CN104903295B - 喹诺酮衍生物 - Google Patents
喹诺酮衍生物 Download PDFInfo
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- CN104903295B CN104903295B CN201380067856.4A CN201380067856A CN104903295B CN 104903295 B CN104903295 B CN 104903295B CN 201380067856 A CN201380067856 A CN 201380067856A CN 104903295 B CN104903295 B CN 104903295B
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- oxygen
- hydroxyl
- formamidos
- acetic acid
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
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- 238000002360 preparation method Methods 0.000 abstract description 115
- 238000000034 method Methods 0.000 abstract description 15
- 150000003839 salts Chemical class 0.000 abstract description 9
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- 235000011054 acetic acid Nutrition 0.000 description 223
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
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- 230000035945 sensitivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
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- 150000008523 triazolopyridines Chemical class 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 102100035070 von Hippel-Lindau disease tumor suppressor Human genes 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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- C07D215/60—N-oxides
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及通式(I)的化合物、它们的互变异构形式、它们的立体异构体、它们的药用盐、含有它们的药物组合物、用于制备它们的方法、这些化合物在药品中的应用以及在它们的制备中涉及的中间体。
Description
技术领域
本发明涉及通式(I)的新型化合物、它们的互变异构形式、它们的立体异构体、它们的药用盐、含有它们的药物组合物、它们的制备方法、这些化合物在药品中的应用以及在它们的制备中涉及的中间体。
背景技术
缺氧诱导因子(HIF)是异源双链,具有α和β亚基。β亚基通常过量存在,而α亚基则是在功能性二聚体的形成中的限制性因素。HIF-α亚基结合于在核中的β亚基,并,借助于辅因子的合作,结合于称作缺氧响应元件的DNA序列,因而诱导靶基因的表达。存在α亚基的三种同种型: HIF-1α、HIF-2α和HIF-3α。通过脯氨酰羟化酶(PHD)的氧敏感家族,称作 PHD1、PHD2和PHD3,借助于在两个脯氨酸残基处的羟基化来调节HIF 的活性。在这些脯氨酸残基的一个或两个处的羟基化允许HIF-α的结合:首先由希-林肿瘤抑制蛋白(pVHL),然后由遍在蛋白连接酶,其导致快速遍在蛋白化和蛋白酶体降解。通过抑制HIF(FIH)的因子,氧依赖性羟化酶,通过在C端天冬酰胺残基处的羟基化,也调节HIF-α亚基。抑制HIF的因子会阻止转录辅激活因子的募集,从而阻断HIF的活性。
在含氧量正常(normoxic)(氧合)条件下,HIF-1α被快速降解,而在缺氧条件下,HIF-1α被稳定(由于PHD和FIH活性的缺氧介导减小)并被易位进入核,其中它与组成型表达的HIF-1β二聚化,从而诱导若干基因的表达,包括葡萄糖转运蛋白、糖酵解酶、血管生成生长因子,以及涉及细胞凋亡和细胞增殖的若干分子如***(EPO)、转铁蛋白、内皮素-1、iNOS、血红素加氧酶1、VEGF、IGF和IGF结合蛋白。
氧敏感PHD家族也依赖于亚铁离子、抗坏血酸和柠檬酸环状中间体, 2-酮戊二酸(2-oxoglutarate)(2OG)的存在。因此,HIF活性取决于氧浓度、可进入的铁和葡萄糖代谢(经由它的通过FIH和PHD的调节)。
因此,HIF脯氨酰羟化酶和HIF天冬酰羟化酶的抑制可以提供用于 HIF的氧非依赖性激活的有效的方法。这样的通过药理方法的HIF激活导致如上文所描述的基因的增强的表达,其实现多种功能以从缺氧/缺血性条件恢复。因此,在各种疾病病症中如各种类型的贫血以及在病症如急性肾损伤、心肌梗死、卒中、肝缺血再灌注损伤、外周血管疾病和肝脏和肾脏移植中由缺氧/缺血引起的组织损伤中,HIF激活可提供显著的治疗益处。
Hb(血红蛋白)是在红细胞(RBC)中的含铁金属蛋白,其传送氧。起因于贫血的降低的Hb水平可以导致在各种器官中的缺氧,因而,引起患者严重的临床并发症,如严重疲劳、呼吸困难、心脏问题、神经损伤、受损的精神功能以及甚至死亡。贫血的原因是多因素的:失血、增加的RBC 破坏(例如,溶血性贫血)、和减少或有缺陷的RBC生产(例如,铁缺乏和镰状细胞贫血)。由于在肾脏中***(EPO)的降低的生产,80%的患有慢性肾病(CKD)的患者发展贫血。EPO是必不可少的生长因子,其刺激红细胞生成,并维持它们的生存能力。患有类风湿性关节炎、慢性炎症和感染性疾病、慢性心脏衰竭、和癌症,或正在接受化疗的患者,由于 EPO生产的不足,经常贫血。
对于慢性疾病中的贫血(包括慢性肾病的贫血)的目前的治疗是铁补充以及用EPO或它的类似物加以治疗。除EPO和它的类似物的高成本之外,这种方式还存在若干缺点。首先,这些都必须皮下或静脉注射,从而使得给予更困难。其次,存在显著比例的耐抗用EPO或它的类似物进行的疗法的患者。用HIF-羟化酶抑制剂对贫血的治疗可以绕过EPO抗性,通过作用于铁代谢,并且避免相关于EPO的超生理水平的增加的死亡和心血管事件。
因此期望这样的化合物,其提供用于抑制HIF羟化酶并从而激活HIF、导致各种基因(包括EPO、血管内皮生长因子(VEGF)、肾上腺髓质素 (adrenomodulin)等)的增强的表达的方式,可用于治疗各种病症,包括不同类型的贫血和相关于缺血/缺氧的病症。
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然而,这些化合物均没有实现市场化并且基于对这样的化合物的显著未满足的医疗需求(基于如以上所讨论的它们的潜在的有益效果),有必要确定可以作为脯氨酰羟化酶抑制剂的另外的化合物。在本文中我们披露了新型化合物,其预期作为这样的抑制剂。
发明内容
本发明披露了如由通式(I)定义的新型化合物,其抑制HIF羟化酶,从而增加缺氧诱导因子(hypoxia inducible factor,HIF)的稳定性和/或活性,因而可用于其中缺血、缺氧和/或贫血发挥作用的任何疾病状态。
具体实施方式
本发明的主要目的是提供由通式(I)表示的新型取代的化合物、它们的互变异构形式、它们的立体异构体、它们的药用盐、以及含有它们或它们的适当的混合物的药物组合物。
在本发明的一种实施方式中,提供了方法,用于制备由通式(I)表示的新型化合物、它们的互变异构形式、它们的立体异构体、它们的药用盐。
在本发明的另一种实施方式中,提供了药物组合物,该组合物包含通式(I)的化合物、它们的互变异构形式、它们的立体异构体、它们的药用盐、或它们结合适宜的载体、溶剂、稀释剂和通常用于制备这类组合物的其它介质的混合物。
在又一种实施方式中,提供了本发明的化合物或它们的适宜的药用盐在药品中使用的应用。
本发明的描述
因此,本发明涉及通式(I)的化合物,
其中
R1表示氢、可选取代的(C1-C10)烷基、(C2-C10)链烯基((C2-C10)alkenyl)、 (C2-C10)炔基、(C3-C8)环烷基、(C5-C8)环烯基、芳基、杂芳基、杂环基、芳烷基、环烷基烷基(cycloalkanylalkyl)、杂芳烷基、杂环烷基;
R2表示氢、可选取代的烷基、环烷基、芳基、杂芳基、杂环基和酰基;
R3和R4各自独立地表示氢、可选取代的烷基、环烷基、芳基、杂环基、杂芳基;或R3和R4与它们所连接的碳原子一起形成环烷基、或杂环基,其中杂环基可以进一步包含选自O、N和S的一个或多个杂原子;
R5选自由–OR6、-COOR6、-NR7COR6和-NR7SO2R6组成的组,其中每个R6和R7在每次出现时独立地选自由氢、选自烷基、环烷基、芳基、杂环基和杂芳基的可选取代的基团组成的组;
‘A’表示5-7元饱和或不饱和的碳环或杂环体系,其中杂环可以包含选自N、O或S(O)m的一个或多个杂原子;
表示‘A’的所述环可以进一步被一个或多个取代基所取代,其中上述取代基选自由R8表示的取代基的组;
R8在每次出现时独立地表示由氢、羟基、氰基、卤基、硝基、氧基、亚氨基、卤代烷基、或可选取代的基团组成的组,上述可选取代的基团选自(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C8)环烷基、(C5-C8)环烯基、芳基、杂环基、杂芳基、芳烷基、杂环烷基、烷基磺酰氧基、-COR9、 -C(O)COR9、-COOR9、-OR9、-S(O)mR9、-NR9R10、-CONR9R10、-N(R9)COR10、 -N(R9)COOR10、-NR9NR10COR9、-OCH2COR9、-N(R9)CH2COR10、 -N(R9)C(O)COR10、-C(O)CONR9R10、-OCONR9R10、-N(R9)CONR9R10、 -P(O)(OR10)2、-SO2NR9R10、-N(R9)SO2R10衍生物,其中R9和R10在每次出现时独立地表示氢、羟基、烷氧基、卤代烷基、可选取代的(C1-C10)烷基、 (C2-C10)链烯基、(C2-C10)炔基、(C3-C8)环烷基、(C5-C8)环烯基、可选取代的氨基、芳基、杂芳基、杂环基、芳烷基、杂环烷基,前提是,任何取代并不形成任何S-S或O-O键;或在可行情况下,R9和R10与它们所连接的原子一起可以形成可选地包含0-2个另外的杂原子的5-8元环,上述杂原子选自–O-、-NR7-和S(O)m-,其中R7是如先前所定义;
当R1或R8的任何一种被进一步取代时,取代基可以选自氢、羟基、氰基、卤基、硝基、氧基、亚氨基、卤代烷基、(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C8)环烷基、(C5-C8)环烯基、芳基、杂环基、杂芳基、芳烷基、杂环烷基、烷基磺酰氧基、-COR9、-C(O)COR9、-COOR9、 -OR9、-S(O)mR9、-NR9R10、-CONR9R10、-N(R9)COR10、-N(R9)COOR10、 -NR9NR10COR9、-OCH2COR9、-N(R9)CH2COR10、-N(R9)C(O)COR10、-C(O)CONR9R10、-OCONR9R10、-N(R9)CONR9R10、-P(O)(OR10)2、 -SO2NR9R10、-N(R9)SO2R10衍生物;
其中每个R9和R10是如先前所定义;
‘m’表示0-2的整数以及‘n’表示1-6的整数。
在一种实施方式中,如在本文中以前使用的,(C1-C10)烷基链可以进一步可选地包含选自O、S或N的1-4个杂原子或基团NRaRb、S(O)m、羰基或亚氨基羰基(-C=NH);其中RaRb的任何一种独立地选自H、(C1-C10) 烷基、(C3-C10)环烷基,前提是,形成的烷基链并不包括S-S或O-O键;
进一步优选的实施方式是下文披露的那些实施方式。
优选的R1可以选自(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C8) 环烷基、环烷基烷基、芳基、杂芳基、杂环基、芳烷基、杂环烷基;
在R1上的优选的取代基可以选自氢、羟基、氰基、卤基、硝基、氧基、亚氨基、卤代烷基、(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C8) 环烷基、芳基、杂环基、杂芳基、芳烷基、杂环烷基、-COR9、-C(O)COR9、 -COOR9、-OR9、-S(O)mR9、-NR9R10、-CONR9R10、-N(R9)COR10、-N(R9)COOR10、-NR9NR10COR9、-OCH2COR9、-N(R9)CH2COR10、 -N(R9)CONR9R10、-P(O)(OR10)2、-SO2NR9R10、-N(R9)SO2R10衍生物;
其中每个R9和R10是如先前所定义;
优选的R2可以选自氢、可选取代的烷基、环烷基和酰基;
优选的R3和R4可以选自氢、可选取代的烷基、环烷基,或R3和R4与它们所连接的碳原子一起形成环烷基、或杂环;
优选的R5可以选自由–OR6、-NR7COR6和-NR7SO2R6组成的组;优选的R6和R7可以独立地选自由氢、可选取代的烷基、环烷基和杂环基组成的组;
优选的R8可以选自由氢、羟基、氰基、卤基、卤代烷基、(C1-C10)烷基、(C2-C10)链烯基、(C2-C10)炔基、(C3-C8)环烷基、芳基、杂环基、杂芳基、芳烷基、杂环烷基、-COR9、-COOR9、-OR9、-S(O)mR9、-NR9R10、 -CONR9R10、-N(R9)COR10、-N(R9)COOR10、-OCH2COR9、-N(R9)CH2COR10、 -N(R9)CONR9R10、-SO2NR9R10、-N(R9)SO2R10衍生物组成的组;
优选的R9和R10可以选自氢、羟基、烷氧基、卤代烷基、可选取代的 (C1-C10)烷基、(C2-C10)炔基、(C3-C8)环烷基、可选取代的氨基、芳基、杂芳基、杂环基、芳烷基、杂环烷基,
在进一步的实施方式中,上述基团、自由基可以选自:
-单独或连同其它基团一起使用的“烷基”是指包含一至六个碳(原子)的直链或支链基团,选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、叔戊基、正戊基、正己基等;
-单独或连同其它基团一起使用的“链烯基(alkenyl)”选自包含2至6 个碳原子的基团,更优选这样的基团,其选自乙烯基、烯丙基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基等;“链烯基”包括直链和支链的二烯和三烯;
-单独或连同其它基团一起使用的“炔基”选自包含2至6个碳原子的直链或支链基团,更优选噻吩基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-己炔基等。术语“炔基”包括二炔和三炔;
-单独或连同其它基团一起使用的“环烷基”、或“脂环族”选自包含3 至6个碳原子的环状基团,更优选环丙基、环丁基、环戊基、环己基等;
-单独或连同其它基团一起使用的“环烯基”优选选自环丙烯基、1-环丁烯基、2-环丁烯基、1-环戊烯基、2-环戊烯基、3-环戊烯基、1-环己烯基、 2-环己烯基、3-环己烯基等;
-单独或连同其它基团一起使用的“烷氧基”选自这样的基团,其包含如上文所定义的烷基直接连接于氧原子,更优选这样的基团,其选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、异丁氧基、戊氧基、己氧基等;
-“卤代烷基”选自如上文所定义的烷基,适当地被一个或多个卤素取代;如氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基、单或多卤基取代的甲基、乙基、丙基、丁基、戊基或己基;
-单独或连同其它基团一起使用的“芳基”或“芳族”基团选自适当的芳族体系,其包含一个、两个或三个环,其中上述环可以以侧挂方式被连接在一起或可以被稠合,更优选基团选自苯基、萘基、四氢萘基、茚满 (indane)、联苯基等;
-单独或连同其它基团一起使用的“杂环基”或“杂环”基因选自适宜的芳族或非芳族基团,其包含选自O、N或S的一个或多个杂原子。非芳族基团可以是饱和的、部分饱和的或不饱和的单、双或三环基团,其包含选自氮、硫和氧的一个或多个杂原子,更优选选自吖丙啶基、氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、哌嗪基、2-氧哌啶基、4-氧哌啶基、 2-氧哌嗪基、3-氧哌嗪基、吗啉基、硫代吗啉基、2-氧吗啉基、氮杂基、二氮杂基、硫氮杂基(oxapinyl)、硫氮杂基(thiazepinyl)、噁唑烷基、噻唑烷基、二氢噻吩、二氢吡喃、二氢呋喃、二氢噻唑、苯并吡喃基、苯并吡喃酮基、苯并二氢呋喃基、苯并二氢噻吩基、吡唑并嘧啶酮基、氮杂喹唑啉酮基(azaquinazolinoyl)、噻吩并嘧啶酮基、喹唑酮基、嘧啶酮基、苯并噁嗪基、苯并噁嗪酮基、苯并噻嗪基、苯并噻嗪酮基、噻吩并哌啶基等;芳族基团可以选自适当的单个或稠合的单、双或三环芳族杂环基团,其包含选自O、N或S的一个或多个杂原子,更优选地基团选自吡啶基、噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、异噻唑基、咪唑基、异噁唑基、噁二唑基、噻二唑基、***基、四唑基、苯并呋喃基、苯并噻吩基、二氢吲哚基、吲哚基、氮杂吲哚基、氮杂二氢吲哚基、吡唑并嘧啶基、氮杂喹唑啉基、吡啶并呋喃基、吡啶并噻吩基、噻吩并嘧啶基、喹啉基、嘧啶基、吡唑基、喹唑啉基、哒嗪基、三嗪基、苯并咪唑基、苯并***基、 2,3-二氮杂萘基(phthalazynil)、1,5-二氮杂萘基(naphthylidinyl)、嘌呤基、咔唑基、吩噻嗪基、吩噁嗪基、苯并噁唑基、苯并噻唑基等;
-在一种实施方式中,杂环基团,只要适用,可以由适当数目的碳原子组成并且包括选自由N、O、和S(O)m(m=0-2)组成的组的1-4个杂原子(如上文所定义的),其中杂环基团可以进一步被1-2个羰基或1-2个亚氨基羰基或选自如前面所定义的R8的一个或多个基团所取代;
-如在本文中所使用的,"碳环"或"碳环残基"是指任何稳定的单环或双环或三环,其中任一种可以是饱和的、部分不饱和的、或芳族的。上述碳环的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、金刚烷基、环辛基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(萘烷)、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、或四氢萘基(四氢萘);
-单独或连同其它基团一起使用的“杂芳基”或“杂芳族”基团选自适当的单个或稠合的单、双或三环芳族杂环基团,其包含选自O、N或S的一个或多个杂原子,更优选地上述基团选自吡啶基、噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、异噻唑基、咪唑基、异噁唑基、噁二唑基、噻二唑基、***基、四唑基、苯并呋喃基、苯并噻吩基、二氢吲哚基、吲哚基、氮杂吲哚基、氮杂二氢吲哚基、吡唑并嘧啶基、氮杂喹唑啉基、吡啶并呋喃基、吡啶并噻吩基、噻吩并嘧啶基、喹啉基、嘧啶基、吡唑基、喹唑啉基、哒嗪基、三嗪基、苯并咪唑基、苯并***基、2,3-二氮杂萘基、1,5- 二氮杂萘基、嘌呤基、咔唑基、吩噻嗪基、吩噁嗪基、苯并噁唑基、苯并噻唑基等;
-单独或连同其它基团一起使用的“酰基”选自包含1至8个碳原子的基团,更优选地选自甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、己酰基、庚酰基、苯甲酰基等,其可以被取代;
-单独或连同其它基团一起使用的“芳烷基”选自这样的基团,其包含如上文所定义的芳基直接连接于如上文所定义的烷基,更优选这样的基团,其选自苄基、苯乙基等;
-单独或连同其它基团一起使用的“杂环烷基”选自这样的基团,其包含如上文所定义的杂环基直接连接于如上文所定义的烷基;
-单独或连同其它基团一起使用的“环烷基烷基”选自这样的基团,其包含如上文所定义的环烷基直接连接于如上文所定义的烷基;
-单独或连同其它基团一起使用的“杂芳烷基”选自这样的基团,其包含如上文所定义的杂芳基直接连接于如上文所定义的烷基;
-单独(-C=O-)或连同其它基团(如上述烷基,例如“烷基羰基”)一起使用的“氧基”或“羰基”是指被上述烷基取代的羰基(–C=O-)如酰基或烷酰基;
-单独或组合使用的“烷基磺酰氧基”是指直接连接于氧原子的烷基磺酰基,其中如上文所定义的适宜的烷基连接于磺酰基;
-单独或连同其它基团一起使用的“单取代氨基”表示被一个基团取代的氨基,上述基团选自(C1-C6)烷基、取代的烷基、芳基、取代的芳基或芳烷基(如前面所定义的),更优选地上述基团选自甲胺、乙胺、正丙胺、正丁胺、正戊胺等;
-单独或连同其它基团一起使用的‘二取代的氨基”表示被两个基团取代的氨基,上述基团可以是相同或不同的并选自(C1-C6)烷基、取代的烷基、芳基、取代的芳基、或芳烷基(如上文所定义的),更优选地上述基团选自二甲基氨基、甲基乙基氨基、二乙基氨基、苯基甲基氨基等;
适宜的基团和在基团上的取代基可以选自在本说明书的任何地方描述的那些基团和取代基。
按照本发明的优选的化合物包括但不限于:
2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
1-(环丙基甲氧基)-4-羟基-N-(2-(甲基亚磺酰氨基)-2-氧乙基)-2-氧-1,2- 二氢喹啉-3-甲酰胺;
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢-1,8-二氮杂萘-3- 甲酰胺基)乙酸;
2-(1,4-二羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-((2-(三氟甲基)噻唑-4-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-(烯丙氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基) 乙酸;
2-(4-羟基-1-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-((2-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-(吡啶-2-基甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-7-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(7-氯-4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-7-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(7-氯-1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((3,5-二甲基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((4-氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((4-氰基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-1-异丙氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((2-氰基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸;
2-(4-羟基-1-异丁氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-6-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(1-(烯丙氧基)-6-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-5-氟-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,6-二氮杂萘-3-甲酰胺基) 乙酸;
2-(1-(烯丙氧基)-4-羟基-6-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-6-甲氧基-2-氧-1-(丙-2-炔-1-氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(5-(环丙基甲氧基)-8-羟基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7-甲酰胺基)乙酸;
2-(5-((2,6-二氟苄基)氧基)-8-羟基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7- 甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-(戊烷-3-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-(烯丙氧基)-7-羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-3-甲基-5-氧-4-丙氧基-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(4,7-二羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(4-((2,6-二氟苄基)氧基)-7-羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b] 吡啶-6-甲酰胺基)乙酸;
2-(4-羟基-1-(2-(甲硫基)乙氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环己基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸;
2-(8-((2,6-二氟苄基)氧基)-5-羟基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-6- 甲酰胺基)乙酸;
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-苯乙酸;
2-(1-(烯丙氧基)-4-羟基-7-吗啉代-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸叔丁酯;
2-(7-氯-1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环戊基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环戊氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸甲酯;
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-4-甲基戊酸;
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-3-甲基丁酸;
3-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸;
2-(1-(烯丙氧基)-4-羟基-2-氧-7-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-3-苯基丙酸;
(S)-4-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-羟基丁酸;
5-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)戊酸;
2-(4-羟基-2-氧-1-(丙-2-炔-1-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((2-氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-乙氧基-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-((4-(三氟甲氧基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((2,4-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸;
2-(4-羟基-1-((4-甲氧基苄基)氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-(2,2,2-三氟乙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,7-二氮杂萘-3-甲酰胺基) 乙酸;
2-(6-氰基-1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(8-(苄氧基)-5-羟基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-6-甲酰胺基)乙酸;
(S)-2-(4-羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)丙酸;
2-(4-羟基-1-(2-甲氧基乙氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-6-苯氧基-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((4-环丙基丁-3-烯-1-基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(庚-4-基氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸乙酯;
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(1-(庚氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-((6-(三氟甲基)吡啶-3-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯乙氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯乙氧基)-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸;
2-(1-(丁-2-炔-1-基氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-(3,3,3-三氟丙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(2-氨基-2-氧乙氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苯并[d]噁唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(1-(苯并[d]噻唑-2-基甲氧基)-6-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-8-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-乙氧基-4-羟基-8-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-1-(噁唑-2-基甲氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-6-氰基-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(烯丙氧基)-4-羟基-6-硝基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-1-甲氧基-2-氧-6-(三氟甲基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4,6-二羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-((4-(叔丁基)苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-([1,1'-联苯基]-4-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-1-((4-(噁唑-2-基)苄基)氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-(吡啶-2-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-(苯硫基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-6-(甲基磺酰基)-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-6-(4-甲氧基苯基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-6-(5-甲氧基吡啶-2-基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-氨磺酰-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-6-(甲基亚磺酰氨基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-6-(三氟甲氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸;
2-(6-苯甲酰基-4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉 -3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-N-甲基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-甲基丙酸;
1-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)环丙烷羧酸;
3-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸;
1-(苄氧基)-4-羟基-N-(2-(甲基亚磺酰氨基)-2-氧乙基)-2-氧-1,2-二氢喹啉-3-甲酰胺;
1-(苄氧基)-4-羟基-2-氧-N-(2-氧-2-(噻吩-2-甲酰胺基)乙基)-1,2-二氢喹啉-3-甲酰胺;
2-(4-羟基-1-甲氧基-2-氧-1,2-二氢-1,5-二氮杂萘-3-甲酰胺基)乙酸;
2-(8-羟基-5-甲氧基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7-甲酰胺基)乙酸;
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-4-甲氧基-1-甲基-5-氧-4,5-二氢-1H-吡咯并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-1-甲基-5-氧-4-丙氧基-4,5-二氢-1H-吡咯并[3,2-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噻唑并[4,5-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢噻唑并[5,4-b]吡啶-6-甲酰胺基)乙酸;
2-(4-羟基-7-甲氧基-1-甲基-6-氧-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸;
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噁唑并[4,5-b]吡啶-6-甲酰胺基)乙酸;
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢噁唑并[4,5-b]吡啶-6-甲酰胺基)乙酸;
2-(4-羟基-1-甲氧基-2-氧-1,2,5,7-四氢噻吩并[3,4-b]吡啶-3-甲酰胺基) 乙酸;
2-(7-乙氧基-4-羟基-6-氧-6,7-二氢噻吩并[2,3-b]吡啶-5-甲酰胺基)乙酸;
2-(7-(环丙基甲氧基)-4-羟基-6-氧-6,7-二氢噻吩并[2,3-b]吡啶-5-甲酰胺基)乙酸;
2-(4-羟基-1-甲氧基-6,6-二环氧-2-氧-1,2,5,7-四氢噻吩并[3,4-b]吡啶-3-甲酰胺基)乙酸;
2-(7-乙氧基-4-羟基-1-甲基-6-氧-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸;
2-(7-乙氧基-4-羟基-6-氧-1-苯基-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸;
2-(7-乙氧基-4-羟基-3-甲基-6-氧-6,7-二氢异噻唑并[5,4-b]吡啶-5-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-(2-(2-氧噁唑烷-3-基)乙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2,5,6,7,8-六氢喹啉-3-甲酰胺基)乙酸;
2-(4-羟基-2-氧-1-丙氧基-1,2,5,6,7,8-六氢喹啉-3-甲酰胺基)乙酸;
可以通过使用适宜的赋形剂和配制剂(formulating agent)(如在本领域中已知的)来配制本发明的化合物。这样的制剂将取决于给予的途径、剂量并且还取决于患者情况(patient profile)。基于这些和其它因素(其需要在心里考虑以保持患者的最佳利益),技术人员能够很好地配制本发明的化合物。
利用如在以下方案中所示的和在本节中描述的反应和技术,可以制备本发明的新型化合物。反应是在适于所采用的试剂和材料的溶剂中进行并且适用于被影响的转化。本领域技术人员应该理解的是,为了优化本发明的化合物的形成的目的,可以变化提出的合成步骤的特性和顺序。还应当很好理解的是,为简便合成,通过本领域技术人员已知的技术,可以保护和去保护一种或多种反应物。还应当理解的是,本发明的一种或多种化合物可以以立体异构体和/或非对映形式存在。这样的立体异构体和/或非对映体以及它们的旋光对映体应当被解释为是在本发明的范围内。还应当很好理解的是,基于在化合物上存在的特定基团,可以将这些化合物的一种或多种转化为它们的盐和其它衍生物,其可以由本领域技术人员很好理解。上述盐和/或其它衍生物(根据具体情况而定)还应当被解释为是在本发明的范围内。
方案1:通式(I)的化合物的合成
其中‘X’表示适宜的离去基团如卤素、甲磺酰基(mesyl)等。R’表示适宜的烷基或芳烷基如甲基、乙基、正丁基、苄基等。
可以利用在文献中描述的一般技术,通过化合物(II)的硝基的部分还原,来获得化合物(III)。优选的方法涉及在酸存在下利用金属的还原。最优选的技术涉及在存在温和酸性环境的条件下利用Zn金属的还原,其中上述温和酸性环境是由在溶剂如醇、THF、乙腈、水等中的NH4Cl或用在 THF:CH3OH的溶剂混合物中的氯化亚锡二水合物和乙酸钠三水合物加以处理来提供。用于反应的优选的温度为0℃至60℃。
通过(III)的烷基化,通过化学式R1-X的适当的试剂,其中R1和‘X’是如先前所定义,利用在文献中报道的各种技术,可以获得通式(V)的化合物。最优选的技术涉及在存在碱的条件下的烷基化,其中上述碱是如在质子溶剂如醇和非质子溶剂如THF、乙腈、DMF等中的碳酸钠、碳酸钾、碳酸铯、氢化钠等。
可替换地,还可以通过用O-取代的羟基胺衍生物(NH2OR1)直接置换来自通式(IV)的化合物的离去基团‘X’来获得通式(V)的化合物。置换技术涉及在存在或不存在溶剂如二氧杂环己烷(dioxane)、DMF、甲苯等的条件下,在存在或不存在有机碱如TEA、DIPEA等的条件下,(IV)与NH2OR1的反应。反应温度为25℃至150℃。
可以利用在文献中报道的用于酰基氯偶联的各种技术,通过(V)和乙基丙二酰氯(ethyl malonyl chloride)反应,来获得通式(VI)的化合物。优选的技术涉及使用在溶剂如DCM、EDC等中的有机碱如TEA、DIPEA、吡啶等的反应。还可以在存在或不存在溶剂如DCM、EDC、CH3CN等的条件下,在0-25℃下,利用POCl3-吡啶偶联方法,通过(V)和丙二酸乙氢酯(丙二酸单乙酯,ethyl hydrogen malonate)反应,来制备通式(VI)的化合物。
可以通过(VI)的环化来获得化学式(VII)的化合物,其中使用在溶剂如甲醇、乙醇、叔丁醇等中的强碱如金属醇盐(NaOCH3、NaOC2H5、叔丁醇钾等)。优选的温度为0-40℃。
可以利用在文献中报道的各种技术,通过用适宜的胺衍生物(VIII)来酰胺化(VII)以获得通式(I)的化合物。优选的方法涉及在存在或不存在有机碱如TEA、DIPEA等的条件下以及在存在或不存在溶剂如二氧杂环己烷、甲苯、二甲苯等的条件下加热(VII)和(VIII)。当(VIII)表示氨基酸衍生物时,优选的方法采用等摩尔碱如甲醇钠(相对于氨基酸衍生物)和溶剂如二氧杂环己烷、甲苯等。可替换地,利用上述方法,接着利用在溶剂如水、THF、甲醇或它们的混合物中的强碱如NaOH、KOH等来水解酯基团,氨基酸的酯衍生物可以偶联(VII)。
通过以下给出的实施例来更详细地说明本发明,其中这些实施例仅通过说明的方式加以提供,因此不应被解释为限制本发明的范围。
在实施例(见下文)中给出的1H NMR光谱数据是利用400MHz分光仪 (BrukerTopspin 2.0)所记录并以δ尺度为单位加以报告。四甲基硅烷用作内部标准物。
实施例1
2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
步骤1:2-(羟基氨基)苯甲酸乙酯的制备
在0℃下,向2-硝基苯甲酸乙酯(32.0g,0.164mol)、氯化铵(22.28g, 0.416mol)在水(240mL)和THF(288mL)的溶剂混合物中的搅拌溶液缓慢地添加锌粉(26.8g,0.410mol)。在0℃-10℃下搅拌反应混合物2小时。然后用水接着用DCM稀释反应混合物,并通过Hyflow床加以过滤。分离和蒸馏出有机层以得到粗产物,利用在己烷中的0-5%EtOAC对其加以柱纯化,以得到作为淡黄色固体的标题化合物,产率为50%。
1HNMR(DMSO-d6):1.30(t,J=7Hz,3H),4.24-4.30(q,J=7.2Hz,2H), 6.77-6.81(m,1H),7.25-7.27(dd,J=0.4和7.6Hz,1H),7.46-7.50(m,1H), 7.78-7.780(dd,J=1.6和8.0Hz,1H),8.88(d,J=1.6Hz,1H),9.16(s,1H)。
步骤2:2-(苄氧基氨基)苯甲酸乙酯的制备
在RT下,向苄基溴(1.038g,6.07mmol)和碳酸铯(2.70g,8.28mmol) 在DMF(4mL)中的搅拌悬浮液添加溶解在2mL DMF中的2-(羟基氨基) 苯甲酸乙酯(1.0g,5.52mmol)并搅拌1小时。用水稀释反应混合物并用 EtOAC提取。分离和蒸馏出有机层以得到粗产物,利用在己烷中的0-3% EtOAC对其加以柱纯化,以得到标题化合物,产率为72%。
1HNMR(DMSO-d6):1.28(t,J=7.2Hz,3H),4.22-4.27(q,J=7.2Hz, 2H),4.89(s,2H),6.86-6.90(m,1H),7.27(d,J=8.4Hz,1H),7.36-7.43(m, 3H),7.45-7.48(dd,J=1.6和8.0Hz,2H),7.50-7.54(m,1H),7.81-7.83(dd,J =1.6和8.0Hz,1H),9.76(s,1H)。
步骤3:2-(N-(苄氧基)-3-乙氧基-3-氧丙酰氨基)苯甲酸乙酯的制备
向丙二酸乙氢酯(0.6g,4.54mmol)和2-(苄氧基氨基)苯甲酸乙酯(1.12 g,4.13mmol)在乙腈(10mL)中的搅拌溶液添加吡啶(1.3g,16.51mmol),然后将反应混合物冷却至0-10℃。在0-10℃下,在15-30分钟内,向其添加 POCl3(0.423mL,4.54mmol),然后继续搅拌1小时。用DCM稀释反应混合物并用水洗涤。分离和蒸馏出有机层以得到粗产物,利用在己烷中的 15%EtOAC对其加以柱纯化,以得到标题化合物,产率为79%。
1HNMR(DMSO-d6):1.14(t,J=7.2Hz,3H),1.25(t,J=7.2Hz,3H), 3.69(s,2H),4.05-4.10(q,J=7.0Hz,2H),4.19-4.24(q,J=7.2Hz,2H),4.88 (s,2H),7.36(m,5H),7.46-7.51(m,2H),7.66-7.70(m,1H),7.77(d,J=7.2Hz, 1H)。
步骤4:1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-羧酸乙酯的制备
在20-25℃下,向2-(N-(苄氧基)-3-乙氧基-3-氧丙酰氨基)苯甲酸乙酯 (1.3g,3.37mmol)在MeOH(10mL)中的搅拌溶液缓慢地添加甲醇钠(0.255 g,4.72mmol)。搅拌反应混合物1小时。蒸馏出过量甲醇,然后用NH4Cl 溶液稀释反应混合物。过滤和干燥沉淀产物以得到标题化合物,产率为 58%。
1HNMR(DMSO-d6):1.31(t,J=7.0Hz,3H),4.26-4.31(q,J=7.0Hz, 2H),5.11(s,2H),7.24(d,J=8.0Hz,1H),7.41-7.49(m,4H),7.60-7.62(dd,J =1.6和7.6Hz,2H),7.66(d,J=7.2Hz,1H)8.01-8.04(dd,J=1.2和8.0Hz, 1H)。
步骤5:2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸乙酯的制备
向1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-羧酸乙酯(700mg,2.063 mmol)、2-氨基乙酸乙酯盐酸盐(387mg,2.77mmol)在二氧杂环己烷(5mL) 中的搅拌悬浮液添加DIPEA(0.660ml,3.78mmol)。在100℃下加热反应混合物12小时。从反应混合物蒸馏出溶剂以得到粗产物,利用在己烷中的 15%EtOAC对其加以柱纯化,以得到标题产物,产率为37%。
1HNMR(DMSO-d6):1.23(t,J=7.2Hz,3H),4.14-4.20(q,J=7.2Hz, 2H),4.23(d,J=5.6Hz,2H),5.22(s,2H),7.40-7.47(m,4H),7.63-7.67(m, 3H),7.84-7.88(m,1H),8.10-8.12(dd,J=1.2和8.0Hz,1H),10.33(t,J=5.8 Hz,1H)。
步骤6:2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
向2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸乙酯(500 mg,1.261mmol)在THF(5mL)中的搅拌溶液添加氢氧化钠(126mg,3.15 mmol)在水(5mL)中的溶液,然后在25-30℃下搅拌2小时。蒸馏出有机溶剂,接着添加冰冷水。然后利用稀盐酸将反应混合物酸化直到pH-2-3。过滤沉淀固体以得到标题化合物,产率为80%。
1HNMR(DMSO-d6):4.17(d,J=6Hz,2H),5.22(s,2H),7.39-7.46(m, 4H),7.63-7.66(m,3H),7.83-7.85(dd,J=2和7.6Hz,1H),8.10-8.13(dd,J= 1.2和8Hz,1H),10.29(t,1H)。
实施例2
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
步骤1:(碘甲基)环丙烷的制备
向环丙基甲醇(30g,0.416mol)在溶剂丙酮(60mL)中的搅拌溶液添加甲磺酰氯(35.7ml,0.46mol),然后将反应混合物冷却至-15至-20℃。在-15 至-20℃下在2小时内,向其添加TEA(63.8ml,0.46mol)在丙酮(60mL)中的溶液,然后继续搅拌另外的1小时。过滤沉淀盐。用丙酮(600mL)稀释滤液并转移到另一个烧瓶。在RT下向其添加碘化钠(68.6g,0.46mol)并回流5小时。用水稀释反应混合物并用己烷提取(萃取)。用硫代硫酸钠洗涤有机层,分离并蒸馏出,以得到作为黄色液体的标题化合物,产率为 66%。
1HNMR(CDCl3):0.29-0.31(m,2H),0.79-0.83(m,2H),1.29-1.33(m, 1H),3.11(d,J=7.6Hz,2H)。
步骤2:2-(羟基氨基)苯甲酸乙酯的制备
在10-20℃下,向2-硝基苯甲酸乙酯(1.0g,5.12mmol)、乙酸钠三水合物(4.18g,30.7mmol)在MeOH(7ml)和THF(7ml)的溶剂混合物中的搅拌溶液缓慢地添加氯化亚锡二水合物(3.47g,15.37mmol)。在25-30℃下搅拌反应混合物16小时。用水稀释反应混合物并用碳酸氢钠水溶液加以碱化。用乙酸乙酯提取产物。分离和蒸馏出有机层以得到粗产物,用己烷对其加以搅拌以得到白色固体,产率为80%。
步骤3:2-((环丙基甲氧基)氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用上述步骤1的产物和2-(羟基氨基)苯甲酸乙酯来制备标题化合物,产率为50%。
1HNMR(DMSO-d6):0.31(m,2H),0.52-0.56(m,2H),1.10-1.17(m,1H), 3.31(t,J=7.0Hz,3H),3.67(d,J=6.8Hz,2H),4.25-4.30(q,J=7.0Hz,2H), 6.86(t,J=7.6Hz,1H),7.25(d,J=8.0Hz,1H),7.49-7.53(m,1H),7.81-7.83 (dd,J=1.6和8.0Hz,1H)9.27(s,1H)。
步骤4:2-(N-(环丙基甲氧基)-3-乙氧基-3-氧丙酰氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤3的产物来制备标题化合物,产率为85%。
1HNMR(DMSO-d6):0.22-0.25(m,2H),0.45-0.50(m,2H),1.01-1.07(m, 1H),1.16-1.27(m,6H),3.66(d,J=7.6Hz,2H),3.70(s,2H),4.10-4.15(q,J =7.0Hz,2H),4.18-4.23(q,J=7.2Hz,2H),7.42-7.48(m,2H),7.64-7.67(m, 1H),7.72(d,J=7.6Hz,1H)。
步骤5:1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤4的产物来制备标题化合物,产率为75%。
1HNMR(DMSO-d6):0.32-0.40(m,2H),0.45-0.50(m,2H),1.22-1.28(m, 1H),1.31(t,J=7.0Hz,3H),3.96(d,J=7.2Hz,2H),4.31-4.37(q,J=7.0Hz, 2H),7.31-7.35(m,1H),7.61(d,J=8.0Hz,1H)7.78-7.82(m,1H),8.05-8.07 (dd,J=1.2和8.0Hz,1H)。
步骤6:2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤5的产物来制备标题化合物,产率为70%。
1HNMR(DMSO-d6):0.39(m,2H),0.56-0.61(m,2H),1.21(t,J=7.0Hz, 3H),1.25-1.30(m,1H),4.03(d,J=7.6Hz,2H),4.12-4.18(q,J=7.2Hz,2H), 4.19(d,J=5.6Hz,2H)7.39-7.43(m,1H),7.70(d,J=8.0Hz,1H),7.85-7.89 (m,1H),8.08-8.11(dd,J=1.2和8.0Hz,1H),10.27(t,J=5.6Hz,1H)。
步骤7:2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为90%。
1H NMR(DMSO-d6):0.38-0.40(m,2H),0.57-0.61(m,2H),1.27-1.30 (m,1H),4.04(d,J=7.6Hz,2H),4.12(d,J=5.2Hz,2H),7.39-7.43(m,1H), 7.70(d,J=8.0Hz,1H),7.85-7.89(m,1H),8.09-8.11(dd,J=1.2和8.0Hz, 1H),10.25(t,J=5.4Hz,1H),12.98(bs,1H)。
实施例3
1-(环丙基甲氧基)-4-羟基-N-(2-(甲基亚磺酰氨基)-2-氧乙基)-2-氧-1,2- 二氢喹啉-3-甲酰胺的制备
向实施例-2的产物(600mg,1.806mmol)在DMF(6mL)中的搅拌溶液添加甲磺酰胺(206mg,2.167mmol)、DMAP(110mg,0.903mmol)、4-乙基吗啉(624mg,5.42mmol)和EDCI.HCl(415mg,2.167mmol)。在RT下搅拌反应混合物16小时。用水稀释反应混合物并用EtOAC提取。分离和蒸馏出有机层以得到粗产物,通过制备性HPLC技术对其加以纯化以得到标题化合物,产率为41%。
1H NMR(DMSO-d6):0.37-0.40(m,2H),0.57-0.61(m,2H),1.27-1.30 (m,1H),3.27(s,3H),4.04(d,J=7.2Hz,2H),4.19(d,J=5.6Hz,2H), 7.39-7.43(m,1H),7.71(d,J=8.4Hz,1H),7.85-7.90(m,1H),8.09(dd,J= 1.2和8.0Hz,1H),10.28(t,J=5.6Hz,1H),12.06(bs,1H).ESI/MS m/z 410 (M+H)+。
实施例4
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢-1,8-二氮杂萘-3- 甲酰胺基)乙酸的制备
步骤1:2-((4-(三氟甲基)苄基)氧基)异吲哚啉-1,3-二酮的制备
在RT下向N-羟基邻苯二酰胺(5.25g,32.3mmol)在DMF(30mL)中的搅拌溶液添加碳酸铯(15.80g,48.5mmol)和1-(溴甲基)-4-(三氟甲基)苯(5 ml,32.3mmol)。搅拌反应混合物3小时,然后用水稀释。过滤并干燥沉淀产物以得到标题化合物,产率为87%。
1H NMR(DMSO-d6):5.28(s,2H),7.75-7.80(m,4H),7.87(m,4H)。
步骤2:O-(4-(三氟甲基)苄基)羟基胺的制备
在RT下向2-((4-(三氟甲基)苄基)氧基)异吲哚啉-1,3-二酮(9g,28.0 mmol)在乙醇(90mL)中的搅拌溶液添加水合肼(1.543g,30.8mmol)。搅拌反应混合物16小时。过滤反应混合物,用水稀释滤液,然后用EtOAC提取。分离和蒸馏出有机层以得到标题化合物,产率为68%。
1H NMR(DMSO-d6):4.65(s,2H),6.17(s,2H),7.53(d,J=8.0Hz,2H), 7.69(d,J=8.0Hz,2H)。
步骤3:2-(((4-(三氟甲基)苄基)氧基)氨基)烟酸乙酯的制备
在120℃下加热2-氯烟酸乙酯(1.4g,7.54mmol)和O-(4-(三氟甲基)苄基)羟基胺(2.163g,11.31mmol)的混合物6小时。用水稀释反应混合物并用EtOAC提取。分离和蒸馏出有机层以得到粗产物,利用在己烷中的 15-20%EtOAc对其加以柱纯化,以得到标题化合物,产率为41%。
1HNMR(DMSO-d6):1.27(t,J=7.2Hz,3H),4.23-4.28(q,J=7.0Hz, 2H),5.09(s,2H),6.93-6.96(dd,J=4.8和7.6Hz,1H),7.67-7.76(m,4H), 8.13-8.16(dd,J=1.6和7.6Hz,1H),8.47-8.48(dd,J=1.6和7.6Hz,1H), 10.14(s,1H)。
步骤4:2-(3-乙氧基-3-氧-N-((4-(三氟甲基)苄基)氧基)丙酰氨基)烟酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤3的产物来制备标题化合物,产率为72%。
1HNMR(DMSO-d6):1.14(t,J=7.0Hz,3H),1.26(t,J=7.2Hz,3H), 3.72(s,2H),4.04-4.09(q,J=7.2Hz,2H),4.21-4.26(q,J=7.0Hz,2H),5.11 (s,2H),7.54-7.57(dd,J=4.8和7.6Hz,1H),7.59(d,J=7.6Hz,2H),7.71(d, J=8.0Hz,2H),8.20-8.23(dd,J=1.6和7.6Hz,1H),8.69(d,J=3.2Hz, 1H)。
步骤5:4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢-1,8-二氮杂萘-3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤4的产物来制备标题化合物,产率为65%。
1HNMR(DMSO-d6):1.22(t,J=7.0Hz,3H),4.07-4.12(q,J=7.0Hz, 2H),5.17(s,2H),7.11-7.14(dd,J=4.8和7.6Hz,1H),7.78(d,J=8.0Hz, 2H),7.89(d,J=8.0Hz,2H),8.23(d,J=6.4Hz,1H),8.48(d,J=3.2Hz, 1H)。
步骤6:2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤5的产物来制备标题化合物,产率为56%。
1HNMR(DMSO-d6):1.23(t,J=7.0Hz,3H),4.14-4.19(q,J=7.2Hz, 2H),4.22(d,J=6.0Hz,2H),5.33(s,2H),7.50-7.53(dd,J=4.8和8.0Hz, 1H),7.82(d,J=8.0Hz,2H),7.91(d,J=8.0Hz,2H),8.51-8.54(dd,J=1.6 和7.6Hz,1H),8.89-8.90(dd,J=1.6和4.8Hz,1H),10.21(t,J=5.6Hz, 1H)。
步骤7:2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为67%。
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.33(s,2H),7.49-7.52 (dd,J=4.4和7.6Hz,1H),7.82(d,J=8.4Hz,2H),7.91(d,J=8.4Hz,2H), 8.51-8.54(dd,J=2.0和8.0Hz,1H),8.89(d,J=4.4Hz,1H),10.19(bs,1H)。
实施例5
2-(1,4-二羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
向实施例-1的产物(383mg,1.261mmol)在溶剂MeOH(2mL)中的搅拌溶液添加10%Pd/C(10mg)。在RT下并在H2气氛下,搅拌反应混合物2 小时。通过Hyflow床来过滤反应混合物。蒸馏出有机层以得到作为固体的标题化合物,产率为57%。
1H NMR(DMSO-d6):4.00(d,J=5.2Hz,2H),7.35(t,J=7.6Hz,1H), 7.71(d,J=8.4Hz,1H),7.80(t,J=7.4Hz,1H),8.06(d,J=7.6Hz,1H), 10.44(bs,1H)。
实施例6
2-(1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
步骤1:2-((苯并[d]噻唑-2-基甲氧基)氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用2-(羟基氨基)苯甲酸乙酯和2-(氯甲基)苯并[d]噻唑来制备标题化合物,产率为52%。
1HNMR(DMSO-d6):1.27(t,J=7.2Hz,3H),4.22-4.28(q,J=7.0Hz, 2H),5.37(s,2H),6.95(t,J=7.6Hz,1H),7.36(d,J=8.4Hz,1H),7.45-7.49 (m,1H),7.52-7.58(m,2H),7.83-7.86(dd,J=1.6和8.0Hz,1H),8.02(d,J= 8.0Hz,1H),8.14(d,J=7.6Hz,1H),10.26(s,1H)。
步骤2:2-(N-(苯并[d]噻唑-2-基甲氧基)-3-乙氧基-3-氧丙酰氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤1的产物来制备标题化合物,产率为77%。
1HNMR(DMSO-d6):1.14(t,J=7.2Hz,3H),1.25(t,J=7.2Hz,3H), 3.84(s,2H),4.02-4.07(q,J=6.6Hz,2H),4.21-4.26(q,J=7.0Hz,2H),5.39 (s,2H),7.45-7.56(m,4H),7.66(d,J=7.2Hz,1H),7.83(d,J=7.6Hz,1H), 8.00(d,J=8.0Hz,1H),8.12(d,J=7.6Hz,1H)。
步骤3:1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤2的产物来制备标题化合物,产率为63%。ESI/MS m/z 397(M+H)+。
步骤4:2-(1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3- 甲酰胺基)乙酸叔丁酯的制备
向1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-羧酸乙酯(930mg,2.346mmol)、2-氨基乙酸叔丁酯(369mg,2.82mmol)在二氧杂环己烷(5mL)中的搅拌悬浮液添加DIPEA(410μl,2.346mmol)。在100℃下加热反应混合物12小时。从反应混合物蒸馏出溶剂以得到粗产物,利用在己烷中的15%EtOAC对其加以柱纯化,以得到标题产物,产率为43%。
1HNMR(DMSO-d6):1.44(s,9H),4.13(d,J=5.6Hz,2H),5.72(s,2H), 7.39-7.43(m,1H),7.51-7.54(m,1H),7.55-7.59(m,1H),7.68(d,J=8.4Hz, 1H),7.81-7.83(m,1H),8.06-8.08(m,1H),8.11-8.13(dd,J=1.2和8.0Hz, 1H),8.18-8.21(m,1H),10.19(t,1H)。
步骤5:2-(1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3- 甲酰胺基)乙酸的制备
在20-25℃下,向2-(1-(苯并[d]噻唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸叔丁酯(0.3g,0.623mmol)在DCM(2ml)中的搅拌溶液缓慢地添加TFA(3.36ml,43.6mmol)。搅拌反应混合物3小时。蒸馏出过量溶剂,然后用水稀释。过滤沉淀产物以得到粗产物,然后在 EtOH:EtOAC中对其加以再结晶,以得到标题产物,产率为87%。
1H NMR(DMSO-d6):4.16(d,J=5.6Hz,2H),5.72(s,2H),7.38-7.42 (m,1H),7.50-7.59(m,2H),7.68(d,J=8.4Hz,1H),7.81-7.85(m,1H), 8.08-8.11(dd,J=1.2和10.0Hz,1H),8.13(d,J=1.2Hz,1H),8.18-8.21(m, 1H),10.20(t,1H),12.96(bs,1H)。
实施例7
2-(4-羟基-2-氧-1-((2-(三氟甲基)噻唑-4-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
步骤1:2-(三氟甲基)噻唑-4-羧酸乙酯的制备
在RT下向2,2,2-三氟硫代乙酰胺(2,2,2-trifluoroethanethioamide)(0.35g,2.71mmol)在THF(12ml)中的搅拌溶液添加乙基溴丙酮酸酯(0.375ml,2.98 mmol)。在90-100℃下加热反应混合物16小时。用水和DCM稀释反应混合物。分离和蒸馏出有机层以得到粗产物,利用在己烷中的0-2%EtOAC 对其加以柱纯化,以得到标题化合物,产率为42%。
1HNMR(CDCl3):1.42(t,J=7.0Hz,3H),4.44-4.49(q,J=7.0Hz,2H), 8.38(s,1H)。
步骤2:(2-(三氟甲基)噻唑-4-基)甲醇的制备
在0-10℃下向2-(三氟甲基)噻唑-4-羧酸乙酯(1.0g,4.44mmol)在 THF(10ml)中的搅拌溶液添加LiAlH4(0.169g,4.44mmol),然后在RT下搅拌1小时。用饱和硫酸钠溶液冷却和骤冷反应混合物直到观察到沉淀物。过滤获得的沉淀物并蒸发滤液,以得到所期望的产物,产率为56%。
1HNMR(CDCl3):2.21(t,J=6.0Hz,1H),4.86(d,J=5.2Hz,2H),7.49 (s,1H)。
步骤3:4-(溴甲基)-2-(三氟甲基)噻唑的制备
在0-5℃下在5-10分钟内,向(2-(三氟甲基)噻唑-4-基)甲醇(550mg, 3.00mmol)在DCM(5ml)中的搅拌溶液添加PBr3(0.283ml,3.00mmol),然后继续搅拌1小时。用DCM稀释反应混合物并用水洗涤。分离和蒸馏出有机层以得到粗产物,利用在己烷中的0-2%EtOAC对其加以柱纯化,以得到标题化合物,产率为36%。
1HNMR(CDCl3):4.61(s,2H),7.57(s,1H)。
步骤4:2-(((2-(三氟甲基)噻唑-4-基)甲氧基)氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用2-(羟基氨基)苯甲酸乙酯和上述步骤3的产物来制备标题化合物,产率为52%。
1HNMR(DMSO-d6):1.29(t,J=7.0Hz,3H),4.23-4.28(q,J=7.0Hz, 2H),5.07(s,2H),6.89(m,1H),7.25(d,J=8.0Hz,1H),7.49(s,1H),7.81(d, J=6.8Hz,1H),8.25(s,1H),9.89(s,1H)。
步骤5:乙基2-(3-乙氧基-3-氧-N-((2-(三氟甲基)噻唑-4-基)甲氧基)丙酰氨基)苯甲酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤4的产物来制备标题化合物,产率为78%。
1HNMR(DMSO-d6):1.16(t,J=7.2Hz,3H),1.25(t,J=7.0Hz,3H), 3.72(s,2H),4.06-4.11(q,J=6.8Hz,2H),4.20-4.25(q,J=7.0Hz,2H),5.09 (s,2H),7.42-7.48(m,2H),7.62-7.66(m,1H),7.76(d,J=7.6Hz,1H),8.22(s, 1H)。
步骤6:4-羟基-2-氧-1-((2-(三氟甲基)噻唑-4-基)甲氧基)-1,2-二氢喹啉 -3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤5的产物来制备标题化合物,产率为62%。
1HNMR(DMSO-d6):1.21(t,J=7.0Hz,3H),4.03-4.08(q,J=7.0Hz, 2H),5.25(s,2H),6.94-6.98(m,1H),7.21(d,J=8.0Hz,1H),7.30-7.34(m, 1H),7.86-7.89(dd,J=1.2和8.0Hz,1H),8.31(s,1H)。
步骤7:2-(4-羟基-2-氧-1-((2-(三氟甲基)噻唑-4-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为79%。
1HNMR(DMSO-d6):1.23(t,J=7.0Hz,3H),4.15-4.20(q,J=7.0Hz, 2H),4.23(d,J=5.6Hz,2H),5.45(s,2H),7.35-7.39(m,1H),7.51(d,J=8.0 Hz,1H),7.72-7.77(m,1H),8.06-8.09(dd,J=1.2和8.0Hz,1H),8.42(s,1H), 10.27(t,1H)。
步骤8:2-(4-羟基-2-氧-1-((2-(三氟甲基)噻唑-4-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤7的产物来制备标题化合物,产率为86%。
1H NMR(DMSO-d6):4.14(d,J=5.6Hz,2H),5.45(s,2H),7.36(t,1H), 7.51(d,J=8.4Hz,1H),7.72-7.76(m,1H),8.06-8.09(dd,J=1.2和8.0Hz, 1H),8.42(s,1H),10.23(t,1H)。
实施例8
2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
步骤1:2-硝基-5-苯氧基苯甲酸乙酯的制备
向5-氯-2硝基苯甲酸乙酯(15g,65.3mmol)和K2CO3(13.54g,98mmol) 在DMF(5ml)中的搅拌悬浮液添加苯酚(6.76g,71.9mmol)。在130℃下加热反应混合物16小时。用水稀释反应混合物并用EtOAc提取。分离和蒸馏出有机层以得到粗产物,利用在己烷中的10%EtOAC对其加以柱纯化,以得到标题化合物,产率为36%。
1HNMR(DMSO-d6):1.25(t,J=7.0Hz,3H),4.27-4.32(q,J=7.2Hz, 2H),7.20-7.23(m,3H),7.27(d,J=2.8Hz,1H),7.30-7.34(m,1H),7.49-7.53 (m,2H),8.13(d,J=9.2Hz,1H)。
步骤2:2-(羟基氨基)-5-苯氧基苯甲酸乙酯的制备
使用和实施例-1(步骤-1)类似的步骤并利用上述步骤1的产物来制备标题化合物。粗产物直接用于下一步骤。
步骤3:2-((烯丙氧基)氨基)-5-苯氧基苯甲酸乙酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用上述步骤2的产物来制备标题化合物。
1HNMR(DMSO-d6):1.26(t,J=7.2Hz,3H),4.22-4.27(q,J=7.0Hz, 2H),4.37-4.4(m,2H),5.27-5.30(m,1H),5.35-5.40(m,1H),6.00-6.07(m, 1H),6.92-7.07(m,2H),7.07-7.11(m,1H),7.28-7.30(m,2H),7.34-7.38(m, 2H),7.44-7.45(m,1H),9.65(s,1H)。
步骤4:2-(N-(烯丙氧基)-3-乙氧基-3-氧丙酰氨基)-5-苯氧基苯甲酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤3的产物来制备标题化合物。粗产物直接用于下一步骤。
步骤5:1-(烯丙氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤4的产物来制备标题化合物。ESI/MS m/z 382(M+H)+。
步骤6:2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤5的产物来制备标题化合物。ESI/MS m/z 439.1(M+H)+。
步骤7:2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为78%。
1H NMR(DMSO-d6):4.12(d,J=5.6Hz,2H),4.74(d,J=6.4Hz,2H), 5.37(d,J=10.4Hz,1H),5.48-5.52(dd,J=1.2和17.2Hz,1H),6.12-6.22(m, 1H),7.09(d,J=7.6Hz,2H),7.21(t,J=7.4Hz,1H),7.36-7.46(m,2H),7.49 (d,J=2.8Hz,1H),7.60-7.63(dd,J=2.4和9.2Hz,1H),7.69(d,J=8.8Hz, 1H),10.27(bs,1H)。
实施例9
2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
步骤1:4-硝基-[1,1'-联苯基]-3-羧酸乙酯的制备
向5-氯-2硝基苯甲酸乙酯(2g,8.71mmol)和苯基硼酸(2.124g,17.42 mmol)在DMF(20ml)中的搅拌溶液添加K3PO4(2.77g,13.07mmol)、乙酸钯(0.098g,0.436mmol)和溴化四丁基铵(4.21g,13.07mmol)。在95℃下加热反应混合物16小时。用水稀释反应混合物并用EtOAc提取。分离和蒸馏出有机层以得到粗产物,利用在己烷中的10%EtOAC对其加以柱纯化,以得到标题化合物,产率为89%。
1HNMR(DMSO-d6):1.30(t,J=7.0Hz,3H),4.32-4.38(q,J=7.2Hz, 2H),7.48-7.57(m,3H),7.80-7.83(m,2H),8.08-8.10(m,2H),8.16-8.19(m, 1H)。
步骤2:4-(羟基氨基)-[1,1'-联苯基]-3-羧酸乙酯的制备
使用和实施例-1(步骤-1)类似的步骤并利用上述步骤1的产物来制备标题化合物。粗产物直接用于下一步骤。
步骤3:4-((烯丙氧基)氨基)-[1,1'-联苯基]-3-羧酸乙酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用上述步骤2的产物来制备标题化合物。ESI/MS m/z 297.9(M+H)+。
步骤4:4-(N-(烯丙氧基)-3-乙氧基-3-氧丙酰氨基)-[1,1'-联苯基]-3-羧酸乙酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤3的产物来制备标题化合物。ESI/MS m/z 412.0(M+H)+。
步骤5:1-(烯丙氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤4的产物来制备标题化合物。ESI/MS m/z 366.0(M+H)+。
步骤6:2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基) 乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤5的产物来制备标题化合物。
1H NMR(DMSO-d6):1.23(t,J=7.2Hz,3H),4.14-4.19(q,J=7.2Hz, 2H),4.22(d,J=5.6Hz,2H),4.78(d,J=6.4Hz,2H),5.38-5.41(dd,J=0.8 和10.0Hz,1H),5.49-5.53(dd,J=1.2和17.2Hz,1H),6.16-6.23(m,1H), 7.40-7.44(m,1H),7.49-7.53(m,2H),7.74-7.76(dd,J=1.6和8.8Hz,3H), 8.17-8.20(dd,J=2.0和8.8Hz,1H),8.28(d,J=2.4Hz,1H),10.28(t,1H)。
步骤7:2-(1-(烯丙氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为79%。
1H NMR(DMSO-d6):4.04(d,J=6.4Hz,2H),4.77(d,J=6.4Hz,2H), 5.38-5.40(m,1H),5.33-5.49(dd,J=1.6和17.2Hz,1H),6.14-6.24(m,1H), 7.41(t,J=7.2Hz,1H),7.49-7.52(m,2H),7.27-7.75(m,3H),8.16-8.19(dd,J =2.0和8.4Hz,1H),8.28(d,J=2.0Hz,1H),10.25(t,J=4.8Hz,1H),12.98 (bs,1H)。
实施例10
2-(4-(烯丙氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基) 乙酸的制备
步骤1:3-硝基噻吩-2-羧酸甲酯的制备
在0-5℃下,向3-氨基噻吩-2-羧酸甲酯(5g,31.8mmol)在浓HCl(4.77 ml)中的搅拌溶液缓慢地添加亚硝酸钠(2.195g,31.8mmol)的水溶液。在 0-5℃下搅拌反应混合物1小时。以1份向其添加四氟硼酸钠(5.24g,47.7 mmol)的水溶液。在30分钟以后,过滤沉淀产物。将产物加入青铜(6.06g, 95mmol)和亚硝酸钠(26.3g,382mmol)在水(100ml)中的搅拌悬浮液。在 25℃下搅拌反应混合物1小时。用水和EtOAc稀释反应混合物并通过 Hyflow床过滤。分离和蒸馏出有机层以得到粗产物,利用在己烷中的0-5% EtOAC对其加以柱纯化,以得到作为淡黄色固体的标题化合物,产率为 63%。
1HNMR(DMSO-d6):3.86(s,3H),7.67(d,J=5.2Hz,1H),8.04(d,J= 5.6Hz,1H)。
步骤2:3-(羟基氨基)噻吩-2-羧酸甲酯的制备
使用和实施例-1(步骤-1)类似的步骤并利用上述步骤1的产物来制备标题化合物。粗产物直接用于下一步骤。
步骤3:3-((烯丙氧基)氨基)噻吩-2-羧酸甲酯的制备
使用和实施例-1(步骤-2)类似的步骤并利用上述步骤2的产物来制备标题化合物,产率为49%。
1H NMR(DMSO-d6):3.86(s,3H),4.36-4.38(m,2H),5.25-5.28(m,1H), 5.32-5.38(m,1H),5.96-6.06(m,1H),6.95(d,J=5.2Hz,1H),7.76(d,J=4.8 Hz,1H),9.33(s,1H)。
步骤4:3-(N-(烯丙氧基)-3-乙氧基-3-氧丙酰氨基)噻吩-2-羧酸甲酯的制备
使用和实施例-1(步骤-3)类似的步骤并利用上述步骤3的产物来制备标题化合物。ESI/MS m/z 328.0(M+H)+。
步骤5:4-(烯丙氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-羧酸乙酯的制备
使用和实施例-1(步骤-4)类似的步骤并利用上述步骤4的产物来制备标题化合物,产率为68%。
1H NMR(DMSO-d6):1.31(t,J=7.2Hz,3H),4.31-4.36(q,J=7.0Hz, 2H),4.70(d,J=6.4Hz,2H),5.32-5.34(dd,J=0.8和10.0Hz,1H),5.40-5.45 (dd,J=1.2和18.4Hz,1H),6.07-6.14(m,1H),7.27(d,J=5.6Hz,1H),8.23 (d,J=5.2Hz,1H),13.36(bs,1H)。
步骤6:2-(4-(烯丙氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸乙酯的制备
使用和实施例-1(步骤-5)类似的步骤并利用上述步骤5的产物来制备标题化合物,产率为62%。
1H NMR(DMSO-d6):1.22(t,J=7.0Hz,3H),4.13-4.18(q,J=7.2Hz, 2H),4.19(d,J=5.6Hz,2H),4.78(d,J=6.4Hz,2H),5.34(d,J=10.4Hz, 1H),5.42-5.46(dd,J=1.6和17.2Hz,1H),6.09-6.19(m,1H),7.36(d,J=5.2 Hz,1H),8.29(d,J=5.6Hz,1H),10.24(t,J=5.6Hz,1H)。
步骤7:2-(4-(烯丙氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸的制备
使用和实施例-1(步骤-6)类似的步骤并利用上述步骤6的产物来制备标题化合物,产率为75%。
1H NMR(DMSO-d6):4.11(d,J=5.6Hz,2H),4.77(d,J=6.8Hz,2H), 5.34(d,J=10.4Hz,1H),5.42-5.47(dd,J=0.8和16.8Hz,1H),6.11-6.17(m, 1H),7.36(d,J=5.2Hz,1H),8.28(d,J=5.2Hz,1H),10.22(t,J=5.4Hz, 1H),12.94(bs,1H)。
利用适当的起始材料和在以上实施例中描述的过程的适当改进,包括步骤的适宜的添加和/或删除(当可能必要时),其是在本领域技术人员的技术范围内,以类似的方式制得以下化合物。
实施例11
2-(4-羟基-1-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.01(s,3H),4.15(d,J=5.6Hz,2H),7.43(t,1H), 7.67(d,J=8.4Hz,1H),7.88(t,1H),8.13(d,J=8Hz,1H),10.25(t,1H)。
实施例12
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):4.16(d,J=5.6Hz,2H),5.32(s,2H),7.42(t,1H), 7.67(d,J=8.4Hz,1H),7.82-7.90(m,5H),8.11-8.13(dd,J=1.2和8Hz,1H), 10.27(t,1H)。
实施例13
2-(4-羟基-2-氧-1-((2-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):4.17(d,J=5.6Hz,2H),5.41(s,2H),7.40(t,1H), 7.51(d,J=8.4Hz,1H),7.67(t,1H),7.79-7.85(m,3H),8.02(d,J=7.6Hz, 1H),8.12(d,J=7.6Hz,1H),10.22(t,1H)。
实施例14
2-(4-羟基-2-氧-1-(吡啶-2-基甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.17(d,J=5.6Hz,2H),5.31(s,2H),7.38-7.45(m, 2H),7.71-7.74(m,2H),7.81-7.85(m,1H),7.87-7.91(m,1H),8.11(d,J=6.8 Hz,1H),8.64(d,J=4Hz,1H),10.27(t,1H)。
实施例15
2-(1-(烯丙氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.14(d,J=6Hz,2H),4.75(d,J=6.8Hz,2H), 5.39(d,J=10.4Hz,1H),5.52(d,J=17.2Hz,1H),6.12-6.22(m,1H),7.42(t, 1H),7.64(t,1H),7.87(t,1H),8.12(d,1H),10.25(t,1H)。
实施例16
2-(1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.17(d,J=6Hz,2H),5.4(s,2H),7.18(t,2H), 7.37(t,1H),7.50-7.56(m,2H),7.78-7.82(m,1H),8.07-8.10(dd,J=1.2和8 Hz,1H),10.22(t,1H)。
实施例17
2-(1-(苄氧基)-7-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.16(d,J=5.6Hz,2H),5.26(s,2H),7.41-7.53(m, 5H),7.62(t,2H),8.09(d,J=8.4Hz,1H),10.21(t,1H)。
实施例18
2-(7-氯-4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.13(d,J=5.2Hz,2H),5.35(s,2H),7.43(d,J= 7.6Hz,1H),7.56(s,1H),7.83(d,J=8.4Hz,2H),7.89(d,J=8Hz,2H),8.10 (d,J=8.4Hz,1H),10.18(t,1H)。
实施例19
2-(1-(烯丙氧基)-7-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.07(d,J=5.2Hz,2H),4.74(d,J=6.4Hz,2H), 5.36(d,1H),5.51(d,1H),6.14-6.20(m,1H),7.42(d,J=8.0Hz,1H),7.63(s, 1H),8.08(d,J=8.4Hz,1H),10.29(t,1H)。
实施例20
2-(7-氯-1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.40(s,2H),7.21(t,2H), 7.40-7.43(dd,J=2.0和J=8.4Hz,1H),7.50(d,J=2.0Hz,1H),7.53-7.59 (m,1H),8.06(d,J=8.4Hz,1H),10.13(t,1H),12.95(bs,1H)。
实施例21
2-(4-羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.06(t,3H),1.79-1.87(m,2H),4.12-4.16(m,4H), 7.41(t,1H),7.62(d,J=8.4Hz,1H),7.85-7.89(m,1H),8.09-8.11(dd,J= 0.8和J=8.0Hz,1H),10.25(t,1H)。
实施例22
2-(1-((3,5-二甲基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):2.32(s,6H),4.16(d,J=5.6Hz,2H),5.11(s,2H), 7.24(s,1H),7.42(t,2H),7.65(d,J=8.4Hz,1H),7.86(d,J=1.2Hz,1H), 7.90(t,1H),8.13(t,1H),10.29(t,1H),12.95(bs,1H)。
实施例23
2-(1-((4-氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.21(s,2H),7.28(t,2H), 7.41(t,1H),7.63(d,J=8.4Hz,1H),7.69-7.73(m,2H),7.84(t,1H),8.10(d, J=8.0Hz,1H),10.28(t,1H)。
实施例24
2-(1-((4-氰基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.14(d,J=5.2Hz,2H),5.32(s,2H),7.42(t,1H), 7.64(d,J=8.4Hz,1H),7.83-7.87(m,3H),7.92(d,J=8.0Hz,2H),8.11(d,J =8.0Hz,1H),10.23(t,1H)。
实施例25
2-(4-羟基-1-异丙氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.29(d,J=6.0Hz,6H),4.12(d,J=5.6Hz,2H), 4.77-4.83(m,1H),7.37-7.41(m,1H),7.70(d,J=8.4Hz,1H),7.81(m,1H), 8.08-8.10(dd,J=1.2和8.0Hz,1H),10.26(t,J=5.2Hz,1H),12.91(bs,1H)。
实施例26
2-(1-((2-氰基苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.43(s,2H),7.37-7.41 (m,1H),7.58-7.66(m,2H),7.76-7.83(m,2H),7.92(d,J=1.2Hz,1H),7.924 (d,J=0.8Hz,1H),8.10-8.12(dd,J=1.2和8.0Hz,1H),10.21(t,1H)。
实施例27
2-(1-(烯丙氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.13(d,J=5.6Hz,2H),4.74(d,J=6.4Hz,2H), 5.31(d,1H),5.40-5.44(m,1H),6.09-6.18(m,1H),7.46-7.50(dd,J=4.4和 7.6Hz,1H),8.48-8.50(dd,J=1.6和8.0Hz,1H),8.85-8.86(dd,J=1.6和4.4 Hz,1H),10.18(t,1H),12.98(bs,1H)。
实施例28
2-(4-羟基-1-异丁氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.07(d,6H),2.13-2.21(m,1H),3.96(d,J=6.8 Hz,2H),4.11(d,J=5.6Hz,2H),7.41(t,1H),7.60(d,J=8.4Hz,1H),7.88(t, 1H),8.10-8.12(dd,J=1.2和8.0Hz,1H),10.25(t,1H)。
实施例29
2-(1-(环丙基甲氧基)-4-羟基-6-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):0.57(m,2H),0.59(m,2H),1.23-1.28(m,1H), 3.86(s,3H),4.03(d,J=7.2Hz,2H),4.12(d,J=6.0Hz,2H),7.51(t,2H), 7.66(d,J=9.6Hz,1H),10.33(t,1H),12.95(bs,1H)。
实施例30
2-(1-(烯丙氧基)-6-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.12(d,J=5.6Hz,2H),4.73(d,J=6.4Hz,2H), 5.46(d,J=1.2Hz,1H),5.51(d,J=1.2Hz,1H),6.10-6.21(m,1H),7.66(d,J =8.8Hz,1H),7.87(d,J=8.8Hz,1H),8.03(d,J=2.4Hz,1H),10.21(t, 1H)。
实施例31
2-(1-(烯丙氧基)-5-氟-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.12(d,J=5.6Hz,2H),4.71(d,J=6.4Hz,2H), 5.47(d,J=1.6Hz,1H),5.52(d,J=1.6Hz,1H),6.12-6.17(m,1H),7.19(t, 1H),7.46(d,J=8.8Hz,1H),7.83(d,J=5.6Hz,1H),10.26(t,1H)。
实施例32
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,6-二氮杂萘-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):0.35-0.39(m,2H),0.56-0.61(m,2H),1.23-1.30 (m,1H),4.05(d,J=7.6Hz,2H),4.12(d,J=5.2Hz,2H),7.61(d,J=6.00 Hz,1H),8.77(d,J=5.6Hz,1H),9.18(s,1H),10.06(t,1H)。
实施例33
2-(1-(烯丙氧基)-4-羟基-6-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.85(s,3H),4.13(d,J=5.6Hz,2H),4.72(d,J= 6.4Hz,2H),5.35-5.38(m,1H),5.45-5.50(dd,J=1.2和16.8Hz,1H), 6.10-6.20(m,1H),7.33-7.62(m,3H),10.32(t,1H)。
实施例34
2-(4-羟基-6-甲氧基-2-氧-1-(丙-2-炔-1-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.66-3.71(m,1H),3.86(s,3H),4.12(d,J=5.6 Hz,2H),5.03(d,2H),7.48(t,2H),7.64(d,J=9.2Hz,1H),10.24(t,1H)。
实施例35
2-(5-(环丙基甲氧基)-8-羟基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.36-0.37(m,2H),0.55-0.59(m,2H),1.23-1.29 (m,1H),4.03(t,2H),4.14(d,J=5.6Hz,2H),8.75(d,J=2.0Hz,1H),8.89(d, J=2.0Hz,1H),10.19(s,1H),12.97(bs,1H)。
实施例36
2-(5-((2,6-二氟苄基)氧基)-8-羟基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7- 甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.14(d,J=5.6Hz,2H),5.38(s,2H),7.11(t,2H), 7.50(t,1H),8.70(s,1H),8.77(s,1H),10.13(t,1H)。
实施例37
2-(1-(环丙基甲氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):0.38-0.39(m,2H),0.58-0.62(m,2H),1.23-1.30 (m,1H),4.05(d,J=7.2Hz,2H),4.10(d,J=5.2Hz,2H),7.09(d,J=8.0Hz, 2H),7.21(t,1H),7.44(t,2H),7.49(d,J=2.8Hz,1H),7.60-7.63(dd,J= 2.4和9.2Hz,1H),7.75(d,J=9.2Hz,1H),10.28(t,1H)。
实施例38
2-(4-羟基-2-氧-1-(戊烷-3-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.94(t,6H),1.58-1.64(m,2H),1.67-1.76(m,2H), 4.12(d,J=5.6Hz,2H),4.45-4.51(m,1H),7.39(t,1H),7.67(d,J=8.4Hz, 1H),7.83(t,1H),8.08(d,J=7.2Hz,1H),10.23(t,1H),12.93(bs,1H)。
实施例39
2-(4-(烯丙氧基)-7-羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):2.47(s,3H),4.04(d,J=5.6Hz,2H),4.75(d,J= 6.0Hz,2H),5.36(d,J=10.4Hz,1H),5.45-5.50(dd,J=1.2和17.2Hz,1H), 6.02-6.09(m,1H),7.89(s,1H),10.20(bs,1H)。
实施例40
2-(7-羟基-3-甲基-5-氧-4-丙氧基-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸的制备
1H NMR(CD3OD):1.07(t,3H),1.84-1.90(m,2H),2.54(s,3H),4.18(d, 2H),4.21(t,2H),7.67(s,1H)。
实施例41
2-(4,7-二羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸的制备
1H NMR(CD3OD):2.53(s,3H),4.18(s,2H),7.62(s,1H)。
实施例42
2-(4-((2,6-二氟苄基)氧基)-7-羟基-3-甲基-5-氧-4,5-二氢噻吩并[3,2-b] 吡啶-6-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):2.27(s,3H),4.10(d,J=5.6Hz,2H),5.43(s,2H), 7.17(t,2H),7.55(m,1H),7.84(s,1H),10.19(t,1H)。
实施例43
2-(4-羟基-1-(2-(甲硫基)乙氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1HNMR(DMSO-d6):2.16(s,3H),2.94(t,J=6.4Hz,2H),4.11(d,J= 5.6Hz,2H),4.35(t,J=6.4Hz,2H),7.40(t,1H),7.79(d,J=8.0Hz,1H), 7.84-7.88(dd,J=7.2和14.4Hz,1H),8.08-8.10(dd,J=1.2和8.0Hz,1H), 10.21(t,1H),12.9(bs,1H)。
实施例44
2-(1-(环己基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.13-1.35(m,5H),1.65-1.76(m,3H),1.88-1.91 (bd,3H),3.98-4.038(m,2H),4.14(d,J=5.6Hz,2H),7.41(t,J=7.6Hz,1H), 7.59(t,J=8.4Hz,1H),7.86-7.90(m,1H),8.09-8.12(dd,J=7.2Hz,1H), 10.25(t,1H),13.06(bs,1H)。
实施例45
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸的制备
1H NMR(DMSO-d6):0.38-0.40(dd,J=4.0和5.6Hz,2H),0.57-0.60(m, 2H),1.23-1.29(m,1H),1.46(d,J=7.2Hz,3H),4.04(d,J=7.6Hz,2H),4.53 (t,J=6.8Hz,1H),7.39-7.44(m,1H),7.70(d,J=8.4Hz,1H),7.85-7.89(m, 1H),8.09-8.11(dd,J=1.2和8.0Hz,1H),10.38(d,1H)。
实施例46
2-(8-((2,6-二氟苄基)氧基)-5-羟基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-6- 甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.05(d,J=6.0Hz,2H),5.38(s,2H),7.19-7.10 (m,2H),7.55-7.47(m,1H),9.17(s,1H),9.31(s,1H),9.94-9.85(m,1H)。
实施例47
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-苯乙酸的制备
1H NMR(DMSO-d6):0.41(m,2H),0.57-0.61(m,2H),1.27-1.31(m, 1H),4.05(d,J=7.6Hz,2H),5.57(d,J=6.4Hz,1H),7.37-7.46(m,6H),7.72 (d,J=8.4Hz,1H),7.85-7.90(m,1H),8.10-8.08(dd,J=0.8和8.0Hz,1H), 10.91(d,J=6.4Hz,1H)。
实施例48
2-(1-(烯丙氧基)-4-羟基-7-吗啉代-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.40(t,J=4.6Hz,4H),3.77(t,J=4.8Hz,4H), 4.10(d,J=5.6Hz,2H),4.72(d,J=6.4Hz,2H),5.35-5.38(dd,J=1.6和 10.4Hz,1H),5.46-5.51(dd,J=1.2和16Hz,1H),6.14-6.20(m,1H),6.82(d, J=2.4Hz,1H),7.05-7.08(dd,J=2.0和9.2Hz,1H),7.87(d,J=9.2Hz,1H), 10.13(t,J=5.6Hz,1H)。
实施例49
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸叔丁酯的制备
1H NMR(DMSO-d6):0.39(d,J=4.4Hz,2H),0.56-0.61(m,2H), 1.26-1.30(m,1H),1.44(s,9H),4.05(d,J=7.2Hz,2H),4.10(d,J=5.6Hz, 2H),7.39-7.43(m,1H),7.72(d,J=8.0Hz,1H),7.85-7.89(m,1H),8.09-8.11 (dd,J=1.2和8.0Hz,1H),10.24(t,J=5.6Hz,1H)。
实施例50
2-(7-氯-1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.30-0.55(m,2H),0.59-0.61(m,2H),1.23-1.35 (m,1H),4.07(d,J=7.6Hz,2H),4.12(t,J=5.6Hz,2H),7.43-7.46(dd,J= 2.0和8.8Hz,1H),7.72(d,J=2.0Hz,1H),8.09(d,J=8.4Hz,1H),10.15(t, J=5.6Hz,1H),12.95(bs,1H)。
实施例51
2-(1-(环戊基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.56-1.63(m,6H),1.81-1.86(m,2H),2.49-2.52 (m,1H),4.07(d,J=6.8Hz,2H),4.13(d,J=5.6Hz,2H),7.40-7.44(m,1H), 7.63(d,J=8.4Hz,1H),7.86-7.90(m,1H),8.10-8.12(dd,J=1.2和2.4Hz, 1H),10.25(t,J=5.6Hz,1H)。
实施例52
2-(1-(环戊氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.60(d,J=8.0Hz,2H),1.75-1.80(m,2H), 1.82-1.89(m,4H),4.13(d,J=5.6Hz,2H),5.10-5.13(m,1H),7.38-7.42(m, 1H),7.61(d,J=8.4Hz,1H),7.84-7.88(m,1H),8.09-8.11(dd,J=1.6和8.4 Hz,1H),10.24(t,J=5.2Hz,1H),12.95(bs,1H)。
实施例53
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸甲酯的制备
1H NMR(DMSO-d6):0.3-0.6(m,2H),0.79-0.80(m,2H),0.56-0.82(m, 1H),3.69(s,3H),4.05(d,J=7.2Hz,2H),4.22(d,J=5.6Hz,2H),7.41(t,J =7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.87(d,J=7.2Hz,1H),8.10(d,J= 7.6Hz,1H),10.28(t,J=6.0Hz,1H)。
实施例54
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-4-甲基戊酸的制备
1H NMR(DMSO-d6):0.2-0.4(m,2H),0.5-0.6(m,2H),0.92-0.95(dd,J =6.0和8.0Hz,6H),1.26-1.31(m,1H),1.67-1.73(m,3H),4.05(d,J=7.6Hz, 2H),4.51-4.56(dd,J=6.8和14.4Hz,1H),7.40-7.44(m,1H),7.71(d,J=8.4 Hz,1H),7.85-7.90(m,1H),8.09-8.11(dd,J=1.2和8.0Hz,1H),10.34(d,J= 7.6Hz,1H)。
实施例55
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-3-甲基丁酸的制备
1H NMR(DMSO-d6):0.2-0.5(m,2H),0.6-0.9(m,2H),1.15-1.26(m, 6H),1.27-1.32(m,1H),2.24-2.30(m,1H),4.02-4.09(m,2H),4.45-4.49(dd,J =4.8和8.4Hz,1H),7.40-7.44(m,1H),7.72(d,J=8.4Hz,1H),7.85-7.90(m, 1H),8.09-8.11(dd,J=0.8和8.0Hz,1H),10.45(d,J=8.4Hz,1H)。
实施例56
3-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸的制备
1H NMR(DMSO-d6):0.34-0.39(m,2H),0.56-0.61(m,2H),1.23-1.29 (m,1H),2.57(t,J=6.4Hz,2H),3.55-3.60(dd,J=6.4和12.8Hz,2H),4.02 (d,J=7.2Hz,2H),7.40(t,J=7.6Hz,1H),7.69(d,J=8.4Hz,1H), 7.83-7.88(m,1H),8.09(d,J=7.2Hz,1H),10.15(t,J=6.0Hz,1H)。
实施例57
2-(1-(烯丙氧基)-4-羟基-2-氧-7-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.09(d,J=5.2Hz,2H),4.63(d,J=6.4Hz,2H), 5.23-5.35(m,2H),5.88-5.98(m,1H),6.92(s,1H),7.03(d,J=9.6Hz,1H), 7.24(d,J=8.0Hz,2H),7.32(t,J=7.2Hz,1H),7.52(t,J=7.6Hz,2H), 8.09(d,J=8.8Hz,1H),10.13(bs,1H)。
实施例58
(S)-2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-3-苯基丙酸的制备
1H NMR(DMSO-d6):0.35-0.38(m,2H),0.56-0.59(m,2H),1.23-1.29 (m,1H),3.15(m,1H),3.22(m,1H),4.02(m,2H),4.80-4.82(m,1H), 7.20-7.30(m,5H),7.38-7.42(m,1H),7.70(d,J=8.4Hz,1H),7.84-7.86(m, 1H),8.07-8.09(dd,J=0.8和8.0Hz,1H),10.34(d,J=7.6Hz,1H)。
实施例59
(S)-4-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-羟基丁酸的制备
1H NMR(DMSO-d6):0.3-0.4(m,2H),0.5-0.7(m,2H),1.22-1.30(m, 1H),1.75-1.84(m,1H),1.91-2.02(m,1H),3.47-3.52(dd,J=6.4和13.2Hz, 2H),4.00-4.05(m,3H),5.42(t,J=2.4Hz,1H),7.40(t,J=7.6Hz,1H),7.69 (d,J=8.4Hz,1H),7.85(t,J=7.2Hz,1H),8.09(d,J=8.0Hz,1H),10.01(t, J=5.2Hz,1H),12.46(bs,1H)。
实施例60
5-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)戊酸的制备
1H NMR(DMSO-d6):0.35-0.39(m,2H),0.56-0.59(m,2H),1.27-1.33 (m,1H),1.57(t,J=3.2Hz,3H),2.27(t,J=6.8Hz,2H),3.83(t,J=6.0Hz, 2H),4.03(d,J=7.6Hz,2H),7.38-7.42(m,1H),7.70(d,J=8.4Hz,1H), 7.83-7.87(m,1H),8.08-8.10(dd,J=1.2和8.0Hz,1H),10.05(t,J=5.6Hz, 1H),12.03(bs,1H)。
实施例61
2-(4-羟基-2-氧-1-(丙-2-炔-1-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.59(bs,1H),4.00(d,J=5.6Hz,2H),5.03(s, 2H),7.37(bs,1H),7.66(bs,1H),7.82(bs,1H),8.09(d,J=7.6Hz,1H),10.19 (bs,1H)。
实施例62
2-(1-((2-氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.32(s,2H),7.26-7.31 (m,2H),7.39(t,J=7.6Hz,1H),7.47-7.52(m,1H),7.57(d,J=8.0Hz,1H), 7.65-7.70(m,1H),7.80-7.84(m,1H),8.08-8.11(dd,J=0.8和8.0Hz,1H), 10.26(t,J=5.6Hz,1H)。
实施例63
2-(1-乙氧基-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.39(t,J=7.0Hz,3H),4.12(d,J=5.6Hz,2H), 4.21-4.26(q,J=6.8Hz,2H),7.42(t,J=7.6Hz,1H),7.65(d,J=8.4Hz,1H), 7.87(t,J=7.8Hz,1H),8.10(d,J=8.0Hz,1H),10.27(bs,1H)。
实施例64
2-(4-羟基-2-氧-1-((4-(三氟甲氧基)苄基)氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.25(s,2H),7.39-7.46 (m,3H),7.63(d,J=8.4Hz,1H),7.78-7.86(m,3H),8.10-8.12(dd,J=1.2和 8.4Hz,1H),10.27(t,J=5.4Hz,1H)。
实施例65
2-(1-((2,4-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.2Hz,2H),5.30(s,2H),7.14-7.19 (m,1H),7.34-7.45(m,2H),7.54(d,J=8.4Hz,1H),7.72-7.78(m,1H), 7.80-7.84(m,1H),8.09(d,J=7.2Hz,1H),10.24(bs,1H)。
实施例66
2-(1-((2,6-二氟苄基)氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.13(d,J=5.2Hz,2H),5.38(s,2H),7.09(t,J= 8.0Hz,2H),7.40-7.51(m,2H),8.45(d,J=7.6Hz,1H),8.71(d,J=2.8Hz, 1H),10.11(bs,1H)。
实施例67
2-(4-羟基-1-((4-甲氧基苄基)氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.78(s,3H),4.17(d,J=5.6Hz,2H),5.14(s,2H), 7.01(d,J=8.4Hz,2H),7.39-7.43(m,1H),7.58(d,J=8.8Hz,2H),7.65(d,J =8.8Hz,1H),7.83-7.87(m,1H),8.09-8.12(dd,J=1.2和8.0Hz,1H),10.30 (t,J=5.6Hz,1H),12.96(bs,1H)。
实施例68
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):0.36-0.39(m,2H),0.54-0.59(m,2H),1.23-1.28 (m,1H),4.02(d,J=7.6Hz,2H),4.13(d,J=5.6Hz,2H),7.45-7.48(dd,J= 4.4和7.6Hz,1H),8.47-8.49(dd,J=2.0和8.0Hz,1H),8.84-8.85(dd,J=1.6 和4.4Hz,1H),10.19(bs,1H)。
实施例69
2-(4-羟基-2-氧-1-(2,2,2-三氟乙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.12(d,J=5.6Hz,2H),4.99-5.06(q,J=9.2Hz, 2H),7.44(bs,1H),7.58(d,J=8.0Hz,1H),7.90(bs,1H),8.12-8.14(dd,J= 1.2和8.0Hz,1H),10.11(bs,1H)。
实施例70
2-(1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢-1,7-二氮杂萘-3-甲酰胺基) 乙酸的制备
1H NMR(DMSO-d6):0.36-0.39(m,2H),0.57-0.60(m,2H),1.29-1.35 (m,1H),4.11-4.14(m,4H),7.94(d,J=5.2Hz,1H),8.57(d,J=5.2Hz,1H), 9.10(s,1H),10.22(bs,1H)。
实施例71
2-(6-氰基-1-(环丙基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.36-0.39(m,2H),0.56-0.61(m,2H),1.26-1.35 (m,1H),4.05(d,J=7.6Hz,2H),4.13(d,J=5.6Hz,2H),7.83(d,J=8.8Hz, 1H),8.19-8.28(m,1H),8.50(d,J=1.6Hz,1H),10.11(bs,1H)。
实施例72
2-(8-(苄氧基)-5-羟基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-6-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):4.15(d,J=5.6Hz,2H),5.21(s,2H),7.43-7.48 (m,3H),7.66-7.68(dd,J=2.0和8.0Hz,2H),9.32(s,1H),9.36(s,1H),10.20 (bs,1H)。
实施例73
(S)-2-(4-羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)丙酸的制备
1H NMR(DMSO-d6):1.06(t,J=7.4Hz,3H),1.45(d,J=7.2Hz,3H), 1.80-1.86(m,2H),4.14(t,J=6.6Hz,2H),4.51-4.55(q,1H),7.40-7.44(m, 1H),7.63(d,J=8.0Hz,1H),7.86-7.90(m,1H),8.10-8.12(dd,J=1.2和8.4 Hz,1H),10.39(d,J=6.8Hz,1H),13.13(bs,1H)。
实施例74
2-(4-羟基-1-(2-甲氧基乙氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):3.30(s,3H),3.68(t,J=3.6Hz,2H),4.11(d,J= 5.6Hz,2H),4.33(t,J=4.0Hz,2H),7.37-7.42(m,1H),7.73(d,J=8.4Hz, 1H),7.83-7.87(m,1H),8.07-8.09(dd,J=1.2和8.0Hz,1H),10.21(t,J=5.6 Hz,1H),12.94(bs,1H)。
实施例75
2-(4-羟基-2-氧-6-苯氧基-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):1.06(t,J=7.4Hz,3H),1.08-1.85(m,2H),4.09(d, J=5.6Hz,2H),4.15(d,J=6.6Hz,2H),7.09-7.11(dd,J=1.2和8.8Hz,2H), 7.21(t,J=7.4Hz,1H),7.42-7.46(m,2H),7.50(d,J=2.8Hz,1H),7.60-7.63 (dd,J=2.8和9.2Hz,1H),7.67(d,J=9.2Hz,1H),10.29(bs,1H)。
实施例76
2-(1-((4-环丙基丁-3-烯-1-基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.32-0.34(m,2H),0.66-0.68(m,2H),1.39-1.42 (m,1H),2.50(m,2H),4.13(d,J=7.6Hz,2H),4.17-4.20(m,2H),5.13-5.19 (m,1H),5.55-5.60(m,1H),7.42(t,J=7.4Hz,1H),7.65(d,J=8.4Hz,1H), 7.84-7.88(m,1H),8.10(d,J=8.0Hz,1H),10.24(bs,1H),12.95(bs,1H)。
实施例77
2-(1-(庚-4-基氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.86(t,J=7.2Hz,6H),1.39-1.48(m,4H), 1.53-1.63(m,4H),4.13(d,J=5.6Hz,2H),4.60-4.64(m,1H),7.39(t,J=7.6 Hz,1H),7.67(d,J=8.4Hz,1H),7.81-7.85(m,1H),8.08(d,J=7.6Hz,1H), 10.21(t,J=5.4Hz,1H),12.91(bs,1H)。
实施例78
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸乙酯的制备
1H NMR(DMSO-d6):0.31-0.34(m,2H),0.53-0.57(m,2H),1.20-1.25 (m,4H),4.09(d,J=7.6Hz,2H),4.12-4.19(m,4H),7.40(d,J=5.2Hz,1H), 8.28(d,J=5.2Hz,1H),10.25(t,J=5.6Hz,1H)。
实施例79
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.32-0.35(m,2H),0.53-0.57(m,2H),1.21-1.27 (m,1H),4.10(t,J=7.2Hz,4H),7.40(d,J=5.2Hz,1H),8.27(d,J=5.6Hz, 1H),10.23(t,J=4.6Hz,1H)。
实施例80
2-(1-(庚氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸的制备
1H NMR(DMSO-d6):0.88(t,J=6.8Hz,3H),1.26-1.38(m,6H), 1.45-1.51(m,2H),1.77-1.84(m,2H),4.12(d,J=5.6Hz,2H),4.17(t,J=6.6 Hz,2H),7.41(t,1H),7.61(d,J=8.8Hz,1H),7.85-7.89(dd,J=1.2和8.4Hz, 1H),8.10(d,J=7.2Hz,1H),10.25(bs,1H)。
可以通过类似于上述那些程序的程序并借助于反应、反应条件、试剂和试剂量的适当变化来制备以下化合物,其是在本领域技术人员的(能力) 范围内。
实施例81
2-(4-羟基-2-氧-1-((6-(三氟甲基)吡啶-3-基)甲氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例82
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯乙氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸
实施例83
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯氧基)-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸
实施例84
2-(4-羟基-2-氧-1-(4-(三氟甲基)苯乙氧基)-1,2-二氢-1,8-二氮杂萘-3-甲酰胺基)乙酸
实施例85
2-(1-(丁-2-炔-1-基氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例86
2-(4-羟基-2-氧-1-(3,3,3-三氟丙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例87
2-(1-(2-氨基-2-氧乙氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例88
2-(1-(苯并[d]噁唑-2-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸
实施例89
2-(1-(苯并[d]噻唑-2-基甲氧基)-6-氯-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例90
2-(1-(烯丙氧基)-4-羟基-8-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例91
2-(1-乙氧基-4-羟基-8-甲氧基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例92
2-(4-羟基-1-(噁唑-2-基甲氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例93
2-(1-(烯丙氧基)-6-氰基-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例94
2-(1-(烯丙氧基)-4-羟基-6-硝基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例95
2-(4-羟基-1-甲氧基-2-氧-6-(三氟甲基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例96
2-(4,6-二羟基-2-氧-1-丙氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例97
2-(1-((4-(叔丁基)苄基)氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例98
2-(1-([1,1'-联苯基]-4-基甲氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例99
2-(4-羟基-1-((4-(噁唑-2-基)苄基)氧基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例100
2-(1-(苄氧基)-4-羟基-2-氧-6-苯氧基-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例101
2-(1-(苄氧基)-4-羟基-2-氧-6-(吡啶-2-基氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例102
2-(1-(苄氧基)-4-羟基-2-氧-6-(苯硫基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例103
2-(1-(苄氧基)-4-羟基-6-(甲基磺酰基)-2-氧-1,2-二氢喹啉-3-甲酰胺基) 乙酸
实施例104
2-(1-(苄氧基)-4-羟基-2-氧-6-苯基-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例105
2-(1-(苄氧基)-4-羟基-6-(4-甲氧基苯基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例106
2-(1-(苄氧基)-4-羟基-6-(5-甲氧基吡啶-2-基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例107
2-(1-(苄氧基)-4-羟基-2-氧-6-氨磺酰-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例108
2-(1-(苄氧基)-4-羟基-6-(甲基亚磺酰氨基)-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例109
2-(1-(苄氧基)-4-羟基-2-氧-6-(三氟甲氧基)-1,2-二氢喹啉-3-甲酰胺基) 乙酸
实施例110
2-(6-苯甲酰基-4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2-二氢喹啉 -3-甲酰胺基)乙酸
实施例111
2-(1-(苄氧基)-4-羟基-N-甲基-2-氧-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例112
2-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)-2-甲基丙酸
实施例113
1-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)环丙烷羧酸
实施例114
3-(1-(苄氧基)-4-羟基-2-氧-1,2-二氢喹啉-3-甲酰胺基)丙酸
实施例115
1-(苄氧基)-4-羟基-N-(2-(甲基亚磺酰氨基)-2-氧乙基)-2-氧-1,2-二氢喹啉-3-甲酰胺
实施例116
1-(苄氧基)-4-羟基-2-氧-N-(2-氧-2-(噻吩-2-甲酰胺基)乙基)-1,2-二氢喹啉-3-甲酰胺
实施例117
2-(4-羟基-1-甲氧基-2-氧-1,2-二氢-1,5-二氮杂萘-3-甲酰胺基)乙酸
实施例118
2-(8-羟基-5-甲氧基-6-氧-5,6-二氢吡啶并[2,3-b]吡嗪-7-甲酰胺基)乙酸
实施例119
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例120
2-(4-(环丙基甲氧基)-7-羟基-5-氧-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例121
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢呋喃并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例122
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噻吩并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例123
2-(7-羟基-4-甲氧基-1-甲基-5-氧-4,5-二氢-1H-吡咯并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例124
2-(7-羟基-1-甲基-5-氧-4-丙氧基-4,5-二氢-1H-吡咯并[3,2-b]吡啶-6-甲酰胺基)乙酸
实施例125
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噻唑并[4,5-b]吡啶-6-甲酰胺基)乙酸
实施例126
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢噻唑并[5,4-b]吡啶-6-甲酰胺基)乙酸
实施例127
2-(4-羟基-7-甲氧基-1-甲基-6-氧-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸
实施例128
2-(7-羟基-4-甲氧基-5-氧-4,5-二氢噁唑并[4,5-b]吡啶-6-甲酰胺基)乙酸
实施例129
2-(7-羟基-5-氧-4-丙氧基-4,5-二氢噁唑并[4,5-b]吡啶-6-甲酰胺基)乙酸
实施例130
2-(4-羟基-1-甲氧基-2-氧-1,2,5,7-四氢噻吩并[3,4-b]吡啶-3-甲酰胺基) 乙酸
实施例131
2-(7-乙氧基-4-羟基-6-氧-6,7-二氢噻吩并[2,3-b]吡啶-5-甲酰胺基)乙酸
实施例132
2-(7-(环丙基甲氧基)-4-羟基-6-氧-6,7-二氢噻吩并[2,3-b]吡啶-5-甲酰胺基)乙酸
实施例133
2-(4-羟基-1-甲氧基-6,6-二环氧-2-氧-1,2,5,7-四氢噻吩并[3,4-b]吡啶-3-甲酰胺基)乙酸
实施例134
2-(7-乙氧基-4-羟基-1-甲基-6-氧-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸
实施例135
2-(7-乙氧基-4-羟基-6-氧-1-苯基-6,7-二氢-1H-吡唑并[3,4-b]吡啶-5-甲酰胺基)乙酸
实施例136
2-(7-乙氧基-4-羟基-3-甲基-6-氧-6,7-二氢异噻唑并[5,4-b]吡啶-5-甲酰胺基)乙酸
实施例137
2-(4-羟基-2-氧-1-(2-(2-氧噁唑烷-3-基)乙氧基)-1,2-二氢喹啉-3-甲酰胺基)乙酸
实施例138
2-(4-羟基-2-氧-1-((4-(三氟甲基)苄基)氧基)-1,2,5,6,7,8-六氢喹啉-3-甲酰胺基)乙酸
实施例139
2-(4-羟基-2-氧-1-丙氧基-1,2,5,6,7,8-六氢喹啉-3-甲酰胺基)乙酸
化合物体内效力的证实
(1)用于估计在小鼠中的循环EPO释放的方案
通过口服管饲法并以10ml/kg,对C57小鼠给予各种剂量(10mg/kg、 30mg/kg、50mg/kg、100mg/kg)的本发明的化合物。在给予化合物6小时以后,在轻度***麻醉(lightether anesthesia)下,通过眼眶穿刺(retro-orbital puncture),在包含2%EDTA(10μl/100μl的血液)的微离心管中,对小鼠进行采血。分离血浆并分析EPO含量(通过小鼠EPOELISA)。如表1 所示,很少选定的化合物显示出EPO水平的显著增加。
表1
ND(未测定)。
在对照中的EPO水平=62ng/mL
(2)用于估计在小鼠中的血红蛋白水平的方案
在早晨每日一次通过口服途径以20mg/kg给予C57小鼠本发明的化合物(10ml/kg)连续7天。在第8天,在轻度***麻醉下,通过眼眶穿刺,在包含2%EDTA(10μl/100μl的血液)的微离心管中对动物进行采血 (全血)。使用标准程序来测量血红蛋白、网织红细胞(reticulocyte)计数和RBC计数。如表2所示,很少选定的化合物显示出Hb水平的显著增加。
表2:
通过如众所周知的技术和方法和浓度,通过结合于适宜的赋形剂,可以将本发明的新型化合物配制成适宜的药用组合物。
化学式(I)的化合物或包含它们的药物组合物可用于治疗各种病症,包括不同类型的贫血和相关于缺血/缺氧的病症。化合物适用于人类和其它温血动物,并且可以通过口服、局部或胃肠道外给予(方式)来给予。
通过采用常规技术来提供药物组合物。优选地,组合物具有单位剂型,其含有有效量的活性成分,即,根据本发明的化学式(I)的化合物。
在药物组合物以及其单位剂型中,活性成分,即根据本发明的化学式 (I)的化合物的量可以广泛地变化或调节,其取决于特定应用方法、特定化合物的效力和所期望的浓度。通常,基于组合物的重量,活性成分的量将是0.5%至90%。
Claims (4)
1.一种化合物,选自由下述化合物组成的组:
2.一种药物组合物,包含治疗有效量的在权利要求1中所述的化合物以及可选的一种或多种药用载体、稀释剂或赋形剂。
3.在权利要求1中所述的化合物或权利要求2所述的药物组合物的应用,用于制造用于治疗由HIF脯氨酰羟化酶介导的病症的药剂。
4.一种药物组合物,包含在权利要求1中所述的化合物以及适宜的赋形剂,适用于通过抑制HIF脯氨酰羟化酶来治疗疾病。
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