CN104411690A - 作为lpar拮抗剂的取代的吡唑化合物 - Google Patents
作为lpar拮抗剂的取代的吡唑化合物 Download PDFInfo
- Publication number
- CN104411690A CN104411690A CN201380032266.8A CN201380032266A CN104411690A CN 104411690 A CN104411690 A CN 104411690A CN 201380032266 A CN201380032266 A CN 201380032266A CN 104411690 A CN104411690 A CN 104411690A
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- Prior art keywords
- phenyl
- base
- methyl
- pyrazoles
- cyclopropane
- Prior art date
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本文提供的是式(I)的化合物,及其药用盐,其中的取代基是如说明书中所公开的那些。这些化合物,以及含有它们的药物组合物,可用于炎性疾病和病症,例如肺纤维化的治疗。
Description
本发明涉及可用于治疗和/或预防哺乳动物中的炎性疾病或病症的有机化合物,并且特别是取代的化合物,它们的制造,含有它们的药物组合物和它们作为溶血磷脂酸(LPA)拮抗剂的用途。
LPA是生物活性磷酸脂质家族,其通过与LPA受体,一种G-蛋白质-结合受体(GPCR)家族相互作用发挥如生长因子调节剂的功能。该脂质家族具有通过酯键连接至甘油的长链饱和的(如C18∶0或C16∶0)或不饱和的(C18∶1或C20∶4)碳链。在生物学系统中,LPA通过膜磷脂的脱酯化由多步酶路径产生。贡献于LPA合成的酶包括溶血磷脂酶D(lysoPLD)、自分泌运动因子(ATX)、磷脂酶A1(PLA1)、磷脂酶A2(PLA2)和酰基甘油激酶(AGK)(British J.of Pharmacology 2012,165,829-844)。
至少有六种LPA受体被识别(LPAR1-6)。LPA信号传导对很多不同的细胞类型施加宽范围的生物学响应,其可以导致细胞生长、细胞增殖、细胞迁移和细胞收缩。LPA路径的增量调节与多种疾病相关,包括癌症,过敏性气管炎,以及肾、肺和肝的纤维化。因此,靶向LPA受体或LPA代谢酶可以对医学上重要的疾病的治疗提供新的方式,所述医学上重要的疾病包括神经精神病学疾病、神经性疼痛、不育、心血管疾病、炎症、纤维化和癌症(Annu.Rev.Pharmacol.Toxicol.2010,50,157-186;J.Biochem.2011,150,223-232)。
纤维化是导致细胞外基质(ECM)的过度积累的不受控组织愈合过程的结果。最近报道,LPA1受体在特发性肺纤维化(IPF)患者中过度表达。敲除LPA1受体的小鼠被保护不受博来霉素诱导的肺纤维化影响(NatureMedicine 2008,14,45-54)。因此,拮抗LPA1受体可用于治疗纤维化,如肾纤维化,肺纤维化,动脉纤维化和系统性硬化症。
在本发明的一个实施方案中,所提供的是通式(I)的化合物:
其中:
X是氧、氮或碳;
R1是低级烷基;
R2是氢、卤素、-CH2C(O)OH、烷氧基、环烷基羧酸、未取代的苯基或被卤素、-CH2C(O)OH、环丙烷甲酸、环丙烷甲酸乙酯、甲磺酰氨基羰基或四唑取代的苯基;并且
R3是环丁基、氧杂环丁基、未取代的低级烷基、被未取代的苯基取代的低级烷基或被卤素或-CF3取代的苯基取代的低级烷基,
或其药用盐。
在本发明的另外的实施方案中,所提供的是一种药物组合物,所述药物组合物包含治疗有效量的根据式(I)的化合物和治疗惰性载体。
在本发明的再另外的实施方案中,所提供的是一种治疗或预防肺纤维化的方法,所述方法包括将治疗有效量的根据式(I)的化合物向需要其的患者给药的步骤。
下面引用或依赖的所有文献通过引用明确地结合至本文中。
除非另外提及,在说明书和权利要求书中使用的以下具体术语和短语定义如下:
如本文所使用的,术语“烷基”,单独或与其他基团组合,是指一个至二十个碳原子,优选一个至十六个碳原子,更优选一个至十个碳原子的支链的或直链的单价饱和脂族烃基团。
术语“低级烷基”,单独或与其他基团组合,是指一个至九个碳原子,优选一个至六个碳原子,更优选一个至四个碳原子的支链的或直链的烷基基团。该术语的进一步的实例是如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、3-甲基-丁基、正己基、2-乙基丁基等的基团。
术语“环烷基”是指三个至十个,优选三个至六个碳原子的、单价的单或多碳环基团。该术语的进一步的实例是如环丙基、环丁基、环戊基、环己基、环庚基、降冰片基、金刚烷基等的基团。在一个优选的实施方案中,“环烷基”部分可以任选地被一个、两个、三个或四个取代基取代,应明白所述取代基不进而被进一步取代。除非另外地具体指出,每个取代基可以独立地为,烷基、烷氧基、卤素、氨基、羟基或氧(O=)。环烷基部分的实例包括,但是不限于,任选地取代的环丙基、任选地取代的环丁基、任选地取代的环戊基、任选地取代的环戊烯基、任选地取代的环己基、任选地取代的亚环己基、任选地取代的环庚基等或本文具体地示例的那些。
术语“杂环烷基”是指单或多环烷基环,其中一个、两个或三个碳环原子被杂原子如N、O或S替代。杂环烷基的实例包括,但是不限于,吗啉基、硫代吗啉基、哌嗪基、哌啶基、吡咯烷基、四氢吡喃基、四氢呋喃基、1,3-二氧己环基等。杂环烷基可以是未被取代的或被取代的,并且可以在合适的地方通过它们的碳框架或通过它们的一个或多个杂原子连接,应明白所述取代基不进而被进一步取代。
术语“芳基”是指具有至少一个芳族环的6至12个碳原子的芳族单或多碳环基团。这种基团的实例包括,但是不限于,苯基、萘基、1,2,3,4-四氢萘、1,2-二氢萘、茚满基、1H-茚基等。
术语″杂芳基″是指具有至少一个含有选自N、O和S的一个、两个或三个环杂原子、余下的环原子是C的芳族环的5至12个原子的芳族单或多环基团。这种基团的实例包括,但是不限于,吡啶、噻唑和吡喃基。
上述烷基、低级烷基、芳基和杂芳基可以独立地被一个、两个或三个取代基取代,应明白所述取代基不进而被进一步取代。取代基可以包括,例如,卤素、低级烷基、-CF3、-SO2CH3、烷氧基、-C(O)CH3、-OH、-SCH3和-CH2CH2OH。
如本文所使用的,术语“烷氧基”意指烷基-O-;并且“烷酰基”意指烷基-CO-。烷氧基取代基或含有烷氧基的取代基可以被,例如,一个或多个烷基取代,应明白所述取代基不进而被进一步取代。
如本文所使用的,术语“卤素”意指氟、氯、溴或碘基团,优选氟、氯或溴基团,并且更优选氟或氯基团。
式I的化合物可以具有一个或多个不对称碳原子并且可以以光学纯对映体、对映体的混合物如外消旋物、光学纯非对映异构体、非对映异构体的混合物、非对映异构体外消旋物或非对映异构体外消旋物的混合物的形式存在。光学活性形式可以例如通过外消旋物的拆分,通过不对称合成或不对称色谱(具有用手性吸附剂或洗脱剂的色谱)获得。本发明包括所有的这些形式。
如本文所使用的,术语“药用盐”意指式(I)的化合物的任何药用盐。盐可以由药用无毒酸和碱包括无机和有机酸和碱制备。这种酸包括,例如,乙酸、苯磺酸、安息香酸、樟脑磺酸、柠檬酸、乙烯磺酸、二氯乙酸、甲酸、富马酸、葡糖酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、草酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、草酸、对甲苯磺酸等。特别优选的是富马酸、盐酸、氢溴酸、磷酸、琥珀酸、硫酸和甲磺酸。药用碱盐包括碱金属(例如钠、钾)、碱土金属(例如钙、镁)和铝盐。
在本发明的方法的实施中,将有效量的本发明的任一种化合物或本发明的任何化合物的组合或其药用盐经由本领域中已知的任何通常的和可接受的方法或单独地或组合地给药。因此可以将化合物或组合物经口(例如,口腔)、舌下、肠胃外(例如,肌肉内、静脉内或皮下)、经直肠(例如,通过栓剂或洗液)、经皮(例如,皮肤电穿孔)或通过吸入(例如,通过气雾剂),并且以固体、液体或气体剂量,包括片剂和悬浮液给药。给药可以任意用连续治疗以单一单位的药物剂型或以单一剂量治疗进行。治疗组合物还可以以与亲脂性盐如扑酸结合的油乳浊液或分散液的形式,或以生物可降解持续释放组合物的形式用于皮下或肌肉内给药。
用于本文的组合物的制备的可用的药物载体可以是固体、液体或气体。因此,组合物可以采取以下形式:片剂、丸剂、胶囊、栓剂、粉末、肠衣或其他被保护的制剂(例如结合在离子交换树脂上或包裹在脂质-蛋白质泡囊中)、缓释剂、溶液、悬浮液、酏剂、气雾剂等。载体可以选自多种油包括源自石油、动物、植物或合成有机物的那些,例如,花生油、大豆油、矿物油、芝麻油等。水、盐水、葡萄糖水溶液和二醇是优选的液体载体,特别是(当与血液等渗压时)用于注射液。例如,用于静脉内给药的制剂包括通过将一种或多种固体活性组分溶解在水中以制备水溶液,并且将溶液灭菌而制备的一种或多种活性组分的无菌水溶液。合适的药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、滑石、明胶、麦芽、大米、面粉、白垩、二氧化硅、硬脂酸镁、硬脂酸钠、甘油单硬脂酸酯、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。该组合物可以附加传统的药物添加剂如防腐剂、稳定剂、湿润剂或乳化剂、用于调节渗透压的盐、缓冲剂等。合适的药物载体和它们的制剂由E.W.Martin描述在Remington′sPharmaceutical Sciences中。这种组合物将,在任何情况下,含有有效量的活性化合物以及合适的载体,以便制备合适的药物剂型用于向受体的适当给药。
本发明的化合物的剂量依赖于多种因素,例如,给药的方式、对象的年龄和体重,以及所要治疗的对象的情况,并且最终将由主治医师或兽医确定。如通过主治医师或兽医确定的活性化合物的这种量在本文中,以及在权利要求书,称为“治疗有效量″。例如,本发明的化合物的剂量典型地在每天约1至约1000mg的范围内。优选地,治疗有效量为每天约1mg至约500mg的量。
在一个实施方案中,本发明提供根据式(I)的化合物,其中X是氧。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中R1是甲基。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中R2是氢、-F、-Cl、-CH2C(O)OH、甲氧基、乙氧基、环丙烷甲酸、未取代的苯基或环己烷乙酸。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中R2是被以下各项取代的苯基:-CH2C(O)OH、环丙烷甲酸或环丙烷甲酸乙基。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中R3是环丁基、氧杂环丁基或未取代的低级烷基。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中R3是被-F、-Cl或-CF3取代的苯基取代的低级烷基。
在另一个实施方案中,所提供的是根据式(I)的化合物,其中X是氧;R1是低级烷基;R2是被以下各项取代的苯基:卤素,-CH2C(O)OH,环丙烷甲酸,环丙烷甲酸乙酯,甲磺酰氨基羰基或四唑;并且R3是被卤素或-CF3取代的苯基取代的低级烷基,或其药用盐。
在再另一个实施方案中,所提供的是根据式(I)的化合物,其中X是氧;R1是甲基;R2是被环丙烷甲酸取代的苯基;并且R3是被卤素或-CF3取代的苯基取代的低级烷基,或其药用盐。
特别的式(I)的化合物包括以下各项:
2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯;
{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-乙酸;
(2-甲基-4-苯基-2H-吡唑-3-基)-氨基甲酸1-(2-氯-苯基)-乙酯;
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸乙酯;
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸;
(4-联苯-4-基-2-甲基-2H-吡唑-3-基)-氨基甲酸(R)-1-苯基-乙酯;
[4-(4-甲氧基-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-苯基-乙酯;
1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸;
{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-乙酸;
[4-(4-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(3-三氟甲基-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯;
(R)-1-{4’-[5-(仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[5-(1,2-二甲基-丙氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[5-((1-(2-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[1-甲基-5-((1-(3-(三氟甲基)苯基)乙氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[5-((1-(4-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[5-(环丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[1-甲基-5-((氧杂环丁烷-3-基氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(S)-1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(3-三氟甲基-苯基)-乙酯;
1-{4′-[5-(3-苄基-脲基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;和1-{4′-[1-甲基-5-((S)-3-苯基-丁酰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。
在本发明的另一个实施方案中,所提供的是用于作为治疗活性物质使用的式(I)的化合物。
在本发明的另一个实施方案中,所提供的是一种药物组合物,所述药物组合物包含治疗有效量的式(I)的化合物和治疗惰性载体。
在本发明的另一个实施方案中,所提供的是根据式(I)的化合物用于治疗或预防肺纤维化的用途。
在本发明的另一个实施方案中,所提供的是根据式(I)的化合物用于制备药物的用途,所述药物用于肺纤维化的治疗或预防。
在本发明的另一个实施方案中,所提供的是根据式(I)的化合物,所述式(I)的化合物用于肺纤维化的治疗或预防。
在本发明的另一个实施方案中,所提供的是根据下面的方法制备的根据式(I)的化合物。
在本发明的另一个实施方案中,所提供的是一种治疗或预防肺纤维化的方法,所述方法包括将治疗有效量的式(I)的化合物向需要其的患者给药的步骤。
在本发明的另一个实施方案中,所提供的是如上所述的发明。
将明白的是,本发明中通式I的化合物可以在官能团处衍生以提供能够在体内转化回母体化合物的衍生物。能够在体内产生通式I的母体化合物的生理学可接受且易代谢的衍生物也在本发明的范围内。
本发明的化合物可以用可商购的原材料开始制备,或采用本领域技术人员已知的一般合成技术和程序制备。化学品可以购自如下公司,例如Aldrich、Argonaut Technologies、VWR、Lancaster、Princeton、Alfa、Oakwood、TCI、Fluorochem、Apollo、Matrix、Maybridge或Meinoah。色谱耗材和设备可以购自如下公司,例如AnaLogix,Inc,Burlington,WI;Biotage AB,Charlottesville,VA;Analytical Sales and Services,Inc.,Pompton Plains,NJ;Teledyne Isco,Lincoln,NE;VWR International,Bridgeport,NJ;Varian Inc.,Palo Alto,CA,以及Multigram II Mettler Toledo InstrumentNewark,DE。Biotage、ISCO和Analogix柱是标准色谱中使用的预填充硅胶柱。最终的化合物和中间体使用MDL ISIS Draw应用软件中的AutoNom2000部件命名。
本发明还针对治疗有效量的式I的化合物与用于治疗炎症性或过敏性病症和疾病的其他药物或活性剂的组合或联合给药。在一个实施方案中,本发明涉及一种用于治疗和/或预防这种病症或疾病的方法,所述方法包括将治疗有效量的式I的化合物和另一种药物或活性剂(如另一种抗炎或抗过敏药物或试剂)同时地、相继地或分别地给药至人类或动物。这些其他的药物或活性剂可以具有相同的、相似的或完全不同的作用模式。合适的其他药物或活性剂可以包括,但是不限于:β2-肾上腺素能激动剂如沙丁胺醇(albuterol)或沙美特罗(salmeterol);皮质类固醇如地塞米松(dexamethasone)或氟替卡松(fluticasone);抗组胺药如氯雷他定(loratidine);白三烯拮抗剂如孟鲁司特(montelukast)或扎鲁司特(zafirlukast);抗IgE抗体治疗药如奥马佐单抗(omalizumab);抗感染药如夫西地酸(fusidic acid)(特别是用于治疗特应性皮炎);抗真菌药如克霉唑(clotrimazole)(特别是用于治疗特应性皮炎);免疫抑制剂如他罗利姆(tacrolimus)和吡美莫司(pimecrolimus);作用于其他受体如DP拮抗剂的PGD2的其他拮抗剂;4型磷酸二酯酶的抑制剂如西洛司特(cilomilast);调节细胞因子产生的药物如TNF-α转化酶(TACE)的抑制剂;调节Th2细胞因子IL-4和IL-5的活性的药物如阻断单克隆抗体和可溶受体;PPAR-γ激动剂如罗格列酮(rosiglitazone);和5-脂肪氧合酶抑制剂如齐留通(zileuton)。
本发明的化合物可以通过任何传统的方式制备。用于合成这些化合物的合适的方法提供在实施例中。通常,式I的化合物可以根据下面所示方案制备。例如,本发明的特定化合物可以使用方案1中列出的方案制备。
方案1
如方案1中所述,溴-取代的N-烷基吡唑羧酸(1),其中R1可以是低级烷基,可以在酸性条件下酯化以提供对应的甲酯(2)。化合物(1)可以是4-溴-2-甲基-2H-吡唑-3-甲酸。在钯催化的Suzuki偶联条件下,化合物(3)可以通过化合物(2)与硼酸的反应形成,其中R2可以是烷基、芳基、卤素和烷氧基。化合物(3)在碱性条件下的水解可以提供对应的羧酸(4),其可以在Curtis重排反应条件下转化至氨基甲酸酯(5),其中R3可以是烷基、环烷基或芳基-取代的烷基。
方案2
备选地,如方案2中所述,溴-取代的N-烷基-氨基吡唑(6)可以在钯催化剂条件下偶联至芳基硼酸以给出化合物(7),其中R1可以是低级烷基,如甲基,并且R2可以是烷基、芳基、卤素和烷氧基。芳基-取代的氨基吡唑中间体(7)可以与三光气和取代的醇在碱性条件下反应以给出氨基甲酸酯(5),其中R3可以是烷基、环烷基或芳基-取代的烷基。
方案3
备选地,如方案3中所述,化合物(1)可以与取代的醇在Curtis重排条件下反应以给出中间体氨基甲酸酯(8),其中R1可以是低级烷基,如甲基,并且R3可以是烷基、环烷基或芳基-取代的烷基。化合物(8)与芳基硼酸在钯催化下的偶联可以提供所需的化合物(5)。
方案4
在所需的芳基硼酸不可商购的情况下,所需的芳基硼酸的制备描述在方案4中。4-溴苯乙酸衍生物(9)可以与4-羟基硼酸(10)在Suzuki偶联条件下反应,其中R1可以是甲基或乙基,R2和R3可以是氢、低级烷基,或者R2和R3可以连接以形成环,如3元、4元或5元碳环,并且R4可以是氢、烷氧基或卤素如氟。联芳基苯酚(11)可以通过与三氟甲磺酸酐反应转化至对应的三氟甲磺酸酯(12)。化合物(12)中的三氟甲磺酸酯至环状硼酸酯(13)的转化可以通过与双-频哪醇基二硼烷在钯催化下的反应完成。
方案5
为了制备方案5中的联芳基-取代的羧酸衍生物(16),氨基甲酸酯(14)可以与频哪醇合硼酸酯(13)偶联以提供联芳基-取代的N-烷基吡唑中间体(15),其中化合物(14)可以是与方案3中描述的化合物(8)相同的结构。钯催化剂可以是在膦配体,如X-Phos的存在下的乙酸钯。化合物(15)在碱性条件下的水解可以提供所需的羧酸(16),其中R2、R3和R4定义在方案4中,R5可以是低级烷基,如甲基,并且R6可以是烷基、环烷基或芳基-取代的烷基。
方案6
备选地,如方案6中所述,溴-取代的N-烷基-氨基吡唑(17)可以与联芳基-取代的频哪醇合硼酸酯(13)在钯催化条件下偶联以提供联芳基-取代的氨基吡唑(18),其中结构(17)可以是与方案2中的结构(6)相同的。偶联条件可以是在膦配体,如X-Phos的存在下的乙酸钯。联芳基-取代的氨基吡唑(18)可以通过与取代的醇在三光气的存在下反应衍生为对应的氨基甲酸酯(15)。酯(15)的水解可以提供所需的羧酸(16)。
方案7
对于环己基取代的芳基硼酸酯的制备,反应描述在方案7中。化合物(19)可以根据文献过程(WO2009/016462)制备。化合物(20)可以由对应的溴苯酚制备,其中R1可以是氢或氟。化合物(19)与化合物(20)在钯催化下的偶联可以提供化合物(21)。化合物(21)的氢化可以给出所需的苯酚(22),其可以转化至对应的频哪醇合硼酸酯(23)。化合物(23)可以如方案6中所述偶联至溴-取代的氨基吡唑,以提供所需的环己基取代的羧酸。
方案8
对于杂环取代的芳基硼酸的制备,反应描述在方案8中。哌啶乙酸衍生物(24)可以是可商购的或根据文献制备。对于原材料(24),其中R2可以是甲基、乙基或叔丁基,R3和R4可以是氢或烷基,R3和R4可以连接以形成环如三元碳环。对于化合物(24),其中R3和R4连接以形成环丙烷环,其制备可以根据文献过程(WO2008/053194)进行。在Buchwald/Hartwig胺化条件下,(24)与(20)的反应可以提供杂环取代的芳基苯酚醚(25),其中R1可以是氢或氟。(25)的氢化之后苯酚(26)至频哪醇合硼酸酯的转化可以提供所需的芳基硼酸酯(27)。化合物(27)可以如方案6中所述偶联至溴-取代的氨基吡唑以提供所需的杂环取代的羧酸。
方案9
羰基磺酰胺衍生物(37)的制备描述在方案9中。可商购的羧酸(28)可以通过与亚硫酰氯反应转化为对应的酰氯(29),其中(28)中的R3可以是氢或氟,R4和R5可以连接以形成3-或4元碳环状环。化合物(29)可以通过与甲磺酰胺反应转化至羰基磺酰胺衍生物(30)。溴吡唑衍生物(2)可以与4-苄基氧基苯基硼酸(31)在Suzuki偶联条件下反应以提供(32)。(32)通过钯催化的氢化可以产生所需的苯酚衍生物(33),其可以转变至对应的三氟甲磺酸酯(34)。三氟甲磺酸酯(34)与频哪醇基二硼烷在钯催化条件下的进一步反应可以提供关键中间体硼酸酯衍生物(35)。(35)与(30)之间在Suzuki偶联条件下的偶联可以给出所需的联苯衍生物(36),其可以在温和碱性条件下水解并且在Curtius重排条件下进一步转化至所需的氨基甲酸酯(37)。
方案10
四唑衍生物(41)的制备描述在方案10中。硼酸酯中间体(35)与可商购的芳基溴(38)在Suzuki偶联条件下的反应可以提供化合物(39)。在温和碱性条件下,化合物(39)可以水解为对应的羧酸,其可以经历Curtius重排以提供化合物(40)。化合物(40)用叠氮基三甲基硅烷和二-正丁基氧化锡在加热的甲苯中的处理可以产生所需的四唑(41)。
方案11
最终,脲(42)和甲酰胺(43)的制备描述在方案11中。来自方案6的中间体(18)可以与三光气和胺反应以提供对应的脲,其可以水解以给出所需的化合物(42)。用相同的中间体(18),可以通过酰胺形成和酯水解获得甲酰胺(43)。
实施例
虽然本文描写并叙述了某些示例性实施方案,本发明的化合物可以使用合适的原材料根据本文一般性描述的方法和/或通过本领域技术人员可得的方法制备。
缩写的定义:DPPA:二苯基磷酰基叠氮;X-Phos:二环己基[2′,4′,6′-三(1-甲基乙基)[1,1′-联苯]-2-基]-膦;S-Phos:二环己基(2′,6′-二甲氧基[1,1′-联苯]-2-基)-膦;DMF:二甲基甲酰胺;TEA:三乙胺;THF:四氢呋喃;TLC:薄层色谱;SFC:超临界流体色谱;ES+:电喷雾正电荷;ES-:电喷雾负电荷。
实施例1
2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯
将4-溴-2-甲基-2H-吡唑-3-甲酸(6g,29.3mmol)加入至150mL用亚硫酰氯(3.5g,29.3mmol)处理的甲醇。将混合物回流18小时。将溶剂蒸发并将残留物用二氯甲烷和0.5N氢氧化钠溶液萃取。将有机层用盐水洗涤并干燥。在溶剂蒸发之后,获得白色固体(4.19g,65.4%产率),为所需的化合物4-溴-2-甲基-2H-吡唑-3-甲酸甲酯。1H NMR(400MHz,CDCl3)δ3.97(s,3H),4.19(s,3H),7.51(s,1H)。将水性萃取物过滤并用1N盐酸中和。将白色固体过滤并干燥,以给出未反应的原材料羧酸(1.51g)。
将4-溴-2-甲基-2H-吡唑-3-甲酸甲酯(438.1mg,2.0mmol)、苯基硼酸(244mg,2.0mmol)和碳酸铯(1.3g,4.0mmol)溶解在DMF中并将溶液用氩脱气。向该混合物加入Pd(PPh3)4(139mg,0.12mmol)。将混合物在80℃搅拌12小时。将所得到的混合物冷却至室温并过滤。将固体用THF冲洗。将滤液浓缩并通过ISCO快速柱色谱(己烷中0%至25%乙酸乙酯,40g硅胶)提纯以给出油性物质,为2-甲基-4-苯基-2H-吡唑-3-甲酸甲酯(388.6mg,89.8%产率)。1H NMR(400MHz,CDCl3)δppm 3.77(s,3H),4.21(s,3H),7.31-7.36(m,1H),7.37-7.42(m,4H),7.52(s,1H);LC/MS对于C12H12N2O2计算值216.0,实测值217.0(M+H,ES+)。
将2-甲基-4-苯基-2H-吡唑-3-甲酸甲酯(388.6mg,1.8mmol)溶解在THF(8mL)中并加入0.5N LiOH溶液(4mL)。将混合物在60℃搅拌2小时并且之后浓缩。将残留物溶解在水(30mL)中并过滤。将滤液用1N盐酸中和并将白色沉淀过滤并在真空烘箱中在60℃干燥过夜以提供2-甲基-4-苯基-2H-吡唑-3-甲酸(338.5mg,93.1%产率)。1H NMR(300MHz,DMSO-d6)δppm 4.06(s,3H),7.25-7.42(m,5H),7.60(s,1H),13.42(s,1H);LC/MS对于C11H10N2O2计算值202.0,实测值201.0(M-H,ES-)。
将2-甲基-4-苯基-2H-吡唑-3-甲酸(100mg,0.495mmol)、(R)-1-苯基乙醇(60.4mg,0.495mmol)、DPPA(136mg,0.495mmol)和TEA(100mg,0.989mmol)与3mL的甲苯混合。将混合物在80℃搅拌1小时。将溶剂蒸发并将残留物通过ISCO快速柱色谱(40g硅胶,己烷中0%至55%乙酸乙酯)提纯以给出2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯,为白色粉末(106mg,66.7%产率)。1H NMR(300MHz,DMSO-d6)δppm1.13-1.29(br,0.7H),1.52(d,J=5.8Hz,2.3H),3.60(s,3H),5.58-5.82(br m,1H),6.92-7.53(m,10H),7.74(s,1H),9.18(br,0.2H),9.55(s,0.8H);LC/MS对于C19H19N3O2计算值321.0,实测值320.0(M-H,ES-)。
实施例2
{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-乙酸
将4-溴-2-甲基-2H-吡唑-3-甲酸(787.2mg,3.84mmol),DPPA(1.16g,4.22mmol),(R)-1-苯基乙醇(491mg,4.02mmol)和TEA(1.10mL,7.68mmol)在15mL的甲苯中合并以给出澄清的溶液。将混合物加热至80℃并搅拌1小时。将溶剂蒸发并将残留物用乙酸乙酯和碳酸氢钠溶液萃取。将有机层干燥并蒸发以给出油性材料(1.38g)。TLC指示无UV吸收。粗材料的1H-NMR指示75%所需的化合物,为4-溴-2-甲基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯。LRMS对于C13H14BrN3O2(m/e)计算值324.0,实测值323.0(M-H,ES-)。
将2-(4-溴苯基)-乙酸乙酯(2.43g,10mmol)、4-羟基苯基硼酸(1.65g,1.20当量),Pd(PPh3)4(693mg,0.06当量)和碳酸钾(2.76g,2.0当量)在14mL的无水DMF中合并。将混合物用氮鼓泡并密封。将混合物在85℃搅拌15小时。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层用盐水洗涤并在硫酸钠上干燥。将溶剂蒸发并将残留物通过ISCO快速柱色谱(己烷中5%至50%乙酸乙酯)提纯。将纯级分合并并浓缩。将残留物溶解在乙酸乙酯(4mL)中并加入热己烷。将白色固体过滤并干燥以给出4’-羟基-联苯-4-基-乙酸乙酯(1.68g,65.6%产率)。1H NMR(400MHz,CDCl3)δppm 1.29(t,J=7.1Hz,3H)3.66(s,2H)4.19(q,J=7.1Hz,2H),4.95(br.s.,1H),6.87(d,J=8.6Hz,2H),7.33(d,J=8.3Hz,2H)7.47(m,4H);LC/MS对于C16H16O3(m/e)计算值256.0,实测值257.1(M+H,ES+)。
将2-(4′-羟基联苯-4-基)-乙酸乙酯(641mg,2.5mmol)溶解在二氯甲烷(15mL)中。向该溶液在-78℃加入三氟甲磺酸酐(706mg,0.42mL)。加入三乙胺(0.35mL,2.5mmol)。将混合物在-78℃搅拌10分钟并升温至室温。在30分钟之后,TLC指示原材料的完全消耗。将混合物用水和二氯甲烷萃取。将有机层用稀盐酸和浓碳酸氢钠溶液洗涤。将溶剂蒸发并将残留物用己烷处理。将灰色晶体材料过滤以给出4’-三氟甲磺酰基氧基-联苯-4-基-乙酸乙酯(812mg,83.6%产率)。1H NMR(400MHz,CDCl3)δppm 1.29(t,J=7.1Hz,3H),3.68(s,2H),4.19(q,J=7.1Hz,2H),7.35(d,J=8.1Hz,2H),7.39(d,J=8.1Hz,2H),7.53(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H)。
将2-(4′-(三氟甲磺酰基氧基)-联苯-4-基)-乙酸乙酯(800mg,2.06mmol)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-联(1,3,2-二氧杂硼杂环戊烷)(628mg,2.47mmol)、乙酸钾(607mg,6.18mmol)和Pd(dppf)Cl2(90.4mg,0.124mmol)合并在无水二烷(15mL)中。将混合物在氩鼓泡通过的情况下搅拌5分钟。将混合物加热至90℃并搅拌4小时。TLC显示与原材料相同的Rf。LC/MS显示原材料的完全消耗和所需的化合物的形成。将混合物通过硅胶层过滤并用乙酸乙酯冲洗。将溶剂蒸发并将残留物通过ISCO快速柱色谱(40g硅胶,己烷中0%至30%乙酸乙酯)提纯,以给出[4’-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-联苯-4-基]-乙酸乙酯,为白色固体(728mg,96.5%产率)。1H NMR(400MHz,CDCl3)δppm 1.28(t,J=7.1Hz,3H),1.37(s,12H),3.67(s,2H),4.18(q,J=7.1Hz,2H),7.37(d,J=8.1Hz,2H),7.60(dd,J=8.0,6.4Hz,4H),7.88(d,J=8.1Hz,2H)。
将乙酸钯(12.5mg,0.055mmol)、X-PHOS(CAS#564483-18-7,52.9mg,0.11mmol)和磷酸三钾(236mg,1.11mmol)在0.5mL的脱气水和1mL的甲苯中混合并搅拌1分钟。之后加入2mL的甲苯中的4-溴-2-甲基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯(180mg,0.55mmol),之后加入[4’-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-联苯-4-基]-乙酸乙酯(203mg,0.55mmol)和1mL的甲苯。将混合物用氩脱气并密封。将混合物在95℃搅拌过夜。所得到的混合物用乙酸乙酯和水萃取。将有机层干燥并蒸发。将残留物通过ISCO快速柱色谱(40g硅胶,乙酸乙酯与己烷中5%甲醇)提纯以给出(R)-2-(4′-(1-甲基-5-((1-苯基乙氧基)羰基氨基)-1H-吡唑-4-基)-联苯-4-基)-乙酸乙酯(78.0mg,29.1%产率),为无定形材料。LC/MS对于C29H29N3O4(m/e)计算值483.0,实测值484.1(M+H,ES+)。
将(R)-2-(4′-(1-甲基-5-((1-苯基乙氧基)羰基氨基)-1H-吡唑-4-基)-联苯-4-基)-乙酸乙酯(78mg,0.161mmol)溶解在6mL的THF中并加入氢氧化锂溶液(1mL,0.5N),之后加入0.2mL的甲醇。将混合物在室温搅拌4小时。TLC指示原材料的完全消耗。将混合物浓缩并且之后溶解在温水(35mL)中。将混合物搅拌并过滤。将滤液用1N盐酸(0.6mL)酸化并将混合物过滤。将固体在真空下干燥过夜以给出浅黄色固体,为{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-乙酸(30mg,40.8%产率)。1H NMR(400MHz,DMSO-d6)δppm 1.15-1.32(br,0.6H),1.56(d,J=5.8Hz,2.4H),3.62(s,2H),3.63(s,3H),5.66-5.83(br m,1H),7.03(br,0.5H),7.18(br,0.5H),7.28-7.38(m,3H),7.38-7.48(m,3H),7.49-7.56(m,1H),7.57-7.68(m,5H),7.81(s,1H),9.24(br,0.2H),9.62(s,0.8H),12.38(s,1H);LC/MS对于C27H25N3O4(m/e)计算值455.0,实测值456.0(M+H,ES+)。
实施例3
(2-甲基-4-苯基-2H-吡唑-3-基)-氨基甲酸1-(2-氯-苯基)-乙酯
将2-甲基-4-苯基-2H-吡唑-3-甲酸(在实施例1中作为中间体制备,60mg,0.297mmol)、1-(2-氯苯基)乙醇(46.5mg,0.297mmol)、DPPA(81.7mg,0.297mmol)和三乙胺(0.09mL)在2.5mL的甲苯中合并。将混合物在85℃搅拌3小时。将溶剂蒸发并将残留物通过ISCO快速柱色谱(己烷中0%至50%乙酸乙酯)提纯以给出(2-甲基-4-苯基-2H-吡唑-3-基)-氨基甲酸1-(2-氯-苯基)-乙酯,为白色绒毛状固体(40mg,38%产率)。1H NMR(400MHz,DMSO-d6)δppm 1.15-1.28(br,0.6H),1.55(d,J=5.8Hz,2.4H),3.54-3.78(m,3H),5.82-6.10(m,1H),7.23(d,J=6.8Hz,1H),7.28-7.54(m,7H),7.59(d,J=6.8Hz,1H),7.76(br s,1H),9.31(br,0.2H),9.68(s,0.8H)。LC/MS对于C19H18ClN3O2(m/e)计算值355.0,实测值356.0(M+H,ES+)。
实施例4
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸乙酯
将1-(4-溴苯基)环丙烷甲酸乙酯(2.5g,9.29mmol)、4-羟基苯基硼酸(1.67g,12.1mmol)、碳酸钾(2.57g,18.6mmol)和Pd(PPh3)4(644mg,0.557mmol)在DMF(15mL)中合并。将混合物用氮脱气并密封。将混合物在85℃搅拌15小时。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层用稀盐酸和水洗涤,在硫酸钠上干燥并过滤。将溶剂蒸发并将残留物从乙酸乙酯和己烷结晶以获得第一批淡黄色固体(1.36g),为1-(4′-羟基联苯-4-基)环丙烷甲酸乙酯。将母液浓缩并从乙酸乙酯和己烷结晶,以给出第二批的晶体化合物(330mg)。两批都给出相同的1H-NMR(总计1.69g,64.4%产率)。1H-NMR(400MHz,CDCl3)δppm 1.15-1.32(m,5H),1.60-1.71(m,2H),4.14(q,J=7.1Hz,2H),5.15(br s,1H),6.85(d,J=8.6Hz,2H),7.39(d,J=8.1Hz,2H),7.42-7.54(m,4H)。
将1-(4′-羟基联苯-4-基)环丙烷甲酸乙酯(1.41g,4.99mmol)和TEA(0.8mL)溶解在二氯甲烷(80mL)中。将溶液在干冰/丙酮条件下搅拌并且通过注射器加入二氯甲烷(4mL)中的三氟甲磺酸酐(1.48g,5.24mmol)。将溶液搅拌30分钟并且将冷却浴移除。将混合物在室温搅拌1小时。将溶液用二氯甲烷和水萃取。将有机层用稀盐酸、水和碳酸氢钠溶液洗涤,在硫酸钠上干燥并过滤。将溶剂蒸发以给出油性材料(1.98g,95.7%产率),为1-(4′-(三氟甲磺酰基氧基)-联苯-4-基)-环丙烷甲酸乙酯。1H-NMR(400MHz,CDCl3)δppm 1.16-1.26(m,5H),1.62-1.70(m,2H),4.13(q,J=7.1Hz,2H),7.35(d,J=8.6Hz,2H),7.44(d,J=8.1Hz,2H),7.51(d,J=8.3Hz,2H),7.65(d,J=8.8Hz,2H)。
将1-(4′-(三氟甲磺酰基氧基)-联苯-4-基)-环丙烷甲酸乙酯(1.98g,4.78mmol)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-联(1,3,2-二氧杂硼杂环戊烷)(1.46g,5.73mmol)和乙酸钾(1.41g,14.3mmol)混合在无水二烷(15mL)中。向该混合物加入Pd(dppf)Cl2(280mg,0.38mmol)并将混合物用氮脱气2分钟。将混合物密封并在预加热至90℃的油浴下搅拌。在4小时搅拌之后,LC/MS指示所需的产物和不再有原材料。将混合物冷却至室温并用乙酸乙酯(40mL)稀释。将混合物通过硅藻土的薄层过滤。将滤液浓缩并将残留物用乙酸乙酯(30mL)和己烷(90mL)处理。将混合物过滤。将滤液浓缩并通过ISCO快速柱色谱(己烷中乙酸乙酯0%至20%,在20分钟内,120g硅胶)提纯,以给出白色固体,为1-(4′-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-联苯-4-基)-环丙烷甲酸乙酯(1.03g,55%产率)。1H-NMR(400MHz,CDCl3)δppm 1.17-1.30(m,5H),1.39(s,12H),1.60-1.71(m,2H),4.14(q,J=7.1Hz,2H),7.43(d,J=8.1Hz,2H),7.54-7.70(m,4H),7.90(d,J=8.0Hz,2H)。
将1-(4′-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-联苯-4-基)-环丙烷甲酸乙酯(100mg,0.255mmol)、4-溴-1-甲基-1H-吡唑-5-胺(67.3mg,1.50当量)、X-PHOS(36.5mg,0.30当量)、磷酸三钾(162mg,3.0当量)和乙酸钯(8.6mg,0.15当量)在4mL的甲苯中混合。将混合物搅拌并加入脱气水(0.8mL)。将混合物用氮脱气并密封。将混合物在100℃搅拌过夜并且之后用乙酸乙酯和水萃取。将溶剂蒸发并将残留物通过ISCO快速柱色谱(二氯甲烷中甲醇0%至10%,12g硅胶)提纯,以给出浅灰色固体,为1-[4′-(5-氨基-1-甲基-1H-吡唑-4-基)-联苯-4-基]-环丙烷甲酸乙酯(48mg,52.1%产率)。1H-NMR(400MHz,CDCl3)δppm 1.19-1.25(m,5H),1.64(m,2H),3.77(s,3H),3.81(br s,2H),4.13(q,J=7.1Hz,2H),7.44(t,J=8.8Hz,4H),7.53(s,1H),7.56(d,J=8.1Hz,2H),7.64(d,J=8.1Hz,2H);LC/MS对于C22H23N3O2(m/e)计算值361.0,实测值362.1(M+H,ES+)。
将1-(4′-(5-氨基-1-甲基-1H-吡唑-4-基)-联苯-4-基)-环丙烷甲酸乙酯(100mg,0.277mmol)和三光气(123mg,0.415mmol)溶解在二氯甲烷(2mL)中以给出溶液。加入甲苯(6mL)并将混合物搅拌之后加入TEA(0.16mL)。将混合物密封并在90℃搅拌10分钟。加入甲苯(2mL)中的(R)-(+)-1-苯基乙醇(68mg,0.553mmol)。将混合物在105℃搅拌2小时。TLC指示一个主要的斑点和原材料的完全消失。将混合物用乙酸乙酯和氯化铵溶液萃取。将有机层在硫酸钠上干燥并过滤。将溶剂蒸发并将残留物通过ISCO快速柱色谱(12g硅胶,己烷中0%至60%乙酸乙酯,在15分钟内)提纯,以给出灰色粉末,为1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸乙酯(101mg,71.6%产率)。1H-NMR(400MHz,CDCl3)δppm 1.20-1.34(m,6H),1.49-1.75(m,4H),3.80(s,3H),4.14(q,J=7.1Hz,2H),5.93(m,1H),6.25(br s,1H),7.35-7.48(m,9H),7.53-7.64(m,4H),7.72(s,1H);LC/MS对于C31H31N3O4(m/e)计算值509.0,实测值510.0(M+H,ES+)。
实施例5
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
将1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸乙酯(80mg,0.157mmol)溶解在4mL的THF中并加入氢氧化锂溶液(0.5N,2mL)。将混合物在室温搅拌5分钟。加入甲醇(1mL)以给出澄清的溶液。将混合物在65℃搅拌5小时并且之后在30℃搅拌过夜。将溶剂蒸发并将残留物溶解在水(12mL)中。加入盐酸(1N,1.3mL)并将固体过滤以给出白色固体(65mg)。LC/MS指示85%纯度,主要杂质为氨基甲酸酯的断裂产物。将该固体溶解在乙腈/二氯甲烷(含有5%甲醇)中并通过ISCO快速柱色谱(12g硅胶,二氯甲烷中0%至5%甲醇,在15分钟内)提纯,以给出白色固体,为1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸(45mg,59.5%产率)。1H-NMR(400MHz,DMSO-d6)δppm 1.19-1.25(m,2H),1.49-1.57(m,5H),3.64(s,3H),5.65-5.83(m,1H),6.95-7.25(br m,1H),7.27-7.48(m,6H),7.49-7.67(m,6H),7.82(br s,1H),9.25(br s,0.2H),9.57(s,0.8H),12.35(s,1H);LC/MS对于C29H27N3O4(m/e)计算值481.0,实测值482.1(M+H,ES+)。
实施例6
1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸
将1-(4′-(5-氨基-1-甲基-1H-吡唑-4-基)-联苯-4-基)-环丙烷甲酸乙酯(来自实施例4的中间体,133mg,0.368mmol)与三光气(164mg,0.552mmol)在二氯甲烷(5mL)中混合。加入甲苯(5mL)并将混合物搅拌。向该混合物加入TEA(0.5mL)并将反应管密封。将混合物在90℃搅拌10分钟并冷却至40℃。加入甲苯(1mL)中的1-(2-氯苯基)-乙醇(115mg,0.736mmol)。将混合物在105℃搅拌1小时。将混合物冷却至室温并在减压下蒸发。将残留物用乙酸乙酯和水萃取,干燥并蒸发。将残留物通过ISCO快速柱色谱(40g硅胶,己烷中10%至65%乙酸乙酯)提纯以给出白色绒毛状固体,为1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸乙酯(141mg,70.4%产率)。LC/MS对于C31H30ClN3O4(m/e)计算值543,实测值544.1(M+H,ES+)。
将1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸乙酯(140mg,0.257mmol)溶解在4mL的THF中并加入LiOH溶液(0.5N,2mL)。将混合物在65℃搅拌过夜。LC/MS指示显著量的脱氨基甲酸酯副产物。将混合物浓缩并用1N盐酸处理。将白色固体过滤并干燥(75mg)。将该材料使用反相HPLC(水中的乙腈)提纯,以给出1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸,为白色冻干无定形材料(20mg,15.1%产率)。1H-NMR(400MHz,DMSO-d6)δppm 1.14-1.30(m,2.6H),1.42-1.52(m,2H),1.57(d,J=5.8Hz,2.4H),6.03(d,J=6.1Hz,1H),7.29-7.69(m,12H),7.83(s,1H),9.37(br s,0.2H),9.74(s,0.8H),12.35(br s,1H);LC/MS对于C29H26ClN3O4(m/e)计算值515.0,实测值516.0(M+H,ES+)。
实施例7
(4-联苯-4-基-2-甲基-2H-吡唑-3-基)-氨基甲酸(R)-1-苯基-乙酯
通过使用联苯-4-基-硼酸和4-溴-2-甲基-2H-吡唑-3-甲酸甲酯,以与对于2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯的制备描述的相同的方法制备该化合物。LC/MS对于C25H23N3O2(m/e)计算值397,实测值398.0(M+H,ES+)。
实施例8
[4-(4-甲氧基-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-苯基-乙酯
通过使用4-甲氧基苯基-硼酸和4-溴-2-甲基-2H-吡唑-3-甲酸甲酯,以与对于2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯的制备描述的相同的方法制备该化合物。1H-NMR(400MHz,DMSO-d6)δppm1.15-1.30(br,0.6H),1.54(d,J=5.8Hz,2.4H),3.60(br s,3H),3.75(s,3H),5.76(d,J=6.1Hz,1H),6.87(d,J=7.6Hz,2H),6.97-7.25(m,1H),7.28-7.51(m,6H),7.67(s,1H),9.12(br s,0.2H),9.48(br s,0.8H);LC/MS对于C25H23N3O2(m/e)计算值397,实测值398.0(M+H,ES+);LC/MS对于C20H21N3O3(m/e)计算值351,实测值350.0(M-H,ES-)。
实施例9
1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸
将4-溴-1-甲基-1H-吡唑-5-基-氨基甲酸(R)-1-苯基乙酯(165mg,0.51mmol)、1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯基)-环丙烷甲酸甲酯(154mg,0.51mmol)、S-PHOS(CAS#657408-07-6,62.7mg,0.153mmol)、乙酸钯(17.1mg,0.076mmol)溶解在甲苯(4mL)中,并加入脱气水(1mL)中的磷酸三钾(324mg,1.53mmol)。将混合物脱气5分钟并密封。将混合物在100℃搅拌过夜并且之后用乙酸乙酯和水萃取。将有机层用盐水洗涤并干燥。将溶剂蒸发并将残留物通过ISCO快速柱色谱使用己烷中的乙酸乙酯(0%至50%,24g硅胶)提纯以给出蜡状浅黄色物质,为1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸甲酯(123mg,57.6%产率)。LC/MS对于C24H25N3O4(m/e)计算值419.0,实测值420.0(M+H,ES+)。
将(R)-1-(4-(1-甲基-5-((1-苯基乙氧基)羰基氨基)-1H-吡唑-4-基)-苯基)-环丙烷甲酸甲酯(123mg,0.29mmol)溶解在THF(4mL)中,并加入氢氧化锂水溶液(0.5N,1mL)。将反应加热至65℃并搅拌4小时。将溶剂蒸发并将残留物用温水(25mL)处理并在室温搅拌1小时。将混合物过滤并将滤液用1N盐酸(0.5mL)处理。将白色固体过滤并用水冲洗并在空气中干燥以给出1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸(42mg,35.4%产率)。LC/MS对于C23H23N3O4(m/e)计算值405,实测值406(M+H,ES+)。
实施例10
{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-乙酸
通过使用2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯基)-乙酸乙酯和4-溴-1-甲基-1H-吡唑-5-基-氨基甲酸(R)-1-苯基乙酯,使用与对于1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸的制备的描述相同的方法制备该化合物。LC/MS对于C21H21N3O4(m/e)计算值379.0,实测值380.0(M+H,ES+)。
实施例11
[4-(4-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯
将4-氟苯基硼酸(211mg,1.51mmol)、4-溴-1-甲基-1H-吡唑-5-甲酸甲酯(300mg,1.37mmol)、碳酸铯(893mg,2.74mmol)和Pd(PPh3)4(95mg,0.082mmol)混合在甲苯(12mL)中。将混合物用氮脱气并密封。将混合物在90℃搅拌过夜并且之后浓缩。将残留物用乙酸乙酯和水萃取。将有机层干燥并蒸发。将残留物通过ISCO快速柱色谱(40g硅胶,己烷中0%至30%乙酸乙酯)提纯以给出油性材料,为4-(4-氟苯基)-2-甲基-2H-吡唑-3-甲酸甲酯(140mg,43.6%产率)。1H-NMR(400MHz,CDCl3)δppm 3.78(s,3H),4.21(s,3H),7.08(t,J=8.5Hz,2H),7.35(m,2H),7.49(s,1H)。
将4-(4-氟苯基)-2-甲基-2H-吡唑-3-甲酸甲酯(140mg,0.60mmol)溶解在THF(4mL)中并加入LiOH溶液(0.5N,2mL)。将混合物在室温搅拌4小时。将混合物浓缩并溶解在水中。将溶液用1N盐酸(1.10mL)处理。将混合物用乙酸乙酯萃取。将有机层干燥并浓缩以给出油性材料(115mg,87.4%产率),为4-(4-氟苯基)-2-甲基-2H-吡唑-3-甲酸。
将4-(4-氟苯基)-2-甲基-2H-吡唑-3-甲酸(106mg,0.48mmol)、DPPA(132mg,0.48mmol)、1-(2-氯苯基)乙醇(76mg,0.48mmol)和TEA(0.2mL)在5mL的甲苯中搅拌。将混合物加热至90℃并搅拌1小时。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层用碳酸氢钠溶液洗涤并干燥。将溶剂蒸发并将残留物通过ISCO快速柱色谱(己烷中0%至60%乙酸乙酯)提纯,以给出[4-(4-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯,为白色固体(116mg,64.5%产率)。1H-NMR(400MHz,DMSO-d6)δppm 1.15-1.30(br,0.6H),1.56(br d,J=5.3Hz,2.4H),3.62(br s,3H),5.86-6.06(m,1H),6.81-7.27(m,3H),7.31-7.65(m,5H),7.76(br s,1H),9.32(s,0.2H),9.65(s,0.8H);LC/MS对于C19H17ClFN3O2(m/e)计算值373.0,实测值374.0(M+H,ES+)。
实施例12
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(3-三氟甲基-苯基)-乙酯
将4-溴-1-甲基-1H-吡唑-5-胺(800mg,4.55mmol)、2-氟苯基硼酸(890mg,6.36mmol)、X-PHOS(217mg,0.45mmol)、乙酸钯(51mg,0.227mmol)和磷酸三钾(1.93g,9.09mmol)合并,并加入甲苯(12mL)。向搅拌下的混合物加入脱气水(4mL)并将混合物脱气并且之后密封。将混合物在95℃搅拌过夜。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层用盐水洗涤并干燥。将溶剂蒸发并将残留物通过ISCO快速柱色谱(己烷中含有3%甲醇的10%至80%乙酸乙酯,40g硅胶)提纯以给出4-(2-氟苯基)-2-甲基-2H-吡唑-3-胺,为棕色油(649mg,74.7%产率)。1H-NMR(400MHz,DMSO-d6)δppm 3.60(s,3H),5.30(br s,2H),7.14-7.25(m,3H),7.30(d,J=2.5Hz,1H),7.39-7.52(m,1H);LC/MS对于C10H10FN3(m/e)计算值191.0,实测值192.0(M+H,ES+)。
将4-(2-氟苯基)-2-甲基-2H-吡唑-3-胺(150mg,0.78mmol)和三光气(303mg,1.02mmol)溶解在二氯甲烷(3mL)中。加入甲苯(8mL)并将混合物密封。将混合物在冰浴中搅拌并加入TEA(0.9mL,8.0当量)。将混合物在85℃搅拌20分钟并加入甲苯(2mL)中的1-(3-(三氟甲基)-苯基)乙醇(194mg,1.02mmol)。将混合物在90℃搅拌2小时。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层用盐水洗涤并干燥。将溶剂蒸发并将残留物通过ISCO快速柱色谱(己烷中0%至60%乙酸乙酯)提纯以给出[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(3-三氟甲基-苯基)-乙酯,为浅黄色蜡状物质(226mg,70.7%产率)。1H-NMR(400MHz,DMSO-d6)δppm 1.11-1.29(m,0.6H),1.55(br d,J=5.81Hz,2.4H),3.65(s,3H),5.73-5.85(m,1H),7.06-7.24(m,2H),7.25-7.52(m,3H),7.56-7.82(m,4H),9.29(br s,0.2H),9.66(s,0.8H);LC/MS对于C20H17F4N3O2(m/e)计算值407.0,实测值408.0(M+H,ES+)。
实施例13
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯
将4-(2-氟苯基)-2-甲基-2H-吡唑-3-胺(110mg,0.575mmol)和三光气(222mg,0.748mmol)混合在二氯甲烷(4mL)中,并加入甲苯(6mL)并将管密封。将混合物在冰浴中搅拌并加入三乙胺(0.7mL)。将混合物在85℃搅拌20分钟并加入1mL的甲苯中的1-(2-氯苯基)乙醇(117mg,0.748mmol)。将混合物在90℃搅拌1小时。将溶剂蒸发并将残留物用乙酸乙酯和水萃取。将有机层干燥并浓缩。将残留物通过ISCO快速柱色谱(己烷中0%至50%乙酸乙酯)提纯以给出[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯,为无定形粉末(134mg,62.3%产率)。1H-NMR(400MHz,DMSO-d6)δppm 1.06-1.28(m,0.6H),1.53(br d,J=5.6Hz,2.4H),3.65(br s,3H),5.83-5.98(m,1H),6.83-7.50(m,7H),7.56(d,J=6.8Hz,1H),7.65(br s,1H),9.31(br,0.2H),9.66(s,0.8H);LC/MS对于C19H17ClFN3O2(m/e)计算值373.0,实测值372.0(M-H,ES-)。
实施例14
(R)-1-{4’-[5-(仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
在250mL圆底烧瓶中,将1-(4-溴苯基)-环丙烷甲酸甲酯(9.4g,36.8mmol)、4-羟基苯基硼酸(6.61g,47.9mmol,1.3当量)和碳酸钾(10.2g,73.7mmol,2.0当量)与DMF(50mL)合并以给出浅棕色悬浮液。加入Pd(Ph3P)4(2.55g,2.21mmol,0.06当量)并将混合物抽真空并用氩吹扫。将反应混合物加热至85℃并在氩下搅拌17h。将粗反应混合物在真空中浓缩。将残留物在H2O与EtOAc之间分配并过滤。将相分离并将有机层用0.1M HCl(15mL)、H2O(15mL)和饱和NaCl(15mL)洗涤。将有机层在Na2SO4上干燥并在真空中浓缩。将残留物置于热EtOAc和己烷中,并且由不溶的红色固体倾析。将黄色上清液汽提并从EtOAc和己烷重结晶以给出4.49g(46%)的1-(4′-羟基联苯-4-基)环丙烷甲酸甲酯,为灰白色固体。将滤液汽提并将残留物由EtOAc/己烷再结晶,以给出另外的1.64g(17%)的所需的产物,为粉色粉末。1H NMR(DMSO-d6)δppm 9.53(s,1H),7.45-7.55(m,4H),7.29-7.38(m,2H),6.82-6.86(m,2H),3.59(s,3H),),1.46-1.52(m,2H),1.20-1.24(m,2H)。
在500mL圆底烧瓶中,将1-(4′-羟基联苯-4-基)环丙烷甲酸甲酯(3g,11.2mmol)和TEA(1.64mL,11.7mmol,1.05当量)与二氯甲烷(200mL)合并以给出黄色悬浮液。将混合物冷却至-78℃并加入三氟甲磺酸酐(3.31g,11.7mmol,1.05当量)。将反应物在-78℃搅拌30分钟,之后在25℃搅拌1h。将反应混合物用H2O稀释并将有机层用0.5M HCl(200mL)、H2O(200mL)和饱和NaHCO3(150mL)洗涤。将有机层在Na2SO4上干燥并在硅胶床上过滤以移除暗红色杂质。将滤液在真空中浓缩以给出1-(4’-三氟甲磺酰基氧基-联苯-4-基)环丙烷甲酸甲酯。将粗材料在不进一步提纯的情况下在接下来的反应中使用。
在1L圆底烧瓶中,将1-(4′-(三氟甲磺酰基氧基)联苯-4-基)环丙烷甲酸甲酯(2.8g,6.99mmol)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-联(1,3,2-二氧杂硼杂环戊烷)(2.13g,8.39mmol,1.2当量)和乙酸钾(2.06g,21.0mmol,3.0当量)与二烷(10mL)合并以给出棕色悬浮液。加入PdCl2(dppf)(457mg,559μmol,0.08当量),将反应混合物加热至90℃并搅拌4h,之后在25℃搅拌12h。将反应物用EtOAc稀释,通过硅藻土过滤并在真空中汽提。将粗材料通过在硅胶上在真空下过滤、用Hex/EtOAc 1∶1洗脱提纯。将滤液汽提为灰白色粉末。将该材料通过快速色谱(硅胶,300g,庚烷中0%至20%EtOAc)再提纯以给出2.11g(78%)的1-[4’-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-联苯-4-基]-环丙烷甲酸甲酯,为灰白色结晶固体。(M+H)+=379.0(m/e)。1H NMR(DMSO-d6)δppm 7.72-7.94(m,2H),7.53-7.72(m,4H),7.26-7.53(m,J=8.6Hz,2H),3.65(s,3H),1.40-1.64(m,2H),1.27-1.40(m,12H),1.21-1.27(m,2H)。
向50mL管加入在甲苯(31mL)和水(6mL)中的1-(4′-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)联苯-4-基)环丙烷甲酸甲酯(2.033g,5.37mmol)、4-溴-1-甲基-1H-吡唑-5-胺(1.23g,6.99mmol,1.3当量)、X-Phos(769mg,1.61mmol,0.30当量)和K3PO4(3.42g,16.1mmol,3.0当量)。加入Pd(OAc)2(181mg,806μmol,0.15当量)并将管密封。将反应物用氩吹扫并在100℃加热21h。将反应物冷却并用EtOAc和水稀释。将悬浮液过滤并且相分离。将有机层在Na2SO4上干燥并在真空中浓缩。将粗材料通过快速色谱(硅胶,300g,二氯甲烷中0%至5%甲醇)提纯。将产物作为不纯的油性红色固体分离。将该材料置于最小量的温二氯甲烷中并且用己烷沉淀。将悬浮液过滤并将滤液在真空中汽提。将残留物置于最小量的温二氯甲烷中并用己烷沉淀。将上清液从茶色固体倾析并将固体用己烷洗涤。将合并的固体在真空下干燥以给出738mg(39%)的1-[4’-(5-氨基-1-甲基-1H-吡唑-4-基)-联苯-4-基]-环丙烷甲酸甲酯。(M+H)+=348.2(m/e);1H NMR(DMSO-d6)δppm 7.37-7.63(m,8H),7.11(s,1H),5.40(s,2H),3.52-3.61(m,6H)1.49(d,J=3.0Hz,2H),1.22(d,J=3.0Hz,2H)。
在25mL管中,将1-(4′-(5-氨基-1-甲基-1H-吡唑-4-基)-联苯-4-基)-环丙烷甲酸甲酯(94mg,271μmol)与2mL的二氯甲烷和5mL的甲苯合并。向该悬浮液加入三光气(120mg,406μmol,1.5当量)之后加入TEA(151μL,1.08mmol,4当量)。将管密封并将混合物在90℃搅拌30分钟。将混合物冷却并加入(R)-丁-2-醇(40.1mg,49.8μL,541μmol,2当量)。将反应混合物密封并加热至90℃持续2h。将反应物在EtOAc与饱和NH4Cl之间分配。将有机层用H2O(25mL)、饱和NaCl(25mL)洗涤,在Na2SO4上干燥并在真空中浓缩。将粗材料通过快速色谱(硅胶,40g,100%EtOAc)提纯以给出60mg(50%)的1-{4’-[5-((R))-仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸甲酯,为灰白色固体。(M+H)+=448.0(m/e)。
在250mL圆底烧瓶中,将(R)-1-(4′-(5-(仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(60mg,134μmol)与四氢呋喃(3mL)和甲醇(3.00mL)合并以给出浅黄色溶液。加入1M NaOH(1.34mLl,1.34mmol,10当量)并将反应混合物在45℃搅拌4h。将反应物浓缩并用1M HCl酸化。将残留物在二氯甲烷与水之间分配。将水层用二氯甲烷(10mL)反萃取。将有机层合并,用H2O(10mL)洗涤并在真空中干燥以给出54mg(93%)的(R)-1-{4’-[5-(仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸,为白色粉末。LC/MS对于C25H27N3O4(m/e)计算值433.0,实测值434.1(M+H,ES+);1H NMR(DMSO-d6)δppm 12.32(br.s.,1H),9.38(br.s.,1H),7.80(s,1H),7.50-7.69(m,6H),7.38(d,J=8.3Hz,2H),4.69(br.s.,1H),3.65(s,3H),1.58(br.s.,2H),1.33-1.52(m,J=2.6Hz,2H),1.22(br.s.,3H),1.14(m,J=2.6Hz,2H),0.91(br.s.,3H)。
实施例15
(R)-1-{4’-[5-(1,2-二甲基-丙氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
除了用(R)-3-甲基丁-2-醇替换(R)-丁-2-醇之外,通过与实施例14相似的程序制备,给出(R)-1-{4’-[5-(1,2-二甲基-丙氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。LC/MS对于C26H29N3O4(m/e)计算值447.0,实测值448.2(M+H,ES+);1H NMR(DMSO-d6)δppm 12.34(br.s.,1H),9.37(br.s.,1H),7.81(s,1H),7.49-7.68(m,6H),7.38(d,J=8.3Hz,2H),4.58(br.s.,1H),3.65(s,3H),1.82(br.s.,1H),1.44(br.s.,2H),1.03-1.30(m,5H),0.92(br.s.,6H)。
实施例16
(R)-1-{4’-[5-((1-(2-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
除了用(R)-1-(2-氟苯基)乙醇替换(R)-丁-2-醇之外,通过与实施例14相似的程序制备,给出(R)-1-{4’-[5-((1-(2-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。LC/MS对于C29H26FN3O4(m/e)计算值499.0,实测值500.1(M+H,ES+);1H NMR(DMSO-d6)δppm 12.37(br.s.,1H),9.67(s,1H),7.80(s,2H),7.45-7.70(m,8H),7.39(d,2H),7.19-7.33(m,1H),5.97(d,J=5.7Hz,1H),3.62(s,3H),1.57(m,2H),1.38-1.52(m,2H),1.22(s,1H),1.15(d,2H)。
实施例17
(R)-1-{4’-[1-甲基-5-((1-(3-(三氟甲基)苯基)乙氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
除了用(R)-1-(3-(三氟甲基)-苯基)乙醇替换(R)-丁-2-醇之外,通过与实施例14相似的程序制备,给出(R)-1-{4’-[1-甲基-5-((1-(3-(三氟甲基)苯基)乙氧基)-羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。LC/MS对于C30H26F3N3O4(m/e)计算值549.0,实测值550.1(M+H,ES+);1H NMR(DMSO-d6)δppm 12.34(br.s.,1H),9.71(br.s.,1H),7.45-7.85(m,10H),7.39(d,J=8.3Hz,3H),5.87(d,J=6.0Hz,1H),3.65(s,3H),1.57(d,J=6.0Hz,2H),1.39-1.51(m,2H),1.22(br.s.,1H),1.09-1.19(m,2H)。
实施例18
1-{4’-[5-((1-(4-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
在250mL圆底烧瓶中,将1-(4′-(5-((1-(4-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(66mg,129μmol)与THF(2mL)和甲醇(2mL)合并以给出黄色溶液。加入NaOH(1.29mL,1.29mmol,10当量)并将反应混合物在45℃加热并搅拌3.5h。将反应物浓缩并用1M HCl酸化。将反应物在二氯甲烷与水之间分配。将水层用二氯甲烷(10mL)反萃取。将有机层合并,用H2O(10mL)洗涤,在Na2SO4上干燥并在真空中浓缩至白色粉末。将粗材料通过快速柱色谱(硅胶,12g,二氯甲烷中0%至5%甲醇)提纯以给出29mg(46%)的1-(4′-(5-((1-(4-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基)联苯-4-基)-环丙烷甲酸,为灰白色粉末。LC/MS对于C29H26FN3O4(m/e)计算值499.0,实测值498.0(M-H,ES-);1H NMR(DMSO-d6)δppm 12.36(br.s.,1H),9.62(br.s.,1H),7.82(s,1H),7.60(d,J=8.1Hz,4H),7.51(d,J=7.8Hz,3H),7.35-7.44(m,2H),7.26(t,J=7.8Hz,2H),6.94-7.18(m,1H),5.79(d,J=5.8Hz,1H),3.68(br.s.,3H),1.56(d,J=5.8Hz,2H),1.42-1.51(m,2H),1.21-1.33(br。m,1H),1.11-1.21(m,2H)。
实施例19
1-{4’-[5-(环丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸的制备
除了用环丁醇替换1-(4-氟苯基)乙醇之外,通过与实施例18相似的程序制备,给出1-{4’-[5-(环丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。LC/MS对于C25H25N3O4(m/e)计算值431.0,实测值432.0(M+H,ES+);1H NMR(甲醇-d4)δppm 7.77(s,1H),7.52-7.72(m,5H),7.44(d,J=8.3Hz,2H),5.01(br.s.,1H),3.79(s,3H),2.40(br.s.,2H),2.05-2.29(m,2H),1.78-1.94(m,1H),1.46-1.76(m,3H),1.12-1.42(m,2H)。
实施例20
1-{4’-[1-甲基-5-((氧杂环丁烷-3-基氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
除了用氧杂环丁烷-3-醇替换1-(4-氟苯基)乙醇之外,通过与实施例18相似的程序制备,给出1-{4’-[1-甲基-5-((氧杂环丁烷-3-基氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。LC/MS对于C24H23N3O5(m/e)计算值433.0,实测值434.1(M+H,ES+);1H NMR(DMSO-d6)δppm 12.33(br.s.,1H),7.93(s,1H),7.66-7.73(m,J=8.3Hz,2H),7.61(d,J=8.3Hz,2H),7.53-7.59(m,J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),5.41(br.s.,1H),4.85-4.94(m,1H),3.90(t,1H),3.66-3.83(m,6H),3.57(br.d.,1H),1.42-1.62(m,2H),1.13-1.22(m,2H)。
实施例21
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(2-氯-苯基)-乙酯
通过实施例13中的对应的外消旋物的手性SFC分离制备该化合物。分离条件如下:手性WHELKO柱,CO2中10%至65%甲醇。将第二级分浓缩以给出所需的化合物。LC/MS对于C19H17ClFN3O2(m/e)计算值373.0,实测值374.0(M+H,ES+)。
实施例22
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(S)-1-(2-氯-苯基)-乙酯
通过实施例13中的对应的外消旋物的手性SFC分离制备该化合物。分离条件如下:手性WHELKO柱,CO2中10%至65%甲醇。将第一级分浓缩以给出所需的化合物。LC/MS对于C19H17ClFN3O2(m/e)计算值373.0,实测值374.0(M+H,ES+)。
实施例23
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(3-三氟甲基-苯基)-乙酯
通过实施例12中的对应的外消旋物的手性SFC分离制备该化合物。分离条件如下:手性WHELKO柱,CO2中10%至65%甲醇。将第二级分浓缩以给出所需的化合物。LC/MS对于C20H17F4N3O2(m/e)计算值407.0,实测值408.0(M+H,ES+)。
实施例24
1-{4′-[5-(3-苄基-脲基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
将矿物油中的氢化钠(40.2mg,1.01mmol)在室温在氮氛下加入至1-(4′-(5-氨基-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(233mg,0.67mmol)在DMF(8mL)中的溶液,并将混合物搅拌5分钟。在加入氢化钠之后反应混合物变为红棕色溶液。之后,加入异氰酸苄酯(89.2mg,0.67mmol)并将反应混合物加热至80℃并搅拌3h,此时LC/MS分析指示所需的产物的存在。将混合物冷却至室温并用水稀释,并且将有机化合物萃取至乙酸乙酯(2x 50mL)中。将合并的萃取物用水和盐水溶液洗涤,并在无水MgSO4上干燥。过滤和浓缩给出粗残留物,将其使用ISCO(40g)柱色谱用己烷中的乙酸乙酯(0-100%)洗脱提纯。将所需的级分合并,并将溶剂在真空下移除以获得1-(4’-(5-(3-苄基脲基)-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(105mg,32%产率),为棕色油。LC/MS对于C29H28N4O3(m/e)计算值480,实测值481.1(M+H,ES+)。
向1-(4′-(5-(3-苄基脲基)-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(105mg,0.22mmol)在THF(6mL)和乙醇(6mL)中的溶液在室温加入过量的氢氧化钠的1.0M溶液(5.83mL,5.83mmol)。将所得到的浅黄色溶液在室温搅拌15h,此时LC/MS分析指示不存在原材料。之后,将溶剂移除并将碱性水层用水稀释并将中性杂质萃取至乙酸乙酯中。将碱性溶液用1.0N HCl中和。所得到的固体通过过滤收集并用水和己烷洗涤。在空气干燥之后,分离1-(4′-(5-(3-苄基脲基)-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸(59mg,57%产率),为灰白色固体。1H NMR(DMSO-d6)δ12.34(br.s.,1H),8.27(s,1H),7.81(s,1H),7.36-7.73(m,9H),7.19-7.36(m,4H),7.03(br.s.,1H),4.31(d,J=5.8Hz,2H),3.60-3.74(m,3H),1.39-1.58(m,2H),1.04-1.30(m,2H)。LC/MS对于C28H26N4O3(m/e)计算值466,实测值467.3(M+H,ES+)。
实施例25
1-{4′-[1-甲基-5-((S)-3-苯基-丁酰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸
向(S)-3-苯基丁酸(181mg,1.1mmol)在甲苯(5mL)中的溶液在室温加入过量的亚硫酰氯(2.62g,1.61mL,22.0mmol)。将所得到的无色溶液在回流温度搅拌15h。之后,将反应混合物冷却至室温并将溶剂在真空下移除。将所得到的残留物用甲苯共沸一次并在高真空下干燥。
向1-(4′-(5-氨基-1-甲基-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(174mg,0.5mmol)和DMAP(67.2mg,0.55mmol)在二氯甲烷(5mL)中的悬浮液加入(S)-3-苯基丁酰氯(上面制备)(95.9mg,0.525mmol)在二氯甲烷(5mL)中的溶液。将所得到的浅棕色悬浮液在室温在氮氛下搅拌2天,此时TLC分析指示不存在原材料。将混合物用水和二氯甲烷稀释,并将两层分离并将水层再用二氯甲烷萃取一次。将合并的萃取物用盐水溶液洗涤并在无水MgSO4上干燥。过滤和浓缩给出粗残留物,将其使用ISCO(80g)柱色谱用己烷中的乙酸乙酯(0-100%)洗脱提纯。将所需的级分合并,并将溶剂在真空下移除以获得(S)-1-(4’-(1-甲基-5-(3-苯基丁酰胺基)-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(50mg,20%产率),为白色固体。LC/MS对于C31H31N3O3(m/e)计算值493,实测值494.1(M+H,ES+)。
向(S)-1-(4′-(1-甲基-5-(3-苯基丁酰胺基)-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸甲酯(43mg,0.087mmol)在THF(5mL)和EtOH(5mL)中的溶液在室温加入过量的氢氧化钠的1M溶液(1.74mL,1.74mmol)。将所得到的溶液在室温搅拌15h,此时TLC和LCMS分析指示不存在原材料。之后,将溶剂在真空下移除并将水层用水稀释并用1NHCl中和。将所得到的固体通过过滤收集并用水和己烷洗涤。在空气干燥之后,分离(S)-1-(4′-(1-甲基-5-(3-苯基丁酰胺基)-1H-吡唑-4-基)联苯-4-基)环丙烷甲酸(32mg,76.6%产率),为灰白色固体。1H NMR(DMSO-d6)δ12.35(br.s.,1H),9.95(s,1H),7.79(s,1H),7.53-7.71(m,4H),7.47(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),7.30-7.38(m,4H),7.25(td,J=6.0,2.6Hz,1H),3.27-3.43(m,4H),2.63-2.86(m,2H),1.41-1.58(m,2H),1.30(d,J=7.0Hz,3H),1.13-1.23(m,2H)。LC/MS对于C30H29N3O3(m/e)计算值479,实测值480.3(M+H,ES+)。
实施例26
使用荧光成像读板仪(FLPR)的钙流量试验
细胞培养条件:含有人重组LPAl溶血磷脂受体的ChemiScreen钙优化的稳定细胞系购自Chemicon International,Inc./Millipore。将细胞在补充有10%胎牛血清、2mM谷氨酰胺、100U/mL青霉素/100μg/mL链霉素、1X非必要氨基酸、10mM HEPES和0.25mg/mL遗传霉素(Geneticin)的DMEM-高葡萄糖中培养。将细胞用胰蛋白酶-EDTA收获并使用ViaCount试剂计数。用完全培养基将细胞悬浮液体积调节至2.0x 105细胞/mL。将50μL等份分配至384孔黑色/透明组织培养处理过的板(BD),并且将微板放置在37℃培养箱中过夜。之后数天,将该板在试验中使用。
染料加载和测试:通过将一瓶的内含物溶解至含有20mM HEPES和2.5mM丙磺舒(probenecid)的100mL Hank's Balanced Salt Solution中制备加载缓冲液(Loading Buffer)(FLIPR钙-4,Molecular Devices)。将板装载至Biotek洗板器上,将培养基移除并用含有20mM HEPES和2.5mM丙磺舒(probenecid)的20μL的Hank's Balanced Salt Solution替代,接着是25μL的加载缓冲液。之后将板在37℃温育30分钟。
在温育过程中,通过加入90μL的HBSS/20mM HEPES/0.1%BSA缓冲液至2μL的连续稀释的化合物制备测试化合物。为制备连续稀释物,在100%DMSO中制备10mM的化合物原液。如下建立化合物稀释板:孔#1接收29μL的化合物原液和31μL DMSO;孔2-10接收40μL的DMSO;将20μL的溶液从孔#1混合并转移至孔#2中;继续用1∶3连续稀释10步;将2μL的稀释化合物转移至384孔“试验板”的孔中,一式两份,并且之后加入90μL的缓冲液。
在温育之后,将细胞板和“试验”板两者置于FLIPR,并且将20μL的稀释化合物通过FLIPR转移至细胞板。通过FLIPR监控化合物加入以检测化合物的任何激动活性。之后将板在室温避光温育30分钟。在温育之后,将板返回至FLIPR,并且将20μL的4.5X浓缩激动剂加入至细胞板。在试验过程中,每1.5秒由细胞板的所有384孔同时取得荧光读数。取五次读数,以建立稳定基线,之后将20μL的样品迅速地(30μL/秒)并同时地加入至细胞板的每个孔。在样品加入之前、过程中和之后在100秒的全部经过时间内连续地监控荧光。测定在激动剂加入之后每个孔中的响应(峰值荧光的增加)。在配体刺激之前,使用来自每个孔的初始荧光读数作为用于来自该孔的数据的零基线值。将响应表示为缓冲液对照的%抑制。通过将10浓度的百分比抑制数据使用Genedata Condoseo程序拟合至S形剂量响应(4参数逻辑)模型[模型205,F(x)=(A+(B-A)/(1+((C/x)^D))))],计算被定义为缓冲液对照的50%抑制所需的化合物浓度的IC50值,并且结果在下表1中给出:
表1
LPA1R和LPA3R拮抗剂活性
应当明白的是,本发明不限于上面描述的本发明的特定实施方案,因为可以进行特定实施方案的变体并且仍落在后附权利要求书的范围之内。
Claims (15)
1.式(I)的化合物:
其中:
X是氧、氮或碳;
R1是低级烷基;
R2是氢,卤素,-CH2C(O)OH,烷氧基,环烷基羧酸,未取代的苯基或被以下各项取代的苯基:卤素、-CH2C(O)OH、环丙烷甲酸、环丙烷甲酸乙酯、甲磺酰氨基羰基或四唑;并且
R3是环丁基、氧杂环丁基、未取代的低级烷基、被未取代的苯基取代的低级烷基或被卤素或-CF3取代的苯基取代的低级烷基,
或其药用盐。
2.根据权利要求1所述的化合物,其中X是氧。
3.根据权利要求1所述的化合物,其中R1是甲基。
4.根据权利要求1所述的化合物,其中R2是氢、F、Cl、-CH2C(O)OH、甲氧基、乙氧基、环丙烷甲酸、环己烷乙酸或未取代的苯基。
5.根据权利要求1所述的化合物,其中R2是被以下各项取代的苯基:-CH2C(O)OH、环丙烷甲酸或环丙烷甲酸乙基。
6.根据权利要求1所述的化合物,其中R3是环丁基、氧杂环丁基或未取代的低级烷基。
7.根据权利要求1所述的化合物,其中R3是被F、Cl或-CF3取代的苯基取代的低级烷基。
8.根据权利要求1所述的化合物,其中所述化合物是:
2-甲基-4-苯基-2H-吡唑-3-基-氨基甲酸(R)-1-苯基-乙酯;
{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-乙酸;
(2-甲基-4-苯基-2H-吡唑-3-基)-氨基甲酸1-(2-氯-苯基)-乙酯;
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸乙酯;
1-{4′-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-(4′-{5-[1-(2-氯-苯基)-乙氧基羰基氨基]-1-甲基-1H-吡唑-4-基}-联苯-4-基)-环丙烷甲酸;
(4-联苯-4-基-2-甲基-2H-吡唑-3-基)-氨基甲酸(R)-1-苯基-乙酯;
[4-(4-甲氧基-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-苯基-乙酯;
1-{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-环丙烷甲酸;
{4-[1-甲基-5-((R)-1-苯基-乙氧基羰基氨基)-1H-吡唑-4-基]-苯基}-乙酸;
[4-(4-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(3-三氟甲基-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸1-(2-氯-苯基)-乙酯;
(R)-1-{4’-[5-(仲丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[5-(1,2-二甲基-丙氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[5-((1-(2-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
(R)-1-{4’-[1-甲基-5-((1-(3-(三氟甲基)苯基)乙氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[5-((1-(4-氟苯基)乙氧基)羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[5-(环丁氧基羰基氨基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
1-{4’-[1-甲基-5-((氧杂环丁烷-3-基氧基)羰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(S)-1-(2-氯-苯基)-乙酯;
[4-(2-氟-苯基)-2-甲基-2H-吡唑-3-基]-氨基甲酸(R)-1-(3-三氟甲基-苯基)-乙酯;
1-{4′-[5-(3-苄基-脲基)-1-甲基-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸;或
1-{4′-[1-甲基-5-((S)-3-苯基-丁酰基氨基)-1H-吡唑-4-基]-联苯-4-基}-环丙烷甲酸。
9.根据权利要求1至8中的任一项所述的化合物,所述化合物用作治疗活性物质。
10.一种药物组合物,所述药物组合物包含治疗有效量的根据权利要求1至8中的任一项所述的化合物和治疗惰性载体。
11.根据权利要求1至8中的任一项所述的化合物用于肺纤维化的治疗或预防的用途。
12.根据权利要求1至8中的任一项所述的化合物用于制备药物的用途,所述药物用于肺纤维化的治疗或预防。
13.根据权利要求1至8中的任一项所述的化合物,所述化合物用于肺纤维化的治疗或预防。
14.一种用于治疗或预防肺纤维化的方法,所述方法包括将有效量的如权利要求1至8中的任一项所述的化合物向需要其的患者给药的步骤。
15.如上所述的本发明。
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BR112020011953A2 (pt) * | 2017-12-19 | 2020-11-17 | Bristol-Myers Squibb Company | ácidos carbamoil ciclo-hexílicos n-ligados a pirazol como antagonistas de lpa |
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TWI843503B (zh) | 2020-06-03 | 2024-05-21 | 美商基利科學股份有限公司 | Lpa受體拮抗劑及其用途 |
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US11980609B2 (en) | 2021-05-11 | 2024-05-14 | Gilead Sciences, Inc. | LPA receptor antagonists and uses thereof |
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CL2014003242A1 (es) | 2015-03-20 |
MX2014014105A (es) | 2015-03-05 |
EP2864294A1 (en) | 2015-04-29 |
CO7160077A2 (es) | 2015-01-15 |
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CR20140516A (es) | 2014-12-01 |
PH12014502364A1 (en) | 2015-01-12 |
EA201492283A1 (ru) | 2015-04-30 |
IL236091A0 (en) | 2015-02-01 |
IN2014DN09347A (zh) | 2015-07-17 |
BR112014031108A2 (pt) | 2017-06-27 |
UA109867C2 (ru) | 2015-10-12 |
SG11201407229UA (en) | 2014-12-30 |
US20150259295A1 (en) | 2015-09-17 |
WO2013189862A1 (en) | 2013-12-27 |
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