CN112707873B - 取代的噁唑类衍生物及其在药物中的应用 - Google Patents
取代的噁唑类衍生物及其在药物中的应用 Download PDFInfo
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- CN112707873B CN112707873B CN202011113265.4A CN202011113265A CN112707873B CN 112707873 B CN112707873 B CN 112707873B CN 202011113265 A CN202011113265 A CN 202011113265A CN 112707873 B CN112707873 B CN 112707873B
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Classifications
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- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Landscapes
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Abstract
本发明公开了取代的噁唑类衍生物及其在药物中的应用;具体地,本发明提供一类取代的噁唑化合物或其立体异构体,几何异构体,互变异构体,氮氧化物,水合物,溶剂化物,代谢产物,药学上可接受的盐或它们的前药,以及含有本发明化合物的药物组合物。本发明还公开了本发明化合物或其药物组合物在制备药物中的用途,该药物用于预防、治疗或减轻与4型磷酸二酯酶(PDE4)相关的疾病,例如特应性皮炎(AD)或慢性阻塞性肺病(COPD)。
Description
技术领域
本发明属于药物领域,具体涉及一类取代的噁唑类化合物、包含所述化合物的药物组合物及其用途和使用方法。特别地,本发明所述的化合物是4型磷酸二酯酶(PDE4)抑制剂,用于治疗与PDE4相关的疾病,例如特应性皮炎(AD)或慢性阻塞性肺病(COPD)。
背景技术
环磷酸腺苷(cAMP)和环磷酸鸟苷(cGMP)是细胞内两种重要的第二信使,主要通过激活蛋白激酶A(PKA)和蛋白激酶G(PKG)途径参与能量代谢、记忆、免疫反应、视觉及嗅觉形成等生理活动,其细胞内浓度的调节主要由腺(鸟)苷酸环化酶的合成和磷酸二酯酶(PDEs)的水解作用之间的平衡决定。PDEs能特异性地以3,5-环核苷酸为底物,催化细胞内的cGMP和cAMP水解生成相应的无活性的5-核苷酸,从而影响生物体的各种代谢功能。因此,抑制PDEs对引起许多细胞活性是一种很有效的途径,能影响炎症细胞和免疫细胞活化及平滑肌细胞收缩反应。
磷酸二酯酶(PDEs)迄今已报道有11个基因家族,每个家族又包括多个亚家族。PDEs分布于多个组织中,其抑制剂具有广泛的生理作用,其中PDE4、PDE7和PDE8主要特异性水解cAMP,PDE5、PDE6和PDE9特异性水解cGMP,而PDE1、PDE2、PDE3、PDE10和PDE11则对cAMP和cGMP都起作用。其中PDE4主要分布于各种炎性细胞内,其组织分布说明它与中枢神经系统和免疫系统息息相关,其抑制剂可用于治疗各种疾病,包括过敏性和炎性疾病、糖尿病、中枢神经系统疾病和疼痛。
目前,对PDE4的研究主要集中在免疫及炎症相关疾病中,世界上许多著名的制药公司都把PDE4作为慢性炎症相关疾病的靶点。PDE4抑制剂发挥抗炎作用主要通过以下几种途径:(1)抑制多种炎症介质的活性;(2)抑制细胞黏附因子的上调和表达;(3)抑制血白细胞的活化;(4)诱导细胞凋亡;(5)诱导具有抑制活性的细胞因子的生成(如白细胞介素-6);(6)诱导儿茶酚胺类物质和内源性激素的释放。第一代PDE4抑制剂主要有茶碱、咯利普兰(Rolipram)和吡拉米司特(Piclamilast)等,咯利普兰对神经系统疾病,如帕金森病、抑郁症和焦虑等都具有一定的治疗作用。但第一代PDE4抑制剂由于严重的恶心、呕吐等副作用,在临床上的应用受到了限制;第二代PDE4抑制剂有罗氟司特(Roflumilast)和西洛司特(Cilomilast)等,其中罗氟司特用于COPD的治疗,对其他炎症性疾病也有一定的治疗效果,如溃疡性结肠炎和克罗恩病。第三代PDE4抑制剂阿普斯特(Apremilast)已经用于自身免疫性疾病如银屑病的治疗,且副作用更小,病人更易耐受。WO/2000/064260披露了PDE4抑制剂Ro 20-1724 1%霜剂治疗银屑病有效。WO 2000/009504披露了另一个PDE4抑制剂CP-80633(0.5%软膏),其明显地改善了特应性皮炎的临床计分(红斑、硬结和表皮脱落)。但是,临床上仍需要更多的可以有效治疗特应性皮炎的PDE4抑制剂。
发明内容
本发明涉及新的取代的噁唑类化合物和治疗特应性皮炎的方法。本发明化合物或包含所述化合物的药物组合物作为PDE4抑制剂,对特应性皮炎有较好的治疗效果。
一方面,本发明涉及一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中:
Ra、Rb、Rc和Rd各自独立地为氢、氘、C1-6烷基、卤代C1-6烷基、氨基取代基C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6亚烷基、(5-10个原子组成的杂环基)-C1-6亚烷基、C6-10芳基-C1-6亚烷基或(5-10个原子组成的杂芳基)-C1-6亚烷基;
L为*-L1-M1-L2-或*-L3-M2-L4-;其中,*表示与噁唑环一端相连;
L1为-C(=O)-、-C(=S)-或C1-6亚烷基;
各L2和L3独立地为一个键或C1-6亚烷基;
L4为-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-或C1-6亚烷基;
M1为-O-或-S-;
M2为-O-、-S-、-N(R1)-或-CR2R3-;
R1、R2和R3各自独立地为氢、氘、C1-6烷基、卤代C1-6烷基、氨基取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基-C1-6亚烷基、(5-10个原子组成的杂环基)-C1-6亚烷基、C6-10芳基-C1-6亚烷基或(5-10个原子组成的杂芳基)-C1-6亚烷基;
A为C6-10芳基、C6-10芳基-S(=O)2-、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)-S(=O)2-、5-10个原子组成的杂环基或C3-8环烷基;其中A任选地被1、2、3或4个R4所取代;
各R4独立地为氘、卤素、氰基、硝基、氨基、羟基、羧基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基-O-C(=O)-、C1-6烷基-C(=O)-、C1-6烷基-C(=O)-O-、C6-10芳基-C1-6亚烷基、(5-10个原子组成的杂芳基)-C1-6亚烷基、-N(R5R6)、-S(=O)2-N(R5R6)、-C(=O)-N(R5R6)、-N(R5)-C(=O)-C1-6烷基、-N(R5)-C(=O)-O-C1-6烷基或-O-C(=O)-N(R5R6);
R5和R6各自独立地为氢、氘、C1-6烷基、卤代C1-6烷基、氨基取代的C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6亚烷基、5-10个原子组成的杂环基、(5-10个原子组成的杂环基)-C1-6亚烷基、C6-10芳基、C6-10芳基-C1-6亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C1-6亚烷基;其中R5和R6各自独立任选地被1、2、3或4个R7所取代;
各R7独立地为氘、卤素、氰基、硝基、氨基、羟基、羧基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-C(=O)-O-C1-6烷基、-C(=O)-C1-6烷基、-O-C(=O)-C1-6烷基、-N(R8R9)、-S(=O)2-N(R8R9)、-C(=O)-N(R8R9)、-N(R8)-C(=O)-C1-6烷基、-N(R8)-C(=O)-O-C1-6烷基或-O-C(=O)-N(R8R9);
R8和R9各自独立地为氢、氘、C1-6烷基、卤代C1-6烷基、氨基C1-6烷基、羟基取代的C1-6烷基、氰基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8环烷基-C1-6亚烷基、5-10个原子组成的杂环基、(5-10个原子组成的杂环基)-C1-6亚烷基、C6-10芳基、C6-10芳基-C1-6亚烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)-C1-6亚烷基。
在一些实施方案中,Ra、Rb、Rc和Rd各自独立地为氢、氘、C1-4烷基、卤代C1-4烷基、氨基取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基、C3-6环烷基-C1-3亚烷基、(5-7个原子组成的杂环基)-C1-4亚烷基、C6-10芳基-C1-4亚烷基或(5-7个原子组成的杂芳基)-C1-4亚烷基。
在另一些实施方案中,Ra、Rb、Rc和Rd各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3、-CH=CH2、环丙基、环丁基、环戊基、环己基、环丙基-亚甲基、环丙基-亚乙基、环丁基-亚甲基、环丁基-亚乙基、环戊基-亚甲基、环戊基-亚乙基、环己基-亚甲基或环己基-亚乙基。
在一些实施方案中,本发明涉及一种化合物,其为式(II)所示的化合物或式(II)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中,所述L和A具有本发明所述的含义。
在一些实施方案中,L为-L1-M1-L2-或-L3-M2-L4-;
L1为-C(=O)-、-C(=S)-或C1-4亚烷基;
L2和L3各自独立地为一个键或C1-4亚烷基;
L4为-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-或C1-4亚烷基;
M1为-O-或-S-;
M2为-O-、-S-、-N(R1)-或-CR2R3-;
R1、R2和R3各自独立地为氢、氘、C1-4烷基、卤代C1-4烷基、氨基取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基-C1-4亚烷基、(5-7个原子组成的杂环基)-C1-4亚烷基、C6-10芳基-C1-4亚烷基、(5-7个原子组成的杂芳基)-C1-4亚烷基、C3-6环烷基、5-7个原子组成的杂环基、C6-10芳基或5-7个原子组成的杂芳基。
在一些实施方案中,A为C6-10芳基、5-10个原子组成的杂芳基、5-10个原子组成的杂环基或C3-6环烷基;其中A任选地被1、2、3或4个R4所取代;其中,所述R4具有本发明所述的含义。
在一些实施方案中,各R4独立地为氘、卤素、氰基、硝基、氨基、羟基、羧基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、-C(=O)-O-C1-4烷基、-C(=O)-C1-4烷基、-O-C(=O)-C1-4烷基、C6-10芳基-C1-4亚烷基、(5-10个原子组成的杂芳基)-C1-4亚烷基、-N(R5R6)、-S(=O)2-N(R5R6)、-C(=O)-N(R5R6)、-N(R5)-C(=O)-C1-4烷基、-N(R5)-C(=O)-O-C1-4烷基或-O-C(=O)-N(R5R6);其中,所述R5和R6具有本发明所述的含义。
在一些实施方案中,R5和R6各自独立地为氢、氘、C1-3烷基、卤代C1-3烷基、氨基取代的C1-3烷基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、C3-6环烷基-C1-3亚烷基、5-7个原子组成的杂环基、(5-7个原子组成的杂环基)-C1-3亚烷基、C6-10芳基、C6-10芳基-C1-3亚烷基、5-7个原子组成的杂芳基或(5-7个原子组成的杂芳基)-C1-3亚烷基;其中R5和R6各自独立任选地被1、2、3或4个R7所取代;其中,所述R7具有本发明所述的含义。
在一些实施方案中,各R7独立地为氘、卤素、氰基、硝基、NH2、羟基、羧基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、-C(=O)-O-C1-4烷基、-C(=O)-C1-4烷基、-O-C(=O)-C1-4烷基、-N(R8R9)、-S(=O)2-N(R8R9)、-C(=O)-N(R8R9)、-N(R8)-C(=O)-C1-4烷基、-N(R8)-C(=O)-O-C1-4烷基或-O-C(=O)-N(R8R9);其中,所述R8和R9具有本发明所述的含义。
在一些实施方案中,R8和R9各自独立地为氢、氘、C1-3烷基、卤代C1-3烷基、氨基取代的C1-3烷基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、C3-6环烷基-C1-3亚烷基、5-6个原子组成的杂环基、(5-6个原子组成杂环基)-C1-3亚烷基、C6-10芳基、C6-10芳基-C1-3亚烷基、5-6个原子组成杂芳基或(5-6个原子组成杂芳基)-C1-3亚烷基。
在另一些实施方案中,L1为-C(=O)-、-C(=S)-、亚甲基、亚乙基或亚丙基;
L2和L3各自独立地为一个键、亚甲基、亚乙基或亚丙基;
L4为-S(=O)2-、-S(=O)-、-C(=O)-、-C(=S)-、亚甲基、亚乙基或亚丙基;
M1为-O-或-S-;
M2为-O-、-S-、-N(R1)-或-CR2R3-;
R1、R2和R3各自独立地为氢、氘、C1-4烷基、卤代C1-4烷基、氨基取代的C1-4烷基、羟基取代的C1-4烷基、氰基取代的C1-4烷基、C2-4烯基、C2-4炔基、C3-6环烷基-C1-3亚烷基、(5-6个原子组成的杂环基)-C1-3亚烷基、C6-10芳基-C1-3亚烷基或(5-6个原子组成的杂芳基)-C1-3亚烷基。
在另一些实施方案中,A为C6-10芳基、5-6个原子组成的杂芳基、5-6个原子组成的杂环基或C3-6环烷基,其中A任选地被1、2、3或4个R4所取代;其中,所述R4具有本发明所述的含义。
在另一些实施方案中,各R4独立地为氘、卤素、氰基、硝基、氨基、羟基、羧基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、-C(=O)-O-C1-4烷基、-C(=O)-C1-4烷基、-O-C(=O)-C1-4烷基、C6-10芳基-C1-4亚烷基、5-6个原子组成的杂芳基-C1-4亚烷基、-N(R5R6)、-S(=O)2-N(R5R6)、-C(=O)-N(R5R6)、-N(R5)-C(=O)-C1-4烷基、-N(R5)-C(=O)-O-C1-4烷基或-O-C(=O)-N(R5R6);
其中,所述R5和R6具有本发明所述的含义。
在另一些实施方案中,R5和R6各自独立地为氢、氘、C1-3烷基、卤代C1-3烷基、氨基取代的C1-3烷基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、C3-6环烷基-C1-3亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C1-3亚烷基、C6-10芳基、C6-10芳基-C1-3亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C1-3亚烷基;其中,R5和R6各自独立任选地被1、2、3或4个R7所取代;其中,所述R7具有本发明所述的含义。
在另一些实施方案中,R8和R9各自独立地为氢、氘、C1-3烷基、卤代C1-3烷基、氨基取代的C1-3烷基、羟基取代的C1-3烷基、氰基取代的C1-3烷基、C2-4烯基、C2-4炔基、C3-6环烷基、C3-6环烷基-C1-3亚烷基、5-6个原子组成的杂环基、(5-6个原子组成杂环基)-C1-3亚烷基、C6-10芳基、C6-10芳基-C1-3亚烷基、5-6个原子组成杂芳基或(5-6个原子组成杂芳基)-C1-3亚烷基。
在又一些实施方案中,R1、R2和R3各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2或-CCl3。
在又一些实施方案中,A为苯基、吲哚基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、噁唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基、吡咯烷基、环丙基、环丁基、环戊基或环己基;其中,A任选地被1、2、3或4个R4所取代;其中,所述R4具有本发明所述的含义。
在又一些实施方案中,各R4独立地为氘、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-C(=O)-O-CH3、-C(=O)-O-CH2CH3、-C(=O)-O-(CH2)2CH3、-C(=O)-O-CH(CH3)2、-C(=O)-O-(CH2)3CH3、-C(=O)-O-CH2CH(CH3)CH3、-C(=O)-O-CH(CH3)CH2CH3、-O-C(=O)-CH3、-O-C(=O)-CH2CH3、-O-C(=O)-(CH2)2CH3、-O-C(=O)-CH(CH3)2、-C(=O)-CH3、-C(=O)-CH2CH3、-C(=O)-CH(CH3)2、-N(R5R6)、-C(=O)-N(R5R6)、-N(R5)-C(=O)-CH3、-N(R5)-C(=O)-CH2CH3、-N(R5)-C(=O)-CH2CH2CH3、-N(R5)-C(=O)-CH(CH3)CH3、-N(R5)-C(=O)-O-CH3、-N(R5)-C(=O)-O-CH2CH3、-N(R5)-C(=O)-O-(CH2)2CH3、-N(R5)-C(=O)-O-CH(CH3)CH3或-O-C(=O)-N(R5R6);
其中,所述R5和R6具有本发明所述的含义。
在又一些实施方案中,R5和R6各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2Cl、-CHCl2、-CH2CH2Cl、-CH2CHCl2、-CH2CCl3、-CH2CH2CH2Cl、-CH2CH2CHCl2、-CH2CH2CCl3、环丙基、环丁基、环戊基、环己基、环丙基-亚甲基、环丙基-亚乙基、环丁基-亚甲基、环丁基-亚乙基、环戊基-亚甲基、环戊基-亚乙基、环己基-亚甲基、环己基-亚乙基、苯基、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、噁唑基、三氮唑基、四氮唑基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、四氢吡喃基或吡咯烷基;其中,R5和R6各自独立任选地被1、2、3或4个R7所取代;其中,所述R7具有本发明所述的含义。
在又一些实施方案中,各R7独立地为氘、氟、氯、溴、氰基、硝基、氨基、羟基、羧基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3、-CH2CH2Cl、-CH2CHCl2、-CH2CCl3、-CH2CH2CH2Cl、-CH2CH2CHCl2、-CH2CH2CCl3、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCH2CF3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-OCH2Cl、-OCHCl2、-OCCl3、-OCH2CH2Cl、-OCH2CHCl2、-OCH2CCl3、-OCH2CH2CH2Cl、-OCH2CH2CHCl2、-OCH2CH2CCl3、-C(=O)-O-CH3、-C(=O)-O-CH2CH3、-C(=O)-O-(CH2)2CH3、-C(=O)-O-CH(CH3)2、-C(=O)-CH3、-C(=O)-CHCH32、-C(=O)-(CH2)2CH3、-C(=O)-CH(CH3)2、-O-C(=O)-CH3、-O-C(=O)-CH2CH3或-O-C(=O)-CH(CH3)2、-N(R8R9)、-C(=O)-N(R8R9)、-N(R8)-C(=O)-CH3、-N(R8)-C(=O)-CH2CH3、-N(R8)-C(=O)-CH2CH2CH3、-N(R8)-C(=O)-CH(CH3)CH3、-N(R8)-C(=O)-O-CH3、-N(R8)-C(=O)-O-CH2CH3、-N(R8)-C(=O)-O-CH2CH2CH3、-N(R8)-C(=O)-O-CH(CH3)CH3或-O-C(=O)-N(R8R9);其中,所述R8和R9具有本发明所述的含义。
在又一些实施方案中,R8和R9各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CH2Cl、-CHCl2、-CCl3、-CH2CH2Cl、-CH2CHCl2、-CH2CCl3、-CH2CH2CH2Cl、-CH2CH2CHCl2、-CH2CH2CCl3、环丙基、环丁基、环戊基、环己基、环丙基甲基、环丙基乙基、环丁基甲基、环丁基乙基、环戊基甲基、环戊基乙基、环己基甲基、环己基乙基、苯基、吡啶基、6H-吡啶基、嘧啶基、呋喃基、噻吩基或吡咯基。
在一些实施方案中,本发明包含但绝不限于具有下列之一结构的化合物或具有下列之一结构化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
在一些实施方案中,本发明式(I)所示的化合物或式(II)所示的化合物,其药学上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
一方面,本发明涉及一种药物组合物,所述药物组合物包含本发明公开的式(I)或式(II)所述的化合物。
在一些实施方案中,本发明所述的药物组合物,其进一步地包含药学上可接受的载体、赋形剂、佐剂或它们的组合。
在一些实施方案中,本发明所述的药物组合物,进一步地包含附加治疗剂,其中所述的附加治疗剂是:丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索(clobatsol)、卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗(Dupilumab)、来金珠单抗、尼莫利珠单抗(Nemolizumab)、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努(Secukinumab)、奥马珠(Omazumilab)、CIM-331、戈利木单抗和聚乙二醇化赛妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、弗维普兰特(Fevipiprant)、和OC-459、SUN 13834、SB-011、VTP-43742、ARN6039、TAK-828、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的任意组合。
另一方面,本发明涉及本发明公开的式(I)或式(II)所示化合物或其药物组合物在制备药物中的用途,其中所述药物用于预防、治疗或减轻与4型磷酸二酯酶(PDE 4)有关的疾病。
在一些实施方案中,所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病。
在另一些实施方案中,所述的呼吸疾病为:慢性阻塞性肺病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症或呼吸道炎症;其中支气管炎包括急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
本发明另一方面涉及式(I)或式(II)所示的化合物的制备、分离和纯化的方法。
前面所述内容只概述了本发明的某些方面,但并不限于这些方面。这些方面及其他方面的内容将在下面作更加具体完整的描述。
本发明详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案,其实施例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
应进一步认识到,本发明的某些特征,为清楚可见,在多个独立的实施方案中进行了描述,但也可以在单个实施例中以组合形式提供。反之,本发明的各种特征,为简洁起见,在单个实施方案中进行了描述,但也可以单独或以任意适合的子组合提供。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明,应当应用本发明所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry"by Michael B.Smith and JerryMarch,John Wiley&Sons,New York:2007中的描述,其全部内容通过引用并入本发明。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象,例如也指灵长类动物(例如人类,男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述受试对象是灵长类动物。在其他实施方案中,所述受试对象是人。本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中,“患者”是指人。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
术语“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何(顺/反)异构体、阻转异构体,等等。
术语“手性”是具有与其镜像不能重叠性质的分子;而“非手性”是指与其镜像可以重叠的分子。
术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。
许多有机化合物以光学活性形式存在,即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时,使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号,其中(-)或l表示化合物是左旋的,前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体,这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体,当在化学反应或过程中没有立体选择性或立体特异性时,可出现这种情况。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
依据起始物料和方法的选择,本发明化合物可以以可能的异构体中的一个或它们的混合物,例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有一个双键,取代基可能为E或Z构型;如果化合物中含有二取代的环烷基,环烷基的取代基可能有顺式或反式构型。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体,如,通过对获得的其非对映异构体的盐进行分离。外消旋的产物也可以通过手性色谱来分离,如,使用手性吸附剂的高效液相色谱(HPLC)。特别地,对映异构体可以通过不对称合成制备,例如,可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles ofAsymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral SeparationTechniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。
一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
术语“任选地被……所取代”这个术语与“未被取代或被……取代”这个术语可以交换使用,即所述结构是未取代的或者被一个或多个本发明所述的取代基取代。本发明所述的取代基包括,但不限于,氘,氟,氯,溴,碘,氰基,羟基,氨基,叠氮基,芳基,杂芳基,烷氧基,烷氨基,烷硫基,烷基,烯基,炔基,杂环基,羧基,卤代烷基,卤代烷氧基,羟基取代的烷基,羟基取代的烷氧基,羟基取代的烷基-C(=O)-,烷基-C(=O)-,烷基-O-C(=O)-,烷基-S(=O)-,烷基-S(=O)2-,羟基取代的烷基-S(=O)-,羟基取代的烷基-S(=O)2-,NH2-C(=O)-,NH2-S(=O)2-、芳基-亚烷基、杂芳基-亚烷基、芳基-S(=O)2-、杂芳基-S(=O)2-、烷基-C(=O)-O-、-NH-C(=O)-烷基、-NH-C(=O)-O-烷基或-O-C(=O)-NH2等等。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。以R15为例,结构式“NR15R16-C(=O)-N(R15)-”和结构式“R14-C(=O)-N(R15)-亚烷基-”两者之间R15的具体选项互相之间不受影响,同时,在同一化学式“NR15R16-C(=O)-N(R15)-”内,多个R15的具体选项互相之间不受影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-C6烷基”或“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了如“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子。在一实施方案中,烷基基团含有1-12个碳原子;在另一实施方案中,烷基基团含有1-6个碳原子;在又一实施方案中,烷基基团含有1-4个碳原子;还在一实施方案中,烷基基团含有1-3个碳原子。
烷基基团的实例包含,但并不限于,甲基(Me、-CH3),乙基(Et、-CH2CH3),正丙基(n-Pr、-CH2CH2CH3),异丙基(i-Pr、-CH(CH3)2),正丁基(n-Bu、-CH2CH2CH2CH3),异丁基(i-Bu、-CH2CH(CH3)2),仲丁基(s-Bu、-CH(CH3)CH2CH3),叔丁基(t-Bu、-C(CH3)3),正戊基(-CH2CH2CH2CH2CH3),2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2),2-甲基-2-丁基(-C(CH3)2CH2CH3),3-甲基-2-丁基(-CH(CH3)CH(CH3)2),3-甲基-1-丁基(-CH2CH2CH(CH3)2),2-甲基-1-丁基(-CH2CH(CH3)CH2CH3),正己基(-CH2CH2CH2CH2CH2CH3),2-己基(-CH(CH3)CH2CH2CH2CH3),3-己基(-CH(CH2CH3)(CH2CH2CH3)),2-甲基-2-戊基(-C(CH3)2CH2CH2CH3),3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3),4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2),3-甲基-3-戊基(-C(CH3)(CH2CH3)2),2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2),2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2),3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3),正庚基,正辛基,等等。
术语“亚烷基”表示从饱和的直链或支链烃中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明,亚烷基基团含有1-12个碳原子。在一实施方案中,亚烷基基团含有1-6个碳原子;在另一实施方案中,亚烷基基团含有1-4个碳原子;在又一实施方案中,亚烷基基团含有1-3个碳原子;还在一实施方案中,亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH2-),亚乙基(-CH2CH2-),亚丙基(-CH2CH2CH2-),亚异丙基(-CH(CH3)CH2-)等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp2双键,其中,所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代,其包括"cis"和"tans"的定位,或者"E"和"Z"的定位。在一实施方案中,烯基基团包含2-8个碳原子;在另一实施方案中,烯基基团包含2-6个碳原子;在又一实施方案中,烯基基团包含2-4个碳原子。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、1-丙烯基(-CH=CH-CH3)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp三键,其中,所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一实施方案中,炔基基团包含2-8个碳原子;在另一实施方案中,炔基基团包含2-6个碳原子;在又一实施方案中,炔基基团包含2-4个碳原子。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)等等。
术语“羧基”,无论是单独使用还是和其他术语连用,如“羧烷基”,表示-CO2H或-COOH。
术语“氘”表示单个氘原子。例如,一个氘原子取代甲基中的一个氢原子,形成单-氘代甲基(-CDH2),两个氘原子取代甲基中的两个氢原子,形成双-氘代甲基(-CD2H),以及三个氘原子取代甲基中的三个氢原子,形成三-氘代甲基(-CD3)。
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。
术语“杂原子”是指O、S、N、P和Si,包括N、S和P任何氧化态的形式;伯、仲、叔胺和季铵盐的形式;或者杂环中氮原子上的氢被取代的形式,例如,N(像3,4-二氢-2H-吡咯基中的N),NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR,其中R表示本发明所述的取代基)。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“羟基取代的烷基”表示烷基基团被一个或多个羟基基团所取代,其中烷基基团具有如本发明所述的含义。这样的实例包含,但并不限于羟甲基、羟基乙基(例如2-羟基乙基)、2-羟基-1-丙基、3-羟基-1-丙基、2,3-二羟基丙基等等。
术语“氰基取代的烷基”表示烷基基团被一个或多个氰基基团所取代,其中烷基基团具有如本发明所述的含义。这样的实例包含,但并不限于氰基甲基(-CH2CN)、氰基乙基(例如2-氰基乙基,-CH2CH2CN)、2-氰基-1-丙基(-CH2CH(CN)CH3)、3-氰基-1-丙基(-CH2CH2CH2CN)、2,3-二氰基丙基(-CH2CH(CN)CH2CN)等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代,其中烷基和烷氧基基团具有如本发明所述的含义。这样的实例包含,但并不限于,-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CH2CF3、-CF2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-CF2CH2CH3、-CH2Cl、-CHCl2、-OCHF2、-OCF3等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子。在一实施方案中,烷氧基基团含有1-6个碳原子;在另一实施方案中,烷氧基基团含有1-4个碳原子;在又一实施方案中,烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH3),乙氧基(EtO、-OCH2CH3),1-丙氧基(n-PrO、n-丙氧基、-OCH2CH2CH3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH3)2),1-丁氧基(n-BuO、n-丁氧基、-OCH2CH2CH2CH3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH2CH(CH3)2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH3)CH2CH3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH3)3),1-戊氧基(n-戊氧基、-OCH2CH2CH2CH2CH3),2-戊氧基(-OCH(CH3)CH2CH2CH3),3-戊氧基(-OCH(CH2CH3)2),2-甲基-2-丁氧基(-OC(CH3)2CH2CH3),3-甲基-2-丁氧基(-OCH(CH3)CH(CH3)2),3-甲基-l-丁氧基(-OCH2CH2CH(CH3)2),2-甲基-l-丁氧基(-OCH2CH(CH3)CH2CH3),等等。
术语“氨基取代的烷基”或“氨基烷基”包括被一个或多个氨基所取代的C1-10直链或支链烷基基团,其中烷基基团具有如本发明所述的含义。其中一些实施例是,氨基烷基是被一个或多个氨基基团所取代的C1-6“较低级的氨基烷基”,这样的实例包括,但并不限于,氨基甲基(-CH2NH2)、氨基乙基(例如2-氨基乙基,-CH2CH2NH2)、2-氨基-1-丙基(-CH2CH(NH2)CH3)、3-氨基-1-丙基(-CH2CH2CH2NH2)、2,3-二氨基丙基(-CH2CH(NH2)CH2NH2)等等。
术语“j-k个原子组成的”,其中j和k各自独立地为任意非零的自然数,且k>j;所述“j-k”包括j、k和两者之间的任意自然数。典型地描述分子中成环原子的数目,在所述分子中成环原子的数目是j-k。例如,“3-8个原子组成的”、“3-6个原子组成的”、“5-10个原子组成的”或“5-6个原子组成的”表示所述环状基团由3-8(即,3、4、5、6、7或8)、3-6(即,3、4、5或6)、5-10(即,5、6、7、8、9或10)或5-6(即,5或6)个环原子所组成,所述的原子包括碳原子和/或O、N、S、P等杂原子。
术语“环烷基”表示含有3-12个碳原子的,单价或多价的饱和单环,双环或三环体系。在一实施方案中,环烷基包含3-12个碳原子,例如C3-12环烷基;在另一实施方案中,环烷基包含3-8个碳原子,例如C3-8环烷基;在又一实施方案中,环烷基包含3-6个碳原子,例如C3-6环烷基。环烷基基团的实例包括,但并不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基,等等。其中,如本发明所述的,C3-8环烷基包括C3-6环烷基;所述的C3-6环烷基包括环丙基、环丁基、环戊基和环己基。所述环烷基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“环烷基烷基”或“环烷基-亚烷基”可以交换使用,都是指烷基基团被一个或多个环烷基基团所取代,其中烷基基团和环烷基基团具有如本发明所述的含义,这样的实例包括,但并不限于环丙基甲基,环丙基乙基,环丙基丙基,环丁基甲基,环丁基乙基,环丁基丙基,环戊基甲基,环戊基乙基,环戊基丙基,环己基甲基,环己基乙基,环己基丙基,环丙基-亚甲基,环丙基-亚乙基,环丁基-亚甲基,环丁基-亚乙基,环戊基-亚甲基,环戊基-亚乙基,环己基-亚甲基,环己基-亚乙基等。
术语“杂环基”和“杂环”在此处可交换使用,都是指包含3-12个环原子的饱和或部分不饱和的单环、双环或三环,其中单环、双环或三环中不包含芳香环,且至少一个环原子选自氮、硫和氧原子;杂环基包括螺杂环基和稠合杂环基。其中,在一些实施方案中,杂环基为3-12个原子组成的环体系,即3-12个原子组成的杂环基;在一些实施方案中,杂环基为5-10个原子组成的环体系,即5-10个原子组成的杂环基;在一些实施方案中,杂环基为5-8个原子组成的环体系,即5-8个原子组成的杂环基;在一些实施方案中,杂环基为6-8个原子组成的环体系,即6-8个原子组成的杂环基;在一些实施方案中,杂环基为5-7个原子组成的环体系,即5-7个原子组成的杂环基;在一些实施方案中,杂环基为5-6个原子组成的环体系,即5-6个原子组成的杂环基;在一些实施方案中,杂环基为3-6个原子组成的环体系,即3-6个原子组成的杂环基;在一些实施方案中,杂环基为3个环原子组成的体系;在一些实施方案中,杂环基为4个原子组成的环体系;在其他一些实施方案中,杂环基为5个原子组成的环体系;在其他一些实施方案中,杂环基为6个原子组成的环体系。除非另外说明,杂环基可以是碳基或氮基,且-CH2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。
杂环基的实例包括,但不限于:环氧乙烷基、氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,吡唑烷基,咪唑烷基,四氢呋喃基,四氢吡喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,氧杂环庚烷基,硫杂环庚烷基。杂环基中-CH2-基团被-C(=O)-取代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环基烷基”或“杂环基-亚烷基”可以交换使用,都是指杂环基取代的烷基;其中杂环基和烷基基团具有如本发明所述的含义。这样的实例包括,但并不限于硫代吗啉-4-基甲基,四氢呋喃-3-基甲基,氧杂环丁烷-3-基甲基,吡咯烷-2-基甲基,吗啉-4-基甲基等。
术语“芳基”表示含有6-14个环原子,或6-12个环原子,或6-10个环原子的单环、双环和三环的碳环体系,其中,至少一个环体系是芳香族的,其中每一个环体系包含3-7个原子组成的环,且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、茚基、2,3-二氢-1H-茚基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基烷基”或“芳基亚烷基”可以交换使用,都是指一个或多个芳基取代的烷基基团,其中所述芳基和烷基具有本发明所述的含义。其中一些实施方案是,芳基烷基基团是指“较低级的芳基烷基”基团,即芳基基团连接到C1-6的烷基或亚烷基基团上。另外一些实施方案是,芳基烷基基团是指含C1-4的烷基的“苯烷基”。其中具体实例包括苄基,二苯基甲基,苯乙基,苯基亚甲基、苯基亚乙基。芳基烷基或芳基亚烷基上的芳基可以进一步被卤素,烷基,烷氧基,卤代烷基和卤代烷氧基所取代。
术语“杂芳基”表示含有5-12环原子的单环、双环和三环的芳香性体系,其中,至少有一个环包含一个或多个杂原子,其中每一个环包含5-7个环原子,其中至少有一个环体系是芳香族的,同时,所述杂芳基有一个或多个附着点与分子其余部分相连。其中,所述杂芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。除非另外说明,所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C,或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。当杂芳基基团存在-CH2-基团时,所述-CH2-基团可以任选地被-C(=O)-替代。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的5-10个原子组成的杂芳基;在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的5-8个原子组成的杂芳基;在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的5-7个原子组成的杂芳基;在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的5-6个原子组成的杂芳基;在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的5个原子组成的杂芳基;在一些实施方案中,杂芳基为包含1,2,3或4个独立选自O,S,P和N的杂原子的6个原子组成的杂芳基。
杂芳基基团的实例包括,但并不限于,呋喃基(如2-呋喃基、3-呋喃基)、咪唑基(如N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、异噁唑基(如3-异噁唑基、4-异噁唑基、5-异噁唑基)、噁唑基(如2-噁唑基、4-噁唑基、5-噁唑基)、吡咯基(如N-吡咯基、2-吡咯基、3-吡咯基)、吡啶基(如2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(如2-嘧啶基、4-嘧啶基、5-嘧啶基)、哒嗪基(如3-哒嗪基)、噻唑基(如2-噻唑基、4-噻唑基、5-噻唑基)、四唑基(如5-四唑基)、三唑基(如2-三唑基、5-三唑基)、噻吩基(如2-噻吩基、3-噻吩基)、吡唑基(如2-吡唑基)、异噻唑基、嘧啶酮基、吡啶酮基;也包括以下的双环,但绝不限于这些双环:苯并咪唑基、苯并呋喃基、苯并四氢呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基,3-喹啉基,4-喹啉基),等等。
术语“杂芳基烷基”或“杂芳基亚烷基”可以交换使用,都是指烷基基团被一个或多个杂芳基所取代,其中杂芳基和烷基基团具有本发明所述的含义,这样的实例包括,但并不限于咪唑-2-基甲基,呋喃-2-基乙基,吲哚-3-基甲基等。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)或式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs ofPhosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰胺化,脱酰胺作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,J.Pharmaceutical Sciences,66:1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐有盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过适当的碱得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸,氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时,可以使用术语“水合物”。在一些实施例中,一个本发明化合物分子可以与一个水分子相结合,比如一水合物;在另外一些实施例中,一个本发明化合物分子可以与多于一个的水分子相结合,比如二水合物,还有一些实施例中,一个本发明化合物分子可以与少于一个的水分子相结合,比如半水合物。应注意,本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
术语“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂,例如二氯甲烷中,使胺化合物与间-氯过苯甲酸(MCPBA)反应。
术语“载体”包括任何溶剂,分散介质,包衣衣料,表面活性剂,抗氧化剂,防腐剂(例如抗细菌剂、抗真菌剂),等渗剂,盐,药物稳定剂,粘合剂,赋形剂,分散剂,润滑剂,甜味剂,调味剂,着色剂,或其组合物,这些载体都是所属技术领域技术人员已知的(如Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329所述)。除了任意常规载体与活性成分不相容的情况外,涵盖其在治疗或药物组合物中的用途。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
术语“防止”或“预防”指获病或障碍的风险的减少(即:使疾病的至少一种临床症状在主体内停止发展,该主体可能面对或预先倾向面对这种疾病,但还没有经历或表现出疾病的症状)。
术语“治疗有效量”是指当给药于主体来治疗疾病时,化合物的分量足够对这种疾病的治疗起效。“治疗有效量”可以随着化合物,疾病和严重程度,以及有待治疗的主体的条件,年龄,体重,性别等而改变。
本发明的可药用盐可以用常规化学方法由母体化合物、碱性或酸性部分来合成。一般而言,该类盐可以通过使这些化合物的游离酸形式与化学计量量的适宜碱(如Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应,或者通过使这些化合物的游离碱形式与化学计量量的适宜酸反应来进行制备。该类反应通常在水或有机溶剂或二者的混合物中进行。一般地,在适当的情况中,需要使用非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。在例如"Remington′s Pharmaceutical Sciences",第20版,Mack Publishing Company,Easton,Pa.,1985;和“药用盐手册:性质、选择和应用(Handbook of PharmaceuticalSalts:Properties,Selection,and Use)”,Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002)中可找到另外一些适宜盐的列表。
另外,本发明公开的化合物、包括它们的盐,也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO,等等)的形式得到,用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物;因此,本发明旨在包括溶剂化的和未溶剂化的形式。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl和125I。
此外,较重同位素特别是氘(即,2H或D)的取代可提供某些治疗优点,这些优点是由代谢稳定性更高带来的。例如,体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解,本发明中的氘被看做式(I)或式(II)所示化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5%的氘掺入)、至少4000(60%的氘掺入)、至少4500(67.5%的氘掺入),至少5000(75%的氘掺入),至少5500(82.5%的氘掺入)、至少6000(90%的氘掺入)、至少6333.3(95%的氘掺入)、至少6466.7(97%的氘掺入)、至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物,包括式(I)或(II)所示化合物或其单独的立体异构体,异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。在本发明的一个实施方式中,所述药物组合物进一步包含至少一种药学上可接受的载体、赋形剂或吸附剂,以及任选地,其它的治疗和/或预防成分。
合适的载体、赋形剂或吸附剂对于本领域技术人员是熟知的并且详细描述于例如Ansel H.C.et al.,Ansel’s Pharmaceutical Dosage Forms and Drug DeliverySystems(2004)Lippincott,Williams&Wilkins,Philadelphia;Gennaro A.R.et al.,Remington:The Science and Practice of Pharmacy(2000)Lippincott,Williams&Wilkins,Philadelphia;和Rowe R.C.,Handbook of Pharmaceutical Excipients(2005)Pharmaceutical Press,Chicago中。
合适的药学上可接受的赋形剂会依所选具体剂型而不同。此外,可根据它们在组合物中的特定功能来选择药学上可接受的赋形剂。例如,可选择能有助于生产均一剂型的某些药学上可接受的赋形剂。可选择能有助于生产稳定剂型的某些药学上可接受的赋形剂。可选择对患者给药时有助于携带或运输本发明化合物从身体的一个器官或部分到身体的另一个器官或部分的某些药学上可接受的赋形剂。可选择增强患者依从性的某些药学上可接受的赋形剂。
一些合适的赋型剂实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、西黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。合适的药学上可接受的赋形剂还包括以下类型的赋形剂:溶媒、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂和助滤剂。技术人员可认识到,某些药学上可接受的赋形剂可提供不止一种功能,并提供可供选择的功能,这取决于制剂中存在多少该赋形剂和制剂中存在哪些其他赋形剂。可以采用本领域的已知方法来配制本发明化合物,以便对患者给药后能快速、持续或延缓释放出活性组份。
合适的药学上可接受的载体取决于药物形式并且是本领域技术人员所知的。
如本发明中使用的,“药学上可接受的载体”包括任何和全部的溶剂和溶剂混合物,涂层,络合剂,固体载体,分散体介质,表面活性赋形剂,抗细菌和抗真菌药,用于药物活性物质的等渗和吸收延迟剂,和其混合物,这些同样是本领域已知的。
用于药学上可接受的载体的非限制性实例包括具有选自如下组分的那些:乳糖,明胶,糖醇(例如淀粉,甘露醇,玉米淀粉等),植物油,滑石,硬脂酸镁,胶体二氧化硅,羧甲基纤维素,微晶纤维素,十二烷硫酸钠,缓冲水溶液,共聚维酮,聚山梨酸酯,乙醇,丙二醇,聚二醇(优选地聚乙二醇,例如PEG400),80(即PEG(20),山梨糖醇一油酸酯),DMSO,水和助溶剂的混合物,例如包括醇如乙醇和/或聚二醇如聚乙二醇的水溶液,多元醇如甘油和/或聚乙二醇与脂肪酸的酯,表面活性剂如阴离子、阳离子、非离子和两性表面活性剂,络合剂如环糊精,例如α-环糊精(α-CD)或者羟丙基-β-环糊精(HP-β-CD),胆汁酸或者脂质,例如动物或者植物磷脂的盐,成胶束剂,和油如玉米油,或前面提及的两种或更多种组分的混合物。
本发明公开的药物组合物使用本领域技术人员已知的技术和方法来制备。本领域一些常用方法的描述可参见Remington's Pharmaceutical Sciences(Mack PublishingCompany)。
因此,另一方面,本发明涉及制备药物组合物的工艺,所述药物组合物包含本发明公开化合物和药学上可接受的赋形剂,载体,辅剂,溶媒或它们的组合,该工艺包括混合各种成分。包含本发明公开化合物的药物组合物,可以在例如环境温度和大气压下混合来制备。
本发明公开的化合物通常被配制成适合于通过所需途径对患者给药的剂型。例如,剂型包括那些适合于以下给药途径的剂型:(1)口服给药,例如片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、香包剂和扁囊剂;(2)胃肠外给药,例如无菌溶液剂、混悬剂和复溶粉末;(3)透皮给药,例如透皮贴片剂;(4)直肠给药,例如栓剂;(5)吸入,例如气雾剂、溶液剂和干粉剂;和(6)局部给药,例如乳膏剂、油膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
可以将各种固体口服剂型用于本发明化合物的给药,例如片剂、胶囊、颗粒、锭剂和散装粉末的固体剂型。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体和赋形剂(例如,蔗糖、甘露醇、乳糖、淀粉)组合给药,包括但不限于助悬剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、调味剂、润滑剂等。定时释放胶囊、片剂和凝胶剂对于本发明化合物的给药也是有利的。
可以将各种外用剂型用于本发明化合物的给药,例如洗剂、软膏剂、酊剂、擦剂、醑剂、粉剂、霜剂、油剂、糊剂、硬膏剂、涂膜剂和气雾剂。局部给药还可以包括通过例如透皮贴片的方式进行的透皮给药。可以将本发明化合物单独给药或与本领域已知的各种药学上可接受的载体、稀释剂和赋形剂组合给药,包括但不限于溶剂、油性溶剂、稀释剂、安定剂、吸收延迟剂、崩散剂、乳化剂、抗氧化剂、粘合剂、结合剂、增粘剂、增溶剂、分散剂、悬乳化剂、润滑剂、吸湿剂、脂质体、微乳和β-环糊精等。
对于呼吸道疾病的治疗,优选本发明的化合物通过吸入给药。
本发明的化合物的剂量取决于多种因素,包括要治疗的具体疾病、症状的严重程度、给药途径、剂量间隔频率、所用的具体化合物、化合物的效力、毒理学特征和药代动力学的特征。
可与载体材料相组合从而产生单剂量形式的活性成分的量将取决于被治疗的宿主和特定的施用方式而变化。例如,意欲涂抹施用给人的制剂可以方便地含有约5mg至约250mg/千克体重/天的活性剂,其与合适且方便的量的载体材料(可占总组合物的大约5%至大约95%)相复合。单位剂量形式一般将包含大约1mg至大约500mg的活性成分。
术语“给药”指给个体提供治疗有效量的药物,给药方式包括口服,舌下,静脉,皮下,经皮,肌内,皮内,鞘内,硬膜上,眼内,颅内,吸入,直肠,阴道等。给药剂型包括膏剂,洗剂,片剂,胶囊剂,丸剂,飞散性粉末剂,颗粒剂,栓剂,丹剂,锭剂,注射剂,无菌溶液或非水溶液剂,悬浮剂,乳剂,贴片剂等。活性组分与无毒的药学上可接受的载体(如葡萄糖,乳糖,阿拉伯树胶,明胶,甘露醇,淀粉糊,三硅酸镁,滑石粉,玉米淀粉,角蛋白,硅胶,土豆淀粉,尿素,右旋糖酐等)复合。
优选的给药途径会随着临床特征而变化,剂量的变化必须依赖于正在治疗的病人的情况,医生会根据个体患者来确定合适的剂量。每单位剂量的治疗有效量取决于体重,生理机能和选择的接种方案。每单位剂量的化合物是指每次给药时化合物的重量,不包括载体的重量(药物里含有载体)。
所用活性成分的有效剂量可随所用的特定化合物、给药方式、治疗的症状和治疗的症状严重程度而变。本领域技术人员容易确定这种剂量。
本发明提供的药物组合物可以配制成单剂量或多剂量给药。所述单剂量制剂被包装在安瓿剂、小瓶或注射器中。所述多剂量肠胃外制剂必须包含抑菌或抑真菌浓度的抗微生物剂。所有的肠胃外制剂都必须是无菌的,如本领域已知和实践的。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制,或者与补充预期的作用的物质共同配制。
在一实施方案中,本发明化合物或包含本发明化合物的药物组合物可以通过任何适合的给药途径来给药,包括全身给药和局部给药。全身给药包括口服给药、胃肠外给药、透皮给药和直肠给药。典型的胃肠外给药是指通过注射或输注给药,包括静脉内、肌内和皮下注射或输注给药。局部给药包括施用于皮肤以及眼内、耳、阴道内、吸入和鼻内给药。在一个实施方案中,本发明化合物或包含本发明化合物的药物组合物可以是口服给药。在另一实施方案中,本发明化合物或包含本发明化合物的药物组合物可以是吸入给药。还在一实施方案中,本发明化合物或包含本发明化合物的药物组合物可以是局部给药。
式(I)或(II)所示的化合物可以与用于预防、治疗或减轻式(I)或(II)所示的化合物适用的疾病或症状的其它药物联用。这些其它药物可通过其常用的途径和量与式(I)或(II)所示的化合物同时或相继给药。当式(I)或(II)所示的化合物与一种或多种其它药物同时使用时,含有这类其它药物以及式(I)或(II)所示的化合物的药物单位剂型是优选的。
本发明化合物和药物组合物的用途
本发明的化合物或药物组合物适用于预防和/或治疗与PDE4有关的以下疾病:疼痛(例如,急性疼痛、急性炎性疼痛、慢性炎性疼痛和神经病性疼痛)、急性炎症、慢性炎症、银屑病关节炎、类风湿性关节炎、牛皮癣、增生性和炎性皮肤病(例如特应性皮炎、脂溢性皮炎、接触性皮炎)、哮喘、慢性阻塞性肺病(COPD)、关节炎、炎性肠道疾病、节段性回肠炎、溃疡性结肠炎、败血性休克、内毒素性休克、格兰氏阴性菌败血症、肾小球性肾炎、帕金森氏病、阿尔茨海默氏病、轻度认知损害(MCI)、抑郁症、焦虑症、急性呼吸道窘迫综合征、骨关节炎、强直性脊柱炎、多发性硬化、牙龈炎、牙周炎、搔痒症、疱疹、中枢神经系统肿瘤、间质性肺炎、过敏、结晶诱发的关节炎、急性胰腺炎、慢性胰腺炎、急性酒精性肝炎、坏死性小肠结肠炎、慢性鼻窦炎、急性呼吸窘迫综合症、肺高血压、痛风、酒精性肝病、狼疮、癌症、过敏性鼻炎、非过敏性鼻炎、自身免疫性溶血综合征、自身免疫性肝炎、自身免疫性神经病变、肝硬化、纤维化疾病、胃炎、肺出血-肾炎综合征、格雷夫斯氏病、巴雷综合征、桥本氏甲状腺炎、HIV-相关的自身免疫性综合征和血液疾病、扁平苔癣、心肌炎(包括病毒性心肌炎)、神经病变(包括例如,IgA神经病变、细胞膜神经病变和特发性神经病变)、肾炎综合征、莱特尔氏综合征、斯耶格伦氏综合征、系统性红斑狼疮,该方法包括施于该病患有效量的至少一种式(I)或式(II)所示化合物或其药学上可接受的盐或溶剂合物。
本发明的药物组合物包括本发明中所述的PDE4抑制剂中的至少一种和附加治疗剂,附加治疗剂的实例包括但不限于:
(1)β2-激动剂,例如沙丁醇胺、福莫特罗、沙美特罗和卡莫昔罗;
(2)皮质类固醇类,例如布地奈德、二丙酸倍氯米松、丙酸氟替卡松、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、美普克莱;
(3)抗胆碱能药或抗毒蕈碱药,例如异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、瑞伐托酯;
(4)局部钙调磷酸酶抑制剂,例如他克莫司、吡美莫司、环孢素;
(5)PDE4抑制剂的局部制剂,例如阿普斯特、异丁司特、E-6005、OPA-15406、LEO-29102、DRM02、罗氟司特、克瑞沙硼;
(6)JAK激酶抑制剂的局部制剂,例如托法替尼、JTE-052、巴瑞替尼、乌帕替尼;
(7)局部非甾体抗炎药物,例如WBI-1001、MRX-6;
(8)局部ROR药剂,例如GSK2981278;
(9)可注射抗IL4、IL-31、IL-22、IL-33、IL-12、IL-23、IL-17、IgE、IL-4治疗药物,例如杜鲁单抗(Dupilumab)、来金珠单抗、尼莫利珠单抗(Nemolizumab)、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、塞库吉努(Secukinumab)、奥马珠(Omazumilab)、CIM-331;
(10)维生素D类似物,例如卡泊三醇、骨化三醇;
(11)口服视黄酸衍生物,例如阿利维A酸;
(12)口服肝X受体(LXR)选择性激动剂,例如VTP-38543;
(13)口服H4受体拮抗剂,例如ZPL-389;
(14)口服NK1受体拮抗剂,例如阿瑞匹坦、曲地匹坦;
(15)口服CRTH2受体拮抗剂,例如弗维普兰特(Fevipiprant)、和OC-459;
(16)口服糜蛋白酶抑制剂,例如SUN 13834。
优选地,给予单独的或与其他活性成分组合的式(I)或式(II)所示的化合物用于预防和/或治疗呼吸疾病或皮肤炎症疾病,例如慢性阻塞性肺病(COPD)、特应性皮炎(AD)或银屑病。
包含本发明化合物或药物组合物给药的治疗方法,进一步包括对患者进行其他抗慢性阻塞性肺病(COPD)或特应性皮炎药物的给药(联合治疗),其中其他抗慢性阻塞性肺病(COPD)或特应性皮炎的药物为上述附加治疗剂中的药物或它们的组合物。
本发明提供在需要这种治疗的患者中治疗肺病(例如,COPD、气喘或纤维囊肿)或炎症(例如,特应性皮炎或银屑病)的方法,该方法包括联合给予所述患者治疗有效量的至少一种式(I)或式(II)所示化合物,或其药学上可接受的盐或溶剂合物,以及至少一种选自下列的化合物:类固醇(如糖皮质激素)、钙调磷酸酶抑制剂、PDE4抑制剂、JAK激酶抑制剂、半胱氨酰基白三烯拮抗剂、非甾体抗炎药物、局部ROR药剂、抗IL4抗体、IL-31抗体、IL-22抗体、IL-33抗体、IL-12抗体、IL-23抗体、IL-17抗体、IgE抗体、IL-4抗体、维生素D类似物、肝X受体(LXR)选择性激动剂、组胺H1拮抗剂、组胺H3拮抗剂、H4受体拮抗剂、NK1受体拮抗剂、CRTH2受体拮抗剂、糜蛋白酶抑制剂、5-脂氧合酶抑制剂、β-2肾上腺素受体(adrenoceptor)激动剂、α-肾上腺素受体激动剂、蕈毒碱M1拮抗剂、蕈毒碱M3拮抗剂、蕈毒碱M2激动剂、NK3拮抗剂、LTB4拮抗剂、支气管扩张剂、PDE抑制剂。
一般合成步骤
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)或式(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa ChemicalCompany,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,青岛腾龙化学试剂有限公司和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振氢谱的测试条件是:室温条件下,布鲁克(Bruker)400MHz或600MHz的核磁仪,以CDC13,DMSO-d6,CD3OD或丙酮-d6为溶剂(报导以ppm为单位),用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),q(quartet,四重峰),m(multiplet,多重峰),br(broadened,宽峰),dd(doublet ofdoublets,双二重峰),dt(doublet of triplets,双三重峰)。偶合常数J,用赫兹(Hz)表示。
低分辨率质谱(MS)数据测定的条件是:Agilent 6120Quadrupole HPLC-MS(柱子型号:Zorbax SB-C18,2.1x30mm,3.5μm,6min,流速为0.6mL/min,流动相:5%-95%(含0.1%甲酸的CH3CN)在(含0.1%甲酸的H2O)中的比例)),在210/254nm用UV检测,用电喷雾电离模式(ESI)。
化合物纯度的表征方式为:Agilent 1260制备型高效液相色谱(Pre-HPLC)或Calesep Pump 250制备型高效液相色谱(Pre-HPLC)(柱子型号:NOVASEP,50/80mm,DAC),在210nm/254nm用UV检测。
下面简写词的使用贯穿本发明:
g 克; HPLC 高效液相色谱
mg 毫克; MeOH 甲醇;
mol 摩尔; CD3OD 氘代甲醇;
mmol 毫摩尔; EtOH 乙醇;
M,mol/L 摩尔每升; HOAc 乙酸;
nM 纳摩尔; ACN,MeCN 乙腈;
pg/μL 皮克每微升; CDCl3 氘代氯仿;
L 升; DCM 二氯甲烷;
mL,ml 毫升; DMSO 二甲基亚砜;
h 小时; DMSO-d6 氘代二甲基亚砜;
r.t,RT 室温 THF 四氢呋喃;
Rt 保留时间 EtOAc 乙酸乙酯;
TEA 三乙胺; DIPEA N,N-二异丙基乙胺;
DBU 1,8-二氮杂双环[5.4.0]十一碳-7- 劳森试剂 2,4-双(对甲氧苯基)-1,3-二硫-二磷杂环丁 烯; 烷-2,4硫化物;
KHMDS 双(三甲基硅基)氨基钾; Me3O BF4 三甲基氧鎓四氟硼酸;
MsCl 甲磺酰氯; Pd/C 钯/碳。
合成方法一:
目标化合物(11)可以通过合成方法一制备得到,其中Ra、Rb、Rc、Rd和R4具有如本发明所述的含义,X为CH或N,n为0、1、2、3或4。化合物(1)与化合物(2)缩合得到化合物(3),化合物(3)通过劳森试剂硫化得到化合物(4),化合物(4)在三甲基氧鎓四氟硼酸的条件下反应得到化合物(5),化合物(5)在碱性条件下(如KHMDS等)与酰氟化合物(6)反应得到化合物(7),化合物(7)在碱性条件下(如LiOH.H2O或NH3 .MeOH等)水解得到化合物(8),化合物(8)与化合物(9)缩合得到化合物(10),化合物(10)在氯化氢的有机溶剂(如乙酸乙酯或异丙醇等)中脱保护基并成盐得到目标化合物(11)。
合成方法二:
目标化合物(15)可以通过合成方法二制备得到,其中Ra、Rb、Rc、Rd和R4具有如本发明所述的含义,X为CH或N,n为0、1、2、3或4。化合物(7)通过还原反应得到化合物(12),化合物(12)与化合物(13)缩合得到化合物(14),化合物(14)在氯化氢的有机溶剂(如乙酸乙酯或异丙醇等)中脱保护基并成盐得到目标化合物(15)。
合成方法三:
目标化合物(20)可以通过合成方法三制备得到,其中Ra、Rb、Rc、Rd和R4具有如本发明所述的含义,X为CH或N,n为0、1、2、3或4。化合物(12)在碱性条件下(如TEA或DIPEA)通过取代反应得到化合物(16),化合物(16)通过叠氮化得到化合物(17);化合物(17)通过氢化还原得到化合物(18),化合物(18)与化合物(13)缩合得到化合物(19),化合物(19)在氯化氢的有机溶剂(如乙酸乙酯或异丙醇等)中脱保护基并成盐得到目标化合物(20)。
合成方法四:
目标化合物(26)可以通过合成方法四制备得到,其中Ra、Rb、Rc和Rd具有如本发明所述的含义,X为CH或N,Re为氢、氘、C1-4烷基、C3-8环烷基或C6-10芳基,Rf为C1-4烷基、C3-8环烷基或C6-10芳基。化合物(18)与化合物(21)通过缩合反应得到化合物(22),化合物(22)在碱性条件下(如LiOH、KOH等)经水解反应得到化合物(23);化合物(23)与化合物(24)发生缩合反应得到化合物(25),化合物(25)在氯化氢的有机溶剂(如乙酸乙酯或异丙醇等)中脱保护基并成盐得到目标化合物(26)。
合成方法五:
目标化合物(29)可以通过合成方法五制备得到,其中Ra、Rb、Rc和Rd具有如本发明所述的含义,X为CH或N,Rg为C1-4烷基。化合物(23)与化合物(27)发生缩合反应得到化合物(28),化合物(28)在氯化氢的有机溶剂(如乙酸乙酯或异丙醇等)中脱保护基并成盐得到目标化合物(29)。
实施例
实施例1:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基对苯二甲酸酯盐酸盐
步骤1:化合物2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯酰氨基)乙酸甲酯的合成
将3-(环丙基甲氧基)-4-(二氟甲氧基)苯甲酸(10g,38.73mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(11.1g,57.90mmol)和N-羟基-7-氮杂苯并三氮唑(5.28g,38.76mmol)加入二氯甲烷(50mL)中,室温搅拌30min,加入氨基乙酸甲酯盐酸盐(5.81g,46.28mmol),在0℃条件下滴加N,N-二异丙基乙胺(27.1mL,164mmol),室温搅拌10h,加水洗(25mL×3),有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1~2/1),得到11.12g白色固体,收率:87%。
1H NMR(400MHz,CDCl3):δ(ppm)7.47(s,1H),7.29(dd,J=8.3Hz,1.9Hz,1H),7.18(d,J=8.3Hz,1H),6.68(t,JF-H=75.0Hz,1H),4.22(d,J=5.0Hz,2H),3.92(d,J=7.0Hz,2H),3.80(s,3H),1.25-1.32(m,1H),0.62-0.67(m,2H),0.33-0.37(m,2H).
MS(ESI,pos.ion)m/z:330.20[M+H]+.
步骤2:化合物2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯硫代酰氨基)乙酸甲酯的合成
将化合物甲基2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯酰氨基)乙酸甲酯(11.12g,33.77mmol)与劳森试剂(13.66g,33.77mmol)加入四氢呋喃(50mL)中,75℃反应2h,加饱和碳酸氢钠溶液洗涤(20mL×3),乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,浓缩液进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1~2/1),得到10.5g黄色固体,收率:90%。
1H NMR(400MHz,CDCl3):δ(ppm)8.07(s,1H),7.55(d,J=2.0Hz,1H),7.24(d,J=2.1Hz,1H),7.16(d,J=8.3Hz,1H),6.68(t,JF-H=75.0Hz,1H),4.56(d,J=4.6Hz,2H),3.94(d,J=7.0Hz,2H),3.85(s,3H),1.27-1.32(m,1H),0.65-0.67(m,2H),0.36-0.38(m,2H).
MS(ESI,pos.ion)m/z:346.20[M+H]+.
步骤3:化合物2-(((3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)(甲硫基)亚甲基)氨基)乙酸甲酯的合成
-78℃条件下,向三甲基氧鎓四氟硼酸(4.28g,28.94mmol)的二氯甲烷(20mL)溶液中滴加化合物2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯硫代酰氨基)乙酸甲酯(5.0g,14.48mmol)的二氯甲烷溶液(40mL),0℃搅拌5h后,用饱和碳酸氢钠溶液洗涤(25mL×3),有机相用无水硫酸钠干燥,除去溶剂,得到5.0g黄色油状物,收率:96%。
1H NMR(400MHz,CDCl3):δ(ppm)7.16–7.20(m,2H),7.10–7.13(m,2H),6.83–6.87(m,2H),6.65(t,JF-H=75.2Hz,1H),4.44(s,2H),4.15(s,2H),3.90(d,J=6.9Hz,2H),3.85(d,J=6.9Hz,2H),3.79(s,3H),3.72(s,3H),2.45(s,3H),2.16(s,3H),1.27-1.29(m,1H),0.62–0.67(m,2H),0.34–0.36(m,2H).
MS(ESI,pos.ion)m/z:360.10[M+H]+.
步骤4:化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸甲酯的合成
将N-叔丁氧羰基-L-丙氨酸(6.5g,34.4mmol)和三乙胺(5.27mL,37.83mmol)溶于二氯甲烷(60mL)中,-40℃条件下,向此溶液中滴加三聚氟氰(5.62mL,68.8mmol),在-10℃条件下反应2h,用冰水洗涤(20mL×5),有机相用无水硫酸钠干燥,除去溶剂,得到(S)-(1-氟-1-氧代丙基-2-基)氨基甲酸叔丁酯,为5.84g白色固体,收率:89%。
将化合物2-(((3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)(甲硫基)亚甲基)氨基)乙酸甲酯(5.2g,14.48mmol)与化合物(S)-(1-氟-1-氧代丙基-2-基)氨基甲酸叔丁酯(4.15g,21.72mmol)溶于无水四氢呋喃(25mL)中,冷却至-78℃,缓慢滴加六甲基二硅氨基钾的四氢呋喃溶液(36.2mL,36.2mmol),-78℃反应1h,用水(20mL×5)洗涤,乙酸乙酯萃取(25mL×3),合并有机相后用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=6/1~3/1),得到5.13g黄色固体,收率:73%。
1H NMR(400MHz,CDCl3):δ(ppm)7.64(s,1H),7.62(d,J=8.4Hz,1H),7.23(d,J=8.3Hz,1H),6.70(t,JF-H=75.0Hz,1H),5.43-5.47(m,1H),3.98(s,3H),3.96(d,J=7.0Hz,2H),1.54(d,J=7.0Hz,3H),1.43(s,9H),1.27-1.29(m,1H),0.65-0.68(m,2H),0.36-0.39(m,2H).
MS(ESI,pos.ion)m/z:483.10[M+H]+.
步骤5:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸甲酯(1.25g,2.59mmol)溶于无水四氢呋喃(8mL)中,冰浴下加入硼氢化锂(550mg,25.9mmol),室温反应1.5h后加入冰水(30mL),用乙酸乙酯萃取(20mL×3),有机相用稀盐酸(15mL×1)洗涤,用饱和氯化钠水溶液(15mL×1)洗涤,有机相用无水硫酸钠干燥,减压浓缩,得到1.1g白色固体,收率93%。
1H NMR(400MHz,CD3OD):δ(ppm)7.72(d,J=1.7Hz,1H),7.61(dd,J=8.4,1.8Hz,1H),7.27(d,J=8.4Hz,1H),6.88(t,JF-H=75.0Hz,1H),4.99–5.04(m,1H),4.62(s,2H),4.02(d,J=6.9Hz,2H),1.56(d,J=6.1Hz,3H),1.31–1.37(m,1H),0.66–0.70(m,2H),0.41–0.45(m,2H).
MS(ESI,pos.ion)m/z:455.20[M+H]+.
步骤6:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基对苯二甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),对苯二甲酸单甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌24h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到58mg浅黄色固体,收率85%。
1H NMR(400MHz,CDCl3):δ(ppm)8.09–8.16(m,4H),7.61(s,1H),7.59(d,J=8.4Hz,1H),7.24(d,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.32–5.52(m,2H),5.15–5.28(m,1H),3.98(d,J=7.0Hz,2H),3.96(s,3H),1.60(d,J=7.0Hz,3H),1.44(s,9H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z:617.90[M+H]+.
步骤7:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基对苯二甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基对苯二甲酸酯(50mg,0.08mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应1.5h,减压除去溶剂,得到42mg白色固体,收率93%。
1H NMR(400MHz,CD3OD):δ(ppm)8.12-8.18(m,4H),7.77(s,1H),7.70(d,J=8.1Hz,1H),7.31(d,J=8.2Hz,1H),6.90(t,JF-H=74.8Hz,1H),5.39–5.48(m,2H),5.13–5.19(m,1H),4.02(d,J=6.8Hz,2H),3.95(s,3H),1.80(d,J=6.7Hz,3H),1.29–1.38(m,1H),0.65–0.70(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:500.65[M-NH2-HCl]+.
实施例2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),2,4-二氟苯甲酸(34mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌24h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1),得到41mg浅黄色固体,收率62%。
1H NMR(400MHz,CDCl3):δ(ppm)8.01–8.07(m,1H),7.61(s,1H),7.59(d,J=8.3Hz,1H),7.24(d,J=8.3Hz,1H),6.86-6.96(m,2H),6.71(t,JF-H=75.2Hz,1H),5.31–5.50(m,2H),5.14–5.26(m,1H),3.98(d,J=6.9Hz,2H),1.60(s,3H),1.44(s,9H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z:595.30[M+H]+.
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酸酯(37mg,0.06mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应1.5h,减压除去溶剂,得到白色固体32mg,收率96%。
1H NMR(400MHz,CD3OD):δ(ppm)8.06-8.12(m,1H),7.77(s,1H),7.70(d,J=8.4Hz,1H),7.31(d,J=8.2Hz,1H),7.06-7.14(m,2H),6.90(t,JF-H=75.0Hz,1H),5.36–5.46(m,2H),5.11–5.17(m,1H),4.02(d,J=6.8Hz,2H),1.79(d,J=6.9Hz,3H),1.29–1.38(m,1H),0.65–0.70(m,2H),0.40–0.44(m,2H).
MS(ESI,pos.ion)m/z:478.20[M–NH2-HCl]+.
实施例3:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基-2-氟对苯二甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基-2-氟对苯二甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(70mg,0.15mmol),2-氟-4-甲氧羰基苯甲酸(61mg,0.31mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(147mg,0.77mmol)和N-羟基-7-氮杂苯并三氮唑(41mg,0.30mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(119mg,0.92mmol),室温搅拌18h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到92mg浅褐色固体,收率94%。
1H NMR(400MHz,CDCl3):δ(ppm)8.04(t,J=7.4Hz,1H),7.86(d,J=8.0Hz,1H),7.79(d,J=10.8Hz,1H),7.61(s,1H),7.58(d,J=8.5Hz,1H),7.24(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.32–5.53(m,2H),5.23(brs,1H),5.10–5.20(m,1H),3.98(d,J=7.0Hz,2H),3.96(s,3H),1.60(d,J=7.1Hz,3H),1.44(s,9H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基-2-氟对苯二甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基-2-氟对苯二甲酸酯(90mg,0.14mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应1.5h,减压除去溶剂,得到79mg白色固体,收率97%。
1H NMR(600MHz,CD3OD):δ(ppm)8.09(t,J=7.5Hz,1H),7.91(d,J=8.0Hz,1H),7.82(d,J=11.0Hz,1H),7.77(s,1H),7.70(d,J=8.2Hz,1H),7.31(d,J=8.3Hz,1H),6.90(t,JF-H=74.7Hz,1H),5.40–5.49(m,2H),5.12–5.16(m,1H),4.02(d,J=6.8Hz,2H),3.96(s,3H),1.81(d,J=6.8Hz,3H),1.29–1.37(m,1H),0.66–0.70(m,2H),0.41–0.43(m,2H).
MS(ESI,pos.ion)m/z:518.25[M-NH2-HCl]+.
实施例4:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-3-甲基-2-氟间苯二甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-3-甲基-2-氟间苯二甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(70mg,0.15mmol),2-氟-3-甲氧羰基苯甲酸(61mg,0.31mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(147mg,0.77mmol)和N-羟基-7-氮杂苯并三氮唑(41mg,0.30mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(119mg,0.92mmol),室温搅拌18h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到92mg浅褐色固体,收率94%。
1H NMR(400MHz,CDCl3):δ(ppm)8.09–8.17(m,2H),7.61(s,1H),7.58(d,J=8.3Hz,1H),7.28(d,J=4.5Hz,1H),7.24(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.32–5.52(m,2H),5.13–5.26(m,1H),3.98(d,J=6.9Hz,2H),3.95(s,3H),1.60(d,J=6.9Hz,3H),1.44(s,9H),1.27–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z:635.30[M+H]+.
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-3-甲基-2-氟间苯二甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-3-甲基-2-氟间苯二甲酸酯(90mg,0.14mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应30min,减压除去溶剂,得到74mg白色固体,收率91%。
1H NMR(600MHz,CD3OD):δ(ppm)8.19–8.21(m,1H),8.14–8.17(m,1H),7.78(s,1H),7.71(d,J=8.4Hz,1H),7.41(t,J=7.8Hz,1H),7.32(d,J=8.4Hz,1H),6.90(t,JF-H=74.7Hz,1H),5.40–5.48(m,2H),5.12–5.15(m,1H),4.03(d,J=6.9Hz,2H),3.94(s,3H),1.80(d,J=6.9Hz,3H),1.29–1.36(m,1H),0.66–0.69(m,2H),0.41–0.43(m,2H).
MS(ESI,pos.ion)m/z:518.25[M-NH2-HCl]+.
实施例5:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)2-乙氧基-3-氟苯甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-3-氟苯甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),2-乙氧基-3-氟苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌11h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(展淋洗剂:石油醚/乙酸乙酯(v/v)=5/1),得到19mg浅褐色固体,收率27%。
MS(ESI,pos.ion)m/z:621.35[M+H]+.
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-3-氟苯甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-3-氟苯甲酸酯(15mg,0.024mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应30min,减压除去溶剂,得到12mg浅黄色固体,收率89%。
1H NMR(400MHz,CD3OD):δ(ppm)7.77(s,1H),7.71(d,J=8.3,Hz,1H),7.61(d,J=7.9Hz,1H),7.44–7.36(m,1H),7.32(d,J=8.3Hz,1H),7.16–7.22(m,1H),6.90(t,JF-H=74.7Hz,1H),5.32–5.47(m,2H),5.10–5.15(m,1H),4.14(q,J=6.9Hz,2H),4.02(d,J=6.9Hz,2H),1.80(d,J=6.8Hz,3H),1.32(t,J=7.0Hz,3H),1.27–1.33(m,1H),0.65–0.69(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:504.30[M-NH2-HCl]+.
实施例6:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),2-乙氧基-4-氟苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌15h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=5/1),得到56mg浅褐色固体,收率82%。
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酸酯(50mg,0.081mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应1h,减压除去溶剂,得到43mg白色固体,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)7.88(dd,J=8.6,6.9Hz,1H),7.77(s,1H),7.70(dd,J=8.4,1.7Hz,1H),7.31(d,J=8.3Hz,1H),6.90(t,JF-H=74.7Hz,1H),6.89(dd,J=11.2,2.2Hz,1H),6.75(td,J=8.5,2.2Hz,1H),5.28–5.42(m,2H),5.10–5.15(m,1H),4.11(q,J=7.0Hz,2H),4.02(d,J=6.9Hz,2H),1.81(d,J=6.9Hz,3H),1.39(t,J=7.0Hz,3H),1.29–1.37(m,1H),0.65–0.69(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:504.10[M-NH2-HCl]+.
实施例7:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酸酯盐酸盐
步骤1:化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),4-乙氧基-2-氟苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌15h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=5/1),得到51mg浅褐色固体,收率75%。
1H NMR(400MHz,CDCl3):δ(ppm)7.93(t,J=8.7Hz,1H),7.61(s,1H),7.58(d,J=8.3Hz,1H),7.23(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),6.70(d,J=6.4Hz,1H),6.62(dd,J=12.8,2.2Hz,1H),5.28–5.46(m,2H),5.19–5.29(m,1H),4.07(q,J=7.0Hz,2H),3.98(d,J=6.9Hz,2H),1.59(d,J=6.5Hz,3H),1.44(s,9H),1.44(t,J=7.0Hz,2H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
步骤2:化合物(S)-1-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酸酯盐酸盐的合成
将化合物(S)-1-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酸酯(47mg,0.076mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应1h,减压除去溶剂,得到41mg白色固体,收率97%。
1H NMR(400MHz,CD3OD):δ(ppm)7.94(t,J=8.7Hz,1H),7.76(s,1H),7.70(d,J=8.4,Hz,1H),7.31(d,J=8.3Hz,1H),6.89(t,JF-H=74.7Hz,1H),6.82(d,J=8.9Hz,1H),6.76(d,J=13.2Hz,1H),5.32–5.42(m,2H),5.10–5.16(m,1H),4.11(q,J=7.0Hz,2H),4.02(d,J=6.9Hz,2H),1.80(d,J=6.9Hz,3H),1.41(t,J=7.0Hz,3H),1.29–1.37(m,1H),0.65–0.69(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:504.10[M-NH2-HCl]+.
实施例8:化合物(S)-4-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)苯甲酸甲酯盐酸盐
步骤1:化合物(S)-(1-(4-(溴甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(750mg,1.65mmol)溶于乙酸乙酯(20mL)中,加入三乙胺(500mg,4.94mmol),冰浴中加入甲磺酰氯(226mg,1.97mmol),室温反应2h后加入溴化锂(862mg,9.93mmol),室温继续反应6h,加水(30mL)停止反应,分离有机相,有机相用无水硫酸钠干燥,浓缩,进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1),得到612mg白色固体,收率71%。
1H NMR(400MHz,CDCl3):δ(ppm)7.61(s,1H),7.58(d,J=8.3Hz,1H),7.24(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.04–5.10(m,1H),4.86–4.96(m,1H),4.61–4.68(m,1H),3.99(d,J=6.9Hz,2H),1.58(d,J=7.1Hz,3H),1.46(s,9H),1.27–1.38(m,1H),0.67–0.72(m,2H),0.39–0.42(m,2H).
MS(ESI,pos.ion)m/z:518.05[M+H]+.
步骤2:化合物(S)-(1-(4-(叠氮甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(溴甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(610mg,1.18mmol)溶于N,N-二甲基甲酰胺(10mL),加入叠氮化钠(388mg,5.97mmol),80℃加热反应2.5h,冷却至室温,加水(30mL),乙酸乙酯(10mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=6/1),得到513mg白色固体,收率90%。
1H NMR(400MHz,CDCl3):δ(ppm)7.62(s,1H),7.58(dd,J=8.3,1.8Hz,1H),7.25(d,J=8.3Hz,1H),6.72(t,JF-H=75.2Hz,1H),4.93–5.04(m,1H),4.38–4.48(m,2H),3.99(d,J=6.9Hz,2H),1.59(d,J=7.0Hz,3H),1.45(s,9H),1.30–1.39(m,1H),0.67–0.72(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:480.65[M+H]+.
步骤3:化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(叠氮甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(510mg,1.06mmol)溶于甲醇(8mL),加入Pd/C(51mg,0.1g/g),常压下氢气室温反应2h,过滤除去催化剂,滤液减压浓缩,得443mg浅褐色固体,收率91%。
1H NMR(400MHz,CD3OD):δ(ppm)7.70(s,1H),7.61(dd,J=8.3,1.5Hz,1H),7.27(d,J=8.3Hz,1H),6.88(t,JF-H=75.0Hz,1H),4.93–4.97(m,1H),4.01(d,J=6.9Hz,2H),3.74–3.86(m,2H),1.55(d,J=7.1Hz,3H),1.44(s,9H),1.30–1.39(m,1H),0.66–0.70(m,2H),0.41–0.44(m,2H).
MS(ESI,pos.ion)m/z:454.20[M+H]+.
步骤4:化合物(S)-4-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)苯甲酸甲酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),对苯二甲酸单甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到61mg白色固体,收率89%。
1H NMR(400MHz,CDCl3):δ(ppm)8.00–8.09(m,4H),7.61(s,1H),7.57(d,J=8.3Hz,1H),7.23(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),4.95–5.03(m,1H),4.86–4.92(m,1H),4.52–4.57(m,1H),3.98(d,J=7.0Hz,2H),3.95(s,3H),1.60(d,J=7.0Hz,3H),1.45(s,9H),1.29–1.38(m,1H),0.66–0.71(m,2H),0.39–0.42(m,2H).
MS(ESI,pos.ion)m/z:616.90[M+H]+.
步骤5:化合物(S)-4-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)苯甲酸甲酯盐酸盐的合成
将化合物(S)-4-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)苯甲酸甲酯(58mg,0.09mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到51mg白色固体,收率98%。
1H NMR(400MHz,CD3OD):δ(ppm)ppm 8.10(d,J=8.3Hz,2H),7.97(d,J=8.3Hz,2H),7.74(s,1H),7.67(d,J=8.4Hz,1H),7.29(d,J=8.3Hz,1H),6.88(t,JF-H=74.8Hz,1H),5.12–5.18(m,1H),4.46–4.61(m,2H),4.01(d,J=6.9Hz,2H),3.94(s,3H),1.82(d,J=6.8Hz,3H),1.29–1.38(m,1H),0.65–0.69(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:499.10[M-NH2-HCl]+.
实施例9:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酰胺盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2,4-二氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),2,4-二氟苯甲酸(55mg,0.35mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(86mg,0.67mmol),室温反应6.5h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到46mg白色固体,收率70%。
1H NMR(400MHz,CDCl3):δ(ppm)8.09–8.15(m,1H),7.58(s,1H),7.54(br.s,1H),7.57(d,J=8.3Hz,1H),7.23(d,J=8.2Hz,1H),6.97–7.01(m,1H),6.83–6.89(m,1H),6.71(t,JF-H=75.2Hz,1H),5.55(br.s,1H),5.07–5.14(m,1H),4.74–4.79(m,1H),4.56–4.59(m,1H),3.98(d,J=6.9Hz,2H),1.59(d,J=7.1Hz,3H),1.44(s,9H),1.29–1.38(m,1H),0.67–0.71(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:594.15[M+H]+.
步骤2:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2,4-二氟苯甲酰胺盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2,4-二氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(44mg,0.074mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到36mg白色固体,收率91%。
1H NMR(400MHz,CD3OD):δ(ppm)7.83–7.89(m,1H),7.74(s,1H),7.68(d,J=8.4Hz,1H),7.31(d,J=8.3Hz,1H),7.07–7.13(m,2H),6.89(t,JF-H=74.8Hz,1H),5.10–5.15(m,1H),4.47–4.59(m,2H),4.01(d,J=6.9Hz,2H),1.81(d,J=6.9Hz,3H),1.30–1.38(m,1H),0.66–0.70(m,2H),0.39–0.49(m,2H).
MS(ESI,pos.ion)m/z:477.10[M-NH2-HCl]+.
实施例10:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基苯甲酰胺盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将2-乙氧基苯甲酸(46mg,0.28mmol)溶解在干燥的四氢呋喃(5mL)溶液中,加入N,N’-羰基二咪唑(49mg,0.30mmol),60℃反应1h后,加入(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(42mg,0.09mmol),60℃继续反应3h,加入水(20mL),乙酸乙酯(10mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到42mg白色固体,收率75%。
1H NMR(400MHz,CDCl3):δ(ppm)8.60(br.s,1H),8.21(d,J=6.5Hz,1H),7.58(s,1H),7.56(d,J=8.3Hz,1H),7.43(t,J=6.9Hz,1H),7.23(d,J=8.6Hz,1H),7.07(t,J=7.5Hz,1H),6.96(d,J=8.3Hz,1H),6.71(t,JF-H=75.2Hz,1H),6.04(br.s,1H),5.11–5.21(m,1H),4.60–4.67(m,2H),4.21(q,J=6.9Hz,2H),3.98(d,J=6.9Hz,2H),1.58(d,J=7.0Hz,3H),1.52(t,J=7.0Hz,3H),1.46(s,9H),1.28–1.38(m,1H),0.67–0.72(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:602.20[M+H]+.
步骤2:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基苯甲酰胺盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(40mg,0.066mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1h,减压浓缩,得到27mg白色固体,收率93%。
1H NMR(400MHz,CD3OD):δ(ppm)7.94(d,J=7.6Hz,1H),7.74(s,1H),7.68(d,J=8.3Hz,1H),7.50(t,J=7.3Hz,1H),7.31(d,J=8.3Hz,1H),7.14(d,J=8.3Hz,1H),7.07(d,J=9.4Hz,1H),6.89(t,JF-H=74.8Hz,1H),5.08–5.13(m,1H),4.50–4.64(m,2H),4.26(q,J=6.9Hz,2H),4.00(d,J=6.9Hz,2H),1.81(d,J=6.8Hz,3H),1.50(t,J=6.9Hz,3H),1.29–1.37(m,1H),0.65–0.70(m,2H),0.40–0.44(m,2H).
MS(ESI,pos.ion)m/z:485.30[M-NH2-HCl]+.
实施例11:化合物(S)-3-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-2-氟苯甲酸甲酯盐酸盐
步骤1:化合物(S)-3-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-2-氟苯甲酸甲酯的合成
将2-氟-3-甲氧羰基苯甲酸(91mg,0.46mmol)溶解在干燥的四氢呋喃(8mL)溶液中,加入N,N’-羰基二咪唑(82mg,0.51mmol),60℃反应20min后,加入(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(70mg,0.15mmol),60℃继续反应3h,加入水(20mL),乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到51mg白色固体,收率52%。
1H NMR(400MHz,CDCl3):δ(ppm)8.25(t,J=6.6Hz,1H),8.05(t,J=6.4Hz,1H),7.70(s,1H),7.57(d,J=8.4Hz,1H),7.33(d,J=7.8Hz,1H),7.23(d,J=8.4Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.07–5.14(m,1H),4.77–4.82(m,1H),4.56–4.61(m,1H),3.99(d,J=6.9Hz,2H),3.94(s,3H),1.59(d,J=7.1Hz,3H),1.43(s,9H),1.29–1.38(m,1H),0.66–0.71(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:634.20[M+H]+.
步骤2:化合物(S)-3-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-2-氟苯甲酸甲酯盐酸盐的合成
将化合物(S)-3-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-2-氟苯甲酸甲酯(47mg,0.074mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到42mg白色固体,收率92%。
1H NMR(400MHz,CD3OD):δ(ppm)8.06(t,J=7.1Hz,1H),7.93(t,J=6.4Hz,1H),7.75(s,1H),7.69(d,J=8.4Hz,1H),7.39(t,J=7.6Hz,1H),7.30(d,J=8.3Hz,1H),6.89(t,JF-H=74.8Hz,1H),5.10–5.15(m,1H),4.51–4.60(m,2H),4.02(d,J=6.9Hz,2H),3.94(s,3H),1.82(d,J=6.8Hz,3H),1.29–1.37(m,1H),0.65–0.70(m,2H),0.39–0.44(m,2H).
MS(ESI,pos.ion)m/z:517.30[M-NH2-HCl]+.
实施例12:化合物(S)-4-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-3-氟苯甲酸甲酯盐酸盐
步骤1:化合物(S)-4-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-3-氟苯甲酸甲酯的合成
将2-氟-4-甲氧羰基苯甲酸(91mg,0.46mmol)溶解在干燥的四氢呋喃(8mL)溶液中,加入N,N’-羰基二咪唑(82mg,0.51mmol),60℃反应20min后,加入(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(70mg,0.15mmol),60℃继续反应3h,加入水(20mL),乙酸乙酯(20mL×2)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到95mg白色固体,收率96%。
1H NMR(400MHz,CDCl3):δ(ppm)8.14(t,J=7.7Hz,1H),7.91(d,J=8.1Hz,1H),7.78(d,J=11.8Hz,1H),7.68(br.s,1H),7.59(s,1H),7.57(d,J=8.4Hz,1H),7.23(d,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.48(br.s,1H),5.06–5.13(m,1H),4.77–4.83(m,1H),4.55–4.60(m,1H),3.99(d,J=7.0Hz,2H),3.96(s,3H),1.60(d,J=7.1Hz,3H),1.43(s,9H),1.27–1.38(m,1H),0.67–0.71(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:634.35[M+H]+.
步骤2:化合物(S)-4-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-3-氟苯甲酸甲酯盐酸盐的合成
将化合物(S)-4-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)-3-氟苯甲酸甲酯(80mg,0.13mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1h,减压浓缩,得到70mg白色固体,收率97%。
1H NMR(600MHz,CD3OD):δ(ppm)7.91–7.92(m,1H),7.81–7.86(m,2H),7.75(s,1H),7.69(d,J=8.2Hz,1H),7.31(d,J=8.3Hz,1H),6.90(t,JF-H=74.7Hz,1H),5.11–5.15(m,1H),4.53–4.59(m,2H),4.02(d,J=6.8Hz,2H),3.96(s,3H),1.81(d,J=6.7Hz,3H),1.29–1.36(m,1H),0.66–0.69(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:517.25[M-NH2-HCl]+.
实施例13:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-3-氟苯甲酰胺盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基-3-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),3-氟-2-乙氧基苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌12h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到58mg浅褐色固体,收率84%。
1H NMR(400MHz,CDCl3):δ(ppm)8.55(s,1H),7.90(d,J=7.9Hz,1H),7.57(s,1H),7.56(d,J=7.6Hz,1H),7.23(d,J=8.3Hz,1H),7.21(d,J=9.0Hz,1H),7.10–7.15(m,1H),6.71(t,JF-H=75.2Hz,1H),5.85(br.s,1H),5.10–5.19(m,1H),4.57–4.70(m,1H),4.55–4.60(m,1H),4.23(q,J=7.0Hz,2H),3.97(d,J=6.9Hz,2H),1.59(d,J=7.0Hz,3H),1.43(s,9H),1.41(t,J=7.0Hz,3H),1.27–1.38(m,1H),0.67–0.72(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:620.40[M+H]+.
步骤2:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-3-氟苯甲酰胺盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基-3-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(45mg,0.073mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应30min,减压浓缩,得到39mg浅黄色固体,收率96%。
1H NMR(400MHz,CD3OD):δ(ppm)7.74(s,1H),7.69(d,J=8.4,Hz,1H),7.59(d,J=7.8Hz,1H),7.30–7.37(m,2H),7.17–7.22(m,1H),6.90(t,JF-H=74.7Hz,1H),5.09–5.14(m,1H),4.57(s,2H),4.20(q,J=6.9Hz,2H),4.01(d,J=6.9Hz,2H),1.82(d,J=6.9Hz,3H),1.33(t,J=7.0Hz,3H),1.29–1.37(m,1H),0.65–0.70(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:503.10[M-NH2-HCl]+.
实施例14:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酰胺盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基-4-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),4-氟-2-乙氧基苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌12h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到58mg浅褐色固体,收率84%。
1H NMR(400MHz,CDCl3):δ(ppm)8.44(br.s,1H),8.21-8.24(m,1H),7.58(d,J=8.4Hz,1H),7.57(s,1H),7.23(d,J=8.3Hz,1H),6.77(t,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),6.67(d,J=10.6Hz,1H),5.94(br.s,1H),5.10–5.18(m,1H),4.59–4.66(m,2H),4.18(q,J=7.0Hz,2H),3.97(d,J=6.9Hz,2H),1.58(d,J=7.0Hz,3H),1.53(t,J=7.0Hz,1H),1.46(s,9H),1.31–1.38(m,1H),0.68–0.71(m,2H),0.39–0.42(m,2H).
步骤2:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-2-乙氧基-4-氟苯甲酰胺盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((2-乙氧基-4-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(35mg,0.056mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应20min,减压浓缩,得到17mg浅黄色固体,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)7.97(dd,J=19.2,10.7Hz,1H),7.73(s,1H),7.68(d,J=8.4,Hz,1H),7.31(d,J=8.4Hz,1H),6.95(d,J=9.2Hz,1H),6.89(t,JF-H=74.7Hz,1H),6.81(t,J=8.3Hz,1H),5.07–5.11(m,1H),4.50–4.62(m,2H),4.25(q,J=6.9Hz,2H),4.01(d,J=6.9Hz,2H),1.81(d,J=6.9Hz,3H),1.51(t,J=6.9Hz,3H),1.29–1.37(m,1H),0.65–0.70(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:503.10[M-NH2-HCl]+.
实施例15:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酰胺盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((4-乙氧基-2-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),4-乙氧基-2-氟苯甲酸(41mg,0.22mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌12h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到57mg浅褐色固体,收率83%。
1H NMR(600MHz,CDCl3):δ(ppm)8.04(t,J=8.9Hz,1H),7.58(s,1H),7.56(d,J=8.4Hz,1H),7.43(br.s,1H),7.23(d,J=8.2Hz,1H),6.77(t,J=8.7Hz,1H),6.70(t,JF-H=75.2Hz,1H),6.60(d,J=14.0Hz,1H),5.82(br.s,1H),5.10–5.16(m,1H),4.57–4.72(m,2H),4.07(q,J=6.8Hz,2H),3.99(d,J=6.8Hz,2H),1.59(d,J=6.9Hz,3H),1.46(s,9H),1.44(t,J=6.9Hz,1H),1.29–1.37(m,1H),0.67–0.71(m,2H),0.40–0.42(m,2H).
MS(ESI,pos.ion)m/z:620.40[M+H]+.
步骤2:化合物(S)-N-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-乙氧基-2-氟苯甲酰胺盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((4-乙氧基-2-氟苯甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(47mg,0.076mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1h,减压浓缩,得到42mg白色固体,收率99%。
1H NMR(400MHz,CD3OD):δ(ppm)7.78(t,J=8.8Hz,1H),7.76(s,1H),7.68(d,J=8.4,Hz,1H),7.30(d,J=8.3Hz,1H),6.89(t,JF-H=74.7Hz,1H),6.83(d,J=8.3Hz,1H),6.78(d,J=13.6Hz,1H),5.08–5.13(m,1H),4.48–4.59(m,2H),4.10(q,J=6.9Hz,2H),4.01(d,J=6.9Hz,2H),1.81(d,J=6.9Hz,3H),1.41(t,J=7.0Hz,3H),1.29–1.37(m,1H),0.65–0.70(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:503.15[M-NH2-HCl]+.
实施例16:化合物(S)-2-乙氧基苄基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯盐酸盐
步骤1:化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸甲酯(5.13g,10.63mmol)与一水合氢氧化锂(2.23g,53.16mmol)溶于四氢呋喃(40mL)和水(20mL)的混合溶剂中,40℃反应2h,加(1M)盐酸调节pH值至1,加乙酸乙酯(20mL×3)萃取,有机相合并后用硫酸钠干燥,除去溶剂,得到4.8g黄色固体,收率96%。
1H NMR(600MHz,CD3OD):δ(ppm)ppm 7.80(d,J=1.8Hz,1H),7.66(dd,J1=8.3Hz,J2=1.9Hz,1H),7.29(d,J=8.3Hz,1H),6.90(t,JF-H=74.8Hz,1H),5.51(m,1H),4.03(d,J=7.0Hz,2H),1.54(d,J=7.1Hz,3H),1.44(s,9H),1.35-1.38(m,1H),0.67-0.70(m,2H),0.42-0.44(m,2H).
MS(ESI,neg.ion)m/z:467.30[M-H]-.
步骤2:化合物(S)-2-乙氧基苄基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸(50mg,0.11mmol),2-乙氧基苯甲醇(48mg,0.32mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温反应44h,有机相加水(20mL×2)洗涤,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=3/1),得到35mg白色固体,收率54%。
1H NMR(400MHz,CDCl3):δ(ppm)7.68(d,J=1.6Hz,1H),7.63(dd,J=8.4,1.7Hz,1H),7.46(d,J=7.7Hz,1H),7.32–7.35(m,1H),7.24(d,J=8.3Hz,1H),6.98(t,J=7.5Hz,1H),6.93(d,J=8.2Hz,1H),6.72(t,JF-H=75.1Hz,1H),5.49–5.56(m,2H),5.37–5.43(m,1H),4.11–4.16(m,2H),3.98(d,J=6.9Hz,2H),1.51(d,J=7.1Hz,3H),1.46(t,J=7.0Hz,2H),1.43(s,9H),1.31–1.37(m,1H),0.68–0.71(m,2H),0.39–0.42(m,2H).
MS(ESI,pos.ion)m/z:603.20[M+H]+.
步骤3:化合物(S)-2-乙氧基苄基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯盐酸盐的合成
将化合物(S)-2-乙氧基苄基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-羧酸酯(35mg,0.058mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应30min,减压浓缩,得到29mg白色固体,收率92%。
1H NMR(400MHz,CD3OD):δ(ppm)7.84(s,1H),7.72(d,J=8.4,Hz,1H),7.45(d,J=6.6Hz,1H),7.37(t,J=8.5Hz,1H),7.32(d,J=8.4Hz,1H),7.05(d,J=8.3Hz,1H),6.98(t,J=7.5Hz,1H),6.92(t,JF-H=74.8Hz,1H),5.46–5.54(m,2H),5.22–5.27(m,1H),4.14(q,J=7.0Hz,2H),4.03(d,J=6.9Hz,2H),1.74(d,J=7.0Hz,3H),1.43(t,J=7.0Hz,3H),1.28–1.35(m,1H),0.66–0.70(m,2H),0.40–0.44(m,2H).
MS(ESI,pos.ion)m/z:503.20[M+H-HCl]+.
实施例17:化合物(S)-2-乙氧基-3-氟苄基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯盐酸盐
步骤1:化合物(S)-2-乙氧基-3-氟苄基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸(80mg,0.17mmol),(2-乙氧基-3-氟苯基)甲醇(43mg,0.25mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(165mg,0.86mmol)和N-羟基-7-氮杂苯并三氮唑(46mg,0.34mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(132mg,1.02mmol),室温反应23h,加入二氯甲烷(15mL),有机相加水(20mL×2)洗涤,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1),得到64mg白色固体,收率60%。
1H NMR(400MHz,CDCl3):δ(ppm)7.66(s,1H),7.62(d,J=8.3Hz,1H),7.25(d,J=8.3Hz,1H),7.02–7.11(m,3H),6.72(t,JF-H=75.1Hz,1H),5.47–5.55(m,2H),5.41–5.47(m,1H),4.22–4.31(m,2H),3.98(d,J=6.9Hz,2H),1.53(d,J=7.1Hz,3H),1.43(s,9H),1.41(t,J=7.0Hz,3H),1.27–1.37(m,1H),0.67–0.72(m,2H),0.39–0.42(m,2H).
步骤2:化合物(S)-2-乙氧基-3-氟苄基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯盐酸盐的合成
将化合物(S)-2-乙氧基-3-氟苄基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯(64mg,0.104mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到53mg浅黄色固体,收率90%。
1H NMR(400MHz,CD3OD):δ(ppm)7.82(s,1H),7.72(d,J=8.3,Hz,1H),7.30–7.34(m,2H),7.11–7.23(m,2H),6.92(t,JF-H=74.7Hz,1H),5.48–5.55(m,2H),5.24–5.30(m,1H),4.25(q,J=7.0Hz,2H),4.03(d,J=6.9Hz,2H),1.76(d,J=6.9Hz,3H),1.42(t,J=7.0Hz,3H),1.30–1.36(m,1H),0.66–0.70(m,2H),0.41–0.44(m,2H).
MS(ESI,pos.ion)m/z:504.10[M-NH2-HCl]+.
实施例18:化合物(S)-(5-(甲氧基羰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯二盐酸盐
步骤1:化合物(S)-(5-(甲氧基羰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸(100mg,0.21mmol),6-羟甲基烟酸甲酯(40mg,0.24mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(190mg,0.99mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(5mL)中,冷却至0℃,加入N,N-二异丙基乙胺(154mg,1.19mmol),室温反应12h,加水(10mL×3)洗涤,有机相用无水硫酸钠干燥,除去溶剂,浓缩液进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到68mg浅黄色固体,收率52%。
1H NMR(400MHz,CDCl3):δ(ppm)ppm 9.26(s,1H),8.36(dd,J1=8.1Hz,J2=2.0Hz,1H),7.68(s,1H),7.65-7.67(m,1H),7.57(d,J=7.9Hz,1H),7.26(d,J=8.3Hz,1H),6.73(t,JF-H=75.0Hz,1H),5.55-5.73(m,2H),5.43-5.52(m,1H),4.00(d,J=6.9Hz,2H),3.99(s,3H),1.58(d,J=7.1Hz,3H),1.44(s,9H),1.27-1.37(m,1H),0.68-0.72(m,2H),0.39-0.43(m,2H).
MS(ESI,pos.ion)m/z:618.20[M+H]+.
步骤2:化合物(S)-(5-(甲氧基羰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯二盐酸盐的合成
将化合物(S)-(5-(甲氧基羰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯(60mg,0.097mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应30min,除去溶剂,得到57mg浅黄色固体,收率99%。
1H NMR(400MHz,CD3OD):δ(ppm)9.23(s,1H),8.64(d,J=7.5Hz,1H),7.91(d,J=7.8Hz,1H),7.83(s,1H),7.75(d,J=8.0Hz,1H),7.34(d,J=8.2Hz,1H),6.94(t,JF-H=74.7Hz,1H),5.71(s,2H),5.32-5.40(m,1H),4.04(d,J=6.8Hz,2H),4.01(s,3H),1.81(d,J=6.2Hz,3H),1.30-1.40(m,1H),0.67-0.70(m,2H),0.41-0.44(m,2H).
MS(ESI,pos.ion)m/z:518.20[M+H-2HCl]+.
实施例19:化合物(S)-(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯二盐酸盐
步骤1:中间体6-(乙基(甲基)氨基甲酰基)吡啶甲酸甲酯的合成
将化合物2,6-吡啶二羧酸单甲酯(500mg,2.76mmol),N-乙基甲基胺(327mg,5.53mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(2.65g,13.8mmol)和N-羟基-7-氮杂苯并三氮唑(750mg,5.51mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入N,N-二异丙基乙胺(2.1g,16.0mmol),室温反应5h,加水洗(20mL×2)有机相,分离有机相,用无水硫酸钠干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:石油醚/乙酸乙酯(v/v)=2/1),得到592mg浅褐色液体,收率96%。
1H NMR(400MHz,CDCl3):δ(ppm)8.16–8.19(m,1H),7.96(t,J=7.8Hz,1H),7.85(t,J=6.3Hz,1H),4.02(s,3H),3.25–3.30(m,2H),3.12(s,3H),1.24–1.28(m,3H).
MS(ESI,pos.ion)m/z:223.20[M+H]+.
步骤2:中间体N-乙基-6-(羟甲基)-N-甲基吡啶酰胺的合成
将化合物6-(乙基(甲基)氨基甲酰基)吡啶甲酸甲酯(370mg,1.66mmol)溶于四氢呋喃(6mL)中,冰浴下加入硼氢化锂(354mg,16.6mmol),室温反应1h后停止,加入饱和氯化钠水溶液(10mL),乙酸乙酯(10mL×2)萃取,有机相用无水硫酸钠干燥,减压浓缩,浓缩液进行硅胶柱层析分离(洗脱剂:二氯甲烷/甲醇(v/v)=30/1),得到116mg浅黄色液体,收率36%。
1H NMR(400MHz,d6-DMSO):δ(ppm)7.90(d,J=7.7Hz,1H),7.53(d,J=7.7Hz,1H),7.36(d,J=7.6Hz,1H),5.49(t,J=5.9Hz,1H),4.56–4.58(m,2H),3.47(q,J=0.8Hz,1H),3.22(q,J=1.2Hz,1H),2.96(s,1.7H),2.88(s,1.3H),1.14(t,J=7.1Hz,1.2H),1.08(t,J=7.0Hz,1.8H).
MS(ESI,pos.ion)m/z:195.20[M+H]+.
步骤3:化合物(S)-(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸(60mg,0.13mmol),N-乙基-6-(羟甲基)-N-甲基吡啶酰胺(32mg,0.16mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(125mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(34mg,0.25mmol)溶于二氯甲烷(5mL)中,冷却至0℃,加入N,N-二异丙基乙胺(101mg,0.78mmol),室温反应7h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/2),得到37mg白色固体,收率44%。
1H NMR(400MHz,CDCl3):δ(ppm)7.85(t,J=7.8Hz,1H),7.68(s,1H),7.65(d,J=8.4Hz,1H),7.54-7.60(m,2H),7.26(d,J=8.3Hz,1H),6.73(t,JF-H=75.1Hz,1H),5.57(s,2H),5.45-5.54(m,1H),3.99(d,J=7.0Hz,2H),3.60-3.65(m,0.8H),3.40-3.45(m,1.2H),3.12(s,1.7H),3.06(s,1.3H),1.56(d,J=7.1Hz,3H),1.43(s,9H),1.30-1.39(m,1H),1.20-1.27(m,3H),0.68-0.72(m,2H),0.39-0.43(m,2H).
MS(ESI,pos.ion)m/z:667.20[M+Na]+.
步骤4:化合物(S)-(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯二盐酸盐的合成
将化合物(S)-(6-(乙基(甲基)氨基甲酰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸酯(37mg,0.06mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到34mg白色固体,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)8.01-8.05(m,1H),7.83(s,1H),7.74(d,J=8.3Hz,1H),7.69(d,J=7.7Hz,1H),7.55-7.58(m,1H),7.33(d,J=8.3Hz,1H),6.92(t,JF-H=74.7Hz,1H),5.58(s,2H),5.31-5.36(m,1H),4.04(d,J=6.8Hz,2H),3.58-3.65(m,0.8H),3.31-3.37(m,1.2H),3.11(s,1.7H),3.00(s,1.3H),1.78(d,J=6.7Hz,3H),1.30-1.39(m,1H),1.17-1.28(m,3H),0.67-0.70(m,2H),0.40-0.44(m,2H).
MS(ESI,pos.ion)m/z:545.20[M+H-2HCl]+.
实施例20:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-5-甲基吡啶-2,5-二羧酸酯二盐酸盐
步骤1:化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-5-甲基吡啶-2,5-二羧酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(100mg,0.22mmol),5-(甲氧基羰基)-2-吡啶羧酸(47mg,0.26mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(210mg,1.10mmol)和N-羟基-7-氮杂苯并三氮唑(59mg,0.43mmol)溶于二氯甲烷(10mL)中,加入N,N-二异丙基乙胺(218mg,1.69mmol),室温搅拌16h,加入二氯甲烷(15mL),有机相用水(10mL×3)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到89mg浅黄色固体,收率65%。
1H NMR(400MHz,CDCl3):δ(ppm)9.34(s,1H),8.46(dd,J1=8.1Hz,J2=2.0Hz,1H),8.26(d,J=8.1Hz,1H),7.60(s,1H),7.58(d,J=8.3Hz,1H),7.23(d,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.69(br.s,1H),5.43-5.57(m,2H),5.20-5.37(m,1H),4.01(s,3H),3.98(d,J=6.9Hz,2H),1.60(d,J=7.1Hz,3H),1.44(s,9H),1.30-1.37(m,1H),0.66-0.71(m,2H),0.38-0.42(m,2H).
MS(ESI,pos.ion)m/z:618.80[M+H]+.
步骤2:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-5-甲基吡啶-2,5-二羧酸酯二盐酸盐的合成
将化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-5-甲基吡啶-2,5-二羧酸酯(85mg,0.14mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应2h,减压除去溶剂,得到79mg浅黄色固体,收率97%。
1H NMR(400MHz,CD3OD):δ(ppm)9.24(s,1H),8.57(d,J=7.7Hz,1H),8.31-8.36(m,1H),7.75(s,1H),7.68(d,J=8.3Hz,1H),7.30(d,J=8.3Hz,1H),6.89(t,JF-H=74.8Hz,1H),5.46-5.54(m,2H),5.17-5.25(m,1H),4.01(d,J=7.0Hz,2H),3.99(m,3H),1.82(d,J=6.5Hz,3H),1.30-1.37(m,1H),0.64-0.69(m,2H),0.40-0.44(m,2H).
MS(ESI,pos.ion)m/z:501.10[M-NH2-2HCl]+.
实施例21:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-6-甲基吡啶-2,6-二羧酸酯二盐酸盐
步骤1:化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-6-甲基吡啶-2,6-二羧酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(70mg,0.15mmol),2,6-吡啶二羧酸单甲酯(33mg,0.18mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(147mg,0.77mmol)和N-羟基-7-氮杂苯并三氮唑(41mg,0.30mmol)溶于二氯甲烷(5mL)中,加入N,N-二异丙基乙胺(119mg,0.92mmol),室温搅拌12h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到43mg浅黄色固体,收率45%。
1H NMR(400MHz,CDCl3):δ(ppm)8.33(t,J=8.0Hz,2H),8.03(t,J=7.8Hz,1H),7.60(s,1H),7.58(d,J=8.3Hz,1H),7.23(d,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.72(br.s,1H),5.42-5.56(m,2H),5.20-5.27(m,1H),4.03(s,3H),3.98(d,J=6.9Hz,2H),1.64(d,J=7.0Hz,3H),1.39(s,9H),1.28-1.37(m,1H),0.66-0.71(m,2H),0.38-0.42(m,2H).
MS(ESI,pos.ion)m/z:640.15[M+Na]+.
步骤2:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-6-甲基吡啶-2,6-二羧酸酯二盐酸盐的合成
将化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-6-甲基吡啶-2,6-二羧酸酯(40mg,0.064mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应2h,减压除去溶剂,得到43mg浅黄色固体,收率96%。
1H NMR(400MHz,CD3OD):δ(ppm)8.41-8.47(m,2H),8.25-8.29(m,1H),7.76(s,1H),7.70(d,J=8.0Hz,1H),7.32(d,J=8.2Hz,1H),6.91(t,JF-H=74.8Hz,1H),5.48-5.58(m,2H),5.34-5.39(m,1H),4.07(s,3H),4.03(d,J=6.9Hz,2H),1.87(d,J=6.8Hz,3H),1.30-1.38(m,1H),0.66-0.72(m,2H),0.41-0.45(m,2H).
MS(ESI,pos.ion)m/z:501.10[M-NH2-2HCl]+.
实施例22:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基吡啶-2,4-二羧酸酯二盐酸盐
步骤1:化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基吡啶-2,4-二羧酸酯的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-(羟甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),吡啶-2,4-二羧酸-4-单甲酯(23mg,0.13mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温搅拌16h,加入二氯甲烷(15mL),有机相用水(20mL×2)洗涤,无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到49mg浅黄色固体,收率72%。
1H NMR(400MHz,CDCl3):δ(ppm)8.94(d,J=4.8Hz,1H),8.70(s,1H),8.05(dd,J=4.8,1.4Hz,1H),7.61(s,1H),7.58(d,J=8.3Hz,1H),7.23(d,J=8.2Hz,1H),6.71(t,JF-H=75.2Hz,1H),5.58(br.s,1H),5.43-5.58(m,2H),5.21-5.31(m,1H),4.01(s,3H),3.98(d,J=6.9Hz,2H),1.61(d,J=7.1Hz,3H),1.44(s,9H),1.28-1.37(m,1H),0.66-0.71(m,2H),0.38-0.42(m,2H).
MS(ESI,pos.ion)m/z:618.20[M+H]+.
步骤2:化合物(S)-2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基吡啶-2,4-二羧酸酯二盐酸盐的合成
将化合物(S)-2-((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-4-甲基吡啶-2,4-二羧酸酯(47mg,0.076mmol)溶解在二氯甲烷(5mL)溶液中,室温下加入氯化氢的乙酸乙酯溶液(4M,5mL),室温搅拌反应2h,减压除去溶剂,得到43mg浅黄色固体,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)8.92(d,J=4.4Hz,1H),8.66(s,1H),8.18(d,J=4.4Hz,1H),7.76(s,1H),7.70(d,J=8.3Hz,1H),7.31(d,J=8.3Hz,1H),6.90(t,JF-H=74.8Hz,1H),5.47-5.55(m,2H),5.19-5.24(m,1H),4.02(d,J=6.9Hz,2H),4.01(m,3H),1.82(d,J=6.8Hz,3H),1.27-1.38(m,1H),0.65-0.69(m,2H),0.41-0.43(m,2H).
MS(ESI,pos.ion)m/z:501.15[M-NH2-2HCl]+.
实施例23:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)烟酸甲酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)烟酸甲酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),5-(甲氧基羰基)-2-吡啶甲酸(30mg,0.17mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到54mg白色固体,收率79%。
1H NMR(400MHz,CDCl3):δ(ppm)9.14(s,1H),8.17(br.s,1H),8.45(dd,J=8.1,1.9Hz,1H),8.30(d,J=8.1Hz,1H),7.59(s,1H),7.56(d,J=8.4Hz,1H),7.22(d,J=8.2Hz,1H),6.70(t,JF-H=75.2Hz,1H),5.61(br.s,1H),5.10–5.17(m,1H),4.77–4.82(m,1H),4.56–4.61(m,1H),3.99(s,3H),3.98(d,J=9.1Hz,2H),1.59(d,J=7.0Hz,3H),1.48(s,9H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z 617.85[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)烟酸甲酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)烟酸甲酯(50mg,0.08mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到43mg浅黄色固体,收率90%。
1H NMR(400MHz,CD3OD):δ(ppm)9.20(s,1H),8.51(d,J=7.2Hz,1H),8.21(d,J=8.0Hz,1H),7.73(s,1H),7.66(d,J=8.3Hz,1H),7.29(d,J=8.4Hz,1H),6.88(t,JF-H=74.8Hz,1H),5.11–5.18(m,1H),4.53–4.66(m,2H),4.00(d,J=9.7Hz,2H),3.98(s,3H),1.81(d,J=6.9Hz,3H),1.30–1.36(m,1H),0.64–0.69(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:500.70[M-NH2-2HCl]+.
实施例24:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸甲酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸甲酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),2,6-吡啶二羧酸单甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到41mg白色固体,收率60%。
1H NMR(400MHz,CDCl3):δ(ppm)8.82(br.s,1H),8.39(d,J=7.8Hz,1H),8.23(d,J=7.8Hz,1H),8.02(t,J=7.8Hz,1H),7.58(s,1H),7.56(d,J=8.3Hz,1H),7.22(d,J=8.2Hz,1H),6.70(t,JF-H=75.2Hz,1H),5.96(br.s,1H),5.16–5.25(m,1H),4.62–4.73(m,2H),4.03(s,3H),3.99(d,J=6.9Hz,2H),1.59(d,J=7.0Hz,3H),1.46(s,9H),1.28–1.38(m,1H),0.66–0.71(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:617.90[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸甲酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸甲酯(40mg,0.064mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到36mg白色固体,收率94%。
1H NMR(400MHz,CD3OD):δ(ppm)8.30–8.36(m,2H),8.18(t,J=7.7Hz,1H),7.75(s,1H),7.67(d,J=8.4Hz,1H),7.29(d,J=8.3Hz,1H),6.88(t,JF-H=74.8Hz,1H),5.11–5.16(m,1H),4.55–4.69(m,2H),4.06(s,3H),4.00(d,J=6.9Hz,2H),1.82(d,J=6.8Hz,3H),1.30–1.37(m,1H),0.64–0.69(m,2H),0.39–0.44(m,2H).
MS(ESI,pos.ion)m/z:500.10[M-NH2-2HCl]+.
实施例25:化合物(S)-2-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)异烟酸甲酯二盐酸盐
步骤1:化合物(S)-2-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)异烟酸甲酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(50mg,0.11mmol),吡啶-2,4-二羧酸-4-单甲酯(30mg,0.17mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(105mg,0.55mmol)和N-羟基-7-氮杂苯并三氮唑(29mg,0.21mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(85mg,0.66mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到48mg白色固体,收率70%。
1H NMR(400MHz,CDCl3):δ(ppm)8.74(s,1H),8.70(d,J=4.8Hz,1H),8.67(br.s,1H),8.00(d,J=3.4Hz,1H),7.58(s,1H),7.56(d,J=8.4Hz,1H),7.22(d,J=8.2Hz,1H),6.70(t,JF-H=75.2Hz,1H),5.71(br.s,1H),5.11–5.19(m,1H),4.75–4.81(m,1H),4.58–4.63(m,1H),4.00(s,3H),3.98(d,J=7.1Hz,2H),1.59(d,J=7.0Hz,3H),1.48(s,9H),1.28–1.37(m,1H),0.66–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z:617.85[M+H]+.
步骤2:化合物(S)-2-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)异烟酸甲酯二盐酸盐的合成
将化合物(S)-2-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)异烟酸甲酯(45mg,0.072mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到41mg浅黄色固体,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)8.85(d,J=4.6Hz,1H),8.58(s,1H),8.08(d,J=4.0Hz,1H),7.74(s,1H),7.67(d,J=8.3Hz,1H),7.29(d,J=8.3Hz,1H),6.88(t,JF-H=74.8Hz,1H),5.13–5.18(m,1H),4.53–4.67(m,2H),4.00(d,J=7.0Hz,2H),3.99(s,3H),1.82(d,J=6.8Hz,3H),1.30–1.36(m,1H),0.64–0.69(m,2H),0.39–0.44(m,2H).
MS(ESI,pos.ion)m/z:500.10[M-NH2-2HCl]+.
实施例26:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N5-乙基-N5-甲基吡啶-2,5-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((5-(乙基(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(60mg,0.13mmol),5-(乙基(甲基)氨基甲酰基)吡啶甲酸(55mg,0.26mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(161mg,0.84mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(132mg,1.02mmol),室温反应6h,加入水(20mL),乙酸乙酯(10mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:二氯甲烷/甲醇(v/v)=50/1),得到19mg白色固体,收率23%。
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N5-乙基-N5-甲基吡啶-2,5-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((5-(乙基(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(15mg,0.023mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1h,减压浓缩,得到12mg白色固体,收率83%。
MS(ESI,pos.ion)m/z:527.20[M-NH2-2HCl]+.
实施例27:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-乙基-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-(乙基(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-(1-(4-(氨基甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(60mg,0.13mmol),6-(乙基(甲基)氨基甲酰基)吡啶甲酸(55mg,0.26mmol),1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(161mg,0.84mmol)和N-羟基-7-氮杂苯并三氮唑(45mg,0.33mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入N,N-二异丙基乙胺(132mg,1.02mmol),室温反应9h,加入水(20mL),乙酸乙酯(10mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:二氯甲烷/甲醇(v/v)=50/1),得到32mg白色固体,收率37%。
1H NMR(400MHz,CDCl3):δ(ppm)8.24–8.27(m,1H),7.96(d,J=7.8Hz,1H),7.72(t,J=8.4Hz,1H),7.55(t,J=7.8Hz,1H),7.56(s,1H),7.55(d,J=7.8Hz,1H),7.23(d,J=8.4Hz,1H),6.70(t,JF-H=75.1Hz,1H),5.12–5.23(m,1H),4.60–4.72(m,2H),3.98(d,J=7.0Hz,2H),3.65(q,J=6.9Hz,0.7H),3.33(q,J=6.9Hz,1.3H),3.13(s,1.8H),3.03(s,1.2H),1.58(d,J=7.1Hz,3H),1.46(s,9H),1.30(t,J=7.1Hz,1H),1.28–1.38(m,1H),1.21(t,J=7.1Hz,2H),0.67–0.71(m,2H),0.38–0.42(m,2H).
MS(ESI,pos.ion)m/z:644.20[M+H]+.
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-乙基-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-(乙基(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(30mg,0.046mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应1.5h,减压浓缩,得到27mg白色固体,收率93%。
1H NMR(400MHz,CD3OD):δ(ppm)8.20–8.21(m,1H),8.10–8.14(m,1H),7.73–7.76(m,2H),7.66(d,J=8.1Hz,1H),7.30(d,J=8.3Hz,1H),6.89(t,JF-H=74.8Hz,1H),5.10–5.18(m,1H),4.86–4.93(m,2H),4.53–4.66(m,2H),4.01(d,J=6.8Hz,2H),3.61–3.67(m,1H),3.29–3.37(m,1H),3.14(s,1.6H),3.03(s,1.4H),1.81(d,J=6.6Hz,3H),1.28–1.34(m,1H),1.25–1.32(m,1H),1.20(t,J=7.1Hz,2H),0.65–0.69(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:527.20[M-NH2-2HCl]+.
实施例28:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸甲酯(617mg,1.00mmol)溶于四氢呋喃(10mL)和水(5mL)的混合溶剂中,再加入一水合氢氧化锂(206mg,4.91mmol),50℃反应2h,加稀盐酸调节溶液pH=1,用二氯甲烷萃取(10mL×3),有机相用无水硫酸钠干燥,减压浓缩,得到601mg白色固体,收率99%。
1H NMR(400MHz,d6-DMSO):δ(ppm)13.15(brs,1H),9.55(brs,1H),8.20–8.30(m,3H),7.56(s,1H),7.54(d,J=8.4Hz,1H),7.51(brs,1H),7.33(d,J=8.3Hz,1H),7.19(t,JF-H=74.2Hz,1H),5.04–5.11(m,1H),4.65–4.70(m,1H),4.37–4.42(m,1H),3.97(d,J=6.9Hz,2H),1.45(d,J=7.0Hz,2H),1.35(s,9H),1.22–1.29(m,1H),0.56–0.61(m,2H),0.37–0.40(m,2H).
MS(ESI,pos.ion)m/z:603.20[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(65mg,0.11mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(3M,3mL),室温反应3h,减压浓缩,得到51mg白色固体,收率82%。
1H NMR(400MHz,d6-DMSO):δ(ppm)9.82(t,J=5.4Hz,1H),8.66–8.74(m,2H),8.21–8.29(m,3H),7.66(s,1H),7.60(d,J=8.4Hz,1H),7.36(d,J=8.3Hz,1H),7.21(t,JF-H=74.1Hz,1H),5.00–5.07(m,1H),4.46–4.63(m,2H),3.98(d,J=6.9Hz,2H),1.65(d,J=6.8Hz,2H),1.22–1.30(m,1H),0.56–0.62(m,2H),0.37–0.40(m,2H).
MS(ESI,pos.ion)m/z:486.10[M-NH2-2HCl]+.
实施例29:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸乙酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸乙酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),乙醇(38mg,0.82mmol)和N-羟基-7-氮杂苯并三氮唑(36mg,0.26mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(128mg,0.67mmol)和N,N-二异丙基乙胺(135mg,1.05mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到71mg浅褐色固体,收率84%。
MS(ESI,pos.ion)m/z:631.30[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸乙酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸乙酯(65mg,0.103mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(3M,2mL),室温反应1h,减压浓缩,得到白色固体51mg,收率82%。
1H NMR(400MHz,d6-DMSO):δ(ppm)9.07(t,J=5.6Hz,1H),8.75(br.s,2H),8.18–8.28(m,3H),7.68(s,1H),7.61(d,J=8.4Hz,1H),7.35(d,J=8.3Hz,1H),7.21(t,JF-H=74.1Hz,1H),4.97–5.05(m,1H),4.47–4.63(m,2H),4.40(q,J=7.0Hz,2H),3.99(d,J=6.9Hz,2H),1.67(d,J=6.7Hz,2H),1.36(t,J=7.1Hz,2H),1.22–1.30(m,1H),0.56–0.61(m,2H),0.37–0.40(m,2H).
MS(ESI,pos.ion)m/z:514.15[M-NH2-2HCl]+.
实施例30:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸异丙酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸异丙酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),异丙醇(38mg,0.82mmol)和N-羟基-7-氮杂苯并三氮唑(37mg,0.27mmol)溶于二氯甲烷(5mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(127mg,0.66mmol)和N,N-二异丙基乙胺(103mg,0.80mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到38mg白色固体,收率44%。
MS(ESI,pos.ion)m/z:645.20[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸异丙酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸异丙酯(32mg,0.04mmol)溶解在二氯甲烷(4mL)溶液中,加入氯化氢的1,4-二氧六环溶液(3M,2mL),室温反应30min,减压浓缩,得到27mg白色固体,收率88%。
1H NMR(400MHz,d6-DMSO):δ(ppm)9.05(t,J=5.5Hz,1H),8.64–8.71(m,2H),8.23–8.28(m,1H),8.21(s,1H),8.19–8.20(m,1H),7.66(s,1H),7.61(d,J=8.1Hz,1H),7.36(d,J=8.3Hz,1H),7.21(t,JF-H=74.1Hz,1H),5.19–5.23(m,1H),4.97–5.05(m,2H),4.48–4.62(m,2H),3.99(d,J=6.8Hz,2H),1.65(d,J=6.5Hz,3H),1.36(d,J=6.1Hz,6H),1.23–1.30(m,1H),0.56–0.62(m,2H),0.36–0.41(m,2H).
MS(ESI,pos.ion)m/z:528.20[M-NH2-2HCl]+.
实施例31:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丁酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),正丁醇(48mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(37mg,0.27mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(127mg,0.66mmol)和N,N-二异丙基乙胺(132mg,1.02mmol),室温反应10h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到58mg浅褐色固体,收率66%。
MS(ESI,pos.ion)m/z:659.30[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丁酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丁酯(50mg,0.075mmol)溶解在二氯甲烷(4mL)溶液中,加入氯化氢的1,4-二氧六环溶液(3M,2mL),室温反应30min,减压浓缩,得到46mg白色固体,收率96%。
1H NMR(400MHz,d6-DMSO):δ(ppm)9.04(t,J=5.5Hz,1H),8.74–8.80(m,2H),8.24–8.29(m,1H),8.22(s,1H),8.19–8.21(m,1H),7.69(s,1H),7.61(d,J=8.3Hz,1H),7.35(d,J=8.3Hz,1H),7.21(t,JF-H=74.1Hz,1H),4.96–5.05(m,1H),4.48–4.62(m,2H),4.35(t,J=6.5Hz,2H),3.99(d,J=6.9Hz,2H),1.68–1.75(m,2H),1.66(d,J=6.4Hz,3H),1.36–1.46(m,2H),1.22–1.30(m,1H),0.92(t,J=7.3Hz,3H),0.56–0.61(m,2H),0.36–0.40(m,2H).
MS(ESI,pos.ion)m/z:542.20[M-NH2-2HCl]+.
实施例32:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丙酯二盐酸盐
步骤1:化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丙酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),正丙醇(39mg,0.65mmol)和N-羟基-7-氮杂苯并三氮唑(37mg,0.27mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(127mg,0.66mmol)和N,N-二异丙基乙胺(132mg,1.02mmol),室温反应7h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到69mg浅褐色固体,收率80%。
MS(ESI,pos.ion)m/z:645.20[M+H]+.
步骤2:化合物(S)-6-(((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丙酯二盐酸盐的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸丙酯(65mg,0.10mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(3M,3mL),室温反应1h,减压浓缩,得到62mg白色固体,收率99%。
1H NMR(400MHz,d6-DMSO):δ(ppm)9.04(t,J=5.7Hz,1H),8.71–8.80(m,2H),8.21–8.28(m,3H),7.68(s,1H),7.61(d,J=8.4Hz,1H),7.35(d,J=8.3Hz,1H),7.21(t,JF-H=74.1Hz,1H),4.95–5.04(m,1H),4.47–4.62(m,2H),4.30(t,J=6.6Hz,2H),3.99(d,J=6.9Hz,2H),1.72–1.78(m,2H),1.66(d,J=6.7Hz,3H),1.22–1.30(m,1H),0.96(t,J=7.4Hz,3H),0.56–0.61(m,2H),0.36–0.40(m,2H).
MS(ESI,pos.ion)m/z:528.20[M-NH2-2HCl]+.
实施例33:化合物(S)-(6-(甲氧基羰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-羧酸酯二盐酸盐
步骤1:化合物(S)-(6-(甲氧基羰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-羧酸酯的合成
将化合物(S)-5-(1-((叔丁氧基羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-甲酸(117mg,0.25mmol),6-(羟甲基)吡啶-2-甲酸甲酯(57mg,0.34mmol),HOAT(2mg,0.53mmol)溶于二氯甲烷(10mL)中,冷却至0℃,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(195mg,1.26mmol),N,N-二异丙基乙胺(168mg,1.30mmol),室温反应7h,加水(15mL)继续搅拌2min,二氯甲烷(15mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到116mg白色固体,收率75%。
1H NMR(400MHz,CDCl3):δ(ppm)8.12(d,J=7.7Hz,1H),7.91(t,J=7.8Hz,1H),7.73(d,J=7.2Hz,1H),7.68(s,1H),7.65(d,J=8.3Hz,1H),7.26(d,J=8.3Hz,1H),6.73(t,JF-H=75.0Hz,1H),5.80(br.s,1H),5.67(s,2H),5.43–5.52(m,1H),4.04(s,3H),3.99(d,J=7.0Hz,2H),1.58(d,J=7.1Hz,3H),1.40(s,9H),1.29–1.37(m,1H),0.67–0.72(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:640.50[M+Na]+.
步骤2:化合物(S)-(6-(甲氧基羰基)吡啶-2-基)甲基5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-羧酸酯二盐酸盐的合成
将化合物(S)-(6-(甲氧基羰基)吡啶-2-基)甲基5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-羧酸酯(116mg,0.19mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯溶液(4M,5mL),室温反应30min,减压浓缩,得到108mg白色固体,收率98%。
1H NMR(600MHz,CD3OD):δ(ppm)8.16(s,1H),8.12(d,J=6.6Hz,1H),7.83(d,J=6.7Hz,1H),7.80(s,1H),7.73(d,J=7.0Hz,1H),7.33(d,J=7.4Hz,1H),6.73(t,JF-H=74.6Hz,1H),5.60–5.72(m,2H),5.38–5.45(m,1H),4.02(s,5H),1.86(d,J=4.9Hz,3H),1.31–1.38(m,1H),0.64–0.72(m,2H),0.39–0.47(m,2H).
MS(ESI,pos.ion)m/z:518.45[M+H-2HCl]+.
实施例34:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-环己基-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(4-((6-(环己基(甲基)氨基甲酰基)吡啶甲酰氨基)甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),N-甲基环己胺(75mg,0.66mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(101mg,0.53mmol)和N,N-二异丙基乙胺(132mg,1.02mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到67mg白色固体,收率72%。
1H NMR(400MHz,CDCl3):δ(ppm)8.52(br.s,0.4H),8.41(br.s,0.6H),8.22–8.28(m,1H),7.93–7.99(m,1H),7.66–7.71(m,1H),7.54–7.56(m,2H),7.22(d,J=8.4Hz,1H),6.70(t,JF-H=75.2Hz,1H),5.87–5.95(m,0.4H),5.67–5.76(m,0.6H),5.11–5.25(m,1H),4.61–4.72(m,2H),4.52–4.60(m,0.4H),3.98(d,J=6.8Hz,2H),3.45–3.51(m,0.6H),3.02(s,1.8H),2.85(s,1.2H),1.79–1.95(m,3H),1.58(d,J=6.8Hz,3H),1.46–1.54(m,2H),1.46(s,9H),1.27–1.38(m,4H),0.97–1.07(m,2H),0.67–0.71(m,2H),0.39–0.42(m,2H).
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-环己基-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(4-((6-(环己基(甲基)氨基甲酰基)吡啶甲酰胺基)甲基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-5-基)乙基)氨基甲酸叔丁酯(62mg,0.088mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(4M,3mL),室温反应2h,减压浓缩,得到白色固体57mg,收率95%。
1H NMR(400MHz,CD3OD):δ(ppm)8.16–8.26(m,1H),8.09–8.16(m,1H),7.73(s,2H),7.66(d,J=8.5,Hz,1H),7.29(d,J=8.3,Hz,1H),6.89(t,JF-H=74.8Hz,1H),5.09–5.20(m,1H),4.52–4.66(m,2H),4.00(d,J=6.5Hz,2H),3.04(s,1.5H),2.89(s,1.5H),1.86–1.95(m,1H),1.81(d,J=6.7Hz,3H),1.59–1.74(m,5H),1.43–1.52(m,2H),1.27–1.39(m,1H),0.85–1.02(m,3H),0.64–0.69(m,2H),0.36–0.43(m,2H).
MS(ESI,pos.ion)m/z:581.20[M-NH2-2HCl]+.
实施例35:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4,4-二氟环己基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4,4-二氟环己基)(甲基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),4,4-二氟-N-甲基环己胺盐酸盐(72mg,0.40mmol)和N-羟基-7-氮杂苯并三氮唑(54mg,0.40mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(101mg,0.53mmol)和N,N-二异丙基乙胺(132mg,1.02mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到89mg白色固体,收率89%。
1H NMR(400MHz,CDCl3):δ(ppm)8.49(br.s,0.6H),8.32(br.s,0.4H),8.25–8.32(m,1H),7.95–8.02(m,1H),7.69–7.78(m,1H),7.54–7.56(m,2H),7.23(d,J=8.6Hz,1H),6.70(t,JF-H=75.1Hz,1H),5.82–5.93(m,0.4H),5.51–5.56(m,0.6H),5.09–5.24(m,1H),4.65–4.77(m,2H),4.54–4.62(m,0.4H),3.97(d,J=6.9Hz,2H),3.67–3.77(m,0.6H),3.03(s,1.4H),2.89(s,1.6H),2.22–2.30(m,1H),1.85–2.11(m,7H),1.58(d,J=7.0Hz,3H),1.44–1.16(m,9H),1.29–1.38(m,1H),0.67–0.71(m,2H),0.39–0.42(m,2H).
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4,4-二氟环己基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4,4-二氟环己基)(甲基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(80mg,0.11mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(4M,3mL),室温反应2h,减压浓缩,得到白色固体76mg,收率98%。
1H NMR(400MHz,CD3OD):δ(ppm)8.19–8.27(m,1H),8.10–8.16(m,1H),7.72–7.79(m,2H),7.66(d,J=8.4,Hz,1H),7.29(d,J=6.4,Hz,1H),6.89(td,JF-H=74.9,6.0Hz,1H),5.12–5.18(m,1H),4.53–4.66(m,2H),4.00(d,J=6.7Hz,2H),3.04(s,1.5H),2.92(s,1.5H),2.18–2.26(m,1H),1.90–2.09(m,6H),1.82(d,J=6.7Hz,3H),1.27–1.39(m,3H),0.65–0.69(m,2H),0.40–0.43(m,2H).
MS(ESI,pos.ion)m/z:617.15[M-NH2-2HCl]+.
实施例36:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4-氟苯基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4-氟苯基)(甲基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(80mg,0.13mmol),4-氟-N-甲基苯胺(49mg,0.39mmol)和N-羟基-7-氮杂苯并三氮唑(55mg,0.41mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(100mg,0.52mmol)和N,N-二异丙基乙胺(68mg,0.53mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=2/1),得到57mg白色固体,收率60%。
1H NMR(400MHz,CDCl3):δ(ppm)8.07(br.s,1H),7.85(d,J=3.9Hz,2H),7.62–7.68(m,3H),7.26(d,J=8.2Hz,1H),7.05–7.13(m,2H),6.88–6.97(m,2H),6.72(t,JF-H=75.2Hz,1H),5.75(br.s,1H),5.09–5.20(m,1H),4.44–4.59(m,2H),4.01(d,J=6.9Hz,2H),3.51(s,3H),1.54(d,J=7.0Hz,3H),1.46(s,9H),1.30–1.39(m,1H),0.67–0.72(m,2H),0.39–0.43(m,2H).
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4-氟苯基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4-氟苯基)(甲基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(53mg,0.074mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(4M,3mL),室温反应2h,减压浓缩,得到白色固体43mg,收率84%。
1H NMR(400MHz,CD3OD):δ(ppm)7.91–8.00(m,2H),7.79(s,1H),7.72(d,J=8.1,Hz,1H),7.32(d,J=8.4,Hz,1H),7.25–7.31(m,2H),6.96–7.01(m,2H),6.90(t,JF-H=74.8Hz,1H),5.10–5.15(m,1H),4.46–4.57(m,2H),4.03(d,J=6.9Hz,2H),3.52(s,3H),1.79(d,J=6.9Hz,3H),1.31–1.39(m,1H),0.65–0.70(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:593.10[M-NH2-2HCl]+.
实施例37:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-甲基-N6-(对甲苯基)吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-甲基(对甲苯基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(70mg,0.12mmol),N-甲基-4-甲基苯胺(42mg,0.35mmol)和N-羟基-7-氮杂苯并三氮唑(47mg,0.35mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(112mg,0.58mmol)和N,N-二异丙基乙胺(76mg,0.59mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物经硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=4/1),得到62mg白色固体,收率75%。
1H NMR(400MHz,CDCl3):δ(ppm)8.03(br.s,1H),7.80(d,J=3.6Hz,2H),7.70–7.76(m,1H),7.63(s,1H),7.62(d,J=8.3Hz,1H),7.26(d,J=8.2Hz,1H),6.98–7.07(m,4H),6.72(t,JF-H=75.2Hz,1H),5.86(br.s,1H),5.11–5.20(m,1H),4.42–4.55(m,2H),4.00(d,J=6.9Hz,2H),3.51(s,3H),2.25(s,3H),1.54(d,J=7.0Hz,3H),1.46(s,9H),1.31–1.39(m,1H),0.67–0.71(m,2H),0.39–0.43(m,2H).
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-甲基-N6-(对甲苯基)吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-甲基(对甲苯基)氨基甲酰基)吡啶甲酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(60mg,0.085mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的1,4-二氧六环溶液(4M,3mL),室温反应1h,减压浓缩,得到白色固体51mg,收率88%。
1H NMR(400MHz,CD3OD):δ(ppm)7.91–8.00(m,2H),7.79(s,1H),7.72(d,J=8.1,Hz,1H),7.32(d,J=8.4,Hz,1H),7.25–7.31(m,2H),6.96–7.01(m,2H),6.90(t,JF-H=74.8Hz,1H),5.10–5.15(m,1H),4.46–4.57(m,2H),4.03(d,J=6.9Hz,2H),3.52(s,3H),1.79(d,J=6.9Hz,3H),1.31–1.39(m,1H),0.65–0.70(m,2H),0.39–0.43(m,2H).
MS(ESI,pos.ion)m/z:589.50[M-NH2-2HCl]+.
实施例38:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4-甲氧基苯基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4-甲氧基苯基)(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(150mg,0.25mmol),N-甲基-4-氨基苯甲醚(50mg,0.37mmol)和N-羟基-7-氮杂苯并三氮唑(102mg,0.75mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(145mg,0.75mmol)和N,N-二异丙基乙胺(129mg,1.0mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物经硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到143mg无色液体,收率80%。
1H NMR(400MHz,CDCl3):δ(ppm)8.01(d,J=7.3Hz,1H),7.85(br.s,1H),7.72–7.79(m,2H),7.62(s,1H),7.59(d,J=8.4Hz,1H),7.23(d,J=8.2Hz,1H),7.01(d,J=8.6Hz,2H),6.73(d,J=8.7Hz,2H),6.69(t,J=75.2Hz,1H),5.80(br.s,1H),5.07–5.12(m,1H),4.33–4.64(m,2H),3.98(d,J=6.9Hz,2H),3.67(s,3H),3.47(s,3H),1.52(d,J=7.0Hz,3H),1.44(s,9H),1.29–1.36(m,1H),0.62–0.70(m,2H),0.35–0.42(m,2H).
步骤2:化合物(S)-N2-((5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-(4-甲氧基苯基)-N6-甲基吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-((4-甲氧基苯基)(甲基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(100mg,0.138mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯(4M,3mL),室温反应2h,减压浓缩,得到白色固体73mg,收率80%。
1H NMR(400MHz,CDCl3):δ(ppm)8.10(s,1H),7.85(d,J=5.6Hz,1H),7.63–7.77(m,2H),7.54–7.62(m,2H),7.14(d,J=7.7Hz,1H),6.99(d,J=7.7Hz,2H),6.74(d,J=7.6Hz,2H),6.66(t,J=75.2Hz,1H),4.91–5.03(m,1H),4.23–4.53(m,2H),3.96(d,J=5.8Hz,2H),3.64(s,3H),3.44(s,3H),1.86(s,3H),1.27–1.38(m,1H),0.49–0.66(m,2H),0.26–0.42(m,2H).
13C NMR(100MHz,CDCl3):δ(ppm)166.8,164.8,160.9,158.4,152.0,150.7,147.4,144.4,142.4,138.0,137.4,135.3,127.9,127.0,125.0,122.8,122.5,119.8,118.5,115.9,114.5,113.3,112.7,74.2,55.4,43.0,38.8,35.4,29.7,17.5,10.1,3.2,3.1.
MS(ESI,pos.ion)m/z:605.20[M-NH2-2HCl]+.
实施例39:化合物(S)-N2-(5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-甲基-N6-((1r,4s)-4-甲基环己基)吡啶-2,6-二甲酰胺二盐酸盐
步骤1:化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-(甲基((1r,4s)-4-甲基环己基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯的合成
将化合物(S)-6-(((5-(1-((叔丁氧羰基)氨基)乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)氨基甲酰基)吡啶甲酸(200mg,0.332mmol),反式N,4-二甲基环己胺(63mg,0.50mmol)和N-羟基-7-氮杂苯并三氮唑(92mg,0.66mmol)溶于二氯甲烷(10mL)中,冷却至0℃后,加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(194mg,1.0mmol)和N,N-二异丙基乙胺(172mg,1.33mmol),室温反应11h,加入二氯甲烷(15mL),有机相用水洗(20mL×2),分离有机相,有机相用无水硫酸钠干燥,减压浓缩,剩余物进行硅胶柱层析分离(淋洗剂:石油醚/乙酸乙酯(v/v)=1/1),得到178mg白色固体,收率75%。
MS(ESI,pos.ion)m/z:712.20[M+H]+
步骤2:化合物(S)-N2-(5-(1-氨基乙基)-2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)噁唑-4-基)甲基)-N6-甲基-N6-((1r,4s)-4-甲基环己基)吡啶-2,6-二甲酰胺二盐酸盐的合成
将化合物(S)-(1-(2-(3-(环丙基甲氧基)-4-(二氟甲氧基)苯基)-4-((6-(甲基((1r,4s)-4-甲基环己基)氨基甲酰基)吡啶酰氨基)甲基)噁唑-5-基)乙基)氨基甲酸叔丁酯(100mg,0.138mmol)溶解在二氯甲烷(5mL)溶液中,加入氯化氢的乙酸乙酯(4M,3mL),室温反应2h,减压浓缩,得到白色固体154mg,收率90%。
1H NMR(400MHz,CD3OD):δ(ppm)8.18–8.22(m,1H),8.08–8.14(m,1H),7.70–7.74(m,2H),7.65–7.67(m,1H),7.28(d,J=8.3Hz,1H),6.87(t,J=74.9Hz,1H),5.11–5.17(m,1H),4.53–4.66(m,2H),4.39–4.45(m,0.3H),4.00(d,J=6.9Hz,2H),3.26–3.32(m,0.7H),3.01(s,1.8H),2.87(s,1.2H),1.76–1.87(m,3H),1.81(d,J=6.8Hz,3H),1.60–1.73(m,1H),1.29–1.41(m,3H),1.13–1.24(m,1H),0.63–0.68(m,2H),0.62(d,J=6.4Hz,3H),0.39–0.42(m,2H).
MS(ESI,pos.ion)m/z:595.40[M-NH2-2HCl]+.
生物试验
生物实施例1
本发明采用以下方法对本发明化合物进行生物试验:(1)采用BPS生产试剂盒(BPS,Cat.No.60343),按照制造商提供的说明书,采用荧光偏振方法检测化合物对PDE4B2酶的抑制作用。(2)将PDE4B2酶浓度配制为83.33pg/μL,终浓度为27.78pg/μL;底物FAM-Cyclic-3’,5’-AMP浓度配制为300nM,反应终浓度为100nM,酶及底物稀释液均使用试剂盒自带缓冲液PDE Assay buffer;Binding Agent利用试剂盒自带Binding Agent Diluent进行100倍稀释,备用。反应体系如表1所示。
表1化合物对PDE4B2酶IC50检测体系
采用384孔板进行检测,实验设置受试样品孔、阳性对照孔、阴性对照孔及空白孔,每个样品利用双复孔检测10个浓度下对PDE4B2酶浓度的抑制作用,利用PDE4B2酶及FAM-Cyclic-3’,5’-AMP底物反应孔作为阳性对照,FAM-Cyclic-3’,5’-AMP底物孔作为阴性对照,缓冲液孔作为空白对照。各孔按表1顺序加入相应样品、酶、底物及缓冲液后,25℃恒温箱孵育1h,然后每孔加入已配置好的Binding Agent 15μL,并于25℃恒温振荡器振摇1h后,利用PHERAstarFS多功能酶标仪(BMG)在FP485/525波长处进行检测。利用Graph Pad Prism5软件对化合物不同浓度下对PDE4B2酶抑制作用进行作图,计算IC50。
按照上述方法测定本发明实施例提供的化合物对PDE4B2酶的抑制作用,结果参见表2,表2为本发明实施例对PDE4B2酶抑制作用的测定结果。
表2本发明化合物对PDE4B2酶抑制作用的测定结果
实施例编号 | IC50(nM) | 实施例编号 | IC50(nM) |
实施例9 | 2.15 | 实施例10 | 0.13 |
实施例11 | 4.88 | 实施例13 | 0.25 |
实施例14 | 2.54 | 实施例16 | 2.05 |
实施例17 | 3.19 | 实施例19 | 0.19 |
实施例21 | 1.08 | 实施例24 | 0.47 |
实施例27 | 1.27 | 实施例29 | 3.68 |
实施例33 | 3.86 | 实施例34 | 1.6 |
实施例35 | 1.6 | 实施例36 | 3.2 |
实施例37 | 1.9 | 实施例38 | 2.77 |
实施例39 | 3.16 | / | / |
表2数据显示,本发明所述化合物在对PDE4B2酶抑制的体外筛选实验中普遍表现出较高的抑制活性。
对于本领域技术人员显而易见的是,本发明内容并不限于前述说明性实施例,而且可以体现在其它具体形式中而又不偏离其实质特性。因此,预期各实施例在所有方面都被视作说明性的且非限制性的,应参照所附权利要求书,而不是前述实施例,因此,在所附权利要求书等同内容的含义和范围内的所有变化都包括在本发明中。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
最后,需要注意的是,还有其他方式用来实施本发明。相应地,本发明的实施例是将作为例证进行说明,但并不限于本发明所描述的内容,还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。
Claims (10)
1.一种化合物,其为式 (II) 所示的化合物或式 (II) 所示化合物的立体异构体或药学上可接受的盐:
(II);
其中:
L为*-L3-M2-L4-;其中,*表示与噁唑环一端相连;
L3为C1-4亚烷基;
L4为-C(=O)-;
M2为-O-或-N(R1)-;
R1为氢;
A为苯基或吡啶基;其中A任选地被1、2、3或4个R4所取代;
各R4独立地为氘、氟、氯、溴、碘、氨基、羟基、羧基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、-C(=O)-O-C1-6烷基或-C(=O)-N(R5R6);
R5和R6各自独立地为氢、氘、C1-6烷基、卤代C1-6烷基或苯基;其中R5和R6各自独立任选地被1、2、3或4个R7所取代;
各R7独立地为氘、氟、氯、溴、碘、氨基或羟基。
2.根据权利要求1所述的化合物,其中,
L3为亚甲基、亚乙基或亚丙基;
L4为-C(=O)-;
M2为-O-或-N(R1)-;
R1为氢。
3.根据权利要求1所述的化合物,其中A为苯基或吡啶基;其中A任选地被1、2、3或4个R4所取代;
各R4独立地为氘、氟、氯、溴、碘、氨基、羟基、羧基、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、-C(=O)-O-C1-4烷基或-C(=O)-N(R5R6);
R5和R6各自独立地为氢、氘、C1-3烷基、卤代C1-3烷基或苯基;其中,R5和R6各自独立任选地被1、2、3或4个R7所取代;
各R7独立地为氘、氟、氯、溴、碘、氨基或羟基。
4.根据权利要求1所述的化合物,其中A为苯基或吡啶基;其中A任选地被1、2、3或4个R4所取代;
各R4独立地为氘、氟、氯、溴、羧基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、-C(=O)-O-CH3、-C(=O)-O-CH2CH3、-C(=O)-O-(CH2)2CH3、-C(=O)-O-CH(CH3)2、-C(=O)-O-(CH2)3CH3、-C(=O)-O-CH2CH(CH3)CH3、-C(=O)-O-CH(CH3)CH2CH3或-C(=O)-N(R5R6);
R5和R6各自独立地为氢、氘、甲基、乙基、正丙基、异丙基、-CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CH2CH2CH2F、-CH2CH2CHF2、-CH2Cl、-CHCl2、-CH2CH2Cl、-CH2CHCl2或苯基;其中R5和R6各自独立任选地被1、2、3或4个R7所取代;
各R7独立地为氘、氟、氯、溴、氨基或羟基。
5.一种化合物,其为具有下列之一结构的化合物或具有下列之一结构化合物的立体异构体或药学上可接受的盐:
(9)、/> (10)、 />(13)、(14)、/> (15)、 (19)、/> (21)、 (23)、 />(24)、 />(25)、(29)、 />(30)、/> (31)、 (32)、/> (36)、/> (37)或 />(38)。
6.根据权利要求1-5任意一项所述的化合物,其中药学上可接受的盐是盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、马来酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、丙酮酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、酒石酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
7.一种药物组合物,包含权利要求1-6任意一项所述的化合物,其进一步地包含药学上可接受的载体。
8. 根据权利要求7所述的药物组合物,其进一步地包含附加治疗剂,其中所述的附加治疗剂是:丙酮酸钠、多索茶碱、替托司特、泰鲁司特、茶碱、福莫特罗、沙美特罗、氟替卡松丙酸酯、咯利普兰、吡拉米斯特、西洛司特、茚达特罗、奥达特罗、米地司坦、齐流通、沙丁醇胺、卡莫昔罗、布地奈德、二丙酸倍氯米松、曲安奈德、氟尼缩松、糠酸莫米松、罗氟奈德、环索奈德、异丙托溴铵、氧托溴铵、噻托溴铵、格隆溴铵、芜地溴铵、维兰特罗、阿地溴铵、Benralizumab、Tralokinumab、瑞伐托酯、克瑞沙硼、氟轻松醋酸酯、去羟米松、莫美他松、曲安西龙、倍他米松、阿氯米松、地索奈德、氢化可的松、氯倍他索 (clobatsol)、卤贝他索、二氟拉松、美普克莱、他克莫司、吡美莫司、他扎罗汀、环孢素、阿普斯特、OPA-15406、DRM02、罗氟司特、异丁司特、托法替尼、JTE-052、巴瑞替尼、乌帕替尼、WBI-1001、MRX-6、GSK2981278、杜鲁单抗 (Dupilumab)、来金珠单抗、Nemolizumab、曲洛吉努单抗、依那西普、阿达木单抗、英夫利昔单抗、尤特可单抗、Secukinumab、奥马珠、戈利木单抗、聚乙二醇化赛妥珠单抗、卡泊三醇、骨化三醇、阿利维A酸、VTP-38543、ZPL-389、阿瑞匹坦、曲地匹坦、Fevipiprant、和SB-011、VTP-43742、ARN6039、JTE-451、PF-04965842、PF-06651600、PF-06700841、PF-06650833、GR-MD-02或它们的组合。
9.权利要求1-6任意一项所述的化合物或权利要求7-8任意一项所述的药物组合物在制备药物中的用途,其中,所述药物用于预防、治疗或减轻与4型磷酸二酯酶有关的疾病。
10.根据权利要求9所述的用途,其中,所述与4型磷酸二酯酶有关的疾病为呼吸疾病、过敏、炎症、中枢神经系统疾病、肺纤维化或非胰岛素依赖糖尿病;
其中所述的呼吸疾病为:慢性阻塞性肺病、肺气肿、哮喘、慢性肺炎、尘肺病、支气管炎、支气管扩张症、肺结核纤维化病变、肺囊性纤维化、急性呼吸窘迫综合症;其中支气管炎包括急性支气管炎、慢性支气管炎、变应性支气管炎、弥漫性泛细支气管炎或闭塞性细支气管炎;
其中所述的炎症为:过敏性结膜炎、特应性皮炎、过敏性皮炎、类风湿性关节炎、间质性膀胱炎、变应性鼻炎、溃疡性结肠炎、强直性脊柱炎、风湿性关节炎或银屑病关节炎。
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