CN113474334A - 用于治疗例如癌症的疾病的吲唑基-异噁唑衍生物 - Google Patents
用于治疗例如癌症的疾病的吲唑基-异噁唑衍生物 Download PDFInfo
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- CN113474334A CN113474334A CN202080013792.XA CN202080013792A CN113474334A CN 113474334 A CN113474334 A CN 113474334A CN 202080013792 A CN202080013792 A CN 202080013792A CN 113474334 A CN113474334 A CN 113474334A
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- Prior art keywords
- fluoro
- oxa
- azaspiro
- methoxyethoxy
- heptane
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
- C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
其中R1、R2、X、Y和Z具有权利要求1中所述含义的式(I)化合物是c‑Kit激酶的抑制剂,可用于治疗癌症。
Description
发明背景
本发明的目的是找到具有有价值特性的新化合物,特别是那些可用于制备药物的化合物。
本发明涉及吲唑基-异噁唑衍生物,其在GIST(胃肠间质肿瘤)患者中可能出现的c-KIT突变和继发突变(外显子13中的V654A继发抗性突变)的宽广范围内抑制c-KIT激酶。
因此,本发明的化合物可用于治疗疾病,例如癌症。
本发明还提供制备这些化合物的方法、包含这些化合物的药物组合物、用于治疗疾病的化合物和利用包含这些化合物的药物组合物治疗疾病的方法。
受体酪氨酸激酶c-KIT的突变形式是几种癌症的驱动因素,并且是有吸引力的治疗靶点。虽然使用KIT激酶活性抑制剂(如伊马替尼)已获得益处,尤其是在GIST中,但某些致癌突变会发生原发抗性。此外,由于继发突变,经常会产生抗性(L.K.Ashman&R.Griffith(2013)Expert Opinion on Investigational Drugs,22:1,103-115)。
L.L.Chen等人在Cancer res.2004;64:5913-5919中描述了“A MissenseMutation in KIT kinase domain 1correlates with imatinib resistance ingastrointestinal stromal tumors(KIT激酶结构域1中的错义突变与胃肠间质肿瘤中的伊马替尼抗性有关)”。
K.G.Roberts等人在Mol.Cancer Ther.2007;6:1159-1166中描述了“Resistanceto c-KIT kinase inhibitors conferred by V654A mutation(V654A突变赋予的对c-KIT激酶抑制剂的抗性)”。
胃肠间质肿瘤(GIST)是胃肠(GI)道最常见的间充质肿瘤。
GIST被定义为c-KIT(CD117,干细胞因子受体)阳性间充质梭形细胞或上皮样肿瘤。
GIST具有KIT基因的普遍原发的激活突变(90%),导致受体酪氨酸激酶c-KIT的配体非依赖性激活,使肿瘤依赖于致癌KIT活性。
伊马替尼治疗具有原发突变的GIST的初始反应率约为70%,但在平均两年40-50%的病例中出现获得性抗性。外显子13中的继发突变V654A是伊马替尼后最常见的抗性突变。
开发针对KIT V654A抗性突变的安全且特异的抑制剂存在高度未满足的医学需求。
已经发现,根据本发明的化合物及其盐具有非常有价值的药理学特性,同时具有良好的耐受性。
本发明具体涉及抑制c-KIT激酶,优选c-KIT激酶的突变体V654A的式I化合物。
此外,式I化合物抑制PDGFRα(V651D)。PDGFRα的功能获得性突变显示在没有KIT突变的GIST的发展中起重要作用(S.Hirota et al.,Gastroenterology 2003;125:660-667)。
主体或患者可以属于任何哺乳动物物种,例如灵长类物种,特别是人;啮齿类动物,包括小鼠、大鼠和仓鼠;兔子;马、牛、狗、猫等。动物模型对于实验研究是令人感兴趣的,其提供了用于治疗人类疾病的模型。
特定细胞对用根据本发明化合物治疗的敏感性可以通过体外试验来确定。通常,将细胞培养物与不同浓度的根据本发明化合物组合一段时间,该时间足以使活性剂如抗IgM诱导细胞响应如表面标志物的表达,通常在约一小时至一周之间。体外测试可以使用来自血液或来自活检样品的培养细胞进行。通过流式细胞术使用识别标志物的特异性抗体评估表面标志物的表达量。
剂量根据所用的具体化合物、具体疾病、患者状态等而变化。治疗剂量通常足以显著减少靶组织中不需要的细胞群,同时维持患者的生存力。治疗通常持续到相当程度的减少发生为止,例如细胞负荷减少至少约50%,并且可以持续到在体内基本上不再检测到不需要的细胞为止。
现有技术
WO2012/084704公开了下式的吲唑基三唑衍生物作为激酶IRAK的抑制剂:
与相应的三唑衍生物相比,本申请所述的异噁唑化合物显示出更高的活性(表2)。
在Hongchan An et al(Bioorganic and Medicinal Chemistry Letters 21(2011)6297-6300中,吲唑基-异噁唑被描述为HIF-1抑制剂:
在Nicolò Vivona et al,Journal of Heterocyclic Chemistry 22(1985)29-32中,描述了以下吲唑基-异噁唑:
发明概述
本发明涉及式I化合物
其中
R1表示Hal、CF3、OA、Het1、COOR3或CON(R3)2,
R2表示H、Hal或CN,
R3表示H或A,
X表示亚苯基、吡啶二基、1,3-噻唑二基或吡唑二基,它们各自未被取代或被Hal和/或A单、二或三取代,
Y不存在或表示CO、O[C(R3)2]n、NR3CO、CONR3、CONR3[C(R3)2]n、CONHCH2C(CH3)2、SO2、SO2N(R3)、-N=或S(=O,=NR3),
Z表示H、A、Hal、OA、[C(R3)2]nHet2或N=S(=O)A2,
A表示具有1-10个C-原子的无支链或支链烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子代替并且其中1-7个H-原子可以被R5代替,
或表示(CH2)nCyc,
Cyc表示具有3-7个C原子的环状烷基,
R5表示F、Cl、OH、SO2A或N(R3)2,
Het1表示可以被A单或二取代的吡唑基,
Het2表示具有1至4个N、O和/或S原子的4至7元单环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代,
或者
表示具有1至4个N、O和/或S原子的7至10元双环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代,
Het3表示具有1至4个N、O和/或S原子的4至7元单环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代,
或者
表示具有1至4个N、O和/或S原子的7至10元双环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代,
Hal表示F、Cl、Br或I,
n表示0、1、2或3,
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
本发明还涉及这些化合物的光学活性形式(立体异构体)、对映体、外消旋物、非对映体和水合物和溶剂化物。
此外,本发明涉及式I的化合物的药学上可接受的衍生物。
术语化合物的溶剂化物是指惰性溶剂分子由于它们的相互吸引力而形成的化合物上的加合。溶剂化物是例如单或二水合物或醇盐。
应理解,本发明还涉及所述盐的溶剂化物。
术语药学上可接受的衍生物是指例如根据本发明的化合物的盐以及所谓的前药化合物。
除非另有说明,否则如本文所用的术语“前药”是指在生物条件下(体外或体内)可水解、氧化或其它的反应以提供活性化合物,特别是式I化合物的,式I化合物的衍生物。前药的实例包括但不限于式I化合物的衍生物和代谢物,其包括可生物水解的部分,例如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸酯、可生物水解的酰脲和可生物水解的磷酸酯类似物。在某些实施方案中,具有羧基官能团的化合物的前药是羧酸的低级烷基酯。羧酸酯方便地通过酯化分子上存在的任何羧酸部分而形成。前药通常可以使用众所周知的方法制备,例如Burger's Medicinical Chemistry和DrugDiscovery第六版描述的那些方法。(Donald J.Abraham ed.,2001,Wiley)和Design andApplication of Prodrugs(H.Bundgaard ed.,1985,Harwood Academic PublishersGmfh)。
表述“有效量”表示在组织、系统、动物或人中引起例如研究人员或医师所寻求或期望的生物学或医学响应的药物或药物活性成分的量。
此外,表述“治疗有效量”表示与未接受该量的相应受试者相比具有以下结果的量:
改善疾病、综合征、病况、不适、病症或副作用的治疗、治愈、预防或消除,或者还减少疾病、不适或病症的进展。
表述“治疗有效量”还包括有效增加正常生理功能的量。
本发明还涉及式I的化合物的混合物(例如两种非对映体的混合物)的用途,所述两种非对映体的比例例如为1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000。
这些是特别优选的立体异构化合物的混合物。
“互变异构体”是指彼此平衡的化合物的异构体形式。异构体形式的浓度将取决于化合物所处的环境,并且可以根据例如化合物是固体还是在有机物中或在水溶液中而不同。
本发明涉及式I化合物及其盐以及制备式I化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于:
a)对于制备式I化合物,
其中
X表示亚苯基,
Y表示CO,
Z表示[C(R3)2]nHet2和
n表示0,
式II的化合物
其中R1和R2具有权利要求1中所述的含义,与式III的化合物反应
Het2 III
其中Het2具有权利要求1中所述的含义,或
b)对于制备式I化合物,
其中
R1表示Het1,
式IV化合物,
其中
R2、X、Y和Z具有权利要求1中所述的含义,与式V的化合物反应
其中Het1具有权利要求1中所述的含义,或
c)对于制备式Ia的化合物,
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义,式VI的化合物
其中
R1和R2具有权利要求1中所述的含义,与式VII的化合物反应
其中
X、Y和Z具有权利要求1中所述的含义,或
d)对于制备式Ib的化合物,
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义,式VIII化合物,
其中
R1和R2具有权利要求1中所述的含义,与式IX的化合物反应
HO-N=CH-X-Y-Z IX
其中
X、Y和Z具有权利要求1中所述的含义,和/或
式I的碱或酸被转化为其盐之一。
对于所有出现超过一次的基团,例如R3,它们的含义是相互独立的。
除非另有明确说明,否则上面和下面的基团R1、R2、X、Y和Z具有对式I所指示的含义。
优选式Ia的化合物,
其中R1、R2、X、Y和Z具有如权利要求1中所述的含义。
此外,优选式Ib的化合物
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义。
A表示烷基,其是无支链的(线性的)或支链的,并且具有1、2、3、4、5、6、7、8、9或10个C原子。A优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外还表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外优选三氟甲基。
A非常特别优选表示具有1、2、3、4、5或6个C原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
Cyc优选表示环丙基、环丁基、环戊基或环己基。
此外,A优选表示CH2OCH3、CH2CH2OH或CH2CH2OCH3。
R1优选表示Hal、CF3、OCH3、OCH2CH2OCH3、OCH2CH2OH、1-甲基-1H-吡唑-4-基、COOCH3、CONH2、CONHCH3或CONHCH2CH2OCH3,
R2优选表示H、Hal或CN。
R3表示H或A,优选H或CH3。
X优选表示1,4-亚苯基、1,3-亚苯基、2-氟-1,4-亚苯基、2-甲基-1,4-亚苯基、吡啶-3,6-二基、1,3-噻唑-3,5-二基、1,3-噻唑-2,4-二基、1,3-噻唑-2,5-二基或吡唑-1,4-二基,其中每一个是未被取代的或被Hal和/或A单、二或三取代。
Y优选表示CO、SO2、NHCO、NCH3、CONH(CH2)n、CONHCH2C(CH3)2、CON(CH3)(CH2)n、O、OCH2、OCH2CH2、S(=O)(=NH)、-N=、SO2N(CH3)或不存在。
Z优选表示H、Hal、OA、Het2、A、N=S(=O)A2。
双环化合物还包括螺环化合物。
不考虑进一步的取代,Het2表示例如2-或3-呋喃基,2-或3-噻吩基,1-、2-或3-吡咯基,1-、2-、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噁唑基,3-、4-或5-异噁唑基,2-、4-或5-噻唑基,3-、4-或5-异噻唑基,2-、3-或4-吡啶基,2-、4-、5-或6-嘧啶基,进一步优选1,2,3-三唑-1-、-4-或-5-基,1,2,4-三唑-1-、-3-或5-基,1-或5-四唑基,1,2,3-噁二唑-4-或-5-基,1,2,4-噁二唑-3-或-5-基,1,3,4-噻二唑-2-或-5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,吡嗪基,1-、2-、3-、4-、5-、6-或7-吲哚基,4-或5-异吲哚基,吲唑基,1-,2-,4-或5-苯并咪唑基,1-,3-,4-,5-,6-或7-苯并吡唑基,2-,4-,5-,6-或7-苯并噁唑基,3-,4-,5-,6-或7-苯并异噁唑基,2-,4-,5-,6-或7-苯并噻唑基,2-,4-,5-,6-或7-苯并异噻唑基,4-,5-,6-或7-苯并-2,1,3-噁二唑基,2-,3-,4-,5-,6-,7-或8-喹啉基,1-,3-,4-,5-,6-,7-或8-异喹啉基,3-,4-,5-,6-,7-或8-噌啉基,2-,4-,5-,6-,7-或8-喹唑啉基,5-或6-喹喔啉,2-,3-,5-,6-,7-或8-2H-苯并-1,4-噁嗪基,吡咯并吡啶基,嘌呤基,进一步优选1,3-苯并二氧杂环戊烯-5-基,1,4-苯并二氧杂环己-6-基,2,1,3-苯并噻二唑-4-或-5-基,2,1,3-苯并噁二唑-5-基,氮杂双环[3.2.1]辛基或二苯并呋喃基。
杂环基团也可以部分或完全氢化。
不考虑进一步的取代,Het2因而也可以表示例如2,3-二氢-2-、-3-、-4-或-5-呋喃基,2,5-二氢-2-、-3-、-4-或-5-呋喃基,四氢-2-或-3-呋喃基,1,3-二氧戊环-4-基,四氢-2-或-3-噻吩基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基,2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基,1-,2-或3-吡咯烷基,四氢-1-、-2-或-4-咪唑基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基,四氢-1-、-3-或-4-吡唑基,1,4-二氢-1-、-2-、-3-或-4-吡啶基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基,1-、2-、3-或4-哌啶基,2-、3-或4-吗啉基,四氢-2-,-3-或-4-吡喃基,1,4-二氧杂环己基,1,3-二氧杂环己-2-,-4-或-5-基,六氢-1-,-3-或-4-哒嗪基,六氢-1-,-2-,-4-或-5-嘧啶基,1-,2-或3-哌嗪基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-喹啉基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-异喹啉基,2-,3-,5-,6-,7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,进一步优选2,3-甲二氧基苯基,3,4-甲二氧基苯基,2,3-乙二氧基苯基,3,4-乙二氧基苯基,3,4-(二氟甲二氧基)苯基,2,3-二氢苯并呋喃-5-或6-基,2,3-(2-氧代甲二氧基)苯基,或者也表示3,4-二氢-2H-1,5-苯并二氧杂环庚(dioxepin)-6-或-7-基,进一步优选2,3-二氢苯并呋喃基,2,3-二氢-2-氧代呋喃基,3,4-二氢-2-氧代-1H-喹唑啉基,2,3-二氢苯并噁唑基,2-氧代-2,3-二氢苯并噁唑基,2,3-二氢苯并咪唑基,1,3-二氢吲哚,2-氧代-1,3-二氢吲哚或2-氧代-2,3-二氢苯并咪唑基。
不考虑进一步的取代,Het3表示例如2-或3-呋喃基,2-或3-噻吩基,1-、2-或3-吡咯基,1-、2-、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噁唑基,3-、4-或5-异噁唑基,2-、4-或5-噻唑基,3-、4-或5-异噻唑基,2-、3-或4-吡啶基,2-、4-、5-或6-嘧啶基,进一步优选1,2,3-三唑-1-、-4-或-5-基,1,2,4-三唑-1-、-3-或5-基,1-或5-四唑基,1,2,3-噁二唑-4-或-5-基,1,2,4-噁二唑-3-或-5-基,1,3,4-噻二唑-2-或-5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,吡嗪基,1-、2-、3-、4-、5-、6-或7-吲哚基,4-或5-异吲哚基,吲唑基,1-,2-,4-或5-苯并咪唑基,1-,3-,4-,5-,6-或7-苯并吡唑基,2-,4-,5-,6-或7-苯并噁唑基,3-,4-,5-,6-或7-苯并异噁唑基,2-,4-,5-,6-或7-苯并噻唑基,2-,4-,5-,6-或7-苯并异噻唑基,4-,5-,6-或7-苯并-2,1,3-噁二唑基,2-,3-,4-,5-,6-,7-或8-喹啉基,1-,3-,4-,5-,6-,7-或8-异喹啉基,3-,4-,5-,6-,7-或8-噌啉基,2-,4-,5-,6-,7-或8-喹唑啉基,5-或6-喹喔啉,2-,3-,5-,6-,7-或8-2H-苯并-1,4-噁嗪基,吡咯并吡啶基,嘌呤基,进一步优选1,3-苯并二氧杂环戊烯-5-基,1,4-苯并二氧杂环己-6-基,2,1,3-苯并噻二唑-4-或-5-基,2,1,3-苯并噁二唑-5-基,氮杂双环[3.2.1]辛基或二苯并呋喃基。
杂环基团也可以部分或完全氢化。
不考虑进一步的取代,Het3因而也可以表示例如2,3-二氢-2-、-3-、-4-或-5-呋喃基,2,5-二氢-2-、-3-、-4-或-5-呋喃基,四氢-2-或-3-呋喃基,1,3-二氧戊环-4-基,四氢-2-或-3-噻吩基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基,2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基,1-,2-或3-吡咯烷基,四氢-1-、-2-或-4-咪唑基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基,四氢-1-、-3-或-4-吡唑基,1,4-二氢-1-、-2-、-3-或-4-吡啶基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基,1-、2-、3-或4-哌啶基,2-、3-或4-吗啉基,四氢-2-,-3-或-4-吡喃基,1,4-二氧杂环己基,1,3-二氧杂环己-2-,-4-或-5-基,六氢-1-,-3-或-4-哒嗪基,六氢-1-,-2-,-4-或-5-嘧啶基,1-,2-或3-哌嗪基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-喹啉基,1,2,3,4-四氢-1-,-2-,-3-,-4-,-5-,-6-,-7-或-8-异喹啉基,2-,3-,5-,6-,7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,进一步优选2,3-甲二氧基苯基,3,4-甲二氧基苯基,2,3-乙二氧基苯基,3,4-乙二氧基苯基,3,4-(二氟甲二氧基)苯基,2,3-二氢苯并呋喃-5-或6-基,2,3-(2-氧代甲二氧基)苯基,或者也表示3,4-二氢-2H-1,5-苯并二氧杂环庚(dioxepin)-6-或-7-基,进一步优选2,3-二氢苯并呋喃基,2,3-二氢-2-氧代呋喃基,3,4-二氢-2-氧代-1H-喹唑啉基,2,3-二氢苯并噁唑基,2-氧代-2,3-二氢苯并噁唑基,2,3-二氢苯并咪唑基,1,3-二氢吲哚,2-氧代-1,3-二氢吲哚或2-氧代-2,3-二氢苯并咪唑基。
Het2优选表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基(苯并咪唑-2-基)、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基(1,3-二氢吡咯并[3,4-c]吡啶-2-基)、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基、四氢呋喃并[3,4-c]吡咯-5-基,
其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代。
Het3优选表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基、1,2,4-三唑基,
其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代。
在本发明中,出现超过一次的所有基团可以相同或不同,即彼此独立。
式I化合物可以具有一个或多个手性中心,因此可以以各种立体异构形式存在。式I包含所有这些形式。
因此,本发明特别涉及其中至少一个所述基团具有上述优选含义之一的式I化合物。一些优选的化合物组可由以下子式Ia至If表示,其符合式I且其中未更详细指定的基团具有式I所指示的含义,但其中
Ia中R1表示Hal、CF3、OCH3、OCH2CH2OCH3、OCH2CH2OH、1-甲基-1H-吡唑-4-基、COOCH3、CONH2、CONHCH3或CONHCH2CH2OCH3,
Ib中R3表示H或CH3;
Ic中X表示1,4-亚苯基、1,3-亚苯基、2-氟-1,4-亚苯基、2-甲基-1,4-亚苯基、吡啶-3,6-二基、1,3-噻唑-3,5-二基、1,3-噻唑-2,4-二基、1,3-噻唑-2,5-二基或吡唑-1,4-二基,其各自未被取代或被Hal和/或A单、二或三取代;
Id中Y表示不存在或表示CO、SO2、NHCO、NCH3、CONH(CH2)n、CONHCH2C(CH3)2、CON(CH3)(CH2)n、O、OCH2、OCH2CH2、S(=O)(=NH)、-N=或SO2N(CH3);
Ie中Het2表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基(苯并咪唑-2-基)、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基(1,3-二氢吡咯并[3,4-c]吡啶-2-基)、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基、四氢呋喃并[3,4-c]吡咯-5-基,其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代;
If中Het3表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基、1,2,4-三唑基,其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代;
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
优选根据权利要求1的式Ib的化合物
其中
R1表示Hal、CF3、OCH3、OCH2CH2OCH3、OCH2CH2OH、1-甲基-1H-吡唑-4-基、COOCH3、CONH2、CONHCH3或CONHCH2CH2OCH3,
R2表示H、Hal或CN,
R3表示H或CH3,
X表示1,4-亚苯基、1,3-亚苯基、2-氟-1,4-亚苯基、2-甲基-1,4-亚苯基、吡啶-3,6-二基、1,3-噻唑-3,5-二基、1,3-噻唑-2,4-二基、1,3-噻唑-2,5-二基或吡唑-1,4-二基,其各自未被取代或被Hal和/或A单、二或三取代,
Y不存在或表示CO、SO2、NHCO、NCH3、CONH(CH2)n、CONHCH2C(CH3)2、CON(CH3)(CH2)n、O、OCH2、OCH2CH2、S(=O)(=NH)、-N=或SO2N(CH3),
Z表示H、A、Hal、OA、[C(R3)2]nHet2或N=S(=O)A2,
A表示具有1-10个C-原子的无支链或支链烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子代替并且其中1-7个H-原子可以被R5代替,
或表示(CH2)nCyc,
Cyc表示具有3-7个C原子的环状烷基,
R5表示F、Cl、OH、SO2A或N(R3)2,
Het1表示吡唑基,可以被A单或二取代,
Het2表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基、四氢呋喃并[3,4-c]吡咯-5-基,其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代;
Het3表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基或1,2,4-三唑基,其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代;
Hal表示F、Cl、Br或I,
n表示0、1、2或3,
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
此外,本发明涉及选自以下的中间体
2-溴-5-氟-4-(2-甲氧基乙氧基)苯甲醛
N'-[(1E)-[2-溴-5-氟-4-(2-甲氧基乙氧基)苯基]亚甲基]-4-甲基苯-1-磺酰肼
5-氟-6-(2-甲氧基乙氧基)-1-(4-甲基苯磺酰基)-1H-吲唑
5-氟-6-(2-甲氧基乙氧基)-1H-吲唑
5-氟-3-碘-6-(2-甲氧基乙氧基)-1H-吲唑
5-氟-3-碘-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
5-氟-6-(2-甲氧基乙氧基)-3-[2-(三甲基甲硅烷基)乙炔基]-1H-吲唑-1-甲酸叔丁酯
3-乙炔基-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑
3-乙炔基-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
5-氟-3-{3-[4-(甲氧基羰基)苯基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸甲酯
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸
此外,式I的化合物以及用于它们的制备的原料通过本身已知的方法制备,如文献中所述(例如在标准著作中,如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart),更确切地说在已知和适用于所述反应的反应条件下制备。在此也可以使用本身已知的变体,在此未对其进行更详细的提及。
式I化合物
其中
X表示亚苯基,
Y表示CO,
Z表示[C(R3)2]nHet2和
n表示0,
可优选通过式II化合物与式III化合物反应获得。
式II和III的起始化合物通常是已知的。然而,如果它们是新的,它们可以通过本身已知的方法制备。
该反应通常在化合物如N-(3-二甲基-氨基丙基)-N'-乙基碳二亚胺盐酸盐和1-羟基苯并三唑存在下进行。
该反应通常在酸结合剂存在下进行,酸结合剂优选有机碱,例如DIPEA、三乙胺、二甲基苯胺、吡啶、喹啉或4-甲基吗啉。
添加碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐或碱金属或碱土金属的另一种弱酸盐可能也是有利的,所述碱金属或碱土金属优选钾、钠、钙或铯。
根据使用的条件,反应时间在几分钟和14天之间,反应温度在约-30°和140°之间,通常在-10°和100°之间,特别是在约30°和约90°之间。
合适的惰性溶剂的例子是烃,例如己烷、石油醚、苯、甲苯或二甲苯;氯化烃,例如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如乙醚、异丙醚、四氢呋喃(THF)或二噁烷;二醇醚,例如乙二醇单甲或单乙醚、乙二醇二甲醚(二甘醇二甲醚);酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲基亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯,或所述溶剂的混合物。
特别优选乙腈、二氯甲烷和/或DMF。
式I化合物
其中
R1表示Het1,
可优选通过式IV化合物与式V化合物反应获得。
式IV和V的起始化合物通常是已知的。然而,如果它们是新的,它们可以通过本身已知的方法制备。
或者,式Va化合物
Het1-B(OH)2Va
可以用来代替式V化合物。
这种偶联通常在升高的温度下使用钯催化剂、碱和惰性溶剂进行。催化剂和反应条件的概述可以在文献中找到[参见例如S.Kotha et al.,Tetrahedron 2002,58,9633-9695;T.E.Barder et al.,J.Am.Chem.Soc.2005,127,4685-4696]。该反应中优选的催化剂是四(三苯基膦)-钯(0)或PdCl2(PPh3)2。优选的碱是作为水溶液使用的碳酸钠。反应在反应条件下呈惰性的有机溶剂中进行,例如1,4-二噁烷、乙腈、N,N-二甲基甲酰胺(DMF)或二甲亚砜(DMSO),或在水或这些溶剂的混合物中进行。优选地,反应在1,4-二噁烷和水或乙腈和水的混合物中进行。该反应通常在+100℃和+250℃之间,优选在+110℃到+150℃的温度下进行,加热优选地由单模微波装置实现。反应通常在惰性气体气氛下进行,优选在氩气下进行。
式Ia的化合物
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义,
优选可通过式VI化合物与式VII化合物反应获得。
式VI和VII的起始化合物通常是已知的。然而,如果它们是新的,它们可以通过本身已知的方法制备。
式Ib化合物
其中
R1、R2、X、Y和Z具有权利要求1中所示的含义,
可优选通过式VIII化合物与式IX化合物反应获得。
式VIII和IX的起始化合物通常是已知的。然而,如果它们是新的,它们可以通过本身已知的方法制备。
药用盐和其它形式
根据本发明的所述化合物可以以其最终的非盐形式使用。另一方面,本发明还包括这些化合物以其药学上可接受的盐的形式的用途,其可以通过本领域已知的程序衍生自各种有机和无机的酸和碱。式I的化合物的药学上可接受的盐形式大部分是通过常规方法制备的。如果式I的化合物含有羧基,则其合适的盐之一可通过使该化合物与合适的碱反应得到相应的碱加成盐而形成。这样的碱是例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,例如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,如哌啶、二乙醇胺和N-甲基谷氨酰胺。式I的化合物的铝盐也包括在内。在某些式I的化合物的情况下,酸加成盐可通过用药学上可接受的有机和无机的酸处理这些化合物来形成,所述有机和无机的酸例如卤化氢,如氯化氢、溴化氢或碘化氢,其它无机酸及其相应的盐,如硫酸盐、硝酸盐或磷酸盐等,和烷基-和单芳基磺酸盐,如乙磺酸盐、甲苯磺酸盐和苯磺酸盐,和其它有机酸及其相应的盐,如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I的化合物的药学上可接受的酸加成盐包括以下:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate(苯磺酸盐))、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、甲酸盐、半乳糖酸盐(来自粘酸)、半乳糖醛酸盐、葡庚酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这不代表限制。
此外,根据本发明的化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但这不是限制性的。在上述盐中,优选铵;碱金属盐钠和钾,和碱土金属盐钙和镁。衍生自药学上可接受的有机非毒性碱的式I的化合物的盐包括伯、仲和叔胺,取代胺,还包括天然存在的取代胺,环胺,和碱性离子交换树脂的盐,例如精氨酸,甜菜碱,咖啡因,氯普鲁卡因,胆碱,N,N'-二苄基乙二胺(苄星),二环己基胺,二乙醇胺,二乙基胺,2-二乙基氨基乙醇,2-二甲基氨基乙醇,乙醇胺,乙二胺,N-乙基吗啉,N-乙基哌啶,葡糖胺,葡萄糖胺,组氨酸,海巴明,异丙胺,利多卡因,赖氨酸,葡甲胺,N-甲基-D-葡糖胺,吗啉,哌嗪,哌啶,聚胺树脂,普鲁卡因,嘌呤,可可碱,三乙醇胺,三乙胺,三甲胺,三丙胺和三(羟基甲基)甲胺(氨丁三醇),但这不是限制性的。
含有碱性含氮基团的本发明的化合物可以使用试剂季铵化,所述试剂例如(C1-C4)烷基卤,例如甲基、乙基、异丙基和叔丁基的氯、溴和碘;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基的硫酸盐;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;和芳基(C1-C4)烷基卤,例如苄基氯和苯乙基溴。根据本发明的水溶性和油溶性化合物两者都可以使用这样的盐制备。
上述优选的药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这不是限制性的。
特别优选盐酸盐、二盐酸盐、氢溴酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和琥珀酸盐。
式I的碱性化合物的酸加成盐通过使游离碱形式与足量的所需酸接触,引起以常规方式形成盐来制备。通过使盐形式与碱接触并以常规方式分离游离碱,可以再生游离碱。游离碱形式在某些方面不同于其相应的盐形式,在某些物理性质方面,例如在极性溶剂中的溶解度;然而,对于本发明的目的,盐在其它方面对应于其各自的游离碱形式。
如上所述,式I化合物的药学上可接受的碱加成盐是与金属或胺,例如碱金属和碱土金属或有机胺形成的。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
根据本发明的酸性化合物的碱加成盐是通过使游离酸形式与足量的所需碱接触,引起以常规方式形成盐来制备。游离酸可以通过使盐形式与酸接触并以常规方式分离游离酸而再生。游离酸形式在某些方面不同于其相应的盐形式,在某些物理性质方面,例如在极性溶剂中的溶解度;然而,对于本发明的目的,盐在其它方面对应于其各自的游离酸形式。
如果根据本发明的化合物含有多于一个能够形成该类型药学上可接受的盐的基团,则本发明还包括多种盐。典型的多种盐形式包括例如酒石酸氢盐、二乙酸盐、富马酸氢盐、二葡甲胺、二磷酸盐、二钠和三盐酸盐,但这不是限制性的。
关于上述内容,可以看出,本文中的表述“药学上可接受的盐”是指如下的活性成分,所述活性成分包含以其盐的一种的形式的式I的化合物,特别是如果该盐形式与活性成分的游离形式或先前使用的活性成分的任何其它盐形式相比,赋予活性成分改善的药代动力学性质。该活性成分的药学上可接受的盐形式还可首次提供该活性成分具有其先前不具有的所需药代动力学性质,并且甚至可就其在体内的治疗功效对该活性成分的药效动力学学产生积极影响。
同位素
此外,式I的化合物包括其同位素标记形式。式I的化合物的同位素标记形式与该化合物相同,除了该化合物的一个或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的一个或多个原子所取代。容易商购且可通过熟知方法掺入式I的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有一个或多个上述同位素和/或其它原子的其它同位素的式I的化合物、其前药或其药学上可接受的盐是本发明的一部分。式I的同位素标记的化合物可以以许多有益的方式使用。例如,其中已掺入放射性同位素如3H或14C的式I同位素标记的化合物适用于药物和/或底物组织分布测定。这些放射性同位素,即氚(3H)和碳-14(14C),由于制备简单和优异的可检测性而是特别优选的。将较重的同位素,例如氘(2H)掺入式I的化合物中具有治疗优势,因为该同位素标记的化合物的较高的代谢稳定性。较高的代谢稳定性直接转化为增加的体内半衰期或较低的剂量,这在大多数情况下代表本发明的优选实施方案。式I同位素标记的化合物通常可通过进行合成方案中公开的程序和本文实施例部分和制备部分中的相关描述,用容易获得的同位素标记的反应物代替非同位素标记的反应物来制备。
为了通过一级动力学同位素效应来控制式I的化合物的氧化代谢,也可将氘(2H)掺入到所述化合物中。一级动力学同位素效应是由同位素核的交换引起的化学反应速率的变化,这反过来又是由在该同位素交换之后形成共价键所必需的基态能量的变化引起的。较重同位素的交换通常导致化学键的基态能量的降低,并因此导致限速键断裂的速率降低。如果键断裂发生在沿着多产物反应的坐标的鞍点区域中或鞍点区域附近,则产物分配比可以显著改变。为了解释:如果氘在不可交换位置键合到碳原子上,则典型的速率差为kM/kD=2-7。如果这种速率差异成功地应用于对氧化敏感的式I的化合物,则该化合物的体内特性可被显著改变,并导致药代动力学性质改善。
当发现和开发治疗剂时,本领域技术人员试图优化药代动力学参数,同时保持所需的体外性质。有理由认为许多药物动力学特性差的化合物对氧化代谢敏感。目前可用的体外肝微粒体测定提供了关于这种类型的氧化代谢过程的有价值的信息,这进而允许合理地设计具有通过对这种氧化代谢的抗性而改善的稳定性的式I的氘化化合物。由此获得式I化合物的药代动力学特性的显着改善,并且可以用体内半衰期(t1/2)、最大治疗效果浓度(Cmax)、剂量响应曲线下面积(AUC)和F的增加定量表示;以及降低清除率、剂量和材料成本。
以下旨在说明上述内容:具有多个潜在的氧化代谢攻击位点,例如苄基氢原子和与氮原子键合的氢原子的式I的化合物被制备成一系列类似物,其中氢原子的各种组合被氘原子取代,使得这些氢原子中的一些、大部分或全部被氘原子取代。半衰期确定使得能够有利和准确地确定抗氧化代谢的改善程度。这样,确定了母体化合物的半衰期由于这种类型的氘-氢交换而可以延长高达100%。
式I的化合物中的氘-氢交换也可用于实现对起始化合物的代谢物谱的有利修饰,以减少或消除不需要的毒性代谢物。例如,如果毒性代谢物通过氧化性碳-氢(C-H)键断裂而产生,则可合理地假定氘化类似物将大大减少或消除不需要的代谢物的产生,即使特定的氧化不是速率决定步骤。关于氘-氢交换的现有技术状态的进一步信息可以在例如Hanzlik等,J.Org.Chem.55,3992-3997,1990,Reider等,J.Org.Chem.52,3326-3334,1987,Foster,Adv.Drug Res.14,1-40,1985,Gillette等,Biochemistry 33(10)2927-2937,1994,and Jarman et al.Carcinogenesis 16(4),683-688,1993。
本发明还涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、溶剂化物和立体异构体,包括其以所有比率的混合物,和任选的赋形剂和/或佐剂。
药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这样的单位可以包含例如0.5mg至1g,优选1mg至700mg,特别优选5mg至100mg的本发明化合物,这取决于所治疗的病症、给药方法和患者的年龄、体重和状况,或者药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选的剂量单位制剂是包含如上所述的日剂量或分剂量或其相应部分的活性成分的那些。此外,这种类型的药物制剂可以使用制药领域通常已知的方法制备。
药物制剂可以适合于通过任何期望的合适方法给予,例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或肠胃外(包括皮下、肌内、静脉内或皮内)方法。可以使用药学领域已知的所有方法,通过例如将活性成分与一种或多种赋形剂或一种或多种佐剂组合来制备此类制剂。
适于口服给药的药物制剂可以作为单独的单位给药,例如胶囊或片剂;粉末或颗粒;在水性或非水性液体中的溶液或悬浮液;可食用泡沫或泡沫食品;或水包油的液体乳液或油包水的液体乳液。
因此,例如,在以片剂或胶囊形式口服给药的情况下,活性成分组分可以与口服、无毒和药学上可接受的惰性赋形剂,例如乙醇、甘油、水等组合。粉末通过将化合物粉碎成合适的细小尺寸并将其与以类似方式粉碎的药物赋形剂混合来制备,所述赋形剂例如可食用碳水化合物,例如淀粉或甘露醇。同样可以存在调味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并用其填充成型的明胶壳来生产。助流剂和润滑剂,例如,固体形式的高分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或聚乙二醇,可以在填充操作之前加入到粉末混合物中。同样可以加入崩解剂或增溶剂,例如琼脂、碳酸钙或碳酸钠,以便在服用胶囊后改善药物的利用度。
此外,如果需要或必要,可同样将合适的粘结剂、润滑剂和崩解剂以及染料掺入混合物中。合适的粘结剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、由玉米制成的甜味剂、天然和合成橡胶例如阿拉伯胶、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过以下制备:例如,制备粉末混合物,将混合物制粒或干压,加入润滑剂和崩解剂,并将整个混合物压制成片剂。通过将以合适方式粉碎的化合物与如上所述的稀释剂或碱,以及任选地与粘结剂,例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮,溶解延缓剂,例如石蜡,吸收促进剂,例如季盐,和/或吸收剂,例如膨润土、高岭土或磷酸二钙混合,制备粉末混合物。粉末混合物可以通过用粘结剂如糖浆、淀粉糊、acadia mucilage或纤维素或聚合物材料的溶液润湿并将其压过筛而造粒。作为造粒的替代方法,粉末混合物可以通过压片机,得到形状不均匀的团块,其被破碎形成颗粒。可以通过加入硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒,以防止粘附于片剂铸模上。然后将润滑的混合物压制得到片剂。本发明的化合物也可以与自由流动的惰性赋形剂混合,然后直接压制得到片剂,而不进行造粒或干压步骤。可以存在由虫胶密封层、糖或聚合物材料层和蜡的光泽层组成的透明或不透明的保护层。可以将染料加入到这些包衣中以便能够区分不同的剂量单位。
口服液体,例如溶液、糖浆和酏剂,可以以剂量单位的形式制备,以便给定量包含预定量的化合物。糖浆可通过将化合物溶解在具有合适香味的水溶液中来制备,而酏剂使用无毒的含醇媒介物来制备。悬浮液可以通过将化合物分散在无毒的媒介物中来配制。同样可以加入增溶剂和乳化剂,例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚,防腐剂,调味剂,例如薄荷油或天然甜味剂或糖精,或其它人造甜味剂等。
如果需要,用于口服给药的剂量单位制剂可以被包封在微胶囊中。制剂还可以以延长或延迟释放的方式制备,例如通过将颗粒材料包衣或包埋在聚合物、蜡等中。
式I的化合物及其药学上的盐、互变异构体和立体异构体也可以脂质体递送系统的形式给药,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可以由各种磷脂形成,例如胆固醇、硬脂胺或磷脂酰胆碱。
式I的化合物及其盐、互变异构体和立体异构体也可以使用单克隆抗体作为偶联有化合物分子的单独载体来递送。该化合物还可以与作为靶向药物载体的可溶性聚合物偶联。这样的聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺苯酚、聚羟乙基天冬酰胺苯酚或聚环氧乙烷聚赖氨酸,其被棕榈酰基取代。此外,化合物可以与一类适于实现药物的控制释放的生物可降解聚合物偶联,例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
适于经皮给药的药物制剂可以作为独立的膏药给药,用于与接受者的表皮延长、紧密接触。因此,例如,活性成分可以通过离子电渗疗法从膏药中释放,如在Pharmaceutical Research,3(6),318(1986)中一般性描述的。
适于局部给药的药物化合物可以配制成软膏、乳膏、悬浮液、洗剂、粉末、溶液、糊剂、凝胶、喷雾剂、气雾剂或油。
对于眼睛或其它外部组织例如口腔和皮肤的治疗,制剂优选作为局部软膏或乳膏给予。在配制为软膏剂的情况下,活性成分可以与石蜡或水混溶性乳膏剂基质一起使用。或者,可以将活性成分配制成具有水包油乳膏基质或油包水基质的乳膏。
适于局部给予于眼的药物制剂包括滴眼剂,其中活性成分溶解或悬浮于合适的载体,特别是水性溶剂中。
适于在口腔中局部给予的药物制剂包括锭剂、软锭剂和漱口水。
适于直肠给药的药物制剂可以栓剂或灌肠剂的形式给药。
适于鼻腔给药的药物制剂,其中载体物质是固体,其包括具有例如20-500微米范围内的颗粒大小的粗粉末,其以鼻吸的方式给药,即通过鼻腔从包含保持在鼻子附近的粉末的容器中快速吸入。适合作为鼻喷雾剂或滴鼻剂与作为载体物质的液体一起给药的制剂包括活性成分的水或油溶液。
适于通过吸入给药的药物制剂包括细颗粒的粉剂或雾剂,其可以通过各种类型的具有气雾剂、喷雾器或吹入器的加压分配器产生。
适于阴道给药的药物制剂可以作为阴道栓剂、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂给药。
适于肠胃外给药的药物制剂包括含水和非水无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,通过其使制剂与待治疗接受者的血液等渗;和水性和非水性无菌悬浮液,其可以包含悬浮介质和增稠剂。制剂可以在单剂量或多剂量容器中给予,例如密封的安瓿瓶和小瓶,并以冷冻干燥(冻干)状态储存,使得仅需要在使用前立即加入无菌载体液体,例如用于注射目的水。根据处方制备的注射液和悬浮液可由无菌粉末、颗粒和片剂制备。
不言而喻,除了上述特别提及的组分之外,制剂还可以包含本领域关于特定类型制剂通常的其它试剂;因此,例如,适于口服给药的制剂可以包含调味剂。
式I的化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的确切病症及其严重性、制剂的性质和给药方法,并最终由治疗医生或兽医决定。然而,本发明化合物的有效量通常为0.1-100mg/kg接受者(哺乳动物)体重/天,特别典型地为1-10mg/kg体重/天。因此,对于体重为70kg的成年哺乳动物,每天的实际量通常为70-700mg,其中该量可以作为每天的单一剂量给药,或通常以每天一系列的部分剂量(例如,二、三、四、五或六)给药,以使总的日剂量相同。其盐或溶剂化物或生理学功能衍生物的有效量可以确定为本发明化合物本身的有效量的分数。可以假定类似的剂量适于治疗上述其它病症。
这种类型的组合处理可以借助于同时、连续或分别分配处理的各个组分来实现。这类组合产品使用本发明的化合物。
本发明还涉及药物,其包含至少一种式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括其以所有比率的混合物,和至少一种另外的药物活性成分。
本发明还涉及由以下单独包装组成的组(试剂盒)
(a)有效量的式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括其以所有比率的混合物,
以及
(b)有效量的另外的药物活性成分。
该组包括合适的容器,例如盒子、单个瓶子、袋子或安瓿瓶。该组可以例如包含单独的安瓿瓶,每个安瓿瓶含有有效量的式I化合物和/或其药学上可接受的盐、互变异构体和立体异构体,包括其以所有比率的混合物,
和有效量的溶解或冻干形式的另外的药物活性成分。
本文所用的“治疗”是指在处于发生疾病或病症的风险中的受试者中,完全或部分减轻与疾病或病症相关的症状,或减缓或停止这些症状的进一步进展或恶化,或防止或预防疾病或病症。
与式I的化合物相关的术语“有效量”可以指能够在患有本文公开的疾病或处于发展本文公开的疾病的风险中的受试者中全部或部分减轻与病症或疾病相关的症状,或减缓或停止那些症状的进一步进展或恶化,或防止或提供对疾病或病症的预防的量,所述疾病或病况例如炎性病症、免疫病况、癌症或代谢病况。
在一个实施方案中,式I的化合物的有效量是例如在体外或体内抑制细胞中c-KIT激酶的量。在一些实施方案中,与未处理细胞中c-KIT激酶的活性相比,有效量的式I化合物抑制细胞中的c-KIT 10%、20%、30%、40%、50%、60%、70%、80%、90%或99%。例如在药物组合物中,式I的化合物的有效量可以是能够产生所需效果的水平;例如,对于口服和肠胃外给药,单位剂量中约0.005mg/kg受试者体重至约10mg/kg受试者体重。
用途
本发明化合物适合作为哺乳动物,尤其是人的药物活性成分,用于治疗癌症,例如胃肠间质肿瘤。
本发明包括式I的化合物和/或其药学上可接受的盐、互变异构体和立体异构体在制备用于治疗或预防癌症,优选用于治疗胃肠间质肿瘤的药物中的用途。
优选地,本发明涉及治疗疾病的方法,其中所述疾病是癌症,优选胃肠间质肿瘤。
特别优选地,本发明涉及其中疾病是癌症的方法,其中给予与至少一种其它活性药剂的给予同时、顺序或交替进行。
所公开的式I的化合物可以与其它已知的治疗剂包括抗癌剂组合给药。如本文所用,术语“抗癌剂”涉及为了治疗癌症而给予癌症患者的任何药剂。
上述定义的抗癌治疗可以作为单一疗法应用,或者除了本文公开的式I化合物之外,可以涉及常规手术或放射疗法或药物疗法。这样的药物治疗,例如化学疗法或靶向疗法,可以包括一种或多种,但优选一种下述抗肿瘤剂:
烷基化剂
如六甲蜜胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、氮芥(chlormethine)、环磷酰胺、达卡巴嗪、异环磷酰胺、英丙舒凡、对甲苯磺酸盐、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、噻替派、曲奥舒凡、氮芥(mechloretamine)、卡波醌;
阿帕兹醌、福莫司汀、葡磷酰胺、帕利伐米、哌泊溴烷、曲磷胺、乌拉莫司汀、TH-3024、VAL-0834;
铂化合物
例如卡铂、顺铂、依铂、miriplatine水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;
洛铂、奈达铂、吡铂、沙铂;
DNA改变剂(DNA altering agent)
例如氨柔比星、比生群、地西他滨、米托蒽醌、丙卡巴肼、曲贝替定、氯法拉滨;
安吖啶、brotllicin、pixantrone、Laromustine1,3;
拓扑异构酶抑制剂
如依托泊苷、伊立替康、雷佐生、sobuzoxane、替尼泊苷、托泊替康;
氨萘非特、贝洛替康、依利醋铵、voreloxin;
微管修饰剂
例如卡巴他赛、多西他赛、艾日布林、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁;
fosbretabulin,tesetaxel;
抗代谢物
如天冬酰胺酶3、阿扎胞苷、左亚叶酸钙、卡培他滨,
克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟;
去氧氟尿苷、阿糖胞苷、雷替曲塞、sapacitabine、替加氟2,3、三甲曲沙;
抗癌抗生素
例如博来霉素、放线菌素D、阿霉素、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链脲霉素、戊柔比星、制嗪他汀、佐柔比星、红诺霉素、普卡霉素;
阿柔比星、peplomycin、吡柔比星;
激素/拮抗剂
例如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡鲁斯酮、氯苯尼索、地加瑞克、地塞米松、雌二醇、氟可托酮
氟甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚;
阿考必芬、达那唑、地洛瑞林、表硫甾烷醇、orteronel、恩杂鲁胺1,3;
芳香酶抑制剂
例如氨鲁米特、阿那曲唑、依西美坦、法屈唑、来曲唑、睾内酯;
福美司坦;
小分子激酶抑制剂
例如克里唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼罗替尼、帕唑帕尼、瑞戈非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿昔替尼;
阿法替尼、阿立替尼、达拉菲尼、达克替尼、地那西利、多维替尼、恩沙司他汀、尼达那尼、来那替尼、linifanib、linsitinib、马赛替尼、米哚妥林、莫替拉尼、奈拉替尼、orantinib、perifosine、ponatinib、radatinib、rigosertib、tipifarnib、tivatinib、tivozanib、曲美替尼、匹马司替尼、briganinate、雪尼布、阿帕替尼4、卡博替尼S-苹果酸盐1,3、依鲁替尼1,3、icotinib4、布帕拉替尼2、环丙替尼4、cobimetinib1,3、艾利替尼1,3、非达替尼1、XL-6474;
光敏剂
例如甲氧沙林3;
卟吩姆钠、他拉泊芬、替莫泊芬;
抗体
例如阿仑单抗、贝塞罗单抗、布鲁昔单抗、西妥昔单抗、地舒单抗、伊匹单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗,
曲妥珠单抗、贝伐单抗、帕妥珠单抗2,3;
catumaxomab,elotuzumab,epratuzumab,farletuzumab,mogamulizumab,necitumumab,nimotuzumab,obinutuzumab,ocaratuzumab,oregovomab,ramucirumab,rilotumumab,siltuximab,tocilizumab,zalutumumab,zanolimumab,matuzumab,dalotuzumab1,2,3,onartuzumab1,3,racotumomab1,
tabalumab1,3,EMD-5257974,nivolumab1,3;
细胞因子
如阿地白介素、干扰素α2、干扰素α2a3、干扰素α2b2,3;
Celmoleukin、他斯潘那汀、Teceleukin、Oprelvekin1,3、重组干扰素β-1a4;
药物缀合物
如腺嘌呤白介素地替托普、替伊莫单抗、碘苄胍I123、泼尼松氮芥、曲妥珠单抗、艾司莫斯汀、吉妥单抗、奥曲霉素、阿柏西普;
Cintrekin Besudotox,依度曲肽,inotuzumab ozogamicin,naptumomabestafenatox,oportuzumamonatox,锝(99mTc)Arcitumomab1,3,
长春氟酯1,3;
疫苗
例如sipuleucel3;vitespen3,emepepimut-S3,oncoVAX4,rindopepimut3,troVax4,MGN-16014,MGN-17034;
其他
阿利替视黄素、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、香菇多糖、美替罗辛、米伐木汀、帕米膦酸、培门冬酶、喷司他丁、sipuleucel3、西佐匹仑、他米巴罗汀、替西罗莫司、沙利度胺、维甲酸、维莫德吉、唑来膦酸、伏立诺他;
塞来昔布、西仑吉肽、恩替诺特、依他硝唑、加奈多司、idronoxil、iniparib、ixazomib、氯尼达明、尼莫拉唑、帕比司他、培瑞维A酸、plitidepsin、泊利度胺、procodazol、ridaforolimus、taskinimmod、telotristat、胸腺法新、替拉扎明、托司他布、乌苯美司、伐斯帕达、gendicine4,
溶菌素4、reolysin4、盐酸雷贝那霉素1,3、曲巴那尼2,3、virulizin4、卡非佐米1,3、内皮抑素4、immucothel4、belinostat3、MGN-17034;
1Prop.INN(建议的国际非专有名称)
2Rec.INN(推荐的国际非专有名称)
3USAN(美国采用名称)
4无INN。
以下缩写分别指以下定义:
aq(水溶液),h(小时),g(克),l(升),mg(毫克),MHz(兆赫),min.(分钟),mm(毫米),mmol(毫摩尔),mM(毫摩尔),m.p.(熔点),eq(当量),ml(毫升),μl(微升),ACN(乙腈),AcOH(乙酸),CDCl3(氘代氯仿),CD3OD(氘代甲醇),CH3CN(乙腈),c-hex(环己烷),DCC(二环己基碳二亚胺),DCM(二氯甲烷),DIC(二异丙基碳二亚胺),DIPEA(二异丙基乙基胺),DMF(二甲基甲酰胺),DMSO(二甲亚砜),DMSO-d6(氘代二甲亚砜),EDC(1-(3-二甲基氨基-丙基)-3-乙基碳二亚胺),ESI(电喷雾电离),EtOAc(乙酸乙酯),Et2O(乙醚),EtOH(乙醇),HATU(二甲基氨基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亚甲基]-二甲基-六氟磷酸铵),HPLC(高效液相色谱法),i-PrOH(2-丙醇),K2CO3(碳酸钾),LC(液相色谱法),MeOH(甲醇),MgSO4(硫酸镁),MS(质谱法),MTBE(甲基叔丁基醚),NaHCO3(碳酸氢钠),NaBH4(硼氢化钠),NMM(N-甲基吗啉)、NMR(核磁共振)、PyBOP(苯并三唑-1-基-氧基-三-吡咯烷-鏻六氟磷酸盐)、RT(室温)、Rt(保留时间)、SPE(固相萃取)、TBTU(2-(1-H-苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸盐)、TEA(三乙胺)、TFA(三氟乙酸)、THF(四氢呋喃)、TLC(薄层色谱法)、UPLC(超高效液相色谱)、UV(紫外)。
在以上和以下,所有温度都以℃表示。
1H NMR在Bruker DPX-300、DRX-400、AVII-400或500MHz谱仪上记录,使用氘代溶剂的残留信号作为内标。化学位移(δ)以相对于残留溶剂信号的ppm报告(对于DMSO-d6中的1H NMR,δ=2.49ppm)。1H NMR数据报告如下:化学位移(多重性、偶合常数和氢的数目)。多重性缩写如下:s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽)、bs(宽单峰)、p(pentet)。
HPLC/MS条件A:
HPLC/MS:Agilent 1200/6100
洗脱液A:水+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
柱:Chromolith HR RP-18e;50-4.6mm
流速:3.3ml/min
梯度:0%->100%B:0.0->2.0min|100%B:2.0->2.5min
UV检测:220nm
MS检测:65-800amu正
HPLC/MS条件B:
HPLC/MS:Agilent 1200/6100
洗脱液A:水+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
柱:Kinetex XB-C18;2.6μm;50-4.6mm
流速:2.5ml/min
梯度:0%->100%B:0.0->1.4min|100%B:1.4->2.0min
UV检测:220nm
MS检测:65-800amu正
UPLC/MS条件:
UPLC/MS:Waters Acquity/SQD
洗脱液A:水+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
柱:Kinetex XB-C18;1.7μm;50-2.1mm
流速:0.9ml/min
梯度:2%->100%B:0.0->1.0min|100%B:1.0->1.3min
UV检测:220nm/254nm/MaxPlot/TotalPlot
MS检测:61-800amu正
检测
c-Kit(V654A)检测:
c-Kit(V654A)(N端GST标记的重组人c-Kit,氨基酸544-末端含有V654A突变)用8mM MOPS pH 7.0、0.2mM EDTA、250μMGGMEDIYEFMGGKKK、10mM乙酸镁和[γ-33P-ATP](比活性约500cpm/pmol,浓度200μM)培养。通过加入MgATP混合物引发反应。在室温下培养40分钟后,加入3%的磷酸溶液终止反应。然后将10μL反应物点在P30 filtermat上并在75mM磷酸中洗涤3次,每次5分钟,在甲醇中洗涤1次,然后干燥和闪烁计数。
cKIT突变抑制剂细胞测试的检测原理
表达突变的组成型活性cKIT受体酪氨酸激酶的GIST430/654细胞系(Δ560-576和V654A)用于评估化合物的细胞效力。突变体cKIT的细胞活性通过使用基于Luminex的珠粒测定在酪氨酸307处的cKIT自磷酸化程度确定。GIST430/654细胞以96孔板的每孔25,000个细胞接种在100μl培养基(85%IMDM/15%FCS,补充有100nM伊马替尼)中。第二天,将化合物连续稀释添加,持续45分钟。然后,用90μl裂解缓冲液(20mM Hepes pH 7.5,200mM NaCl,1.5mM MgCl2x6H2O,0.4mM EDTA,1%Triton-X-100,1%磷酸酶-抑制剂II,20mMβ-甘油磷酸酯,0.1%蛋白酶-抑制剂鸡尾酒III,0.01%Benzonase)裂解细胞,裂解物通过96孔滤板(0.65μm)离心清除。将样品用与抗总cKIT抗体偶联的Luminex珠粒在4℃温和搅拌下培养过夜。为了检测磷酸-Y307-cKIT,添加了磷酸特异性抗体和种特异性PE标记的第二抗体。磷酸-Y307-cKIT的量在Luminex 200仪器中测定,在60秒内测量每孔100个事件。
用化合物处理的样品的计数被计算为溶剂处理(0.3%DMSO)样品的对照的百分比。拟合剂量-反应曲线并使用Genedata Screener软件确定IC50值。
药理数据
表1式I化合物的c-KIT(V654A)和GIST 430/654的抑制(IC50)
说明:1,4E-06表示1.4x10-6
表1中所示的化合物是本发明特别优选的化合物。
表2与相应的三唑衍生物相比,一些代表性的式I化合物的c-KIT(V654A)和GIST430/654的抑制(IC50)
中间体的合成
吲唑
6-(2-甲氧基-乙氧基)-1H-吲唑的合成
向2-氟-4-羟基苯甲醛(2.80g,20.0mmol)在DMF(50ml)中的溶液加入碳酸钾(8.29g,60mmol)并将所得浆液在60℃下搅拌18小时。使反应混合物达到室温并用水和二氯甲烷处理。分离有机相,水相用二氯甲烷萃取两次。合并的有机相用硫酸钠干燥,过滤并蒸发。残余物在高真空下干燥,得到无色油状的2-氟-4-(2-甲氧基-乙氧基)-苯甲醛;HPLC/MS1.36min(A),[M+H]+199。
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.78(t,J=8.6Hz,1H),7.02(dd,J=13.0,2.4Hz,1H),6.96(dd,J=8.7,2.4Hz,1H),4.29–4.19(m,2H),3.74–3.63(m,2H),3.31(s,3H)。
将2-氟-4-(2-甲氧基-乙氧基)-苯甲醛(6.16g,31.1mmol)在氢氧化肼(30.2ml,31.1g,621mmol)中的溶液在搅拌下加热至140℃并保持在该温度16小时。使反应混合物达到室温并用水稀释。然后小心地加入浓盐酸和2N盐酸,直到达到pH值2。混合物用二氯甲烷萃取四次。合并的有机相用饱和氯化钠溶液萃取并用硫酸钠干燥。滤除硫酸钠,将滤液蒸发并真空干燥,得到6-(2-甲氧基-乙氧基)-1H-吲唑,为浅黄色结晶固体;HPLC/MS 1.21min(A),[M+H]+193。
1H NMR(400MHz,DMSO-d6)δ12.76(s,1H),7.93(s,1H),7.61(d,J=8.8Hz,1H),6.93(s,1H),6.75(dd,J=8.8,2.1Hz,1H),4.20–4.11(m,2H),3.88–3.65(m,2H),3.33(s,3H)。
5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑的合成
在氮气下,将叔丁酸钾(6.43g,57.3mmol)分批加入5,6-二氟-1H-吲唑(2.94g,19.1mmol)在乙二醇单甲醚(40ml)中的溶液中。将混合物加热至150℃并在该温度下搅拌五天。允许反应混合物达到室温并用水(150ml)和1N盐酸(39ml)稀释以达到约6的pH值。混合物用二氯甲烷萃取两次。用水洗涤合并的有机相,用硫酸钠干燥并蒸发。将残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱纯化,得到5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑为灰白色固体;HPLC/MS 1.31min(B),[M+H]+211。
1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),7.93(t,J=1.3Hz,1H),7.53(d,J=11.0Hz,1H),7.12(dd,J=7.1,1.0Hz,1H),4.54–4.06(m,2H),4.06–3.58(m,2H),3.34(s,3H)。
5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑的替代合成
在配备冷却和加热夹套的氮气吹扫的10l反应器中,将2-溴-4,5-二氟苯甲醛(500g,2.26mol)溶解在2-甲氧基乙醇(4.5l)中。在20-25℃的温度下在1小时的时间内分批加入叔丁酸钾(381g,3.39mol)。所得溶液在18℃的温度下搅拌16小时。用水(2l)和柠檬酸在水(2l)中的饱和溶液猝灭反应混合物。混合物用叔丁基甲基醚(5l)处理并分离有机相。有机相用水洗涤一次并用盐水洗涤两次并用硫酸钠干燥。滤出硫酸钠,蒸发滤液,得到2-溴-5-氟-4-(2-甲氧基-乙氧基)-苯甲醛,为浅黄色部分结晶油,将其原样用于下一步。通过硅胶柱色谱,用二氯甲烷/乙酸乙酯作为洗脱液,得到纯样品:白色结晶固体;HPLC/MS1.60min(A),[M+H]+277/279。
1H NMR(500MHz,DMSO-d6)δ10.05(d,J=3.0Hz,1H),7.66(d,J=11.3Hz,1H),7.63(d,J=7.5Hz,1H),4.40–4.31(m,2H),3.75–3.68(m,2H),3.32(s,3H)。
4-甲苯磺酰肼(377g,2.02mol)在甲醇(4l)中浆化,浆液在60℃搅拌30分钟。然后,将粗2-溴-5-氟-4-(2-甲氧基-乙氧基)-苯甲醛(700g,约2.02mol)在甲醇(1l)中的溶液在30分钟内加入,并将反应混合物在60℃下搅拌18小时。将反应混合物冷却至0℃。抽滤出沉淀,用甲醇洗涤并在40℃真空干燥,得到N-[(E)-[2-溴-5-氟-4-(2-甲氧基乙氧基)苯基]亚甲基氨基]-4-甲基-苯磺酰胺,为白色结晶;UPLC/MS 0.85min,[M+H]+445/447。
1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.10(d,J=2.0Hz,1H),7.77(d,J=8.3Hz,2H),7.49–7.36(m,4H),4.28–4.21(m,2H),3.70–3.57(m,2H),3.30(s,3H),2.38(s,3H)。
将N-[(E)-[2-溴-5-氟-4-(2-甲氧基乙氧基)苯基]亚甲基氨基]-4-甲基-苯磺酰胺(445g,1.00mol)和氧化铜(I)(100g,700mmol)在1-丁醇(5l)中的悬浮液用氮气吹扫。将混合物加热至117℃并在该温度下搅拌5小时。使反应混合物达到室温并蒸发。将残余物吸收在甲苯(5l)中,将悬浮液加热至80°,用活性炭(100g)处理并在50℃下搅拌1小时。过滤悬浮液并蒸发滤液。固体残余物从庚烷(2l)中结晶,得到5-氟-6-(2-甲氧基-乙氧基)-1-(甲苯-4-磺酰基)-1H-吲唑,为黄色结晶;HPLC/MS 1.66min(B),[M+H]+365。
1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),7.84(d,J=8.4Hz,2H),7.72(d,J=6.9Hz,1H),7.69(d,J=10.4Hz,1H),7.39(d,J=8.1Hz,2H),4.43–4.34(m,2H),3.86–3.71(m,2H),3.36(s,3H),2.34(s,3H)。
将5-氟-6-(2-甲氧基-乙氧基)-1-(甲苯-4-磺酰基)-1H-吲唑(360g,988mmol)和碳酸铯(644g,1.98mol)在THF(2.0l)和2,2,2-三氟乙醇(2.0l)的混合物中的悬浮液在40℃下搅拌18小时。反应混合物用乙酸乙酯稀释并抽滤。残余物用乙酸乙酯洗涤。蒸发滤液并在水和乙酸乙酯之间分配。有机相用硫酸钠干燥并蒸发。残余物从乙酸乙酯/庚烷中重结晶,得到5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑,为灰白色结晶固体;UPLC/MS 0.57min,[M+H]+211。
类似地制备以下化合物:
5-氟-6-甲氧基-1H-吲唑;白色结晶固体;UPLC/MS 0.56min,[M+H]+167。
1H NMR(700MHz,DMSO-d6)δ12.95(s,1H),7.94(s,1H),7.54(d,J=11.1Hz,1H),7.11(d,J=7.1Hz,1H),3.91(s,3H)。
6-乙氧基-5-氟-1H-吲唑;白色固体;UPLC/MS 0.61min,[M+H]+181。
1H NMR(500MHz,DMSO-d6)δ12.87(s,1H),7.92(d,J=1.2Hz,1H),7.52(d,J=11.1Hz,1H),7.08(d,J=7.1Hz,1H),4.15(q,J=7.0Hz,2H),1.40(t,J=6.9Hz,3H)。
5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑的合成
该化合物根据以下合成方案合成
浅黄色结晶固体;HPLC/MS 1.39min(A),[M+H]+227。
1H NMR(300MHz,氯仿-d1)δ10.19(s,1H),7.96(d,J=0.9Hz,1H),7.76(s,1H),6.91(s,1H),4.36–4.16(m,2H),3.99–3.66(m,2H),3.53(s,3H)。
6-(2-甲氧基-乙氧基)-1H-吲唑-5-甲腈的合成
该化合物根据以下合成方案合成
白色结晶固体;HPLC/MS 1.22min(A),[M+H]+281。
1H NMR(400MHz,氯仿-d1)δ8.10(s,1H),8.06(s,1H),7.28(s,2H),7.00(s,1H),4.32–4.26(m,2H),3.95–3.82(m,2H)。
3-乙炔基-吲唑
3-乙炔基-6-三氟甲基-1H-吲唑的合成
向6-三氟甲基吲唑(990mg,5.32mmol)在DMF(200ml)中的溶液中加入碘(2.00g,7.88mmol),然后分批加入氢氧化钾颗粒(1.20g,21.4mmol),在室温下搅拌反应混合物。18小时后,将反应混合物倒入饱和硫代硫酸钠水溶液中,所得混合物用乙酸乙酯萃取两次。合并的有机相用盐水洗涤并经硫酸钠干燥。滤除硫酸钠,蒸发残余物,得到3-碘-6-三氟甲基-1H-吲唑,为米色固体;UPLC/MS 0.80min,[M+H]+313。
1H NMR(400MHz,DMSO-d6)δ13.95(s,1H),7.97(s,1H),7.69(d,J=8.6Hz,1H),7.48(dd,J=8.5,1.5Hz,1H)。
向3-碘-6-三氟甲基-1H-吲唑(1,69g,5.43mmol)在乙腈(100ml)中的悬浮液中加入N,N-二甲基吡啶-4-胺(133mg,1.09mmol)和二碳酸二叔丁酯(1.78g,8.15mmol),并将反应混合物在室温下搅拌3天。在减压下浓缩反应混合物。将残余物用乙酸乙酯吸收并用饱和氯化铵水溶液洗涤两次并用盐水洗涤一次。有机相用硫酸钠干燥并蒸发得到3-碘-6-三氟甲基-吲唑-1-甲酸叔丁酯,为浅黄色固体;UPLC/MS 1.00min,[M-tBu]+357。
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),7.83(d,J=8.5Hz,1H),7.78(dd,J=8.5,1.5Hz,1H),1.67(s,9H)。
将3-碘-6-三氟甲基-吲唑-1-甲酸叔丁酯(1.87g,4.53mmol)在1,4-二噁烷(45ml)中的溶液用氮气吹扫。然后,在氮气下加入双(三苯基膦)钯(II)氯化物(470mg,0.67mmol)、碘化铜(I)(127mg,0.67mmol)、N-乙基二异丙胺(1.57ml,9.07mmol)和三甲基甲硅烷基乙炔(1,34g,13,6mmol)并将反应混合物在80℃下封闭反应瓶中搅拌1小时。使反应混合物达到室温,在硅藻土上吸收并在硅胶柱上以环己烷/乙酸乙酯为洗脱液进行色谱分离,得到6-三氟甲基-3-三甲基甲硅烷基乙炔基-吲唑-1-甲酸叔丁酯,为灰白色固体;UPLC/MS 1.12min,[M-tBu]+327。
1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.80(d,J=8.5Hz,1H),7.55(dd,J=8.4,1.5Hz,1H),1.43(s,9H),0.09(s,9H)。
向6-三氟甲基-3-三甲基甲硅烷基乙炔基-吲唑-1-甲酸叔丁酯(1.60g,4.18mmol)在乙醇(5ml)中的溶液中加入碳酸钾(120mg,0.87mmol),反应混合物在室温下搅拌18小时。在减压下浓缩反应混合物。将残余物溶解在乙酸乙酯中并用水洗涤3次。有机相用硫酸钠干燥并蒸发,得到3-乙炔基-6-三氟甲基-1H-吲唑,为浅棕色固体;UPLC/MS0.75min,[M+H]+211。
1H NMR(400MHz,DMSO-d6)δ13.87(s,1H),7.98(s,1H),7.94(d,J=8.5Hz,1H),7.50(dd,J=8.5,1.5Hz,1H),4.59(s,1H)。
类似地制备以下化合物:
3-乙炔基-6-(2-甲氧基-乙氧基)-1H-吲唑,灰白色固体;UPLC/MS0.63min,[M+H]+217。
1H NMR(500MHz,DMSO-d6)δ13.15(s,1H),7.56(d,J=8.8Hz,1H),6.97(d,J=2.0Hz,1H),6.86(dd,J=8.8,2.1Hz,1H),4.43(s,1H),4.20–4.13(m,2H),3.76–3.66(m,2H),3.33(s,3H)。
6-溴-3-乙炔基-1H-吲唑,浅棕色粉末;UPLC/MS 0.75min,[M+H]+221,223。
5-氯-3-乙炔基-6-(2-甲氧基-乙氧基)-1H-吲唑,浅棕色固体;UPLC/MS 1.05min,[M+H]+251。
3-乙炔基-6-(2-甲氧基-乙氧基)-1H-吲唑-5-甲腈,浅棕色固体;HPLC/MS1.85min(A),[M+H]+242。
3-乙炔基-1H-吲唑-6-甲酸甲酯,灰白色固体;UPLC/MS 0.95min,[M+H]+201。
3-乙炔基-5-氟-6-甲氧基-1H-吲唑,灰白色固体;UPLC/MS 0.65min,[M+H]+191。
1H NMR(400MHz,DMSO-d6)δ13.34(s,1H),7.47(d,J=10.6Hz,1H),7.17(d,J=7.0Hz,1H),4.48(s,1H),3.92(s,3H)。
3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑,浅棕色固体;UPLC/MS 0.66min,[M+H]+235。
1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),7.45(d,J=10.5Hz,1H),7.19(d,J=6.9Hz,1H),4.45(s,1H),4.41–4.17(m,2H),3.80–3.64(m,2H),3.34(s,3H)。
3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯的合成
向5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑(173g,822mmol)在DMF(2.0l)中的溶液中加入碘(228g,905mmol),然后分批加入氢氧化钾粉末(115g,2.57mol),反应混合物在室温下搅拌。18小时后,将反应混合物倒入冷水(12l)和乙酸乙酯(6l)的混合物中。分离各相并用乙酸乙酯(2l)萃取水层。合并的有机层用水(3l)、硫代硫酸钠水溶液(3l)洗涤并用水(2l)洗涤3次。然后用硫酸钠干燥有机层,过滤并浓缩。所得浆液用庚烷(2l)处理。滤出固体并真空干燥,得到5-氟-3-碘-6-(2-甲氧基-乙氧基)-1H-吲唑,为米色固体;UPLC/MS0.71min,[M+H]+337。
1H NMR(400MHz,DMSO-d6)δ13.37(s,1H),7.20(d,J=10.6Hz,1H),7.17(d,J=7.0Hz,1H),4.32–4.16(m,2H),3.82–3.65(m,2H),3.34(s,3H)。
向5-氟-3-碘-6-(2-甲氧基-乙氧基)-1H-吲唑(249g,0.74mmol)在乙腈(2.5l)中的溶液中加入4-(二甲基氨基)-吡啶(133mg,150mmol)。然后缓慢加入二碳酸二叔丁酯(238ml,1.11mol)并将混合物在室温下搅拌18小时。在减压下浓缩反应混合物。将残余物吸收于乙酸乙酯(4l)中并用水(5l)、10%柠檬酸水溶液(3l)、水(3l)和盐水(2l)洗涤。有机相用硫酸钠干燥并减压浓缩。残余物从庚烷中结晶,得到5-氟-3-碘-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯,为白色结晶固体;UPLC/MS0.93min,[M-tBu]+381。
1H NMR(400MHz,DMSO-d6)δ7.71(d,J=7.1Hz,1H),7.40(d,J=10.0Hz,1H),4.35–4.25(m,2H),3.94–3.67(m,2H),3.34(s,3H),1.65(s,9H)。
在氮气下,向5-氟-3-碘-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯(297g,680mmol)和双(三苯基膦)钯(II)氯化物(14.2g,20.3mmol)在三乙胺(2l)中的悬浮液中加入三甲基甲硅烷基乙炔(112ml,810mmol)并将混合物在84℃下搅拌3小时。使反应混合物达到室温并用叔丁基甲基醚稀释。该溶液用水(每次5l)和盐水(4l)洗涤五次。有机层经硫酸钠干燥并蒸发,得到5-氟-6-(2-甲氧基-乙氧基)-3-三甲基甲硅烷基乙炔基-吲唑-1-甲酸叔丁酯,为浅棕色固体;UPLC/MS 1.03min,[M-tBu]+351。
1H NMR(400MHz,DMSO-d6)δ7.73(d,J=7.1Hz,1H),7.59(d,J=9.9Hz,1H),4.31–4.24(m,2H),3.78–3.70(m,2H),3.33(s,3H),1.64(s,9H),0.30(s,9H)。
向5-氟-6-(2-甲氧基-乙氧基)-3-三甲基甲硅烷基乙炔基-吲唑-1-甲酸叔丁酯(273g,671mmol)在乙醇(1.5l)中的溶液中加入碳酸钾(18.6g,143mmol)并将反应混合物在30℃下搅拌3小时。将反应混合物倒入冷水中,滤出固体并用水洗涤。将固体溶解在二氯甲烷(3l)中并用二氯甲烷和叔丁基甲基醚作为洗脱液在硅胶(3kg)上过滤。将洗脱液减压浓缩并从庚烷(300ml)中结晶,得到3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯,为浅棕色固体;HPLC/MS 2.54min(A),[M-tBu]+279。
1H NMR(400MHz,DMSO-d6)δ7.73(d,J=7.1Hz,1H),7.62(d,J=9.9Hz,1H),4.82(s,1H),4.42–4.26(m,2H),3.94–3.72(m,2H),3.35(s,3H),1.66(s,9H)。
类似地制备以下化合物:
6-乙氧基-3-乙炔基-5-氟-1H-吲唑-1-甲酸叔丁酯;灰白色固体;UPLC/MS0.93min,[M-tBu]+249。
1H NMR(400MHz,DMSO-d6)δ7.71(d,J=7.1Hz,1H),7.63(d,J=10.0Hz,1H),4.81(s,1H),4.23(q,J=7.0Hz,2H),1.65(s,8H),1.43(t,J=6.9Hz,3H)。
3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯的替代合成:
向5-氟-6-(2-甲氧基-乙氧基)-3-三甲基甲硅烷基乙炔基-吲唑-1-甲酸叔丁酯(488mg,1.20mmol)在乙醇(12ml)中的溶液中加入氟化钾(3.5mg,0.06mmol)并将反应混合物在室温搅拌3小时。反应混合物在冰浴中冷却。滤出固体,用冰冷的乙醇洗涤并真空干燥,得到3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯,为灰白色固体;HPLC/MS2.54min(A),[M-tBu]+279。
甲酸
4-[5-(6-三氟甲基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸甲酯的合成
将3-乙炔基-6-三氟甲基-1H-吲唑(166mg,0.79mmol)和4-[(Z)-C-氯-N-羟基-碳亚氨基]苯甲酸甲酯(187mg,0.88mmol)在叔丁醇(1.2ml)和THF(0.4ml)的混合物中的悬浮液用氮气吹扫。在氮气下,加入碘化铜(I)(13mg,0.068mmol)并将悬浮液在室温搅拌5分钟。然后,加入碳酸氢钾(80mg,0.80mmol)并将反应混合物在室温下搅拌3天。反应混合物用水处理。滤出所得固体,用水洗涤并风干。残余物用乙酸乙酯研磨,真空干燥,得到4-[5-(6-三氟甲基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸甲酯,为灰白色固体;UPLC/MS 0.93min,[M+H]+388。
1H NMR(400MHz,DMSO-d6)δ14.30(s,1H),8.48(d,J=8.6Hz,1H),8.22(d,J=8.1Hz,2H),8.15(d,J=8.0Hz,2H),8.10(d,J=1.9Hz,1H),7.89(s,1H),7.65(d,J=8.5Hz,1H),3.92(s,3H)。
向4-[5-(6-三氟甲基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸甲酯(124mg,0.32mmol)在甲醇中的溶液中加入2M氢氧化钠水溶液(1.3ml),反应混合物在80℃下搅拌1小时,在室温下搅拌16小时。所得悬浮液用浓盐酸酸化。滤出所得固体,用水洗涤并真空干燥,得到4-[5-(6-三氟甲基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸,为灰白色固体;UPLC/MS 0.82min,[M+H]+374。
1H NMR(500MHz,DMSO-d6)δ14.48(s,1H),13.20(s,1H),8.48(d,J=8.7Hz,1H),8.19(d,J=8.5Hz,2H),8.15–8.08(m,3H),7.88(s,1H),7.65(dd,J=8.7,1.5Hz,1H)。
类似地制备以下化合物:
4-{5-[6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸,棕色固体;HPLC/MS 1.52min(A),[M+H]+380。
4-[5-(6-溴-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸,棕色固体;UPLC/MS0.82min,[M+H]+384/386。
1H NMR(500MHz,DMSO-d6)δ13.99(s,1H),13.1(s,1H),8.20(d,J=8.7Hz,1H),8.17(d,J=8.4Hz,2H),8.11(d,J=8.3Hz,2H),7.95(d,J=1.5Hz,1H),7.81(s,1H),7.50(dd,J=8.7,1.6Hz,1H)。
4-{5-[5-氰基-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸,灰白色固体;HPLC/MS 2.04min(A),[M+H]+405。
4-{5-[5-氯-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸,棕色固体;HPLC/MS 1.05min,[M+H]+414。
4-[5-(5-氟-6-甲氧基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸,棕色固体;UPLC/MS 0.75min,[M+H]+354。
6-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-烟酸,棕色固体;HPLC/MS 2.52min(A),[M+H]+399。
2-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-噻唑-5-甲酸,棕色固体;HPLC/MS 2.57min(A),[M+H]+405。
2-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-噻唑-4-甲酸,棕色固体;HPLC/MS 2.56min(A),[M+H]+405。
4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸的合成
向3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯(205g,614mmol)和4-(羟基亚氨基-甲基)-苯甲酸甲酯在二氯甲烷(2.6l)中的溶液中滴加次氯酸钠水溶液(含量约12%,944ml,约1.84mol)。在添加过程中,通过外部冷却将混合物的温度调节在22℃和26℃之间。反应混合物在室温下搅拌18小时。过滤反应混合物。滤饼用水(1l)洗涤,用乙腈(300ml)洗涤两次,真空干燥,得到5-氟-3-[3-(4-甲氧基羰基-苯基)-异噁唑-5-基]-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯,为浅黄色结晶;HPLC/MS 2.16min(A),[M-tBu]+456。
1H NMR(500MHz,DMSO-d6)δ8.26–8.20(m,3H),8.15(d,J=8.4Hz,2H),8.12(s,1H),7.84(d,J=7.2Hz,1H),4.38–4.34(m,2H),3.92(s,3H),3.82–3.76(m,2H),3.30(s,9H)。
向5-氟-3-[3-(4-甲氧基羰基-苯基)-异噁唑-5-基]-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯(339g,662mmol)在THF(3.36l)中的悬浮液中经由滴液漏斗缓慢加入2M氢氧化钠水溶液(1.33l,2.65mol),并将反应混合物在60℃下搅拌5小时。将反应混合物冷却至室温并真空蒸发有机溶剂。所得悬浮液用冰水(3l)稀释。在连续搅拌下用2.5N盐酸水溶液将悬浮液的pH值从pH11调节至pH2。滤出固体并用水(3次600ml)和叔丁基甲基醚(300ml)洗涤。将固体在45℃下减压干燥数天,得到4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸,灰白色固体;HPLC/MS 1.55min(A),[M+H]+398。
1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),13.20(s,1H),8.18(d,J=8.5Hz,2H),8.11(d,J=8.5Hz,2H),8.06–8.00(m,2H),7.80(s,1H),7.29(d,J=7.1Hz,1H),4.34–4.26(m,2H),3.84–3.72(m,2H),3.36(s,3H).
类似地制备下列化合物
5-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}吡啶-2-甲酸,黄色固体;HPLC/MS 2.51min(A),[M+H]+399。
4-{5-[5-氟-6-(2-羟基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸的合成
向4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸(234mg,0.59mmol)在二氯甲烷(8ml)中的溶液中滴加1M三溴化硼溶液(1.2ml)。反应混合物在室温下搅拌16小时。滤出固体并用二氯甲烷和水洗涤。残余物在高真空下干燥,得到4-{5-[5-氟-6-(2-羟基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸,为灰白色固体;UPLC/MS 0.63min,[M+H]+384。
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.17(d,J=8.5Hz,1H),8.11(d,J=8.5Hz,2H),8.02(d,J=11.0Hz,1H),7.79(s,1H),7.28(d,J=7.1Hz,1H),4.19(t,J=4.9Hz,1H),3.82(t,J=4.8Hz,1H)。
实施例1
2-[1-(4-{5-[6-(三氟甲基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇(“A1”)
向4-[5-(6-三氟甲基-1H-吲唑-3-基)-异噁唑-3-基]-苯甲酸(52mg,0.14mmol)、2-(吡咯烷-2-基)-丙-2-醇(23mg,0.18mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(41mg,0.21mmol)和1-羟基苯并三唑水合物(25mg,153mmol)在DMF(1.4ml)中的悬浮液中加入4-甲基吗啉(63μl,0.57mmol)。将反应混合物加热至80℃并在该温度下搅拌16小时。使反应混合物达到室温并加入饱和碳酸氢钠溶液。滤出固体,用水洗涤并干燥。残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液色谱分离,得到2-[1-(4-{5-[6-(三氟甲基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇,为灰白色粉末;UPLC/MS0.87min,[M+H]+485。
1H NMR(500MHz,DMSO-d6)δ14.28(s,1H),8.47(d,J=8.6Hz,1H),8.12(d,J=8.1Hz,2H),8.10(s,1H),7.84(s,1H),7.74(d,J=8.0Hz,2H),7.64(dd,J=8.7,1.6Hz,1H),4.88(s,1H),4.31(t,J=7.2Hz,1H),3.62–3.47(m,1H),3.44–3.33(m,1H),1.98–1.82(m,3H),1.68–1.55(m,1H),1.17(s,3H),1.14(s,3H).
类似地制备以下化合物:
2-[(2R)-1-(4-{5-[6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇(“A2”)
灰白色固体;HPLC/MS 1.60min(A),[M+H]+491.
1H NMR(500MHz,DMSO-d6)δ13.57(s,1H),8.10(d,J=8.2Hz,2H),8.08(d,J=8.9Hz,1H),7.73(d,J=8.0Hz,2H),7.70(s,1H),7.06(d,J=2.1Hz,1H),6.99(dd,J=8.9,2.1Hz,1H),4.88(s,1H),4.31(t,J=7.2Hz,1H),4.24–4.19(m,2H),3.76–3.70(m,2H),3.56–3.48(m,1H),3.41–3.33(m,4H),2.00–1.81(m,3H),1.68–1.54(m,1H),1.17(s,3H),1.14(s,3H).
3-(3-{4-[(2S)-2,4-二甲基哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A3”)
灰白色固体;HPLC/MS 1.27min(A),[M+H]+494.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.11(d,J=8.3Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.55(d,J=8.3Hz,2H),7.29(d,J=7.1Hz,1H),4.34–4.26(m,2H),3.81–3.74(m,2H),3.36(s,3H),3.20(broad,1H),2.75(broad,1H),2.69–2.59(m,1H),2.18(s,3H),2.10–2.03(m,1H),1.93–1.83(m,1H),1.29(d,J=6.8Hz,3H).
{4-[5-(6-溴-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-[(R)-2-(1-羟基-1-甲基-乙基)-吡咯烷-1-基]-甲酮(“A3a”)
灰白色固体;UPLC/MS 0.86min,[M+H]+495/497.
{4-[5-(6-溴-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-[(S)-2-(1-羟基-1-甲基-乙基)-吡咯烷-1-基]-甲酮(“A4”)
UPLC/MS 0.86min,[M+H]+495/497.
1H NMR(400MHz,DMSO-d6)δ13.96(s,1H),8.20(d,J=8.6Hz,1H),8.12(d,J=8.0Hz,2H),7.95(d,J=1.5Hz,1H),7.79(s,1H),7.74(d,J=7.9Hz,2H),7.50(dd,J=8.7,1.7Hz,1H),4.89(s,1H),4.32(t,J=7.1Hz,1H),3.53(q,J=9.1,8.4Hz,1H),3.38(t,J=9.0Hz,1H),2.04–1.78(m,3H),1.69–1.55(,1H),1.18(s,3H),1.14(s,3H)。
2-[(2S)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇(“A5”)
白色固体;HPLC/MS 1.27min(A),[M+H]+509.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.11(d,J=8.0Hz,2H),8.03(d,J=10.9Hz,1H),7.77(s,1H),7.73(d,J=7.9Hz,2H),7.28(d,J=7.0Hz,1H),4.88(s,1H),4.36–4.23(m,3H),3.79–3.73(m,2H),3.58–3.47(m,1H),3.41-3.34(m,4H),2.00–1.80(m,3H),1.67–1.55(m,1H),1.17(s,3H),1.14(s,3H).
{4-[5-(6-溴-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-((S)-2,4-二甲基-哌嗪-1-基)-甲酮(“A5a”)
灰白色固体;UPLC/MS 0.54min,[M+H]+480/482.
1H NMR(400MHz,DMSO-d6)δ13.96(s,1H),8.20(d,J=8.7Hz,1H),8.11(d,J=8.3Hz,2H),7.95(d,J=1.5Hz,1H),7.78(s,1H),7.55(d,J=8.2Hz,2H),7.50(dd,J=8.6,1.6Hz,1H),2.80–2.71(m,1H),2.64(d,J=10.7Hz,1H),2.18(s,3H),2.06(dd,J=11.3,3.8Hz,1H),1.91–1.83(m,1H),1.29(d,J=6.8Hz,3H).
4-{5-[5-氰基-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基苯甲酰胺(“A6”)
灰白色粉末;HPLC/MS 2.01min(A),[M+H]+432.
1H NMR(700MHz,DMSO-d6)δ13.99(s,1H),8.76(s,1H),8.10(d,J=8.4Hz,2H),7.95(s,1H),7.60(d,J=8.2Hz,2H),7.29(s,1H),4.43–4.32(m,2H),3.95–3.73(m,2H),3.38(s,3H),3.02(s,3H),2.96(s,3H).
5-氟-3-(3-{4-[(2S)-2-(甲烷磺酰基甲基)吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A7”)
白色粉末;HPLC/MS 1.55min(A),[M+H]+543.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.11(d,J=8.3Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.69(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.56(broad,1H),4.34–4.25(m,2H),3.81–3.67(m,3H),3.52(q,J=7.9,7.3Hz,1H),3.42–3.29(m,6H),3.10(s,3H),2.24–2.14(m,1H),2.10–1.90(m,2H),1.85–1,75(m,1H).
3-(3-{4-[(2S)-2,4-二甲基哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-6-(三氟甲基)-1H-吲唑(“A50”)
[(2S)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]甲醇(“A51”)
灰白色固体;UPLC/MS 0.70min,[M+H]+481.
1H NMR(400MHz,DMSO-d6,旋转异构体)δ13.72(s,1H),8.09(d,J=8.1Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.68(d,J=7.9Hz,2H),7.28(d,J=7.1Hz,1H),4.80(broad,1H),4.34–4.22(m,2H),4.18(broad,1H),3.80–3.69(m,2H),3.69–3.41(m,4H),3.36(s,3H),2.03-1.66(m;6H).
[(2R)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]甲醇(“A52”)
灰白色固体;UPLC/MS 0.70min,[M+H]+481.
1H NMR(400MHz,DMSO-d6,旋转异构体)δ13.72(s,1H),8.09(d,J=8.1Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.68(d,J=7.9Hz,2H),7.28(d,J=7.1Hz,1H),4.80(broad,1H),4.34–4.22(m,2H),4.18(broad,1H),3.80–3.69(m,2H),3.69–3.41(m,4H),3.36(s,3H),2.03-1.66(m;6H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A53”)
白色结晶;HPLC/MS 1.33min(A),[M+H]+522.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.10(d,J=8.4Hz,1H),8.02(d,J=11.0Hz,1H),7.83–7.79(m,2H),7.76(s,1H),7.28(d,J=7.1Hz,1H),4.36(t,J=8.1Hz,1H),4.32–4.28(m,2H),4.19(dd,J=9.2,4.9Hz,1H),4.14–4.06(m,1H),3.92(dd,J=10.9,4.4Hz,1H),3.84–3.73(m,2H),3.60(t,J=4.7Hz,4H),3.36(s,3H),3.18(tt,J=7.2,5.0Hz,1H),2.34(broad,4H).
[1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-4-甲基哌嗪-2-基]甲醇(“A54”)
浅棕色固体;HPLC/MS 1.22min(A),[M+H]+510.
1H NMR(500MHz,DMSO-d6,旋转异构体,信号的选择)δ13.72(s,1H),8.08(d,J=7.9Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.57(d,J=7.9Hz,2H),7.28(d,J=7.0Hz,1H),4.83(s,1H),4.31-4.28(m,2H),3.96–3.56(m,5H),3.35(s,3H),2.16(s,3H).
5-氟-3-(3-{4-[(2R)-2-(甲烷磺酰基甲基)吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A55”)
白色固体;UPLC/MS 0.73min,[M+H]+543.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.12(d,J=8.4Hz,2H),8.04(d,J=10.9Hz,1H),7.79(s,1H),7.70(d,J=8.3Hz,2H),7.29(d,J=7.1Hz,1H),4.62–4.51(m,1H),4.35–4.24(m,2H),3.83–3.71(m,3H),3.53(dt,J=10.1,7.0Hz,1H),3.42–3.29(m,5H),3.11(s,3H),2.20(dq,J=13.9,7.1Hz,1H),2.05(dq,J=12.5,6.4Hz,1H),1.96(dp,J=13.1,6.6Hz,1H),1.86–1.75(m,1H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3-甲基氮杂环丁烷-3-胺(“A56”)
三氟乙酸盐;白色固体;HPLC/MS 2.24min(A),[M+H]+465.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),8.28(s,3H),8.15(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.82(d,J=8.3Hz,2H),7.80(s,1H),7.29(d,J=7.1Hz,1H),4.43(d,J=9.5Hz,1H),4.36–4.26(m,3H),4.17(d,J=10.8Hz,1H),4.02(d,J=10.8Hz,1H),3.81–3.73(m,2H),3.35(s,3H),1.58(s,3H).
白色粉末;UPLC/MS 0.68min,[M+H]+570.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.11(d,J=8.4Hz,1H),8.03(d,J=11.0Hz,1H),7.81(d,J=8.4Hz,2H),7.78(s,1H),7.28(d,J=7.1Hz,1H),4.40(t,J=8.1Hz,1H),4.32–4.25(m,2H),4.20(dd,J=9.2,5.0Hz,1H),4.13(dd,J=10.3,7.3Hz,1H),3.92(dd,J=10.5,5.0Hz,1H),3.81–3.74(m,2H),3.48(tt,J=7.2,5.0Hz,1H),3.35(s,3H),3.13(t,J=5.2Hz,4H),2.88–2.76(m,4H).
2-[(2R)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-2-基]丙-2-醇(“A58”)
白色固体;HPLC/MS 1.59min(A),[M+H]+495.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),8.12(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.82(d,J=8.2Hz,2H),7.79(s,1H),7.28(d,J=7.0Hz,1H),5.02(s,1H),4.40(dd,J=9.2,5.6Hz,1H),4.35–4.22(m,3H),3.99(td,J=8.9,5.5Hz,1H),3.83–3.71(m,2H),3.36(s,3H),2.30(qd,J=9.8,6.3Hz,1H),2.13(ddt,J=11.1,9.0,5.6Hz,1H),1.16(s,3H),1.15(s,3H).
2-[(2S)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-2-基]丙-2-醇(“A59”)
浅黄色粉末;UPLC/MS 0.76min,[M+H]+495.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),8.12(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.82(d,J=8.2Hz,2H),7.79(s,1H),7.28(d,J=7.0Hz,1H),5.02(s,1H),4.40(dd,J=9.2,5.6Hz,1H),4.35–4.22(m,3H),3.99(td,J=8.9,5.5Hz,1H),3.83–3.71(m,2H),3.36(s,3H),2.30(qd,J=9.8,6.3Hz,1H),2.13(ddt,J=11.1,9.0,5.6Hz,1H),1.16(s,3H),1.15(s,3H).
7-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-2-氧杂-7-氮杂螺[3.5]壬烷(“A60”)
灰白色固体;UPLC/MS 0.72min,[M+H]+507.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.10(d,J=8.3Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.56(d,J=8.2Hz,2H),7.29(d,J=7.1Hz,1H),4.36(s,4H),4.33–4.28(m,2H),3.80–3.72(m,2H),3.55(bs,2H),3.37(s,3H),3.30(bs,2H),1.84(bs,4H).
5-氟-6-甲氧基-3-(3-{4-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A61”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-((R)-2-羟基甲基-吡咯烷-1-基)-甲酮(“A62”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-((S)-2-羟基甲基-吡咯烷-1-基)-甲酮(“A63”)
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(3-吗啉-4-基-氮杂环丁烷-1-基)-甲酮(“A64”)
白色固体;m.p.200–201℃,[M+H]+538.
1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),8.32(s,1H),8.16-8.09(m,2H),7.88-7.79(m,3H),7.26(s,1H),4.41-4.34(m,1H),4.33-4.27(m,2H),4.24-4.16(m,1H),4.15-4.05(m,1H),3.96-3.88(m,1H),3.82-3.70(m,2H),3.66-3.52(m,4H),3.38(s,3H),3.23-3.13(m,1H),2.43-2.25(m,4H).
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-[3-(4-甲基-哌嗪-1-基)-氮杂环丁烷-1-基]-甲酮(“A65”)
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-((S)-3-羟基甲基-吗啉-4-基)-甲酮(“A66”)
白色固体;m.p.115-116℃,[M+H]+513.
1H NMR(400MHz,DMSO-d6+D2O)δ8.39-8.28(m,1H),8.16-8.01(m,2H),7.95-7.78(m,1H),7.66-7.55(m,2H),7.28(s,1H),4.35-4.25(m,2H),4.22-3.86(m,2H),3.86-3.79(m,2H),3.76-3.45(m,6H),3.39-3.32(m,3H),3.31-2.72(m,1H).
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-((R)-3-羟基甲基-吗啉-4-基)-甲酮(“A67”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A68”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-(3-吗啉-4-基-氮杂环丁烷-1-基)-甲酮(“A69”)
(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-2-甲基-苯基)-(顺式)-四氢-呋喃并[3,4-c]吡咯-5-基-甲酮(“A70”)
(2-氟-4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(顺式)-四氢-呋喃并[3,4-c]吡咯-5-基-甲酮(“A71”)
3-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-N,N-二甲基-苯甲酰胺(“A135”)
白色固体;m.p.160–165℃,[M+H]+424.
1H NMR(400MHz,DMSO-d6):δ13.73(s,1H),8.14-8.05(m,3H),7.83(s,1H),7.64(t,J=7.7Hz,1H),7.56(dt,J=7.7,1.4Hz,1H),7.28(d,J=7.1Hz,1H),4.30(dd,J=5.6,3.3Hz,2H),3.79-3.72(m,2H),3.01(d,J=31.0Hz,6H)。
实施例2
2-[(2R)-1-(4-{5-[6-(1-甲基-1H-吡唑-4-基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇(“A8”)
在微波小瓶中装入{4-[5-(6-溴-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-[(R)-2-(1-羟基-1-甲基-乙基)-吡咯烷-1-基]-甲酮(74mg,0.15mmol)、1-甲基-1H-吡唑-4-硼酸频哪醇酯(47mg,0.23mmol)、氟化铯(69mg,0.45mmol)、双(三苯基膦)氯化钯(II)(11mg,0.016mmol)、二噁烷(800μl)和水(400μl)。小瓶用氮气吹扫并在微波反应器中加热至120℃1小时。向反应混合物中加入水。滤出固体并用水洗涤。残余物在硅胶柱上用乙酸乙酯/甲醇进行色谱纯化,得到2-[(2R)-1-(4-{5-[6-(1-甲基-1H-吡唑-4-基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]丙-2-醇,为白色粉末;UPLC/MS 0.75min,[M+H]+497。
1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.31(s,1H),8.20(dd,J=8.5,0.8Hz,1H),8.13(d,J=8.0Hz,2H),8.02(d,J=0.8Hz,1H),7.78(t,J=1.1Hz,1H),7.77–7.71(m,3H),7.59(dd,J=8.5,1.4Hz,1H),4.89(s,1H),4.32(t,J=7.2Hz,1H),3.91(s,3H),3.54(q,J=9.3,8.7Hz,1H),3.39(t,J=9.2Hz,1H),2.02–1.81(m,3H),1.69–1.57(m,1H),1.18(s,3H),1.15(s,3H)。
类似地制备以下化合物:
3-(3-{4-[(2S)-2,4-二甲基哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-6-(1-甲基-1H-吡唑-4-基)-1H-吲唑(“A9”)
浅黄色固体;UPLC/MS 0.50min(A),[M+H]+482。
1H NMR(500MHz,DMSO-d6)δ13.76(s,1H),8.31(s,1H),8.19(dd,J=8.5,0.8Hz,1H),8.12(d,J=8.2Hz,2H),8.02(d,J=0.8Hz,1H),7.78(s,1H),7.73(s,1H),7.59(dd,J=8.5,1.4Hz,1H),7.55(d,J=8.3Hz,2H),3.91(s,3H),3.30(s,3H),3.3–3.1(宽,1H),2.81–2.71(宽,1H),2.68–2.58(m,0H),2.18(s,1H),2.07(dd,J=11.4,4.0Hz,1H),1.97–1.81(m,1H),1.30(d,J=6.8Hz,3H)。
实施例3
5-氯-3-(5-{4-[(2S)-2,4-二甲基哌嗪-1-羰基]苯基}-1,2-噁唑-3-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A10”)
棕色固体;UPLC/MS 0.91min,[M+H]+510。
1H NMR(500MHz,DMSO-d6)δ13.62(s,1H),8.17(s,1H),8.08(d,J=8.3Hz,1H),7.63(s,1H),7.55(d,J=8.3Hz,2H),7.25(s,1H),4.32–4.26(m,2H),3.81–3.74(m,2H),3.38(s,3H),3.40–3.10(m,3H),2.75(宽,1H),2.64(宽,1H),2.18(s,3H),2.06(d,J=11.4Hz,1H),1.92–1.82(m,1H),1.28(d,J=6.8Hz,3H)。
类似地制备以下化合物:
3-(5-{4-[(2S)-2,4-二甲基哌嗪-1-羰基]苯基}-1,2-噁唑-3-基)-6-(2-甲氧基乙氧基)-1H-吲唑-5-甲腈(“A11”)
棕色固体;HPLC/MS 2.21min(A),[M+H]+501.
1H NMR(500MHz,DMSO-d6)δ13.90(s,1H),8.52(s,1H),8.09(d,J=8.1Hz,2H),7.70(s,1H),7.57(d,J=7.9Hz,2H),7.30(s,1H),4.49–4.22(m,2H),3.99–3.57(m,2H),3.39(s,3H),3.32–3.10(宽,3H),2.80–2.70(宽,1H),2.68–2.56(宽,1H),2.18(s,3H),2.06(d,J=11.1Hz,1H),1.92–1.82(m,1H),1.29(d,J=6.8Hz,3H)。
实施例4
4-{5-[5-氯-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基苯甲酰胺(“A12”)
向5-氯-3-乙炔基-6-(2-甲氧基-乙氧基)-1H-吲唑(97.8mg,0.39mmol)和4-(羟基亚氨基-甲基)-N,N-二甲基-苯甲酰胺(50.0mg,0.26mmol)在甲醇(4ml)和水(800μl)的混合物中的搅拌溶液中每两小时分四份加入双(三氟乙酰氧基)-碘苯(224mg,0.52mmol),并将反应混合物在室温下搅拌16小时。过滤反应混合物。残余物用甲醇洗涤并真空干燥,得到4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-N,N-二甲基-苯甲酰胺,为棕色固体;HPLC/MS 2.61min(A),[M+H]+441。
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.30(s,1H),8.10(d,J=8.3Hz,2H),7.81(s,1H),7.59(d,J=8.3Hz,2H),7.26(s,1H),4.37–4.26(m,2H),3.83–3.73(m,2H),3.38(s,3H),3.02(s,3H),2.96(s,3H)。
类似地制备以下化合物:
浅棕色固体;UPLC/MS 0.99min,[M+H]+385.
1H NMR(700MHz,DMSO-d6)δ13.74(s,1H),9.10(d,J=2.3Hz,1H),8.30-8.27(m,2H),7.82(s,1H),7.46(d,J=8.1Hz,1H),7.25(s,1H),4.32–4.27(m,2H),3.80–3.76(m,2H).
5-氯-6-(2-甲氧基乙氧基)-3-{3-[4-(1H-1,2,4-三唑-1-基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A14”)
灰白色固体;HPLC/MS 2.73min(A),[M+H]+437.
1H NMR(700MHz,DMSO-d6)δ13.74(s,1H),9.44(s,1H),8.30(s,1H),8.29(s,1H),8.24(d,J=8.5Hz,2H),8.08(d,J=8.6Hz,2H),7.84(s,1H),7.25(s,1H),4.30(dd,J=5.5,3.5Hz,2H),3.80–3.74(m,2H),3.38(s,3H).
5-氯-3-[3-(4-甲烷磺酰基苯基)-1,2-噁唑-5-基]-6-(2-甲氧基乙氧基)-1H-吲唑(“A15”)
灰白色固体;HPLC/MS 2.61min(A),[M+H]+448.
1H NMR(500MHz,DMSO-d6)δ13.77(s,1H),8.36–8.29(m,3H),8.12(d,J=8.4Hz,2H),7.91(s,1H),7.26(s,1H),4.34–4.28(m,2H),3.81–3.75(m,2H),3.38(s,3H),3.30(s,3H).
5-氟-3-[3-(4-甲烷磺酰基苯基)-1,2-噁唑-5-基]-6-(2-甲氧基乙氧基)-1H-吲唑(“A16”)
灰白色固体;HPLC/MS 2.52min(A),[M+H]+432.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),8.31(d,J=8.5Hz,1H),8.12(d,J=8.5Hz,2H),8.03(d,J=10.9Hz,1H),7.86(s,1H),7.28(d,J=7.1Hz,1H),4.37–4.17(m,2H),3.89–3.69(m,2H),3.36(s,3H),3.30(s,3H).
N-(4-{5-[5-氯-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)乙酰胺(“A17”)
灰白色固体;HPLC/MS 2.56min(A),[M+H]+427.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),10.17(s,1H),8.28(s,1H),7.96(d,J=8.7Hz,2H),7.75(d,J=8.7Hz,2H),7.68(s,1H),7.24(s,1H),4.32–4.23(m,2H),3.83–3.74(m,2H),3.38(s,3H),2.09(s,3H).
N-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)乙酰胺(“A18”)
灰白色固体;HPLC/MS 2.43min(A),[M+H]+411.
1H NMR(500MHz,DMSO-d6)δ13.67(s,1H),10.16(s,1H),8.00(d,J=11.0Hz,1H),7.95(d,J=8.7Hz,2H),7.75(d,J=8.7Hz,2H),7.63(s,1H),7.26(d,J=7.1Hz,1H),4.33–4.18(m,2H),3.80–3.70(m,2H),3.35(s,3H),2.09(s,3H).
灰白色固体;UPLC/MS 1.01min,[M-H]-389.
1H NMR(700MHz,DMSO-d6)δ14.20(s,1H),8.36(d,J=8.5Hz,1H),8.29(s,1H),8.10(d,J=8.3Hz,2H),7.90(dd,J=8.5,1.3Hz,1H),7.80(s,1H),7.59(d,J=8.3Hz,2H),3.94(s,3H),3.02(s,3H),2.96(s,3H).
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基苯甲酰胺(“A20”)
灰白色固体;HPLC/MS 2.47min(A),[M+H]+425.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.09(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.58(d,J=8.3Hz,1H),7.28(d,J=7.1Hz,1H),4.40–4.17(m,2H),3.85–3.68(m,2H),3.36(s,3H),3.02(s,3H),2.96(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(1H-1,2,4-三唑-1-基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A21”)
灰白色固体;UPLC/MS 1.04min,[M+H]+421.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),9.44(s,1H),8.31(s,1H),8.23(d,J=8.7Hz,2H),8.08(d,J=8.7Hz,2H),8.04(d,J=10.9Hz,1H),7.81(s,1H),7.28(d,J=7.1Hz,1H),4.34–4.24(m,2H),3.79–3.73(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(6-甲基吡啶-3-基)-1,2-噁唑-5-基]-1H-吲唑(“A22”)
白色固体;HPLC/MS 2.08min(A),[M+H]+425.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),9.10(d,J=2.2Hz,1H),8.29(dd,J=8.0,2.3Hz,1H),8.01(d,J=10.9Hz,1H),7.78(s,1H),7.47(d,J=8.1Hz,1H),7.28(d,J=7.1Hz,1H),4.31–4.25(m,2H),3.80–3.69(m,2H),3.35(s,3H).
(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)(亚氨基)甲基-λ6-sulfanone(“A226”)
实施例5
N-(2-甲氧基乙基)-3-(3-{4-[(2-甲氧基乙基)氨基甲酰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-6-甲酰胺(“A23”)
白色粉末;UPLC/MS 0.85min,[M-H]-374.
1H NMR(400MHz,DMSO-d6)δ14.0(宽,1H)8.27(d,J=8.6Hz,1H),8.22–8.17(m,2H),8.11(d,J=8.3Hz,2H),7.84(dd,J=8.6,1.3Hz,1H),7.78(s,1H),7.59(d,J=8.2Hz,2H),7.50(s,1H),3.02(s,3H),2.96(s,3H).
类似地制备以下化合物:
白色固体;HPLC/MS 2.16min(A),[M+H]+390.
1H NMR(400MHz,DMSO-d6)δ14.1(宽,1H),8.65(q,J=4.4Hz,1H),8.28(d,J=8.6Hz,1H),8.15(s,1H),8.11(d,J=8.3Hz,2H),7.80(dd,J=8.6,1.4Hz,1H),7.78(s,1H),7.59(d,J=8.3Hz,2H),3.02(s,3H),2.96(s,3H),2.85(d,J=4.5Hz,3H).
3-{3-[4-(二甲基氨基甲酰基)苯基]-1,2-噁唑-5-基}-N-(2-甲氧基乙基)-1H-吲唑-6-甲酰胺(“A25”)
白色固体;HPLC/MS 2.21min(A),[M+H]+434.
1H NMR(400MHz,DMSO-d6)δ13.9(宽,1H),8.75(t,J=5.1Hz,1H),8.29(dd,J=8.6,0.9Hz,1H),8.18(s,1H),8.11(d,J=8.3Hz,2H),7.82(dd,J=8.6,1.4Hz,1H),7.79(s,1H),7.59(d,J=8.3Hz,2H),3.56–3.44(m,4H),3.30(s,3H),3.02(s,3H),2.96(s,3H)。
实施例6
5-氟-3-{3-[4-(3-氟氮杂环丁烷-1-羰基)苯基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A26”)
向4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸(52mg,0.06mmol)在DMF(2ml)中的溶液中加入3-氟氮杂环丁烷盐酸盐(8.42mg,0.08mmol),然后加入4-甲基吗啉(28μl,0.25mmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓-六氟磷酸盐(36mg,0.09mmol)。反应混合物在室温下搅拌16小时。真空浓缩反应混合物,残余物在硅胶柱上色谱纯化,用乙酸乙酯/甲醇作为洗脱液,得到(3-氟-氮杂环丁烷-1-基)-(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-甲酮,为白色粉末;HPLC/MS 2.51min(A),[M+H]+455。
1H NMR(400MHz,DMSO-d6)δ13.8(宽,1H),8.12(d,J=8.4Hz,1H),8.02(d,J=11.0Hz,1H),7.83(d,J=8.4Hz,1H),7.77(s,1H),7.29(d,J=7.0Hz,1H),5.53(tt,J=6.1,3.2Hz,0.5H),5.39(tt,J=6.2,3.2Hz,0.5H),4.7–4.0(m,4H),4.33–4.23(m,1H),3.85–3.67(m,2H),3.38(s,3H)。
类似地制备以下化合物:
5-氟-3-(3-{4-[(3R)-3-氟吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A27”)
白色固体;HPLC/MS 2.52min(A),[M+H]+469.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.14–8.08(m,2H),8.03(d,J=11.0Hz,1H),7.77(s,1H),7.78–7.67(m,2H),7.28(d,J=7.0Hz,1H),5.49–5.24(m,1H),4.33–4.24(m,2H),3.91–3.47(m,6H),3.36(s,3H),2.29–1.96(m,2H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-3-甲腈(“A28”)
白色固体;HPLC/MS 2.45min(A),[M+H]+462.
1H NMR(700MHz,DMSO-d6)δ13.72(s,1H),8.12(d,J=8.2Hz,2H),8.03(d,J=10.9Hz,1H),7.81(d,J=8.3Hz,2H),7.80(s,1H),7.28(d,J=6.9Hz,1H),4.64(宽,1H),4.57(宽,1H),4.39(宽,1H),4.33–4.26(m,2H),4.22(宽,1H),3.88(tt,J=9.3,6.3Hz,1H),3.78–3.71(m,2H),3.35(s,3H).
5-氟-3-{3-[4-(3-甲烷磺酰基氮杂环丁烷-1-羰基)苯基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A29”)
灰白色固体;HPLC/MS 2.38min(A),[M+H]+515.
1H NMR(700MHz,DMSO-d6)δ13.72(s,1H),8.14(d,J=8.2Hz,2H),8.04(d,J=10.9Hz,1H),7.83(d,J=8.2Hz,2H),7.80(s,1H),7.28(d,J=7.0Hz,1H),4.75–4.64(m,1H),4.54–4.49(m,1H),4.40–4.35(m,2H),4.32–4.25(m,3H),3.79–3.72(m,2H),3.35(s,3H),3.08(s,3H).
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-1λ6-硫代吗啉-1,1-二酮(“A30”)
白色固体;HPLC/MS 2.55min(A),[M+H]+515.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.12(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.78(s,1H),7.69(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.33–4.24(m,2H),4.04(宽,2H),3.80–3.74(m,2H),3,73(宽,2H),3.36(s,3H),3.29(宽,4H).
N-环丙基-4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N-甲基苯甲酰胺(“A31”)
白色固体;HPLC/MS 2.61min(A),[M+H]+451.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.08(d,J=8.3Hz,2H),8.04(d,J=11.0Hz,1H),7.78(s,1H),7.68(d,J=7.9Hz,2H),7.29(d,J=7.1Hz,1H),4.35–4.25(m,2H),3.85–3.69(m,2H),3.36(s,3H),3.05-2.93(m,4H),0.63–0.40(m,4H).
5-氟-3-(3-{4-[(3S)-3-氟吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A32”)
白色固体;HPLC/MS 2.53min(A),[M+H]+469.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.14–8.08(m,2H),8.03(d,J=11.0Hz,1H),7.77(s,1H),7.78–7.67(m,2H),7.28(d,J=7.0Hz,1H),5.49–5.24(m,1H),4.33–4.24(m,2H),3.91–3.47(m,6H),3.36(s,3H),2.29–1.96(m,2H).
5-氟-3-{3-[4-(3-甲氧基氮杂环丁烷-1-羰基)苯基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A33”)
白色固体;HPLC/MS 2.51min(A),[M+H]+467.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.12(d,J=8.4Hz,1H),8.04(d,J=11.0Hz,1H),7.82(d,J=8.4Hz,2H),7.79(s,1H),7.29(d,J=7.1Hz,1H),4.55–4.45(m,0.5),4.41–4.24(m,3.5H),4.23–4.18(m,0.5H),3.92–3.85(m,0.5H),3.83–3.61(m,2H),3.36(s,3H),3.25(s,3H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3-甲基氮杂环丁烷-3-醇(“A34”)
白色固体;HPLC/MS 2.38min(A),[M+H]+467.
1H NMR(700MHz,DMSO-d6)δ13.73(s,1H),8.12(d,J=8.0Hz,2H),8.04(d,J=10.9Hz,1H),7.81(d,J=8.2Hz,2H),7.79(s,1H),5.71(s,1H),4.30(dd,J=5.5,3.4Hz,2H),4.21(d,J=8.7Hz,1H),4.16(d,J=8.8Hz,1H),3.95(d,J=10.0Hz,1H),3.92(d,J=10.1Hz,1H),3.78–3.74(m,2H),3.36(s,3H),1.42(s,3H).
N-[二甲基(氧代)-λ6-亚硫烷基]-4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰胺(“A35”)
白色固体;HPLC/MS 2.49min(A),[M+H]+473.
1H NMR(700MHz,DMSO-d6)δ13.73(s,1H),8.15(d,J=8.5Hz,2H),8.13(d,J=8.3Hz,2H),8.05(d,J=10.9Hz,1H),7.80(s,1H),7.29(d,J=7.0Hz,1H),4.35–4.28(m,2H),3.88–3.72(m,2H),3.51(s,6H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(4-甲基哌嗪-1-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A36”)三氟乙酸盐
白色固体;HPLC/MS 2.19min(A),[M+H]+480.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),9.76(s,1H),8.15(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.79(s,1H),7.65(d,J=8.3Hz,2H),7.30(s,1H),4.58(宽,1H),4.33–4.29(m,2H),3.80(宽,1H),3.81–3.70(m,2H),3,43(宽,4H)3.36(s,3H),3.13(宽,2H),2.85(s,3H).
N-[2-(二甲基氨基)乙基]-4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰胺(“A72”)
三氟乙酸盐;白色固体;HPLC/MS 2.24min(A),[M+H]+468.
1H NMR(500MHz,DMSO-d6)δ13.75(s,1H),9.30(s,1H),8.84(t,J=5.7Hz,1H),8.19(d,J=8.4Hz,2H),8.08–8.00(m,3H),7.81(s,1H),7.29(d,J=7.1Hz,1H),4.33–4.16(m,2H),3.80–3.74(m,2H),3.65(q,J=5.9Hz,2H),3.31(q,J=5.9Hz,2H),2.88(d,J=4.7Hz,6H).
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N-(1-甲基氮杂环丁烷-3-基)苯甲酰胺(“A73”)
三氟乙酸盐;白色固体;UPLC/MS 0.86min;[M+H]+466.
1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),9.67(s,1H),9.20(d,J=6.8Hz,1H),8.23–8.13(m,2H),8.11–8.00(m,3H),7.80(s,1H),7.30(d,J=7.1Hz,1H),4.92–4.72(m,1H),4.59-4.39(m,2H),4.35–4.26(m,2H),4.25–4.04(m,H),3.82–3.72(m,2H),3.36(s,3H),2.93(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{2-氧杂-6-氮杂螺[3.3]庚烷-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A74”)
白色固体;HPLC/MS 2.55min(A),[M+H]+479.
1H NMR(700MHz,DMSO-d6)δ13.74(s,1H),8.12(d,J=8.3Hz,2H),8.04(d,J=10.8Hz,1H),7.81–7.78(m,3H),7.29(d,J=7.0Hz,1H),4.73–4.68(m,4H),4.54(s,2H),4.37–4.28(m,2H),4.26(s,2H),3.82–3.69(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(1H-吡唑-1-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A75”)
白色固体;HPLC/MS 2.62min(A),[M+H]+503.
1H NMR(400MHz,DMSO-d6)δ13.7(s,1H),8.14(d,J=8.4Hz,2H),8.03(d,J=11.0Hz,1H),7.95(d,J=2.3Hz,1H),7.87(d,J=8.4Hz,2H),7.79(s,1H),7.60(d,J=1.8Hz,0H),7.29(d,J=7.1Hz,1H),6.33(t,J=2.1Hz,1H),5.38(tt,J=8.2,5.4Hz,1H),4.82(t,J=7.9Hz,1H),4.70–4.63(m,1H),4.58(t,J=9.1Hz,1H),4.40–4.32(m,1H),4.33–4.22(m,2H),3.81–3.69(m,2H),3.37(s,3H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-N,N-二甲基氮杂环丁烷-3-胺(“A76”)
三氟乙酸盐;白色固体;UPLC/MS 0.84min,[M+H]+480.
1H NMR(700MHz,DMSO-d6)δ13.75(s,1H),10.28(s,1H),8.15(d,J=8.3Hz,2H),8.03(d,J=10.8Hz,1H),7.82(d,J=8.3Hz,2H),7.80(s,1H),7.29(d,J=7.0Hz,1H),4.65(t,J=9.4Hz,1H),4.51–4.46(m,1H),4.37–4.23(m,4H),4.17–4.05(m,1H),3.79–3.73(m,2H),3.35(s,3H),2.88–2.73(m,6H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{6-氧杂-2-氮杂螺[3.4]辛烷-2-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A77”)
无色树脂;HPLC/MS 2.63min(A),[M+H]+493.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.11(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.82(d,J=8.4Hz,2H),7.78(s,1H),7.28(d,J=7.0Hz,1H),4.38–4.32(m,2H),4.32–4.27(m,2H),4.09–4.03(m,2H),3.86–3.66(m,6H),3.36(s,3H),2.15(td,J=7.0,2.5Hz,2H).
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-1λ4-硫代吗啉-1-酮(“A78”)
无色树脂;HPLC/MS 2.38min(A),[M+H]+499.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.12(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.77(s,1H),7.64(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.37(宽,1H),4.33–4.27(m,2H),3.87(宽,1H),3.79–3.73(m,3H),3.58(宽,1H),3.36(s,3H),3.00(td,J=12.8,11.6,3.5Hz,2H),2.94–2.67(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{1-氧杂-6-氮杂螺[3.3]庚烷-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A79”)
无色树脂;HPLC/MS 2.61min(A),[M+H]+479.
1H NMR(500MHz,DMSO-d6)δ13.72(s,1H),8.11(d,J=8.4Hz,2H),8.03(d,J=11.0Hz,1H),7.85–7.75(m,2H),7.28(d,J=7.1Hz,1H),4.62–4.23(m,7H),4.22–4.04(m,1H),3.80–3.73(m,2H),3.36(s,3H),2.86(t,J=7.5Hz,2H).
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-1-亚氨基-1λ6-硫代吗啉-1-酮(“A80”)
白色固体;HPLC/MS 2.32min(A),[M+H]+514.
1H NMR(700MHz,DMSO-d6)δ13.72(s,1H),8.13(d,J=8.3Hz,2H),8.03(d,J=10.9Hz,1H),7.78(s,1H),7.69(d,J=8.2Hz,2H),7.28(d,J=7.0Hz,1H),4.39(s,1H),4.31–4.24(m,2H),4.12–3.12(宽,8H),3.79–3.75(m,2H),3.36(s,3H).
5-氟-3-{3-[5-(3-氟氮杂环丁烷-1-羰基)吡啶-2-基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A81”)
白色泡沫;HPLC/MS 2.56min(A),[M+H]+456.
1H NMR(500MHz,DMSO-d6)δ13.76(s,1H),9.00(dd,J=2.2,0.9Hz,1H),8.26(dd,J=8.2,2.2Hz,1H),8.21(dd,J=8.2,0.9Hz,1H),7.99(d,J=10.8Hz,1H),7.61(s,1H),7.29(d,J=7.0Hz,1H),5.48(dtt,J=57.5,6.3,3.2Hz,1H),4.80–4.38(m,3H),4.33–4.27(m,2H),4.16(dd,J=24.6,12.1Hz,1H),3.81–3.73(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{5-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]吡啶-2-基}-1,2-噁唑-5-基)-1H-吲唑(“A82”)
三氟乙酸盐,浅黄色泡沫;HPLC/MS 2.19min(A),[M+H]+523.
1H NMR(700MHz,DMSO-d6,部分很宽的信号,信号的选择)δ13.78(s,1H),10.57(s,1H),9.01(s,1H),8.30–8.22(m,2H),7.98(d,J=10.7Hz,1H),7.61(s,1H),7.30(d,J=7.0Hz,1H),4.72–4.46(m,2H),4.37–4.19(m,2H),3.94–3.69(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{5-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]-1,3-噻唑-2-基}-1,2-噁唑-5-基)-1H-吲唑(“A83”)
三氟乙酸盐,白色泡沫;HPLC/MS 2.23min(A),[M+H]+529.
1H NMR(700MHz,DMSO-d6,部分很宽的信号,信号的选择)δ13.84(s,1H),10.8(s,1H),8.47(s,1H),8.01(d,J=10.8Hz,1H),7.65(s,1H),7.29(d,J=6.9Hz,1H),4.91–4.5(m,2H),4.32–4.28(m,2H),3.88–3.66(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]-1,3-噻唑-2-基}-1,2-噁唑-5-基)-1H-吲唑(“A84”)
三氟乙酸盐,白色泡沫;HPLC/MS 2.33min(A),[M+H]+529.
1H NMR(700MHz,DMSO-d6,部分很宽的信号,信号的选择)δ13.86(s,1H),10.53(s,1H),8.63(s,1H),7.96(d,J=10.7Hz,1H),7.66(s,1H),7.30(d,J=6.9Hz,1H),5.07–4.66(m,2H),4.36–4.23(m,2H),3.85–3.73(m,2H).
5-氟-3-(3-{4-[3-(1H-咪唑-1-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A85”)
三氟乙酸盐,白色泡沫;HPLC/MS 2.26min(A),[M+H]+503.
1H NMR(700MHz,DMSO-d6)δ14.53(s,1H),13.75(s,1H),8.16(d,J=8.3Hz,2H),8.12(s,1H),8.04(d,J=10.9Hz,1H),7.89(d,J=8.3Hz,2H),7.81(s,1H),7.77(s,1H),7.29(d,J=7.0Hz,1H),5.44(tt,J=8.2,5.3Hz,1H),4.84(t,J=8.8Hz,1H),4.76(dd,J=10.1,5.3Hz,1H),4.63(t,J=9.7Hz,1H),4.36(dd,J=11.3,5.2Hz,1H),4.32–4.28(m,2H),3.79–3.75(m,2H),3.36(s,3H).
5-氟-3-{3-[5-(3-氟氮杂环丁烷-1-羰基)-1,3-噻唑-2-基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A86”)
白色泡沫;HPLC/MS 2.66min(A),[M+H]+462.
1H NMR(700MHz,DMSO-d6)δ13.83(s,1H),8.48(s,1H),8.02(d,J=10.8Hz,1H),7.65(s,1H),7.30(d,J=7.0Hz,1H),5.52(dtt,J=57.5,6.2,3.1Hz,1H),4.87(d,J=20.1Hz,1H),4.78–4.67(m,1H),4.51–4.32(m,1H),4.36–4.27(m,2H),4.16(dd,J=24.5,12.5Hz,1H),3.82–3.69(m,2H),3.36(s,3H).
5-氟-3-{3-[4-(3-氟氮杂环丁烷-1-羰基)-1,3-噻唑-2-基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑(“A87”)
白色泡沫;HPLC/MS 2.74min(A),[M+H]+462.
1H NMR(700MHz,DMSO-d6)δ13.85(s,1H),8.59(s,1H),8.03(d,J=10.7Hz,1H),7.68(s,1H),7.30(d,J=7.0Hz,1H),5.51(dtt,J=57.8,6.0,3.1Hz,1H),5.04(dddd,J=22.5,12.0,5.9,1.9Hz,1H),4.82(ddt,J=25.3,12.4,2.6Hz,1H),4.45(dddd,J=21.6,11.8,6.0,1.9Hz,1H),4.34–4.26(m,2H),4.15(ddt,J=24.8,11.8,2.3Hz,1H),3.82–3.72(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{6-甲基-2,6-二氮杂螺[3.3]庚烷-2-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A88”)
三氟乙酸盐,白色泡沫;HPLC/MS 2.24min(A),[M+H]+492.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),9.56–9.43(m,1H),8.19–8.10(m,2H),8.03(d,J=11.0Hz,1H),7.81–7.76(m,3H),7.29(d,J=7.1Hz,1H),4.58(s,1H),4.52(s,1H),4.45–4.35(m,2H),4.34–4.28(m,3H),4.24(s,1H),4.20–4.07(m,2H),3.85–3.71(m,2H),3.36(s,3H),2.84–2.78(m,3H).
(顺式)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-八氢吡咯并[3,4-b]吡咯-6-酮(“A89”)
UPLC/MS 0.65min,[M+H]+506.
N-{[(2S)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]甲基}甲烷磺酰胺(“A90”)
灰白色固体;HPLC/MS 1.53min(A),[M+H]+558.
1H NMR(500MHz,DMSO-d6)δ13.73(s,1H),8.14–8.08(m,2H),8.04(d,J=11.0Hz,1H),7.78(s,1H),7.72(d,J=8.1Hz,2H),7.29(d,J=7.1Hz,1H),7.25(t,J=6.5Hz,1H),4.34–4.28(m,2H),4.27–4.21(m,1H),3.80–3.74(m,2H),3.50(dt,J=10.2,6.9Hz,1H),3.39–3.28(m,4H),3.23(dt,J=12.9,6.5Hz,1H),2.94(s,3H),2.81–2.69(m,3H),2.07–1.84(m,3H),1.81–1.66(m,1H).
6-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基吡啶-3-甲酰胺(“A91”)
2-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基-1,3-噻唑-5-甲酰胺(“A92”)
2-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基-1,3-噻唑-4-甲酰胺(“A93”)
N-{[(2R)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]甲基}甲烷磺酰胺(“A94”)
[(2S)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-2-基]甲醇(“A95”)
灰白色固体;HPLC/MS 1.94min(A),[M+H]+467.
1H NMR(700MHz,DMSO-d6,旋转异构体,信号的选择)δ13.73(s,1H),8.11(d,J=7.9Hz,2H),8.03(d,J=10.9Hz,1H),7.83–7.71(m,3H),7.28(d,J=7.0Hz,1H),5.02–4.84(m,1H),4.57–4.46(m,1H),4.37–4.25(m,3H),4.10(q,J=8.1Hz,1H),3.78–3.74(m,2H),3.68–3.58(m,1H),3.36(s,3H),2.45–2.07(m,3H).
1-(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-羰基)-氮杂环丁烷-3-甲腈(“A96”)
[(2R)-1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-2-基]甲醇(“A97”)
灰白色固体;HPLC/MS 1.45min(A),[M+H]+467.
1H NMR(700MHz,DMSO-d6,旋转异构体,信号的选择)δ13.73(s,1H),8.11(d,J=7.9Hz,2H),8.03(d,J=10.9Hz,1H),7.83–7.71(m,3H),7.28(d,J=7.0Hz,1H),5.02–4.84(m,1H),4.57–4.46(m,1H),4.37–4.25(m,3H),4.10(q,J=8.1Hz,1H),3.78–3.74(m,2H),3.68–3.58(m,1H),3.36(s,3H),2.45–2.07(m,3H).
(3-氟-氮杂环丁烷-1-基)-(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-甲酮(“A98”)
5-氟-3-(3-{6-[(3R)-3-氟吡咯烷-1-羰基]吡啶-3-基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A100”)
5-氟-3-[3-(4-{3-氟-[1,3'-二氮杂环丁烷]-1'-羰基}苯基)-1,2-噁唑-5-基]-6-(2-甲氧基乙氧基)-1H-吲唑(“A101”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(4-甲基哌嗪-1-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A102”)
1-[1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-3-基]哌啶-4-醇(“A103”)
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(吗啉-4-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A104”)
白色固体;UPLC/MS 0.72min,[M+H]+467.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.11(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.60(d,J=8.3Hz,1H),7.28(d,J=7.1Hz,1H),4.35–4.24(m,2H),3.80–3.74(m,2H),3.75–3.30(宽,8H),3.36(s,3H).
[(3R)-4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吗啉-3-基]甲醇(“A105”)
[(3S)-4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吗啉-3-基]甲醇(“A106”)
灰白色固体;HPLC/MS 1.42min(A),[M+H]+497.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.16–8.07(m,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.61(d,J=8.0Hz,2H),7.29(d,J=7.0Hz,1H),4.93(bs,1H),4.37–4.24(m,2H),4.08–3.01(宽,11H),3.36(s,3H).
2-[(2S)-1-(5-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}吡啶-2-羰基)吡咯烷-2-基]丙-2-醇(“A107”)
灰白色固体;m.p.119–121℃,[M+H]+510.
1H NMR(400MHz,DMSO-d6)δ13.78(s,1H),9.26(dd,J=2.2,0.9Hz,1H),8.54(dd,J=8.2,2.2Hz,1H),8.03(d,J=11.0Hz,1H),7.91-7.84(m,2H),7.30(d,J=7.1Hz,1H),5.05(s,1H),4.34-4.27(m,3H),3.80-3.74(m,2H),3.63-3.48(m,2H),3.36(s,3H),1.98-1.87(m,3H),1.69-1.62(m,1H),1.17(d,J=5.8Hz,6H).
6-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3λ6-硫杂-6-氮杂双环[3.1.1]庚烷-3,3-二酮(“A108”)
灰白色固体;UPLC/MS 0.70min,[M+H]+527.
1H NMR(500MHz,DMSO-d6)δ13.72(s,1H),8.16(d,J=8.4Hz,1H),8.03(d,J=11.0Hz,1H),7.86(d,J=8.3Hz,2H),7.79(s,1H),7.29(d,J=7.0Hz,1H),4.96(bs,1H),4.73(bs,1H),4.34–4.25(m,2H),4.10(bs,1H),3.83–3.71(m,3H),3.36(s,3H),3.02(dt,J=10.1,7.0Hz,1H),2.10(d,J=10.4Hz,1H),1.24(s,1H).
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-[(R)-2-(1-羟基-1-甲基-乙基)-吡咯烷-1-基]-甲酮(“A109”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(3S)-3-(甲氧基甲基)吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A110”)
灰白色固体;HPLC/MS 1.56min(A),[M+H]+511.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.11(d,J=8.3Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.59(d,J=7.9Hz,2H),7.29(d,J=7.1Hz,1H),4.35–4.23(m,2H),4.18–3.05(宽,12H),3.80–3.73(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(3R)-3-(甲氧基甲基)吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A111”)
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{6-氧杂-1-氮杂螺[3.3]庚烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A112”)
白色结晶;HPLC/MS 1.54min(A),[M+H]+479.
1H NMR(700MHz,DMSO-d6)δ13.72(s,1H),8.12(d,J=8.0Hz,2H),8.04(d,J=10.9Hz,1H),7.81(d,J=8.2Hz,2H),7.79(s,1H),7.28(d,J=7.0Hz,1H),5.39(d,J=6.6Hz,2H),4.59(d,J=6.6Hz,2H),4.37–4.27(m,2H),4.17(t,J=7.5Hz,2H),3.76(dd,J=3.9,2.3Hz,2H),3.35(s,3H),2.57(t,J=7.5Hz,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(3R)-3-甲基吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A114”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(3S)-3-甲基吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A115”)
白色固体;UPLC/MS 0.74min,[M+H]+481.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.12(d,J=8.2Hz,2H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.58(d,J=8.2Hz,2H),7.29(d,J=7.1Hz,1H),4.49–4.19(m,2H),3.90–3.74(m,3H),3.69–3.56(m,2H),3.51–3.38(m,1H),3.37(s,3H),1.29(d,J=6.9Hz,3H).
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-1-甲基哌嗪-2-酮(“A116”)
5-氟-3-(3-{4-[(2S)-2-(甲烷磺酰基甲基)吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-甲氧基-1H-吲唑(“A117”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-[(S)-2-(1-羟基-1-甲基-乙基)-氮杂环丁烷-1-基]-甲酮(“A118”)
(5-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-吡啶-2-基)-[(R)-2-(1-羟基-1-甲基-乙基)-氮杂环丁烷-1-基]-甲酮(“A119”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吡啶-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A120”)
白色固体;UPLC/MS 0.54min,[M+H]+514.
1H NMR(400MHz,DMSO-d6)δ13.77(s,1H),8.70–8.59(m,2H),8.18(d,J=8.3Hz,2H),8.08(d,J=11.0Hz,1H),7.92(d,J=8.4Hz,2H),7.83(s,1H),7.54–7.46(m,2H),7.34(d,J=7.0Hz,1H),4.80(t,J=8.9Hz,1H),4.65–4.48(m,2H),4.41–4.30(m,2H),4.16(t,J=8.0Hz,2H),4.12–4.01(m,1H),3.84–3.76(m,2H),3.41(s,3H).
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3-甲基-1λ6-硫代吗啉-1,1-二酮(“A121”)
白色固体;UPLC/MS 0.72min,[M+H]+529.
1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.12(d,J=8.3Hz,2H),8.01(d,J=11.0Hz,1H),7.75(s,1H),7.67(d,J=8.2Hz,2H),7.28(d,J=7.1Hz,1H),4.38–4.22(m,2H),3.85–3.71(m,2H),3.65–3.08(m,7H),3.36(s,3H),1.44(d,J=7.1Hz,3H).
实施例7
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(4-甲基哌嗪-1-基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A37”)
灰白色粉末;HPLC/MS 1.68min(A),[M+H]+452.
1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.00(d,J=11.0Hz,1H),7.85(d,J=8.7Hz,2H),7.57(s,1H),7.26(d,J=7.0Hz,1H),7.07(d,J=8.8Hz,2H),4.31–4.27(m,2H),4.03–3.60(m,2H),3.35(s,3H),3.32–3.23(宽,4H),2.50–2.44(宽,4H)2.24(s,3H).
类似地制备以下化合物:
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)-1λ6-硫代吗啉-1,1-二酮(“A122”)
浅黄色固体;HPLC/MS 2.06min(A),[M+H]+487.
1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.01(d,J=11.0Hz,1H),7.91(d,J=8.9Hz,2H),7.62(s,1H),7.27(d,J=7.1Hz,1H),7.19(d,J=9.0Hz,1H),4.36–4.23(m,2H),3.92(t,J=5.1Hz,4H),3.82–3.69(m,2H),3.36(s,3H),3.25–3.11(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A123”)
灰白色固体;HPLC/MS 1.31min(A),[M+H]+487.
1H NMR(400MHz,DMSO-d6)δ13.63(s,1H),7.99(d,J=11.0Hz,1H),7.80(d,J=8.9Hz,2H),7.52(s,1H),7.27(d,J=7.1Hz,1H),6.83(d,J=9.0Hz,2H),4.36–4.26(m,2H),3.81–3.73(m,2H),3.64–3.57(m,2H),3.52(t,J=6.2Hz,2H),3.36(s,3H),2.68–2.62(m,2H),2.50–2.44(m,2H),2.28(s,3H),1.92(p,J=5.9Hz,2H).
3-(3-{4-[(顺式)-4-甲基-八氢吡咯并[3,2-b]吡咯-1-基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A125”)
3-(3-{4-[(反式)-4-甲基-八氢吡咯并[3,2-b]吡咯-1-基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A126”)
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)-1λ4-硫代吗啉-1-酮(“A127”)
浅黄色固体;HPLC/MS 1.95min(A),[M+H]+471.
1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.01(d,J=11.0Hz,1H),7.90(d,J=8.9Hz,2H),7.60(s,1H),7.27(d,J=7.1Hz,1H),7.23–7.03(m,2H),4.36–4.15(m,2H),3.92(ddd,J=12.9,11.0,2.1Hz,2H),3.85–3.71(m,4H),3.36(s,3H),2.96(ddd,J=13.7,10.7,3.2Hz,2H),2.78–2.65(m,2H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)哌啶-4-醇(“A128”)
1-[(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)亚氨基]-1λ6-硫代吗啉-1-酮(“A129”)
盐酸盐,灰白色固体;HPLC/MS 1.29min(A),[M+H]+486.
1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),9.38(s,2H),8.00(d,J=11.0Hz,1H),7.91(d,J=8.5Hz,1H),7.61(s,1H),7.28(d,J=7.1Hz,1H),7.17(d,J=8.6Hz,1H),4.40–4.28(m,2H),3.96–3.40(m,10H),3.36(s,3H).
实施例8
3-[3-(6-乙氧基吡啶-3-基)-1,2-噁唑-5-基]-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A38”)
灰白色固体;UPLC/MS 0.68min,[M+H]+399.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.83(d,J=2.4Hz,1H),8.29(dd,J=8.7,2.5Hz,1H),7.99(d,J=11.0Hz,1H),7.71(s,1H),7.28(d,J=7.0Hz,1H),6.99(d,J=8.6Hz,1H),4.41(q,J=7.0Hz,2H),4.36–4.27(m,2H),3.83–3.73(m,2H),3.36(s,3H),1.37(t,J=7.0Hz,3H).
类似地制备以下化合物:
5-氟-6-(2-甲氧基-乙氧基)-3-[3-(6-甲氧基-吡啶-3-基)-异噁唑-5-基]-1H-吲唑(“A130”)
白色固体;m.p.210–213℃;[M+H]+385.
1H NMR(400MHz,DMSO-d6)13.73(s,1H),8.85(d,J=2.4Hz,1H),8.31(dd,J=8.7,2.5Hz,1H),8.00(d,J=11.0Hz,1H),7.73(s,1H),7.28(d,J=7.1Hz,1H),7.03(d,J=8.7Hz,1H),4.30(dd,J=5.6,3.4Hz,2H),3.95(s,3H),3.80-3.73(m,2H),3.36(s,3H).
实施例9
5-氟-6-(2-甲氧基乙氧基)-3-{3-[6-(4-甲基哌嗪-1-基)吡啶-3-基]-1,2-噁唑-5-基}-1H-吲唑(“A39”)
灰白色粉末;UPLC/MS0.49min,[M+H]+453.
1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),8.75(dd,J=2.4,0.7Hz,1H),8.10(dd,J=9.0,2.4Hz,1H),7.64(s,1H),7.27(d,J=7.1Hz,1H),7.00(d,J=9.0Hz,1H),4.36–4.02(m,2H),3.84–3.69(m,2H),3.71–3.52(m,4H),3.36(s,3H),2.44–2.39(m,4H),2.24(s,3H).
类似地制备以下化合物:
4-(5-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}吡啶-2-基)-1λ6-硫代吗啉-1,1-二酮(“A131”)
灰白色固体;UPLC/MS 0.73min,[M+H]+488.
1H NMR(700MHz,DMSO-d6)δ13.70(s,1H),8.81(d,J=2.4Hz,1H),8.19(dd,J=8.9,2.4Hz,1H),7.99(d,J=10.9Hz,1H),7.68(s,1H),7.28(d,J=7.0Hz,1H),7.21(d,J=8.9Hz,1H),4.39–4.26(m,2H),4.17(t,J=5.2Hz,4H),3.89–3.65(m,2H),3.36(s,3H),3.18(t,J=5.2Hz,4H).
实施例10
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[2-(吗啉-4-基)乙氧基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A40”)
灰白色粉末;HPLC/MS 1.29min(A),[M+H]+483.
1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),8.01(d,J=11.0Hz,1H),7.97(d,J=8.3Hz,2H),7.65(s,1H),7.27(d,J=7.1Hz,1H),7.13(d,J=8.3Hz,2H),4.33–4.27(m,2H),4.21(宽,2H),3.80–3.71(m,2H),3.62(宽,4H),3.35(s,3H),2.74(宽,2H).
类似地制备以下化合物:
4-[2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯氧基)乙基]-1λ6-硫代吗啉-1,1-二酮(“A132”)
白色粉末;HPLC/MS 2.06min(A),[M+H]+531.
1H NMR(500MHz,DMSO-d6)δ13.66(s,1H),8.00(d,J=11.0Hz,1H),7.96(d,J=8.8Hz,2H),7.63(s,1H),7.27(d,J=7.1Hz,1H),7.12(d,J=8.8Hz,2H),4.32–4.24(m,2H),4.18(t,J=5.6Hz,2H),3.85–3.67(m,2H),3.35(s,3H),3.14–3.04(m,8H),2.97(t,J=5.6Hz,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[2-(4-甲基哌嗪-1-基)乙氧基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A133”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[2-(哌嗪-1-基)乙氧基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A134”)
实施例11
1-(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-1H-吡啶-2-酮(“A41”)盐酸盐
灰白色固体;HPLC/MS 1.54min(A),[M+H]+447.
1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.17(d,J=8.0Hz,2H),8.03(d,J=11.0Hz,1H),7.78(s,1H),7.73(d,J=6.9Hz,1H),7.62(d,J=8.1Hz,2H),7.54(t,J=8.0Hz,1H),7.28(d,J=7.0Hz,1H),6.52(d,J=9.3Hz,1H),6.36(t,J=6.8Hz,1H),4.33–4.28(m,2H),3.79–3.74(m,2H),3.36(s,3H).
类似地制备以下化合物:
2-(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-6-甲基-2H-哒嗪-3-酮(“A136”)
5-氟-6-(2-甲氧基-乙氧基)-3-[3-(1-甲基-1H-吡唑-4-基)-异噁唑-5-基]-1H-吲唑(“A137”)
2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)-1λ6,2-噻唑烷-1,1-二酮(“A138”)
4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)吗啉-3-酮(“A139”)
灰白色固体;HPLC/MS 0.71min,[M+H]+453.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.08(d,J=8.6Hz,1H),8.02(d,J=11.0Hz,1H),7.72(s,1H),7.63(d,J=8.6Hz,1H),7.29(d,J=7.1Hz,1H),4.34–4.28(m,2H),4.26(s,2H),4.07–4.00(m,2H),3.89–3.81(m,2H),3.81–3.73(m,2H),3.36(s,3H).
4-(5-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}吡啶-2-基)-1λ4-硫代吗啉-1-酮(“A140”)
灰白色粉末;HPLC/MS 1.43min(A),[M+H]+472.
1H NMR(500MHz,DMSO-d6)δ13.66(s,1H),8.79(dd,J=2.4,0.7Hz,1H),8.15(dd,J=8.9,2.4Hz,1H),7.98(d,J=10.9Hz,1H),7.64(s,1H),7.27(d,J=7.1Hz,1H),7.14(d,J=8.8Hz,1H),4.42–4.22(m,4H),3.99(ddd,J=14.7,11.1,2.0Hz,2H),3.82–3.62(m,2H),3.35(s,3H),2.92(ddd,J=14.1,11.1,3.3Hz,2H),2.77–2.66(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[6-(吗啉-4-基)吡啶-3-基]-1,2-噁唑-5-基}-1H-吲唑(“A141”)
2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)-2,3-二氢哒嗪-3-酮(“A142”)
白色固体;HPLC/MS 1.55min(A),[M+H]+448.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.16(d,J=8.6Hz,2H),8.12(dd,J=3.8,1.6Hz,1H),8.03(d,J=11.0Hz,1H),7.79(d,J=8.6Hz,2H),7.77(s,1H),7.53(dd,J=9.5,3.8Hz,1H),7.28(d,J=7.0Hz,1H),7.12(dd,J=9.5,1.6Hz,1H),4.33–4.20(m,2H),3.79–3.70(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(吡啶-2-基氧基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A143”)
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基苯-1-磺酰胺(“A144”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{6-[3-(吗啉-4-基)氮杂环丁烷-1-基]吡啶-3-基}-1,2-噁唑-5-基)-1H-吲唑(“A145”)
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(吗啉-4-磺酰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A227”)
实施例12
3-{3-[4-(1,4-二氮杂环庚烷-1-基)苯基]-1,2-噁唑-5-基}-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A42”)盐酸盐
浅橙色固体;HPLC/MS 1.32min(A),[M+H]+452.
1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),9.05(s,2H),7.99(d,J=11.0Hz,1H),7.86(d,J=8.9Hz,2H),7.56(s,1H),7.27(d,J=7.1Hz,1H),6.93(d,J=9.0Hz,2H),4.33–4.18(m,2H),3.81(t,J=5.1Hz,2H),3.79–3.73(m,2H),3.61(t,J=6.1Hz,2H),3.36(s,3H),3.27(p,J=4.8Hz,3H),3.19–3.11(m,2H),2.13(p,J=5.9Hz,2H).
实施例13
(4-{3-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-5-基}-苯基)-吗啉-4-基-甲酮(“A43”)
白色固体;m.p.220–221℃,[M+H]+467.
1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.15-8.05(m,2H),7.82(d,J=10.8Hz,1H),7.67-7.58(m,3H),7.27(d,J=7.1Hz,1H),4.33-4.26(m,2H),3.80-3.73(m,2H),3.73-3.53(m,6H),3.48-3.43(m,5H).
类似地制备以下化合物:
(4-{3-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-5-基}-苯基)-(4-甲基-哌嗪-1-基)-甲酮(“A113”)
灰白色固体;m.p.210–211℃,[M+H]+480.
1H NMR(400MHz,DMSO-d6)δ13.63(s,1H),8.12-8.05(m,2H),7.84(d,J=10.8Hz,1H),7.65(s,1H),7.62-7.55(m,2H),7.27(d,J=7.0Hz,1H),4.33-4.26(m,2H),3.80-3.74(m,2H),3.65(s,2H),3.36(s,5H),2.34(d,J=31.8Hz,4H),2.21(s,3H).
(4-{3-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-5-基}-苯基)-(3-吗啉-4-基-氮杂环丁烷-1-基)-甲酮(“A146”)
白色固体;m.p.229–230℃,[M+H]+522.
1H NMR(400MHz,DMSO-d6)δ13.63(s,1H),8.09(d,J=8.1Hz,2H),7.84(dd,J=9.6,4.6Hz,3H),7.69(s,1H),7.27(d,J=7.0Hz,1H),4.41-4.33(m,1H),4.33-4.26(m,2H),4.24-4.16(m,1H),4.15-4.05(m,1H),3.96-3.88(m,1H),3.80-3.73(m,2H),3.66-3.55(m,4H),3.36(s,3H),3.23-3.12(m,1H),2.44-2.26(m,4H).
(4-{3-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-5-基}-苯基)-[(R)-2-(1-羟基-1-甲基-乙基)-氮杂环丁烷-1-基]-甲酮(“A147”)
灰白色固体;m.p.210–211℃,[M+H]+495.
1H NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.14-8.07(m,2H),7.88-7.79(m,3H),7.69(s,1H),7.28(d,J=7.1Hz,1H),5.01(s,1H),4.39(dd,J=9.0,5.6Hz,1H),4.34-4.22(m,3H),4.01-3.92(m,1H),3.80-3.73(m,2H),3.36(s,3H),2.34-2.27(m,1H),2.18-2.10(m,1H),1.15(s,6H).
(4-{3-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-5-基}-苯基)-[(S)-2-(1-羟基-1-甲基-乙基)-氮杂环丁烷-1-基]-甲酮(“A148”)
实施例14
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(1,4-氧杂氮杂环庚烷-4-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A44”)
向4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸(79.5mg,0.20mmol)在DMF(1.0ml)中的悬浮液中加入高吗啉(24.3mg,0.24mmol),然后加入1-羟基苯并三唑水合物(6.1mg,0.04mmol)和N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(61mg,0.32mmol)。反应混合物在室温下搅拌16小时。向反应混合物中加入水。滤出所得沉淀并用水洗涤。残余物在硅胶柱上用甲醇/二氯甲烷进行色谱纯化得到(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-[1,4]氧杂氮杂环庚烷-4-基-甲酮,为白色固体;UPLC/MS0.71min,[M+H]+481。
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.10(d,J=6.7Hz,3H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.57(d,J=7.3Hz,2H),7.28(d,J=7.0Hz,1H),4.33–4.24(m,2H),3.82–3.67(m,7H),3.62(t,J=5.1Hz,1H),3.49–3.46(m,2H),3.36(s,3H),1.94–1.87(m,1H),1.81–1.69(m,1H)。
类似地制备以下化合物:
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A45”)
白色粉末;HPLC/MS 1.26min(A),[M+H]+522.
1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.11(d,J=8.3Hz,2H),8.04(d,J=11.0Hz,1H),7.78(s,1H),7.58(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.55(t,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.33–4.26(m,2H),3.82–3.73(m,2H),3.68(宽,2H),3.51–3.37(m,3H),2.35(宽,2H),2.27(宽,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吡啶-2-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A149”)
白色固体;UPLC/MS 0.67min,[M+H]+514.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.68–8.56(m,1H),8.13(d,J=8.4Hz,2H),8.04(d,J=11.0Hz,1H),7.86(d,J=8.4Hz,2H),7.84–7.76(m,2H),7.41(d,J=7.8Hz,1H),7.36–7.24(m,2H),4.75(t,J=8.6Hz,1H),4.54(t,J=7.2Hz,1H),4.47(t,J=9.3Hz,1H),4.35–4.28(m,2H),4.25(t,J=8.0Hz,1H),4.10(tt,J=8.9,6.1Hz,1H),3.80–3.73(m,2H),3.36(s,3H).
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N-(2-甲烷磺酰基乙基)-N-甲基苯甲酰胺(“A150”)
5-氟-3-(3-{4-[(2S)-2-(甲烷磺酰基甲基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A152”)
白色固体;UPLC/MS 0.71min,[M+H]+529.
1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.12(d,J=8.4Hz,2H),8.01(d,J=11.0Hz,1H),7.80(d,J=8.4Hz,2H),7.75(s,1H),7.28(d,J=7.1Hz,1H),4.89(bs,1H),4.46(bs,1H),4.35–4.21(m,2H),4.17(bs,1H),3.85(bs,1H),3.82–3.63(m,3H),3.35(s,3H),3.07(s,3H),2.56(bs,1H),2.44–2.26(m,1H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吗啉-4-基)吡咯烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A153”)
白色粉末;HPLC/MS 1.25min,[M+H]+536.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.09(d,J=7.9Hz,1H),8.02(d,J=11.0Hz,0H),7.76(s,0H),7.73–7.66(m,2H),7.28(d,J=7.1Hz,1H),4.36–4.26(m,2H),3.81–3.71(m,2H),3.72–3.40(m,8H),3.36(s,3H),2.92-2.74(m,1H),2.50-2.36(m,3H),2.34–2.24(m,1H),2.20–2.10(m,1H),1.85–1.65(m,1H).
5-氟-3-(3-{4-[(2R)-2-(甲烷磺酰基甲基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-6-(2-甲氧基乙氧基)-1H-吲唑(“A154”)
5-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-2,8-二氧杂-5-氮杂螺[3.5]壬烷(“A155”)
白色固体;UPLC/MS 0.73min,[M+H]+509.
1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.14(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.78(s,1H),7.74(d,J=8.4Hz,2H),7.28(d,J=7.1Hz,1H),4.78(d,J=6.8Hz,2H),4.41(d,J=6.9Hz,2H),4.35–4.20(m,2H),3.99(s,2H),3.81–3.74(m,2H),3.43(t,J=4.7Hz,2H),3.39–3.34(m,5H).
N-[(1H-1,3-苯并二唑-2-基)甲基]-4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰胺(“A156”)
7-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-2-氧杂-7-氮杂螺[4.4]壬烷(“A157”)
白色固体;HPLC/MS 1.54min(A),[M+H]+507.
1H NMR(400MHz,DMSO-d6;旋转异构体的混合物)δ13.71(s,1H),8.10(d,J=8.4Hz,2H),8.06–8.00(m,1H),7.76(d,J=3.9Hz,1H),7.74–7.66(m,2H),7.28(d,J=7.1Hz,1H),4.35–4.28(m,2H),3.87–3.46(m,9H),3.41(s,1H),3.36(s,3H),2.04–1.72(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{2-氧杂-6-氮杂螺[3.4]辛烷-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A158”)
白色固体;HPLC/MS 1.48min(A),[M+H]+493.
1H NMR(700MHz,DMSO-d6;旋转异构体的混合物)δ13.72(d,J=2.6Hz,1H),8.13–8.07(m,2H),8.04(d,J=10.8Hz,1H),7.79–7.77(m,1H),7.73–7.67(m,2H),7.29–7.26(m,1H),4.64(d,J=5.9Hz,1H),4.51(d,J=5.9Hz,1H),4.49(d,J=6.3Hz,1H),4.45(d,J=6.3Hz,1H),4.32–4.28(m,2H),3.78–3.65(m,2H),3.74(s,1H),3.69(s,1H),3.52(t,J=7.2Hz,1H),3.47(t,J=6.8Hz,1H),3.36(s,3H),2.20(t,J=7.2Hz,1H),2.16(t,J=6.8Hz,1H).
2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-8-氧杂-2-氮杂螺[4.5]癸烷(“A159”)
白色固体;HPLC/MS 1.50min(A),[M+H]+521.
1H NMR(700MHz,DMSO-d6;旋转异构体的混合物)δ13.72(s,1H),8.12–8.07(m,2H),8.04(d,J=10.8Hz,1H),7.79–7.77(m,1H),7.76–7.66(m,2H),7.30–7.27(m,1H),4.31–4.28(m,2H),3.84–3.73(m,2H),3.68–3.50(m,5H),3.49–3.44(m,1H),3.43(s,1H),3.36(s,3H),3.33(s,1H),1.86(t,J=7.3Hz,1H),1.80(t,J=7.0Hz,1H),1.63–1.53(m,2H),1.50–1.42(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{2-甲基-2,6-二氮杂螺[3.4]辛烷-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A160”)
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{6-氧杂-3-氮杂双环[3.1.1]庚烷-3-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A161”)
白色固体;UPLC/MS 0.69min,[M+H]+479.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.11(d,J=8.4Hz,1H),8.03(d,J=11.0Hz,1H),7.76(s,1H),7.68(d,J=8.4Hz,1H),7.28(d,J=7.1Hz,1H),4.67(s,1H),4.50(s,1H),4.38–4.23(m,2H),3.99(d,J=13.9,1H),3.85–3.71(m,3H),3.66–3.56(m,1H),3.55–3.45(m,1H),3.36(s,3H),3.14–3.02(m,1H),1.88(d,J=8.9Hz,1H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(1S,4S)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A162”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(1R,4R)-2-氧杂-5-氮杂双环[2.2.1]庚烷-5-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A163”)
白色固体;UPLC/MS 0.69min,[M+H]+479.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物)δ13.70(s,1H),8.15–8.07(m,2H),8.05–8.00(m,1H),7.76(d,J=2.2Hz,1H),7.73(d,J=8.1Hz,1H),7.67(m,1H),7.28(d,J=7.0Hz,1H),4.87(s,0.5H),4.68(s,1H),4.59(s,0.5H),4.41(s,0.5H),4.34–4.27(m,2H),3.93(d,J=7.4Hz,0.5H),3.85(d,J=7.5Hz,0.5H),3.83–3.65(m,3H),3.61–3.51(m,1H),3.36(s,3H),1.98–1.73(m,2H).
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N-[2-甲基-2-(吗啉-4-基)丙基]苯甲酰胺(“A164”)
2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-7-氧杂-2-氮杂螺[3.5]壬烷(“A165”)
白色固体;HPLC/MS 1.57min(A),[M+H]+507.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.14–8.09(m,2H),8.02(d,J=11.0Hz,1H),7.82(d,J=8.4Hz,2H),7.77(s,1H),7.28(d,J=7.1Hz,1H),4.34–4.23(m,2H),4.11(s,2H),3.82(s,2H),3.79–3.74(m,2H),3.63–3.43(m,4H),3.36(s,3H),1.79–1.69(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(3-甲基-1,2,4-氧杂二唑-5-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A166”)
白色固体;HPLC/MS 1.57min,[M+H]+519.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.13(d,J=8.4Hz,2H),8.03(d,J=11.0Hz,1H),7.83(d,J=8.4Hz,2H),7.78(s,1H),7.28(d,J=7.1Hz,1H),4.78(t,J=7.7Hz,2H),4.64–4.46(m,4H),4.36–4.22(m,5H),3.83–3.71(m,2H),3.36(s,3H),2.36(s,3H).
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-甲基-哌嗪-1-基)-甲酮(“A167”)
白色固体;m.p.105–106℃,[M+H]+496.
1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.32(s,1H),8.16-8.09(m,2H),7.83(s,1H),7.61-7.53(m,2H),7.27(s,1H),4.34-4.27(m,2H),3.82-3.75(m,2H),3.71-3.59(m,2H),3.41-.33(m,5H),2.43-2.26(m,4H),2.22(s,3H).
(2-氟-4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(3-吗啉-4-基-氮杂环丁烷-1-基)-甲酮(“A168”)
白色固体;m.p.119–120℃,[M+H]+540.
1H NMR(400MHz,DMSO-d6)δ13.76-13.68(m,1H),8.09-7.91(m,3H),7.82(s,1H),7.72(t,J=7.5Hz,1H),7.27(d,J=7.1Hz,1H),4.36-4.25(m,2H),4.15-4.04(m,2H),3.94-3.85(m,2H),3.81-3.73(m,2H),3.68-3.47(m,4H),3.36(s,3H),3.24-3.14(m,1H),2.43-2.19(m,4H).
(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-2-甲基-苯基)-(6-氧杂-1-氮杂-螺[3.3]庚-1-基)-甲酮(“A169”)
白色固体;m.p.129–130℃,[M+H]+493.
1H NMR(400MHz,DMSO-d6)δ13.7(s,1H),8.09-7.94(m,2H),7.90(d,J=7.8Hz,1H),7.74(s,1H),7.47(d,J=7.9Hz,1H),7.28(d,J=7.1Hz,1H),5.37(d,J=6.7Hz,2H),4.64(d,J=6.7Hz,2H),4.34-4.27(m,2H),3.80-3.69(m,4H),3.37(s,3H),2.55(m,2H),2.42(s,3H).
(2-氟-4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(6-氧杂-1-氮杂-螺[3.3]庚-1-基)-甲酮(“A170”)
(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-2-甲基-苯基)-(3-吗啉-4-基-氮杂环丁烷-1-基)-甲酮(“A171”)
白色固体;m.p.125–126℃,[M+H]+536.
1H NMR(400MHz,DMSO-d6)δ13.78-13.66(m,1H),8.04(d,J=11.0Hz,1H),7.99-7.94(m,1H),7.89(d,J=7.9Hz,1H),7.75(s,1H),7.47(d,J=7.9Hz,1H),7.28(d,J=7.1Hz,1H),4.36-4.25(m,2H),4.12-4.05(m,1H),3.98-3.86(m,2H),3.84-3.71(m,3H),3.59(t,J=4.5Hz,4H),3.41-3.26(m,3H),3.21-3.13(m,1H),2.41(s,3H),2.37-2.21(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(嘧啶-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A172”)
白色固体;HPLC/MS 1.49min(A),[M+H]+515.
1H NMR(400MHz,DMSO-d6)δ13.75(s,1H),9.22(d,J=1.3Hz,1H),8.77(d,J=5.2Hz,1H),8.13(d,J=8.5Hz,2H),8.04(d,J=11.1Hz,1H),7.85(d,J=8.4Hz,2H),7.80(s,1H),7.57(dd,J=5.2,1.4Hz,1H),7.28(d,J=7.1Hz,1H),4.75(t,J=8.7Hz,1H),4.54(dd,J=8.5,5.9Hz,1H),4.47(t,J=9.4Hz,1H),4.35–4.27(m,2H),4.24(dd,J=9.8,6.0Hz,1H),4.10(tt,J=8.8,5.9Hz,1H),3.85–3.70(m,2H),3.35(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(2-甲基嘧啶-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A173”)
三氟乙酸盐,黄色粉末;UPLC/MS 0.71min,[M+H]+529.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.65(d,J=5.2Hz,1H),8.13(d,J=8.4Hz,1H),8.03(d,J=11.0Hz,1H),7.85(d,J=8.4Hz,1H),7.77(s,1H),7.36(d,J=5.2Hz,1H),7.28(d,J=7.1Hz,1H),4.72(t,J=8.7Hz,1H),4.54(t,J=7.3Hz,1H),4.46(t,J=9.4Hz,1H),4.33–4.27(m,2H),4.24(t,J=8.0Hz,1H),4.06(tt,J=9.0,6.1Hz,1H),3.80–3.72(m,2H),3.36(s,3H),2.64(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A174”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环戊烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A175”)
7-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-2-甲基-2,7-二氮杂螺[3.5]壬烷(“A176”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(哌啶-1-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A177”)
白色固体;HPLC/MS 1.28min(A),[M+H]+520.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.15–8.07(m,2H),8.02(d,J=11.0Hz,1H),7.81(d,J=8.4Hz,2H),7.77(s,1H),7.28(d,J=7.1Hz,1H),4.34(t,J=8.1Hz,1H),4.15(dd,J=8.7,5.2Hz,1H),4.12–4.05(m,1H),3.87(dd,J=10.2,5.2Hz,1H),3.79–3.74(m,2H),3.36(s,3H),3.12(tt,J=7.2,5.3Hz,1H),2.25(bs,4H),1.51(dq,J=11.0,5.1Hz,4H),1.45–1.38(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吡咯烷-1-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A178”)
白色固体;HPLC/MS 1.27min(A),[M+H]+506.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.10(d,J=8.4Hz,2H),8.02(d,J=11.0Hz,1H),7.80(d,J=8.4Hz,2H),7.77(s,1H),7.28(d,J=7.1Hz,1H),4.39(t,J=8.0Hz,1H),4.33–4.26(m,2H),4.18(dd,J=8.8,4.7Hz,1H),4.16–4.09(m,2H),3.92(dd,J=10.2,4.7Hz,1H),3.79–3.74(m,2H),3.36(s,3H),3.34–3.30(m,1H),2.48–2.41(m,4H),1.75–1.67(m,4H).
3-(3-{4-[4-(环丙基甲基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A179”)
白色固体;UPLC/MS 0.51min,[M+H]+520.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.10(d,J=8.3Hz,1H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.56(d,J=8.3Hz,1H),7.28(d,J=7.1Hz,1H),4.34–4.22(m,2H),3.81–3.73(m,2H),3.66(bs,2H),3.38(bs,2H),3.36(s,3H),2.44(bs,4H),2.23(d,J=6.6Hz,2H),0.90–0.78(m,1H),0.52–0.43(m,2H),0.12–0.05(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(2R)-2-甲基吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A180”)
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-N,N,3-三甲基氮杂环丁烷-3-胺(“A181”)
三氟乙酸盐,白色固体;UPLC/MS 0.79min,[M+H]+494.
1H NMR(500MHz,DMSO-d6)δ13.74(s,1H),10.66(bs,1H),8.15(d,J=8.5Hz,2H),8.02(d,J=10.9Hz,1H),7.83(d,J=8.4Hz,2H),7.79(s,1H),7.29(d,J=7.1Hz,1H),4.51(d,J=10.0Hz,1H),4.38–4.25(m,4H),3.98(d,J=11.2Hz,1H),3.81–3.72(m,2H),3.36(s,3H),2.74(bs,6H),1.62(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-氧杂-6-氮杂双环[3.1.1]庚烷-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A182”)
白色固体;HPLC/MS 1.54min(A),[M+H]+479.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.12(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.82(d,J=8.3Hz,2H),7.76(s,1H),7.28(d,J=7.1Hz,1H),4.64(bs,1H),4.43(bs,1H),4.35–4.22(m,2H),3.87–3.73(m,3H),3.69(d,J=10.7Hz,1H),3.36(s,3H),2.77(q,J=6.9Hz,1H),1.82(d,J=8.2Hz,1H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{1H,2H,3H-吡咯并[3,4-c]吡啶-2-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A183”)
白色固体;HPLC/MS 1.34min(A),[M+H]+500.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物),δ13.71(s,1H),8.72(s,0.5H),8.60–8.51(m,1.5H),8.20–8.12(m,4H),8.03(d,J=10.9Hz,2H),7.81(d,J=8.1Hz,2H),7.79(s,1H),7.58(d,J=5.2Hz,0.5H),7.45(d,J=5.1Hz,0.5H),7.29(d,J=7.1Hz,1H),5.02–4.95(m,2H),4.91(s,2H),4.36–4.17(m,2H),3.87–3.72(m,2H),3.36(s,3H).
(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-((R)-3-甲烷磺酰基甲基-吗啉-4-基)-甲酮(“A184”)
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{4-[(3R)-氧杂环戊烷-3-基]哌嗪-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A185”)
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{4-[(3S)-氧杂环戊烷-3-基]哌嗪-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A186”)
白色固体;HPLC/MS 1.26min(A),[M+H]+536.
1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.11(d,J=7.9Hz,2H),8.04(d,J=11.0Hz,1H),7.78(s,1H),7.58(d,J=7.9Hz,2H),7.28(d,J=7.1Hz,1H),4.37–4.26(m,2H),3.86–3.71(m,4H),3.64(q,J=7.9Hz,2H),3.55–3.48(m,1H),3.35(s,3H),2.96(t,J=7.1Hz,1H),2.48–2.28(m,5H),2.03–1.93(m,1H),1.81–1.70(m,1H).
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(3-{2-氧杂-6-氮杂螺[3.3]庚-6-基}氮杂环丁烷-1-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A187”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环己烷-4-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A188”)
灰白色固体;HPLC/MS 1.23min(A),[M+H]+550.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.10(d,J=8.3Hz,2H),8.02(d,J=10.9Hz,1H),7.75(s,1H),7.57(d,J=8.2Hz,2H),7.28(d,J=7.1Hz,1H),4.52–4.20(m,2H),4.03–3.82(m,2H),3.82–3.68(m,2H),3.64(bs,2H),3.37(bs,2H),3.36(s,3H),3.30–3.24(m,2H),2.62–2.40(m,5H),1.74–1.65(m,2H),1.41(qd,J=12.1,4.3Hz,2H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(2S)-2-甲基吗啉-4-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A189”)
白色固体;UPLC/MS 0.73min,[M+H]+481.
1H NMR(500MHz,DMSO-d6,旋转异构体,峰的选择)δ13.70(s,1H),8.11(d,J=8.3Hz,1H),8.02(d,J=11.0Hz,1H),7.76(s,1H),7.59(d,J=8.3Hz,1H),7.28(d,J=7.1Hz,1H),4.33–4.25(m,2H),3.79–3.73(m,2H),3.58–3.40(m,2H),3.36(s,3H),2.94(宽,1H),1.29–0.94(m,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(2R)-2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A190”)
白色固体;HPLC/MS 1.34min,[M+H]+536.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.10(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.55(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.54(td,J=6.5,4.4Hz,2H),4.46(t,J=6.1Hz,1H),4.39(t,J=6.0Hz,1H),4.32–4.27(m,2H),4.2(宽,2H),3.80–3.73(m,2H),3.41(p,J=6.3Hz,1H),3.36(s,3H),3.28–3.12(m,1H),2.73(bs,1H),2.61–2.53(m,1H),2.03(dd,J=11.1,3.8Hz,1H),1.86(td,J=11.4,3.4Hz,1H),1.32(d,J=6.8Hz,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(2S)-2-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A191”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吡啶-3-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A192”)
白色粉末;UPLC/MS 0.57min,[M+H]+514.
1H NMR(700MHz,DMSO-d6)δ13.71(s,1H),8.61(d,J=2.4Hz,1H),8.50(dd,J=4.8,1.6Hz,1H),8.12(d,J=8.3Hz,2H),8.02(d,J=10.9Hz,1H),7.93(dt,J=7.9,2.1Hz,1H),7.87(d,J=8.4Hz,2H),7.77(s,1H),7.45–7.40(m,1H),7.28(d,J=7.1Hz,1H),4.75(t,J=8.8Hz,1H),4.51(dt,J=31.8,8.7Hz,2H),4.31–4.27(m,2H),4.14–4.08(m,1H),4.03(tt,J=9.1,6.3Hz,1H),3.78–3.74(m,2H),3.35(s,3H).
(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-2-甲基-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A193”)
白色固体;m.p.138–139℃,[M+H]+536.
1H NMR(400MHz,DMSO-d6)δ13.74(s,1H),8.04(d,J=11.0Hz,1H),7.99-7.94(m,1H),7.90(d,J=7.8,1.7Hz,1H),7.75(s,1H),7.35(d,J=7.9Hz,1H),7.28(d,J=7.1Hz,1H),4.54(t,J=6.5Hz,2H),4.43(t,J=6.1Hz,2H),4.33-4.26(m,2H),3.81-3.75(m,2H),3.72-3.60(m,2H),3.49-3.42(m,1H),3.35(s,3H),3.24-3.17(m,2H),2.40-2.30(m,5H),2.26-2.13(m,2H).
(4-{5-[5-氯-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A194”)
白色固体;m.p.123–124℃,[M+H]+538.
1H NMR(400MHz,DMSO-d6)δ13.83-13.66(m,1H),8.30(s,1H),8.15-8.08(m,2H),7.81(s,1H),7.61-7.54(m,2H),7.26(s,1H),4.55(t,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.33-4.26(m,2H),3.81-3.74(m,2H),3.73-3.61(m,2H),3.53-3.36(m,6H),2.40-2.22(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[4-(2-甲氧基乙基)-4H-1,2,4-三唑-3-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A195”)
(2-氟-4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A196”)
黄色固体;m.p.161–162℃,[M+H]+540.
1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.06-8.01(m,1H),8.01-7.93(m,2H),7.84(s,1H),7.65-7.57(m,1H),7.29(d,J=7.2Hz,1H),4.55(t,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.34-4.27(m,2H),3.80-3.73(m,2H),3.73-3.69(m,2H),3.50-3.43(m,1H),3.36(s,3H),3.33-3.30(m,2H),2.38-2.34(m,2H),2.28-2.24(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[4-(氧杂环丁烷-3-基)哌嗪-1-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A197”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)-1,4-二氮杂环庚烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A198”)
白色固体;HPLC/MS 1.24min(A),[M+H]+536.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.09(d,J=8.3Hz,2H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.62–7.52(m,2H),7.28(d,J=7.1Hz,1H),4.55(t,J=6.5Hz,1H),4.50(t,J=6.4Hz,1H),4.40(t,J=6.1Hz,1H),4.34(t,J=6.1Hz,1H),4.31–4.28(m,2H),3.79–3.74(m,1H),3.72–3.59(m,3H),3.47–3.38(m,3H),3.35(s,2H),2.60–2.52(m,1H),2.50–2.36(m,3H),1.90–1.81(m,1H),1.79–1.67(m,1H).
2-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-7-(氧杂环丁烷-3-基)-2,7-二氮杂螺[3.5]壬烷(“A199”)
白色固体;HPLC/MS 1.23min(A),[M+H]+562.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.10(d,J=8.4Hz,2H),8.02(d,J=11.0Hz,1H),7.81(d,J=8.4Hz,2H),7.76(s,1H),7.28(d,J=7.1Hz,1H),4.51(t,J=6.5Hz,2H),4.41(t,J=6.1Hz,2H),4.33–4.27(m,2H),4.05(s,2H),3.81–3.73(m,4H),3.36(s,3H),3.36–3.30(m,1H),2.29–1.98(m,4H),1.79–1.71(m,4H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[(3S)-3-甲基吗啉-4-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A200”)
三氟乙酸盐,白色固体;HPLC/MS 1.27min(A),[M+H]+536.
1H NMR(500MHz,DMSO-d6,部分很宽的信号,峰的选择)δ13.72(s,1H),10.55(s,1H),8.15(d,J=8.4Hz,2H),8.01(d,J=10.9Hz,1H),7.83(d,J=8.4Hz,2H),7.78(s,1H),7.28(d,J=7.1Hz,1H),4.79–4.4(m,2H),4.35–4.23(m,2H),3.80–3.73(m,2H),3.36(s,3H),1.30–1.30(bs,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[(3R)-3-甲基吗啉-4-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A201”)
3-(3-{4-[(顺式)-六氢-1H-呋喃并[3,4-c]吡咯e-5-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A202”)
白色固体;UPLC/MS 0.69min,[M+H]+493.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),8.15–8.07(m,2H),8.02(d,J=11.0Hz,1H),7.75(s,1H),7.66(d,J=8.3Hz,2H),7.28(d,J=7.0Hz,1H),4.35–4.20(m,2H),3.90–3.64(m,5H),3.65–3.44(m,3H),3.36(s,3H),3.34–3.31(m,1H),2.93(bs,2H).
(顺式)-5-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-八氢吡咯并[2,3-c]吡咯-2-酮(“A203”)
4-[1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)氮杂环丁烷-3-基]吗啉-3-酮(“A204”)
白色固体;HPLC/MS 1.41min(A),[M+H]+536.
1H NMR(500MHz,DMSO-d6)δ13.70(s,1H),8.15–8.05(m,2H),8.02(d,J=11.0Hz,1H),7.87–7.80(m,2H),7.77(s,1H),7.28(d,J=7.1Hz,1H),5.22(p,J=7.1Hz,1H),4.64–4.45(m,2H),4.35–4.18(m,4H),4.07(s,2H),3.96–3.84(m,2H),3.79–3.73(m,2H),3.71–3.52(m,2H),3.36(s,3H).
2-{[5-氟-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-6-基]氧基}乙-1-醇(“A205”)
白色固体;HPLC/MS 1.13min(A),[M+H]+508.
1H NMR(500MHz,DMSO-d6)δ13.67(s,1H),8.10(d,J=8.2Hz,2H),8.01(d,J=10.9Hz,1H),7.75(s,1H),7.57(d,J=8.3Hz,2H),7.27(d,J=7.1Hz,1H),4.96(t,J=5.4Hz,1H),4.55(t,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.19(t,J=4.9Hz,2H),3.82(q,J=5.1Hz,2H),3.68(bs,2H),3.47(p,J=6.3Hz,1H),3.40(bs,2H),2.41–2.19(m,4H).
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3-(吡啶-4-基)氮杂环丁烷-3-醇(“A206”)
灰白色固体;HPLC/MS 1.27min(A),[M+H]+530.
1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.96–8.51(m,2H),8.18–8.11(m,2H),8.02(d,J=11.0Hz,1H),7.95–7.86(m,4H),7.78(s,1H),7.28(d,J=7.1Hz,1H),6.96(bs,1H),4.81–4.65(m,1H),4.58–4.44(m,1H),4.39–4.26(m,4H),3.81–3.70(m,2H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{5H,6H,7H-吡咯并[3,4-d]嘧啶-6-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A207”)
灰白色固体;UPLC/MS 0.66min(A),[M+H]+501.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物)δ13.71(s,1H),9.11(d,J=13.4Hz,1H),8.88(s,0.5H),8.73(s,0.5H),8.19–8.12(m,2H),8.06–8.01(m,1H),7.86–7.73(m,2H),7.28(d,J=7.1Hz,1H),4.98(s,1H),4.92(s,1H),4.90(s,2H),4.33–4.28(m,2H),3.79–3.72(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A208”)
灰白色固体;UPLC/MS 0.65min(A),[M+H]+489.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物)δ13.71(bs,1H),12.72(s,1H),8.19–8.10(m,2H),8.06–7.96(m,1H),7.86–7.72(m,3H),7.59(s,0.5H),7.49(s,0.5H),7.28(d,J=7.1Hz,1H),4.65(s,2H),4.59(s,1H),4.54(s,1H),4.38–4.26(m,2H),3.93–3.72(m,2H),3.36(s,3H).
2-{[5-氟-3-(3-{4-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-6-基]氧基}乙-1-醇(“A209”)
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[(2S)-2-甲基吗啉-4-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A210”)
白色固体;HPLC/MS 1.30min(A),[M+H]+536.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物)δ13.69(s,1H),8.10(d,J=8.3Hz,2H),8.02(d,J=10.9Hz,1H),7.81(d,J=8.4Hz,2H),7.76(s,1H),7.28(d,J=7.0Hz,1H),4.35(t,J=8.1Hz,1H),4.32–4.25(m,2H),4.23–4.16(m,1H),4.09(t,J=8.8Hz,1H),3.92(dd,J=10.5,5.0Hz,1H),3.81–3.71(m,3H),3.56–3.46(m,2H),3.36(s,3H),3.20–3.13(m,1H),2.78(d,J=11.0Hz,0.5H),2.71(d,J=11.2Hz,1H),2.67–2.60(m,0.5H),1.92(t,J=11.4Hz,1H),1.67–1.55(m,1H),1.12–1.00(m,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{3-[(2R)-2-甲基吗啉-4-基]氮杂环丁烷-1-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A211”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(嘧啶-5-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A212”)
白色固体;HPLC/MS 1.40min(A),[M+H]+515.
1H NMR(500MHz,DMSO-d6)δ13.68(s,1H),9.11(s,1H),8.92(s,2H),8.12(d,J=8.4Hz,2H),8.01(d,J=10.9Hz,1H),7.87(d,J=8.3Hz,2H),7.75(s,1H),7.28(d,J=7.1Hz,1H),4.72(d,J=8.9Hz,1H),4.65–4.47(m,4H),4.39–4.26(m,2H),4.19(s,1H),4.05(tt,J=9.1,6.3Hz,1H),3.83–3.70(m,2H),3.36(s,3H).
5-氟-6-(2-甲氧基乙氧基)-3-[3-(4-{1-甲基-1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-羰基}苯基)-1,2-噁唑-5-基]-1H-吲唑(“A213”)
灰白色固体;UPLC/MS 0.69min,[M+H]+503.
1H NMR(500MHz,DMSO-d6,旋转异构体的混合物)δ13.69(s,1H),8.19–8.09(m,2H),8.08–7.98(m,1H),7.82–7.70(m,3H),7.32–7.26(m,1.5H),7.18(s,0.5H),4.76(s,0.5H),4.68(m,0.5H),4.61(s,0.5H),4.51(s,0.5H),4.35–4.26(m,2H),3.81(s,1.5H),3.80–3.74(m,2H),3.69(s,1.5H),3.36(s,3H).
3-(3-{4-[(顺式)-八氢吡喃并[3,4-c]吡咯e-2-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A214”)
白色固体;HPLC/MS 1.54min(A),[M+H]+507.
1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),8.09(d,J=8.3Hz,2H),8.02(d,J=10.9Hz,1H),7.75(s,1H),7.71(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.34–4.17(m,2H),3.82–3.29(m,13H),2.44–2.36(m,1H),2.37–2.30(m,2H),2.31–2.22(m,1H).
3-(3-{4-[(顺式)-八氢呋喃并[3,4-c]吡啶-5-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A215”)
白色固体;HPLC/MS 1.53min(A),[M+H]+507.
1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),8.10(d,J=8.3Hz,2H),8.02(d,J=10.9Hz,1H),7.74(s,1H),7.56(d,J=8.2Hz,2H),7.28(d,J=7.0Hz,1H),4.33–4.23(m,2H),3.86–3.32(m,12H),3.26–3.21(m,1H),2.44–2.27(m,2H),2.03–1.33(m,2H).
3-(3-{4-[(顺式)-5-(氧杂环丁烷-3-基)-八氢吡咯并[3,4-c]吡咯e-2-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A216”)
三氟乙酸盐,白色固体;UPLC/MS 0.48min,[M+H]+548.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),11.05(s,1H),8.11(d,J=8.3Hz,2H),8.01(d,J=10.9Hz,1H),7.75(s,1H),7.69(d,J=8.3Hz,2H),7.29(d,J=7.1Hz,1H),4.77(t,J=7.3Hz,2H),4.64(s,2H),4.48(bs,1H),4.33–4.27(m,2H),3.9–2.7(宽信号,8H),3.80–3.70(m,2H),3.36(s,3H).
(顺式)-5-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-六氢-1H-2λ6-噻吩并[3,4-c]吡咯e-2,2-二酮(“A217”)
白色固体;UPLC/MS 0.66min,[M+H]+541.
1H NMR(500MHz,DMSO-d6)δ13.69(s,1H),8.10(d,J=8.3Hz,2H),8.01(d,J=11.0Hz,1H),7.75(s,1H),7.70(d,J=8.3Hz,2H),7.28(d,J=7.1Hz,1H),4.36–4.15(m,2H),3.93(bs,1H),3.80–3.69(m,2H),3.52(bs,2H),3.36(s,3H),3.43–3.19(宽信号),3.12(bs,3H).
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(1-甲基-1H-吡唑-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A218”)
白色固体;UPLC/MS 0.70min,[M+H]+517.
1H NMR(400MHz,DMSO-d6)δ13.91(s,1H),8.12(d,J=8.4Hz,2H),8.03(d,J=11.0Hz,1H),7.84(d,J=8.4Hz,2H),7.79(s,1H),7.75(s,1H),7.48(s,1H),7.28(d,J=7.1Hz,1H),4.67(t,J=8.6Hz,1H),4.44(t,J=9.3Hz,1H),4.38–4.22(m,3H),4.01–3.91(m,1H),3.89–3.76(m,4H),3.78–3.74(m,1H),3.35(s,3H).
{4-[5-(5-氟-6-甲氧基-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A219”)
{4-[5-(5-氟-6-甲氧基-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-(顺式)-四氢-呋喃并[3,4-c]吡咯-5-基-甲酮(“A220”)
1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)-3-(吡啶-3-基)氮杂环丁烷-3-醇(“A221”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)(2,2,3,3,5,5,6,6-2H8)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A233”)
2-{[5-氟-3-(3-{4-[4-(氧杂环丁烷-3-基)(2,2,3,3,5,5,6,6-2H8)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-6-基]氧基}乙-1-醇(“A234”)
实施例15
5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(哌嗪-1-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑(“A46”)盐酸盐
向4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯甲酸(79.5mg,0.20mmol)在DMF(1.0ml)中的悬浮液中加入1-Boc-哌嗪(45.2mg,0.24mmol),然后加入1-羟基苯并三唑水合物(6.1mg,0.04mmol)和N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(61mg,0.32mmol)。反应混合物在室温下搅拌16小时。将饱和碳酸氢钠溶液加入到反应混合物中。滤出所得沉淀并用水洗涤。残余物在硅胶柱上用环己烷/乙酸乙酯作为洗脱液进行色谱纯化,得到4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)哌嗪-1-甲酸叔丁酯,为白色固体;HPLC/MS 1.75min,[M+H]+566。
将4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)哌嗪-1-甲酸叔丁酯(90mg,0.16mmol)溶于4N HCl/二噁烷,并将反应混合物在室温下搅拌2.5小时。减压除去溶剂,得到5-氟-6-(2-甲氧基乙氧基)-3-{3-[4-(哌嗪-1-羰基)-苯基]-1,2-噁唑-5-基}-1H-吲唑盐酸盐,为白色固体;HPLC/MS 1.21min(A),[M+H]+466。
1H NMR(500MHz,DMSO-d6)δ13.75(s,1H),9.22(s,2H),8.13(d,J=8.3Hz,1H),8.02(d,J=10.9Hz,1H),7.77(s,1H),7.66(d,J=8.3Hz,1H),7.28(d,J=7.0Hz,1H),4.33–4.26(m,2H),3.79–3.74(m,2H),3.72(宽,4H),3.36(s,3H),3.18(宽,4H)。
类似地制备以下化合物:
{[1-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)吡咯烷-2-基]甲基}(甲基)胺(“A222”)
浅黄色固体;HPLC/MS 1.31min(A),[M+H]+494.
1H NMR(500MHz,DMSO-d6,旋转异构体,峰的选择)δ8.09(d,J=8.3Hz,1H),8.04(d,J=11.0Hz,1H),7.77(s,1H),7.67(d,J=8.0Hz,2H),7.28(d,J=7.1Hz,1H),4.35–4.28(m,2H),4.27–4.20(m,1H),3.81–3.72(m,2H),3.52–3.44(m,1H),3.36(s,3H),2.81(dd,J=11.6,3.9Hz,1H),2.69–2.56(m,1H),2.34(s,3H),2.05–1.83(m,4H),1.71(宽,1H).
3-(3-{4-[(顺式)-八氢吡咯并[3,4-c]吡咯-2-羰基]苯基}-1,2-噁唑-5-基)-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑(“A223”)盐酸盐
2-[(5-氟-3-{3-[4-(哌嗪-1-羰基)苯基]-1,2-噁唑-5-基}-1H-吲唑-6-基)氧基]乙-1-醇(“A224”)
{4-[5-(5-氟-6-甲氧基-1H-吲唑-3-基)-异噁唑-3-基]-苯基}-哌嗪-1-基-甲酮(“A225”)
5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[(2,2,3,3,5,5,6,6-2H8)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑盐酸盐(“A232”)
实施例16
[(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯基)亚氨基]二甲基-λ6-sulfanone(“A47”)
白色固体;HPLC/MS 2.52min(A),[M+H]+445.
1H NMR(500MHz,DMSO-d6)δ13.66(s,1H),8.00(d,J=11.0Hz,1H),7.84(d,J=8.6Hz,1H),7.59(s,1H),7.26(d,J=7.1Hz,1H),7.07(d,J=8.6Hz,2H),4.32–4.26(m,2H),3.80–3.74(m,2H),3.35(s,3H),3.29(s,6H).
实施例17
5-氟-6-(2-甲氧基乙氧基)-3-[3-(1,3-噻唑-5-基)-1,2-噁唑-5-基]-1H-吲唑(“A48”)
浅棕色固体;HPLC/MS 2.61min(A),[M+H]+361.
1H NMR(500MHz,DMSO-d6)δ13.77(s,1H),9.31(d,J=0.7Hz,1H),8.68(d,J=0.7Hz,1H),7.96(d,J=10.8Hz,1H),7.78(s,1H),7.29(d,J=7.0Hz,1H),4.38–4.23(m,2H),3.86–3.67(m,2H),3.35(s,3H).
实施例18
4-{5-[5-氟-6-(3-羟基-2-甲氧基丙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}-N,N-二甲基苯甲酰胺(“A49”)
浅黄色固体;UPLC/MS 0.65min(A),[M+H]+455.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.09(d,J=8.3Hz,2H),8.03(d,J=10.8Hz,1H),7.76(s,1H),7.59(d,J=8.3Hz,2H),7.29(d,J=7.0Hz,1H),4.81(t,J=5.3Hz,1H),4.30(dd,J=10.4,3.2Hz,1H),4.17(dd,J=10.4,5.3Hz,1H),3.64–3.56(p,J=4.0Hz,3H),3.42(s,3H),3.02(s,3H),2.96(s,3H).
实施例19
3-{3-[4-(3,3-二甲基-哌啶-4-基)-苯基]-异噁唑-5-基}-5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑(“A230”)
和
5-氟-6-(2-甲氧基-乙氧基)-3-{3-[4-(1,3,3-三甲基-哌啶-4-基)-苯基]-异噁唑-5-基}-1H-吲唑(“A231”)
合成方案:
“A230”:
黄色固体;[M+H]+465;1H NMR(400MHz,DMSO-d6)δ8.02(d,J=11.0Hz,1H),7.96-7.91(m,2H),7.67(s,1H),7.35-7.31(m,2H),7.27(d,J=7.1Hz,1H),4.33-4.26(m,2H),3.80-3.73(m,2H),3.35(s,3H),3.13-3.05(m,1H),2.65-2.52(m,3H),2.49-2.41(m,1H),2.12-2.01(m,1H),1.44-1.36(m,1H),0.85(s,3H),0.70(s,3H)
“A231”:
白色固体;[M+H]+479;1H NMR(300MHz,DMSO-d6)δ13.70(s,1H),8.00(d,J=11.0Hz,1H),7.92(d,J=8.1Hz,2H),7.67(s,1H),7.33(d,J=8.1Hz,2H),7.26(d,J=7.1Hz,1H),4.32-4.23(m,2H),3.79-3.69(m,2H),3.33(s,3H),2.97-2.89(m,1H),2.44-2.34(m,2H),2.28-2.13(m,4H),1.92-1.75(m,2H),1.53-1.43(m,1H),0.86(s,3H),0.72(s,3H).
实施例20
2-[4-(4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酰基)哌嗪-1-基]丙烷-1,3-二醇(“A228”)
三氟乙酸盐;白色粉末;UPLC/MS 0.47min,[M+H]+540.
1H NMR(500MHz,DMSO-d6)δ13.71(s,1H),9.65(宽,1H),8.13(d,J=8.3Hz,2H),8.01(d,J=10.9Hz,1H),7.76(s,1H),7.66(d,J=8.3Hz,2H),7.29(d,J=7.1Hz,1H),5.40(宽,2H),4.51(宽,1H),4.38–4.21(m,2H),3.80(d,J=5.0Hz,4H),3.78–3.75(m,2H),3.54(宽信号),3.36(s,3H).
实施例21
“A45”的替代合成:
向对苯二甲醛酸(300mg,2.00mmol)在DMF(10ml)中的溶液中加入1-(氧杂环丁烷-3-基)哌嗪(313mg,2.20mmol),然后加入1-羟基苯并三唑水合物(15.3mg,0.10mmol)和N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(403mg,2.10mmol)。反应混合物在室温下搅拌90分钟。将反应混合物蒸发至干。残余物用饱和碳酸氢钠溶液处理并用二氯甲烷萃取3次。合并的有机相用硫酸钠干燥并蒸发,得到4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯甲醛,为黄色油;HPLC/MS 0.82min(A),[M+H]+275。
1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),7.97(d,J=8.2Hz,2H),7.60(d,J=8.1Hz,2H),4.53(t,J=6.5Hz,2H),4.44(t,J=6.1Hz,2H),3.67宽,2H),3.49–3.43(m,1H),3.30(宽,2H),2.42–2.19(m,4H)。
将4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯甲醛(403mg,1.47mmol)在乙醇(3ml)中的浆液加热至80℃。使所得澄清溶液达到室温并加入氯化羟铵(204mg,2.93mmol)在水(500μl)中的溶液,并将混合物在室温下搅拌1小时。反应混合物用1N氢氧化钠溶液(2ml)中和。滤出所得沉淀,用水洗涤并真空干燥,得到N-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}亚甲基)羟胺,为白色粉末;UPLC/MS 0.30min,[M+H]+290。
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.18(s,1H),7.65(d,J=8.2Hz,2H),7.41(d,J=8.3Hz,2H),4.53(t,J=6.5Hz,3H),4.44(t,J=6.1Hz,3H),3.62(bs,2H),3.45(p,J=6.3Hz,1H),3.37(bs,2H),2.28(bs,4H)。
向3-乙炔基-5-氟-6-(2-甲氧基-乙氧基)-吲唑-1-甲酸叔丁酯(41.6mg,0.11mmol)和N-({4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}亚甲基)羟胺在二氯甲烷(500μl)中的溶液中滴加次氯酸钠水溶液中(含量约14%,143μl,约0.33mmol)。反应混合物在室温下搅拌18小时。反应混合物用水和二氯甲烷处理。分离水相并用二氯甲烷萃取两次。合并的有机相用硫酸钠干燥并蒸发。残余物在硅胶柱上用二氯甲烷/甲醇作为洗脱液进行色谱纯化,得到5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-1-甲酸叔丁酯,为无色树脂;UPLC/MS 0.69min,[M+H]+622。
向5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑-1-甲酸叔丁酯(62mg,0.12mmol)在甲醇(1ml)中的悬浮液中加入氢氧化钠(9.26mg,0.23mmol),并将混合物在室温下搅拌2小时。反应混合物用饱和氯化铵溶液处理。滤出所得沉淀,用水洗涤并真空干燥,得到5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑,为灰白色固体;UPLC/MS 0.53min,[M+H]+522。
类似地制备以下化合物:
6-乙氧基-5-氟-3-(3-{4-[4-(氧杂环丁烷-3-基)哌嗪-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A229”)
灰白色结晶;HPLC/MS 1.34min(A),[M+H]+492.
1H NMR(500MHz,DMSO-d6)δ13.66(s,1H),8.10(d,J=8.3Hz,2H),8.00(d,J=11.0Hz,1H),7.74(s,1H),7.57(d,J=8.3Hz,2H),7.23(d,J=7.1Hz,1H),4.54(t,J=6.5Hz,2H),4.45(t,J=6.1Hz,2H),4.22(q,J=7.0Hz,2H),3.67(宽,2H),3.47(p,J=6.2Hz,1H),3.40(宽,2H),2.31(宽,4H),1.43(t,J=6.9Hz,3H).
实施例22-盐的形成
向(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A45”)(104mg,0.20mmol)在2-丙醇(3ml)中的悬浮液中加入甲磺酸(18.6μl,0.28mmol),并将悬浮液在75℃搅拌1小时。使混合物达到室温。滤出固体,用水洗涤并真空干燥,得到(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮甲磺酸盐,为白色粉末。
1H NMR(500MHz,DMSO-d6,没有注释的很宽信号)δ13.71(s,1H),10.79(s,1H),8.14(d,J=8.2Hz,2H),8.01(d,J=10.9Hz,1H),7.77(s,1H),7.65(d,J=7.9Hz,2H),7.29(d,J=7.0Hz,1H),4.74(s,4H),4.41–4.24(m,2H),3.80–3.72(m,2H),3.36(s,3H),3.03(宽,4H),2.31(s,3H)。
类似地制备(4-{5-[5-氟-6-(2-甲氧基-乙氧基)-1H-吲唑-3-基]-异噁唑-3-基}-苯基)-(4-氧杂环丁烷-3-基-哌嗪-1-基)-甲酮(“A45”)的以下的盐:
-盐酸盐
-马来酸盐
-半乙烷二磺酸盐
-半磷酸盐
-硫酸盐
-苯磺酸盐
-对甲苯磺酸盐
类似地制备5-氟-6-(2-甲氧基乙氧基)-3-(3-{4-[3-(吗啉-4-基)氮杂环丁烷-1-羰基]苯基}-1,2-噁唑-5-基)-1H-吲唑(“A53”)的以下的盐:
-甲磺酸盐
-三氟乙酸盐。
以下实施例与药物有关:
实施例A:注射小瓶
用2N盐酸将100g式I的活性成分和5g磷酸氢二钠在3l重蒸水中的溶液调节至pH6.5,无菌过滤,转移到注射小瓶中,在无菌条件下冻干,并在无菌条件下密封。每个注射小瓶含有5mg活性成分。
实施例B:栓剂
将20g式I的活性成分与100g大豆卵磷脂和1400g可可脂的混合物熔化,倒入模具中并使其冷却。每个栓剂含有20mg活性成分。
实施例C:溶液
由1g式I的活性成分、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940ml重蒸水中制备溶液。将pH调节至6.8,将溶液补充至1l,并通过照射灭菌。该溶液可以以滴眼剂的形式使用。
实施例D:药膏
在无菌条件下将500mg式I的活性成分与99.5g凡士林混合。
实施例E:片剂
将1kg式I的活性成分、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物以常规方式压制成片剂,使得每个片剂含有10mg活性成分。
实施例F:糖衣丸
类似于实施例E压制片剂,随后以常规方式用蔗糖、马铃薯淀粉、滑石、黄蓍胶和染料的包衣材料进行包衣。
实施例G:胶囊
将2kg式I的活性成分以常规方式加入硬明胶胶囊中,使得每个胶囊含有20mg活性成分。
实施例H:安瓿瓶
将1kg式I的活性成分在60l重蒸水中的溶液无菌过滤,转移到安瓿瓶中,在无菌条件下冻干并在无菌条件下密封。每个安瓿瓶含有10mg活性成分。
Claims (13)
1.式I的化合物
其中
R1表示Hal、CF3、OA、Het1、COOR3或CON(R3)2,
R2表示H、Hal或CN,
R3表示H或A,
X表示亚苯基、吡啶二基、1,3-噻唑二基或吡唑二基,它们各自未被取代或被Hal和/或A单、二或三取代,
Y不存在或表示CO、O[C(R3)2]n、NR3CO、CONR3、CONR3[C(R3)2]n、CONHCH2C(CH3)2、SO2、SO2N(R3)、-N=或S(=O,=NR3),
Z表示H、A、Hal、OA、[C(R3)2]nHet2或N=S(=O)A2,
A表示具有1-10个C-原子的无支链或支链烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子代替并且其中1-7个H-原子可以被R5代替,
或表示(CH2)nCyc,
Cyc表示具有3-7个C原子的环状烷基,
R5表示F、Cl、OH、SO2A或N(R3)2,
Het1表示可以被A单或二取代的吡唑基,
Het2表示具有1至4个N、O和/或S原子的4至7元单环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代,
或者
表示具有1至4个N、O和/或S原子的7至10元双环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代,
Het3表示具有1至4个N、O和/或S原子的4至7元单环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代,
或者
表示具有1至4个N、O和/或S原子的7至10元双环芳族、不饱和或饱和杂环,其可以未被取代或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代,
Hal表示F、Cl、Br或I,
n表示0、1、2或3,
及其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括其所有比例的混合物。
2.根据权利要求1的化合物,其中
Het2表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基或四氢呋喃并[3,4-c]吡咯-5-基,其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代,
及其药学上可接受的溶剂化物、盐、互变异构体和立体异构体,包括其所有比例的混合物。
3.根据权利要求1或2的化合物,其中
Het3表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基或1,2,4-三唑基,其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代,
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
4.根据权利要求1的化合物,其中
R1表示Hal、CF3、OCH3、OCH2CH2OCH3、OCH2CH2OH、1-甲基-1H-吡唑-4-基、COOCH3、CONH2、CONHCH3或CONHCH2CH2OCH3,
R2表示H、Hal或CN,
R3表示H或CH3,
X表示1,4-亚苯基、1,3-亚苯基、2-氟-1,4-亚苯基、2-甲基-1,4-亚苯基、吡啶-3,6-二基、1,3-噻唑-3,5-二基、1,3-噻唑-2,4-二基、1,3-噻唑-2,5-二基或吡唑-1,4-二基,其各自未被取代或被Hal和/或A单、二或三取代,
Y不存在或表示CO、SO2、NHCO、NCH3、CONH(CH2)n、CONHCH2C(CH3)2、CON(CH3)(CH2)n、O、OCH2、OCH2CH2、S(=O)(=NH)、-N=或SO2N(CH3),
Z表示H、A、Hal、OA、[C(R3)2]nHet2或N=S(=O)A2,
A表示具有1-10个C-原子的无支链或支链烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子代替并且其中1-7个H-原子可以被R5代替,
或表示(CH2)nCyc,
Cyc表示具有3-7个C原子的环状烷基,
R5表示F、Cl、OH、SO2A或N(R3)2,
Het1表示吡唑基,可以被A单或二取代,
Het2表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基或四氢呋喃并[3,4-c]吡咯-5-基,其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代;Het3表示
Het3表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基或1,2,4-三唑基,其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代;
Hal表示F、Cl、Br或I,
n表示0、1、2或3,
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
5.根据权利要求1的化合物,具有式Ib
其中
R1表示Hal、CF3、OCH3、OCH2CH2OCH3、OCH2CH2OH、1-甲基-1H-吡唑-4-基、COOCH3、CONH2、CONHCH3或CONHCH2CH2OCH3,
R2表示H、Hal或CN,
R3表示H或CH3,
X表示1,4-亚苯基、1,3-亚苯基、2-氟-1,4-亚苯基、2-甲基-1,4-亚苯基、吡啶-3,6-二基、1,3-噻唑-3,5-二基、1,3-噻唑-2,4-二基、1,3-噻唑-2,5-二基或吡唑-1,4-二基,其各自未被取代或被Hal和/或A单、二或三取代,
Y不存在或表示CO、SO2、NHCO、NCH3、CONH(CH2)n、CONHCH2C(CH3)2、CON(CH3)(CH2)n、O、OCH2、OCH2CH2、S(=O)(=NH)、-N=或SO2N(CH3),
Z表示H、A、Hal、OA、[C(R3)2]nHet2或N=S(=O)A2,
A表示具有1-10个C-原子的无支链或支链烷基,其中一个或两个不相邻的CH-和/或CH2-基团可以被O-原子代替并且其中1-7个H-原子可以被R5代替,
或表示(CH2)nCyc,
Cyc表示具有3-7个C原子的环状烷基,
R5表示F、Cl、OH、SO2A或N(R3)2,
Het1表示吡唑基,可以被A单或二取代,
Het2表示吡咯烷基、哌嗪基、哌啶基、三唑基、氮杂环丁烷基、吗啉基、硫代吗啉基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、6-氧杂-2-氮杂螺[3.4]辛烷-2-基、1-氧杂-6-氮杂螺[3.3]庚烷-6-基、2,6-二氮杂螺[3.3]庚烷-2-基、八氢吡咯并[3,4-b]吡咯基、八氢吡咯并[3,2-b]吡咯基、1,4-二氮杂环庚烷基、吡啶基、1H-吡啶基、2H-哒嗪基、2,3-二氢哒嗪基、八氢-1H-吡咯并[3.2-b]吡啶基、3-硫杂-6-氮杂双环[3.1.1]庚基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、1H-吡唑基、噻唑烷基、2-氧杂-7-氮杂螺[3.5]壬烷-7-基、1,4-氧杂氮杂环庚烷基、2-硫杂-6-氮杂螺[3.3]庚烷-6-基、2,8-二氧杂-5-氮杂螺[3.5]壬烷-5-基、1H-1,3-苯并二唑-2-基、2-氧杂-7-氮杂螺[4.4]壬烷-7-基、2-氧杂-6-氮杂螺[3.4]辛烷-6-基、8-氧杂-2-氮杂螺[4.5]癸烷-2-基、2,6-二氮杂螺[3.4]辛烷-6-基、6-氧杂-3-氮杂双环[3.1.1]庚烷-3-基、2-氧杂-5-氮杂双环[2.2.1]庚烷-5-基、7-氧杂-2-氮杂螺[3.5]壬烷-2-基、6-氧杂-1-氮杂螺[3.3]庚烷-1-基、2,7-二氮杂螺[3.5]壬烷-7-基、3-氧杂-6-氮杂双环[3.1.1]庚烷-6-基、1H,2H,3H-吡咯并[3,4-c]吡啶-2-基、2,7-二氮杂螺[3.5]壬烷-2-基、六氢-1H-呋喃并[3,4-c]吡咯-5-基、八氢吡咯并[2,3-c]吡咯-5-基、5H,6H,7H-吡咯并[3,4-d]嘧啶-6-基、1H,4H,5H,6H-吡咯并[3,4-c]吡唑-5-基、八氢吡喃并[3,4-c]吡咯-2-基、八氢呋喃并[3,4-c]吡啶-5-基、八氢吡咯并[3,4-c]吡咯-2-基、六氢-1H-2λ6-噻吩并[3,4-c]吡咯-5-基或四氢呋喃并[3,4-c]吡咯-5-基,其中每一个都可以是未被取代的或被A、Hal、CN、OR3、[C(R3)2]nN(R3)2、[C(R3)2]nSO2A、[C(R3)2]nNR3SO2A、Het3、=NR3和/或=O单、二或三取代;Het3表示
Het3表示吗啉基、1H-吡唑基、1λ6-硫代吗啉基、咪唑基、氮杂环丁烷基、哌嗪基、哌啶基、吡啶基、氧杂环丁烷基、1,2,4-噁二唑基、嘧啶基、氧杂环戊烷基、吡咯烷基、2-氧杂-6-氮杂螺[3.3]庚烷-6-基、氧杂环己烷-4-基、1,2,3-三唑基或1,2,4-三唑基,其中每一个可以是未被取代的或被A、Hal、OR3、氧杂环丁烷基和/或=O单或二取代;
Hal表示F、Cl、Br或I,
n表示0、1、2或3,
及其药学上可接受的盐、互变异构体和立体异构体,包括其所有比例的混合物。
7.制备根据权利要求1-6的式I化合物及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体的方法,其特征在于
a)对于制备式I化合物,
其中
X表示亚苯基,
Y表示CO,
Z表示[C(R3)2]nHet2和
n表示0,
式II的化合物
其中R1和R2具有权利要求1中所述的含义,
与式III的化合物反应
Het2 III
其中Het2具有权利要求1中所述的含义,
或
b)对于制备式I化合物,
其中
R1表示Het1,
式IV化合物,
其中
R2、X、Y和Z具有权利要求1中所述的含义,
与式V的化合物反应
其中Het1具有权利要求1中所述的含义,
或
c)对于制备式Ia的化合物,
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义,
式VI的化合物
其中
R1和R2具有权利要求1中所述的含义,
与式VII的化合物反应
其中
X、Y和Z具有权利要求1中所述的含义,
或
d)对于制备式Ib的化合物,
其中
R1、R2、X、Y和Z具有权利要求1中所述的含义,
式VIII化合物,
其中
R1和R2具有权利要求1中所述的含义,
与式IX的化合物反应
HO-N=CH-X-Y-Z IX
其中
X、Y和Z具有权利要求1中所述的含义,
和/或
式I的碱或酸被转化为其盐之一。
8.药物,包含至少一种根据权利要求1的式I化合物和/或其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括其所有比例的混合物,以及任选的药学上可接受的载体、赋形剂或媒介物。
9.用于治疗和/或预防癌症的根据权利要求1的式I及其药学上可接受的盐、溶剂化物、互变异构体和立体异构体,包括其所有比例的混合物使用的化合物。
10.根据权利要求10的使用的化合物,用于治疗和/或预防癌症,其中所述癌症是胃肠间质肿瘤。
11.药物,包含根据权利要求1的式I的至少一种化合物和/或其药学上可接受的盐、溶剂化物和立体异构体,包括其所有比例的混合物,以及至少一种其他药物活性成分。
12.套装(药盒),由以下的单独的包装组成:
(a)有效量的根据权利要求1的式I化合物和/或其药学上可接受的盐、溶剂化物、盐和立体异构体,包括其所有比例的混合物,和
(b)有效量的其他药物活性成分。
13.选自以下的中间体:
2-溴-5-氟-4-(2-甲氧基乙氧基)苯甲醛
N'-[(1E)-[2-溴-5-氟-4-(2-甲氧基乙氧基)苯基]亚甲基]-4-甲基苯-1-磺酰肼
5-氟-6-(2-甲氧基乙氧基)-1-(4-甲基苯磺酰基)-1H-吲唑
5-氟-6-(2-甲氧基乙氧基)-1H-吲唑
5-氟-3-碘-6-(2-甲氧基乙氧基)-1H-吲唑
5-氟-3-碘-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
5-氟-6-(2-甲氧基乙氧基)-3-[2-(三甲基甲硅烷基)乙炔基]-1H-吲唑-1-甲酸叔丁酯
3-乙炔基-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑
3-乙炔基-5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
5-氟-3-{3-[4-(甲氧基羰基)苯基]-1,2-噁唑-5-基}-6-(2-甲氧基乙氧基)-1H-吲唑-1-甲酸叔丁酯
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸甲酯
4-{5-[5-氟-6-(2-甲氧基乙氧基)-1H-吲唑-3-基]-1,2-噁唑-3-基}苯甲酸
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