CN103533835A - S1p调节剂 - Google Patents
S1p调节剂 Download PDFInfo
- Publication number
- CN103533835A CN103533835A CN201280007619.4A CN201280007619A CN103533835A CN 103533835 A CN103533835 A CN 103533835A CN 201280007619 A CN201280007619 A CN 201280007619A CN 103533835 A CN103533835 A CN 103533835A
- Authority
- CN
- China
- Prior art keywords
- methyl
- oxygen base
- piperidines
- naphthalene
- formic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000001301 oxygen Substances 0.000 claims description 359
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- 238000002360 preparation method Methods 0.000 claims description 244
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 108
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- 150000003839 salts Chemical class 0.000 claims description 62
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Abstract
式(I)或(II)的化合物可调节S1P受体的活性。
Description
优先权主张
本申请主张2011年2月7日申请的美国临时专利申请61/440,254的优先权,将所述专利申请的全部内容并入本文作为参考。
技术领域
本发明涉及作为S1P调节剂的化合物以及制备及使用所述化合物的方法。
背景技术
鞘氨醇1-磷酸酯(S1P)为通过刺激内皮细胞分化基因(EDG)受体家族的五个成员而引起多种细胞应答的溶血磷脂介体。EDG受体为G蛋白偶联受体(GPCR),且在刺激后,通过激活异源三聚G蛋白α(Gα)亚基及β-γ(Gβγ)二聚体来传播第二信使信号。最终,这种由S1P驱动的信号传导导致细胞存活、细胞迁移增加且常引起有丝分裂发生。靶向S1P受体的激动剂的新近发展已提供关于此信号传导系统在生理稳态方面的作用的理解。例如,免疫调节剂FTY720(2-氨基-2-[2-(4-辛基苯基)乙基]丙烷1,3-二醇)在磷酸化后为5种S1P受体中的4种S1P受体的激动剂,且披露影响S1P受体活性会影响淋巴细胞移行。此外,S1P第1型受体(S1P1)拮抗剂引起肺毛细血管内皮渗漏,表示S1P可能涉及在一些组织床中维持内皮屏障的完整性。S1P第4型受体(S1P4)主要表达于白细胞中,且具体地,S1P4通过抑制效应细胞因子增殖及分泌,同时增强抑制性细胞因子IL-10分泌来介导S1P的免疫抑制作用。参见例如Wang,W.等人,(2005)FASEB J.19(12):1731-3,将其全部内容并入本文作为参考。S1P第5型受体(S1P5)仅表达于少突胶质细胞及少突胶质细胞前体细胞(OPC)中,且对于细胞迁移而言为重要的。刺激S1P5可抑制OPC迁移,OPC在脑发育期间通常迁移相当长的距离。参见例如Novgorodov,A.等人,(2007)FASEB J,21:1503-1514,将其全部内容并入本文作为参考。
S1P已经表明可诱导许多细胞过程,包括引起血小板聚集、细胞增殖、细胞形态、肿瘤细胞浸润、内皮细胞趋化性及血管生成的细胞过程。出于这些原因,S1P受体为治疗性应用(诸如伤口愈合、肿瘤生长抑制及自身免疫疾病)的良好标靶。
鞘氨醇-1-磷酸酯部分地通过一组称为S1P1、S1P2、S1P3、S1P4及S1P5(以前称为EDG1、EDG5、EDG3、EDG6及EDG8)的G蛋白偶联受体对细胞进行信号传导。EDG受体为G蛋白偶联受体(GPCR),且在刺激后,通过激活异源三聚G蛋白α(Gα)亚基及β-γ(Gβγ)二聚体来传播第二信使信号。这些受体共享50%至55%氨基酸序列一致性且与结构上相关的溶血磷脂酸(LPA)的其它三种受体(LPA1、LPA2及LPA3(以前称为EDG2、EDG4及EDG7))簇集。
当配体结合至G蛋白偶联受体(GPCR)时,诱导所述受体出现构象转变,使得在缔合的G蛋白的α亚基上GDP由GTP置换,且继而将G蛋白释放至细胞质中。α亚基接着与βγ亚基解离且各亚基接着可与活化第二信使的效应蛋白缔合,引起细胞应答。最终,G蛋白上的GTP水解成GDP且G蛋白的亚基与彼此再缔合且接着与受体再缔合。放大作用在一般GPCR路径中起主要作用。一个配体结合至一个受体会引起许多G蛋白活化,所述G蛋白各自能够与许多效应蛋白缔合,引起放大的细胞应答。
由于各个S1P受体具有组织特异性及应答特异性,所以S1P受体成为良好的药物标靶。S1P受体的组织特异性合乎需要,因为针对一种受体具有选择性的激动剂或拮抗剂的研发可将细胞应答局限于含有所述受体的组织,从而限制不需要的副作用。S1P受体的应答特异性也为重要的,因为其使得研发引发或抑制某些细胞应答而不影响其它应答的激动剂或拮抗剂成为可能。例如,S1P受体的应答特异性使得引发血小板聚集而不影响细胞形态的S1P模拟剂成为可能。
鞘氨醇-1-磷酸酯在它与鞘氨醇激酶反应中作为鞘氨醇代谢物形成,且丰富地储存于存在高含量的鞘氨醇激酶且缺乏鞘氨醇裂解酶的血小板聚集物中。S1P在血小板聚集期间释放,积聚于血清中且也见于恶性腹水中。S1P的可逆生物降解最可能通过外磷酸水解酶(ectophosphohydrolase),具体地,鞘氨醇-1-磷酸酯磷酸水解酶导致的水解而进行。S1P的不可逆降解由S1P裂解酶催化,得到磷酸乙醇胺及十六碳烯醛。
发明内容
在一方面中,化合物可具有式(I):
其中:
A1可为-CH=或-N=;A2可为-CH=或-N=;A3可为-CH2-、-CH=或-N=;A4可为-CH2-、-CH=或-N=;A5可为-CH2-、-CH=或-N=;且A6可为-CH=或-N=。
W可为-O-、=CR5-或-CHR5-。
R5可为氢、卤素、烷基或卤代烷基。
Cy可为4元至7元环烷基、4元至7元环烯基,或Cy可为具有1个可为O的杂原子的杂环烷基;其中Cy可任选经1至4个R1取代。各R1可独立地为卤素、烷基、卤代烷基、羟烷基、环烷基、三烷基甲硅烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基。或两个R1一起可为C1至C5亚烷基。
L1可为-C(O)-或-C(R3)2-。各R3可独立地为氢、烷基或卤代烷基。
x可为0、1、2、3、4或5;y可为0、1、2、3、4或5;其中x与y的和为4或5。
各Ra及各Rb可独立地为氢、卤素、羟基、-CO2Rc、烷基或芳基。
R2可为-(CH2)n-CO2Rc,其中n为0或1。Rc可为氢、烷基、卤代烷基、环烷基或芳基。
式(I)不包括以下化合物:1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-4-甲酸、1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3R-甲酸及1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3S-甲酸。
化合物可呈药学上可接受的盐形式。
在一些实施方案中,Cy可为4元至7元环烷基或Cy可为具有1个可为O的杂原子的杂环烷基;其中Cy可任选经1至4个R1取代,其中各R1可独立地为卤素、烷基、卤代烷基、环烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起为C2至C5亚烷基;各Ra及各Rb可独立地为氢、卤素、羟基、烷基或芳基。
在一些实施方案中,A1、A2、A3、A4、A5及A6中的不多于两个可为-N=。
当A1为-CH=时,A2可为-CH=且A5可为-CH=。在一些实施方案中,A1、A2、A3、A4、A5及A6可为-CH=。当A3为-CH=时,A4可为-CH=且A5可为-CH=;或当A3为-N=时,A4可为-CH=且A5可为-CH=;或当A3为-N=时,A4可为-N=且A5可为-CH=;或当A2为-N=时,A6可为-N=;或当A1为-N=时,A6可为-N=;或当A3为-CH2-时,A4可为-CH2-且A5可为-CH2-。
x与y的和可为4。x可为2且y可为2。
Cy可为二环或螺二环。Cy可具有下式:
一个R1可为氢且其它R1可为乙基、异丙基、正丁基或叔丁基;或两个R1一起可为C2至C5亚烷基。Cy可具有下式:
L1可为-C(R3)2-,其中至少一个R3为氢。L1可为-CH2-。
W可为-O-。
在一些情况下,A1可为-CH=,A2可为-CH=,A3可为-CH=,A4可为-CH=,A5可为-CH=,且A6可为-CH=;L1可为-C(R3)2-,其中至少一个R3可为氢;x与y的和可为4;Cy具有下式:
W可为-O-。
在另一方面中,化合物或其药学上可接受的盐可选自:1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸;1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸;1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(顺式-4-叔丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸;1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;1-((2-(反式-4-叔丁基环己基氧基)喹啉-6-基)甲基)哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-丙基-哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-苯基-哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-全氢-氮杂-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-羟基-哌啶-4-甲酸;{1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-4-基}-乙酸;1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸;1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-2-甲酸;1-((6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸;1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸;1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸;1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸;1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸;2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸;1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸;1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸;1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;1-[6-(1,3,3-三甲基-二环[2.2.1]庚-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸;1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸;1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸;及1-((6-(((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸。
化合物可对S1P受体(例如S1P4受体、S1P1受体或S1P5受体)具有选择性。化合物对S1P4受体的亲和力可为对S1P1受体、S1P2受体、S1P3受体或S1P5受体的亲和力的至少5倍。化合物可对一种或多种S1P受体具有作为受体激动剂或受体拮抗剂的活性。
在另一方面中,一种药物组合物可包括式(I)或(II)的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂或载体。
在另一方面中,提供一种预防或治疗哺乳动物的涉及S1P受体活性的病理性病症或症状的方法,其包括给予所述哺乳动物有效量的式(I)或(II)的化合物或其药学上可接受的盐。
在另一方面中,式(I)或(II)化合物或其药学上可接受的盐可促进髓鞘形成或髓鞘再生。治疗方法可包括给予细胞式(I)或(II)的化合物以促进髓鞘形成或髓鞘再生。
在另一方面中,预防或治疗以下疾病的方法可包括给予所述哺乳动物有效量的式(I)或(II)的化合物或其药学上可接受的盐:多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病(Crohn's disease)、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
在另一方面中,预防或治疗哺乳动物的神经病的方法包括给予所述哺乳动物有效量的式(I)或(II)的化合物或其药学上可接受的盐。所述神经病可为阿尔茨海默病(Alzheimer's disease)、帕金森病(Parkinson's disease)、亨廷顿病(Huntington's disease)、运动神经元病、肌萎缩侧索硬化、多发性硬化、神经元创伤或脑缺血症。病理性病症的预防或治疗可包括多发性硬化的髓鞘再生及轴突再生、阻断星形胶质化(astrogliosis)或神经炎症相关疾病的微神经胶质活化。
在另一方面中,预防或治疗哺乳动物的神经性疼痛的方法包括给予所述哺乳动物有效量的式(I)或(II)的化合物或其药学上可接受的盐。
在另一方面中,预防或治疗哺乳动物的自身免疫疾病的方法包括给予所述哺乳动物有效量的式(I)或(II)的化合物或其药学上可接受的盐。
在另一方面中,提供式(I)或(II)的化合物或其药学上可接受的盐,其用于治疗或预防多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
在另一方面中,提供式(I)或(II)的化合物或其药学上可接受的盐用于制备药物的用途,所述药物用于治疗或预防多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
根据以下对若干实施方案的详细说明以及所附权利要求,其它特征或优点将为显而易见的。
具体实施方式
所披露的化合物可对一种或多种S1P受体具有作为受体激动剂或受体拮抗剂的活性。具体地,所述化合物可为S1P4拮抗剂。
化合物可具有式(I):
其中:
A1可为-CH=或-N=,A2可为-CH=或-N=,A3可为-CH2-、-CH=或-N=,A4可为-CH2-、-CH=或-N=,A5可为-CH2-、-CH=或-N=,且A6可为-CH=或-N=。W可为-O-、=CR5-或-CHR5-。R5可为氢、卤素、烷基或卤代烷基。
Cy可为4元至7元环烷基、4元至7元环烯基或具有1个为O的杂原子的4元至7元杂环烷基;其中Cy任选经1至4个R1取代,其中各R1可独立地为卤素、烷基、卤代烷基、羟烷基、环烷基、三烷基甲硅烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起可为C1至C5亚烷基。
L1可为-C(O)-或-C(R3)2-。各R3可独立地为氢、烷基或卤代烷基。x可为0、1、2、3、4或5,且y可为0、1、2、3、4或5,其中x与y的和为4或5。
各Ra及各Rb可独立地为氢、卤素、羟基、-CO2Rc、烷基或芳基。
R2可为-(CH2)nCO2Rc,其中n为0或1。Rc可为氢、烷基、卤代烷基、环烷基或芳基。
式(I)不包括以下化合物:1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-4-甲酸;1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3R-甲酸;及1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3S-甲酸。
化合物可呈药学上可接受的盐形式。
在一些状况下,各R1独立地为卤素、烷基、卤代烷基、环烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起为C2至C5亚烷基;各Ra及各Rb独立地为氢、卤素、羟基、烷基或芳基;且R2为-(CH2)n-CO2Rc。
在一些状况下,A1、A2、A3、A4、A5及A6中的不多于两个为-N=。在一些状况下,A1、A2、A3、A4、A5及A6为-CH=。在某些化合物中,A1为-CH=,A2为-CH=且A5为-CH=。在一些化合物中,A1、A2、A3、A4、A5及A6为-CH=。在一些化合物中,以下中的一个适用:A3为-CH=,A4为-CH=且A5为-CH=;或A3为-N=,A4为-CH=且A5为-CH=;或A3为-N=,A4为-N=且A5为-CH=;或A2为-N=且A6为-N=;或A1为-N=且A6为-N=;或A3为-CH2-,A4为-CH2-且A5为-CH2-。
x与y的和可为4,例如当x为2且y为2时。
Cy可为二环或螺二环,例如当两个R1一起为C2至C5亚烷基时。在此状况下,若两个R1连接至不同原子,则Cy为二环;若两个R1连接至同一原子,则Cy为螺二环。Cy可具有下式:
在一些状况下,一个R1可为氢且其它R1可为乙基、异丙基、正丁基或叔丁基,或两个R1一起可为C2至C5亚烷基。
L1可为-C(R3)2-,其中至少一个R3为氢。L1可为-CH2-。
W可为-O-。
在一些实施方案中,W为-O-且Cy具有下式:
在一些实施方案中,A1、A2、A3、A4、A5及A6各自为-CH=;L1为-C(R3)2-,其中至少一个R3为氢;x与y的和为4;Cy具有下式:
W为-O-。
在一些状况下,Cy可具有下式:
化合物可具有式(II):
其中:
A3、A4及A6各自独立地为-CH=或-N=;
W为-O-、=CR5-或-CHR5-;
R5为氢、卤素、烷基或卤代烷基;
Cy为4元至7元环烷基或具有1个为O的杂原子的4元至7元杂环烷基;其中Cy任选经1至4个R1取代;
各R1独立地为卤素、烷基、卤代烷基、环烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起为C2至C5亚烷基;
R3为氢、烷基或卤代烷基;
Cy2为6元或7元环烷基;
各Ra独立地为氢、卤素、羟基、烷基或芳基;
R2为-(CH2)n-CO2Rc,其中n为0或1;Rc为氢、烷基、卤代烷基、环烷基或芳基;
前提条件为:所述化合物不为1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-4-甲酸、1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3R-甲酸或1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3S-甲酸;
或其药学上可接受的盐。
在一些状况下,A3、A4及A6中的不多于两个为-N=。例如,在某些实施方案中,当A3为-N=时,A4可为-N=或-CH=且A6可为-CH=;当A4为-N=时,A3可为-N=或-CH=,且A6可为-CH=;或当A6为-N=时,A3可为-CH且A4可为-CH=。
Cy可具有下式:
在一些状况下,一个R1可为氢且其它R1可为乙基、异丙基、正丁基或叔丁基,或两个R1一起可为C2至C5亚烷基。
在一些实施方案中,W为-O-且Cy具有下式:
在一实施方案中,本发明提供式II化合物或其药学上可接受的盐,其中:
A3、A4及A6各自独立地为-CH=;
W为-O-;
R1为卤素、烷基、卤代烷基或环烷基;
R3为氢;
Cy2为哌啶基;
各Ra独立地为氢、卤素、羟基、烷基或芳基;
R2为-(CH2)n-CO2Rc,其中n为0或1;Rc为氢或烷基。
所述化合物可为:
1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸;
1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸;
1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(顺式-4-叔丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸;
1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;
1-((2-(反式-4-叔丁基环己基氧基)喹啉-6-基)甲基)哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-丙基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-苯基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-羟基-哌啶-4-甲酸;
{1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-4-基}-乙酸;
1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸;
1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;
1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-2-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸;
1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸;
1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸;
1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸;
1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸;
2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸;
1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;
1-[6-(1,3,3-三甲基-二环[2.2.1]庚-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;
1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸;
1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸;
1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸;或
1-((6-(((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
或其药学上可接受的盐。
本申请使用的术语“烷基”是指完全饱和的支链的或无支链的烃部分。烷基优选包含1至20个碳原子,更优选包含1至16个碳原子、1至10个碳原子、1至6个碳原子或1至4个碳原子。烷基的代表性实例包括(但不限于)甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基或正癸基。
“亚烷基”是指二价烷基。亚烷基的实例包括亚甲基、亚乙基、亚丙基、亚正丁基等。亚烷基通过单键连接至分子其余部分且通过单键连接至基团。亚烷基与分子其余部分和与基团的连接点可通过碳链内的一个碳或任何两个碳。
本申请使用的术语“卤代烷基”是指经如本文所定义的一个或多个卤素取代的如本文所定义的烷基。卤代烷基优选可为单卤代烷基、二卤代烷基或多卤代烷基(包括全卤代烷基)。单卤代烷基可具有一个碘、溴、氯或氟取代基。二卤代烷基及多卤代烷基可经两个或两个以上相同卤素原子或不同卤素的组合取代。卤代烷基的非限制性实例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基及二氯丙基。全卤代烷基是指所有氢原子全部经卤素原子置换的烷基。优选的卤代烷基为三氟甲基及二氟甲基。
“卤素”或“卤代”可为氟、氯、溴或碘。
本申请使用的术语“羟烷基”是指经一个或多个羟基(也即-OH)取代的烷基。
本申请使用的术语“烯基”是指具有至少一个双键的烯属不饱和支链或直链基团。烯基包括(但不限于)1-丙烯基、2-丙烯基、1,3-丁二烯基、1-丁烯基、己烯基、戊烯基、己烯基、庚烯基、辛烯基等。
本申请使用的术语“烷氧基”是指烷基-O-,其中烷基定义于上文中。烷氧基的代表性实例包括(但不限于)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基、环丙氧基-、环己基氧基-等。烷氧基优选具有约1至6个碳原子,更优选具有约1至4个碳原子。
本申请使用的术语“卤代烷氧基”是指卤代烷基-O-,其中卤代烷基定义于上文中。卤代烷氧基的代表性实例为三氟甲氧基、二氟甲氧基及1,2-二氯乙氧基。优选地,卤代烷氧基具有约1至6个碳原子,更优选具有约1至4个碳原子。
本申请使用的术语“烷氧基烷基”是指经一个或多个如本文所定义的烷氧基取代的如本文所定义的烷基。
本申请使用的术语“碳环基”是指饱和或部分不饱和(而非芳族)的单环、二环或三环烃基,其具有3至14个碳原子,优选具有3至9个碳原子,或更优选具有3至8个碳原子。碳环基包括稠合、桥连或螺环系统。术语“碳环基”涵盖环烷基。术语“环烷基”是指完全饱和的单环、二环或三环烃基,其具有3至12个碳原子,优选具有3至9个碳原子,或更优选具有3至8个碳原子。示例性单环碳环基包括(但不限于)环丙基、环丁基、环戊基、环戊烯基、环己基或环己烯基。示例性二环碳环基包括冰片基、十氢萘基、二环[2.1.1]己基、二环[2.2.1]庚基、二环[2.2.1]庚烯基、6,6-二甲基二环[3.1.1]庚基、2,6,6-三甲基二环[3.1.1]庚基或二环[2.2.2]辛基。示例性三环碳环基包括金刚烷基。
本申请使用的术语“卤代环烷基”是指经一个或多个如本文所定义的卤素取代的如本文所定义的环烷基。卤代环烷基优选可为单卤代环烷基、二卤代环烷基或多卤代环烷基(包括全卤代环烷基)。单卤代环烷基可具有一个碘、溴、氯或氟取代基。二卤代环烷基及多卤代环烷基可经两个或两个以上相同卤素原子或不同卤素的组合取代。
本申请使用的术语“环烯基”是指烯属不饱和单环、二环或三环烃基,其具有3至12个碳原子,优选具有3至9个碳原子,或更优选具有3至8个碳原子且具有一个或多个双键。示例性单环环烯基包括(但不限于)环戊烯基、环戊二烯基、环己烯基等。示例性二环环烯基包括(但不限于)二环[2.2.1]庚-5-烯基及二环[2.2.2]辛-2-烯基。
本申请使用的术语“环烷氧基”是指环烷基-O-,其中环烷基定义于上文中。
本申请使用的术语“卤代环烷氧基”是指卤代环烷基-O-,其中卤代环烷基定义于上文中。
本申请使用的术语“环烷氧基烷基”是指经一个或多个如本文所定义的环烷氧基取代的如本文所定义的烷基。
本申请使用的术语“二环”或“二环系统”可包括稠环系统、桥环系统或螺环系统。
本申请使用的术语“稠环系统”为具有两个或三个共享一侧的独立地选自碳环基、杂环基、芳基或杂芳基环的环(优选两个环)的环系统。稠环系统可具有4至15个环成员,优选具有5至10个环成员。稠环系统的实例包括八氢异喹啉-2(1H)-基、2,3-二氢-1H-茚基、八氢-1H-吡啶并[1,2-a]吡嗪基及十氢异喹啉基。
本申请使用的术语“桥环系统”为具有碳环基或杂环基环的环系统,其中所述环的两个不相邻原子由一个或多个(优选一个至三个)原子连接(桥连)。桥环系统在环系统内可具有一个以上桥键(例如金刚烷基)。桥环系统可具有6至10个环成员,优选具有7至10个环成员。桥环系统的实例包括金刚烷基、9-氮杂二环[3.3.1]壬-9-基、8-氮杂二环[3.2.1]辛基、二环[2.2.2]辛基、3-氮杂二环[3.1.1]庚基、二环[2.2.1]庚基、(1R,5S)-二环[3.2.1]辛基、3-氮杂二环[3.3.1]壬基及二环[2.2.1]庚基。更优选地,桥环系统选自:9-氮杂二环[3.3.1]壬-9-基、8-氮杂二环[3.2.1]辛基及二环[2.2.2]辛基。
本申请使用的术语“螺环系统”为具有两个各自独立地选自碳环基或杂环基的环的环系统,其中所述两个环结构共同具有一个原子。螺环系统具有5至14个环成员。螺环系统的实例包括2-氮杂螺[3.3]庚基、螺戊基、2-氧杂-6-氮杂螺[3.3]庚基、2,7-二氮杂螺[3.5]壬基、2-氧杂-7-氮杂螺[3.5]壬基、6-氧杂-9-氮杂螺[4.5]癸基、6-氧杂-2-氮杂螺[3.4]辛基、5-氮杂螺[2.3]己基及2,8-二氮杂螺[4.5]癸基。
术语“芳基”是指在环部分中具有6至14个碳原子的单环、二环或三环芳族烃基。在一实施方案中,术语芳基是指具有6至10个碳原子的单环及二环芳族烃基。芳基的代表性实例包括苯基、萘基、芴基及蒽基。
术语“芳基”也指至少一个环为芳环且稠合至一或两个非芳族烃环的二环或三环基团。非限制性实例包括四氢萘、二氢萘基及茚满基。
本申请使用的术语“杂环基”是指饱和或不饱和的非芳族单环、二环或三环系统,其具有3至15个环成员,其中至少一个环成员为杂原子,且其中至多10个环成员可为杂原子,其中所述杂原子独立地选自O、S及N,且其中N及S可任选氧化成各种氧化态。在一实施方案中,杂环基为3元至8元单环杂环基。在另一实施方案中,杂环基为6元至12元二环杂环基。在另一实施方案中,杂环基为10元至15元三环系统。杂环基可在杂原子或碳原子上连接。杂环基包括稠环或桥环系统。术语“杂环基”涵盖杂环烷基。术语“杂环烷基”是指包含3至15个环成员的完全饱和的单环、二环或三环杂环基,其中至少一个环成员为杂原子,且其中至多10个环成员可为杂原子,其中所述杂原子独立地选自O、S及N,且其中N及S可任选氧化成各种氧化态。杂环基的实例包括二氢呋喃基、[1,3]二氧杂环戊烷、1,4-二噁烷、1,4-二噻烷、哌嗪基、1,3-二氧杂环戊烷、咪唑烷基、咪唑啉基、吡咯烷、二氢吡喃、氧硫杂环戊烷、二硫杂环戊烷、1,3-二噁烷、1,3-二噻烷基、氧硫杂环己烷基、硫代吗啉基、环氧乙基、氮丙啶基、氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、吗啉基、哌嗪基、氮杂基、氧杂基、氧氮杂基及二氮杂基。
本申请使用的术语“螺杂环烷基”为与所连接的基团共同具有一个环原子的杂环烷基。螺杂环烷基可具有3至15个环成员。在一优选实施方案中,螺杂环烷基具有3至8个选自碳、氮、硫及氧的环原子且为单环螺杂环烷基。
本申请使用的术语“杂芳基”是指5元至14元单环、二环或三环系统,其具有1至10个独立地选自N、O或S的杂原子,其中N及S可任选氧化成各种氧化态且其中环系统中的至少一个环为芳环。在一实施方案中,杂芳基为单环杂芳基且具有5或6个环成员。单环杂芳基的实例包括吡啶基、噻吩基、呋喃基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基及四唑基。在另一实施方案中,杂芳基为二环杂芳基且具有8至10个环成员。二环杂芳基的实例包括吲哚基、苯并呋喃基、喹啉基、异喹啉基、吲唑基、吲哚啉基、异吲哚基、吲嗪基、苯并咪唑基、喹啉基、5,6,7,8-四氢喹啉及6,7-二氢-5H-吡咯并[3,2-d]嘧啶。
氨基为具有式NH2-的基团。术语N-烷基氨基为一个氢原子经烷基置换的氨基。术语N,N-二烷基氨基为各氢原子经可能相同或不同的烷基置换的氨基。
术语“三烷基甲硅烷基”是指(烷基)3-Si-,其中各烷基可能相同或不同。
基团中的碳原子数目在本文中由前缀“Cx-xx”说明,其中x及xx为整数。例如,“C1-4烷基”为具有1至4个碳原子的烷基;C1-6烷氧基为具有1至6个碳原子的烷氧基;C6-10芳基为具有6至10个碳原子的芳基;且C1-4卤代烷基为具有1至4个碳原子的卤代烷基。
所披露的化合物在分子中可含有一个或多个不对称中心。根据本发明,未指定立体化学的任何结构应理解为涵盖呈纯或实质上纯形式的所有各种光学异构体(例如非对映异构体及对映异构体),以及其混合物(诸如外消旋混合物或对映异构富集混合物)。在本领域中熟知如何制备所述光学活性形式(例如,通过重结晶技术拆分外消旋形式、自光学活性起始物质合成、通过手性合成或使用手性固定相色谱分离)。化合物可为同位素标记化合物,例如包括氢、碳、氮、氧、磷、氟、碘或氯的各种同位素的化合物。所披露的化合物可以互变异构形式及混合物形式存在且涵盖分离的各个互变异构体。另外,一些化合物可展现多态现象。
式(I)或(II)化合物可调节S1P受体的活性。式(I)或(II)化合物可具有S1P受体激动剂或拮抗剂活性。化合物对S1P4受体可具有选择性。化合物可为选择性S1P4拮抗剂。具有选择性可意味着化合物结合至复杂混合物中的受体(或相对小的相关分子或蛋白质群组),或换句话说,当暴露于多种密切相关的受体类型时,化合物可仅优先地结合至一种受体类型。化合物对S1P4受体的亲和力可为对S1P1受体、S1P2受体、S1P3受体或S1P5受体的亲和力的至少100倍、至少50倍、至少10倍、至少5倍或至少2倍。
具有S1P4介导的活性的抑制剂可阻断S1P与S1P4受体相互作用。例如,所述抑制剂可为S1P4受体拮抗剂。拮抗剂可为对受体具亲和力但不诱导受体的活性或特异性活性的分子。拮抗剂可以小于1μM、小于750nM、小于500nM、小于250nM或小于100nM的IC50值与S1P4受体结合。拮抗剂可以1nM至1μM、1nM至500nM、10nM至250nM、25nm至100nM或50nM至100nM范围内的IC50值与S1P4受体结合。
所述化合物也可促进少突胶质细胞祖细胞分化。所述化合物可促进髓鞘形成或髓鞘再生。
“S1P调节剂”是指能够体内或体外诱导S1P受体活性出现可检测改变的化合物或组合物(例如,S1P活性增加或降低至少10%,如由给定分析如实施例中所述且在本领域中已知的生物分析所测量)。除非指示特定亚型,否则“S1P受体”是指所有S1P受体亚型(例如S1P受体S1P1、S1P2、S1P3、S1P4或S1P5)。在本领域中熟知如何使用本文所述的标准测试或使用在本领域中熟知的其它类似测试测定S1P激动剂或拮抗剂活性。在一些状况下,视所用细胞类型及条件而定,S1P调节剂可具有激动剂或拮抗剂活性,甚至对同一受体亚型。
S1P调节剂的生物作用可视化合物具有S1P受体激动剂或者拮抗剂活性而不同。S1P调节剂的潜在用途包括(但不限于)预防或治疗哺乳动物的病理性病症或症状。例如,病症可包括哮喘、炎症性神经病、关节炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病或胰岛素依赖型糖尿病及非胰岛素依赖型糖尿病。作为治疗神经性疼痛、炎症诱发性疼痛(例如其中涉及前列腺素)或治疗自身免疫病理学(诸如葡萄膜炎、I型糖尿病、类风湿性关节炎、慢性炎症性障碍、炎性肠病(例如克罗恩病及溃疡性结肠炎)、多发性硬化)的方法以及在药物洗脱支架中,所述化合物可改变淋巴细胞移行。其它用途可包括治疗脑退化性疾病、心脏病、癌症或丙型肝炎。参见例如WO2005/085295、WO2004/010987、WO03/097028及WO2006/072562,将其全部内容并入本文作为参考。一类S1P受体激动剂描述于2007年8月15日申请的美国临时申请60/956,111及2008年8月15日申请的PCT/US2008/073378中,将其全部内容并入本文作为参考。也参见2009年8月5日申请的美国临时申请61/231,539及2010年8月5日申请的PCT/US2010/44607中,将其全部内容并入本文作为参考。
S1P调节剂的其它潜在用途包括(但不限于)预防或治疗哺乳动物的病理性病症或症状。例如,病症可包括少突胶质细胞前体细胞(OPC)的细胞迁移受抑制。S1P受体拮抗剂及S1P4受体型选择性拮抗剂的潜在用途尤其包括(但不限于)预防或治疗哺乳动物的病理性病症或症状。
“治疗”多发性硬化包括治疗所述疾病的各种形式,包括复发-缓解型多发性硬化、慢性进行性多发性硬化,且S1P受体激动剂/拮抗剂可单独使用或连同其它减轻所述疾病的体征及症状以及预防所述疾病的药剂一起使用。
另外,作为延长同种异体移植存活期(例如移植,包括实体器官移植)、治疗移植物抗宿主疾病、骨髓移植等方法,所披露的化合物可用于改变淋巴细胞移行。
另外,所披露的化合物可适用于抑制S1P裂解酶。S1P裂解酶为一种不可逆地降解S1P的细胞内酶。抑制S1P裂解酶会干扰淋巴细胞移行,同时伴随淋巴细胞减少。因此,S1P裂解酶抑制剂可适用于调节免疫系统功能。因此,所披露的化合物可用于抑制S1P裂解酶。此抑制作用可与对S1P受体的活性协作或与对任何S1P受体的活性无关。
另外,所披露的化合物可适用作大麻类CB1受体的拮抗剂。拮抗CB1与体重减轻及血液脂质概况改善有关。拮抗CB1可与对S1P受体的活性协作或与对任何S1P受体的活性无关。
另外,所披露的化合物可适用于抑制IVA群组胞溶质PLA2(cPLA2)。cPLA2催化花生酸(例如花生四烯酸)释放。花生酸转化成促炎性类花生酸(诸如前列腺素及白细胞三烯)。因此,所披露的化合物可用作消炎剂。此抑制作用可与对S1P受体的活性协作或与对任何S1P受体的活性无关。
另外,所披露的化合物可适用于抑制多底物脂质激酶(MuLK)。MuLK高表达于许多人类肿瘤细胞中,且因此对它进行抑制可能减缓肿瘤生长或扩散。
药物组合物可包括式(I)或(II)的化合物。更具体地,所述化合物可使用为本领域技术人员所知的药学上可接受的标准载体、填充剂、增溶剂及稳定剂配制成药物组合物。例如,使用包括如本文所述的式(I)或(II)化合物或其盐、类似物、衍生物或修饰物的药物组合物给予受试者适当化合物。
式(I)或(II)的化合物适用于治疗疾病或障碍,包括给予有需要的受试者治疗学上可接受的量的式(I)或(II)化合物,或包含治疗有效量的式(I)或(II)化合物及药学上可接受的载体的药物组合物。
式(I)或(II)的化合物可与至少一种其它活性成分组合使用,诸如用于治疗多发性硬化的药物,诸如、反丁烯二酸二甲酯、干扰素(诸如聚乙二醇化或非聚乙二醇化干扰素,优选为干扰素β-1a或聚乙二醇化干扰素β-1a)、醋酸格拉默(glatiramer acetate)、改善血管功能的化合物、免疫调节剂(诸如芬戈莫德(Fingolimod)、环孢素(cyclosporin)、雷帕霉素(rapamycin)或子囊霉素(ascomycin),或其免疫抑制类似物,例如环孢素A、环孢素G、FK-506、ABT-281、ASM981、雷帕霉素、40-O-(2-羟基)乙基-雷帕霉素等);皮质类固醇;环磷酰胺(cyclophosphamide);硫唑嘌呤(azathioprine);米托蒽醌(mitoxanthrone)、甲胺喋呤(methotrexate);来氟米特(leflunomide);咪唑立宾(mizoribine);霉酚酸(mycophenolicadd);霉酚酸吗乙酯(mycophenolatemofetil);15-脱氧司加林(15-deoxyspergualine);戊酸二氟米松(diflucortolonevalerate);二氟泼尼酯(difluprednate);二丙酸阿氯米松(Alclometasonedipropionate);安西奈德(amcinonide);安吖啶(amsacrine);天冬酰胺酶;硫唑嘌呤;巴利昔单抗(basiliximab);二丙酸倍氯米松(beclometasonedipropionate);倍他米松(betamethasone);二丙酸倍他米松;磷酸倍他米松钠盐;戊酸倍他米松;布地奈德(budesonide);卡托普利(captopril);盐酸氮芥(chlormethinechlorhydrate);丙酸氯倍他索(clobetasolpropionate);醋酸可的松(cortisoneacetate);可的伐唑(cortivazol);环磷酰胺;阿糖胞苷(cytarabine);达珠单抗(daclizumab);放线菌素(dactinomycine);地奈德(desonide);去羟米松(desoximetasone);地塞米松(dexamethasone);醋酸地塞米松;异烟酸地塞米松;间磺基苯甲酸地塞米松钠盐;磷酸地塞米松;叔丁乙酸地塞米松;醋酸二氯松(dichlorisoneacetate);盐酸多柔比星(doxorubicineechlorhydrate);盐酸表柔比星(epirubicinechlorhydrate);氟氯奈德(flucloroloneacetonide);醋酸氟氢可的松(fludrocortisoneacetate);氟氢缩松(fludroxycortide);特戊酸氟米松(flumetasonepivalate);氟尼缩松(flunisolide);氟轻松(fluocinoloneacetonide);醋酸氟轻松(fluocinonide);氟可龙(fluocortolone);己酸氟可龙;特戊酸氟可龙;氟米龙(fluorometholone);乙酸氟泼尼定(fluprednideneacetate);丙酸氟替卡松(fluticasonepropionate);盐酸吉西他滨(gemcitabinechlorhydrate);哈西奈德(halcinonide);氢化可的松(hydrocortisone);醋酸氢化可的松;丁酸氢化可的松;半丁二酸氢化可的松;美法仑(melphalan);甲泼尼松(meprednisone);巯基嘌呤(mercaptopurine);甲泼尼龙(methylprednisolone);乙酸甲泼尼龙;半丁二酸甲泼尼龙;米索前列醇(misoprostol);莫罗单抗(muromonab)-cd3;霉酚酸吗乙酯;乙酸帕拉米松(paramethansoneacetate);泼那唑啉(prednazoline)、泼尼龙(prednisolone);醋酸泼尼龙;己酸泼尼龙;间磺基苯甲酸泼尼龙钠盐;磷酸泼尼龙钠盐;强的松(prednisone);泼尼立定(prednylidene);利福平(rifampicine);利福平钠盐;他克莫司(tacrolimus);特立氟胺(teriflunomide);沙立度胺(thalidomide);硫替派(thiotepa);特戊酸替可的松(tixocortolpivalate);曲安西龙(triamcinolone);半丁二酸曲安奈德(triamcinoloneacetonidehemisuccinate);苯曲安奈德(triamcinolonebenetonide);二乙酸曲安西龙;己曲安奈德(triamcinolonehexacetonide);免疫抑制性单克隆抗体,例如针对白细胞受体的单克隆抗体,例如针对MHC、CD2、CD3、CD4、CD7、CD20(例如利妥昔单抗(rituximab)及奥克丽珠单抗(ocrelizumab))、CD25、CD28、B7、CD40、CD45、CD56(例如达珠单抗)或CD58或其配体的单克隆抗体;或其它免疫调节化合物,例如CTLA41g,或其它粘附分子抑制剂,例如mAb或低分子量抑制剂,包括选择素拮抗剂及VLA-4拮抗剂(诸如);髓鞘再生剂,诸如BIIB033。式(I)或式(II)的化合物也可与治疗多发性硬化的症状的药剂(诸如胺吡啶(fampridine))组合使用。
轴突及树突可自神经元延伸。延伸的轴突或神经突的远端顶部可包括称为生长锥的特定区域。生长锥可感测局部环境且可导引轴突朝向神经元目标细胞生长。生长锥可对环境线索(例如表面粘附性、生长因子、神经递质及电场)起反应。生长锥可以每天1至2毫米的速率前进。生长锥可借助于分类为片状伪足(lamellipodia)及外肉伪足(filopodia)的伸长段探索其前方及两侧的区域。当伸长段接触不利表面时,其可退回。当伸长段接触有利生长表面时,其可继续延伸且沿所述方向导引生长锥。当生长锥到达适当目标细胞时,可建立突触连接。
神经细胞功能可受神经元与其临近环境中的其它细胞之间的接触影响(Rutishauser等人,1988,Physiol.Rev.68:819,将其全部内容并入本文作为参考)。这些细胞可包括特定胶质细胞、中枢神经系统(CNS)中的少突胶质细胞以及周围神经系统(PNS)中的许旺细胞(Schwann cell),其可用髓鞘覆盖神经元轴突(Lemke,1992,An Introduction to Molecular Neurobiology,Z.Hall编,第281页,Sinauer,将其各自全部内容并入本文作为参考)。
CNS神经元可具有在损伤后再生的固有潜能,但髓鞘中存在的抑制性蛋白可抑制其进行再生(Brittis等人,2001,Neuron30:11-14;Jones等人,2002,J.Neurosci.22:2792-2803;Grimpe等人,2002,J.Neurosci.:22:3144-3160,将其各自全部内容并入本文作为参考)。
少突胶质细胞上发现的若干髓鞘抑制性蛋白已经表征。髓鞘抑制性蛋白的已知实例可包括NogoA(Chen等人,Nature,2000,403,434-439;Grandpre等人,Nature2000,403,439-444,将其各自全部内容并入本文作为参考)、髓鞘相关糖蛋白(MAG)(McKerracher等人,1994,Neuron13:805-811;Mukhopadhyay等人,1994,Neuron 13:757-767,将其各自全部内容并入本文作为参考)或少突胶质细胞糖蛋白(OM-gp)(Mikol等人,1988,J.Cell.Biol.106:1273-1279,将其各自全部内容并入本文作为参考)。这些蛋白质各自可为神经元Nogo受体-1(NgR1)的配体(Wang等人,Nature2002,417,941-944;Grandpre等人,Nature 2000,403,439-444;Chen等人,Nature,2000,403,434-439;Domeniconi等人,Neuron 2002,2002年6月28日在线发表,将其各自全部内容并入本文作为参考)。
Nogo受体-1(NgR1)可为GPI锚定膜蛋白,其含有8个富含亮氨酸的重复单位(Fournier等人,2001,Nature 409:341-346,将其全部内容并入本文作为参考)。在与抑制性蛋白(例如NogoA、MAG及OM-gp)相互作用时,NgR1复合物可转导引起生长锥塌陷及抑制神经突长出的信号。
需要抑制NgR1介导的生长锥塌陷及所引起的神经突长出抑制的分子及方法。另外,需要增强神经元存活及轴突再生,尤其用于治疗涉及轴突损伤、神经元或少突胶质细胞死亡、脱髓鞘或髓鞘形成障碍或一般涉及神经系统的疾病、障碍或损伤的分子。
所述疾病、障碍或损伤可包括(但不限于)多发性硬化(MS)、进行性多病灶脑白质病(PML)、脑脊髓炎(EPL)、中央脑桥髓鞘分解(CPM)、肾上腺脑白质营养不良、亚历山大病(Alexander'sdisease)、佩-梅二氏病(PMZ)、球形细胞脑白质病(球形细胞脑白质营养不良(Krabbe's disease))及Waller变性(Wallerian Degeneration)、视神经炎、横贯性脊髓炎、肌萎缩侧索硬化(ALS)、亨廷顿病、阿尔茨海默病、帕金森病、脊髓损伤、创伤性脑损伤、辐射后损伤、化学疗法的神经系统并发症、中风、急性缺血性视神经病变、维生素E缺乏、孤立性维生素E缺乏综合征、AR、巴-科综合征(Bassen-Kornzweigsyndrome)、马-比二氏综合征(Marchiafava-Bignami syndrome)、异染性脑白质营养不良、三叉神经痛或贝尔麻痹(Bell's palsy)。在这些疾病中,MS可为最广泛的,全世界约250万人患有此病。
MS可始于牵涉神经系统的复发-缓解模式,其接着可随神经损害增强而发展至慢性阶段。MS可与定位于慢性损害的髓鞘、少突胶质细胞或轴突破坏有关。在MS中所观测到的脱髓鞘未必总是永久的且已经证明在疾病早期阶段有髓鞘再生。神经元髓鞘再生可能需要少突胶质细胞。
各种疾病改善治疗(disease-modifying treatment)可用于MS,包括使用皮质类固醇及免疫调节剂,诸如干扰素β或。另外,由于少突胶质细胞及髓鞘形成在MS中的重要作用,所以试图研发增加少突胶质细胞数目或增强髓鞘形成的疗法。参见例如Cohen等人,美国专利第5,574,009号;Chang等人,N.Engl.J.Med.346:165-73(2002),将其各自全部内容并入本文作为参考。然而,急需研发其它用于MS及其它脱髓鞘及髓鞘形成障碍的障碍的疗法。
式(I)或(II)的化合物可促进髓鞘形成或髓鞘再生。方法可包括给予细胞式(I)或(II)的化合物。促进少突胶质细胞祖细胞分化的方法可包括给予细胞式(I)或(II)的化合物。治疗多发性硬化的方法可包括给予受试者式(I)或(II)的化合物。
给予受试者的式(I)或(II)的化合物的剂量可为10μg以下、25μg以下、50μg以下、75μg以下、0.10mg以下、0.25mg以下、0.5mg以下、1mg以下、2.5mg以下、5mg以下、10mg以下、15mg以下、20mg以下、50mg以下、75mg以下、100mg以下或500mg以下。
给药可包括通过局部、肠内、肠胃外、经皮、经粘膜、吸入、脑池内、硬膜外、阴道内、静脉内、肌内、皮下、真皮内或玻璃体内给药来给予。
给药的持续时间可为30秒以内、1分钟以内、约1分钟、1分钟至5分钟、5分钟至10分钟、10分钟至20分钟、20分钟至30分钟、30分钟至1小时、1小时至3小时、3小时至6小时、6小时至12小时、12小时至24小时或24小时以上。
给予抑制剂或化合物可包括多次给予。各次给予之间的持续时间可为30秒以内、1分钟以内、约1分钟、1分钟至5分钟、5分钟至10分钟、10分钟至20分钟、20分钟至30分钟、30分钟至1小时、1小时至3小时、3小时至6小时、6小时至12小时、12小时至24小时或24小时以上。
依序给予之间的持续时间可为30秒以内、1分钟以内、约1分钟、1分钟至5分钟、5分钟至10分钟、10分钟至20分钟、20分钟至30分钟、30分钟至1小时、1小时至3小时、3小时至6小时、6小时至12小时、12小时至24小时、24小时至48小时、48小时至72小时、72小时至1周或1周至2周。
给予细胞抑制剂或化合物可包括体外或体内系统或模型的细胞。细胞可为细胞系的一部分。细胞系可为初级细胞系或次级细胞系。细胞系可为无限增殖细胞系。细胞可破裂且呈细胞裂解物形式。细胞可为活有机体(也即受试者,例如哺乳动物)的一部分。哺乳动物可包括大鼠、小鼠、沙鼠、仓鼠、兔或人类。人类可为受试者或患者。
方法可进一步包括监测样品或受试者的特性。样品可自受试者移出。例如,样品可包括受试者的细胞或组织样品。样品可包括血液、血浆或神经元组织(包括神经元或胶质细胞)。样品也可保留于受试者体内。例如,样品可为在患者体内观测到的组织或细胞。
方法可进一步包括提供未经处理的对照细胞、样品或受试者及测量未经处理的对照细胞样品、样品或受试者的特性。
特性可包括存在或不存在分子、分子的浓度,例如髓鞘碱性蛋白、髓鞘相关糖蛋白或髓鞘少突胶质细胞糖蛋白。在一些实施方案中,确定分子的存在可包括测定所述分子的浓度、测定所述分子的纯度或测定所述分子的量。
特性可为组织或细胞的传导率。特性可为发射,例如电磁辐射。
监测特性可包括观测样品或受试者单独的特性。监测特性可包括在给予样品或受试者式(I)或(II)的化合物之前监测特性。监测特性可包括在给予样品或受试者化合物之后监测特性。监测特性可包括在给予样品或受试者已知浓度的化合物之后监测特性。
监测样品或受试者的特性可包括通过显微镜观测特性。监测组合物的特性可包括使用显微镜测量特性。监测组合物的特性可包括使用静态照片或电影监测特性。照片或电影可呈薄膜媒体(film media)或数字形式。监测特性可包括进行扫描,例如MRI或CT扫描。
促进髓鞘形成、髓鞘再生或少突胶质细胞祖细胞分化可预防或可治疗哺乳动物的病理性病症或症状。病理性病症可为多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤及瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
化合物可以药物组合物形式给予。药物组合物可包括式(I)或(II)的化合物。更具体地,可将式(I)或(II)的化合物使用为本领域技术人员所知的药学上可接受的标准载体、填充剂、增溶剂及稳定剂配制成药物组合物。例如,包括如本文所述的式(I)或(II)化合物或其盐、类似物、衍生物或修饰物的药物组合物可用于给予受试者适当化合物。
式(I)或(II)的化合物可用于例如在包括以下的方法中治疗疾病或障碍:给予有需要的受试者治疗学上可接受的量的式(I)或(II)化合物,或包含治疗有效量的式(I)或(II)化合物及药学上可接受的载体的药物组合物。
在式(I)或(II)的化合物呈足够碱性或酸性以形成稳定无毒酸式盐或碱式盐的状况下,以药学上可接受的盐形式制备及给予化合物可为适合的。药学上可接受的盐的实例可为与形成生理学上可接受的阴离子的酸形成的有机酸加成盐,例如甲苯磺酸盐、甲烷磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、丁二酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐或α-甘油磷酸盐。也可形成无机盐,包括盐酸盐、硫酸盐、硝酸盐、碳酸氢盐及碳酸盐。
药学上可接受的盐可使用在本领域中熟知的标准操作获得,例如通过使足够碱性化合物(诸如胺)与提供生理学上可接受的阴离子的适合酸反应。也可制成羧酸的碱金属(例如钠、钾或锂)或碱土金属(例如钙)盐。
药学上可接受的碱加成盐可由无机碱及有机碱制备。无机碱的盐可包括(但不限于)钠盐、钾盐、锂盐、铵盐、钙盐或镁盐。源自有机碱的盐可包括(但不限于)伯、仲或叔胺盐,诸如烷基胺盐、二烷基胺盐、三烷基胺盐、经取代的烷基胺盐、二(经取代的烷基)胺盐、三(经取代的烷基)胺盐、烯基胺盐、二烯基胺盐、三烯基胺盐、经取代的烯基胺盐、二(经取代的烯基)胺盐、三(经取代的烯基)胺盐、环烷基胺盐、二(环烷基)胺盐、三(环烷基)胺盐、经取代的环烷基胺盐、二取代的环烷基胺盐、三取代的环烷基胺盐、环烯基胺盐、二(环烯基)胺盐、三(环烯基)胺盐、经取代的环烯基胺盐、二取代的环烯基胺盐、三取代的环烯基胺盐、芳基胺盐、二芳基胺盐、三芳基胺盐、杂芳基胺盐、二杂芳基胺盐、三杂芳基胺盐、杂环胺盐、二杂环胺盐、三杂环胺盐,或混合的二胺盐及三胺盐,其中胺上至少两个取代基可不同且可为烷基、经取代的烷基、烯基、经取代的烯基、环烷基、经取代的环烷基、环烯基、经取代的环烯基、芳基、杂芳基或杂环等。也包括两个或三个取代基与氨基氮一起形成杂环基或杂芳基的胺。胺的非限制性实例可包括异丙胺、三甲胺、二乙胺、三(异丙基)胺、三(正丙基)胺、乙醇胺、2-二甲氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因(procaine)、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、N-烷基还原葡糖胺、可可碱、嘌呤、哌嗪、哌啶、吗啉或N-乙基哌啶等。其它羧酸衍生物可适用,例如羧酸酰胺,包括羧酰胺、低级烷基羧酰胺或二烷基羧酰胺等。
式(I)或(II)的化合物可配制成药物组合物且以多种适合于所选给药途径(例如,口服或肠胃外,以滴眼剂形式,通过静脉内、肌内、局部或皮下途径)的形式给予哺乳动物宿主,诸如人类患者。
因此,式(I)或(II)的化合物可与药学上可接受的媒介物(诸如惰性稀释剂或可同化可食用载体)组合全身(例如口服)给予。其可封闭于硬壳或软壳明胶胶囊剂中,可压成片剂,或可直接混入患者膳食的食物中。对于口服治疗性给药,活性化合物可与一种或多种赋形剂组合且以可摄取片剂、口含片剂、糖锭、胶囊剂、酏剂、混悬剂、糖浆剂或粉片等形式使用。所述组合物及制剂应含有至少约0.1%的活性化合物。占组合物及制剂的百分比当然可变化且可适宜介于给定单位剂型的约2重量%至约60重量%之间。所述治疗可用的组合物中活性化合物的量可为获得有效剂量水平的量。
片剂、糖锭、丸剂、胶囊剂等可包括以下:粘合剂,诸如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,诸如磷酸二钙;崩解剂,诸如玉米淀粉、马铃薯淀粉、藻酸等;润滑剂,诸如硬脂酸镁;或甜味剂,诸如蔗糖、果糖、乳糖或阿斯巴甜,或可添加矫味剂,诸如薄荷、冬青油或樱桃矫味剂。当单位剂型为胶囊剂时,其除上述类型的物质之外也可含有液体载体,诸如植物油或聚乙二醇。各种其它物质可以包衣形式存在或以其它方式改变固体单位剂型的物理形式。例如,片剂、丸剂或胶囊剂可以明胶、蜡、虫胶或糖等包衣。糖浆剂或酏剂可含有活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、染料及矫味剂如樱桃味或橙味香料。当然,任何用于制备任何单位剂型的物质应为药学上可接受的且在所用量下基本上无毒。另外,活性化合物可混入持续释放制剂及装置中。
活性化合物也可通过静脉内或腹膜内输注或注射来给予。活性化合物或其盐的溶液可在水中制备,任选与无毒表面活性剂混合。分散液也可在甘油、液体聚乙二醇、三醋汀及其混合物中及在油中制备。在一般储存及使用条件下,这些制剂可含有防腐剂以防止微生物生长。
用于注射或输注的示例性药物剂型可包括无菌水溶液或分散液或任选包封于脂质体中的包含活性成分的适于临时制备无菌可注射或可输注溶液或分散液的无菌粉末。在所有状况下,最终剂型在制造及储存条件下应为无菌的、流动的且稳定的。液体载体或媒介物可为溶剂或液体分散介质,包含例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油或无毒甘油酯及其混合物。适当流动性可例如通过形成脂质体、在分散液的状况下通过维持所需粒度或通过使用表面活性剂来维持。可通过各种抗细菌剂及抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸或硫柳汞等)来防止微生物作用。在许多状况下,优选包括等张剂,例如糖、缓冲剂或氯化钠。可通过在组合物中使用延迟吸收剂,例如单硬脂酸铝或明胶来延长可注射组合物的吸收。
无菌可注射溶液可通过以下方法来制备:将所需量的活性化合物必要时连同上文所列举的各种其它成分一起混入适当溶剂中,然后过滤器杀菌。在用于制备无菌可注射溶液的无菌粉末的状况下,优选制备方法可为真空干燥及冷冻干燥技术,这些技术可得到先前经无菌过滤的溶液中存在的活性成分连同任何其它所需成分的粉末。
对于局部给予,式(I)或(II)的化合物可以纯形式施用,例如当其为液体时。然而,一般需要以组合物或制剂形式将其与皮肤学上可接受的载体组合给予皮肤,所述载体可为固体或液体。
示例性固体载体可包括细粉状固体,诸如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。适用的液体载体包括水、醇或二醇或水-醇/二醇共混物,其中本发明化合物可任选在无毒表面活性剂辅助下以有效程度溶解或分散。可添加助剂(诸如芳香剂及其它抗微生物剂)以优化特性以用于给定用途。所得液体组合物可从吸收垫施用,用于浸渍绷带及其它敷料,或使用泵型或气溶胶喷雾器喷至患处。
增稠剂(诸如合成聚合物、脂肪酸、脂肪酸盐或酯、脂肪醇、改性纤维素或改性矿物物质)也可与液体载体一起用于形成可铺展糊剂、凝胶剂、软膏剂、皂等,以直接涂覆至使用者的皮肤。
可用于递送式(I)或(II)的化合物至皮肤的适用皮肤组合物的实例在本领域中为已知的;例如,参见Jacquet等人(美国专利4,608,392)、Geria(美国专利4,992,478)、Smith等人(美国专利4,559,157)及Wortzman(美国专利4,820,508),将其各自全部内容并入本文作为参考。
式(I)或(II)化合物的适用剂量可通过比较其体外活性及对动物模型的体内活性来确定。自小鼠及其它动物的有效剂量外推人类的有效剂量的方法在本领域中为已知的;例如参见美国专利4,938,949,将其全部内容并入本文作为参考。
一般而言,液体组合物(诸如洗剂)中式(I)或(II)的化合物的浓度可为约0.1重量%至约25重量%,优选为约0.5重量%至10重量%。半固体或固体组合物(诸如凝胶或粉剂)中的浓度可为以组合物的总重量计约0.1重量%至5重量%,优选为约0.5重量%至2.5重量%。
用于治疗所需的化合物或其活性盐或衍生物的量可不仅随所选的特定盐且也随给药途径、所治疗病症的性质及患者的年龄及病症而变化,且可最终由主治医师或临床医生酌情处理。然而,一般而言,剂量可处于每天每公斤体重约0.1mg至约10mg范围内。
化合物可便利地以单位剂型给予;例如,每单位剂型含有0.01mg至10mg,或0.05mg至1mg活性成分。在一些实施方案中,5mg/kg或5mg/kg以下的剂量可为适合的。
活性成分可经给予以实现活性化合物的所需峰值血浆浓度。所需峰值血浆浓度可为约0.5μM至约75μM,优选为约1μM至50μM,或约2μM至约30μM。这可例如通过以下方法实现:静脉内注射任选在盐水中的0.05%至5%的活性成分溶液,或以含有约1mg至约100mg活性成分的大丸剂(bolus)形式口服给予。
所需剂量可便利地每天以单次剂量或分次剂量形式提供,所述分次剂量是以适当时间间隔例如以两次、三次、四次或四次以上亚剂量形式给予。亚剂量本身可进一步划分,例如分成多次离散的间隔宽松的给药;诸如自吹入器多次吸入或通过施加复数滴至眼睛中。
所披露的方法可包括一种试剂盒,其包含式(I)或(II)的化合物及说明材料,所述说明材料可描述给予细胞或受试者化合物或包含所述化合物的组合物。这应视作包括为本领域技术人员所知的试剂盒的其它实施方案,诸如包含用于在给予细胞或受试者化合物或组合物之前溶解或悬浮化合物或组合物的溶剂(优选无菌)的试剂盒。优选地,受试者可为人类。
根据所披露的方法,如上文所述或如以下实施例中所论述,可使用为本领域技术人员所知的常规化学、细胞、组织化学、生物化学、分子生物学、微生物学及体内技术。所述技术在文献中得到充分阐明。
实施例
实施例1:甲烷磺酸顺式-4-叔丁基环己酯
将顺式-4-叔丁基环己醇(6.0g,38.5mmol,1.0当量)溶解于二氯甲烷(10mL)中。接着在0℃将甲烷磺酸酐(8.03g,46.2mmol,1.1当量(eq))缓慢添加至混合物中。接着将三乙胺(6.4mL,46.2mmol,1.5当量)添加至混合物中且在室温搅拌混合物3小时(h)。用二氯甲烷萃取混合物且浓缩有机层,得到呈白色粉末状的产物(8.0g,产率:90%)。产物未经进一步纯化即用于下一步。1HNMR(400MHz,CDCl3)δ4.99-4.98(m,1H),3.02(s,3H),2.14-2.12(m,2H),1.65-1.28(m,7H),0.84(s,9H)。
实施例2:2-溴-6-(反式-4-叔丁基环己基氧基)萘
将6-溴萘-2-醇(CAS编号15231-91-1)(3.0g,14.8mmol,1.0当量)溶解于叔丁醇/2-丁酮(4mL/2mL)的混合物中。接着将碳酸铯(12g,37.2mmol,2.5当量)添加至混合物中且在110℃搅拌混合物10分钟。接着将甲烷磺酸反式-4-叔丁基环己酯(3.48g,16.2mmol,1.1当量)添加至混合物中。在110℃于氮气气氛下搅拌悬浮液15小时。用乙酸乙酯萃取反应混合物且通过硅胶柱色谱使用石油醚作为洗脱剂纯化有机层,得到呈微黄色固体状的2-溴-6-(反式-4-叔丁基环己基氧基)萘(1.7g,产率:32%)。ESI-MS:361.0(M+H)+。1HNMR(400MHz,CDCl3)δ7.89(s,1H),7.63(d,1H),7.56(d,1H),7.47(d,1H),7.15-7.11(m,2H),4.26-4.24(m,1H),2.27-2.25(m,2H),1.89-1.87(m,2H),1.45-1.09(m,5H),0.89(s,9H)。
实施例3:6-(反式-4-叔丁基环己基氧基)-2-萘醛
在氮气气氛下将2-溴-6-(反式-4-叔丁基环己基氧基)萘(2.249g,6.25mmol,1.0当量)溶解于THF(10mL)中。接着将混合物冷却至-78℃且将n-BuLi(正丁基锂)的THF溶液(2.5M,7.5mL,18.8mmol,3.0当量)逐滴添加至混合物中。在-78℃搅拌混合物15分钟。接着将DMF(2.4mL,31.2mmol,5.0当量)添加至混合物中且在-78℃搅拌1小时。当反应完成时,添加1MHCl以将pH值调节至6。用EtOAc萃取混合物且浓缩有机层且通过硅胶色谱使用石油醚/乙酸乙酯(10/1)作为洗脱剂纯化,得到呈白色固体状的6-(反式-4-叔丁基环己基氧基)-2-萘醛(1.16g,60%)。EDI-MS:311.1(M+H)+。1HNMR(400MHz,CDCl3)δ10.08(s,1H),8.24(s,1H),7.92-7.87(m,2H),7.77(d,1H),7.22-7.19(m,2H),4.42-4.30(m,1H),2.30-2.28(m,2H),1.93-1.90(m,2H),1.48-1.11(m,5H),0.82(s,9H)。
实施例4:6-溴-2-(反式-4-叔丁基环己基氧基)-1-碘萘
在氩气气氛下吹洗2-溴-6-(反式-4-叔丁基环己基氧基)萘(160.0g,444.4mmol)于二氯甲烷(2.5L)中的溶液。添加N-碘代丁二酰亚胺(202.1g,888.8mmol)及四氯化锆(20.4g,88.9mmol)且在室温(r.t.)于氩气气氛下搅拌反应混合物。通过1H NMR监测反应且在30分钟后显示完全转化成产物。接着在减压下浓缩混合物,得到约250g呈棕色固体状的粗物质。通过硅胶色谱用己烷纯化粗物质,得到200g呈棕色固体状的所需产物(产率:92.6%)。EDI-MS:487.1(M+H)+。
实施例7:(5-甲氧基-2-硝基苯基)甲醇
在0℃向5-甲氧基-2-硝基苯甲酸(20g,1.0mol)于THF(100mL)中的溶液中添加BH3(1.0MTHF溶液,30.4mL,3.0当量)。使混合物回流3小时,用水(200mL)稀释且用DCM(100ml×3)萃取。经MgSO4干燥合并的有机层,蒸发,得到呈白色固体状的(5-甲氧基-2-硝基苯基)甲醇(18g,产率:97%)。1HNMR(400MHz,DMSO-d6)δ:8.13(d,J=6.4Hz,1H),7.34(d,J=6.4Hz,1H),7.02(s,1H),5.60~5.58(m,1H),4.84(d,J=8.0Hz,2H),3.89(s,3H);ESI-MS:m/z 184.1([M+1]+)。
实施例8:5-甲氧基-2-硝基苯甲醛
向(5-甲氧基-2-硝基苯基)甲醇(18g,0.098mol)于无水DCM(0.2L)中的溶液中逐份添加PDC(11.5g,0.147mol,1.5当量)及4A MS(120g)。在室温搅拌混合物16小时,经硅藻土(Celite)垫过滤。在真空中将滤液蒸发至干燥,得到呈淡黄色固体状的5-甲氧基-2-硝基苯甲醛(10g,产率:57%)。1HNMR(400MHz,DMSO-d6)δ:10.24(s,1H),8.14(d,J=8.8Hz,1H),7.31(dd,J=8.8,3.2Hz,1H),7.20(d,J=3.2Hz,1H),3.89(s,3H);ESI-MS:m/z182.0([M+1]+)。
实施例9:乙酸2-(2-甲酰基-4-甲氧基苯基氨基)-2-氧代乙酯
向5-甲氧基-2-硝基苯甲醛(6g,0.33mol)于EtOAc(100mL)中的溶液中添加20%PtO2/C(1.2g,20%)及NaOAc(1.2g,20%)。在氢气下于室温搅拌反应混合物0.5小时。经硅藻土垫过滤混合物,且经无水Na2SO4干燥滤液。过滤后,将溶液冷却至-78℃,且向其中添加DIPEA(6.4g,0.5mol,1.5当量)及乙酸2-氯-2-氧代乙酯(4.5g,0.33mol,1.0当量)。使所得混合物逐渐升温至室温且搅拌过夜。用水洗涤反应混合物两次,经Na2SO4干燥且在真空中蒸发大部分溶剂。接着通过过滤收集分离出的固体,得到呈淡黄色固体状的乙酸2-(2-甲酰基-4-甲氧基苯基氨基)-2-氧代乙酯(5.6g,产率:71%)。1HNMR(400MHz,DMSO-d6)δ:10.95(s,1H),9.95(s,1H),8.10(d,J=8.8Hz,1H),7.46(d,J=3.2Hz,1H),7.30(dd,J=8.8,3.2Hz,1H),4.69(s,2H),3.81(s,3H),2.22(s,3H);ESI-MS:m/z 252.1([M+1]+)。
实施例10:(6-甲氧基喹唑啉-2-基)甲醇
在高压(30psi)下于135℃使乙酸2-(2-甲酰基-4-甲氧基苯基氨基)-2-氧代乙酯(5g,0.02mol)及氨(6.8g,0.4mol,20当量)于EtOH(30mL)中的溶液反应5小时。冷却至室温后,在真空中蒸发溶剂。用DCM(100mL×3)萃取残余水溶液。经无水Na2SO4干燥合并的萃取物且在真空中蒸发至干燥。通过色谱(用DCM/MeOH=100/1洗脱)纯化粗产物,得到呈白色固体状的(6-甲氧基喹唑啉-2-基)甲醇(4.1g,产率:90%)。1HNMR(400MHz,DMSO-d6)δ:9.46(s,1H),7.90(d,J=8.8Hz,1H),7.63(d,J=8.8,3.2Hz,1H),7.52(d,J=2.8Hz,1H),5.34(t,J=6.4Hz,1H),4.72(d,J=6.4Hz,2H),3.91(m,3H);ESI-MS:m/z191.1([M+1]+)。
实施例11:6-甲氧基喹唑啉-2-甲醛
向(6-甲氧基喹唑啉-2-基)甲醇(4g,0.21mol)于EA(30mL)中的溶液中添加IBX(11.6g,4.2mol,2当量)。在80℃搅拌反应混合物16小时。过滤后,在真空中蒸发溶液,得到呈白色固体状的6-甲氧基喹唑啉-2-甲醛(3.8g,产率:95%)。ESI-MS:m/z 189.2([M+1]+)。
实施例12:1-((6-甲氧基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯
向化合物6-甲氧基喹唑啉-2-甲醛(3.8g,0.019mol)及哌啶-4-甲酸甲酯(2.8g,0.021mmol,1.1当量)于CH2Cl2(20mL)中的溶液中添加乙酸(3.4g,0.057mol,3当量)及NaBH(OAc)3(8g,0.038mol,2当量)。在室温搅拌所得混合物16小时。通过添加50mL饱和Na2CO3水溶液淬灭反应,用DCM(100mL×3)萃取。经Na2SO4干燥合并的有机层且浓缩。通过硅胶柱(洗脱:PE/EA=3/1)纯化残余物,得到呈浅棕色固体状的1-((6-甲氧基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(3.8g,产率:60%)。1HNMR(400MHz,DMSO-d6)δ:9.45(s,1H),7.90(d,J=9.2Hz,1H),7.62(dd,J=8.8Hz,2.8Hz,1H),7.51(d,J=2.8Hz,1H),3.92(s,3H),3.78(s,2H),3.57(s,3H),2.88~2.85(m,2H),2.28(m,1H),2.17(m,2H),1.78~1.77(m,2H),1.54(m,2H);ESI-MS:m/z316.2([M+1]+)。
实施例13:1-((6-羟基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯
在0℃于N2下向1-((6-甲氧基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(3.0g,9.5mmol)于DCM(15mL)中的溶液中添加BBr3(9.5mmol,1.0当量)。在室温搅拌反应混合物16小时。移除溶剂后,在0℃添加SOCl2(2.8g,0.238mol,1.5当量)及MeOH(20mL)。在80℃使混合物回流3小时,倾注于NaHCO3水溶液中且用DCM(100mL×3)萃取。经无水Na2SO4干燥合并的萃取物且在真空中蒸发至干燥。通过色谱(用DCM/MeOH=25/1洗脱)纯化粗产物,得到呈黄色固体状的1-((6-羟基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(1.7g,产率:77%)。1HNMR(400MHz,DMSO-d6)δ:10.36(s,1H),9.35(s,1H),7.84(d,J=9.2Hz,1H),7.51(dd,J=9.2,2.4Hz,1H),7.25(d,J=2.4Hz,1H),3.74(s,2H),3.57(s,3H),2.86~2.84(m,2H),2.27(m,1H),2.16(m,2H),1.77(m,2H),1.56(m,2H);ESI-MS:m/z 302.1([M+1]+)。
实施例14:1-((6-((反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯
在N2气氛下,向25mL圆底烧瓶中添加1-((6-羟基喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(0.5g,1.6mmol)、顺式-4-叔丁基环己醇(0.38g,0.24mmol,1.5当量)、PPh3(0.87g,3.3mmol,2当量)及无水THF(0.5mL)。接着在室温一次性快速添加DIAD(0.53g,0.33mmol,2当量)。在室温搅拌反应混合物0.5小时,用水(20mL)稀释且用DCM(20ml×3)萃取。经MgSO4干燥合并的有机层且浓缩。通过制备性TLC(DCM/MeOH=15/1)纯化残余物,得到呈棕色油状的1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(300mg,产率:20%)。1HNMR(400MHz,CDCl3)δ:9.27(s,1H),7.87(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.8Hz,1H),7.07(d,J=2.8Hz,1H),4.30~4.20(m,1H),3.94(s,2H),3.59(s,3H),3.00~2.98(m,2H),2.28~2.18(m,4H),1.85-1.82(m,6H),1.40~1.34(m,2H),1.18~1.03(m,4H),0.86(s,9H);ESI-MS:m/z 440.1(M+1)+。
实施例15:1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸
在80℃搅拌1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸甲酯(150mg,0.34mmol)及NaOH(27mg,0.68mmol,2.0当量)于EtOH(5mL)中的混合物16小时。冷却至室温后,添加1N HCl(5mL)水溶液以调节pH值=3-4。在真空中蒸发溶剂。通过制备性HPLC(30%至95%v/v的在0.05%TFA/H2O中的MeOH作为移动相)纯化残余物,得到呈浅黄色固体状的1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸(105mg,产率:75%)。
1HNMR(400MHz,CD3OD)δ:9.45(s,1H),7.96(d,J=9.6Hz,1H),7.64(dd,J=9.2,2.8Hz,1H),7.49(d,J=2.8Hz,1H),4.69(s,2H),4.47~4.39(m,1H),3.81~3.80(m,2H),3.31~3.27(m,1H),2.70~2.69(m,1H),2.30~2.26(m,5H),2.08~2.07(m,2H),1.92~1.89(m,2H),1.46~1.42(m,2H)1.29~1.26(m,2H)1.12~1.11(m,1H),0.81(s,9H);ESI-MS:m/z426([M+1]+)。
实施例16:1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯
在室温搅拌分子筛(Ms)、6-羟基-2-萘醛(1.0g,5.81mmol)、哌啶-4-甲酸乙酯(0.91g,5.81mmol)、NaBH(OAc)3(3.76g,17.43mmol)及TsOH(0.1g,0.581mmol)的混合物2小时且接着用水(5mL)淬灭。用DCM(20mL×2)萃取混合物。用饱和盐水(20mL×3)洗涤合并的有机物且接着浓缩。过滤白色沉淀物且将其溶解于水(10mL)及EtOAc(10mL)中,添加NaHCO3以调节pH值=8至9。用EtOAc(20mL×2)萃取混合物。用饱和盐水(20ml×2)洗涤合并的有机物,经Na2SO4干燥,浓缩且用EtOAc使其重结晶,得到呈白色固体状的1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯(0.83g,产率:41%),ESI-MS:314.1(M+H)+。1H NMR(400MHz,DMSO-d6)δ:9.65(s,1H),7.71(d,J=8.8Hz,1H),7.61-7.63(m,2H),7.32-7.35(m,1H),7.03-7.08(m,2H),4.02-4.03(q,J=7.2Hz,2H),3.52(s,2H),2.72-2.75(m,2H),2.25-2.32(m,2H),1.98-2.03(m,1H),1.77-1.79(m,2H),1.51-1.61(m,2H),1.17(t,J=7.2Hz,3H)。
实施例17:2,2,2-三氟-1-(6-甲氧基萘-2-基)乙醇
在室温搅拌2,2,2-三氟-1-(6-甲氧基萘-2-基)乙酮(1g,3.9mmol)及NaBH4(312mg,7.8mmol,2当量)于DCM(20mL)中的混合物5小时。用水(5mL)淬灭反应混合物,用盐水(10mL×2)洗涤,经Na2SO4干燥且浓缩,得到呈白色固体状的2,2,2-三氟-1-(6-甲氧基萘-2-基)乙醇(800mg,产率:80%)。ESI-MS(M+1)+:255.1。1HNMR(400MHz,CDCl3)δ:7.80(s,1H),7.72-7.68(m,2H),7.46(d,J=8.4Hz,1H),7.13-7.07(m,2H),5.09(q,J=6.4Hz,1H),3.85(s,3H)。
实施例18:甲烷磺酸2,2,2-三氟-1-(6-甲氧基萘-2-基)乙酯
在0℃向2,2,2-三氟-1-(6-甲氧基萘-2-基)乙醇(500mg,2mmol)及TEA(610mg,6mmol,3当量)于DCM(10mL)中的溶液中逐滴添加MsCl(680mg,6mmol,2当量)。在室温搅拌反应混合物3小时。用饱和NaHCO3(5mL)淬灭反应混合物,用盐水(5mL×3)洗涤,经Na2SO4干燥且浓缩,得到呈白色固体状的甲烷磺酸2,2,2-三氟-1-(6-甲氧基萘-2-基)乙酯(420mg,产率:65%)。ESI-MS(M+1)+:335.1。1HNMR(400MHz,CDCl3)δ:7.90(s,1H),7.83-7.78(m,2H),7.54(d,J=8.0Hz,1H),7.22(dd,J=8.4,2.4Hz,1H),7.16(s,1H),5.90(q,J=6.4Hz,1H),3.94(s,3H),2.93(s,3H)。
实施例19:1-(2,2,2-三氟-1-(6-甲氧基萘-2-基)乙基)哌啶-4-甲酸甲酯
在130℃于微波下搅拌甲烷磺酸2,2,2-三氟-1-(6-甲氧基萘-2-基)乙酯(500mg,1.5mmol)、哌啶-4-甲酸甲酯(330mg,2.3mmol,1.5当量)及TEA(450mg,4.5mmol,3当量)于CH3CN(4mL)中的溶液1小时。在室温搅拌反应混合物12小时。用乙酸乙酯(20mL)稀释反应混合物,用盐水(5mL×3)洗涤,经Na2SO4干燥且浓缩,得到粗产物。通过硅胶柱色谱(石油醚:乙酸乙酯=3:1)纯化粗产物,得到呈黄色固体状的1-(2,2,2-三氟-1-(6-甲氧基萘-2-基)乙基)哌啶-4-甲酸甲酯(340mg,产率:60%)。ESI-MS(M+1)+:382.1。1HNMR(400MHz,CDCl3)δ:7.76-7.73(m,3H),7.46(d,J=8.4Hz,1H),7.19-7.14(m,2H),4.20(q,J=8.8Hz,1H),3.93(s,3H),3.65(s,3H),3.04-2.97(m,2H),2.46-2.44(m,1H),2.26-2.22(m,2H),1.87-1.73(m,4H)。
实施例20:1-(2,2,2-三氟-1-(6-羟基萘-2-基)乙基)哌啶-4-甲酸甲酯
在0℃向1-(2,2,2-三氟-1-(6-甲氧基萘-2-基)乙基)哌啶-4-甲酸甲酯(500mg,1.3mmol)于DCM(10mL)中的溶液中添加BBr3(3N DCM溶液,0.9mL,2.6mmol,2当量)。接着在0℃搅拌反应混合物5小时。将甲醇(5mL)添加至混合物中。在室温再搅拌反应混合物2小时,且接着将其倾注于NaHCO3水溶液中,用DCM(10mL×3)萃取。用水(5mL×3)洗涤合并的有机层且浓缩,得到粗产物,将其通过色谱(石油醚:乙酸乙酯=1:1)纯化,得到呈黄色固体状的1-(2,2,2-三氟-1-(6-羟基萘-2-基)乙基)哌啶-4-甲酸甲酯(230mg,产率:47%)。ESI-MS(M+1)+:368.1。1HNMR(400MHz,CDCl3)δ:7.69-7.67(m,2H),7.60(d,J=8.4Hz,1H),7.37(d,J=8.8Hz,1H),7.09-7.05(m,2H),4.13(q,J=8.8Hz,1H),3.59(s,3H),2.97-2.90(m,2H),2.39-2.37(m,1H),2.19-2.17(m,2H),1.72-1.59(m,4H)。
实施例21:1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸甲酯
在室温于N2气氛下向1-(2,2,2-三氟-1-(6-羟基萘-2-基)乙基)哌啶-4-甲酸甲酯(300mg,0.8mmol)、顺式-4-(叔丁基)环己醇(245mg,1.6mmol,2当量)及PPh3(420mg,1.6mmol,2当量)于THF(3mL)中的经搅拌混合物中添加DIAD(323g,1.6mmol,2当量)。在80℃搅拌混合物2小时,用乙酸乙酯(10mL)稀释且用水(5mL×3)洗涤。在真空中移除有机溶剂且通过硅胶色谱(石油醚:乙酸乙酯=1:1)纯化残余物,得到呈黄色固体状的1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸甲酯(130mg,产率:31%)。ESI-MS(M+1)+:506.1。1HNMR(400MHz,CDCl3)δ:7.86~7.80(m,3H),7.46(d,J=8.8Hz,1H),7.27(s,1H),7.16(d,J=8.8Hz,1H),4.68~4.66(m,1H),4.39~4.36(m,1H),3.56(s,3H),3.32~3.30(m,2H),2.65-2.64(m,1H),2.44-2.43(m,1H),2.30-2.27(m,3H),1.93-1.90(m,3H),1.80-1.79(m,2H),1.44~1.41(m,2H),1.29~1.27(m,3H),1.14~1.13(m,1H),0.90(s,9H)。
实施例22:1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸
向1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸甲酯(100mg,0.2mmol)于MeOH(5mL)中的溶液中添加NaOH(32mg,0.8mmol,4.0当量)及H2O(0.5mL)。在85℃搅拌反应混合物2小时。接着将反应混合物冷却至0℃,且用3N HCl将溶液的pH值调节至6。过滤混合物,且黄色固体为所需产物1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸(78mg,产率:80%)。ESI-MS(M+1)+:492.1。
1HNMR(400MHz,CD3OD)δ:7.82~7.78(m,3H),7.47(d,J=8.8Hz,1H),7.27(s,1H),7.16(dd,J=8.8Hz,2.4Hz,1H),4.68~4.67(m,1H),4.38~4.36(m,1H),3.32~3.30(m,2H),2.65-2.64(m,1H),2.44-2.43(m,1H),2.30-2.28(m,3H),1.93-1.90(m,3H),1.80-1.79(m,2H),1.44~1.41(m,2H),1.29~1.26(m,3H),1.13~1.12(m,1H),0.92(s,9H)。HPLC:100.00%。
实施例23:1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
在N2下,向25mL圆底烧瓶中添加1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯(313mg,0.1mmol,2当量)、4-异丙基环己醇(284mg,0.2mmol,2当量)、PPh3(562mg,0.2mmol,2当量)及无水甲苯(0.5mL)。接着在室温一次性快速添加DIAD(404mg,0.2mmol,2当量)。在室温搅拌反应混合物0.5小时。在减压下移除溶剂且通过硅胶柱色谱(PE:EA=4:1)纯化残余物,得到呈微黄色油状的1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(213mg,产率:51%)。ESI-MS(M+1)+:438.1。1HNMR(400MHz,CDCl3)δ:7.64-7.57(m,3H),7.36(d,J=8.4Hz,1H),7.10-7.08(m,2H),4.60-4.58(m,1H),4.05(q,J=7.2Hz,2H),3.56(s,2H),2.85-2.81(m,2H),2.07-2.04(m,1H),2.01-1.97(m,2H),1.83-1.71(m,4H),1.51-1.40(m,6H),1.24-1.15(m,6H),1.11-1.06(m,1H),0.83(d,J=6.4Hz,6H)。
实施例24:1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
将1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(120mg,0.27mmol)溶解于EtOH(5mL)中。在室温一次性添加NaOH(55mg,1.4mmol,5当量)。在80℃搅拌混合物16小时。移除溶剂且将残余物溶解于H2O(3mL)中。添加1M HCl水溶液以调节pH值=7。过滤混合物,得到呈白色固体状的1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸(85mg,产率:61%)。ESI-MS(M+1)+:410.3。HPLC:100.00%。1HNMR(400MHz,DMSO-d6)δ:10.24(s,1H),7.96(s,1H),7.86-7.84(m,2H),7.62-7.60(m,1H),7.39(s,1H),7.24(d,J=9.2Hz,1H),4.77-4.76(m,1H),4.42-4.36(m,2H),3.40(s,2H),2.95-2.93(m,2H),2.50-2.49(m,1H),2.03-2.00(m,4H),1.85-1.75(m,2H),1.62-1.34(m,7H),1.19-1.12(m,1H),0.88(d,J=6.8Hz,6H)。
实施例25:1-((6-(顺式-4-叔丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
合成与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的合成相同。重量:120mg,黄色固体,产率:30%。ESI-MS(M+1)+:452.1。1HNMR(400MHz,CDCl3)δ:7.75~7.73(m,3H),7.48(br,1H),7.18~7.15(m,2H),4.80~4.76(m,1H),4.40(s,2H),4.05(q,J=6.8Hz,2H),3.60(br,2H),2.90(br,2H),2.62-2.60(m,1H),2.20-2.16(m,4H),1.80(br,2H),1.63-1.45(m,5H),1.30-1.17(m,5H),0.92(s,9H)。
实施例26:1-((6-(顺式-4-叔丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
合成与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的合成相同。重量:80mg,黄色固体,产率:70%。ESI-MS(M+1)+:424.3。1HNMR(400MHz,CD3OD)δ:7.91(s,1H),7.87~7.83(m,2H),7.48(dd,J=8.8Hz,1.6Hz,1H),7.29(s,1H),7.24(dd,J=8.8Hz,2.0Hz,1H),4.77(br,1H),4.43(s,2H),3.59~3.56(m,2H),3.08-3.07(m,2H),2.62-2.61(m,1H),2.22-2.16(m,4H),1.85-1.77(m,2H),1.63-1.47(m,5H),1.29-1.16(m,2H),0.92(s,9H)。HPLC:100.00%。
实施例27:1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。80mg,黄色固体,产率:11%,ESI-MS(M+H)+:464.1。1HNMR(400MHz,CDCl3),:7.66(m,3H),7.59(d,J=7.6Hz1H),7.19-7.08(m,2H),4.60-4.58(m,1H),4.06(q,J=7.2Hz,2H),3.54(s,2H),2.86-2.83(m,2H),2.23-2.15(m,6H),1.78-1.70(m,8H),1.34-1.25(m,2H),1.12(t,J=7.2Hz,3H)。
实施例28:1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。40mg,黄色固体,产率:70%。ESI-MS(M+H)+:436.1,HPLC:97.77%。
1HNMR(400MHz,CD3O:7.93(s,1H),7.88-7.81(m,2H),7.53(d,J=8.4Hz,1H),7.34(d,J=8.4Hz,1H),7.20(dd,J=8.8,2.4Hz,1H),4.81-4.80(m,0.45H),4.50-4.46(m,0.55H),4.42(s,2H),3.46-3.45(m,2H),3.15-3.14(m,2H),2.65-2.64(m,1H),2.32-2.03(m,6H),1.77-1.27(m,7H)。
实施例29:1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。浅黄色固体,75mg,产率:37%,ESI-MS(M+H)+:424.1。1HNMR(400MHz,CDCl3 ,7.64-7.56(m,3H),7.36(d,J=8.4Hz,1H),7.09-7.07(m,2H),4.58-4.56(m,1H),4.12(q,J=6.8Hz,2H),3.53(s,2H),2.83-2.81(m,2H),2.24-1.98(m,2H),1.89-1.69(m,6H),1.56-1.48(m,7H),1.25(t,J=7.2Hz,3H),1.12-1.10(m,2H),0.86(t,J=6.8Hz,3H)。
实施例30:1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。黄色油状物,70mg,产率:89%。
1HNMR(400MHz,CD3OD:7.89(s,1H),7.84(dd,J=8.4,3.2Hz,2H),7.49(d,J=8.8Hz,1H),7.29(d,J=2.0Hz,1H),7.24(dd,J=8.8,2.4Hz1H),4.75-4.74(m,1H),4.33(s,2H),3.41-3.32(m,2H),3.03-2.98(m,2H),2.44-2.42(m,1H),2.09-2.06(m,4H),1.91-1.88(m,2H),1.66-1.59(m,4H),1.43-1.41(m,2H),1.34-1.29(m,3H),0.95(t,J=8.0Hz,3H)。ESI-MS(M+H)+:396.1。HPLC:100.00%。
实施例31:1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。170mg,黄色油状物,产率:30%。ESI-MS(M+H)+:452.1。1HNMR(400MHz,CDC)(顺式异构体与反式异构体的混合物7.70-7.62(m,3H),7.42(d,J=8.8Hz,1H),7.07-7.05(m,2H),4.59-4.56(m,0.45H),4.42-4.34(m,0.55H),4.14(q,J=6.8Hz,2H),3.52(s,2H),2.80-2.79(m,2H),2.23-1.98(m,5H),1.82-1.80(m,5H),1.78-1.52(m,8H),1.18(t,J=6.8Hz,3H),1.00(t,J=7.2Hz,3H),1.12-1.10(m,4H)。
实施例32:1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。120mg,黄色油状物,产率:86%。ESI-MS(M+H)+:424.1。HPLC:100.00%。1HNMR(400MHz,CD3O(顺式异构体与反式异构体的混合物:7.89(s,1H),7.85-7.79(m,2H),7.49(dd,J=8.4,1.2Hz,1H),7.28(s,1H),7.19(dd,J=8.8,2.4Hz,1H),4.81-4.80(m,0.45H),4.42-4.34(m,0.55H),4.33(s,2H),3.42-3.39(m,2H),3.02-3.01(m,2H),2.48-2.47(m,1H),2.20-1.90(m,4H),1.89-1.80(m,3H),1.66-1.58(m,4H),1.34-1.16(m,8H),0.92(t,J=5.6Hz,3H)。
实施例33:1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。1.01g,无色油状物,产率:76%,ESI-MS(M+H)+:450.1。
实施例34:1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。62mg,黄色固体,产率:7%,ESI-MS(M+H)+:422.0,HPLC:95%。1HNMR(400MHz,CD3O :1.37-2.08(m,18H),2.25(d,J=15.94Hz,2H),2.55-2.72(m,1H),3.09(td,J=12.74,1.76Hz,2H),3.55-3.67(m,2H),4.44(s,2H),4.54(双五重峰,J=8.09,3.86,3.86,3.86,3.86Hz,1H),7.23(dd,J=8.91,2.38Hz,1H),7.31(s,1H),7.50(dd,J=8.47,1.76Hz,1H),7.84(d,J=9.04Hz,1H),7.88(d,J=8.47Hz,1H),7.93(s,1H)。
实施例35:1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
向1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯(2.43g,8mmol,1.0当量)于共溶剂叔丁醇/丁-2-酮(40mL/20mL)中的溶液中添加碳酸铯(5.0g,16mmol,2.0当量)。在80℃搅拌混合物10分钟且接着引入甲烷磺酸反式-4-乙基环己酯(3.2g,16mmol,2.0当量)。在80℃于N2下搅拌悬浮液15小时。接着浓缩反应混合物且通过硅胶柱色谱(EtOAc/PE=1:5)纯化残余物,得到呈微黄色固体状的1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(1.6g,产率:46%)。ESI-MS(M+H)+:424.3。1HNMR(400MHz,CD3OD)δ:7.63-7.56(m,3H),7.30(dd,J=8.4,1.6Hz,1H),7.10(d,J=2.4Hz,1H),7.03(dd,J=8.8,2.4Hz,1H),4.68-4.66(m,1H),4.01(q,J=7.2Hz,2H),3.66(s,2H),2.85-2.80(m,2H),2.25-2.22(m,1H),2.11-2.08(m,2H),1.96-1.92(m,2H),1.81-1.77(m,2H),1.65-1.45(m,6H),1.33-1.30(m,2H),1.22-1.12(m,3H),1.13(t,J=7.2Hz,3H),0.82(t,J=7.2Hz,3H)。
实施例36:1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
使1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(1.6g,0.004mol,1.0当量)及NaOH(0.48g,0.012mol,3.0当量)于乙醇(10mL)及水(2mL)中的混合物回流2小时。在真空中移除溶剂后,将残余物溶解于水(20mL)中且用1NHCl酸化至pH值=7。用二氯甲烷(50mL×3)萃取混合物且用盐水(30mL)洗涤合并的有机层,经硫酸钠干燥,浓缩且使其于乙酸乙酯中重结晶,得到呈白色固体状的1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸(1.1g,产率:71%)。ESI-MS(M+H)+:396.3。HPLC:100%。1H NMR(400MHz,DMSO-d6)δ:7.77(d,J=9.2Hz,1H),7.72(d,J=8.4Hz,1H)7.63(s,1H),7.39(dd,J=8.4,1.2Hz,1H),7.29(d,J=2.0Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),4.71-4.69(m,1H),3.54(s,2H),2.78-2.74(m,2H),2.16-2.15(m,1H),2.01-1.93(m,4H),1.77-1.75(m,2H),1.63-1.50(m,6H),1.34-1.24(m,5H),0.87(t,J=7.2Hz,3H)。
实施例37:1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的合成与1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的合成相似。
得到呈微黄色固体状的1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(产率:55%)。ESI-MS(M+H)+:424.3。1H NMR(400MHz,CD3OD)δ:7.71(dd,J=8.8,3.2Hz,2H),7.66(s,1H),7.42(dd,J=8.4,1.6Hz,1H),7.21(d,J=2.0Hz,1H),7.10(dd,J=8.8,2.4Hz,1H),4.42-4.20(m,1H),4.11(q,J=7.2Hz,2H),3.63(s,2H),2.90-2.87(m,2H),2.38-2.35(m,1H),2.24-2.02(m,4H),1.88-1.85(m,4H),1.76-1.72(m,2H),1.34-1.29(m,4H),1.27-1.11(m,6H),0.94(t,J=7.2Hz,3H)。
实施例38:1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的合成与1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的合成相似。
得到呈白色固体状的1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸(产率:70%)。ESI-MS(M+H)+:396.3。HPLC:100%。1H NMR(400MHz,DMSO-d6)δ:7.78(d,J=9.2Hz,1H),7.75(d,J=8.4Hz,1H)7.68(s,1H),7.40(d,J=8.4Hz,1H),7.33(d,J=2.4Hz,1H),7.13(dd,J=8.8,2.4Hz,1H),4.42-4.40(m,1H),3.57(s,2H),2.78-2.75(m,2H),2.21-2.15(m,3H),2.03-2.02(m,2H),1.84-1.82(m,4H),1.58-1.56(m,2H),1.40-1.37(m,2H),1.29-1.25(m,3H),1.17-1.10(m,2H),0.91(t,J=7.2Hz,3H)。
实施例39:6-(反式-4-叔丁基环己基氧基)-2-甲基喹啉
向在冰浴中冷却的2-甲基-喹啉-6-醇(4.13g,0.0259mol)、顺式-4-叔丁基-环己醇(4.86g,0.0311mol)及三苯基膦(9.53g,0.0363mol)于四氢呋喃(100mL,1mol)中的溶液中添加四氢呋喃(10mL,0.1mol)中的偶氮二甲酸二异丙酯(7.61mL,0.0363mol)。在室温搅拌反应混合物72小时。在减压下移除溶剂且将残余物吸收于二氯甲烷中,使其吸附至硅胶上且通过快速色谱(0%至30%乙酸乙酯/己烷)纯化,得到标题化合物(56%产率)。ESI-MS(M+H+):298.3。
实施例40:6-(反式-4-叔丁基环己基氧基)喹啉-2-甲醛
将过氧化二叔丁基(1.93mL,10.5mmol)添加至二氧化硒(2.68g,24.1mmol)于1,4-二噁烷(24.00mL,307.5mmol)中的悬浮液中。搅拌混合物30分钟,接着添加6-(反式-4-叔丁基-环己基氧基)-2-甲基-喹啉(3.12g,10.5mmol)于1,4-二噁烷中的溶液且在50℃加热混合物过夜。接着将反应混合物冷却至室温,在氯仿中稀释且经硅藻土垫过滤。用水洗涤滤液。分离各层且经MgSO4干燥合并的有机相,过滤,在减压下浓缩,使其吸附至硅胶上且通过快速色谱(0%至30%EtOAc/己烷)纯化,得到呈浅黄色固体状的标题化合物(20%产率)。ESI-MS(M+H+):312.27。
实施例41:1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸甲酯
在室温搅拌6-(反式-4-叔丁基环己基氧基)喹啉-2-甲醛(490mg,1.58mmol)、AcOH(283mg,4.7mmol,3.0当量)及哌啶-4-甲酸甲酯(389mg,2.36mmol,1.5当量)于DCM(5mL)中的溶液10分钟。接着添加NaBH(OAc)3(100mg,4.7mmol,3.0当量)。在室温搅拌反应混合物1小时。用水(5mL)淬灭反应混合物。接着用DCM(3×10mL)萃取混合物。用盐水(10mL)洗涤合并的有机层,经Na2SO4干燥且浓缩,得到粗产物。通过硅胶柱色谱(DCM:MeOH=40:1)纯化粗产物,得到呈黄色油状的1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸甲酯(480mg,产率:30%)。ESI-MS(M+1)+:439.2。1HNMR(400MHz,CDCl3)δ:7.98(d,1H),7.94(d,1H),7.56(d,1H),7.32(d,1H),7.08(s,1H),4.30~4.20(m,1H),3.77(s,2H),3.67(s,3H),2.91~2.88(m,2H),2.33~2.14(m,5H),1.91~1.79(m,5H),1.47~1.43(m,2H),1.98~1.10(m,4H),0.89(s,9H)。
实施例42:1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
向1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸甲酯(150mg,0.34mmol)于MeOH(5mL)中的溶液中添加NaOH(68mg,1.7mmol,5.0当量)及H2O(0.5mL)。在85℃搅拌反应混合物2小时。接着将反应混合物冷却至0℃,用3N HCl将溶液的pH值调节至6。过滤混合物,且黄色固体为所需产物1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸(90mg,产率:46%)。ESI-MS(M+1)+:425.3,HPLC:100%。1HNMR(400MHz,DMSO-d6)δ:8.32(d,1H),7.93(d,1H),7.70(d,1H),7.48(s,1H),7.41(d,1H),4.53(br,1H),4.44~4.40(m,1H),3.33(br,3H),3.14(br,2H),2.49(br,1H),2.22~2.20(m,2H),2.04~1.80(m,6H),1.37~1.32(m,2H),1.25~1.20(m,2H),1.10~1.08(m,1H),0.87(s,9H)。
实施例45:1-(6-乙酰氧基-萘-2-甲酰基)哌啶-4-甲酸甲酯
在室温搅拌6-乙酰氧基-2-萘甲酸(1g,4.34mmol,1.0当量)、哌啶-4-甲酸甲酯(684mg,4.78mmol,1.1当量)、HBTU(2.47g,6.51mmol,1.5当量)及TEA(658mg,6.51mmol,1.5当量)于DCM(20mL)中的混合物16小时。用乙酸乙酯(200mL)稀释反应混合物。用水(100mL×2)及盐水(100mL)洗涤合并的有机层,经Na2SO4干燥且浓缩,得到呈黄色油状的1-(6-乙酰氧基-萘-2-甲酰基)哌啶-4-甲酸甲酯(2g,产率:100%)。ESI-MS:356.0(M+H)+。1HNMR(400MHz,DMSO-d6)δ:8.05(d,1H),8.01-7.96(m,2H),7.73(s,1H),7.53-7.51(m,1H),7.40-7.37(m,1H),3.63(s,3H),3.18-2.95(m,2H),2.71-2.65(m,3H),2.34(s,3H),1.97-1.76(m,2H),1.61-1.50(m,2H)。
实施例46:1-(6-羟基-萘-2-甲酰基)哌啶-4-甲酸甲酯
在室温搅拌1-(6-乙酰氧基-萘-2-甲酰基)哌啶-4-甲酸甲酯(1g,2.814mmol,1.0当量)、K2CO3(1.94g,14.07mmol,5.0当量)于MeOH(20mL)中的混合物2小时。过滤反应混合物。浓缩滤液且通过制备性HPLC(MeOH:0.05%TFA/H2O=0%-95%)纯化残余物,得到呈白色固体状的1-(6-羟基-萘-2-甲酰基)哌啶-4-甲酸甲酯(350mg,产率:40%)。ESI-MS:314.0(M+H)+。1HNMR(400MHz,DMSO-d6)δ:9.94(s,1H),7.86-7.84(m,2H),7.73(d,1H),7.38(d,1H),7.16-7.12(m,2H),3.63(s,3H),3.16-2.97(m,2H),2.69-2.63(m,3H),1.96-1.79(m,2H),1.61-1.51(m,2H)。
实施例47:1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸甲酯
在室温于N2气氛下向1-(6-羟基-萘-2-甲酰基)哌啶-4-甲酸甲酯(500mg,1.59mmol)、顺式-4-(叔丁基)环己醇(487mg,3.18mmol,2当量)及PPh3(833mg,3.18mmol,2当量)于THF(5mL)中的经搅拌混合物中添加DIAD(642g,3.18mmol,2当量),接着在80℃搅拌混合物12小时。用乙酸乙酯(20mL)稀释反应混合物且用水(5mL×3)洗涤。在真空中移除有机溶剂且通过硅胶色谱(石油醚:乙酸乙酯=1:1)纯化残余物,得到呈黄色固体状的1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸甲酯(230mg,产率:32%)。ESI-MS(M+1)+:453.2。1HNMR(400MHz,CDCl3)δ:7.76-7.70(m,3H),7.43(d,1H),7.18(d,1H),7.16(s,1H),4.32-4.26(m,1H),3.71(s,3H),3.08-3.06(m,2H),2.60-2.58(m,1H),2.28-2.26(m,2H),1.91-1.88(m,4H),1.67-1.65(m,4H),1.29-1.26(m,2H),1.12-1.11(m,3H),0.88(s,9H)。
实施例48:1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸
向1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸甲酯(150mg,0.33mmol)于MeOH(5mL)中的溶液中添加NaOH(68mg,1.7mmol,5.0当量)及H2O(0.5mL)。在85℃搅拌反应混合物2小时。将反应混合物冷却至0℃后,用3N HCl将溶液的pH值调节至6。过滤混合物且黄色固体为所需产物1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸(90mg,产率:70%)。ESI-MS(M+1)+:438.3。1HNMR(400MHz,CD3OD)δ:7.83~7.81(m,3H),7.41(d,1H),7.28(s,1H),,7.16(d,1H),4.44~4.37(m,1H),3.30(br,2H),2.65~2.60(m,1H),2.29~2.27(m,2H),1.93~1.90(m,4H),1.44~1.41(m,3H),1.32~1.31(m,2H),1.28~1.25(m,3H),1.15~1.12(m,1H),0.92(s,9H)。HPLC:98.45%。
实施例49:1-叔丁基-4-亚甲基环己烷
在-78℃向溴化甲基三苯基鏻(5.36g,15mmol,1.5当量)于无水THF(40mL)中的溶液中添加n-BuLi(2.5M)(6mL,15mmol,1.5当量)。在室温搅拌混合物1小时。在-78℃将4-叔丁基环己酮(1.54g,10mmol)于THF(10mL)中的溶液添加至反应混合物中。在70℃搅拌混合物12小时。移除溶剂且将残余物悬浮于己烷中。过滤混合物且浓缩滤液,得到呈黄色油状的1-叔丁基-4-亚甲基环己烷(0.80g,产率:50%)。1HNMR(400MHz,CDCl3)δ:4.58(s,2H),2.34-2.31(m,2H),2.01-1.95(m,2H),1.88-1.84(m,2H),1.14-1.06(m,3H),0.86(s,9H)。
实施例50:1-((6-(三氟甲基磺酰氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
在0℃向1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯(1g,3.19mmol)及TEA(0.64g,6.38mmol,2当量)于DCM(20mL)中的溶液中逐滴添加Tf2O(1.8g,6.38mmol,2当量)。在室温搅拌混合物12小时。在0℃用水淬灭反应,用饱和NaHCO3(10mL)及盐水(5mL×3)洗涤。经Na2SO4干燥有机层且浓缩,得到呈棕色固体状的1-((6-(三氟甲基磺酰氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(350mg,产率:90%)。ESI-MS:446.1(M+H)+。1HNMR(400MHz,CDCl3)δ:7.88(d,J=9.2Hz,1H),7.84-7.82(m,2H),7.79(s,1H),7.60(d,J=7.6Hz,1H),7.35(d,J=9.2Hz,1H),4.13(q,J=7.6Hz,2H),3.66(s,2H),2.89-2.86(m,2H),2.32-2.28(m,1H),2.11-2.07(m,2H),1.88-1.78(m,4H),1.26(t,J=7.6Hz,3H)。
实施例51:1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯
向密封管中添加1-((6-(三氟甲基磺酰氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(500mg,1.12mmol)、1-叔丁基-4-亚甲基环己烷(340mg,2.24mmol,2当量)、K2CO3(309mg,2.24mmol,2当量)、Xantphos(130mg,0.22mmol,0.2当量)、Pd(OAc)2(25mg,0.11mmol,0.1当量)及NMP(2mL)。用N2吹洗混合物5分钟。接着在120℃搅拌反应混合物12小时。用乙酸乙酯(20mL)稀释反应混合物且用水(5mL×3)洗涤。在真空中移除有机溶剂且通过硅胶色谱(石油醚:乙酸乙酯=2:1)纯化残余物,得到呈黄色固体状的1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(180mg,产率:35%)。ESI-MS(M+1)+:448.3。1HNMR(400MHz,CDCl3)δ:7.76-7.73(m,2H),7.68(s,1H),7.61(s,1H),7.46(d,J=8.0Hz,1H),7.34(d,J=8.8Hz,1H),6.34(s,1H),4.13(q,J=8.8Hz,2H),3.64(s,2H),2.92-2.89(m,2H),2.30-2.25(m,2H),2.08-2.05(m,2H),1.94-1.77(m,8H),1.60(br,2H),1.26-1.23(m,5H),0.87(s,9H)。
实施例52:1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸
向1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(50mg,0.11mmol)于MeOH(3mL)中的溶液中添加NaOH(22mg,0.55mmol,5.0当量)及H2O(0.5mL)。在80℃搅拌反应混合物4小时。用3NHCl将溶液的pH值调节至6。过滤混合物且黄色固体为所需产物1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸(35mg,产率:81%)。ESI-MS(M+1)+:420.1。1HNMR(400MHz,CD3OD)δ:7.86(s,1H),7.83~7.80(m,1H),7.77-7.74(m,1H),7.60(br,1H),7.43(d,J=8.4Hz,1H),7.35~7.32(m,1H),6.30(s,1H),4.29(s,2H),3.33(br,2H),2.97-2.94(m,3H),2.42-2.38(m,2H),2.20-2.03(m,1H),2.03-2.00(m,2H),1.89-1.80(m,5H),1.22-1.12(m,3H),0.80(s,9H)。HPLC:100%。
实施例53:6-溴-2-(4-叔丁基-环己基氧基)-喹啉
按照2-溴-6-(反式-4-叔丁基环己基氧基)萘,使用6-溴-喹啉-2-醇作为起始物质来合成。ESI-MS(M+H+):362.1/364.10)。
实施例54:2-(反式-4-叔丁基-环己基氧基)-喹啉-6-甲醛
在-78℃向四氢呋喃(24mL)中的6-溴-2-(反式-4-叔丁基-环己基氧基)-喹啉(1.0933g,3.0176mmol)中添加1.6M正丁基锂的己烷溶液(5.6mL,9.0mmol)且搅拌反应混合物15分钟。添加N,N-二甲基甲酰胺(1.2mL)且搅拌反应混合物30分钟。添加1M HCl且使反应混合物升温至室温。添加饱和碳酸氢钠溶液且用乙酸乙酯萃取混合物。用饱和氯化钠洗涤有机层,用硫酸钠干燥,过滤且蒸发。通过硅胶色谱使用己烷/乙酸乙酯(0%-50%)作为洗脱剂纯化残余物,得到产物(603mg,产率64%)。ESI-MS(M+H+):312.20。
实施例55:1-((2-(反式-4-叔丁基环己基氧基)喹啉-6-基)甲基)哌啶-4-甲酸
将2-(4-叔丁基-环己基氧基)-喹啉-6-甲醛(350mg,1.1mmol)及哌啶-4-甲酸(145mg,1.12mmol)于乙醇(8mL,100mmol)中的溶液加热至回流并维持2小时。将黄色溶液冷却至室温且添加氰基硼氢化钠(84.8mg,1.35mmol)且加热至回流并维持1小时。冷却至室温后,添加柠檬酸且浓缩。将固体悬浮于水中且过滤,且用水充分洗涤收集的固体。HPLC纯化固体,得到产物。77mg,产率:16%。ESI-MS(M+1)+:425.00。1HNMR(400MHz,d-MeOD)δ:0.93(s,9H),1.02-1.57(m,10H),1.70-2.01(m,2H),2.30(br.s.,2H),3.03-3.16(m,2H),3.53-3.68(m,2H),4.46(s,2H),5.10-5.27(m,1H),6.97(d,J=8.85Hz,1H),7.71(dd,J=8.63,2.04Hz,1H),7.89(d,J=8.60Hz,1H),7.93(d,J=2.01Hz,1H),8.15(d,J=8.97Hz,1H)。
实施例56:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸
将4-乙基哌啶-4-甲酸(0.184g,1.17mmol)与6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.3g,0.9mmol)、乙酸(0.19mL,3.4mmol)在甲醇(1.9mL,48mmol)中组合且搅拌30分钟。接着将反应混合物经冰浴冷却至0℃且添加氰基硼氢化钠(90.9mg,1.4mmol)。接着使反应混合物升温至室温,同时搅拌过夜。接着将反应混合物浓缩至约4mL至5mL,接着通过反相色谱(5%-95%CH3CN/水(0.1%TFA),C18,150mm)直接纯化。接着将产物冻干至干燥,得到7mg呈白色固体状的1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸(2%)。ESI-MS:452(M+1)+。1H NMR(DMSO-d6,400MHz):δ(ppm)7.75-8.00(m,3H),7.47-7.61(m,1H),7.43(s,1H),7.07-7.28(m,1H),4.44(m,3H),3.29-3.54(m,2H),2.74-3.03(m,2H),2.20(s,3H),1.64-1.98(m,3H),1.02-1.65(m,9H),0.89(s,9H),0.76-0.83(m,3H)。
实施例57:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-丙基-哌啶-4-甲酸
以与1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸相似的方式,使用甲醇(1.8mL,44mmol)中的4-丙基-哌啶-4-甲酸(0.185g,1.08mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.3g,0.9mmol)及乙酸(0.18mL,3.1mmol)以及氰基硼氢化钠(84.101mg,1.3383mmol)制备化合物,得到16mg1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-丙基-哌啶-4-甲酸(4%)。ESI-LCMS 466(M+H)。1H NMR(甲醇-d4,400MHz):δ(ppm)7.54-7.88(m,3H),7.31-7.43(m,1H),7.14-7.25(m,1H),6.98-7.12(m,1H),4.12-4.40(m,2H),3.33-3.50(m,2H),2.82-3.08(m,2H),2.05-2.42(m,3H),1.74-1.95(m,2H),0.94-1.64(m,12H),0.82(s,13H)。
实施例58:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸
以与对于1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸所述的方式相似的方式,使用甲醇(1.8mL,44mmol)中的3-甲基-哌啶-4-甲酸(0.154g,1.08mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.3g,0.9mmol)及乙酸(0.18mL,3.1mmol)以及氰基硼氢化钠(84.101mg,1.3383mmol)制备化合物,得到6mg1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸(2%)。ESI-LCMS 438(M+H)。1H NMR(DMSO-d6,400MHz):δ(ppm)7.73-8.05(m,3H),7.50-7.67(m,1H),7.44(s,1H),7.12-7.30(m,1H),4.45(br.s.,3H),2.99-3.49(m,3H),2.59-2.74(m,1H),1.70-2.28(m,7H),1.03-1.48(m,6H),0.96(d,J=6.8Hz,3H),0.89(s,9H)。
实施例59:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-苯基-哌啶-4-甲酸
以与对于1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸所述的方式相似的方式,使用4-苯基-哌啶-4-甲酸(0.198g,0.967mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.250g,0.805mmol)、乙酸(0.16mL,2.8mmol)、甲醇(1.6mL,4.0E1mmol)及氰基硼氢化钠(75.314mg,1.1985mmol)制备化合物,得到21mg呈白色固体状的标题化合物(5%)。ESI-LCMS(500M+H)。1H NMR(DMSO-d6,400MHz):位移(ppm)7.80-7.98(m,3H),7.16-7.63(m,8H),4.51(br.s.,3H),3.45-3.64(m,2H),2.96-3.18(m,2H),2.68(m,2H),2.13-2.31(m,2H),1.74-2.09(m,4H),1.00-1.53(m,5H),0.89(s,9H)。
步骤1:全氢-氮杂-4-甲酸盐酸盐
以与对于1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸所述的方式相似的方式,使用全氢-氮杂-4-甲酸盐酸盐(0.138g,0.967mmol)、250mg固体负载型碳酸酯树脂(1.34mmol/g)、甲醇(1.6mL,4.0E1mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.250g,0.805mmol)及乙酸(0.16mL,2.8mmol)制备化合物,得到86mg呈白色固体状的标题化合物(24%)。ESI-LCMS 438(M+H)。1H NMR(DMSO-d6,400MHz):δ(ppm)7.96(s,1H),7.81-7.91(m,2H),7.51-7.65(m,1H),7.43(d,J=1.8Hz,1H),7.14-7.26(m,1H),4.45(br.s.,3H),3.00-3.57(m,4H),2.63-2.75(m,1H),1.58-2.33(m,10H),1.00-1.51(m,6H),0.89(s,9H)。
实施例61:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-羟基-哌啶-4-甲酸
以与对于1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸所述的方式相似的方式,使用4-羟基-哌啶-4-甲酸(0.0561g,0.387mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.100g,0.322mmol)、乙酸(0.064mL,1.1mmol)及氰基硼氢化钠(30.126mg,0.47939mmol)制备化合物,得到51mg1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-羟基-哌啶-4-甲酸(36%)。ESI-LCMS440(M+H)。1H NMR(DMSO-d6,400MHz):δ(ppm)9.37-9.69(m,1H),7.75-8.07(m,4H),7.50-7.64(m,1H),7.43(d,J=2.0Hz,1H),7.13-7.27(m,1H),4.47(d,J=3.8Hz,3H),3.05-3.47(m,4H),1.97-2.29(m,4H),1.83(d,J=13.3Hz,4H),1.02-1.45(m,5H),0.89(s,9H)。
实施例62:{1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-4-基}-乙酸
以与对于1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸所述的方式相似的方式,使用哌啶-4-基-乙酸(0.0554g,0.387mmol)、6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.100g,0.322mmol)及三乙酰氧基硼氢化钠(0.212g,0.9mol)制备化合物,得到85mg{1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-4-基}-乙酸(60%)。ESI-LCMS(438M+H)。1HNMR(DMSO-d6,400MHz):位移(ppm)7.71-8.01(m,3H),7.43(d,J=2.0Hz,2H),7.10-7.30(m,1H),4.38(d,J=4.8Hz,3H),3.28-3.55(m,2H),2.82-3.14(m,2H),2.20(d,J=6.3Hz,4H),1.85(br.s.,5H),1.38(br.s.,7H),0.89(s,9H)。
实施例69:1,1-二甲氧基-N-(3-甲氧基苯甲基)丙-2-胺
将(3-甲氧基苯基)甲胺(100g,730mmol,1当量)及1,1-二甲氧基丙-2-酮(172.2g,1.46mol,2当量)溶解于乙酸(1.8L)中。添加无水硫酸钠(207g,1.46mol,2当量)。在室温搅拌混合物1.5小时。经40分钟逐份添加三乙酰氧基硼氢化钠(463g,2.19mmol,3当量)。再搅拌混合物2小时。在减压下移除大部分乙酸。将所得黑色油状物溶解于乙酸乙酯(2L)中且缓慢添加饱和碳酸氢钠水溶液(1L),继而添加固体碳酸钾以将pH值调节至7。分离有机层,经硫酸钠干燥且过滤。在减压下浓缩滤液,得到黑色油状物,将其通过硅胶色谱纯化,得到标题化合物(120g,约85%纯度(通过LC/MS测定),68%产率)。
实施例70:7-甲氧基-3-甲基异喹啉
将1,1-二甲氧基-N-(3-甲氧基苯甲基)丙-2-胺(92.1g,385mmol)溶解于三氟乙酸(500mL)中。在氮气气氛下于55℃加热此溶液过夜。在减压下移除三氟乙酸,得到棕色油状物(约150g)。将此油状物溶解于异丙醇(800mL)中且添加催化性CuI(8g)。在55℃在对空气开放下搅拌此混合物6小时,接着在室温搅拌2天。经硅藻土垫过滤此混合物。用甲醇(100mL)洗涤硅藻土滤饼。在减压下浓缩滤液,得到棕色油状物。添加二氯甲烷(1.2L)以溶解油状物且用10%氢氧化铵水溶液(2×300mL)及饱和盐水洗涤溶液。经硫酸钠干燥有机相,且过滤。用硅胶处理滤液且在减压下浓缩至干燥。通过硅胶色谱完成纯化,得到标题化合物(约10g)。合并混合的级份且通过硅胶柱再纯化。分离总共15g(15%产率)产物。
实施例71:3-甲基异喹啉-7-醇
将7-甲氧基-3-甲基异喹啉(15g,89mmol,1当量)溶解于二氯甲烷(150mL)中。在室温,将1.0M BBr3的二氯甲烷溶液(240mL,240mmol,2.7当量)缓慢添加至此溶液中,同时观测到轻微放热。在室温搅拌此溶液2.5小时。冷却至0℃后,缓慢添加甲醇(150mL)以淬灭反应。再搅拌溶液15分钟。在减压下浓缩溶液且用甲醇(150mL)处理且在减压下浓缩。在搅拌下用饱和碳酸氢钠水溶液缓慢处理所得油状物直至实现pH约7至8为止。在真空过滤下收集所得固体且用水(300mL)及二氯甲烷(200mL)洗涤,得到棕褐色固体,将其在真空烘箱中于50℃干燥过夜,得到3-甲基异喹啉-7-醇(13.1g,92%产率)。
实施例72:7-(反式-4-叔丁基环己基氧基)-3-甲基异喹啉
将三苯基膦(5.14g,19.6mmol)添加至3-甲基异喹啉-7-醇(2.08g,13.1mmol)及顺式-4-叔丁基环己醇(3.06g,19.6mmol)于甲苯(60mL,600mmol)中的溶液中。搅拌混合物15分钟,接着添加偶氮二甲酸二异丙酯(3.86mL,19.6mmol)。接着在室温搅拌混合物过夜。在真空下移除溶剂。将粗产物溶解于二氯甲烷中,使其吸附至硅胶上且通过快速色谱纯化,得到标题化合物(2.01g,52%产率)。ESI-MS(M+H+):298.46。
实施例73:7-(反式-4-叔丁基环己基氧基)异喹啉-3-甲醛
将二氧化硒(2.25g,20.3mmol)添加至7-(反式-4-叔丁基-环己基氧基)-3-甲基-异喹啉(2.01g,6.76mmol)于二苯醚(50mL,300mmol)中的溶液中且在200℃于密封管中加热混合物4小时。接着将反应混合物冷却至室温。添加硅胶且将烧瓶置放于冷水浴中以使二苯醚溶剂凝固。通过快速色谱纯化此含有粗产物的固体混合物,得到标题化合物(1.04g,49%产率)。ESI-MS(M+H+):312.27。
实施例74:1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸乙酯
将三乙胺(65μL,0.47mmol)添加至7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-甲醛(0.106g,0.340mmol)及哌啶-4-甲酸乙酯(79mg,0.50mmol)于1,2-二氯乙烷(5.00mL)中的溶液中且在室温搅拌混合物1小时。接着添加三乙酰氧基硼氢化钠(0.101g,0.476mmol)且继续搅拌2小时。在二氯甲烷中稀释反应混合物且用饱和碳酸氢钠水溶液洗涤。经硫酸镁干燥有机相,过滤,蒸发。将残余物吸收于二氯甲烷中且添加硅胶。通过蒸发移除溶剂且通过硅胶色谱纯化残余物。分离出101mg(66%)。ESI-MS(M+H+):453.10。
实施例75:1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸
将2M氢氧化锂水溶液(1.00mL,2.00mmol)添加至1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸乙酯(0.101g,0.223mmol)于四氢呋喃(1.00mL)及甲醇(1.00mL)中的溶液中。在室温搅拌混合物。1小时后,在真空下浓缩溶剂。将残余物吸收于DMSO中且浓缩。添加HCl(250μL)以增溶。通过制备性HPLC进行纯化,得到呈二TFA盐形式的产物(13.2mg,产率9%)。ESI-MS(M+H+):425.0。1HNMR(400MHz,DMSO-d6)δ12.49(br.s.,1H),9.24(s,1H),7.87(d,J=9.04Hz,1H),7.83(s,1H),7.61(d,J=1.76Hz,1H),7.40(dd,J=2.26,8.78Hz,1H),4.33-4.49(m,3H),3.04(br.s.,1H),2.16(d,J=10.29Hz,2H),1.95(d,J=11.80Hz,2H),1.71-1.86(m,4H),1.24-1.38(m,2H),1.09-1.23(m,2H),0.96-1.08(m,1H),0.82(s,9H)。
实施例76:1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸乙酯
在室温搅拌6-(反式-4-叔丁基环己基氧基)-2-萘醛(500mg,1.6mmol)、AcOH(288mg,4.8mmol,3.0当量)及4-甲基哌啶-4-甲酸乙酯(410mg,2.4mmol,1.5当量)于DCM(5mL)中的溶液10分钟。接着添加NaBH3CN(300mg,4.8mmol,3.0当量)。在室温搅拌反应混合物12小时,用水(5mL)淬灭且用DCM(3×10mL)萃取。用盐水(10mL)洗涤合并的有机层,经Na2SO4干燥且浓缩。通过硅胶柱色谱(石油醚:乙酸乙酯=3:1)纯化残余物,得到呈黄色油状的1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸乙酯(480mg,产率:30%)。ESI-MS(M+1)+:466.2。1HNMR(400MHz,CDCl3)δ:7.75~7.73(m,3H),7.48(d,1H),7.18~7.15(m,2H),4.28~4.26(m,1H),4.19~4.12(q,2H),4.01(s,2H),3.17~3.15(m,2H),2.59(br,2H),2.29~2.17(m,4H),1.91~1.82(m,4H),1.46~1.43(m,3H),1.30~1.18(m,8H),0.88(s,9H)。
实施例77:1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸
向1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸乙酯(150mg,0.3mmol)于MeOH(5mL)中的溶液中添加NaOH(60mg,1.5mmol,5.0当量)及H2O(0.5mL)。在85℃搅拌反应混合物2小时。用3N HCl将溶液的pH值调节至6。过滤混合物且黄色固体为所需产物1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸(100mg,产率:80%)。ESI-MS(M+1)+:438.3,HPLC:100%。1HNMR(400MHz,DMSO-d6)δ:10.21(s,1H),8.02(br,1H),7.93~7.88(m,2H),7.67(br,1H),7.48(s,1H),7.26(d,1H),4.51~4.45(m,2H),3.35(s,2H),3.32(br,1H),2.92(br,1H),2.29~2.14(m,4H),1.92~1.76(m,4H),1.47~1.12(m,9H),0.93(s,9H)。
实施例78:1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。140mg,黄色油状物,产率:15%。ESI-MS(M+H)+:382.3。1HNMR(400MHz,CDCl3)δ:7.62-7.55(m,3H),7.34(d,J=10Hz,1H),7.02-7.01(m,2H),4.82-4.81(m,1H),4.04(q,J=7.2Hz,2H),3.52(s,2H),2.83-2.80(m,2H),2.21-2.17(m,1H),1.97-1.72(m,12H),1.58-1.56(m,2H),1.18-1.14(m,3H)。
实施例79:1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。100mg,黄色固体,产率:90%。ESI-MS(M+H)+:354.2,HPLC:97.41%。1HNMR(400MHz,CD3OD),δ:7.94(s,1H),7.87(d,J=8.4Hz,1H),7.83(d,J=8.8Hz,1H),7.53(dd,J=8.4,1.2Hz,1H),7.26(s,1H),7.11(dd,J=8.8,2.4Hz,1H),5.00-4.98(m,1H),4.43(s,2H),3.48-3.46(m,2H),3.15-3.12(m,2H),2.63-2.61(m,1H),2.19-2.15(m,2H),2.03-2.00(m,3H),1.91-1.87(m,5H),1.72-1.68(m,2H)。
实施例80:1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。200mg,无色油状物,产率:60%。ESI-MS(M+H)+:410.1。1HNMR(400MHz,DMSO-d6),δ:7.78-7.71(m,2H),7.66(s,1H),7.38(dd,J=8.4,1.6Hz,1H),7.23(d,J=2.0Hz,1H),7.10(dd,J=8.8,2.8Hz,1H),4.66-4.62(m,1H),4.04(q,J=7.2Hz,2H),3.54(s,2H),2.79-2.75(m,2H),2.31-2.56(m,1H),2.04-1.98(m,4H),1.79-1.71(m,6H),1.59-1.45(m,11H)。
实施例81:1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。60mg,白色固体,产率:64%。ESI-MS(M+H)+:382.1。HPLC:100%。1HNMR(400MHz,DMSO-d6δ:7.78-7.71(m,2H),7.66(s,1H),7.38(dd,J=8.4,1.6Hz,1H),7.23(d,J=2.0Hz,1H),7.09(dd,J=9.2,2.4Hz,1H),4.65-4.61(m,1H),3.53(s,2H),2.76-2.73(m,2H),2.16-2.13(m,1H),2.06-1.95(m,4H),1.79-1.66(m,6H),1.59-1.49(m,8H)。
实施例82:1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。120mg,黄色油状物,产率:13%。ESI-MS(M+H)+:398.1。1H NMR(400MHz,CDCl3)δ:7.65(d,J=9.2Hz,1H),7.60-7.58(m,2H),7.38(d,J=9.6Hz,1H),7.07-7.06(m,2H),4.58-4.54(m,1H),4.05(q,J=7.2Hz,2H,),3.97-3.92(m,2H),3.58-3.52(m,4H),2.83-2.80(m,2H),2.23-2.17(m,1H),2.04-1.99(m,4H),1.83-1.72(m,6H),1.17(t,J=7.2Hz,3H)。
实施例83:1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。90mg,微黄色固体,产率:90%。ESI-MS(M+H)+:370.1,HPLC:97.18%。1HNMR(400MHz,CD3OD)δ:7.85(s,1H),7.78-7.74(m,2H),7.43(d,J=8.8Hz,1H),7.26(s,1H),7.14(dd,J=9.2,2.4Hz,1H),4.69-4.65(m,1H),4.32(s,2H),3.91-3.82(m,2H),3.58-3.52(m,2H),3.37-3.35(m,2H),3.06-3.03(m,2H),2.54-2.52(m,1H),2.07-1.99(m,4H),1.87-1.86(m,2H),1.73-1.64(m,2H)。
实施例84:1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。1.03g,黄色油状物,产率:74%。ESI-MS(M+H)+:464.10。
实施例85:1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。14mg,微黄色固体,产率:5%。ESI-MS(M+H)+:436.0,HPLC:95%。1HNMR(400MHz,CD3OD)δ:7.92(s,1H),7.88(d,J=8.47Hz,1H),7.84(d,J=9.04Hz,1H),7.50(dd,J=8.47,1.76Hz,1H),7.30(s,1H),7.22(dd,J=8.97,2.38Hz,1H),4.53(双五重峰,J=8.07,4.18,4.18,4.18,4.18Hz,1H),4.44(s,2H),3.59(d,J=12.74Hz,2H),3.09(td,J=13.13,2.85Hz,2H),2.57-2.70(m,1H),2.17-2.32(m,2H),1.21-2.01(m,20H)。
实施例86:1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。977mg,黄色油状物,产率:76%。ESI-MS(M+H)+:436.0。
实施例87:1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。14mg,微黄色固体,产率:2%。ESI-MS(M+H)+:408.0,HPLC:95%。1HNMR(400MHz,CD3OD)δ:1.43-2.06(m,16H),2.25(d,J=16.82Hz,2H),2.64(tt,J=12.44,3.78Hz,1H),3.00-3.14(m,2H),3.59(d,J=13.68Hz,2H),4.44(s,2H)4.46-4.56(m,1H),7.22(dd,J=8.88,2.48Hz,1H),7.30(s,1H),7.50(dd,J=8.53,1.76Hz,1H),7.84(d,J=9.04Hz,1H),7.88(d,J=8.66Hz,1H),7.92(s,1H)。
实施例88:1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-2-甲酸
将呈HCl盐形式的哌啶-2-甲酸(0.125g,0.967mmol)与6-(4-叔丁基-环己基氧基)-萘-2-甲醛(0.250g,0.805mmol)在1,2-二氯乙烷(5mL,60mmol)及乙酸(0.500mL,8.79mmol)中组合。将混合物加热至回流,同时搅拌过夜。将反应混合物冷却至室温且接着逐小份添加三乙酰氧基硼氢化钠(546mg,2.58mmol)。接着搅拌反应混合物过夜。接着通过反相色谱(5%-95%CH3CN/水(0.1%TFA),C18,150mm)直接纯化反应混合物。接着将产物冻干至干燥,得到3mg呈黄色固体状的1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-2-甲酸(0.8%)。ESI-LCMS(424M+H)。1HNMR(DMSO-d6,400MHz):δ(ppm)12.34-12.58(m,1H),11.20-11.53(m,1H),8.01(s,1H),7.68-7.93(m,3H),7.41(s,1H),7.02-7.22(m,1H),4.35(br.s.,3H),3.23-3.43(m,2H),2.86-3.09(m,2H),1.74-2.30(m,8H),1.00-1.52(m,5H),0.87(s,9H)。
实施例89:6-羟基-1,2,3,4-四氢萘-2-甲酸甲酯
向6-羟基-1,2,3,4-四氢萘-2-甲酸(0.5g,3mmol)于甲醇(6mL,200mmol)中的溶液中添加硫酸(0.05g,0.5mmol)且历经周末搅拌。浓缩后,将残余物溶解于EtOAc中且用水、盐水洗涤且经Na2SO4干燥,得到呈白色固体状的纯产物(0.55g,100%)。LCMS:Rt=1.17分钟,m/z=207.00[M+],100%。
实施例90:6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-甲酸甲酯
搅拌6-羟基-1,2,3,4-四氢-萘-2-甲酸甲酯(0.280g,1.36mmol)、反式-4-叔丁基环己醇(0.2338g,1.496mmol)及三苯基膦(0.7122g,2.715mmol)于甲苯(5mL,50mmol)中的混合物20分钟,接着在0℃逐滴添加偶氮二甲酸二异丙酯(0.34mL,1.6mmol)。在回流下搅拌溶液过夜。向反应混合物中添加硅胶且浓缩溶剂。用硅胶(用0%至20% EtOAc/己烷洗脱)纯化残余物,得到呈白色沉淀物状的产物(73mg,16%)。LCMS Rt=1.50分钟,m/z=450.10[M+H]。
实施例91:(6-(((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-基)甲醇
向四氢呋喃(0.86mL,1.0E1mmol)中的6-(反式-4-叔丁基-环己基氧基)-1,2,3,4-四氢-萘-2-甲酸甲酯(73mg,0.21mmol)中添加1.00M四氢铝酸锂的四氢呋喃溶液(0.64mL,0.64mmol)。在室温搅拌1小时后,添加EtOAc及罗谢尔盐溶液(Rochele's salt solution)且搅拌30分钟。用EtOAc萃取混合物且用硅胶纯化,得到产物(73mg,100%)。LCMS:Rf=2.24分钟,m/z=317.10。
实施例92:6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-甲醛
向[6-(反式-4-叔丁基-环己基氧基)-1,2,3,4-四氢-萘-2-基]-甲醇(73mg,0.23mmol)于二氯甲烷(1.478mL,23.07mmol)中的溶液中添加戴斯-马丁高碘烷(Dess-Martin periodinane)(0.1468g,0.3460mmol)且在室温搅拌1小时。通过硅胶塞后,浓缩溶剂,得到产物(27mg,37%)。LCMS:Rf=2.39分钟,m/z=315.00。
实施例93:1-((6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-基)甲基)哌啶-4-甲酸
将6-(反式-4-叔丁基-环己基氧基)-1,2,3,4-四氢-萘-2-甲醛(34.5mg,0.110mmol)及哌啶-4-甲酸(14.2mg,0.110mmol)于乙醇(0.8mL,10mmol)中的溶液加热至回流并维持2小时。将黄色溶液冷却至室温且添加氰基硼氢化钠(8.27mg,0.132mmol)且加热至回流并维持1小时。冷却至室温后,添加柠檬酸且浓缩。将固体悬浮于水中且过滤且用水充分洗涤收集的固体。HPLC纯化固体,得到产物(1.6mg,3.4%)。LCMS Rt=1.76分钟,m/z=428.42[M+1]。1HNMR(400MHz,甲醇-d4)δppm 0.91(s,9H),1.02-1.48(m,10H),1.80-2.47(m,11H),2.47-3.01(m,3H),3.66-3.96(m,3H),4.07-4.26(m,1H),6.67-6.83(m,2H),6.99-7.15(m,1H)。
实施例94:1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
搅拌1-(6-羟基-萘-2-基甲基)-哌啶-4-甲酸乙酯(0.400g,1.28mmol)、4-苯基-环己醇(0.2479g,1.406mmol)及三苯基膦(0.6695g,2.553mmol)于甲苯(5mL,40mmol)中的混合物20分钟,接着在0℃逐滴添加偶氮二甲酸二异丙酯(0.32mL,1.5mmol)。在回流下搅拌溶液过夜。向反应混合物中添加硅胶且浓缩溶剂。用硅胶(用0%至20%EtOAc/己烷洗脱)纯化残余物,得到呈油状的产物(0.3g,50%)。LCMS:Rt=1.75分钟,m/z=472.45[M+H]。
实施例95:1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
在室温搅拌1-[6-(顺式-4-苯基-环己基氧基)-萘-2-基甲基]-哌啶-4-甲酸乙酯(0.9g,2mmol)及氢氧化锂(457mg,19.1mmol)于四氢呋喃(7.74mL,95.4mmol)及水(1.72mL,95.4mmol)中的溶液过夜。LCMS显示单一所需产物峰Rt=1.60分钟,m/z=444.35,[M+1],100%。浓缩溶剂且用浓HCl中和且浓缩且经HPLC纯化,得到产物(245mg,30%)。1HNMR(400MHz,甲醇-d4)δppm 1.59-2.17(m,13H),2.26(d,J=10.35Hz,2H),2.59-2.73(m,1H),2.93(d,J=11.61Hz,2H),3.64(s,2H),4.84(br.s.,1H),7.19(s,1H),7.23(d,J=11.36Hz,1H),7.28(s,5H),7.45(d,J=8.41Hz,1H),7.65-7.74(m,2H),7.77(d,J=8.97Hz,1H)。
实施例96:1-((6-((顺式-4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
搅拌1-(6-羟基-萘-2-基甲基)-哌啶-4-甲酸乙酯(0.400g,1.28mmol)、反式-4-(1,1-二甲基-丙基)-环己醇(0.2395g,1.406mmol)及三苯基膦(0.6695g,2.553mmol)于甲苯(5mL,40mmol)中的混合物20分钟,接着在0℃逐滴添加偶氮二甲酸二异丙酯(0.32mL,1.5mmol)。在回流下搅拌溶液过夜。将反应混合物添加至硅胶中且浓缩溶剂。用硅胶(用0%至20%EtOAc/己烷洗脱)纯化残余物,得到呈油状的产物(0.6g,100%)。LCMS:Rt=1.95分钟,m/z=466.49[M+H]。
实施例97:1-((6-((顺式-4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
在室温搅拌1-{6-[顺式-4-(1,1-二甲基-丙基)-环己基氧基]-萘-2-基甲基}-哌啶-4-甲酸乙酯(0.382g,0.820mmol)及氢氧化锂(196mg,8.20mmol)于四氢呋喃(3.32mL,41.0mmol)及水(0.738mL,41.0mmol)中的溶液过夜。LCMS显示单一所需产物峰Rt=1.78分钟,m/z=438.40[M+1],100%。浓缩溶剂且用浓HCl中和。用水使固体悬浮且过滤且用水及乙醚充分洗涤,接着干燥,得到白色固体(86.9mg,24%)。1HNMR(400MHz,甲醇-d4)δppm0.81-0.90(m,9H),1.19-1.70(m,10H),2.19(d,J=13.99Hz,2H),2.67(s,2H),4.45(s,2H),4.78(t,J=2.45Hz,1H),7.26(dd,J=8.91,2.45Hz,1H),7.31(d,J=2.26Hz,1H),7.53(dd,J=8.50,1.73Hz,1H),7.86(dd,J=8.69,3.42Hz,2H),7.96(s,1H)。
实施例98:合成3-甲基哌啶-4-甲酸乙酯盐酸盐:
在回流下搅拌3-甲基哌啶-4-甲酸盐酸盐(3.3g,18.4mmol,1.0当量)及SOCl2(6.6g,55.3mmol,3.0当量)于EtOH(30mL)中的混合物3小时,且接着通过真空浓缩反应混合物,得到呈黄色油状的化合物3-甲基哌啶-4-甲酸乙酯盐酸盐,其供下一步用。ESI-MS(M+H)+:172.2。
实施例99:合成1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯:
在50℃搅拌6-((反式-4-(叔丁基)环己基)氧基)-2-萘醛(6.85g,22.10mmol,1.2当量)及3-甲基哌啶-4-甲酸乙酯盐酸盐(3.15g,18.42mmol,1.0当量)于无水DCE(30mL)中的混合物3小时,且接着冷却至室温,添加NaBH(OAc)3(7.81g,36.84mmol,2.0当量)。在室温搅拌所得混合物4小时。用Na2CO3水溶液将反应混合物调节至pH值=7。接着用水(20mL)稀释混合物且用DCM(30mL×3)萃取。经无水Na2SO4干燥合并的有机层且在真空中浓缩,得到残余物,将其通过硅胶柱色谱(PE/EA=5:1)纯化,得到呈黄色油状的1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯(5.0g,产率:58%(两个步骤))。ESI-MS(M+H)+:466.2。1HNMR(400MHz,CDCl3)(异构体的混合物)δppm7.63-7.56(m,3H),7.38-7.37(m,1H),7.07-7.03(m,2H),4.21-4.16(m,1H),4.09-4.03(m,2H),3.58-3.41(m,2H),2.82-2.78(m,1H),2.62-2.59(m,1H),2.44-2.38(m,1H),2.22-1.80(m,8H),1.64-1.52(m,1H),1.40-1.31(m,2H),1.17(t,J=6.8Hz,3H),1.13-1.02(m,3H),0.93(d,J=6.8Hz,3H),0.82(s,9H)。
实施例100:1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸
向1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯(750mg,1.62mmol,1.0当量)于THF/H2O(8/1,9.0mL)中的溶液中添加NaOH(130mg,3.24mmol,2.0当量)。将混合物加热至60℃且搅拌16小时。冷却至室温后,用HCl水溶液将反应混合物调节至pH值=7。在真空中移除溶剂,得到残余物,将其通过硅胶(DCM/MeOH=15:1)纯化,得到呈白色固体状的1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸(620mg,产率:88%)。ESI-MS(M+H)+:438.3。HPLC:100.00%;1HNMR(400MHz,CDCl3)δppm 10.82(br,1H),7.65-7.54(m,3H),7.41-7.40(m,1H),7.04-7.02(m,2H),4.20-4.14(m,1H),3.85(s,2H),3.15-3.07(m,2H),2.77-2.71(m,1H),2.50-2.46(m,1H),2.18-2.16(m,3H),1.96-1.92(m,2H),1.81-1.78(m,2H),1.36-0.96(m,9H),0.82(s,9H)。
在IC(2×15cm)上在20%乙醇(0.2%DEA)/CO2(100巴,60毫升/分钟,220nm,注射体积:1mL,3mg/mL1:2DCM:甲醇)下用SFC分离1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸(2.8g,6.4mmol),得到1.4g异构体-1(化学纯度>95%,ee>99%)及1.4g异构体2(化学纯度>99%,ee>99%)。异构体-1:LCMS Rt=1.66分钟,m/z=438.20。1H NMR(400MHz,甲醇-d4)δppm 7.75(d,J=6.53Hz,3H),7.47(d,J=8.53Hz,1H),7.25(s,1H),7.13(d,J=8.78Hz,1H),4.36(t,J=11.42Hz,1H),3.62(q,J=7.19Hz,4H),2.84-3.06(m,4H),1.10-2.46(m,22H),1.06(d,J=6.8Hz,3H),0.94(s,12H);
异构体-2:LCMSRt=1.66分钟,m/z=438.20。1HNMR(400MHz,甲醇-d4)δppm7.75(d,J=6.53Hz,3H),7.47(d,J=8.53Hz,1H),7.25(s,1H),7.13(d,J=8.78Hz,1H),4.36(t,J=11.42Hz,1H),3.62(q,J=7.19Hz,4H),2.84-3.06(m,4H),1.10-2.46(m,22H),1.06(d,J=6.8Hz,3H),0.94(s,12H)。
实施例101:1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。82mg,微黄色油状物,产率:38%。ESI-MS(M+1)+:452.2。1H NMR(400MHz,CDCl3)δ:7.66-7.63(m,3H),7.40-7.39(m,1H),7.08-7.05(m,2H),4.12-4.03(m,3H),3.54(s,2H),2.84-2.80(m,1H),2.25-2.15(m,2H),1.81-1.69(m,1H),1.70-1.66(m,2H),1.25-1.15(m,11H),1.10-0.91(m,4H),0.87(d,J=6.8Hz,6H),0.71(d,J=6.8Hz,3H)。
实施例102:1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。62mg,微黄色固体,产率:51%。ESI-MS(M+1)+:424.4,HPLC:98.67%。1H NMR(400MHz,DMSO-d6)δ:7.80-7.73(m,3H),7.44-7.37(m,2H),7.14(d,J=7.6Hz,1H),4.30(t,J=6.4Hz,1H),3.44(s,2H),2.86-2.81(m,2H),2.19-2.12(m,3H),1.84-1.81(m,2H),1.73-1.47(m,6H),1.26-1.12(m,3H),1.02-0.96(m,2H),0.90(d,J=6.8Hz,6H),0.75(d,J=7.2Hz,3H)。
实施例103:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。400mg,黄色油状物,产率:75%。ESI-MS(M+H)+:424.1。1HNMR(400MHz,CDCl3)δ:7.45-7.38(m,3H),7.18(d,J=8.4Hz,1H),6.89-6.82(m,2H),4.14-4.09(m,1H),3.87(q,J=7.6Hz,2H),3.35-3.25(m,3H),2.63-2.57(m,2H),2.58-2.54(m,1H),2.09-1.72(m,7H),1.00-0.93(m,6H),0.74-0.72(m,6H),0.68-0.65(m,3H)。
实施例104:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。150mg,微黄色固体,产率:40%。ESI-MS(M+H)+:396.3,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.94(s,1H),7.87(d,J=8.4Hz,1H),7.84(d,J=9.2Hz,1H),7.51(dd,J=8.8,1.6Hz,1H),7.30(d,J=2.0Hz,1H),7.22(dd,J=9.2,2.4Hz,1H),4.56-4.51(m,1H),4.44(s,2H),3.58-3.55(m,2H),3.09-3.04(m,2H),2.63-2.60(m,1H),2.23-2.21(m,2H),1.98-1.74(m,6H),1.59-1.54(m,2H),1.41-1.37(m,2H),1.01(d,J=3.6Hz,6H)。
实施例105:1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。370mg,黄色固体,产率:53%,ESI-MS(M+1)+:438.2。1HNMR(400MHz,CDCl3)(顺式异构体与反式异构体的混合物)δ:7.92(s,1H),7.88-7.82(m,2H),7.50(d,J=8.8Hz,1H),7.31(s,1H),7.20(d,J=8.8Hz,1H),4.58-4.55(m,0.4H),4.22-4.20(m,0.4H),4.13(q,J=7.2Hz,2H),3.55-3.54(m,1H),3.12-3.00(m,2H),2.66-2.60(m,2H),2.25-2.23(m,3H),2.08-2.01(m,2H),1.93-1.90(m,3H),1.57-1.52(m,1H),1.44-1.15(m,13H),0.94(t,J=7.2Hz,3H)。
实施例106:1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。120mg,产率:85%。ESI-MS(M+1)+:410.3。HPLC:100%。1HNMR(400MHz,CD3OD)(顺式异构体与反式异构体的混合物)δ:7.92(s,1H),7.89-7.81(m,2H),7.50(dd,J=8.8,2.0Hz,1H),7.30(s,1H),7.19(d,J=8.8Hz,1H),4.82-4.80(m,0.4H),4.44(s,2H),4.43-4.40(m,0.6H),3.55-3.52(m,1H),3.10-3.09(m,2H),2.64-2.62(m,1H),2.24-2.22(m,3H),2.08-2.02(m,1H),1.91-1.88(m,3H),1.59-1.50(m,1H),1.44-1.13(m,10H),0.93(t,J=7.2Hz,3H)。
实施例107:1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。100mg,黄色油状物,产率:20%。ESI-MS(M+H)+:368.3。1HNMR(400MHz,CDCl3)δ:7.71-7.67(m,3H),7.43(d,J=10Hz,1H),7.09(d,J=8.8Hz,1H),6.99(s,1H),4.81-4.76(m,1H),4.14(q,J=7.2Hz,2H),3.92(t,J=6.4Hz,1H),3.61(s,2H),2.90-2.87(m,2H),2.55-2.52(m,1H),2.27-2.20(m,2H),2.05-2.02(m,3H),1.80-1.76(m,5H),1.26-1.23(m,5H)。
实施例108:1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸
1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。80mg,黄色油状物,产率:85%。ESI-MS(M+H)+:340.3,HPLC:97.37%。1H NMR(400MHz,CDCl3)δ:7.93(s,1H),7.87-7.81(m,2H),7.51(dd,J=8.0,1.2Hz,1H),7.19-7.15(m,2H),4.86-4.83(m,1H),4.42(s,2H),3.48(br,2H),3.15(br,2H),2.58-2.55(m,3H),2.21-2.16(m,4H),1.81-1.78(m,4H)。
实施例109:1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸乙酯
在室温搅拌1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙酮(200mg,0.62mmol)及4-哌啶甲酸乙酯(146mg,0.93mmol,1.5当量)于无水EtOH(5mL)中的混合物15分钟,接着添加Ti(OEt)4(356mg,1.23mmol,2当量)。在回流下于N2下搅拌反应混合物16小时。冷却至室温后,浓缩混合物且将残余物溶解于EtOH(3mL)中且添加NaBH3CN(125mg,1.85mmol,3当量)。在室温搅拌反应混合物2小时。浓缩混合物且通过硅胶(PE/EA=4/1)纯化,得到呈黄色油状的1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸乙酯(140mg,产率:53%)。ESI-MS(M+H+):466.4。1HNMR(400MHz,CDCl3)δ:7.71-7.65(m,2H),7.60(s,1H),7.44(d,J=8.0Hz,1H),7.14-7.11(m,2H),4.29-4.24(m,1H),4.11(q,J=7.2Hz,2H),3.56(br,1H),3.07(br,1H),2.84(br,1H),2.29-2.20(m,3H),2.08-2.01(m,4H),1.90-1.81(m,5H),1.45-1.38(m,5H),1.26-1.09(m,6H),0.89(s,9H)。
实施例110:1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸
将1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸乙酯(100mg,0.22mmol)溶解于EtOH(5mL)中。接着添加水(0.5mL)中的氢氧化钠(44mg,1.1mmol,5.0当量)。在85℃搅拌混合物2小时。移除溶剂且将残余物溶解于H2O(3mL)中。添加1MHCl水溶液以调节pH值=7。过滤混合物,得到呈白色固体状的1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸(50mg,50%)。ESI-MS(M+H+):438.3。HPLC:100%。1HNMR(400MHz,CD3OD)δ:7.80-7.78(m,2H),7.34(d,J=8.8Hz,1H),7.42(dd,J=8.4,1.6Hz,1H),7.22(d,J=2.0Hz,1H),7.11(dd,J=8.8,2.0Hz,1H),4.37-4.28(m,2H),3.24-3.17(m,2H),2.82-2.76(m,2H),2.23-2.19(m,3H),1.97-1.84(m,5H),1.71(d,J=6.8Hz,3H),1.41-1.32(m,2H),1.26-1.16(m,3H),1.10-1.04(m,1H),0.86(s,9H)。
实施例111:1-(叔丁基)-4-亚甲基环己烷
在-78℃向溴化甲基三苯基鏻(5.36g,15mmol,1.5当量)于无水THF(40mL)中的溶液中添加n-BuLi(2.5M)(6mL,15mmol,1.5当量)。在室温搅拌混合物1小时。在-78℃将4-(叔丁基)环己酮(1.54g,10mmol)于THF(10mL)中的溶液添加至反应混合物中。在70℃搅拌混合物12小时。移除溶剂且将残余物悬浮于己烷中。过滤混合物且浓缩滤液,得到呈黄色油状的1-(叔丁基)-4-亚甲基环己烷(0.80g,产率:50%)。1HNMR(400MHz,CDCl3)δ:4.58(s,2H),2.34-2.31(m,2H),2.01-1.95(m,2H),1.88-1.84(m,2H),1.14-1.06(m,3H),0.86(s,9H)。
实施例112:1-((6-(((三氟甲基)磺酰基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
在0℃向1-((6-羟基萘-2-基)甲基)哌啶-4-甲酸乙酯(1g,3.19mmol)及TEA(0.64g,6.38mmol,2当量)于DCM(20mL)中的溶液中逐滴添加Tf2O(1.8g,6.38mmol,2当量)。在室温搅拌混合物12小时。在0℃用水淬灭反应,用饱和NaHCO3(10mL)及盐水(5mL×3)洗涤。经Na2SO4干燥有机层且浓缩,得到呈棕色固体状的1-((6-(((三氟甲基)磺酰基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(350mg,产率:90%)。ESI-MS:446.1(M+H)+。1HNMR(400MHz,CDCl3)δ:7.88(d,J=9.2Hz,1H),7.84-7.82(m,2H),7.79(s,1H),7.60(d,J=7.6Hz,1H),7.35(d,J=9.2Hz,1H),4.13(q,J=7.6Hz,2H),3.66(s,2H),2.89-2.86(m,2H),2.32-2.28(m,1H),2.11-2.07(m,2H),1.88-1.78(m,4H),1.26(t,J=7.6Hz,3H)。
实施例113:1-((6-((4-(叔丁基)亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯
向密封管中添加1-((6-(((三氟甲基)磺酰基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯(500mg,1.12mmol)、1-(叔丁基)-4-亚甲基环己烷(340mg,2.24mmol,2当量)、K2CO3(309mg,2.24mmol,2当量)、Xantphos(130mg,0.22mmol,0.2当量)、Pd(OAc)2(25mg,0.11mmol,0.1当量)及NMP(2mL)。用N2吹洗混合物5分钟。接着在120℃搅拌反应混合物12小时。用乙酸乙酯(20mL)稀释反应混合物且用水(5mL×3)洗涤。在真空中移除有机溶剂且通过硅胶色谱(石油醚:乙酸乙酯=2:1)纯化残余物,得到呈黄色固体状的1-((6-((4-(叔丁基)亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(180mg,产率:35%)。ESI-MS(M+1)+:448.3。1HNMR(400MHz,CDCl3)δ:7.76-7.73(m,2H),7.68(s,1H),7.61(s,1H),7.46(d,J=8.0Hz,1H),7.34(d,J=8.8Hz,1H),6.34(s,1H),4.13(q,J=8.8Hz,2H),3.64(s,2H),2.92-2.89(m,2H),2.30-2.25(m,2H),2.08-2.05(m,2H),1.94-1.77(m,8H),1.60(br,2H),1.26-1.23(m,5H),0.87(s,9H)。
实施例114:1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯
向100mL圆底烧瓶中添加1-((6-((4-(叔丁基)亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(200mg,0.45mmol)、Pd/C(20%,20mg)及THF(30mL)。用氢气吹洗反应混合物3次且在H2气氛下搅拌48小时。过滤反应混合物且在真空中浓缩滤液,得到呈紫色油状的所需化合物1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(150mg,产率:30%)。ESI-MS(M+1)+:450.3。
实施例115:1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸
向1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸乙酯(150mg,0.33mmol)于MeOH(5mL)中的溶液中添加NaOH(68mg,1.7mmol,5.0当量)及H2O(0.5mL)。在80℃搅拌反应混合物4小时。用3NHCl将溶液的pH值调节至6。过滤混合物且通过制备性HPLC(CH3CN:H2O/0.05%TFA=0%-95%)纯化黄色固体,得到所需产物1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸(120mg,85%)。ESI-MS(M+1)+:422.3。1HNMR(400MHz,CD3OD)δ:7.89(s,1H),7.84~7.81(m,1H),7.77-7.74(m,1H),7.58(d,J=10Hz,1H),7.43(d,J=8.8Hz,1H),7.35~7.32(m,1H),4.36(s,2H),3.50~3.46(m,2H),3.22-3.20(m,2H),2.77-2.75(m,1H),2.58-2.56(m,2H),2.15-2.11(m,2H),1.91(br,1H),1.75-1.66(m,3H),1.56-1.25(m,6H),1.00-0.88(m,2H),0.81(s,9H)。HPLC:96.20%。
实施例116:1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。150mg,黄色油状物,产率:40%。ESI-MS(M+H)+:384.2。1H NMR(400MHz,CDCl3)δ:7.65-7.60(m,3H),7.38(d,J=8.4Hz,1H),7.06(dd,J=8.8,2.4Hz,1H),6.97(s,1H),4.93-4.91(m,1H),4.89-4.85(m,2H),4.03-3.98(m,5H),3.87-3.84(m,1H),3.55(s,2H),2.84-2.81(m,2H),2.22-2.15(m,3H),2.02-1.98(m,3H),1.80-1.70(m,4H)。
实施例117:1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。100mg,微黄色固体,产率:85%。ESI-MS(M+H)+:356.1,HPLC:100.0%。1HNMR(400MHz,CD3OD)δ:7.94(s,1H),7.89-7.83(m,2H),7.43(dd,J=8.4,1.6Hz,1H),7.25(s,1H),7.20(dd,J=8.8,2.4Hz,1H),5.17-5.14(m,1H),4.43(s,2H),4.04-3.99(m,3H),3.92-3.89(m,1H),3.52-3.50(m,2H),3.15-3.12(m,2H),2.68-2.65(m,1H),2.34-2.30(m,1H),2.18-2.14(m,3H),2.00-1.94(m,2H)。
实施例118:1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。200mg,黄色固体,产率:55%。ESI-MS(M+H)+:396.1。1HNMR(400MHz,CDCl3)δ:7.72-7.65(m,3H),7.44(d,J=8.4Hz,1H),7.16-7.13(m,2H),4.41-4.39(m,1H),4.13(q,J=7.2Hz,2H),3.62(s,2H),2.92-2.89(m,2H),2.31-2.29(m,2H),2.09-2.06(m,4H),1.91-1.78(m,7H),1.64-1.56(m,4H),1.27-1.25(m,3H)。
实施例119:1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。130mg,微黄色固体,产率:80%。ESI-MS(M+H)+:368.3,HPLC:99.06%。1H NMR(400MHz,CD3OD)δ:7.92(s,1H),7.88-7.82(m,2H),7.50(dd,J=8.8,1.6Hz,1H),7.30(s,1H),7.21(dd,J=8.8,2.4Hz,1H),4.52-4.51(m,1H),4.43(s,2H),3.57-3.55(m,2H),3.12-3.09(m,2H),2.67-2.64(m,1H),2.22-2.19(m,2H),2.08-2.04(m,2H),1.86-1.84(m,3H),1.57-1.37(m,7H)。
实施例120:6-((叔丁基二甲基甲硅烷基)氧基)-2-甲基喹啉
在0℃向2-甲基喹啉-6-醇(6.36g,40mmol)及咪唑(5.44g,80mmol,2当量)于DMF(100mL)中的溶液中添加TBSCl(9g,60mmol,1.5当量)。接着使反应混合物升温至室温且搅拌1小时。用乙酸乙酯(200mL)稀释反应混合物,用H2O(2×200mL)及盐水(200mL)洗涤。干燥(Na2SO4)合并的有机层且浓缩,得到呈黄色固体状的粗6-((叔丁基二甲基甲硅烷基)氧基)-2-甲基喹啉(14g,产率:100%)。ESI-MS(M+H)+:274.2。1HNMR(400MHz,CDCl3)δ:7.94-7.92(m,2H),7.26(dd,J=8.8,2.0Hz,1H),7.21(d,J=8.4Hz,1H),7.13(d,J=2.4Hz,1H),2.73(s,3H),1.05(s,9H),0.28(s,6H)。
实施例121:6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-甲醛
在回流下于N2下搅拌6-((叔丁基二甲基甲硅烷基)氧基)-2-甲基喹啉(6.5g,23.8mmol)及SeO2(11g,95.2mmol,4当量)于甲苯(100mL)中的混合物2小时。冷却至室温后,过滤混合物且浓缩滤液,得到呈黄色固体状的6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-甲醛(5.3g,产率:78%),其未经进一步纯化即用于下一步。ESI-MS(M+H)+:288.2。1HNMR(400MHz,CDCl3)δ:10.19(s,1H),8.15-8.13(m,2H),7.98(d,J=8.4Hz,1H),7.40(dd,J=9.2,2.8Hz,1H),7.20(d,J=2.8Hz,1H),1.03(s,9H),0.30(s,6H)。
实施例122:1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
在室温搅拌DCE(100mL)中的6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-甲醛(5.74g,20mmol)、AcOH(3.6g,60mmol,3当量)及4-哌啶甲酸乙酯(6.28g,40mmol,2当量)30分钟。接着在室温将NaBH(OAc)3(12.7g,60mmol,3当量)添加至混合物中且搅拌3小时。用水(300mL)淬灭反应混合物,且用浓NH3水溶液调节至pH值=8。接着用DCM(3×400mL)萃取混合物。通过盐水(300mL)洗涤合并的有机层,干燥(Na2SO4)且浓缩。通过硅胶色谱(PE:EA=4:1)纯化粗产物,得到呈黄色油状的1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯(6.65g,产率:77%)。ESI-MS(M+H)+:429.3。1H NMR(400MHz,CDCl3)δ:7.97(d,J=8.4Hz,1H),7.94(d,J=9.2Hz,1H),7.57(d,J=8.4Hz,1H),7.27(dd,J=9.2,2.4Hz,1H),7.12(d,J=2.8Hz,1H),4.12(q,J=7.2Hz,2H),3.78(s,2H),2.92-2.89(m,2H),2.30-2.25(m,1H),2.20-2.15(m,2H),1.91-1.79(m,4H),1.25(t,J=7.2Hz,3H),1.02(s,9H),0.25(s,6H)。
实施例123:1-((6-羟基喹啉-2-基)甲基)哌啶-4-甲酸乙酯
在0℃向1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯(6.5g,15.2mmol)于乙醇(100mL)中的溶液中逐滴添加浓HCl(13mL)。在室温搅拌反应混合物3小时。通过饱和NaHCO3中和混合物且移除溶剂。接着用DCM(3×30mL)萃取混合物。通过盐水(30mL)洗涤合并的有机层,经Na2SO4干燥且浓缩,得到呈白色固体状的粗产物1-((6-羟基喹啉-2-基)甲基)哌啶-4-甲酸乙酯(3.9g,产率:80%)。ESI-MS(M+H)+:315.2。1HNMR(400MHz,CDCl3)δ:7.88(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),7.53(d,J=8.4Hz,1H),7.22(dd,J=9.2,2.4Hz,1H),7.04(s,1H),4.11(q,J=7.2Hz,2H),3.80(s,2H),2.93-2.90(m,2H),2.28-2.16(m,3H),1.89-1.76(m,4H),1.22(t,J=7.2Hz,3H)。
实施例124:合成1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
在N2下,向25mL圆底烧瓶中添加1-((6-羟基喹啉-2-基)甲基)哌啶-4-甲酸乙酯(314mg,0.1mmol)、环己醇(200mg,0.2mmol,2当量)、PPh3(562mg,0.2mmol,2当量)及无水甲苯(0.5mL)。接着在室温一次性快速添加DIAD(404mg,0.2mmol,2当量)。在30℃搅拌反应混合物30分钟。在减压下移除溶剂且通过硅胶柱色谱(PE:EA=4:1)纯化残余物,得到呈微黄色油状的1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯(168mg,产率:43%)。ESI-MS(M+H)+:397.2。1H NMR(400MHz,CDCl3)δ:7.99(d,J=8.4Hz,1H),7.94(d,J=9.6Hz,1H),7.69-7.64(m,1H),7.33(dd,J=8.8,2.4Hz,1H),7.07(d,J=2.0Hz,1H),4.43-4.37(m,1H),4.13(q,J=7.2Hz,2H),3.78(s,2H),2.93-2.89(m,2H),2.08-2.03(m,3H),1.87-1.82(m,4H),1.63-1.55(m,5H),1.46-1.26(m,5H),1.23(t,J=7.2Hz,3H)。
实施例125:1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
将1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯(117mg,0.30mmol)溶解于EtOH(5mL)中。在室温一次性添加NaOH(24mg,0.60mmol,2当量)。在回流下搅拌混合物2小时。移除溶剂,且将残余物溶解于H2O(3mL)中且用HCl(1M)调节至pH值=7。收集沉淀物且在真空下干燥,得到呈白色固体状的1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸(40mg,产率:58%)。ESI-MS(M+H)+:369.2,HPLC:97.89%。1HNMR(400MHz,CD3OD)δ:8.18(d,J=8.8Hz,1H),7.89(d,J=9.2Hz,1H),7.37(d,J=8.4Hz,1H),7.33(dd,J=8.8,2.4Hz,1H),7.21(d,J=2.4Hz,1H),4.51(s,2H),4.45-4.40(m,1H),3.56-3.52(m,2H),3.23-3.20(m,2H),2.65-2.62(m,1H),2.16-2.11(m,2H),2.00-1.93(m,4H),1.75-1.71(m,2H),1.53-1.23(m,6H)。
实施例126:1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,175mg,白色固体。产率:26%,ESI-MS(M+H+):411.2。1HNMR(400MHz,CDCl3)δ:7.73(d,J=8.8Hz,1H),7.70(d,J=9.2Hz,1H),7.31(d,J=8.0Hz,1H),7.07(dd,J=9.2,2.8Hz,1H),6.83(d,J=2.8Hz,1H),4.09-4.01(m,1H),3.87(q,J=7.2Hz,2H),3.51(s,2H),2.65-2.63(m,2H),2.09-2.02(m,1H),1.96-1.88(m,4H),1.65-1.54(m,6H),1.25-1.19(m,3H),0.99(t,J=7.2Hz,3H),0.86-0.83(m,2H),0.68(d,J=6.4Hz,3H)。
实施例127:1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,80mg,黄色固体。产率:49%,ESI-MS(M+H)+:383.2,HPLC:100%。1HNMR(400MHz,CD3OD)δ:8.30(d,J=8.4Hz,1H),8.00(d,J=9.2Hz,1H),7.49(d,J=8.4Hz,1H),7.42(dd,J=9.2,2.8Hz,1H),7.33(d,J=2.4Hz,1H),4.62(s,2H),4.47-4.39(m,1H),3.66-3.63(m,2H),3.34-3.28(m,2H),2.77-2.72(m,1H),2.27-2.20(m,4H),2.11-2.08(m,2H),1.85-1.82(m,2H),1.51-1.44(m,3H),1.24-1.14(m,2H),0.97(d,J=6.4Hz,3H)。
实施例128:1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,270mg,黄色固体。产率:28%,ESI-MS(M+H+):425.2。1HNMR(400MHz,CDCl3)δ:7.73(d,J=8.8Hz,1H),7.70(d,J=9.6Hz,1H),7.31(d,J=8.4Hz,1H),7.07(dd,J=9.2,3.2Hz,1H),6.83(d,J=2.8Hz,1H),4.06-3.99(m,1H),3.87(q,J=7.2Hz,2H),3.51(s,2H),2.66-2.63(m,2H),2.09-1.87(m,5H),1.65-1.50(m,6H),1.26-1.16(m,2H),1.04-0.96(m,6H),0.85-0.75(m,2H),0.65(t,J=7.2Hz,3H)。
实施例129:1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,19mg,白色固体。产率:14%,ESI-MS(M+H)+:397.2,HPLC:100%。1HNMR(400MHz,CD3OD)δ:8.27(d,J=8.8Hz,1H),8.00(d,J=9.2Hz,1H),7.50-7.45(m,2H),7.31(d,J=2.4Hz,1H),4.78-4.76(m,1H),4.63(s,2H),3.66-3.63(m,2H),3.34-3.31(m,2H),2.76-2.74(m,1H),2.27-2.22(m,2H),2.10-2.06(m,4H),1.71-1.59(m,4H),1.43-1.40(m,2H),1.32-1.30(m,3H),0.93(t,J=6.8Hz,3H)。
实施例130:1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,180mg,呈黄色油状。产率:38%。ESI-MS(M+H)+:467.3。1HNMR(400MHz,CDCl3)δ:7.92(d,J=8.4Hz,1H),7.87(d,J=9.2Hz,1H),7.50(s,1H),7.25(dd,J=9.2,2.4Hz,1H),7.01(d,J=2.8Hz,1H),4.23-4.15(m,1H),4.06(q,J=7.2Hz,2H),3.70(s,2H),2.85-2.82(m,2H),2.22-2.19(m,3H),2.10-2.06(m,1H),1.79-1.75(m,5H),1.58-1.55(m,1H),1.39-1.36(m,2H),1.22-1.17(m,9H),0.77-0.75(m,9H)。
实施例131:1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,130mg,呈黄色固体状。产率:80%。ESI-MS(M+H)+:439.4,HPLC:99.08%。1HNMR(400MHz,CD3OD)δ:8.22(d,J=8.4Hz,1H),7.92(d,J=9.2Hz,1H),7.53(d,J=8.4Hz,1H),7.36(d,J=9.2Hz,1H),7.29(s,1H),4.39-4.36(m,1H),4.15(s,2H),3.25-3.22(m,2H),2.71-2.66(m,2H),2.32-2.26(m,3H),2.01-1.96(m,2H),1.91-1.84(m,5H),1.31-1.24(m,6H),0.85-0.84(m,9H)。
实施例132:1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,150mg,黄色固体。产率:35%,ESI-MS(M+H)+:465.2。1H NMR(400MHz,CDCl3)δ:7.93(d,J=8.4Hz,1H),7.89(d,J=9.2Hz,1H),7.52(d,J=7.2Hz,1H),7.24(dd,J=9.2,2.8Hz,1H),7.02(d,J=2.8Hz,1H),4.26-4.25(m,1H),4.06(q,J=7.2Hz,2H),3.71(s,2H),2.84-2.83(m,2H),2.28-2.27(m,3H),2.10-2.04(m,6H),1.81-1.74(m,4H),1.47-1.43(m,3H),1.18(t,J=7.2Hz,3H)。
实施例133:1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,100mg,呈黄色固体状。产率:78%,ESI-MS(M+H)+:437.3,HPLC:98.94%。1H NMR(400MHz,CD3OD)δ:8.22(d,J=8.4Hz,1H),7.92(d,J=9.2Hz,1H),7.56(d,J=8.4Hz,1H),7.37(dd,J=8.8,2.4Hz,1H),7.32(d,J=2.4Hz,1H),4.48-4.44(m,1H),4.07(s,2H),3.18-3.15(m,2H),2.60-2.55(m,2H),2.33-2.29(m,4H),2.06-2.02(m,4H),1.90-1.85(m,2H),1.59-1.48(m,4H)。
实施例134:1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,170mg,黄色固体。产率:30%,ESI-MS(M+H)+:425.3。1H NMR(400MHz,CDCl3)δ:7.91(d,J=8.4Hz,1H),7.88(d,J=9.2Hz,1H),7.51(d,J=7.6Hz,1H),7.24(dd,J=8.8,2.4Hz,1H),7.01(d,J=2.8Hz,1H),4.33-4.29(m,1H),4.06(q,J=7.2Hz,2H),3.71(s,2H),2.85-2.82(m,2H),2.24-2.22(m,1H),2.11-2.09(m,2H),1.85-1.66(m,8H),1.50-1.47(m,2H),1.28-1.24(m,2H),1.18(t,J=7.2Hz,3H),0.93(s,3H),0.90(s,3H)。
实施例135:1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,100mg,黄色固体。产率:60%,ESI-MS(M+H)+:397.3,HPLC:98.99%。1H NMR(400MHz,CD3OD)δ:8.19(d,J=8.4Hz,1H),7.90(d,J=8.8Hz,1H),7.37(d,J=8.4Hz,1H),7.35(dd,J=9.2,2.4Hz,1H),7.23(d,J=2.4Hz,1H),4.52(s,2H),4.52-4.40(m,1H),3.57-3.54(m,2H),3.22-3.18(m,2H),2.67-2.61(m,1H),2.17-2.12(m,2H),2.03-1.98(m,2H),1.89-1.85(m,2H),1.67-1.62(m,2H),1.49-1.45(m,2H),1.31-1.28(m,2H),0.91(s,3H),0.90(s,3H)。
实施例136:1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,200mg,白色固体。产率:38%。ESI-MS(M+H)+:437.2。
实施例137:1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,75mg,微黄色固体,产率:40%。ESI-MS(M+H)+:409.3,HPLC:100%。1H NMR(400MHz,CD3OD)δ:8.29(d,J=8.4Hz,1H),8.00(d,J=9.2Hz,1H),7.48(d,J=8.4Hz,1H),7.43(dd,J=9.2,2.4Hz,1H),7.32(d,J=2.4Hz,1H),4.61(s,2H),4.51-4.49(m,1H),3.65-3.62(m,2H),3.31-3.28(m,2H),2.73-2.71(m,1H),2.25-2.07(m,4H),1.91-1.80(m,10H),1.64-1.54(m,2H),1.52-1.49(m,2H)。
实施例138:1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,300mg,微黄色油状物。产率:65%。ESI-MS(M+1)+:464.3。
实施例139:1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,60mg,白色固体。产率:64%。ESI-MS(M+H)+:437.2,HPLC:98.17%。1H NMR(400MHz,CD3OD)δ:8.36(d,J=8.4Hz,1H),8.11(d,J=9.2Hz,1H),7.62(d,J=8.4Hz,1H),7.57(dd,J=9.2,2.4Hz,1H),7.36(d,J=2.0Hz,1H),4.70(s,2H),4.65-4.60(m,1H),3.75-3.71(m,2H),3.46-3.42(m,2H),2.89-2.84(m,1H),2.41-2.37(m,2H),2.29-2.21(m,2H),2.10-2.04(m,2H),1.90-1.83(m,4H),1.60-1.56(m,8H),1.48-1.42(m,4H)。
实施例140:1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,129mg,微黄色油状物。产率:32%。ESI-MS(M+1)+:425.3。1H NMR(400MHz,CDCl3)δ:7.93-7.86(m,2H),7.50-7.49(m,1H),7.31-7.28(m,1H),7.02(d,J=2.4Hz,1H),4.60-4.58(m,1H),4.06(q,J=7.2Hz,2H),3.70(s,2H),2.84-2.82(m,2H),2.24-2.23(m,1H),2.10-1.97(m,4H),1.81-1.72(m,3H),1.58-1.47(m,5H),1.40-1.33(m,2H),1.30-1.20(m,3H),1.18(t,J=7.2Hz,3H),0.84(t,J=7.2Hz,3H)。
实施例141:1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,69mg,白色固体。产率:57%。ESI-MS(M+H)+:397.2,HPLC:99.65%。1H NMR(400MHz,CD3OD)δ:8.25(d,J=8.0Hz,1H),7.98(d,J=9.2Hz,1H),7.53(d,J=8.4Hz,1H),7.45(dd,J=9.2,2.8Hz,1H),7.31(d,J=2.4Hz,1H),4.78-4.76(m,1H),4.30(s,2H),3.39-3.35(m,2H),2.89-2.87(m,2H),2.44-2.38(m,1H),2.11-2.04(m,4H),1.99-1.91(m,2H),1.72-1.60(m,4H),1.47-1.42(m,2H),1.39-1.30(m,3H),0.94(t,J=7.2Hz,3H)。
实施例142:1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。黄色油状物,550mg,产率:40%。ESI-MS(M+1)+:422.2。1H NMR(400MHz,DMSO-d6):δ7.73-7.61(m,3H),7.34-7.28(m,2H),7.09(d,J=11.2Hz,1H),4.55-4.51(m,1H),3.99(q,J=7.2Hz,2H),3.48(s,2H),2.73-2.70(m,2H),2.27-2.20(m,1H),1.98-1.92(m,4H),1.74-1.71(m,2H),1.63-1.45(m,6H),1.30-1.21(m,5H),0.28-0.18(m,4H)。
实施例143:1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。黄色油状物,550mg,产率:17.6%。ESI-MS(M+1)+:394.1,HPLC:100%。1H NMR(400MHz,DMSO-d6):δ7.77-7.72(m,2H),7.66(s,1H),7.39(dd,J=8.8,1.6Hz,1H),7.33(d,J=2.4Hz,1H),7.14(dd,J=8.4,2.0Hz,1H),4.61-4.57(m,1H),3.52(s,2H),2.76-2.73(m,2H),2.01-1.92(m,5H),1.73-1.50(m,8H),1.30-1.27(m,2H),0.34-0.23(m,4H)。
实施例144:1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,380mg,白色固体。产率:75%。ESI-MS(M+H)+:451.1。1H NMR(400MHz,CDCl3)δ:7.98(d,J=8.4Hz,1H),7.95(d,J=9.2Hz,1H),7.56(d,J=8.4Hz,1H),7.33(dd,J=9.6,3.2Hz,1H),7.09(d,J=2.8Hz,1H),4.42-4.37(m,1H),4.13(q,J=7.2Hz,2H),3.77(s,2H),2.91-2.88(m,2H),2.33-2.28(m,1H),2.19-2.14(m,2H),2.00-1.79(m,6H),1.71-1.60(m,7H),1.50-1.38(m,6H),1.26-1.24(m,4H)。
实施例145:1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,138mg,白色固体。产率:39%。ESI-MS(M+H)+:423.1。1H NMR(400MHz,CD3OD)δ:8.14(d,J=8.4Hz,1H),7.86(d,J=9.2Hz,1H),7.42(d,J=8.4Hz,1H),7.31(dd,J=9.2,2.8Hz,1H),7.21(d,J=2.8Hz,1H),4.45-4.40(m,1H),4.16(s,2H),3.24-3.21(m,2H),2.73(m,2H),2.32-2.25(m,1H),1.97-1.79(m,6H),1.65-1.51(m,8H),1.44-1.32(m,6H)。
实施例146:1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,122mg,呈黄色油状,产率:28%。ESI-MS(M+H)+:438.3。1H NMR(400MHz,CDCl3)δ:7.72-7.67(m,3H),7.45(d,J=8.4Hz,1H),7.14-7.10(m,2H),4.56-4.51(m,1H),4.13(q,J=7.2Hz,2H),3.63(s,2H),2.92-2.90(m,2H),2.30-2.20(m,2H),2.07-1.79(m,8H),1.64-1.61(m,3H),1.44-1.40(m,3H),1.05(s,3H),1.00(s,3H),0.96(d,J=6.4Hz,3H),0.96-0.86(m,1H)。
实施例147:1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,32mg,呈黄色固体状,产率:29%。ESI-MS(M+H)+:410.3,HPLC:98.56%。1H NMR(400MHz,CD3OD)δ:7.90(s,1H),7.85-7.79(m,2H),7.48(dd,J=8.8,1.6Hz,1H),7.26(d,J=2.4Hz,1H),7.17(dd,J=8.8,2.4Hz,1H),4.65-4.60(m,1H),4.39(s,2H),3.47-3.44(m,2H),3.14-3.10(m,2H),2.63-2.61(m,1H),2.21-2.13(m,3H),1.95-1.82(m,4H),1.43-1.40(m,1H),1.23-1.20(m,1H),1.06(s,3H),0.98(s,3H),0.95(d,J=6.4Hz,3H),0.93-0.84(m,2H)。
实施例148:1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,180mg,白色固体。产率:35%,ESI-MS(M+H)+:439.2。1H NMR(400MHz,CDCl3)δ:7.72(d,J=8.0Hz,1H),7.71(d,J=8.8Hz,1H),7.30(d,J=8.4Hz,1H),7.11(dd,J=9.2,2.8Hz,1H),6.83(d,J=2.8Hz,1H),4.42-4.38(m,1H),3.87(q,J=7.2Hz,2H),3.51(s,2H),2.65-2.62(m,2H),2.09-2.02(m,1H),1.93-1.88(m,4H),1.62-1.53(m,4H),1.31-1.21(m,7H),0.99(t,J=7.6Hz,3H),0.89-0.77(m,1H),0.64(d,J=6.8Hz,6H)。
实施例149:1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,130mg,白色固体。产率:77%,ESI-MS(M+H)+:411.3,HPLC:100%。1H NMR(400MHz,CD3OD)δ:8.27(d,J=8.4Hz,1H),8.00(d,J=9.2Hz,1H),7.47-7.45(m,2H),7.31(d,J=2.8Hz,1H),4.77-4.76(m,1H),4.58(s,2H),3.63-3.60(m,2H),3.28-3.20(m,2H),2.74-2.67(m,1H),2.24-2.06(m,6H),1.69-1.44(m,7H),1.24-1.16(m,1H),0.91(d,J=6.8Hz,6H)。
实施例150:1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,30mg,米色固体,产率:40%。ESI-MS(M+H)+:410.3。1H NMR(400MHz,CDCl3)(异构体的混合物)δ:7.70-7.62(m,3H),7.41(d,J=8.0Hz,1H),7.15-7.13(m,2H),4.79-4.76(m,0.6H),4.46-4.38(m,0.4H),4.11(q,J=7.2Hz,2H),3.59(s,2H),2.90-2.87(m,2H),2.30-2.18(m,2H),2.06-2.01(m,3H),1.89-1.67(m,7H),1.57-1.34(m,3H),1.25-1.23(m,4H),0.97-0.88(m,3H)。
实施例151:1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,10mg,白色固体,产率:80%。ESI-MS(M+H)+:382.3,HPLC:100%。1H NMR(400MHz,DMSO-d6)(异构体的混合物)δ:7.79-7.70(m,2H),7.66(s,1H),7.39(d,J=8.4Hz,1H),7.32-7.29(m,1H),7.15-7.09(m,1H),4.82-4.76(m,0.6H),4.45-4-38(m,0.4H),3.53(s,2H),2.77-2.74(m,2H),2.16-2.11(m,2H),2.01-1.90(m,3H),1.85-1.39(m,9H),1.30-1.23(m,1H),1.06-0.97(m,1H),0.94-0.86(m,3H)。
实施例152:1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,45mg,呈黄色油状,产率:58%。ESI-MS(M+H)+:466.3。1H NMR(400MHz,CDCl3)δ:7.75-7.65(m,3H),7.45-7.42(m,1H),7.18-7.11(m,2H),4.70-4.68(m,0.6H),4.30-4.23(m,0.4H),4.13(q,J=7.2Hz,2H),3.63(s,2H),2.92-2.89(m,2H),2.30-2.20(m,3H),2.03-2.00(m,2H),1.74-1.71(m,2H),1.52-1.50(m,2H),1.28-1.20(m,9H),0.83-0.77(m,12H)。
实施例153:1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,30mg,呈白色固体状,产率:71%。ESI-MS(M+H)+:438.2。HPLC:100%。1HNMR(400MHz,DMSO-d6)(异构体的混合物)δ:12.17(s,1H),7.78-7.66(m,3H),7.39-7.28(m,2H),7.16-7.08(m,1H),4.74-4.72(m,0.7H),4.37-4.35(m,0.3H),3.53(s,2H),2.77-2.75(m,2H),2.21-1.97(m,5H),1.78-1.75(m,2H),1.59-1.18(m,11H),0.81-0.78(m,9H)。
实施例154:1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,110mg,呈黄色油状,产率:23%。ESI-MS(M+H)+:454.3。1HNMR(400MHz,CDCl3)δ:7.72-7.64(m,3H),7.43(d,J=8.4Hz,1H),7.17-7.14(m,2H),4.69-4.67(m,1H),4.12(q,J=6.8Hz,2H),3.62(s,2H),3.49(q,J=6.8Hz,2H),3.30(d,J=6.0Hz,2H),2.91-2.89(m,2H),2.11-2.07(m,4H),1.86-1.65(m,6H),1.59-1.49(m,4H),1.48-1.43(m,2H),1.23-1.18(m,6H)。
实施例155:1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,45mg,黄色固体,产率:57%。ESI-MS(M+H)+:426.2,HPLC:95.42%。1HNMR(400MHz,DMSO-d6)δ:12.20(s,1H),7.78(d,J=9.2Hz,1H),7.72(d,J=8.4Hz,1H),7.66(s,1H),7.39(dd,J=8.8,1.6Hz,1H),7.30(d,J=2.4Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),4.73-4.72(m,1H),3.54(s,2H),3.41(q,J=6.8Hz,2H),3.23(d,J=6.4Hz,2H),2.78-2.75(m,2H),2.21-2.16(m,1H),2.02-1.94(m,4H),1.78-1.76(m,2H),1.65-1.53(m,7H),1.41-1.32(m,2H),1.10(t,J=7.2Hz,3H)。
实施例156:1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。170mg,黄色油状物,产率:25%。ESI-MS(M+H)+:436.3。1H NMR(400MHz,CDCl3)δ:7.72-7.65(m,3H),7.44(d,J=8.0Hz,1H),7.15-7.11(m,2H),4.61-4.55(m,0.4H),4.37-4.30(m,0.6H),4.13(q,J=6.8Hz,2H),3.63(s,2H),2.92-2.90(m,2H),2.29-2.23(m,1H),2.05-1.88(m,8H),1.82-1.58(m,12H),1.25(t,J=6.8Hz,3H)。
实施例157:1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。80mg,微黄色固体,产率:50%。ESI-MS(M+H)+:408.3,HPLC:100.00%。1H NMR(400MHz,MeOD-d4)δ:7.81(s,1H),7.77-7.71(m,2H),7.39(d,J=7.2Hz,1H),7.18(d,J=2.0Hz,1H),7.12-7.07(m,1H),4.61-4.57(m,0.4H),4.38-4.36(0.6H),4.32(s,2H),3.43-3.38(m,2H),3.07-3.00(m,2H),2.57-2.53(m,1H),2.07-1.82(m,8H),1.71-1.53(m,4H),1.42-1.26(m,6H)。
实施例158:1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,330mg,白色固体。产率:52%。ESI-MS(M+H)+:423.3。1H NMR(400MHz,CDCl3)δ:7.92(d,J=8.4Hz,1H),7.88(d,J=9.2Hz,1H),7.51(d,J=8.4Hz,1H),7.29(dd,J=9.2,2.4Hz,1H),7.04(d,J=2.4Hz,1H),4.45-4.41(m,1H),4.06(q,J=7.2Hz,2H),3.71(s,2H),2.85-2.82(m,2H),2.27-1.95(m,5H),1.84-1.68(m,6H),1.48-1.29(m,4H),1.21-1.19(m,3H),0.29-0.20(m,4H)。
实施例159:1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,22mg,白色固体。产率:23%。ESI-MS(M+H)+:395.2。HPLC:100%。1H NMR(400MHz,DMSO-d6)δ:11.91(s,1H),8.09(d,J=8.4Hz,1H),7.85(d,J=9.2Hz,1H),7.55(d,J=8.0Hz,1H),7.32(dd,J=9.2,2.4Hz,1H),7.24(d,J=2.0Hz,1H),4.58-4.54(m,1H),3.71(s,2H),2.85-2.82(m,2H),2.22-2.01(m,5H),1.85-1.62(m,6H),1.55-1.50(m,2H),1.38-1.34(m,2H),0.35-0.27(m,4H)。
实施例160:1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,144mg,呈黄色油状,产率:68%。ESI-MS(M+H)+:424.3。
实施例161:1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,75mg,呈黄色固体状,产率:81%。ESI-MS(M+H)+:396.3,HPLC:100%。1HNMR(400MHz,DMSO-d6)(异构体的混合物)δ:12.05(s,1H),7.89-7.71(m,2H),7.66(s,1H),7.39(d,J=8.4Hz,1H),7.31-7.29(m,1H),7.16-7.10(m,1H),4.80-4.76(m,0.6H),4.66-4.62(m,0.1H),4.44-4.40(m,0.3H),3.54(s,2H),2.78-2.75(m,2H),2.22-2.16(m,1H),2.02-1.95(m,3H),1.79-1.76(m,3H),1.61-1.25(m,7H),1.12-1.04(m,1H),0.93-0.85(m,6H)。
实施例162:1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,110mg,呈黄色固体状,产率:33%。ESI-MS(M+H)+:440.3。1HNMR(400MHz,CDCl3)δ:7.65-7.62(m,3H),7.36(d,J=8.0Hz,1H),7.10-7.07(m,2H),4.62-4.60(m,1H),4.05(q,J=7.2Hz,2H),3.57(s,2H),3.28(s,3H),3.20(d,J=6.8Hz,2H),2.84-2.82(m,2H),2.24-2.22(m,1H),2.04-2.01(m,3H),1.94-1.91(m,1H),1.81-1.73(m,4H),1.57-1.39(m,7H),1.17(t,J=7.6Hz,3H)。
实施例163:1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,50mg,呈黄色固体状,产率:50%。ESI-MS(M+H)+:412.2,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.67-7.63(m,3H),7.35(dd,J=8.4,2.0Hz,1H),7.14(d,J=2.0Hz,1H),7.07(dd,J=8.8,2.4Hz,1H),4.66-4.65(m,1H),3.84(s,2H),3.23(s,3H),3.17(d,J=6.4Hz,2H),3.04-3.01(m,2H),2.43-2.38(m,2H),2.15-2.09(m,1H),2.00-1.96(m,2H),1.87-1.83(m,2H),1.76-1.70(m,2H),1.59-1.48(m,5H),1.42-1.36(m,2H)。
实施例164:1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,20mg,白色固体,产率:4%,ESI-MS(M+H)+:482.3。1HNMR(400MHz,CDCl3)δ:7.64-7.56(m,3H),7.35(d,J=8.4Hz,1H),7.09-7.07(m,2H),4.62-4.57(m,1H),4.05(q,J=7.2Hz,2H),3.53(s,2H),3.14(d,J=6.4Hz,2H),2.83-2.80(m,2H),2.23-2.18(m,1H),2.01-1.97(m,4H),1.82-1.69(m,4H),1.58-1.52(m,5H),1.41-1.35(m,2H),1.16(t,J=7.2Hz,3H),1.11(s,9H)。
实施例165:1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。17mg,白色固体,产率:90%,ESI-MS(M+H)+:454.2,HPLC:100%。1H NMR(400MHz,CD3OD)δ:7.85(s,1H),7.74(d,J=8.8Hz,2H),7.44(d,J=8.4Hz,1H),7.19(d,J=2.0Hz,1H),7.13(dd,J=8.8,2.0Hz,1H),4.67-4.65(m,1H),4.33(s,2H),3.38-3.35(m,2H),3.15(d,J=6.4Hz,2H),3.06-3.04(m,2H),2.57-2.54(m,1H),2.09-2.05(m,2H),1.98-1.88(m,4H),1.60-1.48(m,5H),1.39-1.18(m,2H),1.09(s,9H)。
实施例166:1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。190mg,白色固体,产率:37%。ESI-MS(M+H)+:482.1。1HNMR(400MHz,CDCl3)δ:7.71-7.64(m,3H),7.42(d,J=8.4Hz,1H),7.16-7.14(m,2H),4.68-4.65(m,1H),4.12(q,J=7.2Hz,2H),3.61(s,2H),3.28(d,J=6.8Hz,2H),3.18(d,J=6.8Hz,2H),2.91-2.87(m,2H),2.31-2.25(m,1H),2.11-2.02(m,4H),1.88-1.78(m,6H),1.71-1.61(m,3H),1.31-1.22(m,6H),0.90(d,J=6.8Hz,6H)。
实施例167:1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。94mg,白色固体,产率:53%。ESI-MS(M+H)+:454.1,HPLC:98.62%。1H NMR(400MHz,CD3OD)δ:7.77(s,1H),7.73(d,J=8.4Hz,1H),7.71(d,J=9.2Hz,1H),7.37(dd,J=8.4,2.0Hz,1H),7.19(d,J=2.0Hz,1H),7.12(dd,J=8.8,2.4Hz,1H),4.68-4.66(m,1H),4.17(s,2H),3.27-3.20(m,3H),3.10(d,J=6.4Hz,2H),2.84-2.82(m,2H),2.29-2.22(m,1H),2.01-1.93(m,4H),1.84-1.70(m,3H),1.67-1.51(m,6H),1.44-1.34(m,2H),0.81(d,J=6.8Hz,6H)。
实施例168:1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。110mg,白色固体,产率:20%。ESI-MS(M+H)+:482.1。1HNMR(400MHz,CDCl3)δ:7.65-7.57(m,3H),7.37(d,J=8.8Hz,1H),7.09-7.05(m,2H),4.26-4.22(m,1H),4.07(q,J=7.2Hz,2H),3.54(s,2H),3.14(d,J=6.4Hz,2H),2.85-2.82(m,2H),2.21-2.19(m,3H),2.04-2.01(m,4H),1.99-1.71(m,6H),1.51-1.39(m,3H),1.22-1.17(m,3H),1.14(s,9H)。
实施例169:1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。70mg,微黄色固体,产率:68%。ESI-MS(M+H)+:454.3,HPLC:100%。1H NMR(400MHz,CD3OD)δ:7.86(s,1H),7.80-7.74(m,2H),7.44(d,J=8.4Hz,1H),7.23(s,1H),7.12(dd,J=8.8,2.0Hz,1H),4.37-4.32(m,3H),3.48-3.41(m,2H),3.18(d,J=6.4Hz,2H),3.08-3.04(m,2H),2.71-2.58(m,1H),2.18-2.12(m,4H),1.87-1.84(m,4H),1.46-1.34(m,3H),1.18-0.84(m,11H)。
实施例170:合成1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。50mg,白色固体,产率:10%。ESI-MS(M+H)+:482.1。1HNMR(400MHz,CDCl3)δ:7.70-7.63(m,3H),7.42(d,J=8.0Hz,1H),7.14-7.10(m,2H),4.32-4.27(m,1H),4.12(q,J=7.2Hz,2H),3.60(s,2H),3.28(d,J=6.4Hz,2H),3.17(d,J=6.8Hz,2H),2.90-2.87(m,2H),2.30-2.24(m,2H),2.07-2.02(m,2H),1.95-1.76(m,6H),1.67-1.62(m,2H),1.54-1.44(m,2H),1.32-1.27(m,6H),0.91(d,J=6.4Hz,6H)。
实施例171:1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。30mg,白色固体,产率:64%。ESI-MS(M+H)+:454.1,HPLC:99.28%。1H NMR(400MHz,CD3OD)δ:7.78-7.71(m,3H),7.40(dd,J=8.4,1.2Hz,1H),7.21(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),4.37-4.30(m,1H),4.15(s,2H),3.27-3.21(m,3H),3.12(d,J=6.4Hz,2H),2.82-2.80(m,2H),2.29-2.24(m,1H),2.18-2.15(m,2H),1.98-1.94(m,2H),1.86-1.79(m,6H),1.64-1.53(m,1H),1.44-1.34(m,2H),1.21-1.09(m,2H),0.84(d,J=6.8Hz,6H)。
实施例172:1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。190mg,白色固体,产率:44%。ESI-MS(M+H)+:468.1。1H NMR(400MHz,CDCl3)δ:7.70-7.64(m,3H),7.42(dd,J=8.0,1.2Hz,1H),7.17-7.09(m,2H),4.34-4.26(m,1H),4.12(q,J=7.2Hz,2H),3.63(s,2H),3.38(t,J=6.8Hz,2H),3.27(d,J=6.4Hz,2H),2.90-2.87(m,2H),2.32-2.25(m,3H),2.07-2.02(m,2H),1.95-1.78(m,4H),1.50-1.32(m,2H),1.31-1.17(m,10H),0.93(t,J=7.2Hz,3H)。
实施例173:1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。30mg,白色固体,产率:17%。ESI-MS(M+H)+:440.1,HPLC:97.18%。1HNMR(400MHz,CD3OD)δ:7.81(s,1H),7.74-7.69(m,2H),7.42(dd,J=8.4,1.2Hz,1H),7.17(d,J=2.0Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),4.32-4.27(m,1H),4.26(s,2H),3.32-3.27(m,3H),3.21-3.17(m,3H),2.97-2.90(m,2H),2.41-2.39(m,1H),2.14-2.10(m,2H),2.02-1.98(m,2H),1.89-1.78(m,4H),1.54-1.45(m,3H),1.38-1.29(m,2H),1.15-1.07(m,2H),0.83(t,J=7.2Hz,3H)。
实施例174:1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,61mg,呈黄色油状,产率:10%。ESI-MS(M+H)+:410.1。1H NMR(400MHz,CDCl3)(异构体的混合物)δ:7.76(s,1H),7.72-7.69(m,2H),7.40-7.38(m,1H),7.20-7.15(m,1H),7.13(s,1H),4.48-4.46(m,0.6H),4.28-4.25(m,2H),4.18-4.06(m,2H),3.69-3.58(m,0.4H),3.44-3.31(m,2H),2.91-2.65(m,2H),2.24-2.03(m,5H),1.88-1.32(m,7H),1.24-1.17(m,5H),0.99-0.88(m,3H)。
实施例175:1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,45mg,呈白色固体状,产率:79%。ESI-MS:382.2(M+H)+。1H NMR(400MHz,CD3OD)(异构体的混合物)δ:7.82(s,1H),7.72-7.69(m,2H),7.42(d,J=8.8Hz,1H),7.16(s,1H),7.11-7.06(m,1H),4.46-4.44(m,0.6H),3.93-3.87(m,0.4H),3.30-3.25(m,2H),2.96-2.91(m,2H),2.39-2.31(m,1H),2.18-1.90(m,3H),1.80-1.15(m,12H),0.92-0.88(m,3H)。
实施例176:1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,35mg,黄色油状物。产率:7.4%,ESI-MS(M+H)+:473.3。1H NMR(400MHz,CDCl3)δ:8.00(d,J=8.8Hz,1H),7.97(d,J=9.2Hz,1H),7.58(d,J=8.4Hz,1H),7.37-7.31(m,3H),7.25-7.22(m,3H),7.13(d,J=2.8Hz,1H),4.46-4.38(m,1H),4.13(q,J=7.2Hz,2H),3.78(s,2H),2.92-2.89(m,2H),2.65-2.59(m,1H),2.37-2.31(m,3H),2.19-2.16(m,2H),2.08-2.03(m,2H),1.90-1.79(m,5H),1.69-1.64(m,3H),1.25(t,J=7.2Hz,3H)。
实施例177:1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸的制备相同,20mg,黄色油状物。产率:80%,ESI-MS(M+H)+:445.2,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:8.26(d,J=8.4Hz,1H),7.97(d,J=9.2Hz,1H),7.61(d,J=8.8Hz,1H),7.43(dd,J=9.2,2.8Hz,1H),7.34(d,J=2.8Hz,1H),7.33-7.28(m,4H),7.21-7.17(m,1H),4.61-4.54(m,1H),4.07(s,2H),3.19-3.16(m,2H),2.68-2.54(m,3H),2.40-2.27(m,3H),2.03-1.97(m,4H),1.94-1.87(m,2H),1.83-1.68(m,4H)。
实施例178:1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。80mg,黄色油状物,产率:15%,ESI-MS(M+H)+:468.3。1HNMR(400MHz,CDCl3)δ:7.71-7.64(m,3H),7.44(d,J=6.8Hz,1H),7.15-7.11(m,2H),4.34-4.28(m,1H),4.14(q,J=6.8Hz,2H),3.61(s,2H),3.58-3.52(m,1H),3.28(d,J=6.4Hz,2H),2.91-2.89(m,2H),2.28-2.25(m,3H),2.09-2.04(m,2H),1.97-1.74(m,8H),1.64-1.61(m,1H),1.55-1.45(m,2H),1.25(t,J=7.2Hz,3H),1.17(d,J=6.4Hz,6H)。
实施例179:1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。18mg,白色固体,产率:45%,ESI-MS(M+H)+:440.2,HPLC:96.86%。1H NMR(400MHz,CD3OD)δ:7.82(s,1H),7.77-7.71(m,2H),7.40(d,J=8.8Hz,1H),7.20(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.8Hz,1H),4.35-4.29(m,1H),4.28(s,2H),3.51-3.45(m,1H),3.39-3.35(m,2H),3.05-3.01(m,2H),2.59-2.50(m,1H),2.15-2.04(m,4H),1.84-1.81(m,4H),1.52-1.46(m,1H),1.41-1.31(m,2H),1.18-1.06(m,3H),0.93(d,J=6.4Hz,6H),0.81-0.75(m,1H)。
实施例180:1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同,80mg,白色固体,产率:12%,ESI-MS(M+H)+:468.3。1H NMR(400MHz,CDCl3)δ:7.64-7.58(m,3H),7.36(d,J=8.4Hz,1H),7.10-7.08(m,2H),4.56-4.54(m,1H),3.99(q,J=7.2Hz,2H),3.48(s,2H),3.26(t,J=6.4Hz,2H),3.17(d,J=6.4Hz,2H),2.78-2.75(m,2H),2.17-2.15(m,1H),1.99-1.90(m,4H),1.77-1.58(m,6H),1.53-1.45(m,5H),1.39-1.33(m,2H),1.11(t,J=7.2Hz,3H),0.87(t,J=7.6Hz,3H)。
实施例181:1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。15mg,黄色固体,产率:20%,ESI-MS(M+H)+:440.2,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.83(s,1H),7.76-7.73(m,2H),7.42(d,J=8.4Hz,1H),7.19(s,1H),7.13(d,J=9.2Hz,1H),4.67-4.65(m,1H),4.32(s,2H),3.36(d,J=7.2Hz,2H),3.28(t,J=7.6Hz,2H),3.04-3.02(m,2H),2.59-2.53(m,1H),2.08-1.87(m,6H),1.65-1.35(m,10H),1.19-1.17(m,1H),0.83(t,J=7.6Hz,3H)。
实施例182:2-(哌啶-3-基)乙酸
向2-(吡啶-3-基)乙酸(274mg,2.0mmol,1.0当量)于AcOH(2mL)中的溶液中添加PtO2(226mg,1.0mmol,0.5当量)。在室温于H2下搅拌混合物16小时。滤出催化剂且浓缩滤液,得到呈微黄色固体状的2-(哌啶-3-基)乙酸(300mg,产率:81%)。ESI-MS(M+H)+:143.1。1H NMR(400MHz,CD3OD)δ:3.34-3.31(m,1H),2.84-2.77(m,1H),2.64-2.57(m,3H),2.18-2.10(m,3H),1.86-1.83(m,2H),1.71-1.67(m,1H),1.24-1.22(m,1H)。
实施例183:2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-3-基)乙酸
2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-3-基)乙酸的制备与1-((2-(反式-4-叔丁基环己基氧基)喹啉-6-基)甲基)哌啶-4-甲酸的制备相同。30mg,呈白色固体状,产率:28%。ESI-MS(M+H)+:438.1。HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.82(s,1H),7.77(d,J=8.8Hz,1H),7.72(d,J=8.4Hz,1H),7.40(dd,J=8.4,1.6Hz,1H),7.20(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),4.33(s,2H),4.32-4.25(m,1H),3.51-3.39(m,2H),2.88-2.79(m,1H),2.71-2.65(m,1H),2.29-2.17(m,5H),1.90-1.81(m,4H),1.73-1.63(m,1H),1.39-1.29(m,2H),1.23-1.13(m,3H),1.04-0.98(m,1H),0.83(s,9H)。
实施例184:1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸乙酯
1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同,270mg,呈黄色油状,产率:60%,ESI-MS(M+H)+:429.3。1H NMR(400MHz,CDCl3)δ:7.97(d,J=8.4Hz,1H),7.94(d,J=9.2Hz,1H),7.57(d,J=8.0Hz,1H),7.27(dd,J=9.2,2.4Hz,1H),7.12(d,J=2.8Hz,1H),4.11(q,J=7.2Hz,2H),3.83-3.80(m,2H),3.01-3.00(m,1H),2.77-2.64(m,2H),2.43-2.39(m,1H),2.22-2.20(m,1H),1.95-1.92(m,1H),1.74-1.51(m,3H),1.22(t,J=7.2Hz,3H),1.02(s,9H),0.25(s,6H)。
实施例185:1-((6-羟基喹啉-2-基)甲基)哌啶-3-甲酸乙酯
在0℃向1-((6-((叔丁基二甲基甲硅烷基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸乙酯(240mg,0.56mmol)于EtOH(30mL)中的溶液中逐滴添加HCl(3N,1mL)。在室温搅拌反应混合物2小时。用饱和NaHCO3中和混合物且移除有机溶剂。接着用DCM(3×10mL)萃取混合物。用盐水(10mL)洗涤合并的有机层,干燥(Na2SO4)且浓缩,得到呈白色固体状的1-((6-羟基喹啉-2-基)甲基)哌啶-3-甲酸乙酯,120mg,产率:60%,ESI-MS(M+H)+:315.2。1H NMR(400MHz,CDCl3)δ:7.86(d,J=8.8Hz,2H),7.54(d,J=8.8Hz,1H),7.29(dd,J=9.2,2.4Hz,1H),7.05(d,J=2.0Hz,1H),4.09(q,J=6.4Hz,2H),3.90(ABq,J=21.6,13.6Hz,2H),3.12-3.09(m,1H),2.89-2.86(m,1H),2.70-2.68(m,1H),2.49-2.44(m,1H),2.31-2.26(m,1H),1.95-1.92(m,1H),1.75-1.70(m,2H),1.50-1.48(m,1H),1.20(t,J=7.2Hz,3H)。
实施例186:1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸乙酯
1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸乙酯的制备与2-溴-6-(反式-4-叔丁基环己基氧基)萘的制备相同,58mg,呈黄色油状,产率:44%。ESI-MS(M+H)+:453.3。1H NMR(400MHz,CDCl3)δ:8.38-8.35(m,1H),8.15-8.11(m,1H),7.84(d,J=8.4Hz,1H),7.52-7.48(m,1H),7.18(d,J=2.4Hz,1H),4.77(s,2H),4.36-4.29(m,1H),4.14(q,J=7.2Hz,2H),3.71-3.69(m,1H),3.50-3.39(m,1H),3.15-3.06(m,3H),2.29-1.91(m,7H),1.63-1.46(m,3H),1.23(t,J=7.2Hz,3H),1.17-1.09(m,3H),0.91(s,9H)。
实施例187:1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸
1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,20mg,呈黄色固体状,产率:28%。ESI-MS(M+H)+:425.3,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:8.15(d,J=8.8Hz,1H),7.89(d,J=8.8Hz,1H),7.39(d,J=8.4Hz,1H),7.49(dd,J=9.2,2.8Hz,1H),7.20(d,J=2.4Hz,1H),4.32(s,2H),4.29-4.24(m,1H),3.07-3.05(m,2H),2.63-2.61(m,1H),2.19-2.16(m,2H),1.90-1.71(m,6H),1.38-1.28(m,2H),1.24-1.12(m,4H),1.06-1.00(m,1H),0.82(s,9H)。
实施例188:1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。50mg,呈白色固体状,产率:23%。ESI-MS(M+H)+:432.1。
实施例189:1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。15mg,呈白色固体状,产率:32%。ESI-MS(M+H)+:404.1,HPLC:100%。1HNMR(400MHz,CD3OD)δ:7.94(s,1H),7.89(d,J=8.4Hz,1H),7.86(d,J=9.2Hz,1H),7.52(dd,J=8.4,1.6Hz,1H),7.38(d,J=1.6Hz,1H),7.26(dd,J=8.8,2.4Hz,1H),4.79-4.76(m,1H),4.43(s,2H),3.49-3.46(m,2H),3.16-3.13(m,2H),2.65-2.60(m,1H),2.20-2.12(m,4H),2.06-1.94(m,8H)。
实施例190:1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。220mg,呈无色油状,产率:55%。ESI-MS(M+H)+:396.2。1H NMR(400MHz,CDCl3)δ:7.69-7.63(m,3H),7.43-7.41(m,1H),7.13-7.07(m,2H),4.68-4.65(m,0.6H),4.40-4.36(m,0.4H),4.12(q,J=6.8Hz,2H),3.60(s,2H),2.31-2.24(m,1H),2.15-1.98(m,4H),1.93-1.76(m,7H),1.66-1.57(m,2H),1.29-1.22(m,5H),1.11-1.08(m,3H)。
实施例191:1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。80mg,呈白色固体状,产率:60%。ESI-MS(M+H)+:368.2,HPLC:97.19%。1H NMR(400MHz,CD3OD)δ:7.93(s,1H),7.87(d,J=8.8Hz,1H),7.83(d,J=9.2Hz,1H),7.50(d,J=8.4Hz,1H),7.27(s,1H),7.23-7.19(m,1H),4.91-4.89(m,0.6H),4.49-4.47(m,0.4H),4.44(s,2H),3.60-3.43(m,2H),3.22-3.05(m,2H),2.86-2.43(m,1H),2.26-1.99(m,5H),1.90-1.58(m,5.5H),1.35-1.30(m,0.5H),1.12(d,J=6.8Hz,3H)。
实施例192:1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。170mg,呈白色固体状,产率:24%。ESI-MS(M+H)+:454.2。1HNMR(400MHz,DMSO-d6)δ:7.69(d,J=9.2Hz,1H),7.65(d,J=8.4Hz,1H),7.63(s,1H),7.42(dd,J=8.8Hz,J=2.0Hz,1H),7.14(d,J=2.4Hz,1H),7.12(d,J=8.4Hz,1H),4.33-4.24(m,1H),4.12(q,J=6.8Hz,2H),3.60(s,2H),2.90-2.88(m,2H),2.32-2.28(m,3H),2.08-1.96(m,4H),1.86-1.76(m,5H),1.49-1.29(m,3H),1.27-1.22(m,4H),1.20(s,6H)。
实施例193:1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同,40mg,呈白色固体状,产率:32%。ESI-MS(M+H)+:426.2,HPLC:98.86%。1HNMR(400MHz,DMSO-d6)δ:7.77(s,1H),7.73(d,J=8.4Hz,1H),7.69(d,J=8.8Hz,1H),7.37(dd,J=8.8,1.6Hz,1H),7.18(d,J=2.0Hz,1H),7.07(dd,J=8.8,2.0Hz,1H),4.31-4.28(m,1H),4.17(s,2H),3.26-3.23(m,1H),2.85-2.82(m,2H),2.25-2.17(m,3H),1.93-1.79(m,6H),1.33-1.21(m,6H),1.18(s,6H)。
实施例194:1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。180mg,呈黄色油状,产率:45%。ESI-MS(M+H)+:396.2。
实施例195:1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。60mg,呈白色固体状,产率:50%。ESI-MS(M+H)+:368.2,HPLC:95.36%。1H NMR(400MHz,CD3OD)δ:7.88(s,1H),7.84(d,J=8.8Hz,1H),7.81(d,J=9.2Hz,1H),7.49(dd,J=8.8,2.0Hz,1H),7.21(d,J=2.0Hz,1H),7.18-7.14(m,1H),4.99-4.97(m,1H),4.29(s,2H),3.39-3.36(m,2H),2.98-2.93(m,2H),2.41-2.37(m,1H),2.30-2.24(m,1H),2.10-1.82(m,7H),1.59-1.53(m,1H),1.45-1.38(m,1H),1.28-1.21(m,1H),1.12-1.06(m,3H)。
实施例196:1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。90mg,呈黄色油状,产率:36%。ESI-MS(M+H)+:394.2。1H MR(400MHz,CDCl3)δ:7.68-7.63(m,3H),7.44-7.42(m,1H),7.09-7.07(m,2H),4.58-4.51(m,1H),4.12(q,J=7.2Hz,2H),3.61(s,2H),2.90-2.88(m,2H)2.46-2.41(m,2H),2.32-2.23(m,1H),2.08-2.03(m,2H),2.01-1.95(m,2H),1.89-1.86(m,2H),1.82-1.76(m,2H),1.40-1.38(m,2H),1.24(t,J=7.2Hz,3H),0.51-0.46(m,1H),0.13-0.10(m,1H)。
实施例197:1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。40mg,呈白色固体状,产率:45%。ESI-MS(M+H)+:366.2。HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.89(s,1H),7.85(d,J=8.8Hz,1H),7.78(d,J=8.8Hz,1H),7.48(dd,J=8.4Hz,J=1.6Hz,1H),7.23(s,1H),7.16(dd,J=9.2,2.0Hz,1H),4.68-4.61(m,1H),4.41(s,2H),3.57-3.41(m,2H),3.19-3.03(m,2H),2.84-2.58(m,1H),2.47-2.42(m,2H),2.32-2.20(m,2H),2.01-1.85(m,4H),1.40-1.39(m,2H),0.51-0.46(m,1H),0.20-0.17(m,1H)。
实施例198:1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。275mg,呈黄色油状,产率:63%。ESI-MS(M+H)+:438.3。
实施例199:1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。60mg,呈黄色固体状,产率:49%。ESI-MS(M+H-56)+:410.3。1H NMR(400MHz,DMSO-d6)δ:9.98(s,1H),7.94(s,1H),7.87(d,J=8.4Hz,1H),7.83(d,J=9.2Hz,1H),7.55(d,J=8.4Hz,1H),7.42(s,1H),7.20(dd,J=8.8,2.4Hz,1H),4.42-4.39(m,3H),3.45-3.42(m,2H),3.00-2.98(m,2H),2.51-2.46(m,1H),2.26-1.64(m,8H),1.53-1.06(m,6H),0.88(d,J=6.8Hz,6H)。
实施例200:哌啶-1,4-二甲酸1-叔丁酯4-甲酯
向哌啶-4-甲酸甲酯(3.0g,21.0mmol,1.0当量)于CH2Cl2(70mL)中的溶液中添加Et3N(3.18g,31.5mmol,1.5当量)及(Boc)2O(5.04g,23.1mmol,1.1当量)。接着在室温搅拌反应混合物16小时。浓缩后,通过硅胶柱(PE:EA=3:1)纯化残余物,得到呈无色胶状的哌啶-1,4-二甲酸1-叔丁酯4-甲酯(3.8g,产率:75%)。ESI-MS(M+H)+:244.1。1H NMR(400MHz,CDCl3)δ:4.03-4.00(m,2H),3.67(s,3H),2.86-2.79(m,2H),2.48-2.42(m,1H),1.89-1.85(m,2H),1.67-1.57(m,2H),1.45(s,9H)。
实施例201:哌啶-1,4,4-三甲酸1-叔丁酯4,4-二甲酯
在-78℃于N2下向哌啶-1,4-二甲酸1-叔丁酯4-甲酯(1.3g,5.35mmol,1.0当量)于无水THF(35mL)中的溶液中逐滴添加LDA(2N,3.25mL,6.42mmol,1.2当量)。接着在-78℃搅拌混合物1小时。接着将氯甲酸甲酯(0.55g,5.89mmol,1.1当量)逐滴添加至此混合物中。使所得混合物缓慢升温至室温并维持4小时。将饱和NH4Cl溶液添加至此混合物中,用EtOAc(75mL×2)萃取,用盐水(20mL)洗涤,经Na2SO4干燥,过滤且在真空中浓缩,得到呈黄色油状的哌啶-1,4,4-三甲酸1-叔丁酯4,4-二甲酯(1.25g,产率:78%)。
实施例202:哌啶-4,4-二甲酸二甲酯
在室温向哌啶-1,4,4-三甲酸1-叔丁酯4,4-二甲酯(1.2g,3.98mmol,1.0当量)于CH2Cl2(30.0mL)中的溶液中小心地添加TFA(6.0mL)。在室温搅拌反应溶液16小时。移除溶剂,得到呈黄色油状的粗产物哌啶-4,4-二甲酸二甲酯(0.72g,产率:90%),其未经进一步纯化即直接用于下一步。ESI-MS(M+H)+:202.2。1H NMR(400MHz,CDCl3)δ:3.74(s,6H),2.86-2.83(m,2H),2.08-2.04(m,4H),1.26-1.19(m,2H)。
实施例203:1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸二甲酯
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸二甲酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同,180mg,呈黄色固体状,产率:75%。ESI-MS(M+H)+:496.3。1H NMR(400MHz,CDCl3)δ:7.68(d,J=8.8Hz,1H),7.65(d,J=8.4Hz,1H),7.61(s,1H),7.41(d,J=8.4Hz,1H),7.14-7.10(m,2H),4.28-4.23(m,1H),3.73(s,6H),3.57(s,2H),2.48-2.45(m,3H),2.29-2.26(m,2H),2.17-2.14(m,3H),1.91-1.87(m,4H),1.47-1.39(m,2H),1.19-1.09(m,3H),0.89(s,9H)。
实施例204:1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸的制备与1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。120mg,呈白色固体状,产率:75%。ESI-MS(M+H)+:468.3,HPLC:99.33%。1H NMR(400MHz,DMSO-d6)δ:7.82-7.77(m,3H),7.51-7.48(m,1H),7.36(d,J=1.6Hz,1H),7.14(dd,J=8.4,1.6Hz,1H),4.39-4.36(m,1H),3.94(s,2H),3.11-2.79(m,4H),2.22-2.18(m,2H),2.02-2.00(m,4H),1.83-1.80(m,2H),1.36-1.07(m,5H),0.88(s,9H)。
实施例205:2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸甲酯
2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸甲酯的制备与2-(((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)(甲基)氨基)-2-甲基丙酸甲酯的制备相同。100mg,呈白色固体状,产率:44%。ESI-MS(M+H)+:452.3。1H NMR(400MHz,CD3OD)δ:7.71(d,J=9.2Hz,1H),7.69(d,J=8.0Hz,1H),7.66(s,1H),7.42(dd,J=8.4,1.2Hz,1H),7.21(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),4.60(s,1H),4.36-4.31(m,1H),4.01-3.98(m,1H),3.68(s,3H),3.51-3.48(m,1H),2.97-2.95(m,1H),2.91-2.86(m,1H),2.77-2.71(m,1H),2.55-2.50(m,1H),2.29-2.22(m,3H),1.93-1.90(m,2H),1.79-1.66(m,2H),1.56-1.49(m,3H),1.43-1.37(m,2H),1.32-1.22(m,2H),1.17-1.13(m,1H),0.93(s,9H)。
实施例206:2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸
2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸的制备与2-(((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)(甲基)氨基)-2-甲基丙酸的制备相同。36mg,呈白色固体状,产率:52%。ESI-MS(M+H)+:438.3,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.80(s,1H),7.73(d,J=8.4Hz,1H),7.69(d,J=9.2Hz,1H),7.38(dd,J=8.4,1.2Hz,1H),7.16(d,J=2.4Hz,1H),7.06(dd,J=9.2,2.4Hz,1H),4.61-4.58(m,1H),4.25-4.21(m,2H),3.60-3.57(m,1H),3.15-3.13(m,1H),2.85-2.97(m,3H),2.17-2.12(m,2H),1.98-1.92(m,1H),1.79-1.71(m,5H),1.53-1.50(m,1H),1.31-1.28(m,2H),1.20-1.11(m,3H),1.05-0.96(m,1H),0.80(s,9H)。
实施例207:2-溴-6-((4,4-二甲基环己基)氧基)萘
2-溴-6-((4,4-二甲基环己基)氧基)萘的制备与2-溴-6-((顺式-4-乙基环己基)氧基)萘的制备相同。6.27g,呈白色固体状,产率:82%。ESI-MS(M+H)+:333.1。1H NMR(400MHz,CD3OD)δ:7.93(s,1H),7.69(d,J=8.8Hz,1H),7.68(d,J=8.8Hz,1H),7.47(dd,J=8.8,1.6Hz,1H),7.22(d,J=1.2Hz,1H),7.15(dd,J=8.8,2.0Hz,1H),4.48-4.44(m,1H),1.98-1.91(m,2H),1.78-1.69(m,2H),1.59-1.53(m,2H),1.39-1.32(m,2H),1.00(s,3H),0.99(s,3H)。
实施例208:6-((4,4-二甲基环己基)氧基)-2-萘醛
6-((4,4-二甲基环己基)氧基)-2-萘醛的制备与2-(反式-4-叔丁基-环己基氧基)-喹啉-6-甲醛的制备相同。2.7g,呈黄色固体状,产率:78%。ESI-MS(M+H)+:283.2。1H NMR(400MHz,CDCl3)δ:10.08(s,1H),8.23(s,1H),7.91-7.87(m,2H),7.76(d,J=8.8Hz,1H),7.22(dd,J=8.8,2.4Hz,1H),7.18(d,J=2.0Hz,1H),4.48-4.42(m,1H),1.99-1.92(m,2H),1.81-1.72(m,2H),1.59-1.54(m,2H),1.37-1.30(m,2H),1.00(s,3H),0.98(s,3H)。
实施例209:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸乙酯
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸乙酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。140mg,呈白色固体状,产率:52%。ESI-MS(M+H)+:424.3。
实施例210:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸的制备与2-(((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)(甲基)氨基)-2-甲基丙酸的制备相同。80mg,呈白色固体状,产率:61%。ESI-MS(M+H)+:396.2,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.82(s,1H),7.75(d,J=8.8Hz,1H),7.11(d,J=9.2Hz,1H),7.40(d,J=8.4Hz,1H),7.18(d,J=2.4Hz,1H),7.10(dd,J=8.8,2.0Hz,1H),4.41-4.35(m,3H),3.59-3.38(m,2H),2.96-2.73(m,3H),2.10-2.06(m,1H),1.90-1.58(m,7H),1.47-1.41(m,2H),1.29-1.21(m,2H),0.88(s,3H),0.87(s,3H)。
实施例211:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸甲酯
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸甲酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。187mg,呈白色固体状,产率:66%。ESI-MS(M+H)+:424.2。
实施例212:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸的制备与2-(((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)(甲基)氨基)-2-甲基丙酸的制备相同。90mg,呈白色固体状,产率:63%。ESI-MS(M+H)+:410.2,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.80(s,1H),7.74-7.69(m,2H),7.38(d,J=8.4Hz,1H),7.16(d,J=1.2Hz,1H),7.09(dd,J=8.8,2.4Hz,1H),4.41-4.36(m,1H),4.29(s,2H),3.37-3.27(m,2H),3.13-2.91(m,2H),2.25-2.04(m,2H),1.85-1.81(m,2H),1.66-1.55(m,2H),1.47-1.41(m,3H),1.27-1.21(m,3H),1.14(s,3H),0.88(s,3H),0.87(s,3H)。
实施例213:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸甲酯
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸甲酯的制备与1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸乙酯的制备相同。50mg,呈白色固体状,产率:24%。ESI-MS(M+H)+:438.3。
实施例214:1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸的制备与2-(((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)(甲基)氨基)-2-甲基丙酸的制备相同。31mg,呈白色固体状,产率:66%。ESI-MS(M+H)+:424.3,HPLC:100.00%。1H NMR(400MHz,CD3OD)δ:7.80(s,1H),7.74(d,J=8.8Hz,1H),7.71(d,J=9.6Hz,1H),7.38(d,J=8.8,1.6Hz,1H),7.17(d,J=2.0Hz,1H),7.10(dd,J=9.2,2.4Hz,1H),4.42-4.36(m,1H),4.31(s,2H),3.36-3.33(m,2H),3.01-2.98(m,2H),2.25-2.22(m,2H),1.88-1.81(m,2H),1.68-1.43(m,8H),1.29-1.18(m,2H),0.90(s,3H),0.89(s,3H),0.78(t,J=7.2Hz,3H)。
实施例215:1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸乙酯
将三苯基膦添加至1-(6-羟基-萘-2-基甲基)-哌啶-4-甲酸乙酯(0.4319g,0.001378mol)及二环[2.2.1]庚-5-烯-2-醇(0.243g,0.00220mol)于甲苯(0.881mL,0.00827mol)中的溶液中且搅拌混合物几分钟。接着逐滴添加偶氮二甲酸二异丙酯(0.434mL,0.00220mol)且在室温搅拌混合物72小时。接着在乙酸乙酯中稀释反应混合物且用水洗涤,接着用盐水洗涤。经MgSO4干燥有机相,过滤,在减压下浓缩,且通过快速色谱(0%至40%EtOAc/庚烷)纯化,得到标题化合物(8%产率)。ESI-MS(M+H+):406.2。
实施例216:1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸
将2M单水合氢氧化锂的水溶液(0.5mL,1mmol)添加至1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸乙酯(0.047g,0.12mmol)于THF及甲醇(1.00mL,24.7mmol)中的溶液中且在室温搅拌混合物2小时。接着在减压下将混合物浓缩至干燥。将所得残余物溶解于二氯甲烷中且用1MHCl水溶液(3mL,3mmol)洗涤。分离各层且将有机相浓缩至干燥且通过制备性HPLC纯化,得到呈TFA盐形式的所需产物。ESI-MS(M+H+):378.3。1H NMR(400MHz,甲醇-d4)δppm1.18-1.37(m,1H)1.53-1.60(m,1H)1.64-1.70(m,1H)1.79-1.96(m,4H)2.21-2.31(m,2H)2.60-2.69(m,1H)2.92-2.97(m,1H)3.05-3.12(m,2H)3.56-3.64(m,2H)4.44-4.50(m,3H)6.12-6.16(m,1H)6.36-6.41(m,1H)7.20-7.25(m,1H)7.26-7.29(m,1H)7.49-7.54(m,1H)7.83-7.87(m,1H)7.88-7.92(m,1H)7.93-7.96(m,1H)。
实施例217:1-[6-(1,3,3-三甲基-二环[2.2.1]庚-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸
使用1-(6-羟基-萘-2-基甲基)-哌啶-4-甲酸乙酯(0.4510g,0.001439mol),如1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸来合成1-[6-(1,3,3-三甲基-二环[2.2.1]庚-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸。ESI-MS(M+H+):422.4。1H NMR(400MHz,甲醇-d4)δppm0.95(s,3H)1.06(s,3H)1.13(s,3H)1.21-1.34(m,2H)1.66-1.75(m,1H)1.78-1.92(m,5H)2.01-2.10(m,1H)2.21-2.30(m,2H)2.59-2.69(m,1H)3.04-3.15(m,2H)3.56-3.63(m,2H)4.28-4.32(m,1H)4.44(s,2H)5.50(s,1H)7.16-7.21(m,1H)7.23-7.26(m,1H)7.48-7.53(m,1H)7.81-7.86(m,1H)7.87-7.91(m,1H)7.92-7.94(m,1H)。
实施例218:6-溴-2-(4-叔丁基-环己基氧基)-喹喔啉
将三苯基膦(0.6988g,0.002664mol)添加至6-溴-喹喔啉-2-醇(0.4283g,0.001903mol)及(1s,4s)-4-(叔丁基)环己醇(0.4164g,0.002664mol)于四氢呋喃(20mL,0.2mol)中的溶液中。在冰/水浴中冷却混合物且缓慢添加偶氮二甲酸二异丙酯(0.5246mL,0.002664mol)。搅拌混合物96小时,同时使其达到室温。接着在乙酸乙酯中稀释反应混合物且用水洗涤,接着用盐水洗涤。经MgSO4干燥有机层,过滤,在减压下浓缩,且通过快速色谱(24gSiO2柱;0%至20%乙酸乙酯/庚烷洗脱剂)纯化,得到标题化合物。ESI-MS(M+H+):365。
实施例219:1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸乙酯
将6-溴-2-(4-叔丁基-环己基氧基)-喹喔啉(0.2879g,0.0007925mol)、((4-(乙氧羰基)哌啶-1-基)甲基)三氟硼酸钾(0.4392g,0.001585mol)、乙酸钯(0.01068g,4.755E-5mol)、2-(二环己基膦基)-2',4',6'-三-异丙基-1,1'-联苯(0.06800g,0.0001426mol)及碳酸铯(0.7746g,0.002377mol)添加至装备有磁性搅拌子的加盖的40mL小瓶中。将小瓶脱气且用氩气吹洗。添加四氢呋喃(7.713mL,0.09510mol)及水(1.142mL,0.06340mol)且将反应混合物脱气,用氩气吹洗,接着在60℃搅拌24小时。再添加1当量((4-(乙氧羰基)哌啶-1-基)甲基)三氟硼酸钾;0.03当量乙酸钯;0.09当量2-(二环己基膦基)-2',4',6'-三-异丙基-1,1'-联苯及1.5当量碳酸铯。将混合物脱气,用氩气吹洗且在60℃加热过夜。将混合物冷却至室温,用乙酸乙酯稀释且用水洗涤,接着用盐水洗涤。分离各层且经MgSO4干燥有机层,过滤,在减压下浓缩且通过快速色谱(24gSiO2柱;0%至10% MeOH/二氯甲烷)纯化,得到标题化合物。ESI-MS(M+H+):454.1。
实施例220:1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸
向1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸乙酯(0.2255g,0.4971mmol)于四氢呋喃(6.00mL,74.0mmol)及甲醇(2.00mL,49.4mmol)中的溶液中添加2.00mL的2M单水合氢氧化锂水溶液(4.00mmol)且搅拌混合物过夜。在减压下将混合物浓缩至干燥。将残余物溶解于二氯甲烷中且用1NHCl洗涤。分离各层且在减压下将有机层浓缩至干燥。将粗产物溶解于DMSO中且通过制备性HPLC纯化,得到呈TFA盐形式的标题化合物。ESI-MS(M+H+):426.34。1H NMR(400MHz,甲醇-d4)δppm0.95(s,9H)1.12-1.23(m,1H)1.24-1.37(m,2H)1.47-1.61(m,2H)1.80-2.01(m,3H)2.22-2.38(m,4H)3.08-3.20(m,2H)3.58-3.66(m,1H)4.54(br.s.,2H)5.15-5.25(m,1H)7.82(dd,J=8.66,2.13Hz,1H)7.96(d,J=8.53Hz,1H)8.16(d,J=2.01Hz,1H)8.48(s,1H)。
实施例221:甲烷磺酸4-叔丁基-环己酯
在0℃将甲烷磺酰氯(2.840mL,36.70mmol)逐滴添加至(1s,4s)-4-(叔丁基)环己醇(5.120g,32.76mmol)及三乙胺(5.115mL,36.70mmol)于二氯甲烷(42.00mL,655.3mmol)中的溶液中。注意到白色沉淀物形成。搅拌溶液过夜,同时使其达到室温。用柠檬酸(5%水溶液)、碳酸氢钠水溶液及接着水依序洗涤所得浆料。经MgSO4干燥有机层,过滤且在减压下浓缩,得到呈白色固体状的所需化合物。
实施例222:6-溴-2-(4-叔丁基-环己基氧基)-喹唑啉
将碳酸铯(3.1308g,9.6089mmol)添加至6-溴喹唑啉-2-醇(1.0812g,4.8044mmol)于叔丁醇(15mL,160mmol)、甲苯(25mL,230mmol)及2-丁酮(10mL,100mmol)中的混合物中。在密封管中于110℃加热混合物1小时,接着冷却至室温且添加甲烷磺酸4-叔丁基-环己酯(2.2519g,9.6089mmol)。接着在110℃加热反应混合物过夜。将反应混合物冷却至室温,接着经硅藻土垫过滤。在减压下浓缩滤液,使其吸附至硅胶上且通过快速色谱(80gSiO2柱;0%至40%EtOAc/庚烷洗脱剂)纯化,得到标题化合物(20%产率)。ESI-MS(M+H+):365.1。
实施例223:1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸乙酯
类似于1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸乙酯来合成1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸乙酯。ESI-MS(M+H+):454.1。
实施例224:1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸
类似于1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸来合成1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸。ESI-MS(M+H+):426.3。1H NMR(400MHz,甲醇-d4)δppm0.92(s,9H)1.06-1.20(m,1H)1.20-1.34(m,2H)1.45-1.59(m,2H)1.76-1.98(m,3H)2.19-2.36(m,4H)3.04-3.18(m,1H)3.55-3.66(m,1H)4.50(s,2H)5.08-5.18(m,1H)7.89(s,1H)7.94-7.99(m,1H)8.15(d,J=1.51Hz,1H)9.37(s,1H)。
实施例225:6-溴-2-(4-叔丁基-环己基氧基)-1,8-二氮杂萘
类似于6-溴-2-(4-叔丁基-环己基氧基)-喹喔啉来合成6-溴-2-(4-叔丁基-环己基氧基)-1,8-二氮杂萘。请注意,通过快速色谱分离所需化合物。ESI-MS(M+H+):365.5。
实施例226:1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸乙酯
类似于1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸乙酯来合成1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸乙酯。ESI-MS(M+H+):454.1。
实施例227:1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸
类似于1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸来合成1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸。ESI-MS(M+H+):426.2。1H NMR(400MHz,甲醇-d4)δppm0.94(s,9H)1.11-1.22(m,1H)1.24-1.38(m,2H)1.45-1.58(m,2H)1.90-2.00(m,2H)2.19-2.38(m,3H)3.09-3.25(m,1H)3.57-3.72(m,1H)4.57(s,2H)5.27-5.37(m,1H)7.14(d,J=9.04Hz,1H)8.30(d,J=8.78Hz,1H)8.54(d,J=2.51Hz,1H)8.97(d,J=2.51Hz,1H)。
实施例228:(4-甲氧基苯基)三甲基甲硅烷
将4-溴苯甲醚(9.35g,50.0mmol,1.0当量)溶解于无水THF(200mL)中。在0℃添加Me3SiCl(12.7mL,100.0mmol,2.0当量),继而添加n-BuLi(2.5M己烷溶液,40mL,100.0mmol,2.0当量)。在室温搅拌反应混合物1小时。接着添加水(150mL),分离有机层且用Et2O(150mL×2)萃取水层。经无水Na2SO4干燥合并的有机萃取物,过滤且在真空中浓缩,得到呈淡黄色油状的(4-甲氧基苯基)三甲基硅烷(8.1g,90%产率)。1H NMR(300MHz,CDCl3)δ:7.48(d,J=11.2Hz,2H),6.95(d,J=11.2Hz,2H),3.84(s,3H),0.27(s,9H)。
实施例229:4-(三甲基甲硅烷基)环己酮
在-78℃液化氨(100mL)。添加无水Et2O(110mL)中的(4-甲氧基苯基)三甲基硅烷(18.0g,0.1mol,1.0当量),继而在-33℃逐份添加EtOH(80mL)及钠(23.0g,1.0mol,10.0当量)。再添加EtOH(50mL)且经16小时蒸发氨。接着将水(250mL)添加至残余物中且用Et2O(250mL×3)萃取混合物。经无水Na2SO4干燥合并的有机萃取物,过滤且在真空中浓缩。将粗产物溶解于EtOH(20mL)及H2O(20mL)中且接着添加乙二酸(2.71g,0.03mol,0.3当量)。在室温搅拌所得无色溶液2小时。接着添加水(100mL)且用Et2O(100mL×3)萃取混合物。用盐水洗涤合并的有机萃取物,经无水Na2SO4干燥,过滤且在真空中浓缩。通过硅胶柱色谱(石油醚/EtOAc=10:1)纯化残余物,得到呈淡黄色油状的4-(三甲基甲硅烷基)环己酮(14.0g,72%产率)。1H NMR(300MHz,CDCl3)δ:2.44-2.39(m,2H),2.33-2.22(m,2H),2.11-2.05(m,2H),1.53-1.47(m,2H),0.96-0.87(m,1H),0.00(s,9H)。
实施例230:顺式-4-(三甲基甲硅烷基)环己醇
在-78℃向三仲丁基硼氢化锂(L-selectride)(165mL,0.165mol,1.5当量)于无水THF(200mL)中的溶液中逐滴添加4-(三甲基甲硅烷基)环己酮(20g,0.11mol,1.0当量)于无水THF(100mL)中的溶液。维持温度3小时,且接着在室温搅拌反应混合物16小时。接着将混合物冷却至0℃,之后用水淬灭。使所得混合物升温至室温,且接着添加氢氧化钠水溶液(80mL,3M),继而添加过氧化氢(80mL,30%)。搅拌3小时后,用EtOAc(300mL×3)萃取混合物,且用H2O及盐水洗涤合并的有机层,经Na2SO4干燥,浓缩,得到残余物,将其通过硅胶柱色谱(石油醚/EtOAc=10:1)纯化,得到呈白色固体状的产物顺式-4-(三甲基甲硅烷基)环己醇(10.0g,51%产率)。1H NMR(300MHz,CDCl3)δ:4.05(s,1H),1.75(bs,2H),1.58-1.43(m,7H),0.55(bs,1H),0.00(s,9H)。
实施例231:1-((6-((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯
1-((6-((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸乙酯的制备相同。黄色油状物(130mg,40%产率)。LCMS m/z 468.3[M+H]+。
实施例232:1-((6-(((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸
1-((6-(((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸的制备与1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸的制备相同。用反相制备性HPLC(乙腈及含0.05%TFA的H2O作为移动相)纯化粗产物化合物,得到呈黄色油状的标题化合物(40mg,35%产率)。LCMS m/z 440.3[M+H]+;1H NMR(400MHz,CD3OD)δ:7.91(s,1H),7.85(d,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),7.48(dd,J=1.6,8.0Hz,1H),7.30(s,1H),7.18(dd,J=2.4,8.8Hz,1H),4.42(s,2H),4.40-4.35(m,1H),3.65-3.40(m,2H),3.26-3.07(m,2H),2.85-2.62(m,1H),2.29-2.21(m,4H),2.02-1.83(m,4H),1.41-1.29(m,4H),0.60-0.55(m,1H),0.00(s,9H)。
实施例233:活性测量
S1P受体活性分析
通过分析样品化合物且参考图表化(profiled)的各受体Emax对照来获得激动剂活化百分比测定结果。通过分析样品化合物且参考图表化的各受体对照EC80孔来获得拮抗剂抑制百分比测定结果。对于激动剂及拮抗剂分析操作,使用“单一添加”分析规程操作样品。规程设计如下:
化合物制备
母储备溶液:除非另外说明,否则在100%无水DMSO中稀释所有样品化合物,包括所有连续稀释。所有对照孔所含的溶剂最终浓度与样品化合物孔所含的溶剂最终浓度相同。
用于分析的化合物培养板:将样品化合物自母储备溶液转移至用于分析的子培养板中。将各样品化合物以适当浓度在分析缓冲液(1×含20mMHEPES及2.5mM丙磺舒(Probenecid)的HBSS)中稀释以获得最终浓度。
钙通量分析:激动剂分析形式
将样品化合物以八点,四倍连续稀释一式两份涂板,其中最高浓度为10μM。此处所述的浓度反映在拮抗剂分析期间化合物的最终浓度。在激动剂分析期间,化合物浓度为最终所需浓度的1.25倍,以允许在通过拮抗剂分析期间的参照激动剂的EC80进一步稀释的情况下实现最终所需浓度。
如上所述处理参照激动剂用作分析对照。如上文对于Emax所述处理参照激动剂。
使用FLIPRTETRA读取分析180秒(此分析操作将样品化合物及参照激动剂添加至相应的孔中)。在第一“单一添加”分析操作完成时,自FLIPRTETRA中移出分析培养板且置放于25℃七(7)分钟。
钙通量分析:拮抗剂分析形式
使用在激动剂分析期间测定的EC80值,以参照激动剂的EC80刺激所有预先孵育的样品化合物孔及参照拮抗剂孔(适当时)。使用FLIPRTETRA读取180秒(此分析将参照激动剂添加至相应的孔中,接着收集荧光测量值以计算抑制百分比值)。
数据处理
对所有培养板进行适当基线校正。在处理基线校正后,输出最大荧光值且处理数据以计算活化百分比、抑制百分比及Z'。
对于S1P1激动剂活性,实施例32、34、42、56、58、60、61、75、77、100、106、131、139、145、153、171、177、179、183、187、204及232的化合物的EC50值处于50nM至10μM的范围内。对于S1P4拮抗剂活性,实施例15、26、28、30、32、34、36、38、42、56、57、58、60、61、75、77、100、104、106、131、133、137、139、141、143、145、147、149、153、155、163、171、177、179、183、187、191、192、195、197、199、204、210、212、214及232的化合物的IC50值处于10nM至10μM范围内。对于S1P5拮抗剂活性,实施例28、32、34、38、42、104、106、131、137、139、141、143、145、149、155、161、171、177、179、183、191、192、195、197、199及204的化合物的IC50值处于100nM至5μM的范围内。
OPC分化分析
富集的少突胶质细胞群体从出生后第2天(P2)的雌性斯普拉格-道利鼠(Sprague Dawley rat)生长。解剖出前脑且置放于汉克缓冲盐水溶液(Hank'sbuffered saline solution,HBSS;Invitrogen,Grand Island,NY)中。将组织切成1mm片段且在37℃于0.01%胰蛋白酶及10μg/mL脱氧核糖核酸酶中孵育15分钟。将解离的细胞接种在涂有聚L-赖氨酸的T75组织培养烧瓶上且在37℃于含20%胎牛血清(Invitrogen)的达尔伯克改良伊格尔培养基(Dulbecco'smodified Eagle's medium,DMEM)中生长10天。通过在200rpm及37℃振荡烧瓶过夜来收集A2B5+OPC,产生95%纯群体。
对于分化分析,将2μM及20μM拮抗剂或相同浓度的媒介物(DMSO)施加于在含CNTF/T3的培养基中培养的OPC中。孵育3天后,裂解细胞且接着进行MSD(Meso Scale Discovery-R)分析。通过Prism使用非线性S型剂量-应答曲线计算EC50。或者,在4℃于80μL裂解缓冲液(50mM HEPES[4-(2-羟基乙基)-1-哌嗪乙烷磺酸](pH 7.5)、150mM NaCl、1.5mM MgCl2、1mM乙二醇四乙酸[EGTA]、1% Triton X-100及10%甘油)中裂解细胞30分钟。以14,000g离心15分钟后,将上清液在Laemmli样品缓冲液中煮沸,进行4%至20% SDS-PAGE,且通过western印迹法用抗MBP抗体、抗髓鞘相关糖蛋白(MAG)抗体或抗β肌动蛋白抗体分析。所用二次抗体分别为抗小鼠IgG-HRP(辣根过氧化酶)及抗兔IgG-HRP。
实施例22、26、30、32、34、36、38、42、48、52、57、58、61、62、75、77、81、83、85及87的化合物在OPC分析中以20微摩尔浓度显示+至++++范围内的活性。实施例15、22、30、32、36、42、48、55、56、57、58、59、60、61、62、75、77、83、85、88的化合物在OPC分析中以2微摩尔浓度显示+至++++范围内的活性。实施例22、24、26、30、32、42、58、60、61及77的化合物的EC50值<10μM。
OPC少突胶质细胞髓鞘形成分析
从胚胎期第18天(E18)的斯普拉格-道利鼠解剖胚胎脑新皮层神经元,且接着接种于涂有聚D-赖氨酸(100μg/mL)的盖玻片上且在补充有B27(Invitrogen)的神经基础培养基中生长1周。如上所述制备A2B5+OPC且接着将其添加至培养的脑新皮层神经元中。一天后,将不同浓度的S1P4受体拮抗剂及对照试剂施加于共培养物中。每三天一次提供含有不同浓度的S1P4受体拮抗剂或对照化合物的新鲜培养基。十天后,对共培养物进行十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)/western印迹分析以定量MAG、MBP及MOG。
脑切片培养物的髓鞘再生分析
从出生后第17天的斯普拉格-道利鼠(Charles River,Willmington,MA)的胼胝体与海马的接合点获取约三至四个连续300μm切片。在补充有25%马血清的基础DMEM中培养切片三天,之后用6mg/mLLPC(Sigma L-4129)再处理三天。接着更换培养基,且用含有S1P4受体拮抗剂或媒介物对照的培养基孵育切片最后三天时段,之后通过遵循制造商规程的黑金(black gold)染色(Millipore,Bedford,MA)使髓鞘形成显现。使用Leica M420显微镜(Bannockburn,IL)获得影像且使用Metamorph软件(Molecular Devices,Downingtown,PA)分析胼胝体的染色强度。每个处理组使用三或四个脑切片。
溶血卵磷脂脱髓鞘模型
通过腹膜内注射由氯胺酮(Ketamine)(35mg/kg)、赛拉嗪(Xylazine)(6mg/kg)及乙酰丙嗪(Acepromazine)(1mg/kg)组成的混合液使成年斯普拉格-道利鼠(220g-260g)麻醉。自下胸廓至腰区对动物背部进行剃毛,然后用70%异丙醇、贝他汀擦洗溶液(Betadine Scrub solution)消毒且再用70%异丙醇消毒。接着将动物置于立体定位框架上。
在确保足够麻醉度后,在胸廓区域上沿中线切割皮肤。切割背部筋膜且使脊旁肌肉与胸椎T-9至T-11的棘状突起分离。破坏T-10椎骨,且用小咬骨钳移出椎板。暴露背部脊髓区域后,将微毛细管玻璃针插入脊柱中达0.6mm的深度。以由微型泵(World Precision Instrument编号micro4)控制的2奈升/秒的输注速率注射脱髓鞘试剂(1.5μL于盐水中的1%溶血卵磷脂(LPC,Sigma编号L1381))。注射完成后,再置放针1分钟,之后移除。用缝合线(第5号,丝线)闭合脊旁肌肉及腰筋膜。用创伤夹闭合皮肤切口。允许动物自麻醉恢复知觉且在加湿的孵育器中观测。
在手术后,每天两次皮下(s.c.)给予丁基原啡因(buprenorphine)(0.05mg/kg),历时2天。
在初次手术后第3天,在初次注射区域处以如上文所示的相同输注速度注射1.5μL体积的S1P4受体拮抗剂(30pmol)、LPA(30pmol)或对照物(含0.1%DMSO的盐水)进行处理。在初次手术后第九天,使动物麻醉且经贲门灌注盐水中的肝素(10iu/mL),继而灌注PBS中的4%PFA。移出脊髓且之后在PFA中固定过夜。接着将脊髓纵向切成100μM厚度且接着用1%罗克沙尔固蓝(loxuol fast blue)进行染色且在显微镜下评定对髓鞘再生及修复的组织学评估。
对于全身性治疗,在初次手术后每日一次腹膜内给予动物S1P4受体拮抗剂(10mg/kg)或对照物(15%HPCD(羟基丙基-β-环糊精))2天。初次手术后第九天,处死动物且如上文所示处理脊髓。
钙动员
对特定S1P受体不具特异性的化合物可能引起不合需要的副作用。因此,测试化合物以识别具特异性的化合物。因此,在钙动员分析中测试测试化合物。操作基本上如Davis等人(2005)Journal of Biological Chemistry,第280卷,第9833-9841页中所述,所述文献的全部内容并入本文作为参考,并进行以下修改。在购自Millipore(Billerica,MA)的表达人类S1P1、S1P2、S1P3、S1P4或S1P5的重组CHEM细胞中进行钙动员分析。为检测游离细胞内钙,使S1P1、S1P2、S1P3、S1P4或S1P5细胞装载有来自MolecularDevices(Sunnyvale,CA)的FLIPR钙4染料。使用装备有96孔分配头的FLIPRTETRA获得细胞的钙动员的影像。
体内筛选分析
测量循环淋巴细胞:将化合物溶解于30%HPCD中。通过口服管饲给予小鼠(C57bl/6雄性,6至10周龄)0.5mg/kg及5mg/kg化合物。包括30%HPCD作为阴性对照。
在短暂异氟烷(isoflurane)麻醉下,在给予药物后第5小时及第24小时自后眼眶窦采集血液。对全血样品进行血液学分析。使用自动分析器(HEMAVETTM3700)测定周围淋巴细胞计数。通过荧光染料结合特异性抗体对周围血淋巴细胞的子群进行染色且使用荧光活化细胞分选仪(FACSCALIBURTM)分析。使用三只小鼠评定所筛选的各化合物的淋巴细胞消耗活性。
式(I)化合物可在短至4小时或4小时以内至长达48小时或48小时以上;例如4小时至36小时或5小时至24小时的时间内诱导完全淋巴细胞减少。在一些状况下,式I的化合物可在5小时诱导完全淋巴细胞减少且在24小时诱导部分淋巴细胞减少。诱导淋巴细胞减少所需的剂量可在例如0.001mg/kg至100mg/kg;或0.01mg/kg至10mg/kg范围的内。剂量可为10mg/kg或10mg/kg以下,诸如5mg/kg或5mg/kg以下、1mg/kg或1mg/kg以下或0.1mg/kg或0.1mg/kg以下。
其它实施方案在以下权利要求的范围内。
Claims (32)
1.一种式(I)化合物或其药学上可接受的盐:
其中:
A1为-CH=或-N=;
A2为-CH=或-N=;
A3为-CH2-、-CH=或-N=;
A4为-CH2-、-CH=或-N=;
A5为-CH2-、-CH=或-N=;
A6为-CH=或-N=;
W为-O-、=CR5-或-CHR5-;
R5为氢、卤素、烷基或卤代烷基;
Cy为4元至7元环烷基、4元至7元环烯基,或Cy为具有1个为O的杂原子的4元至7元杂环烷基;其中Cy任选经1至4个R1取代;
各R1独立地为卤素、烷基、卤代烷基、羟烷基、环烷基、三烷基甲硅烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起为C1至C5亚烷基;
L1为-C(O)-或-C(R3)2-;
各R3独立地为氢、烷基或卤代烷基;
x为0、1、2、3、4或5;
y为0、1、2、3、4或5;
其中x与y的和为4或5;
各Ra及各Rb独立地为氢、卤素、羟基、-CO2Rc、烷基或芳基;
R2为-(CH2)nCO2Rc,其中n为0或1;
Rc为氢、烷基、卤代烷基、环烷基或芳基;
前提条件为:所述化合物不为1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-4-甲酸、1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3R-甲酸或1-((2-(反式-4-叔丁基环己基氧基)萘-6-基)甲基)哌啶-3S-甲酸。
2.如权利要求1的化合物或其药学上可接受的盐,其中:
Cy可为4元至7元环烷基或Cy可为具有1个可为O的杂原子的杂环烷基;其中Cy可任选经1至4个R1取代,
各R1独立地为卤素、烷基、卤代烷基、环烷基、烷氧基、环烷氧基、烷氧基烷基、环烷氧基烷基或芳基,或两个R1一起为C2至C5亚烷基;
各Ra及各Rb独立地为氢、卤素、羟基、烷基或芳基。
3.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中A1、A2、A3、A4、A5及A6中的不多于两个为-N=。
4.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中A1、A2、A3、A4、A5及A6为-CH=。
5.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中A1为-CH=,A2为-CH=且A5为-CH=。
6.如权利要求1至3中任意项的化合物或其药学上可接受的盐,其中:
A3为-CH=,A4为-CH=,且A5为-CH=;或
A3为-N=,A4为-CH=,且A5为-CH=;或
A3为-N=,A4为-N=,且A5为-CH=;或
A2为-N=且A6为-N=;或
A1为-N=且A6为-N=;或
A3为-CH2-,A4为-CH2-,且A5为-CH2-。
7.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中x与y的和为4。
8.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中x为2且y为2。
9.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中Cy为二环或螺二环。
11.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中一个R1为氢且其它R1为乙基、异丙基、正丁基或叔丁基;或两个R1一起为C2至C5亚烷基。
12.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中L1为-C(R3)2-,其中至少一个R3为氢。
13.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中L1为-CH2-。
14.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中W为-O-。
17.一种化合物或其药学上可接受的盐,所述化合物选自:
1-((6-(反式-4-叔丁基环己基氧基)喹唑啉-2-基)甲基)哌啶-4-甲酸;
1-(1-(6-(反式-4-叔丁基环己基氧基)萘-2-基)-2,2,2-三氟乙基)哌啶-4-甲酸;
1-((6-(4-异丙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(顺式-4-叔丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-(三氟甲基)环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(4-丁基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[4.5]癸-8-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(顺式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(反式-4-乙基环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(反式-4-叔丁基环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-(6-(反式-4-叔丁基环己基氧基)-萘-2-甲酰基)哌啶-4-甲酸;
1-((6-((4-叔丁基亚环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;
1-((2-(反式-4-叔丁基环己基氧基)喹啉-6-基)甲基)哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-乙基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-丙基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-3-甲基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-苯基-哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-4-羟基-哌啶-4-甲酸;
{1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-4-基}-乙酸;
1-[7-(反式-4-叔丁基-环己基氧基)-异喹啉-3-基甲基]-哌啶-4-甲酸;
1-((6-(反式-4-叔丁基环己基氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;
1-((6-(环戊基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环庚基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(四氢-2H-吡喃-4-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[5.5]十一烷-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[3.5]壬-7-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-[6-(4-叔丁基-环己基氧基)-萘-2-基甲基]-哌啶-2-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)-1,2,3,4-四氢萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-苯基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)-3-甲基哌啶-4-甲酸;
1-((6-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-环丁氧基萘-2-基)甲基)哌啶-4-甲酸;
1-(1-(6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)乙基)哌啶-4-甲酸;
1-((6-((4-(叔丁基)环己基)甲基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((四氢呋喃-3-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环己基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(环己基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔戊基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(三氟甲基)环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[3.5]壬-7-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[5.5]十一烷-3-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-乙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[2.5]辛-6-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[4.5]癸-8-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3,3,5-三甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-异丙基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-(叔戊基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(乙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((八氢-1H-茚-5-基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(螺[2.5]辛-6-基氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((3,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(甲氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(异丁氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((2-甲基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-苯基环己基)氧基)喹啉-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(异丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((顺式-4-(丙氧基甲基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)喹啉-2-基)甲基)哌啶-3-甲酸;
1-((6-((4,4-二氟环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((2-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((4-(2-羟基丙-2-基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((3-甲基环戊基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-(二环[3.1.0]己-3-基氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-异丙基环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸;
1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-4,4-二甲酸;
2-(1-((6-((反式-4-(叔丁基)环己基)氧基)萘-2-基)甲基)哌啶-2-基)乙酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)哌啶-3-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-甲基哌啶-4-甲酸;
1-((6-((4,4-二甲基环己基)氧基)萘-2-基)甲基)-4-乙基哌啶-4-甲酸;
1-[6-(二环[2.2.1]庚-5-烯-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;
1-[6-(1,3,3-三甲基-二环[2.2.1]庚-2-基氧基)-萘-2-基甲基]-哌啶-4-甲酸;
1-[2-(4-叔丁基-环己基氧基)-喹喔啉-6-基甲基]-哌啶-4-甲酸;
1-[2-(4-叔丁基-环己基氧基)-喹唑啉-6-基甲基]-哌啶-4-甲酸;
1-[7-(4-叔丁基-环己基氧基)-[1,8]二氮杂萘-3-基甲基]-哌啶-4-甲酸;及
1-((6-(((反式-4-(三甲基甲硅烷基)环己基)氧基)萘-2-基)甲基)哌啶-4-甲酸。
18.如前述权利要求中任意项的化合物或其药学上可接受的盐,其中所述化合物对S1P4受体具有选择性。
19.如前述权利要求中任意项的化合物,其中所述化合物对所述S1P4受体的亲和力为对S1P1受体、S1P2受体、S1P3受体或S1P5受体的亲和力的至少5倍。
20.一种药物组合物,其包含如权利要求1至19中任一项的化合物或其药学上可接受的盐以及药学上可接受的赋形剂或载体。
21.一种预防或治疗哺乳动物的涉及S1P受体活性的病理性病症或症状的方法,其包括给予所述哺乳动物有效量的如权利要求1至19中任意项的化合物或其药学上可接受的盐。
22.一种预防或治疗哺乳动物的以下疾病的方法:多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病,其包括给予所述哺乳动物有效量的如权利要求1至19中任一项的化合物或其药学上可接受的盐。
23.一种预防或治疗哺乳动物的神经病的方法,其包括给予所述哺乳动物有效量的如权利要求1至19中任一项的化合物或其药学上可接受的盐。
24.如权利要求23的方法,其中所述神经病为阿尔茨海默病、帕金森病、亨廷顿病、运动神经元病、肌萎缩侧索硬化、多发性硬化、神经元创伤或脑缺血症。
25.如权利要求21的方法,其中所述病理性病症的预防或治疗包括针对多发性硬化的髓鞘再生及轴突再生、阻断星形胶质化或针对神经炎症相关疾病的微神经胶质活化。
26.一种预防或治疗哺乳动物的神经性疼痛的方法,其包括给予所述哺乳动物有效量的如权利要求1至19中任一项的化合物或其药学上可接受的盐。
27.一种预防或治疗哺乳动物的自身免疫疾病的方法,其包括给予所述哺乳动物有效量的如权利要求1至19中任一项的化合物或其药学上可接受的盐。
28.如权利要求27的方法,其中所述自身免疫疾病为多发性硬化。
29.一种促进髓鞘形成或髓鞘再生的方法,其包括给予细胞如权利要求1至19中任一项的化合物或其药学上可接受的盐。
30.一种促进有需要的哺乳动物髓鞘形成或髓鞘再生的方法,其包括给予细胞如权利要求1至19中任一项的化合物或其药学上可接受的盐。
31.如权利要求1至19中任一项的化合物或其药学上可接受的盐,其用于治疗或预防多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
32.一种如权利要求1至19中任一项的化合物或其药学上可接受的盐用于制备药物的用途,所述药物用于治疗或预防:多发性硬化、自身免疫疾病、慢性炎症性障碍、哮喘、炎症性神经病、关节炎、移植排斥、克罗恩病、溃疡性结肠炎、红斑狼疮、银屑病、缺血再灌注损伤、实体瘤、瘤转移、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒性疾病、炎症性肠病、胰岛素依赖型糖尿病或非胰岛素依赖型糖尿病。
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