺基)-2-{3-[2-(4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例24。通过制备型手性HPLC分离对映异构体(方法参见实施例25),得到25mg的标题化合物(在Rt=21.7-24.5min时,19%产率)。
分析型手性HPLC(方法参见实施例25):Rt=5.49min.
旋光度:[α]D=2.5°+/-1.93°(c=2,7mg/ml在甲醇中)
实施例27
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体27,24.0mg,47.8μmol)溶于甲醇(650μl)中,加入甲醛(7.2μl,37%纯度,96μmol)和乙酸(2.7μl,48μmol),并将该混合物在室温下搅拌15分钟。加入三乙酰氧基硼氢化钠(15.2mg,71.7μmol),并将该混合物在室温下搅拌1小时。将混合物用甲醇稀释,通过SCX柱过滤,并用甲醇和氨溶液(7M的甲醇溶液)洗涤。将滤液蒸发,并通过制备型HPLC(方法9,梯度:0.00-0.50min 15%B,0.50-6.00min15-55%B)纯化,得到17.3mg(95%纯度,61%产率)的标题化合物,为其甲酸盐。
LC-MS(方法2):Rt=1.01min;MS(ESIpos):m/z=516[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:2.189(13.49),2.330(5.06),2.729(5.60),2.861(7.86),3.348(16.00),3.419(15.57),3.624(4.81),3.830(14.46),3.908(6.49),7.633(4.30),8.098(4.59),8.146(8.39).
将3-(3-氯-5-氟-2-甲氧基-苯胺基)-2-[3-[[(2S)-4-甲基吗啉-4-鎓-2-基]甲氧基]-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮;甲酸盐溶于DCM中,用饱和的NaHCO3水溶液和盐水洗涤,得到9.00mg(90%纯度,33%产率)的目标化合物,为其游离碱。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.79-1.96(t,1H),1.97-2.05(td,1H),2.19(s,3H),2.63(br d,1H),2.71-2.82(br d,1H),2.86(t,2H),3.43(td,2H),3.58-3.67(m,1H),3.83(s,3H),3.87-4.01(m,2H),4.14(dd,1H),4.29(dd,1H),5.85(dd,1H),6.56(dd,1H),7.13(s,1H),7.33(d,1H),7.64(d,1H),8.07-8.12(d,1H),8.43(s,1H),11.18(s,1H).
实施例28
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例22中所述的类似方法,使用3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体27,25.0mg,49.8μmol)和三氟甲磺酸2,2,2-三氟乙基酯(CAS6226-25-1,11μl,75μmol)作为起始原料;经制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)后,制备得到15.1mg(95%纯度,49%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.35(t,1H),2.77-2.95(m,4H),3.21(dd,2H),3.42(td,2H),3.60-3.69(m,1H),3.83(s,3H),3.88-4.01(m,2H),4.14-4.28(m,2H),5.84(dd,1H),6.56(dd,1H),7.13(s,1H),7.32(d,1H),7.62-7.66(m,1H),8.10(d,1H),8.43(s,1H),11.16(s,1H).
LC-MS(方法2):Rt=1.19min;MS(ESIpos):m/z=584[M+H]+
实施例29
3-(3-氯-2-乙基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-2-乙基苯基)-4-[({3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-29,300mg,566μmol)作为起始原料;经制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)后,制备得到3.00mg(85%纯度,1%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.851(0.47),1.210(0.41),1.230(2.24),1.352(0.41),2.206(1.49),2.331(2.92),2.336(1.36),2.518(16.00),2.522(10.31),2.539(1.02),2.673(3.05),2.678(1.42),2.864(0.41),6.728(0.41),6.735(0.47),7.188(0.47),7.201(0.47),7.962(0.54),7.975(0.47),8.365(0.68).
LC-MS(方法2):Rt=1.07min;MS(ESIpos):m/z=496[M+H]+
实施例30
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
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使用实施例1中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-[({3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-30,55.0mg,101μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)纯化后,制备得到28.00mg(98%纯度,53%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.066(9.57),1.234(8.81),2.074(0.42),2.326(1.06),2.331(0.74),2.518(3.90),2.522(2.65),2.668(1.04),2.673(0.76),2.819(1.08),2.837(2.21),2.853(1.18),3.398(1.96),3.409(1.62),3.416(1.61),3.427(2.05),3.580(0.57),3.588(0.65),3.609(1.17),3.618(1.13),3.629(1.85),3.654(1.43),3.657(1.70),3.679(1.32),3.709(0.74),3.868(16.00),3.894(0.49),3.902(0.53),3.910(0.64),3.918(0.58),3.927(0.42),4.155(0.76),4.171(0.72),4.181(1.01),4.198(0.88),4.295(0.97),4.304(0.99),4.322(0.76),4.330(0.67),6.143(1.40),6.155(1.71),6.167(1.40),6.653(0.46),6.663(5.26),6.673(3.14),6.676(2.88),7.138(1.48),7.270(2.51),7.283(2.51),7.475(3.39),8.033(3.36),8.045(2.98),8.404(4.26),11.073(1.66).
LC-MS(方法6):Rt=0.80min;MS(ESIpos):m/z=513[M+H]+
实施例31
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例30中的标题化合物(26.3mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,11.00mg,在Rt=10.7-13.4min时)和对映异构体2(10mg,在Rt=14.0-19.9min时,参见实施例32)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:Chiralcel OD-H 5μ,250x20;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;恒溶剂:70%A+30%B;流速:20ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:Chiralcel OD-H 5μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=6.72min.
实施例32
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例30。通过制备型手性HPLC分离对映异构体(方法参见实施例31),得到10mg的标题化合物(在Rt=14.0-19.9min时)。
分析型手性HPLC(方法参见实施例31):Rt=10.04min.
实施例33
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用4-{[(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-33,125mg,236μmol)作为起始原料,经制备型HPLC(方法7)后,制备得到15.00mg(80%纯度,10%产率)的标题化合物,。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.068(15.53),1.236(15.37),2.517(2.98),2.522(2.00),2.817(1.52),2.834(3.10),2.851(1.65),2.903(0.47),2.921(0.89),2.936(0.48),3.402(2.87),3.408(2.55),3.415(2.29),3.431(3.39),3.580(0.97),3.588(1.12),3.609(2.52),3.618(2.17),3.633(3.03),3.651(2.10),3.661(2.34),3.677(2.32),3.706(1.26),3.900(16.00),3.917(5.39),3.933(0.80),3.942(0.71),4.147(1.18),4.163(1.12),4.173(1.56),4.189(1.34),4.294(1.63),4.302(1.37),4.320(1.26),4.329(0.93),4.769(0.55),4.780(0.55),4.787(0.58),4.797(0.52),5.696(0.85),5.759(1.92),5.985(0.55),6.000(1.88),6.020(1.84),6.455(0.97),6.476(1.43),6.479(1.49),6.503(1.30),6.597(0.86),6.612(1.11),6.618(1.49),6.625(0.60),6.633(1.47),6.638(0.71),6.653(0.62),7.141(2.11),7.277(3.15),7.289(3.21),7.297(1.00),7.479(4.43),7.531(1.26),8.030(3.74),8.042(3.54),8.399(6.35),11.053(2.30),11.085(0.73).
LC-MS(方法6):Rt=0.71min;MS(ESIpos):m/z=497[M+H]+
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例33中的标题化合物(15.0mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,5.00mg,在Rt=10.9-13.1min时,32%产率)和对映异构体2(4mg,在Rt=13.5-18.3min时,参见实施例34)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:Chiralcel OD-H 5μ,250x20;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:70%A+30%B;流速:20ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:Chiralcel OD-H 5μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=6.58min.
旋光度:[α]D=2.6°+/-1.66°(c=2,3mg/ml在甲醇中)
实施例34
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
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外消旋的标题化合物的制备参见实施例33。通过制备型手性HPLC分离对映异构体(方法参见实施例33),得到4mg的标题化合物(在Rt=13.5-18.3min时,24%产率)。
分析型手性HPLC(方法参见实施例33):Rt=9.21min.
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.046(0.67),1.068(13.52),1.108(0.86),1.185(0.55),1.236(13.07),1.259(0.64),2.084(0.44),2.331(0.49),2.518(2.88),2.523(1.93),2.673(0.47),2.817(1.52),2.834(3.11),2.851(1.67),3.403(2.57),3.409(2.57),3.416(2.39),3.431(2.89),3.581(0.83),3.589(0.95),3.611(1.68),3.618(1.66),3.633(2.61),3.652(1.72),3.661(2.23),3.678(1.86),3.707(1.00),3.901(16.00),3.917(1.07),3.926(0.91),3.934(0.65),3.943(0.58),4.148(1.01),4.165(0.96),4.174(1.36),4.190(1.18),4.294(1.36),4.303(1.36),4.320(1.03),4.329(0.91),6.000(1.83),6.021(1.91),6.455(0.83),6.459(0.87),6.476(1.19),6.480(1.27),6.486(0.94),6.503(1.10),6.506(1.01),6.597(0.86),6.612(1.01),6.618(1.47),6.633(1.44),6.638(0.75),6.654(0.61),7.141(2.15),7.277(2.70),7.290(2.68),7.479(4.53),8.030(2.67),8.043(2.48),8.400(4.07),11.054(2.33).
实施例35
2-(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
使用实施例1中所述的类似方法,使用4-{[(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲基]氨基}-N-(3-氟-2-甲氧基苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-35,130mg,252μmol)作为起始原料,经制备型HPLC(方法7)后,制备得到30.0mg(90%纯度,22%产率)的外消旋的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.229(0.48),1.827(0.71),1.843(1.74),1.859(2.06),1.869(1.50),1.885(0.63),2.331(0.40),2.517(2.30),2.522(1.50),2.539(4.51),2.669(0.55),2.673(0.48),2.831(1.19),2.842(2.22),2.848(2.06),2.858(1.19),2.865(1.11),3.162(1.27),3.174(0.71),3.207(1.35),3.233(2.14),3.236(2.14),3.262(1.58),3.406(4.44),3.412(3.88),3.428(2.22),3.456(1.90),3.462(1.82),3.484(1.50),3.490(1.50),3.522(1.27),3.527(1.35),3.550(1.66),3.556(1.90),3.578(0.95),3.583(1.27),3.624(2.22),3.651(2.14),3.671(3.25),3.681(1.50),3.695(2.22),3.700(1.98),3.716(2.06),3.721(1.98),3.728(1.35),3.745(1.50),3.780(0.71),3.862(0.95),3.889(16.00),3.906(1.19),4.074(0.71),4.222(2.14),4.238(3.96),4.253(1.82),4.754(0.55),5.960(1.98),5.981(1.98),6.430(0.95),6.433(0.95),6.451(1.43),6.455(1.43),6.461(0.95),6.478(1.19),6.482(1.11),6.572(0.95),6.587(1.11),6.593(1.58),6.608(1.58),6.613(0.79),6.628(0.63),7.108(2.30),7.292(2.77),7.305(2.77),7.455(4.67),8.017(2.61),8.030(2.46),8.344(4.04),11.175(2.46).
LC-MS(方法6):Rt=0.63min;MS(ESIpos):m/z=483[M+H]+
将外消旋的2-(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(25.0mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,12.00mg,在Rt=15.1-17.0min时,)和对映异构体2(4mg,在Rt=19.8-26.8min时,参见实施例36)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:Chiralpak IF 5μ,250x30;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;恒溶剂:70%A+30%B;流速:50ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:Chiralpak IF 3μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=4.68min.
旋光度:[α]D=-12.9°+/-1.72°(c=1,4mg/ml在甲醇中)
实施例36
2-(3-{2-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例35。通过制备型手性HPLC分离对映异构体(方法参见实施例35),得到4mg的标题化合物(在Rt=19.8-26.8min时)。
分析型手性HPLC(方法参见实施例35):Rt=6.58min.
旋光度:[α]D=-21.4°+/-1.94°(c=1,3mg/ml在甲醇中)
实施例37
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氟-2-甲氧基苯基)-4-{[(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-37,130mg,252μmol)作为起始原料,经制备型HPLC(方法7)后,制备得到35.00mg(92%纯度,27%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.277(13.00),2.292(1.54),2.307(0.96),2.324(0.70),2.329(0.89),2.334(0.66),2.407(0.69),2.428(1.27),2.435(1.36),2.520(2.98),2.525(1.88),2.667(0.63),2.671(0.83),2.676(0.62),2.777(0.67),2.801(0.82),2.818(1.61),2.825(0.99),2.835(1.02),2.844(1.23),2.860(0.82),2.911(1.23),2.940(1.09),3.388(0.53),3.408(0.96),3.425(1.66),3.431(1.41),3.441(1.54),3.455(0.69),3.548(1.12),3.576(1.89),3.592(1.35),3.597(1.35),3.602(1.33),3.621(0.70),3.626(0.70),3.783(1.37),3.785(1.33),3.818(1.11),3.843(1.97),3.849(2.06),3.870(1.11),3.878(0.99),3.941(16.00),3.954(1.12),4.078(0.56),4.349(0.43),4.358(0.42),4.376(1.85),4.388(2.91),4.416(0.47),6.013(1.90),6.034(1.91),6.516(0.95),6.520(0.92),6.537(1.27),6.541(1.33),6.547(0.95),6.564(1.12),6.568(1.03),6.657(0.94),6.672(1.04),6.678(1.61),6.693(1.51),6.698(0.80),6.714(0.65),7.180(2.21),7.313(3.72),7.325(3.57),7.605(4.51),7.980(4.40),7.993(4.17),8.360(6.21),8.414(0.59),12.014(2.24).
LC-MS(方法6):Rt=0.51min;MS(ESIpos):m/z=482[M+H]+
实施例38
2-[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]-3-(3-氟-2-甲基-苯胺基)-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮
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使用实施例1中所述的类似方法,使用4-[[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]甲基氨基]-N-(3-氟-2-甲基-苯基)-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺(中间体6-38,190mg,369μmol)作为起始原料,经制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-5.59min 15-51.7%B,5.59-5.88min 51.7%B,5.88-5.93min51.7-52.1%B,5.93-5.95min 52.1%B,5.95-6.32min 52.1-55%B)后,制备得到30.2mg(98%纯度,17%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.073(16.00),1.243(14.37),2.177(9.43),2.180(9.37),2.520(3.20),2.525(2.30),2.542(0.63),2.826(1.74),2.843(3.73),2.861(2.01),3.406(3.15),3.417(2.63),3.424(2.71),3.434(3.36),3.569(0.91),3.577(1.10),3.598(1.87),3.607(1.84),3.643(4.40),3.671(4.37),3.699(1.24),3.881(0.69),3.890(0.81),3.898(1.03),3.907(0.94),3.915(0.67),3.923(0.65),4.121(1.26),4.137(1.17),4.147(1.71),4.163(1.45),4.265(1.62),4.274(1.65),4.291(1.24),4.300(1.11),6.059(2.34),6.080(2.42),6.427(1.06),6.449(1.94),6.470(1.21),6.721(0.73),6.742(1.51),6.759(1.47),6.779(0.63),7.168(2.42),7.232(4.19),7.244(4.24),7.308(4.82),7.997(5.22),8.009(4.80),8.373(6.80),11.029(2.61).
LC-MS(方法6):Rt=0.74min;MS(ESIpos):m/z=481[M+H]+
实施例39
2-[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]-3-(3-氟-2-甲基-苯胺基)-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例38中的标题化合物(30.2mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,10.00mg,Rt=30.4-36.0min,5%产率)和对映异构体2(9mg,Rt=45.9-51.7min)。
制备型手性HPLC方法:NPB
仪器:PrepCon Labomatic HPLC;柱:Chiralpak IF 5μ,250x30;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;恒溶剂:90%A+10%B;流速:50ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:NPB
仪器:Waters Alliance 2695;柱:Chiralpak IF 3μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:90%A+10%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=11.60min.
旋光度:[α]D=-6.4°+/-0.47°(c=6,2mg/ml在DMSO中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.700(5.10),0.744(1.84),0.764(1.85),0.836(0.93),0.854(1.20),1.073(15.11),1.152(5.69),1.235(8.54),1.243(16.00),1.296(2.78),1.350(0.95),1.378(0.62),1.672(0.88),2.179(9.59),2.525(2.28),2.827(1.75),2.844(3.61),2.861(1.95),3.407(3.22),3.418(2.68),3.424(2.72),3.434(3.38),3.570(0.86),3.578(1.00),3.599(1.76),3.607(1.71),3.644(4.10),3.671(4.05),3.700(1.09),3.882(0.67),3.890(0.80),3.899(1.00),3.907(0.92),3.915(0.66),3.924(0.61),4.121(1.09),4.138(1.06),4.147(1.50),4.164(1.30),4.267(1.44),4.275(1.48),4.292(1.11),4.301(1.01),6.060(2.24),6.080(2.31),6.428(1.04),6.450(1.90),6.472(1.17),6.722(0.70),6.742(1.49),6.759(1.45),6.780(0.58),6.959(0.44),7.170(2.40),7.201(0.51),7.222(0.55),7.234(1.95),7.246(1.95),7.309(4.47),7.999(1.12),8.010(1.08),8.375(1.57),11.031(2.61).
实施例40
3-[2-(2,2-二氟乙基)-3-氟-苯胺基]-2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-[2-(2,2-二氟乙基)-3-氟苯基]-4-{[(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-40,19.5mg,36.3μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-6.00min 30-70%B)纯化后,制备得到3.80mg(92%纯度,19%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.86(t,2H),3.22-3.30(m,1H),3.39-3.48(m,3H),3.50-3.58(td,1H),3.67-3.93(m,5H),3.97-4.06(m,1H),4.09-4.18(m,1H),4.25-4.31(dd,1H),6.07-6.17(d,1H),6.29-6.63(q,2H),6.83-6.94(m,1H),7.10(s,1H),7.34(s,1H),7.37(d,2H),8.00(d,1H),8.38(s,1H),11.07(s,1H).
LC-MS(方法2):Rt=0.99min;MS(ESIpos):m/z=503[M+H]+
实施例41
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体41,22.0mg,43.9μmol)悬浮于MeOH中,加入甲醛(6.6μl,37%纯度,在水中,88μmol)和乙酸(2.5μl,44μmol)。将该反应混合物在室温下搅拌15分钟。加入三乙酰氧基硼氢化钠(13.9mg,65.8μmol),并将该混合物在室温下搅拌1小时。将混合物通过SCX柱过滤,并用MeOH和氨溶液(7M的MeOH溶液)洗涤。将氨滤液蒸发,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min15-55%B)纯化,得到8.8mg(90%纯度,35%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=2.07(m,3H),2.22(s,3H),2.63-2.83(m,2H),2.86(t,2H),3.27-3.31(m,1H),3.35-3.38(m,1H),3.42(td,2H),3.68(td,1H),3.91-4.00(m,2H),4.12-4.19(dd,1H),4.33(dd,1H),6.13(d,1H),6.29-6.64(m,1H),6.89(q,1H),7.07-7.14(m,1H),7.33-7.40(t,2H),7.99(d,1H),8.39(s,1H),11.07(s,1H).
LC-MS(方法2):Rt=0.98min;MS(ESIpos):m/z=516[M+H]+
实施例42
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例41中所述的类似方法,使用3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体42,18.0mg,38.5μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到10.9mg(94%纯度,55%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.234(0.45),1.874(1.12),1.901(1.88),1.928(1.19),2.006(0.51),2.015(0.63),2.035(1.18),2.043(1.18),2.064(0.68),2.072(0.56),2.207(15.79),2.324(0.67),2.329(0.91),2.334(0.71),2.338(0.45),2.357(16.00),2.374(1.16),2.520(2.98),2.525(1.85),2.647(1.22),2.671(1.61),2.676(1.69),2.736(1.32),2.764(1.23),2.847(1.67),2.865(3.57),2.882(1.86),3.411(1.24),3.417(1.33),3.428(2.40),3.434(2.36),3.445(1.17),3.451(1.06),3.639(0.62),3.645(0.95),3.667(1.35),3.672(1.38),3.695(0.78),3.701(0.66),3.937(1.97),3.960(1.51),4.111(1.22),4.128(1.10),4.137(1.63),4.153(1.36),4.253(1.46),4.262(1.52),4.279(1.14),4.287(1.03),6.190(1.81),6.194(1.78),6.209(1.99),6.213(1.81),6.722(0.90),6.726(1.25),6.742(3.67),6.746(2.96),6.753(2.81),6.773(2.59),6.792(0.84),7.190(2.30),7.232(3.39),7.244(3.38),7.377(4.48),7.990(3.43),8.003(3.19),8.370(5.23),11.051(2.53).
LC-MS(方法6):Rt=0.52min;MS(ESIpos):m/z=482[M+H]+
实施例43
3-(3-氯-2-甲基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例41中所述的类似方法,使用3-(3-氯-2-甲基苯胺基)-2-(3-{[(3R)-吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(30.0mg,64.1μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-6.00min15-55%B)纯化后,制备得到7.0mg(94%纯度,21%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=-0.002(3.00),0.879(0.57),2.085(5.27),2.272(14.21),2.318(0.47),2.382(16.00),2.397(1.43),2.423(1.05),2.431(1.10),2.460(1.63),2.518(5.17),2.523(3.38),2.660(0.46),2.810(0.81),2.828(2.27),2.845(1.96),2.864(0.87),2.909(1.32),2.938(1.16),3.411(0.70),3.428(1.64),3.435(1.37),3.444(1.50),3.464(0.63),3.540(1.08),3.568(2.41),3.595(2.18),3.620(0.70),3.818(1.11),3.844(2.09),3.864(1.06),3.872(0.93),4.357(1.94),4.368(3.51),4.395(0.46),6.209(1.79),6.212(1.85),6.228(1.98),6.232(1.91),6.756(1.10),6.760(1.40),6.776(3.46),6.779(2.93),6.793(2.52),6.813(2.75),6.833(0.95),7.200(2.25),7.250(3.55),7.263(3.70),7.431(4.31),7.946(3.93),7.958(3.66),8.338(5.51),12.003(2.32).
LC-MS(方法6):Rt=0.57min;MS(ESIpos):m/z=512[M+H]+
实施例44
3-(3-氯-2-甲基-苯胺基)-2-[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(3-氯-2-甲基-苯基)-4-[[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺(中间体6-44,320mg,603μmol),在室温下搅拌2小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-5.92min 15-54.2%B,5.92-7.34min 54.2%B,7.34-7.42min54.2-55%B)纯化后,制备得到32mg的标题化合物(98%纯度,10%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.072(14.59),1.241(13.05),2.325(0.47),2.329(0.73),2.344(16.00),2.520(1.82),2.525(1.27),2.671(0.54),2.828(1.59),2.845(3.40),2.862(1.80),3.402(2.68),3.417(2.39),3.423(2.57),3.431(2.75),3.565(0.87),3.574(1.01),3.595(1.70),3.603(1.65),3.640(3.45),3.668(4.15),3.697(1.17),3.872(0.64),3.880(0.75),3.888(0.95),3.897(0.88),3.905(0.63),3.914(0.58),4.122(1.12),4.139(1.05),4.149(1.54),4.165(1.34),4.254(1.47),4.263(1.52),4.281(1.10),4.289(0.98),6.196(1.81),6.199(1.76),6.215(1.97),6.218(1.81),6.705(0.97),6.709(1.30),6.725(3.57),6.729(2.82),6.738(2.56),6.757(2.50),6.778(0.82),7.165(2.26),7.230(3.85),7.243(3.87),7.323(4.45),8.004(5.13),8.016(4.69),8.374(6.56),11.049(2.45).
LC-MS(方法6):Rt=0.79min;MS(ESIpos):m/z=497[M+H]+
实施例45
3-(3-氯-2-甲基-苯胺基)-2-[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例44中的标题化合物(32.0mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,15.50mg,Rt=12.1-14.2min)和对映异构体2(12.6mg,Rt=14.5-19.0min,参见实施例46)。
制备型手性HPLC方法:POB
仪器:PrepCon Labomatic HPLC;柱:Chiralcel OD-H 5μ,250x20;洗脱剂A:乙醇+0.1体积%二乙胺;洗脱剂B:甲醇;恒溶剂:70%A+30%B;流速:10ml/min;温度:25℃;UV:280nm
分析型手性HPLC方法:POB
仪器:Waters Alliance 2695;柱:Chiralcel OD-H 5μ,100x4.6;洗脱剂A:乙醇+0.1体积%二乙胺;洗脱剂B:甲醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:280nm
分析型手性HPLC:Rt=3.52min.
旋光度:[α]D=30.31°+/-1.05°(c=2,7mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.050(0.51),1.070(14.54),1.119(0.40),1.137(0.77),1.155(0.80),1.190(0.47),1.239(13.63),2.085(0.73),2.318(0.77),2.323(1.71),2.327(2.48),2.332(2.11),2.342(16.00),2.518(7.25),2.523(5.03),2.660(0.73),2.665(1.64),2.669(2.30),2.673(1.60),2.679(0.73),2.825(1.60),2.842(3.43),2.859(1.86),3.306(0.95),3.399(2.77),3.415(2.44),3.421(2.59),3.429(2.84),3.563(0.87),3.572(1.02),3.592(1.71),3.601(1.68),3.638(3.46),3.665(4.15),3.695(1.17),3.869(0.77),3.878(0.77),3.886(0.95),3.894(0.87),3.903(0.62),3.911(0.58),4.120(1.13),4.137(1.06),4.147(1.53),4.163(1.31),4.252(1.46),4.261(1.53),4.278(1.09),4.287(0.98),6.193(1.82),6.197(1.75),6.212(1.93),6.216(1.82),6.703(0.98),6.707(1.28),6.723(3.50),6.727(2.81),6.736(2.59),6.756(2.51),6.775(0.84),7.162(2.22),7.228(3.64),7.241(3.64),7.321(4.48),8.002(4.30),8.014(4.01),8.372(5.94),11.046(2.48).
LC-MS(方法6):Rt=0.80min;MS(ESIpos):m/z=497[M+H]+
实施例46
3-(3-氯-2-甲基-苯胺基)-2-[3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例44。通过制备型手性HPLC分离对映异构体(方法参见实施例45),得到12.6mg的标题化合物(Rt=14.5-19.0min)。
分析型手性HPLC(方法参见实施例45):Rt=4.43min.
旋光度:[α]D=-26.44°+/-1.41°(c=2,9mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.748(0.44),0.764(0.44),1.053(0.52),1.070(14.81),1.154(1.45),1.239(13.86),2.085(1.85),2.318(0.46),2.323(0.99),2.327(1.45),2.332(1.39),2.342(16.00),2.518(4.03),2.523(2.82),2.540(0.54),2.665(0.89),2.669(1.25),2.673(0.85),2.825(1.61),2.843(3.39),2.859(1.81),3.399(2.78),3.415(2.48),3.421(2.64),3.429(2.88),3.563(0.83),3.572(0.99),3.593(1.69),3.601(1.67),3.638(3.49),3.665(4.15),3.695(1.15),3.869(0.83),3.878(0.77),3.886(0.95),3.895(0.89),3.903(0.64),3.912(0.58),4.120(1.09),4.137(1.03),4.147(1.53),4.163(1.33),4.252(1.45),4.261(1.51),4.278(1.09),4.287(0.97),6.193(1.77),6.197(1.75),6.212(1.97),6.216(1.85),6.703(0.95),6.707(1.27),6.723(3.51),6.727(2.82),6.736(2.58),6.756(2.54),6.775(0.85),7.162(2.26),7.228(3.10),7.241(3.12),7.321(4.45),8.002(2.54),8.015(2.36),8.372(3.89),11.046(2.46).
LC-MS(方法6):Rt=0.80min;MS(ESIpos):m/z=497[M+H]+
实施例47
2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-3-(3-氟-2-甲基-苯胺基)-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-N-(3-氟-2-甲基-苯基)-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺(中间体6-47,399mg,820μmol),于60℃搅拌过夜,并通过制备型HPLC(方法9,梯度:0.00-0.50min 15%B,0.50-6.00min 15-55%B)纯化后,制备得到135mg的标题化合物(97%纯度,35%产率)。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.154(4.20),1.172(8.22),1.189(3.94),1.987(16.00),2.185(2.36),2.189(2.36),2.518(0.75),2.522(0.47),2.843(0.44),2.860(0.94),2.877(0.50),3.398(0.42),3.425(1.01),3.451(0.56),3.709(0.44),3.740(0.57),3.999(1.26),4.017(3.61),4.035(3.57),4.053(1.15),4.125(0.48),4.230(0.43),4.239(0.42),5.758(0.88),6.052(0.58),6.072(0.60),6.459(0.48),7.186(0.59),7.234(1.00),7.247(1.01),7.345(1.17),7.990(1.32),8.002(1.20),8.361(1.76),11.030(0.60).
LC-MS(方法6):Rt=0.65min;MS(ESIpos):m/z=453[M+H]+
实施例48
2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-3-(3-氟-2-甲基-苯胺基)-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例47中的标题化合物(15.0mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,3.0mg,Rt=5.5-6.2min)和对映异构体2(2.0mg,Rt=9.0-9.9min,参见实施例49)。
制备型手性HPLC方法:MTBE
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:55%B+45%A;流速:80ml/min;温度:25℃;UV:280nm;
分析型手性HPLC方法:MTBE
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.2体积%二乙胺;洗脱剂B:乙腈;恒溶剂:50%A+50%B;流速:1.4ml/min;温度:25℃;UV:280nm;
分析型手性HPLC:Rt=2.90min.
旋光度:[α]D=-19.1°+/-1.65°(c=2,19mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=-0.008(0.55),0.000(16.00),0.008(0.53),0.700(0.57),0.752(0.76),0.770(0.76),1.140(1.18),1.160(2.36),1.234(1.64),1.296(0.42),2.189(11.55),2.191(11.53),2.521(2.85),2.525(1.90),2.846(2.15),2.863(4.59),2.880(2.42),3.401(1.96),3.410(1.71),3.417(1.88),3.428(4.95),3.444(1.64),3.454(2.68),3.505(0.67),3.510(0.82),3.532(1.56),3.539(1.58),3.560(1.14),3.569(1.03),3.712(2.13),3.721(1.35),3.743(2.76),3.750(1.24),3.771(1.14),3.778(0.84),3.800(1.69),3.806(1.85),3.829(1.52),3.835(1.54),3.885(1.66),3.912(1.22),3.992(0.42),4.001(0.68),4.008(1.01),4.017(1.14),4.025(1.10),4.033(0.93),4.042(0.78),4.049(0.53),4.103(1.71),4.119(1.24),4.129(2.26),4.145(1.73),4.233(2.09),4.243(2.05),4.259(1.54),4.269(1.33),6.056(2.82),6.076(2.91),6.440(1.29),6.463(2.36),6.484(1.46),6.734(0.89),6.754(1.85),6.771(1.77),6.792(0.72),7.187(2.91),7.237(3.80),7.250(3.82),7.348(5.65),7.994(2.64),8.006(2.47),8.365(4.17),11.029(3.12).
LC-MS(方法6):Rt=0.66min;MS(ESIpos):m/z=453[M+H]+
实施例49
2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-3-(3-氟-2-甲基-苯胺基)-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例47。通过制备型手性HPLC分离对映异构体(方法参见实施例48),得到2.0mg的标题化合物(Rt=9.0-9.9min)。
分析型手性HPLC(方法参见实施例48):Rt=4.67min.
旋光度:[α]D=24.3°+/-7.66°(c=1,29mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:-0.008(0.54),0.000(16.00),0.008(0.54),0.700(0.74),0.752(0.54),0.771(0.57),0.854(0.52),1.139(0.91),1.160(1.70),1.234(2.19),1.296(0.52),2.087(0.66),2.189(11.26),2.191(11.28),2.521(4.55),2.525(3.00),2.846(2.09),2.863(4.47),2.880(2.36),3.401(1.99),3.410(1.67),3.417(1.87),3.428(4.87),3.444(1.65),3.454(2.65),3.505(0.69),3.510(0.84),3.532(1.52),3.539(1.55),3.560(1.13),3.569(1.03),3.712(2.09),3.721(1.35),3.744(2.70),3.750(1.23),3.771(1.16),3.778(0.81),3.800(1.67),3.806(1.77),3.829(1.50),3.835(1.52),3.885(1.62),3.912(1.20),3.992(0.42),4.001(0.66),4.009(0.98),4.017(1.11),4.025(1.08),4.033(0.91),4.042(0.76),4.049(0.54),4.103(1.70),4.119(1.20),4.129(2.19),4.145(1.72),4.233(2.04),4.243(2.04),4.259(1.52),4.269(1.33),6.055(2.75),6.076(2.85),6.440(1.25),6.463(2.31),6.484(1.45),6.734(0.86),6.754(1.79),6.772(1.72),6.792(0.74),7.187(2.83),7.237(3.37),7.250(3.42),7.349(5.43),7.994(2.24),8.007(2.14),8.365(3.56),11.030(3.02).
实施例50
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例1中所述的类似方法,使用N-(3-氯-2-甲基-苯基)-4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺(中间体6-50,150mg,298μmol)作为起始原料,经制备型HPLC(方法10,梯度:0.00-0.50min15%B,0.50-6.00min 15-55%B)后,制备得到35.0mg(25%产率)的外消旋的标题化合物。
LC-MS(方法6):Rt=0.71min;MS(ESIpos):m/z=469[M+H]+
将外消旋的3-(3-氯-2-甲基-苯胺基)-2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮(35.0mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,12.5mg,Rt=14.3-16.6min,)和对映异构体2(13.4mg,Rt=21.1-25.3min,参见实施例51)。
制备型手性HPLC方法:MTBE
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙醇;梯度:;流速:40ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:MTBE
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙醇;梯度:;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=3.23min.
旋光度:[α]D=-20.5°+/-1.23°(c=2,7mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.234(0.41),2.338(0.44),2.355(16.00),2.520(2.76),2.524(1.87),2.847(1.60),2.864(3.40),2.882(1.80),3.398(1.50),3.410(1.20),3.416(1.35),3.427(3.93),3.432(2.41),3.444(1.16),3.451(2.30),3.502(0.46),3.508(0.60),3.530(1.13),3.537(1.16),3.558(0.85),3.566(0.78),3.711(1.87),3.718(1.04),3.740(2.36),3.768(0.89),3.775(0.60),3.796(1.27),3.802(1.36),3.825(1.15),3.831(1.16),3.883(1.23),3.909(0.88),3.994(0.48),4.001(0.77),4.009(0.80),4.018(0.79),4.025(0.69),4.033(0.55),4.104(1.32),4.120(0.96),4.130(1.76),4.146(1.34),4.223(1.59),4.232(1.56),4.249(1.15),4.258(1.00),6.190(1.73),6.194(1.69),6.210(2.01),6.213(1.79),6.718(0.97),6.722(1.27),6.738(3.59),6.742(2.81),6.751(2.54),6.771(2.47),6.790(0.80),7.184(2.17),7.234(3.49),7.247(3.51),7.364(4.36),7.999(3.35),8.012(3.08),8.365(4.78),11.044(2.32).
LC-MS(方法6):Rt=0.70min;MS(ESIpos):m/z=469[M+H]+
由1-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲胺(中间体2-8)开始的对映体选择性合成确认该标题化合物为3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮。
实施例51
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
外消旋的标题化合物的制备参见实施例50。通过制备型手性HPLC分离对映异构体(方法参见实施例50),得到13.4mg的标题化合物(Rt=21.1-25.3min)。
分析型手性HPLC(方法参见实施例50):Rt=5.22min.
旋光度:[α]D=20.4°+/-1.23°(c=2,69mg/ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.173(0.44),1.234(0.51),2.355(16.00),2.521(2.29),2.525(1.50),2.848(1.58),2.865(3.44),2.882(1.83),3.346(0.44),3.399(1.49),3.410(1.19),3.416(1.34),3.428(3.98),3.432(2.45),3.444(1.19),3.452(2.35),3.503(0.46),3.508(0.62),3.531(1.13),3.538(1.20),3.558(0.84),3.567(0.81),3.711(1.90),3.718(1.09),3.740(2.39),3.768(0.88),3.775(0.62),3.797(1.26),3.803(1.39),3.825(1.14),3.832(1.17),3.883(1.25),3.910(0.90),3.995(0.49),4.001(0.76),4.010(0.82),4.018(0.79),4.026(0.71),4.035(0.56),4.042(0.40),4.104(1.30),4.121(0.95),4.130(1.77),4.147(1.36),4.224(1.60),4.233(1.58),4.250(1.15),4.259(0.99),6.191(1.74),6.195(1.73),6.210(1.96),6.214(1.81),6.719(0.94),6.723(1.27),6.738(3.57),6.743(2.82),6.752(2.56),6.771(2.49),6.791(0.81),7.185(2.19),7.235(3.09),7.248(3.12),7.365(4.33),8.000(2.48),8.013(2.34),8.366(3.75),11.045(2.33).
LC-MS(方法6):Rt=0.70min;MS(ESIpos):m/z=469[M+H]+
实施例52
3-(3-氯-2-乙基-苯胺基)-2-[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]-1,5,6,7-四氢吡咯并[3,2-c]吡啶-4-酮
按照类似于实施例1,使用N-(3-氯-2-乙基-苯基)-4-[[3-(1,4-二氧杂环己烷-2-基甲氧基)-4-吡啶基]甲基氨基]-6-氧代-2,3-二氢-1H-吡啶-5-硫代甲酰胺(中间体6-52,150mg,290μmol),于60℃搅拌4小时,并通过制备型HPLC(方法10,梯度:0.00-0.50min 10%B,0.50-8.06min 10-20%B,8.06-9.02min 20%B,9.02-24.12min 20-50%B,24.12-27.44min 50%B)纯化后,制备得到23.2mg的标题化合物(95%纯度,16%产率)。
1H-NMR(400MHz,DMSO-d6):δppm=1.23(t,3H),2.86(s,4H),3.38-3.46(m,4H),3.49-3.58(m,1H),3.68-3.78(m,2H),3.78-3.85(m,1H),3.86-3.92(m,1H),3.98-4.06(m,1H),4.09-4.17(m,1H),4.21-4.28(m,1H),6.22(dd,1H),6.67-6.78(m,2H),7.20(d,2H),7.45(s,1H),7.98(d,1H),8.32-8.39(m,1H).
LC-MS(方法2):Rt=1.08min;MS(ESIpos):m/z=483[M+H]+
实施例53
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
将实施例52中的标题化合物(23.2mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(对映异构体1,6.0mg,Rt=6.6-7.-3min)和对映异构体2(5.0mg,Rt=10.7-11.6min,参见实施例54)。
制备型手性HPLC方法:MTBE
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:50%A+50%B;流速:60ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:MTBE
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:50%A+50%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=2.40min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23(t,3H),2.81-2.91(m,4H),3.40-3.45(m,3H),3.53(dt,1H),3.69-3.79(m,2H),3.79-3.85(m,1H),3.86-3.93(m,1H),3.99-4.06(m,1H),4.12(dd,1H),4.24(dd,1H),6.23(dd,1H),6.69-6.78(m,2H),7.15-7.23(m,2H),7.43-7.47(m,1H),7.98(d,1H)8.36(s,1H),11.03(br s,1H).
对映体选择性合成确认该标题化合物为3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮。按照类似于实施例1,通过使用N-(3-氯-2-乙基苯基)-4-{[(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-53,320mg,0.62mmol)作为起始原料,随后使用制备型HPLC(方法10,梯度:0.00-0.50min 5%B,0.50-7.99min 5-60%B,7.99-11.20min 60%B)纯化,制备得到标题化合物(25mg,7.6%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=11.03(s,1H),8.36(s,1H),7.98(d,1H),7.43-7.49(m,1H),7.15-7.24(m,2H),6.68-6.80(m,2H),6.14-6.28(m,1H),4.21-4.33(m,1H),4.10-4.17(m,1H),4.00-4.05(m,1H),3.70-3.92(m,4H),3.51-3.59(m,1H),3.39-3.47(m,3H),2.81-2.90(m,4H),1.23(t,3H).
实施例54
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
外消旋的标题化合物的制备参见实施例52。通过制备型手性HPLC分离对映异构体(方法参见实施例53),得到5.0mg的标题化合物(Rt=10.7-11.6min)。
分析型手性HPLC(方法参见实施例53):Rt=3.22min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.14-1.34(m,6H),2.81-2.91(m,4H),3.38-3.48(m,3H),3.55(dd,1H),3.69-3.85(m,3H),3.85-3.93(m,1H),3.99-4.06(m,1H),4.09-4.17(m,1H),4.25(dd,1H),6.23(dd,1H),6.69-6.79(m,2H),7.14-7.23(m,2H),7.39-7.49(m,1H),7.91-8.04(m,1H),8.31-8.40(m,1H),10.97-11.12(m,1H).
实施例55
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例41中所述的类似方法,使用3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体55,58.0mg,120μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-7.00min 30-70%B)纯化后,制备得到27.5mg(95%纯度,44%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23(t,3H),1.90(t,1H),1.99-2.09(td,1H),2.21(s,3H),2.63-2.71(d,1H),2.73-2.78(d,1H),2.78-2.89(m,4H),3.40-3.47(td,2H),3.67(td,1H),3.92-3.98(m,2H),4.14(dd,1H),4.27(dd,1H),6.23(dd,1H),6.71-6.78(m,2H),7.16-7.21(m,2H),7.46(s,1H),7.97(d,1H),8.36(s,1H),11.04(s,1H).
LC-MS(方法2):Rt=1.10min;MS(ESIpos):m/z=496[M+H]+
实施例56
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例41中所述的类似方法,使用3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(中间体56,68.0mg,141μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 30%B,0.50-7.00min 30-70%B)纯化后,制备得到37.8mg(95%纯度,51%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23(t,3H),1.90(t,1H),2.00-2.08(td,1H),2.21(s,3H),2.63-2.72(d,1H),2.72-2.81(d,1H),2.81-2.90(m,4H),3.44(td,2H),3.67(td,1H),3.91-3.99(m,2H),4.13(dd,1H),4.29(dd,1H),6.23(dd,1H),6.71-6.78(m,2H),7.16-7.21(m,2H),7.46(s,1H),7.97(d,1H),8.36(s,1H),11.04(s,1H).
LC-MS(方法2):Rt=1.10min;MS(ESIpos):m/z=496[M+H]+
实施例57
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
在微波管中,将N-(3-氯-2-甲氧基苯基)-4-([{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}甲基)氨基]-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-57,380mg,713μmol)的甲醇(1.5ml)溶液用TFA(55μl,710μmol)、随后用过氧化氢(9.2μl,0.106mmol)处理,加热至60℃,并搅拌16小时。将该反应混合物减压浓缩至干,溶于DMSO中,并通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-5.00min 15-50%B,5.00-8.00min 50%B)纯化,冷冻干燥后,得到所需的产物(174mg,44%产率),为两种立体异构体的混合物。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.176(0.47),1.192(0.46),1.245(3.61),1.261(3.63),1.326(5.41),1.342(5.34),2.074(0.90),2.518(2.00),2.523(1.30),2.832(0.58),2.853(1.78),2.871(2.29),2.889(1.20),3.374(0.58),3.402(1.93),3.412(1.77),3.419(2.47),3.427(2.74),3.435(1.67),3.442(1.31),3.455(1.30),3.464(0.88),3.485(1.04),3.493(0.81),3.500(0.81),3.522(0.58),3.614(0.42),3.643(1.28),3.650(1.69),3.669(0.97),3.699(1.00),3.725(1.81),3.734(0.89),3.748(1.07),3.754(0.91),3.768(0.44),3.777(0.54),3.783(0.42),3.806(1.65),3.813(2.16),3.823(1.17),3.836(1.62),3.843(1.75),3.850(1.00),3.863(9.50),3.890(16.00),3.919(0.92),3.948(0.61),4.068(2.33),4.626(0.70),4.630(0.86),4.643(1.15),4.653(0.66),4.658(0.86),6.133(0.95),6.143(2.18),6.148(0.96),6.151(1.32),6.158(1.98),6.167(1.48),6.638(1.70),6.643(2.02),6.653(3.46),6.678(0.58),6.690(6.05),6.699(2.71),6.706(2.31),7.122(0.98),7.161(1.50),7.264(0.72),7.285(0.52),7.294(1.80),7.299(2.64),7.307(1.85),7.312(2.64),7.440(2.17),7.519(3.36),7.631(0.44),7.998(3.33),8.011(3.08),8.031(2.20),8.044(1.98),8.396(4.10),8.411(2.66),11.072(1.20),11.085(1.69).
LC-MS(方法6):Rt=0.72min;MS(ESIpos):m/z=499[M+H]+
实施例58
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例57中的标题化合物(170mg)通过制备型手性HPLC分离成立体异构体,得到标题化合物(立体异构体1,58mg,Rt=16.2-18.8min)和立体异构体2(35mg,Rt=19.3-21.6min,参见实施例60)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SC 5μ,250x30;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;梯度:0-15min 20-30%B;流速:40ml/min;温度:25℃;UV:254nm
分析型手性分析HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SC 3μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=5.19min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.157(0.42),1.326(5.83),1.342(5.94),2.518(2.45),2.523(1.64),2.854(1.00),2.872(2.23),2.889(1.30),3.159(0.76),3.172(0.81),3.403(0.88),3.409(0.98),3.420(1.66),3.427(1.98),3.435(0.89),3.456(1.40),3.469(0.49),3.485(1.09),3.493(0.89),3.500(0.89),3.522(0.63),3.530(0.42),3.699(1.04),3.725(1.77),3.748(1.00),3.755(0.79),3.777(0.55),3.783(0.42),3.806(1.16),3.812(1.76),3.824(0.88),3.836(1.39),3.843(1.20),3.850(0.51),3.890(16.00),3.919(1.02),3.948(0.70),4.631(0.81),4.646(0.95),4.659(0.80),6.143(1.46),6.151(1.29),6.159(1.42),6.167(1.47),6.679(0.61),6.691(6.25),6.699(2.81),6.706(2.43),6.727(0.42),7.159(1.65),7.298(2.69),7.311(2.69),7.518(3.71),7.998(3.52),8.010(3.22),8.395(4.49),11.084(1.82).
旋光度:[α]D=30.21°+/-0.60°(c=1.0g/100ml氯仿)
LC-MS(方法6):Rt=0.72min;MS(ESIpos):m/z=499[M+H]+
实施例59
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1S)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
将实施例57中的标题化合物(170mg)通过制备型手性HPLC分离成立体异构体,得到标题化合物立体异构体2(35mg,Rt=19.3-21.6min,对于分离方法参见实施例58)。
分析型手性HPLC:Rt=5.91min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.798(0.48),0.815(0.56),0.822(0.55),0.905(0.48),1.084(0.46),1.137(0.84),1.156(0.69),1.233(1.00),1.246(6.21),1.261(6.32),2.084(0.60),2.332(0.57),2.518(3.49),2.522(2.23),2.673(0.60),2.833(1.01),2.850(2.05),2.867(1.22),3.308(0.48),3.373(0.98),3.402(2.29),3.412(2.05),3.418(2.16),3.427(2.02),3.435(1.84),3.442(1.19),3.465(0.79),3.607(0.46),3.614(0.62),3.643(2.17),3.670(1.14),3.726(0.62),3.732(0.73),3.738(0.65),3.744(0.72),3.751(0.57),3.757(0.63),3.762(0.57),3.768(0.57),3.805(1.25),3.815(1.51),3.821(1.12),3.834(1.01),3.844(1.36),3.850(1.08),3.863(16.00),3.889(0.74),4.625(0.83),4.637(0.87),4.641(0.90),4.653(0.81),6.133(1.40),6.143(1.44),6.147(1.32),6.157(1.50),6.639(2.71),6.643(3.20),6.653(5.57),6.663(0.45),7.120(1.71),7.294(2.55),7.307(2.61),7.438(3.73),8.031(2.89),8.043(2.69),8.411(4.05),11.071(1.88).
旋光度:[α]D=19.87°+/-0.91°(c=1.0g/100ml氯仿)
LC-MS(方法6):Rt=0.72min;MS(ESIpos):m/z=499[M+H]+
实施例60
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1R)-1-(1,4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
使用实施例57中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-{[(3-{(1R)-1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-60,340mg,638μmol)作为起始原料;通过制备型HPLC(方法10,梯度:0.00-0.50min 15%B,0.50-5.00min 15-50%B,5.00-8.00min 50%B)纯化,随后通过手性制备型HPLC纯化后,制备得到76.0mg(99%纯度,24%产率)的标题化合物(立体异构体1,Rt=18.7-22.0min)。另外分离出7mg的立体异构体2(实施例61)(Rt=16.5-17.9min)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇+0.1体积%二乙胺;恒溶剂:80%A+20%B;流速:60ml/min;温度:25℃;UV:254nm
分析型手性分析HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:乙醇;恒溶剂:80%A+20%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=6.96min.
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.245(5.93),1.261(5.97),2.518(0.96),2.522(0.61),2.833(0.89),2.850(1.81),2.868(1.07),3.374(0.88),3.398(1.92),3.402(2.05),3.412(1.84),3.418(1.88),3.427(1.81),3.435(1.62),3.442(1.07),3.465(0.71),3.608(0.45),3.614(0.62),3.643(2.07),3.669(1.04),3.726(0.57),3.733(0.70),3.736(0.65),3.744(0.69),3.751(0.53),3.757(0.58),3.762(0.53),3.768(0.55),3.805(1.12),3.815(1.32),3.821(0.99),3.834(0.89),3.844(1.24),3.850(0.97),3.864(16.00),3.890(0.81),4.068(0.46),4.626(0.76),4.637(0.80),4.641(0.83),4.653(0.76),6.133(1.41),6.143(1.51),6.148(1.26),6.158(1.48),6.638(2.78),6.643(3.34),6.653(5.70),6.663(0.46),7.122(1.57),7.294(2.67),7.307(2.70),7.440(3.53),8.031(3.75),8.044(3.34),8.411(4.42),11.072(1.72).
LC-MS(方法6):Rt=0.72min;MS(ESIpos):m/z=499[M+H]+
实施例61
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1R)-1-[(1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
用于制备作为两种非对映异构体混合物的标题化合物参见实施例60。通过制备型手性HPLC分离对映异构体(方法参见实施例60),得到7.0mg的标题化合物(Rt=9.4-10.8min)。
分析型手性HPLC(方法参见实施例60):Rt=6.10min.
旋光度:[α]D=-3.38°+/-0.78°(c=3,7mg/ml,氯仿).
实施例62
3-(3-氟-2-甲基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
向N-(3-氟-2-甲基苯基)-4-{[(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)甲基]氨基}-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-62,110mg,220μmol)的乙酸(1.1ml)溶液中加入过氧化氢水溶液(45μl,30%纯度,440μM),并将混合物于80℃加热2小时。将该反应混合物用饱和的硫代硫酸钠溶液淬灭,并通过加入4M氢氧化钠水溶液调节pH为7。加入DCM后,将该混合物在室温下搅拌15分钟。分离各相,并将水相用DCM萃取。将合并的有机层通过疏水滤纸干燥,并减压浓缩。将混合物通过制备型HPLC(方法10)纯化,得到标题化合物28mg(97%纯度,26%产率)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.877(1.11),1.904(1.76),1.931(1.15),2.007(0.48),2.016(0.62),2.036(1.18),2.044(1.14),2.064(0.65),2.074(0.91),2.188(9.04),2.191(9.20),2.204(16.00),2.326(0.50),2.518(1.93),2.522(1.23),2.647(1.09),2.669(1.06),2.673(1.34),2.743(1.21),2.770(1.13),2.844(1.64),2.861(3.54),2.878(1.85),3.410(1.18),3.415(1.29),3.426(2.35),3.432(2.33),3.443(1.13),3.449(1.04),3.642(0.55),3.648(0.70),3.670(1.28),3.675(1.30),3.698(0.76),3.703(0.63),3.935(1.65),3.942(1.53),3.951(0.92),3.962(1.44),3.967(1.29),4.109(1.20),4.126(1.08),4.135(1.56),4.151(1.27),4.276(1.43),4.285(1.48),4.301(1.18),4.310(1.07),6.056(2.20),6.076(2.25),6.442(1.00),6.464(1.83),6.486(1.13),6.735(0.68),6.755(1.42),6.772(1.36),6.793(0.57),7.188(2.26),7.230(3.88),7.242(3.85),7.346(4.43),7.979(5.07),7.991(4.58),8.368(6.78),11.029(2.41).
LC-MS(方法6):Rt=0.46min;MS(ESIpos):m/z=466[M+H]+
实施例63
3-(3-氟-2-甲基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例62中的标题化合物(21mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(立体异构体1,7.0mg,Rt=7.1-8.1min)和立体异构体2(9.0mg,Rt=9.4-10.8min,参见实施例64)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 5μ,250x30;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:50%A+50%B;流速:60ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:50%A+50%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=2.60min.
旋光度:[α]D=21.60°+/-1.04°(c=1.0g/100ml氯仿)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.232(0.89),1.877(1.15),1.904(1.74),1.931(1.14),2.008(0.48),2.016(0.62),2.036(1.17),2.044(1.15),2.064(0.65),2.073(0.56),2.188(9.17),2.191(9.34),2.204(16.00),2.322(0.45),2.327(0.62),2.332(0.45),2.518(2.49),2.523(1.54),2.646(1.12),2.669(1.21),2.673(1.46),2.743(1.23),2.770(1.15),2.844(1.60),2.861(3.42),2.878(1.82),3.410(1.23),3.415(1.32),3.426(2.40),3.432(2.38),3.444(1.15),3.449(1.07),3.641(0.56),3.648(0.70),3.670(1.28),3.675(1.31),3.698(0.76),3.703(0.61),3.935(1.67),3.942(1.57),3.951(0.95),3.962(1.45),4.109(1.14),4.126(1.03),4.135(1.51),4.152(1.21),4.276(1.39),4.285(1.43),4.301(1.14),4.310(1.03),6.056(2.16),6.076(2.23),6.442(1.01),6.464(1.85),6.486(1.14),6.735(0.67),6.755(1.42),6.772(1.37),6.793(0.56),7.188(2.29),7.230(3.04),7.243(3.00),7.345(4.40),7.979(3.05),7.991(2.83),8.368(4.67),11.030(2.40).
LC-MS(方法6):Rt=0.46min;MS(ESIpos):m/z=466[M+H]+
实施例64
3-(3-氟-2-甲基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例63。通过制备型手性HPLC分离对映异构体(方法参见实施例63),得到9.0mg的标题化合物(Rt=9.4-10.8min)。
分析型手性HPLC(方法参见实施例63):Rt=3.37min.
旋光度:[α]D=-20.75°+/-1.29°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.232(0.99),1.877(1.12),1.904(1.80),1.931(1.15),2.008(0.49),2.016(0.64),2.036(1.17),2.044(1.15),2.065(0.66),2.073(0.57),2.188(9.36),2.191(9.48),2.204(16.00),2.323(0.47),2.327(0.62),2.332(0.47),2.518(2.39),2.522(1.44),2.647(1.15),2.669(1.24),2.673(1.48),2.743(1.24),2.770(1.16),2.844(1.63),2.861(3.47),2.878(1.82),3.410(1.27),3.415(1.36),3.426(2.43),3.432(2.39),3.443(1.17),3.449(1.07),3.642(0.56),3.648(0.70),3.670(1.30),3.675(1.30),3.698(0.75),3.703(0.63),3.935(1.71),3.942(1.60),3.962(1.47),4.109(1.17),4.126(1.03),4.135(1.51),4.152(1.22),4.276(1.40),4.285(1.45),4.301(1.13),4.310(1.03),6.056(2.19),6.076(2.26),6.442(1.05),6.464(1.87),6.486(1.15),6.735(0.70),6.755(1.43),6.772(1.38),6.793(0.56),7.188(2.30),7.230(3.03),7.243(3.07),7.346(4.46),7.979(3.01),7.992(2.84),8.368(4.73),11.030(2.43).
LC-MS(方法6):Rt=0.46min;MS(ESIpos):m/z=466[M+H]+
实施例65
2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例62中所述的类似方法,使用4-{[(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-N-(2-乙基-3-氟苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-65,215mg,429μmol)作为起始原料;通过制备型HPLC(碱性条件)纯化后,制备得到76.0mg(95%纯度,36%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.097(0.45),1.206(6.70),1.225(16.00),1.244(6.93),2.322(0.88),2.327(1.21),2.332(0.88),2.518(4.46),2.522(2.73),2.664(1.18),2.669(1.70),2.673(2.02),2.697(3.88),2.715(3.73),2.732(1.31),2.847(3.66),2.864(7.84),2.881(4.11),3.404(3.38),3.415(2.84),3.420(3.17),3.432(8.74),3.437(5.90),3.449(2.86),3.457(4.93),3.506(1.16),3.511(1.46),3.533(2.58),3.540(2.78),3.562(2.02),3.570(1.77),3.711(3.25),3.719(1.53),3.726(2.41),3.738(2.86),3.749(3.64),3.756(2.33),3.777(2.11),3.783(1.59),3.804(2.97),3.810(3.25),3.833(2.65),3.839(2.67),3.887(2.80),3.915(2.07),4.005(0.73),4.013(1.16),4.021(1.72),4.029(1.94),4.036(1.90),4.045(1.57),4.054(1.36),4.061(0.97),4.106(3.19),4.123(2.20),4.132(4.05),4.149(3.10),4.246(3.66),4.255(3.60),4.272(2.73),4.281(2.45),6.084(4.91),6.104(5.10),6.433(2.28),6.454(4.07),6.476(2.61),6.720(1.92),6.741(3.81),6.758(3.70),6.778(1.62),7.180(5.15),7.199(8.92),7.212(8.89),7.427(9.02),7.964(12.58),7.976(11.33),8.358(15.85),11.012(5.43).
LC-MS(方法6):Rt=0.70min;MS(ESIpos):m/z=467[M+H]+
实施例66,实施例67
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
实施例66
2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将实施例65中的标题化合物(74mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(立体异构体1,30mg,Rt=4.5-5.3min)和立体异构体2(31mg,Rt=5.3-6.2min,参见实施例67)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC;柱:YMC Cellulose SB 10μ,250x50;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:甲醇;恒溶剂:90%A+10%B;流速:150ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:甲醇;恒溶剂:90%A+10%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=4.41min.
旋光度:[α]D=-21.9°+/-0.60°(c=1.0g/100ml氯仿)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.097(0.44),1.104(0.61),1.206(6.68),1.225(16.00),1.243(7.03),2.074(3.21),2.322(1.00),2.326(1.39),2.332(1.01),2.518(6.14),2.522(3.75),2.664(1.33),2.669(1.92),2.673(2.17),2.696(3.92),2.715(3.83),2.732(1.29),2.846(3.62),2.864(7.78),2.881(4.15),3.404(3.29),3.414(2.85),3.420(3.24),3.431(8.73),3.437(6.06),3.448(2.90),3.457(4.88),3.505(1.14),3.511(1.37),3.533(2.57),3.540(2.76),3.562(1.97),3.570(1.73),3.711(3.19),3.719(1.56),3.726(2.37),3.738(2.90),3.749(3.58),3.755(2.31),3.777(1.96),3.783(1.46),3.804(2.93),3.810(3.13),3.833(2.59),3.839(2.71),3.887(2.80),3.914(2.06),4.013(1.15),4.020(1.68),4.029(1.97),4.036(1.90),4.045(1.59),4.053(1.40),4.060(0.95),4.106(3.06),4.122(2.09),4.132(3.85),4.148(2.90),4.245(3.58),4.255(3.47),4.271(2.68),4.280(2.36),6.083(4.88),6.104(5.09),6.433(2.24),6.454(4.08),6.476(2.56),6.720(1.80),6.741(3.65),6.758(3.54),6.778(1.53),7.179(5.11),7.199(8.20),7.211(8.15),7.426(8.99),7.963(9.54),7.976(8.80),8.357(13.39),11.012(5.48).
LC-MS(方法6):Rt=0.70min;MS(ESIpos):m/z=467[M+H]+
实施例67
2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例65。通过制备型手性HPLC分离对映异构体(方法参见实施例66),得到31mg的标题化合物。
分析型手性HPLC(方法参见实施例63):Rt=4.49min.
旋光度:[α]D=22.51°+/-0.86°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.104(0.57),1.164(0.90),1.206(6.89),1.225(16.00),1.244(7.18),2.322(0.60),2.326(0.81),2.332(0.59),2.518(3.44),2.522(2.12),2.665(0.84),2.669(1.32),2.677(1.68),2.696(3.95),2.715(3.83),2.732(1.33),2.847(3.68),2.864(7.81),2.881(4.16),3.404(3.21),3.415(2.88),3.421(3.23),3.432(8.92),3.437(6.02),3.449(2.91),3.457(4.87),3.506(1.11),3.511(1.37),3.533(2.61),3.540(2.72),3.562(2.00),3.570(1.74),3.712(3.25),3.719(1.51),3.726(2.32),3.738(2.93),3.749(3.59),3.756(2.31),3.777(1.96),3.784(1.44),3.804(2.94),3.810(3.18),3.833(2.64),3.839(2.70),3.887(2.87),3.915(2.12),4.005(0.70),4.014(1.17),4.020(1.70),4.029(2.01),4.037(1.92),4.045(1.57),4.053(1.42),4.060(0.95),4.106(3.05),4.123(2.12),4.132(3.86),4.148(2.88),4.246(3.51),4.255(3.49),4.271(2.68),4.281(2.35),6.084(4.92),6.105(5.14),6.433(2.23),6.454(4.07),6.476(2.59),6.720(1.81),6.741(3.64),6.758(3.58),6.778(1.55),7.180(5.16),7.199(7.86),7.212(7.80),7.426(9.02),7.963(7.86),7.976(7.32),8.358(12.12),11.012(5.54).
LC-MS(方法6):Rt=0.70min;MS(ESIpos):m/z=467[M+H]+
实施例68
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例62中所述的类似方法,使用4-{[(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)甲基]氨基}-N-(2-乙基-3-氟苯基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-68,350mg,662μmol)作为起始原料;通过制备型HPLC(碱性条件)纯化后,制备得到82mg(85%纯度,21%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.051(1.89),1.073(11.18),1.171(0.57),1.182(0.76),1.197(3.04),1.216(5.73),1.234(3.31),1.243(10.52),2.326(0.46),2.518(1.69),2.522(1.07),2.539(16.00),2.669(0.94),2.673(0.76),2.688(1.36),2.706(1.38),2.828(1.23),2.845(2.62),2.862(1.40),3.412(2.22),3.422(1.93),3.428(1.91),3.440(2.37),3.574(0.81),3.582(0.90),3.604(1.34),3.612(1.29),3.629(0.40),3.646(2.91),3.674(3.37),3.703(0.90),3.896(0.52),3.903(0.59),3.912(0.74),3.920(0.70),3.929(0.49),3.938(0.47),4.129(0.89),4.146(0.81),4.155(1.16),4.172(1.00),4.284(1.20),4.292(1.15),4.310(0.88),4.319(0.81),5.758(2.21),6.089(1.68),6.110(1.75),6.420(0.77),6.443(1.38),6.464(0.88),6.709(0.64),6.729(1.28),6.746(1.24),6.767(0.55),7.165(1.72),7.200(2.88),7.213(2.92),7.249(0.48),7.369(0.47),7.382(0.67),7.392(2.91),7.972(3.81),7.985(3.48),8.067(0.61),8.080(0.54),8.372(5.10),8.439(0.78),11.018(1.92).
LC-MS(方法6):Rt=0.79min;MS(ESIpos):m/z=495[M+H]+
实施例69,实施例70
2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
实施例69
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶4-酮(立体异构体1)
将实施例68中的标题化合物(32mg)通过制备型手性HPLC分离成对映异构体,得到标题化合物(立体异构体1,13mg,Rt=36.8-46.0min)和立体异构体2(10mg,Rt=21.9-26.4min.,参见实施例70)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC-4;柱:Chiralcel OD-H 5μ,250x20;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:2-丙醇;恒溶剂:70%A+30%B;流速:10ml/min;温度:25℃;UV:254nm
分析型手性HPLC方法:
仪器:Thermo Fisher UltiMate 3000;柱:Chiralcel OD-H 5μ,100x4.6;洗脱剂A:己烷+0.1体积%二乙胺;洗脱剂B:2-丙醇;恒溶剂:70%A+30%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=7.38min.
旋光度:[α]D=-24.42°+/-0.72°(c=1.0g/100ml氯仿)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.698(1.11),0.742(0.61),0.834(0.47),0.851(0.63),1.072(16.00),1.147(1.48),1.195(4.00),1.214(8.27),1.233(6.80),1.242(15.37),1.294(0.70),2.322(0.63),2.326(0.85),2.331(0.63),2.517(3.89),2.522(2.40),2.664(1.17),2.668(1.54),2.673(1.19),2.687(1.95),2.705(1.86),2.722(0.66),2.826(1.78),2.843(3.74),2.860(2.02),3.411(3.06),3.420(2.79),3.427(2.73),3.440(3.33),3.573(0.89),3.581(1.05),3.603(1.84),3.611(1.82),3.646(3.73),3.674(4.44),3.703(1.16),3.893(0.70),3.901(0.84),3.910(1.06),3.918(0.98),3.926(0.71),3.935(0.66),4.126(1.20),4.143(1.14),4.152(1.62),4.169(1.39),4.281(1.52),4.290(1.61),4.307(1.22),4.316(1.10),6.088(2.37),6.108(2.47),6.417(1.08),6.440(1.96),6.461(1.24),6.707(0.87),6.728(1.74),6.745(1.70),6.765(0.75),7.159(2.50),7.197(3.08),7.209(3.08),7.378(4.32),7.967(2.35),7.980(2.25),8.368(3.77),11.014(2.75).
LC-MS(方法6):Rt=0.78min;MS(ESIpos):m/z=495[M+H]+
实施例70
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例68。通过制备型手性HPLC分离对映异构体(方法参见实施例69),得到10mg的标题化合物。
分析型手性HPLC(方法参见实施例69):Rt=5.50min.
旋光度:[α]D=33.52°+/-1.07°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.852(0.50),1.072(16.00),1.147(0.81),1.195(3.63),1.214(8.06),1.233(5.99),1.242(15.29),2.322(0.67),2.326(0.93),2.331(0.67),2.518(4.20),2.522(2.70),2.664(1.19),2.668(1.61),2.673(1.22),2.687(1.88),2.705(1.81),2.722(0.65),2.826(1.76),2.843(3.72),2.860(1.98),3.411(2.99),3.420(2.72),3.427(2.69),3.440(3.28),3.573(0.90),3.582(1.04),3.603(1.85),3.611(1.82),3.646(3.73),3.674(4.50),3.703(1.19),3.893(0.69),3.901(0.82),3.910(1.04),3.918(0.98),3.927(0.70),3.935(0.65),4.126(1.23),4.143(1.15),4.152(1.63),4.169(1.40),4.281(1.53),4.290(1.62),4.307(1.24),4.316(1.12),6.088(2.36),6.108(2.47),6.419(1.10),6.440(1.96),6.461(1.24),6.707(0.90),6.728(1.77),6.744(1.72),6.765(0.75),7.159(2.47),7.196(3.38),7.209(3.41),7.378(4.36),7.967(2.84),7.980(2.69),8.368(4.39),11.014(2.71).
LC-MS(方法6):Rt=0.78min;MS(ESIpos):m/z=495[M+H]+
实施例71
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
使用实施例62中所述的类似方法,使用N-(3-氯-2-甲氧基苯基)-4-({[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]甲基}氨基)-2-氧代-1,2,5,6-四氢吡啶-3-硫代甲酰胺(中间体6-71,420mg,769μmol)作为起始原料;通过制备型HPLC(碱性条件)纯化后,制备得到139mg(95%纯度,33%产率)的标题化合物。
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.277(4.27),1.293(4.32),1.333(0.47),1.350(0.67),1.358(4.99),1.374(4.94),1.824(0.55),1.851(0.91),1.878(0.61),1.893(0.74),1.906(0.40),1.920(1.17),1.934(0.70),1.947(0.76),1.956(0.54),1.965(0.55),1.987(0.64),1.995(0.65),2.128(0.82),2.159(7.74),2.180(8.74),2.322(0.51),2.326(0.68),2.332(0.49),2.518(2.39),2.522(1.49),2.577(0.56),2.606(0.54),2.642(0.72),2.665(0.85),2.669(1.29),2.673(1.01),2.748(1.31),2.775(1.22),2.835(0.82),2.852(2.10),2.867(2.15),2.882(1.06),3.403(1.26),3.414(1.72),3.420(2.29),3.437(1.06),3.546(0.63),3.551(0.64),3.640(0.42),3.663(1.06),3.668(1.07),3.680(0.51),3.691(0.88),3.696(0.73),3.712(0.46),3.717(0.51),3.724(0.46),3.729(0.51),3.738(0.48),3.743(0.44),3.750(0.47),3.754(0.43),3.867(12.16),3.891(16.00),3.969(0.62),3.993(0.54),4.637(0.80),4.650(1.17),4.659(0.74),4.665(1.09),4.675(0.61),6.146(2.23),6.155(2.15),6.162(1.69),6.170(2.32),6.642(2.11),6.647(2.51),6.657(4.69),6.667(0.52),6.672(0.41),6.680(0.65),6.692(5.88),6.701(2.71),6.709(2.25),7.122(1.19),7.160(1.40),7.290(2.01),7.300(2.69),7.303(2.35),7.313(2.45),7.426(0.41),7.435(2.71),7.520(3.23),7.989(3.33),8.002(3.13),8.019(2.70),8.031(2.40),8.402(3.96),8.421(3.26),11.070(1.28),11.110(1.54).
LC-MS(方法6):Rt=0.54min;MS(ESIpos):m/z=512[M+H]+
实施例72,实施例73,实施例74,实施例75
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
实施例72
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体1)
将得自实施例71的标题化合物(135mg)通过制备型手性HPLC分离成四个立体异构体。除了立体异构体2(27mg,Rt=9.6-10.9min.,参见实施例73)、立体异构体3(37mg,参见实施例74)和立体异构体4(37mg,参见实施例75)之外,还得到了标题化合物立体异构体1(20mg,Rt=6.8-7.6min)。
制备型手性HPLC方法:
仪器:PrepCon Labomatic HPLC4;柱:YMC Cellulose SB 10μ,250x50;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:80%A+20%B;流速:140mL/min;温度:25℃;UV:254nm
分析型手性HPLC方法:
仪器:Waters Alliance 2695;柱:YMC Cellulose SB 3μ,100x4.6;洗脱剂A:甲基叔丁基醚+0.1体积%二乙胺;洗脱剂B:乙腈;恒溶剂:80%A+20%B;流速:1.4ml/min;温度:25℃;UV:254nm
分析型手性HPLC:Rt=3.85min.
旋光度:[α]D=16.84°+/-0.40°(c=1.0g/100ml氯仿)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.137(0.95),1.159(0.63),1.232(0.54),1.277(5.83),1.293(5.97),1.826(0.63),1.853(1.16),1.880(0.71),1.907(0.46),1.928(0.77),1.935(0.78),1.956(0.45),2.160(9.53),2.326(0.58),2.522(2.28),2.579(0.94),2.608(0.86),2.665(0.41),2.669(0.54),2.673(0.40),2.748(0.95),2.776(0.90),2.835(1.17),2.852(2.46),2.869(1.37),3.402(1.17),3.413(1.92),3.419(1.92),3.431(0.97),3.523(0.52),3.545(0.95),3.551(0.92),3.573(0.56),3.660(0.71),3.670(0.67),3.690(0.73),3.866(16.00),3.891(0.61),4.649(0.83),4.659(0.85),4.664(0.85),4.675(0.80),5.758(1.51),6.145(1.46),6.155(1.45),6.159(1.36),6.169(1.48),6.643(2.83),6.647(3.21),6.657(5.61),6.667(0.55),7.123(1.81),7.291(2.03),7.303(2.10),7.435(3.81),8.018(1.65),8.031(1.59),8.420(2.63),11.071(2.01).
LC-MS(方法6):Rt=0.53min;MS(ESIpos):m/z=512[M+H]+
实施例73
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体2)
外消旋的标题化合物的制备参见实施例71。通过制备型手性HPLC(方法参见实施例72)分离立体异构体,得到27mg的标题化合物立体异构体2。
分析型手性HPLC(方法参见实施例72):Rt=5.24min.
旋光度:[α]D=16.84°+/-0.40°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.137(0.95),1.159(0.63),1.232(0.54),1.277(5.83),1.293(5.97),1.826(0.63),1.853(1.16),1.880(0.71),1.907(0.46),1.928(0.77),1.935(0.78),1.956(0.45),2.160(9.53),2.326(0.58),2.522(2.28),2.579(0.94),2.608(0.86),2.665(0.41),2.669(0.54),2.673(0.40),2.748(0.95),2.776(0.90),2.835(1.17),2.852(2.46),2.869(1.37),3.402(1.17),3.413(1.92),3.419(1.92),3.431(0.97),3.523(0.52),3.545(0.95),3.55l(0.92),3.573(0.56),3.660(0.71),3.670(0.67),3.690(0.73),3.866(16.00),3.891(0.61),4.649(0.83),4.659(0.85),4.664(0.85),4.675(0.80),5.758(1.51),6.145(1.46),6.155(1.45),6.159(1.36),6.169(1.48),6.643(2.83),6.647(3.21),6.657(5.61),6.667(0.55),7.123(1.81),7.291(2.03),7.303(2.10),7.435(3.81),8.018(1.65),8.03l(1.59),8.420(2.63),11.071(2.01).
LC-MS(方法6):Rt=0.53min;MS(ESIpos):m/z=512[M+H]+
实施例74
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体3)
外消旋的标题化合物的制备参见实施例71。为了分离立体异构体3和立体异构体4(参见实施例75),首先使用实施例72中所述的方法进行制备型手性HPLC。使用以下方法通过另一制备型手性HPLC将一个级分(Rt=5.5-6.5分钟)进一步分离,得到37mg的标题化合物立体异构体3。
制备型手性HPLC方法:
仪器:Sepiatec:Prep SFC100;柱:Chiralpak IG 5μ250x30mm;洗脱剂A:CO2;洗脱剂B:2-丙醇+0.4体积%二乙胺;恒溶剂:40%B;流速:100ml/min;温度:40℃;BPR:150bar;UV:254nm
分析型手性HPLC方法:
仪器:Agilent:1260,Aurora SFC-Modul;柱:Chiralpak IG 5μ100x4.6mm;洗脱剂A:CO2;洗脱剂B:2-丙醇+0.4体积%二乙胺;恒溶剂:40%B;流速:4ml/min;温度:37.5℃;BPR:100bar;UV:254nm
分析型手性HPLC:Rt=3.98min.
旋光度:[α]D=30.08°+/-0.91°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.697(0.90),1.026(1.27),1.042(1.28),1.088(0.45),1.137(0.56),1.232(1.77),1.293(0.50),1.358(5.47),1.374(5.50),1.893(0.68),1.920(1.22),1.947(0.76),1.959(1.07),1.966(0.44),1.987(0.74),1.995(0.74),2.016(0.44),2.180(9.88),2.327(0.45),2.523(1.85),2.643(0.83),2.669(1.19),2.749(0.84),2.776(0.82),2.847(0.81),2.865(1.90),2.882(1.25),3.409(0.92),3.419(1.42),3.425(1.62),3.439(0.79),3.640(0.45),3.663(0.82),3.668(0.85),3.691(0.49),3.712(0.49),3.718(0.58),3.724(0.55),3.730(0.61),3.738(0.58),3.744(0.54),3.750(0.58),3.755(0.50),3.891(16.00),3.970(0.75),3.993(0.66),4.638(0.75),4.653(0.92),4.666(0.75),6.146(1.43),6.154(1.30),6.162(1.45),6.170(1.48),6.681(0.60),6.693(6.14),6.701(2.75),6.709(2.40),6.729(0.44),7.162(1.65),7.301(1.65),7.313(1.71),7.521(3.68),7.990(1.16),8.002(1.10),8.403(1.76),11.111(1.82).
LC-MS(方法6):Rt=0.53min;MS(ESIpos):m/z=512[M+H]+
实施例75
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(立体异构体4)
外消旋的标题化合物的制备参见实施例71。为了分离立体异构体3(参见实施例74)和立体异构体4(实施例75),首先使用实施例72中所述的方法进行制备型手性HPLC。通过另一制备型手性HPLC(方法参见实施例74)将一个级分(Rt=5.5-6.5分钟)进一步分离,得到37mg的标题化合物立体异构体4。
分析型手性HPLC:Rt=7.23min.
旋光度:[α]D=-24.97°+/-0.50°(c=1.0g/100ml在氯仿中)
1H-NMR(400MHz,DMSO-d6)δ[ppm]:0.697(2.05),0.742(1.32),0.760(1.30),0.832(0.55),0.851(0.74),0.973(0.66),0.984(0.67),0.991(0.96),0.999(0.64),1.009(0.72),1.026(0.75),1.042(0.77),1.070(0.82),1.088(1.27),1.106(1.27),1.151(4.27),1.232(4.01),1.293(1.22),1.358(5.91),1.373(6.07),1.894(0.71),1.921(1.28),1.948(0.80),1.959(1.52),1.988(0.82),1.995(0.85),2.017(0.51),2.181(10.00),2.322(0.74),2.326(0.99),2.331(0.74),2.522(4.96),2.643(0.98),2.669(1.77),2.749(0.99),2.777(0.93),2.849(0.99),2.865(2.18),2.882(1.43),3.408(1.14),3.424(1.91),3.640(0.51),3.663(0.93),3.668(0.95),3.692(0.56),3.718(0.67),3.730(0.69),3.743(0.64),3.750(0.64),3.891(16.00),3.969(0.87),3.993(0.79),4.638(0.82),4.653(1.03),4.667(0.80),6.145(1.44),6.154(1.38),6.161(1.41),6.169(1.51),6.681(0.63),6.693(5.87),6.701(2.92),6.709(2.49),6.729(0.47),7.162(1.85),7.300(1.91),7.313(1.96),7.520(3.80),7.990(1.46),8.002(1.40),8.402(2.29),11.110(1.99).
LC-MS(方法6):Rt=0.53min;MS(ESIpos):m/z=512[M+H]+
实验部分-生物学测定
本发明化合物的药理学活性可以使用本领域技术人员已知的体外和/或体内测定来评估。以下实施例描述了根据本发明的化合物的生物活性,但本发明不限于所述实施例。
根据本发明的实施例化合物在选定的生物学测定中测试了一次或多次。当测试超过一次时,数据报道为平均值或中值,其中
·平均值,也称为算术平均值,代表获得的值的总和除以测试的次数,以及
·中值代表当以升序或降序排列时值的组的中间数。如果数据集中的值的数目为奇数,则中值为中间的值。如果数据集中的值的数目为偶数,则中值为两个中间值的算术平均值。
实施例化合物被合成一次或多次。当合成超过一次时,得自生物学测定的数据表示利用获得自一次或多次合成批次的测试的数据集计算的平均值或中值。
本发明化合物的体外活性可在以下试验中证明:
用于生化激酶测定的EGFR蛋白的表达和纯化
生化激酶活性抑制测定中使用的不同EGFR蛋白是通过如下段落中所述使用杆状病毒系统在昆虫细胞中表达并随后纯化在内部产生的。
表达构建体:
编码得自人类EGFR人类(P00533)的各种蛋白质序列的cDNA被优化用于在真核细胞中表达,并由Life Technologies的GeneArt Technology合成。
这些DNA序列编码了以下序列:
构建体EGFR#1氨基酸R669至A1210
构建体EGFR#2氨基酸R669至A1210,并且在V769和D770之间插入氨基酸序列ASV
构建体EGFR#3氨基酸R669至A1210,并且在D770和N771之间插入氨基酸序列SVD
此外,所有编码的构建体EGFR#1至#3:在N端有TEV(烟草蚀刻病毒)蛋白酶切割位点(DYDIPTTENLYFQG),在C端有两个终止密码子和另外5′和3′att-DNA序列用于Gateway克隆。
四种EFGR构建体中的每一种都使用Gateway Technology亚克隆到目标载体pD-Ins1中。载体pD-Ins1是杆状病毒转移载体(基于载体pVL1393,Pharmingen),它提供了GST-标签与整合基因构建体的N-端融合。各自的转移载体被称为pD-Ins1_EGFR#1、pD-Ins1_EGFR#2、pD-Ins1_EGFR#3。
EGFR氨基酸序列:
GST-EGFR#1(野生型)
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GST-EGFR#2(V769和D770之间的ASV)
GST-EGFR#3(D770和N771之间的SVD)
重组杆状病毒的产生:
在不同的方法中,使用Fugene HD(Roche)将三种转移载体中的每一种与杆状病毒DNA(Flashbac Gold DNA,Oxford Expression Technologies)共转染到Sf9细胞中。5天后,将含有编码各种EGFR蛋白的重组杆状病毒的转染细胞的上清液用于进一步感染Sf9细胞以进行病毒扩增,由此使用qPCR监测病毒滴度。
使用生物反应器在Sf9细胞中表达EGFR:
在具有一次性培养袋的Wave生物反应器中培养的Sf9细胞(Insect-xpress培养基,Lonza,27℃)以106个细胞/ml的细胞密度用一种重组杆状病毒原种以感染复数为1进行感染,并孵育48小时。随后通过离心收获细胞并将细胞沉淀在-80℃冷冻。
GST-EGFR融合蛋白的纯化:
使用谷胱甘肽琼脂糖凝胶4B基质(GE Healthcare Life Sciences)通过亲和色谱法纯化GST-EGFR融合蛋白。
将沉淀的细胞(得自4l细胞培养物)重新悬浮在裂解缓冲液(50mM HEPES pH 7.4,150mM NaCl,5%甘油,1mM MgCl2,1mM MnCl2,0.5mM Na3VO4)中,并通过冻融循环裂解,然后在冰上孵育60分钟。将上清液在4℃下以4000x g离心30分钟。然后将上清液与谷胱甘肽琼脂糖凝胶4B基质一起孵育(在玻璃瓶中,在4℃下旋转16小时)以结合GST EGFR融合蛋白,用洗涤缓冲液冲洗,并最后使用洗脱缓冲液(裂解缓冲液加25mM谷胱甘肽)洗脱结合的蛋白质,并用液氮急速冷冻(shock frozen)。
WT-EGFR激酶测定
外显子20-突变-EGFR(D770_N771insSVD)激酶测定
如下面段落中所述,使用基于TR-FRET的激酶活性测定法定量本发明化合物对在D770和N771之间插入氨基酸序列SVD的表皮生长因子受体(EGFR)的抑制活性。
N-末端谷胱甘肽-S-转移酶(GST)和人类EGFR变体的片段(在D770和N771之间插入了氨基酸序列SVD的氨基酸R669至A1210(“EGFR ins SVD”))的重组融合蛋白(其在Sf9昆虫细胞中表达,并如上所述使用谷胱甘肽琼脂糖凝胶通过亲和色谱法纯化)用作激酶。作为激酶反应的底物,使用可以例如从公司Biosynthan GmbH(Berlin-Buch,Germany)购买的生物素化肽生物素-Ahx-AEEEEYFELVAKKK(酰胺形式的C末端)。
对于该测定,将50nl测试化合物在DMSO中的100倍浓缩溶液移液到黑色小体积384孔微量滴定板或黑色1536孔微量滴定板(两个Greiner Bio-One,Frickenhausen,Germany)中,加入2μl EGFR在测定缓冲水溶液[50mM Hepes pH 7.0,10mM MgCl2,1mM二硫苏糖醇,0.5mM EGTA,0.3mM活化的正钒酸钠,0.005%(w/v)牛血清白蛋白,0.005%(v/v)Tween-20]中的溶液,并将混合物在22℃下孵育15分钟,以使测试化合物在激酶反应开始前与酶预先结合。然后,通过添加3μl的三磷酸腺苷(ATP,3.33mM=>5μl测定体积中的终浓度为2mM)和底物(1.67μM=>5μl测定体积中的终浓度为1μM)在测定缓冲液中的溶液而开始该激酶反应,并将所得混合物在22℃下孵育30分钟的反应时间。EGFR的浓度根据酶批次的活性进行调整,并适当选择以具有线性范围内的测定(通常浓度为15pg/μl)。通过添加3μl的HTRF检测试剂(83.3nM链霉亲和素-XL665[Cisbio Bioassays,Codolet,France]和1.67nM PT66-Tb-穴状化合物(一种得自Cisbio Bioassays的Tb-穴状化合物标记的抗磷酸酪氨酸抗体)[也可以使用得自Perkin Elmer的PT66 Tb穴状化合物PT66 Eu螯合物代替])在EDTA水溶液(133.3mM EDTA,0.2%(w/v)牛血清白蛋白,在50mM HEPES中,pH 7.5)中的溶液来停止该反应。
将生成的混合物在22℃下孵育1小时,使生物素化磷酸化肽与链霉亲和素-XL665和PT66-Tb-穴状化合物结合。随后,通过测量从PT66-Tb-穴状化合物到链霉亲和素-XL665的共振能量转移来评估磷酸化底物的量。为此,在HTRF读板器如Pherastar(BMGLabtechnologies,Offenburg,Germany)或Viewlux(Perkin-Elmer)中测量在337nm处激发之后在620nm和665nm处的荧光发射。在665nm和622nm处的发射比率被作为磷酸化底物量的量度。将该数据归一化(没有抑制剂的酶反应=0%抑制,所有其他测定组分但没有酶=100%抑制)。通常,在相同的微量滴定板中以20μM至0.07nM范围内的11种不同的浓度(20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、11nM、3.1nM、0.9nM、0.25nM和0.07nM,在测定之前在DMSO中通过连续稀释100倍浓缩溶液的水平分别制备稀释系列,确切浓度可以根据所使用的移液器而不同)测试受试化合物,每个浓度一式两份,并且使用Genedata ScreenerTM软件计算IC50值。
外显子20-突变-EGFR(V769_D770insASV)激酶测定
如下面段落中所述,使用基于TR-FRET的激酶活性测定法定量本发明化合物对在V769和D770之间插入氨基酸序列ASV的表皮生长因子受体(EGFR)的抑制活性。
N-末端谷胱甘肽-S-转移酶(GST)和人类EGFR变体的片段(在V769和D770之间插入了氨基酸序列ASV的氨基酸R669至A1210(“EGFR ins ASV”))的重组融合蛋白(其在Sf9昆虫细胞中表达,并如上所述使用谷胱甘肽琼脂糖凝胶通过亲和色谱法纯化)用作激酶。作为激酶反应的底物,使用可以例如从公司Biosynthan GmbH(Berlin-Buch,Germany)购买的生物素化肽生物素-Ahx-AEEEEYFELVAKKK(酰胺形式的C末端)。
对于该测定,将50nl测试化合物在DMSO中的100倍浓缩溶液移液到黑色小体积384孔微量滴定板或黑色1536孔微量滴定板(两个Greiner Bio-One,Frickenhausen,Germany)中,加入2μl EGFR在测定缓冲水溶液[50mM Hepes pH 7.0,10mM MgCl2,1mM二硫苏糖醇,0.5mM EGTA,0.3mM活化的正钒酸钠,0.005%(w/v)牛血清白蛋白,0.005%(v/v)Tween-20]中的溶液,并将混合物在22℃下孵育15分钟,以使测试化合物在激酶反应开始前与酶预先结合。然后,通过添加3μl的三磷酸腺苷(ATP,3.33mM=>5μl测定体积中的终浓度为2mM)和底物(1.67μM=>5μl测定体积中的终浓度为1μM)在测定缓冲液中的溶液而开始该激酶反应,并将所得混合物在22℃下孵育30分钟的反应时间。EGFR的浓度根据酶批次的活性进行调整,并适当选择以具有线性范围内的测定(通常浓度为2.5pg/μl)。通过添加3μl的HTRF检测试剂(83.3nM链霉亲和素-XL665[Cisbio Bioassays,Codolet,France]和1.67nM PT66-Tb-穴状化合物(一种得自Cisbio Bioassays的Tb-穴状化合物标记的抗磷酸酪氨酸抗体)[也可以使用得自Perkin Elmer的PT66 Tb穴状化合物PT66 Eu螯合物代替])在EDTA水溶液(133.3mM EDTA,0.2%(w/v)牛血清白蛋白,在50mM HEPES中,pH 7.5)中的溶液来停止该反应。
将生成的混合物在22℃下孵育1小时,使生物素化磷酸化肽与链霉亲和素-XL665和PT66-Tb-穴状化合物结合。随后,通过测量从PT66-Tb-穴状化合物到链霉亲和素-XL665的共振能量转移来评估磷酸化底物的量。为此,在HTRF读板器如Pherastar(BMGLabtechnologies,Offenburg,Germany)或Viewlux(Perkin-Elmer)中测量在337nm处激发之后在620nm和665nm处的荧光发射。在665nm和622nm处的发射比率被作为磷酸化底物量的量度。将该数据归一化(没有抑制剂的酶反应=0%抑制,所有其他测定组分但没有酶=100%抑制)。通常,在相同的微量滴定板中以20μM至0.07nM范围内的11种不同的浓度(20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、11nM、3.1nM、0.9nM、0.25nM和0.07nM,在测定之前在DMSO中通过连续稀释100倍浓缩溶液的水平分别制备稀释系列,确切浓度可以根据所使用的移液器而不同)测试受试化合物,每个浓度一式两份,并且使用Genedata ScreenerTM软件计算IC50值。表2显示了突变EGFR生化测定中抑制作用的结果。
表2:
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Bub1高ATP激酶测定
如下面段落中所述,使用Bub1 TR-FRET高ATP激酶测定定量本发明化合物在高ATP浓度下的Bub1抑制活性。
在昆虫细胞(Hi5)中表达并通过Ni-NTA亲和色谱法和随后的尺寸排阻色谱法纯化的人类Bub1的N-末端His6-标记的重组催化结构域(氨基酸704-1085)用作酶。作为激酶反应的底物,使用可以例如从公司Biosyntan(Berlin,Germany)购买的生物素化肽生物素-Ahx-VLLPKKSFAEPG-SEQ ID 5(酰胺形式的C末端)。
对于该测定,将50nl测试化合物在DMSO中的100倍浓缩溶液移液到黑色小体积384孔微量滴定板或黑色1536孔微量滴定板(两个Greiner Bio-One,Frickenhausen,Germany)中,加入3μl的三磷酸腺苷(ATP,3.33mM=>5μl测定体积中的终浓度为2mM)和底物(1.67μM=>5μl测定体积中的终浓度为1μM)在测定缓冲水溶液[50mM Tris/HCl pH 7.5,10mM氯化镁(MgCl2),200mM氯化钾(KCl),1.0mM二硫苏糖醇(DTT),0.1mM正钒酸钠,1%(v/v)甘油,0.01%(w/v)牛血清白蛋白(BSA),0.005%(v/v)Trition X-100(Sigma),1x完全不含EDTA的蛋白酶抑制剂混合物(Roche)]中的溶液。然后通过添加2μl Bub1在测定缓冲液中的溶液开始该激酶反应,并将所得混合物在22℃下孵育60分钟的反应时间。Bub1的浓度根据酶批次的活性进行调整,并适当选择以具有线性范围内的测定(通常浓度为约200ng/ml)。通过添加3μl的TR-FRET检测试剂(0.167μM链霉亲和素-XL665[Cisbio Bioassays,Codolet,France]和1.67nM抗磷酸丝氨酸抗体[Merck Millipore,cat.#35-002]和0.67nM LANCEEU-W1024标记的抗小鼠IgG抗体[Perkin-Elmer,产品编号AD0077,作为替代,可以使用得自Cisbio Bioassays的Tb-穴状化合物标记的抗小鼠IgG抗体])在EDTA水溶液(83.3mM EDTA,0.2%(w/v)牛血清白蛋白,在100mM HEPES中,pH 7.5)中的溶液来停止该反应。
将生成的混合物在22℃下孵育1小时,使磷酸化生物素化肽和检测试剂之间形成复合物。随后,通过测量从Eu螯合物到链霉亲和素-XL的共振能量转移来评估磷酸化底物的量。为此,在TR-FRET读板器如Pherastar或Pherastar FS(两个都得自BMGLabtechnologies,Offenburg,Germany)或Viewlux(Perkin-Elmer)中测量在350nm处激发之后在620nm和665nm处的荧光发射。在665nm和622nm处的发射比率被作为磷酸化底物量的量度。将该数据归一化(没有抑制剂的酶反应=0%抑制,所有其他测定组分但没有酶=100%抑制)。通常,在相同的微量滴定板中以20μM至0.07nM范围内的11种不同的浓度(20μM、5.7μM、1.6μM、0.47μM、0.13μM、38nM、11nM、3.1nM、0.9nM、0.25nM和0.07nM,在测定之前在DMSO中通过连续稀释100倍浓缩溶液的水平分别制备稀释系列,确切浓度可以根据所使用的移液器而不同)测试受试化合物,每个浓度一式两份,并且IC50值通过4参数拟合计算。表3显示了Bub1高ATP激酶测定中抑制作用的结果。
表3:
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本发明的化合物可表现出额外的有利特性,例如与对野生型EGFR的抑制作用相比,对具有外显子20插入的突变EGFR的抑制作用更有效,这可用于降低因过度抑制野生型EGFR引起的潜在毒性。
细胞数据说明(WT,insSVD)
使用得自Promega的Fugene-6转染试剂,用pBABEpuro表达构建体转染得自ATCC的293T细胞,用于WTEGFR或EGFR-insSVD和pCL-Eco包装载体。将板在37℃下孵育48小时。通过0.45μm过滤器过滤培养基上清液,收获逆转录病毒。
从DSMZ购买的Ba/F3细胞在RPMI+10%FBS+10ng/mL IL-3中生长,并用1∶2稀释的过滤逆转录病毒上清液感染。添加聚凝胺至8μg/mL的浓度,将板旋转90分钟,并在37℃下孵育过夜。感染后24小时将2μg/mL嘌呤霉素加入到受感染的细胞中,细胞在嘌呤霉素和10ng/mL IL-3存在下持续生长。产生以下稳定表达的Ba/F3细胞系:Ba/F3-EGFR-WT、Ba/F3-EGFR-insSVD、(Ba/F3-载体-对照)。
对于细胞存活测定,Ba/F3细胞生长至每毫升1-2百万个细胞的密度,离心并重新悬浮在不含IL-3的培养基中,并以每毫升200,000-500,000个细胞的浓度重新铺板。异位表达WT EGFR或EGFR-insSVD的细胞用10ng/mL Millipore培养级EGF铺板。异位表达pBABEpuro空载体的细胞用10ng/mL IL-3铺板。
2天后,对于在IL-3不存下测定的细胞,将细胞以每孔4000个细胞的浓度,以50μL接种在384孔板中,并且对于在IL-3存在下测定的细胞,将细胞以每孔2000个细胞的浓度,以50μL接种在384孔板中。使用100nL针头将100nL化合物添加到每个孔中,并将板在37℃下孵育48小时。
通过加入20μL在PBS中按1∶3稀释的Cell Titer-Glo发光法细胞活力检测试剂,测量细胞活力。将板用Perkin Elmer Top-Seal密封,倒置数次混合,并立即以1000rpm离心2分钟。将板在低光条件下孵育8-10分钟并测量发光。实施例的IC50值显示在表4中。
表4:
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与本发明要求保护的化合物相比,在最接近的现有技术WO 2016/120196中要求保护的化合物没有显示出上述有利的组合特性。这可以在表5中看到。
表5:
细胞数据说明(过表达与insSVD不同的突变EGFR的Ba/F3细胞)
使用得自Promega的Fugene-6转染试剂,用pBABEpuro表达构建体转染得自ATCC的293T细胞,用于突变EGFR(V769_D770insASV、D770_N771insNPG、N771_P772insH、H773_V774insNPH、E746_A750del、L858R、D770_N771insSVD C797S、E746_A750del C797S、L858RC797S、L861Q)或突变ERBB2(A775_G776insYVMA)和pCL-Eco包装载体。将板在37℃下孵育48小时。通过0.45μm过滤器过滤培养基上清液,收获逆转录病毒。
购自DSMZ的Ba/F3细胞在RPMI+10%FBS+10ng/mL IL-3中生长,并用1∶2稀释的过滤后的逆转录病毒上清液感染。添加聚凝胺至8μg/mL的浓度,将板旋转90分钟,并在37℃下孵育过夜。感染后24小时将2μg/mL嘌呤霉素加入到受感染的细胞中,并将细胞在嘌呤霉素和10ng/mL IL-3存在下持续生长。生成以下稳定表达的Ba/F3细胞系:Ba/F3-EGFR-V769_D770insASV、Ba/F3-EGFR-D770_N771insNPG、Ba/F3-EGFR-N771_P772insH、Ba/F3-EGFR-H773_V774insNPH、Ba/F3-EGFR-E746_A750del、Ba/F3-EGFR-L858R、Ba/F3-EGFR-D770_N771insSVD C797S、Ba/F3-EGFR-E746_A750del C797S、Ba/F3-EGFR-L858R C797S、Ba/F3-EGFR L861Q和Ba/F3-ERBB2-A775_G776insYVMA(Ba/F3-载体-对照)。
对于细胞存活测定,Ba/F3细胞生长至每毫升1-2百万个细胞的密度,离心并重新悬浮在不含IL-3的培养基中,并以每毫升200,000-500,000个细胞的浓度重新铺板。异位表达WT EGFR的细胞用10ng/mL Millipore培养级EGF铺板,并且含有突变EGFR或突变ERBB2的Ba/F3细胞在没有EGF的情况下培养。异位表达pBABEpuro空载体的细胞用10ng/mL IL-3铺板。
2天后,对于在IL-3不存下测定的细胞,将细胞以每孔4000个细胞的浓度,以50μL接种在384孔板中,并且对于在IL-3存在下测定的细胞,将细胞以每孔2000个细胞的浓度,以50μL接种在384孔板中。使用100nL针头将100nL化合物添加到每个孔中,并将板在37℃下孵育48小时。
通过加入20μL在PBS中按1∶3稀释的Cell Titer-Glo发光法细胞活力检测试剂,测量细胞活力。将板用Perkin Elmer Top-Seal密封,倒置数次混合,并立即以1000rpm离心2分钟。将板在低光条件下孵育8-10分钟并测量发光。实施例的IC50值显示在表6、7、8和9中。
细胞数据说明(PC9细胞,EGFRex19del)
PC9细胞购自ATCC。将每孔400个PC9细胞接种在384孔板(CORNING#3571)中的生长培养基(DMEM,10%FCS)中。在同一天接种参照板用于时间0测定。将所有板在37℃下孵育过夜。24小时后,使用HP化合物打印机以7步稀释加入测试化合物,并在37℃下孵育72小时。3天后,每孔加入30μL/孔CTG溶液(Promega Cell Titer Glo溶液;目录号#G755B和G756B),孵育30分钟,并在PheraStar上读取该板。在从第4天的值中减去时间0的发光值并与未处理的孔进行比较后计算增殖。
使用四参数拟合确定IC50值。实施例的IC50值显示在表9中。
细胞数据说明(HCC-827细胞,EGFRex19del)
HCC-827细胞购自ATCC。将每孔400个HCC-829细胞接种在384孔板(CORNING#3571)中的生长培养基(RPMI1640,10%FCS)中。在同一天接种参照板用于时间0测定。将所有板在37℃下孵育过夜。24小时后,使用HP化合物打印机以7步稀释加入测试化合物,并在37℃下孵育72小时。3天后,每孔加入30μL/孔CTG溶液(Promega Cell Titer Glo溶液;目录号#G755B和G756B),孵育30分钟,并在PheraStar上读取该板。在从第4天的值中减去时间0的发光值并与未处理的孔进行比较后计算增殖。
使用四参数拟合确定IC50值。实施例的IC50值显示在表9中。
表6:(EGFR外显子20插入突变)
表7:(经典激活和不常见的EGFR突变)
表8:(获得性抗性空间(space))
表9:(ERBB2突变,PC9,HCC-827)
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Claims (42)
1.式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,
其中:
R1代表甲基、乙基、三氟甲基、2,2-二氟乙基、氰基、氯、溴、甲氧基或二氟甲氧基;
R2代表氢、甲基、乙基、氟、氯或溴;
R3代表氢或氟;
R4代表氢或甲基;
R5在每次出现时独立地代表氢、三氟甲基或C1-C3烷基,R5与该环的任何碳原子结合;
R6在每次出现时独立地代表氢、C1-C3-烷基或C1-C3-卤代烷基;
R7代表C1-C3-烷基或C2-C3-卤代烷基;
R8代表C1-C3-烷基或C2-C3-卤代烷基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1、2或3;
n代表0或1。
2.根据权利要求1的式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,其中:
R1代表甲基、乙基、氯、甲氧基或二氟甲氧基;
R2代表甲基、乙基、氟或氯;
R3代表氢或氟;
R4代表氢或甲基;
R5代表氢、甲基或三氟甲基,R5与该环的任何碳原子结合;
R6代表氢、甲基或三氟甲基;
R7代表C1-C2-烷基或C2-C3-氟代烷基;
R8代表C1-C2-烷基或C2-C3-氟代烷基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1或2;
n代表0或1。
3.根据权利要求1或2的式(I)化合物、或所述化合物的N-氧化物、盐或互变异构体,或所述N-氧化物或互变异构体的盐,其中:
R1代表甲基、乙基、氯或甲氧基;
R2代表氟或氯;
R3代表氢或氟;
R4代表氢;
R5代表氢或甲基,R5与该环的任何碳原子结合;
R6代表氢;
R7代表甲基;
R8代表甲基、2,2,2-三氟乙基或2,2-二氟乙基;
X代表NR7或O;
Y代表NR8或O;
m代表0、1或2;
n代表0或1。
4.根据权利要求1至3中任一项的式(I)化合物,所述化合物选自:
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(2,3-二氯苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(3S)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-4-(2,2-二氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[2-(4-二氧杂环己烷-2-基)乙氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{2-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{2-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-5-氟-2-甲氧基苯胺基)-2-(3-{[(2S)-4-(2,2,2-三氟乙基)吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{2-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{2-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-3-(3-氟-2-甲氧基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲氧基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-[2-(2,2-二氟乙基)-3-氟苯胺基]-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(3R)-4-甲基吗啉-3-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-{3-[(5,5-二甲基-1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(3-氟-2-甲基苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-{3-[(1,4-二氧杂环己烷-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-乙基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{1-[1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1S)-1-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1S)-1-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1R)-1-[(2S)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-(3-{(1R)-1-[(2R)-1,4-二氧杂环己烷-2-基]乙氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-{3-[(4-甲基吗啉-2-基)甲氧基]吡啶-4-基}-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-(3-{[(2R)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氟-2-甲基苯胺基)-2-(3-{[(2S)-4-甲基吗啉-2-基]甲氧基}吡啶-4-基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2R)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
2-(3-{[(2S)-5,5-二甲基-1,4-二氧杂环己烷-2-基]甲氧基}吡啶-4-基)-3-(2-乙基-3-氟苯胺基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({1-[4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1R)-1-[(2S)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮
3-(3-氯-2-甲氧基苯胺基)-2-[3-({(1S)-1-[(2R)-4-甲基吗啉-2-基]乙基}氧基)吡啶-4-基]-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮。
5.根据权利要求1至4中任一项的通式(I)化合物在治疗或预防疾病中的用途。
6.根据权利要求5的通式(I)化合物的用途,其中所述疾病是过度增殖性疾病和/或对诱导细胞死亡有响应的病症。
7.根据权利要求6的通式(I)化合物的用途,其中所述过度增殖性疾病和/或对诱导细胞死亡有响应的病症是血液肿瘤、实体瘤和/或其转移瘤。
8.根据权利要求7的式(I)化合物的用途,其中所述肿瘤携带突变EGFR和/或其转移。
9.根据权利要求7的式(I)化合物的用途,其中所述肿瘤是肺癌,特别是携带具有外显子20插入突变的突变EGFR的肺癌,和/或其转移瘤。
10.根据权利要求7的式(I)化合物的用途,其中所述肿瘤是肺癌,特别是携带具有外显子19框内缺失(例如EGFR E746_A750del)或外显子21中点突变(例如L858R)的突变EGFR的肺癌,和/或其转移瘤。
11.根据权利要求7的式(I)化合物的用途,其中所述肿瘤是肺癌,特别是携带具有D770_N771insSVD C797S、E746_A750del C797S或L858R C797S获得性抗性突变的突变EGFR的肺癌,和/或其转移瘤。
12.根据权利要求7的式(I)化合物的用途,其中所述肿瘤是肺癌,特别是携带具有外显子20插入突变的突变ERBB2(例如ERBB2 A775_G776insYVMA)的肺癌,和/或其转移瘤。
13.药物组合物,其包含至少一种根据权利要求1至4中任一项的通式(I)化合物以及至少一种药学上可接受的助剂。
14.根据权利要求13的组合物,其用于治疗血液肿瘤、实体瘤和/或其转移瘤。
15.组合,其包含一种或多种选自根据权利要求1至4中任一项的通式(I)化合物的第一活性成分和一种或多种选自化学治疗性抗癌剂和靶标特异性抗癌剂的第二活性成分。
16.抑制癌细胞中EGF-受体激酶活性的方法,该方法包括使癌细胞与根据权利要求1至4中任一项的通式(I)化合物接触。
17.根据权利要求16的方法,其中所述癌细胞是体外或体内的。
18.降低癌细胞存活或诱导癌细胞死亡的方法,该方法包括使包含EGF-受体突变的癌细胞与根据权利要求1至4中任一项的通式(I)化合物接触。
19.根据权利要求16至18中任一项的方法,其中所述EGF受体包含外显子20中的突变。
20.根据权利要求16至19中任一项的方法,其中所述癌细胞来源于选自白血病、骨髓增生异常综合征、恶性淋巴瘤、头颈部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿系统肿瘤、皮肤肿瘤和肉瘤的癌症。
21.根据权利要求20的方法,其中所述癌细胞来源于选自鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌的癌症。
22.治疗受试者癌症的方法,该方法包括向受试者给药有效量的根据权利要求1至4中任一项的通式(I)化合物。
23.治疗受试者癌症的方法,其中所述癌症对抗EGF受体疗法具有或已经获得抗性,所述方法包括向所述受试者给药有效量的根据权利要求1至4中任一项的通式(I)化合物。
24.增强抗EGF受体疗法效力的方法,该方法包括向受试者施用抗EGF受体疗法与根据权利要求1至4中任一项的通式(I)化合物的组合。
25.根据权利要求22至24中任一项的方法,其中所述癌症选自:白血病、骨髓增生异常综合征、恶性淋巴瘤、头颈部肿瘤、胸部肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿系统肿瘤、皮肤肿瘤和肉瘤。
26.根据权利要求25的方法,其中所述癌症选自鼻腔鼻窦内翻性乳头状瘤或鼻腔鼻窦内翻性乳头状瘤相关的鼻腔鼻窦鳞状细胞癌。
27.根据权利要求25的方法,其中所述胸部肿瘤是非小细胞肺癌。
28.根据权利要求16至27中任一项的方法,其中所述EGF受体包含突变。
29.根据权利要求28的方法,其中所述EGF受体包含外显子20中的突变。
30.根据权利要求29的方法,其中所述EGF受体包含外显子20中的插入。
31.根据权利要求30的方法,其中所述EGF受体包含氨基酸V769-D770之间和/或D770-N771之间的插入。
32.根据权利要求31的方法,其中所述插入是ASV和/或SVD插入。
33.根据权利要求30的方法,其中所述EGF受体包含氨基酸V769-D770之间的ASV插入和/或氨基酸D770-N771之间的SVD插入。
34.选择用根据权利要求1至4中任一项的通式(I)化合物治疗癌症的患者的方法,该方法包括检测受试者生物样品中EGF受体的外显子20中突变的存在,从而确定应该用所述化合物治疗该患者。
35.治疗癌症患者的方法,该方法包括向受试者施用抗EGF受体疗法与根据权利要求1至4中任一项的通式(I)化合物的组合,其中通过检测受试者生物样品中EGF受体的外显子20中突变的存在来选择用于治疗的受试者。
36.根据权利要求34或35的方法,其中所述EGF受体包含外显子20中的插入。
37.根据权利要求36的方法,其中所述EGF受体包含氨基酸V769-D770之间和/或氨基酸D770-N771之间的插入。
38.根据权利要求37的方法,其中所述插入为ASV和/或SVD插入。
39.根据权利要求36的方法,其中所述EGF受体包含氨基酸V769-D770之间的ASV插入和/或氨基酸D770-N771之间的SVD插入。
40.根据权利要求16、18、24、34和35中任一项的方法,其中所述癌症是肺癌,特别是携带具有外显子19框内缺失(例如EGFR E746_A750del)或外显子21中的点突变(例如L858R)的突变EGFR的肺癌,和/或其转移瘤。
41.根据权利要求16、18、24、34和35中任一项的方法,其中所述癌症是肺癌,特别是携带具有D770_N771insSVD C797S、E746_A750del C797S或L858R C797S获得性抗性突变的突变EGFR的肺癌,和/或其转移瘤。
42.根据权利要求16、18、24、34和35中任一项的方法,其中所述癌症是肺癌,特别是携带具有外显子20插入突变的突变ERBB2(例如ERBB2 A775_G776insYVMA)的肺癌,和/或其转移瘤。
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