CN113164763A - Nlrp3抑制剂 - Google Patents
Nlrp3抑制剂 Download PDFInfo
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- CN113164763A CN113164763A CN201980081864.1A CN201980081864A CN113164763A CN 113164763 A CN113164763 A CN 113164763A CN 201980081864 A CN201980081864 A CN 201980081864A CN 113164763 A CN113164763 A CN 113164763A
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- pyrazole
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Abstract
本申请涉及具有NLRP3抑制活性的化合物以及相关的盐、溶剂合物、前药和药物组合物。本申请还涉及此类化合物在最尤其通过NLRP3抑制来治疗和预防医学病症和疾病中的用途。
Description
技术领域
本发明涉及具有NLRP3抑制活性的化合物以及相关的盐、溶剂合物、前药和药物组合物。本发明还涉及此类化合物在最尤其通过NLRP3抑制来治疗和预防医学病症和疾病中的用途。
背景技术
NOD样受体(NLR)家族,即含炎素(pyrin)结构域的蛋白质3(NLRP3)炎性体是炎症过程的组分,并且其异常活性在遗传性病症(如冷炎素相关周期性综合征(cryopyrin-associated periodic syndrome,CAPS))和复杂疾病(如多发性硬化、2型糖尿病、阿兹海默氏病(Alzheimer's disease)以及动脉粥样硬化)中具有致病性。
NLRP3是感测许多病原体源性、环境和宿主源性因子的细胞内信号传导分子。在活化时,NLRP3与含半胱天冬酶活化和募集结构域(ASC)的细胞凋亡相关斑点样蛋白质结合。ASC随后聚合形成大聚集体,称为ASC斑点。聚合的ASC进而与半胱氨酸蛋白酶半胱天冬酶-1相互作用以形成复合物,称为炎性体。这使得半胱天冬酶-1活化,从而使促炎细胞因子IL-1β和IL-18的前体形式(分别称为IL-1β前体(pro-IL-1β)和IL-18前体(pro-IL-18))裂解,由此使这些细胞因子活化。半胱天冬酶-1还介导一类炎症性细胞死亡,称为细胞焦亡。ASC斑点还可募集和活化半胱天冬酶-8,这可对IL-1β前体和IL-18前体进行加工并且触发细胞凋亡性细胞死亡。
半胱天冬酶-1使IL-1β前体和IL-18前体裂解成其活性形式,所述活性形式是从细胞分泌。活性半胱天冬酶-1还裂解消皮素-D(gasdermin-D)以触发细胞焦亡。经由控制细胞焦亡性细胞死亡路径,半胱天冬酶-1还介导警报素分子如IL-33和高迁移率族框1蛋白(HMGB1)的释放。半胱天冬酶-1还裂解细胞内IL-1R2,导致其降解并且允许释放IL-1α。在人细胞中,半胱天冬酶-1还可控制IL-37的加工和分泌。多种其他半胱天冬酶-1底物(如细胞骨架和糖解路径的组分)可能导致半胱天冬酶-1依赖性炎症。
NLRP3依赖性ASC斑点释放至细胞外环境中,在细胞外环境中它们可活化半胱天冬酶-1,诱导半胱天冬酶-1底物的加工并且使炎症扩散。
来源于NLRP3炎性体活化的活性细胞因子是炎症的重要驱动剂并且与其他细胞因子路径相互作用以形成针对感染和损伤的免疫应答。举例来说,IL-1β信号传导诱导促炎细胞因子IL-6和TNF的分泌。IL-1β和IL-18与IL-23协同作用以诱导记忆CD4 Th17细胞和γδT细胞在不存在T细胞受体接合的情况下产生IL-17。IL-18和IL-12也协同作用以诱导记忆T细胞和NK细胞产生IFN-γ,从而驱动Th1应答。
遗传性CAPS疾病穆-韦二氏综合征(Muckle-Wells syndrome,MWS)、家族性寒冷型自身炎症性综合征(FCAS)和新生儿发作型多系统炎症性疾病(NOMID)由NLRP3的功能获得型突变引起,由此将NLRP3定义为炎症过程的关键组分。NLRP3还参与多种复杂疾病(特别地包括代谢病症如2型糖尿病、动脉粥样硬化、肥胖症和痛风)的发病机制。
NLRP3在中枢神经系统疾病中的作用正在浮现,并且还已显示肺病受NLRP3影响。此外,NLRP3在肝病、肾病和老化的发展中起作用。许多这些关联是使用Nlrp3-/-确定的,但也有人对这些疾病中NLRP3的特异性活化提出见解。在2型糖尿病(T2D)中,胰岛淀粉样蛋白多肽在胰腺中的沉积使NLRP3和IL-1β信号传导活化,导致细胞死亡和炎症。
已显示若干小分子抑制NLRP3炎性体。格列苯脲(Glyburide)响应于NLRP3而非NLRC4或NLRP1的活化在微摩尔浓度下抑制IL-1β产生。其他先前表征的弱NLRP3抑制剂包括小白菊内酯、3,4-亚甲基二氧基-β-硝基苯乙烯和二甲亚砜(DMSO),但这些剂具有有限的功效并且是非特异性的。
NLRP3相关疾病的当前治疗包括靶向IL-1的生物剂。这些生物剂是重组IL-1受体拮抗剂阿那白滞素(anakinra)、中和IL-1β抗体卡那单抗(canakinumab)和可溶性诱饵IL-1受体利纳西普(rilonacept)。这些方法已被证实成功治疗CAPS,并且这些生物剂已被用于其他IL-1β相关疾病的临床试验中。
一些含二芳基磺酰脲的化合物已被鉴定为细胞因子释放抑制药物(CRID)(Perregaux等人;J.Pharmacol.Exp.Ther.,299,187-197,2001)。CRID为一类含二芳基磺酰脲的化合物,所述化合物抑制IL-1β的翻译后加工。IL-1β的翻译后加工伴随着半胱天冬酶-1的活化和细胞死亡。CRID阻止活化的单核细胞以使得半胱天冬酶-1保持无活性并且保持质膜潜伏。
还公开了某些作为NLRP3的抑制剂的含磺酰脲化合物(参见,例如,Baldwin等人,J.Med.Chem.,59(5),1691-1710,2016;以及WO 2016/131098 A1、WO 2017/129897 A1、WO2017/140778 A1、WO 2017/184623 A1、WO 2017/184624 A1、WO 2018/015445 A1、WO 2018/136890 A1、WO 2018/215818 A1、WO 2019/008025 A1、WO 2019/008029 A1、WO 2019/034686 A1、WO 2019/034688 A1、WO 2019/034690 A1、WO 2019/034692 A1、WO 2019/034693 A1、WO 2019/034696 A1、WO 2019/034697 A1、WO 2019/043610 A1、WO 2019/092170 A1、WO 2019/092171 A1和WO 2019/092172 A1)。此外,WO 2017/184604 A1和WO2019/079119 A1公开了多种作为NLRP3抑制剂的含磺酰胺化合物。还公开了某些作为NLRP3的抑制剂的含亚磺胺亚胺化合物(WO 2018/225018 A1、WO 2019/023145 A1、WO 2019/023147 A1和WO 2019/068772 A1)。
需要提供具有改善的药理学和/或生理学和/或物理化学特性的化合物和/或提供已知化合物的有用替代形式的化合物。
发明内容
本发明的第一方面提供一种式(I)化合物:
其中:
R1为C1-C3烷基;
R11为C1-C3烷基;
R12为氢或C1-C3烷基;并且
R13为氢或C1-C3烷基;或者
R12和R13与它们所连接的碳原子一起形成C3-C6环烷基。
在一个实施方案中,R1为甲基、乙基、正丙基或异丙基。在一个实施方案中,R1为甲基或乙基。在一个实施方案中,R1为甲基。
在一个实施方案中,R11为甲基、乙基、正丙基或异丙基。在一个实施方案中,R11为甲基或乙基。在一个实施方案中,R11为甲基。
在一个实施方案中,R12为氢或甲基、乙基、正丙基或异丙基。在一个实施方案中,R12为氢或甲基或乙基。在一个实施方案中,R12为氢或甲基。在一个实施方案中,R12为甲基。
在一个实施方案中,R13为氢或甲基、乙基、正丙基或异丙基。在一个实施方案中,R13为氢或甲基或乙基。在一个实施方案中,R13为氢或甲基。
在一个实施方案中,R12和R13与它们所连接的碳原子一起形成环丙基、环丁基、环戊基或环己基。在一个实施方案中,R12和R13与它们所连接的碳原子一起形成环丁基或环戊基。
在一个实施方案中,-C(OR11)R12R13为-C(CH3)2(OCH3)、-CH(CH3)(OCH3)或
本发明的第一方面还提供一种式(II)化合物:
其中R2为C1-C3卤代烷基。
在一个实施方案中,R2为被1-7个独立地选自氟和氯原子的卤原子取代的C1-C3烷基。在一个实施方案中,R2为被1-7个氟原子取代的C1-C3烷基。在一个实施方案中,R2为被1-5个氟原子取代的C1-C2烷基。在一个实施方案中,R2为被2或3个氟原子取代的乙基。在一个实施方案中,R2为-CH2CF3或-CH2CHF2。
本发明的第一方面还提供一种式(III)化合物:
其中:
R3为C1-C6烷基、C3-C6环烷基、(C3-C6亚环烷基)(C1-C2烷基)或(C1-C2亚烷基)(C3-C6环烷基)基团,所述基团中的每一者均被-NRaRb取代;
Ra为C1-C3烷基;并且
Rb为C1-C3烷基;或者
Ra和Rb与它们所连接的氮原子一起形成4至6元饱和杂环;
前提条件是R3包含8个或更多个除氢或卤素以外的原子。
在一个实施方案中,R3为-(C1-C6亚烷基)-NRaRb或-(C3-C6亚环烷基)(C1-C2亚烷基)-NRaRb基团。
在一个实施方案中,R3为
其中A1和A2各自独立地为键或C1-C2亚烷基;n为1、2、3或4;R’和R”各自独立地为甲基或乙基。在一个实施方案中,A1和A2中的一者为键,并且A1和A2中的另一者为-CH2-;n为2或3;R’和R”均为甲基。
在一个实施方案中,R3为
本发明的第一方面还提供一种式(IV)化合物:
其中:
R4为C1-C3卤代烷基;
R5选自:
X1为H、F、Cl、Br或CN;并且
X2为F、Cl、Br或CN。
在一个实施方案中,R4为被1-7个独立地选自氟和氯原子的卤原子取代的C1-C3烷基。在一个实施方案中,R4为被1-7个氟原子取代的C1-C3烷基。在一个实施方案中,R4为被1-5个氟原子取代的C1-C2烷基。在一个实施方案中,R4为被2或3个氟原子取代的乙基。在一个实施方案中,R4为-CH2CF3或-CH2CHF2。
在一个实施方案中,R5选自:
本发明的第一方面还提供一种式(V)化合物:
其中:
R6为C2-C4烷基;
R7为C1-C3烷基;
q为0或1;并且
X3为H、F、Cl、Br或CN。
在一个实施方案中,R6为乙基、正丙基或异丙基。在一个实施方案中,R6为异丙基。
在一个实施方案中,R7为甲基或乙基。在一个实施方案中,R7为甲基。在一个实施方案中,q为1。在一个实施方案中,q为0。
在一个实施方案中,X3为H或Br。
在一个实施方案中,化合物具有式(Va):
本发明的第一方面还提供一种式(VI)化合物:
其中:
R8选自:
X4为F、Cl、Br或CN。
在一个实施方案中,R8为
本发明的第一方面还提供一种式(VII)化合物:
其中:
R9为卤基或-CR91R92(OH)基团;
R91为氢或C1-C3烷基;
R92为氢或C1-C3烷基;
R10选自:
X5为H、F、Cl、Br或CN;并且
X6为F、Cl、Br或CN。
在一个实施方案中,R9为氟、氯或-CR91R92(OH)基团;其中R91和R92独立地为氢或甲基或乙基。在一个实施方案中,R9为氟、氯或-CR91R92(OH)基团;其中R91和R92独立地为氢或甲基。在一个实施方案中,R9为氟、-C(CH3)2(OH)、-CH(CH3)(OH)或-CH2(OH)。
在一个实施方案中,R10选自:
在一个实施方案中,化合物具有式(VIIa):
本发明的第一方面还提供一种式(VIII)化合物:
其中:
R14为被-NRcRd取代的C1-C3烷基;
Rc为C1-C3烷基;
Rd为C1-C3烷基;或者
Rc和Rd与它们所连接的氮原子一起形成4至6元饱和杂环;
R15为C1-C3烷基;并且
r为0、1或2。
在一个实施方案中,R14为被-NMe2、-NMeEt或-NEt2取代的C1-C2烷基。在一个实施方案中,R14为-CH2NMe2。
在一个实施方案中,R15为甲基或乙基并且r为0或1。在一个实施方案中,R15为甲基并且r为0或1。
本发明的第一方面还提供一种式(IX)化合物:
其中:
R16为饱和或不饱和烃基,其中烃基可为直链或支链的,或者为环状基团或包括环状基团,其中烃基可任选地被取代,并且其中烃基在其碳骨架中可任选地包括一个或多个(如一个、两个或三个)杂原子N、O或S;并且
R17为在α位被取代的环状基团,其中R17可任选地被进一步取代。
在一个实施方案中,R16为饱和或不饱和C1-C20(如C1-C15或C1-C10)烃基,其中烃基可为直链或支链的,或者为环状基团或包括环状基团,其中烃基可任选地被取代,并且其中烃基在其碳骨架中可任选地包括一个或多个(如一个、两个或三个)杂原子N、O或S。
在一个实施方案中,R16为3至10元环状基团,其中所述环状基团可任选地被取代。在一个实施方案中,R16为4至7元单环基团,其中所述单环基团可任选地被取代。在一个实施方案中,R16为4至6元单环杂环基团,其中所述单环杂环基团可任选地被取代。通常,单环杂环基团包含一个或多个(如一个、两个或三个)氮原子。在一个实施方案中,R16为环烷基、环烯基、非芳族杂环、芳基或杂芳基,所述基团全部可任选地被取代。在一个实施方案中,R16为环丙基、环丁基、环戊基、环己基、苯基、萘基、氮杂环丁烯基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、二氧杂环戊烷基、氧硫杂环戊烷基、哌啶基、四氢吡喃基、噻烷基、哌嗪基、二噁烷基、二噻烷基、吗啉基、硫代吗啉基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、噁三唑基或噻三唑基,所述基团全部可任选地被取代。在一个实施方案中,R16为氮杂环丁烷基、吡咯烷基、哌啶基、吡咯基、吡唑基或咪唑基,所述基团全部可任选地被取代。在一个实施方案中,R16为氮杂环丁烷基或吡唑基,所述基团均可任选地被取代。
在一个实施方案中,R16为C1-C15烷基、C2-C15烯基或C2-C15炔基,所述基团全部可任选地被取代,并且所有基团全部在其碳骨架中可任选地包含一个或多个(如一个、两个或三个)杂原子N、O或S。
在一个实施方案中,R16被一个或多个(如一个、两个或三个)独立地选自以下的取代基取代:-Rα-卤基;-Rα-CN;-Rα-NO2;-Rα-N3;-Rα-Rβ;-Rα-OH;-Rα-ORβ;-Rα-SH;-Rα-SRβ;-Rα-SORβ;-Rα-SO2H;-Rα-SO2Rβ;-Rα-SO2NH2;-Rα-SO2NHRβ;-Rα-SO2N(Rβ)2;-Rα-Si(Rβ)3;-Rα-O-Si(Rβ)3;-Rα-NH2;-Rα-NHRβ;-Rα-N(Rβ)2;-Rα-N+(Rβ)3;-Rα-CHO;-Rα-CORβ;-Rα-COOH;-Rα-COORβ;-Rα-OCORβ;-Rα-CONH2;-Rα-CONHRβ;-Rα-CON(Rβ)2;和氧代基(=O);
其中每个-Rα-独立地选自键或亚烷基、亚烯基或亚炔基,其中亚烷基、亚烯基或亚炔基在其主链中含有1至6个原子,其中亚烷基、亚烯基或亚炔基的主链中的一个或多个碳原子可任选地被一个或多个(如一个、两个或三个)杂原子N、O或S替代,并且其中亚烷基、亚烯基或亚炔基可任选地被一个或多个(如一个、两个或三个)卤基和/或-Rβ基团取代;并且
其中每个-Rβ独立选自C1-C6烷基、C2-C6烯基、C2-C6炔基或4至6元杂环基团,或者其中连接至同一氮原子的任何两个-Rβ可与它们所连接的氮原子一起形成4至6元杂环基团,并且其中任何-Rβ可任选地被一个或多个(如一个、两个或三个)C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、C3-C7卤代环烷基、-O(C1-C4烷基)-O(C1-C4卤代烷基)、-O(C3-C7环烷基)、-O(C3-C7卤代环烷基)、-CO(C1-C4烷基)、-CO(C1-C4卤代烷基)、-COO(C1-C4烷基)、-COO(C1-C4卤代烷基)、卤基、-OH、-NH2、-CN、-C≡CH或氧代基(=O)。
在一个实施方案中,R16被一个或多个(如一个、两个或三个)独立地选自以下的取代基取代:-Rα-卤基;-Rα-CN;-Rα-NO2;-Rα-N3;-Rα-Rβ;-Rα-OH;-Rα-ORβ;-Rα-SH;-Rα-SRβ;-Rα-SORβ;-Rα-SO2H;-Rα-SO2Rβ;-Rα-SO2NH2;-Rα-SO2NHRβ;-Rα-SO2N(Rβ)2;-Rα-Si(Rβ)3;-Rα-O-Si(Rβ)3;-Rα-NH2;-Rα-NHRβ;-Rα-N(Rβ)2;-Rα-N+(Rβ)3;-Rα-CHO;-Rα-CORβ;-Rα-COOH;-Rα-COORβ;-Rα-OCORβ;-Rα-CONH2;-Rα-CONHRβ;-Rα-CON(Rβ)2;和氧代基(=O);
其中每个-Rα-独立地选自键或C1-C6亚烷基;并且
其中每个-Rβ独立地选自任选地被一个或多个(如一个、两个或三个)卤基、-OH、-NH2、-CN或氧代基(=O)取代的C1-C6烷基。
在一个实施方案中,R16被一个或两个C1-C4烷基取代。在一个实施方案中,R16被一个甲基、乙基、正丙基或异丙基取代。
在一个实施方案中,R17为芳基或杂芳基(如苯基),其中芳基或杂芳基在α位被取代,并且其中R17可任选地被进一步取代。
在一个实施方案中,R17为芳基或杂芳基(如苯基),其中芳基或杂芳基在α和α’位被取代,并且其中R17可任选地被进一步取代。
R17的母体环状基团的α和/或α'位的典型取代基包含碳原子。
在一个实施方案中,R17的环状基团在α和/或α'位被C1-C6烷基和/或在α,β和/或α',β’位被-(CH2)s-取代,其中s为2、3或4。
在一个实施方案中,R17的环状基团进一步被卤基或CN取代。
在另一个实施方案中,R17为稠合芳基或稠合杂芳基(如稠合苯基),其中第一环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至芳基或杂芳基的α,β位并且第二环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至芳基或杂芳基的α',β’位,并且其中R17可任选地被进一步取代,例如被卤基或CN取代。典型地,在此类实施方案中,R17为三环。
在一个实施方案中,R17选自:
X7为H、F、Cl、Br或CN;并且
X8为F、Cl、Br或CN。
在一个实施方案中,R17选自:
在另一个实施方案中,R17为在α位被单价杂环基和单价芳族基团取代的环状基团(如苯基),其中杂环或芳族基团的环原子直接连接至环状基团的α环原子,其中杂环或芳族基团可任选地被取代,并且其中环状基团可任选地被进一步取代。
在一个实施方案中,R17的α取代的环状基团进一步在α'位被C1-C6烷基取代或在α',β’位被-(CH2)s-取代,其中s为2、3或4。
在一个实施方案中,R17的α取代的环状基团进一步被卤基或CN取代。
在一个实施方案中,α位的单价杂环或芳族基团为苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三唑基、噁二唑基、氮杂环丁烯基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、1,3-二氧杂环戊烷基、1,2-氧硫戊环基、1,3-氧硫戊环基、哌啶基、四氢吡喃基、哌嗪基、1,4-二噁烷基、噻烷基、吗啉基、硫代吗啉基或1-甲基-2-氧代-1,2-二氢吡啶基,所述这些基团均可任选地被取代。在一个实施方案中,单价杂环或芳族基团为苯基、吡啶基、嘧啶基、吡唑基、咪唑基、异噁唑基、噻唑基或四氢吡喃基,所述基团全部可任选地被取代。在一个实施方案中,单价杂环或芳族基团为苯基、吡啶基、嘧啶基或吡唑基,所述基团全部可任选地被取代。在一个实施方案中,单价杂环或芳族基团为任选地被取代的吡啶基。
在一个实施方案中,R17选自:
X9为H、F、Cl、Br或CN;并且
R18为苯基、吡啶基、嘧啶基、吡唑基、咪唑基、异噁唑基、噻唑基或四氢吡喃基,所述基团全部可任选地被取代。
在一个实施方案中,R18为苯基、吡啶基、嘧啶基或吡唑基,所述基团全部可任选地被取代。在一个实施方案中,R18为任选地被取代的吡啶基。
在一个实施方案中,α位的单价杂环或芳族基团(其可为R18)被一个或两个独立地选自卤基、-OH、-NH2、-CN、-NO2、-Rγ、-ORγ、-NHRγ或-N(Rγ)2的取代基取代,其中每个Rγ独立地选自C1-C4烷基、C2-C4烯基或C2-C4炔基,所述基团全部可任选地被卤基取代。在一个实施方案中,单价杂环或芳族基团(其可为R18)被一个或两个独立地选自卤基、-OH、-NH2、-CN、C1-C3烷基或-O(C1-C3烷基)的取代基取代。
在一个实施方案中,R17为苯基或5元或6元杂芳基(如苯基、吡啶基、哒嗪基、嘧啶基或吡嗪基);其中
(i)苯基或5元或6元杂芳基在α位被选自-R19、-OR19和-COR19的取代基取代,其中R19选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团并且其中R19任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基在α’位进一步被选自-R20、-OR20和-COR20的取代基取代,其中R20选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团并且其中R20任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基进一步被取代(典型地被一个、两个或三个独立地选自卤基、-NO2、-CN、-COOR21、-CONH2、-CONHR21或-CON(R21)2的取代基取代,其中每个-R21独立地选自C1-C4烷基或C1-C4卤代烷基);或者
(ii)苯基或5元或6元杂芳基被环烷基、环烯基、非芳族杂环、芳基或杂芳基环取代,所述环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至母体苯基或5元或6元杂芳基的α,β位并且任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基在α’位进一步被选自-R19、-OR19和-COR19的取代基取代,其中R19选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团并且其中R19任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基进一步被取代(典型地被一个或两个独立地选自卤基、-NO2、-CN、-COOR21、-CONH2、-CONHR21或-CON(R21)2的取代基取代,其中每个-R21独立地选自C1-C4烷基或C1-C4卤代烷基);或者
(iii)苯基或5元或6元杂芳基被环烷基、环烯基、非芳族杂环、芳基或杂芳基环取代,所述环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至母体苯基或5元或6元杂芳基的α,β位并且任选地被一个或多个卤基取代;并且
苯基或5元或6元杂芳基被第二环烷基、环烯基、非芳族杂环、芳基或杂芳基环取代,所述第二环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至母体苯基或5元或6元杂芳基的α',β'位并且任选地被一个或多个卤基取代;并且
任选地,苯基进一步被取代(典型地被选自卤基、-NO2、-CN、-COOR21、-CONH2、-CONHR21或-CON(R21)2的取代基取代,其中每个-R21独立地选自C1-C4烷基或C1-C4卤代烷基);或者
(iv)苯基或5元或6元杂芳基在α位被选自苯基、吡啶基、嘧啶基、吡唑基、咪唑基、三唑基或四氢吡喃基的单价杂环基或单价芳族基团取代、其中单价杂环或芳族基团可任选地被一个或两个独立地选自卤基、C1-C3烷基、C1-C3卤代烷基、-R22-OR23、-R22-N(R23)2、-R22-CN或-R22-C≡CR23的取代基取代,并且其中单价杂环或芳族基团的环原子直接连接至母体苯基或5元或6元杂芳基的α环原子;其中R22独立地选自键或C1-C3亚烷基;并且R23独立地选自氢或C1-C3烷基或C1-C3卤代烷基;并且
任选地,苯基或5元或6元杂芳基在α’位进一步被选自-R19、-OR19和-COR19的取代基取代,其中R19选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团并且其中R19任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基进一步被取代(典型地被一个、两个或三个独立地选自卤基、-NO2、-CN、-COOR21、-CONH2、-CONHR21或-CON(R21)2的取代基取代,其中每个-R21独立地选自C1-C4烷基或C1-C4卤代烷基);或者
(v)苯基或5元或6元杂芳基在α位被选自苯基、吡啶基、嘧啶基、吡唑基、咪唑基、三唑基或四氢吡喃基的单价杂环基或单价芳族基团取代、其中单价杂环或芳族基团可任选地被一个或两个独立地选自卤基、C1-C3烷基、C1-C3卤代烷基、-R22-OR23、-R22-N(R23)2、-R22-CN或-R22-C≡CR23的取代基取代,并且其中单价杂环或芳族基团的环原子直接连接至母体苯基或5元或6元杂芳基的α环原子;其中R22独立地选自键或C1-C3亚烷基;并且R23独立地选自氢或C1-C3烷基或C1-C3卤代烷基;并且
任选地,苯基或5元或6元杂芳基进一步被环烷基、环烯基、非芳族杂环、芳基或杂芳基环取代,所述环烷基、环烯基、非芳族杂环、芳基或杂芳基环稠合至母体苯基或5元或6元杂芳基的α',β'位并且任选地被一个或多个卤基取代;并且
任选地,苯基或5元或6元杂芳基进一步被取代(典型地被一个或两个独立地选自卤基、-NO2、-CN、-COOR21、-CONH2、-CONHR21或-CON(R21)2的取代基取代,其中每个-R21独立地选自C1-C4烷基或C1-C4卤代烷基)。
在本说明书的背景下,“烃基”取代基或取代基中的烃基部分仅包括碳和氢原子,但除非另外陈述,否则在其碳骨架中不包括任何杂原子,如N、O或S。烃基基团/部分可为饱和或不饱和的(包括芳族的),并且可为直链或支链的,或者为环状基团或包括环状基团,其中除非另外陈述,否则环状基团在其碳骨架中不包括任何杂原子,如N、O或S。烃基的实例包括烷基、烯基、炔基、环烷基、环烯基和芳基基团/部分以及所有这些基团/部分的组合。典型地,烃基为C1-C20烃基。更典型地,烃基为C1-C15烃基。更典型地,烃基为C1-C10烃基。“亚烃基”以类似方式定义为二价烃基。
“烷基”取代基或取代基中的烷基部分可为直链(linear)(即直链(straight-chained)的)或支链的。烷基基团/部分的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基和正戊基基团/部分。除非另外陈述,否则术语“烷基”不包括“环烷基”。典型地,烷基为C1-C12烷基。更典型地,烷基为C1-C6烷基。“亚烷基”以类似方式定义为二价烷基。
“烯基”取代基或取代基中的烯基部分是指具有一个或多个碳-碳双键的不饱和烷基基团或部分。烯基基团/部分的实例包括乙烯基、丙烯基、1-丁烯基、2-丁烯基、1-戊烯基、1-己烯基、1,3-丁二烯基、1,3-戊二烯基、1,4-戊二烯基和1,4-己二烯基基团/部分。除非另外陈述,否则术语“烯基”不包括“环烯基”。典型地,烯基为C2-C12烯基。更典型地,烯基为C2-C6烯基。“亚烯基”以类似方式定义为二价烯基。
“炔基”取代基或取代基中的炔基部分是指具有一个或多个碳-碳三键的不饱和烷基基团或部分。炔基基团/部分的实例包括乙炔基、炔丙基、丁-1-炔基和丁-2-炔基基团/部分。典型地,炔基为C2-C12炔基。更典型地,炔基为C2-C6炔基。“亚炔基”以类似方式定义为二价炔基。
“环状”取代基或取代基中的环状部分是指任何烃基环,其中烃基环可为饱和或不饱和的(包括芳族的)并且可在其碳骨架中包括一个或多个杂原子,如N、O或S。环状基团的实例包括如下文所论述的环烷基、环烯基、杂环、芳基和杂芳基。环状基团可为单环、双环(例如桥接环、稠合环或螺环)或多环。典型地,环状基团为3至12元环状基团,这意指它含有3至12个环原子。更典型地,环状基团为3至7元单环基团,这意指它含有3至7个环原子。
“杂环”取代基或取代基中的杂环部分是指在环结构中包括一个或多个碳原子以及一个或多个(如一个、两个、三个或四个)杂原子(例如N、O或S)的环状基团或部分。杂环基的实例包括如下文所论述的杂芳基和非芳族杂环基,如氮杂环丁烯基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、二氧杂环戊烷基、氧硫杂环戊烷基、哌啶基、四氢吡喃基、噻烷基、哌嗪基、二噁烷基、吗啉基和硫代吗啉基。
“环烷基”取代基或取代基中的环烷基部分是指含有(例如)3至7个碳原子的饱和烃基环,其实例包括环丙基、环丁基、环戊基和环己基。除非另外陈述,否则环烷基取代基或部分可包括单环、双环或多环烃基环。
“环烯基”取代基或取代基中的环烯基部分是指具有一个或多个碳-碳双键并且含有(例如)3至7个碳原子的非芳族不饱和烃基环,其实例包括环戊-1-烯-1-基、环己-1-烯-1-基和环己-1,3-二烯-1-基。除非另外陈述,否则环烯基取代基或部分可包括单环、双环或多环烃基环。
“芳基”取代基或取代基中的芳基部分是指芳族烃基环。术语“芳基”包括单环芳族烃和其中所有稠合环体系(不包括为任选取代基的一部分或由任选取代基形成的任何环体系)为芳族环的多环稠合环芳族烃。芳基基团/部分的实例包括苯基、萘基、蒽基和菲基。除非另外陈述,否则术语“芳基”不包括“杂芳基”。
“杂芳基”取代基或取代基中的杂芳基部分是指芳族杂环基团或部分。术语“杂芳基”包括单环芳族杂环和其中所有稠合环体系(不包括为任选取代基的一部分或由任选取代基形成的任何环体系)为芳族环的多环稠合环芳族杂环。杂芳基基团/部分的实例包括以下各项:
其中G=O、S或NH。
出于本说明书的目的,在将多个部分的组合称为一个基团时,例如芳基烷基、芳基烯基、芳基炔基、烷基芳基、烯基芳基或炔基芳基,最后提到的部分含有如下原子,所述基团通过所述原子连接至分子的其余部分。芳基烷基的实例为苄基。
典型地,取代的基团包含1、2、3或4个取代基,更典型地1、2或3个取代基,更典型地1或2个取代基,并且更典型地1个取代基。
术语“卤基”包括氟基、氯基、溴基和碘基。
除非另外陈述,否则当基团以术语“卤基”为前缀时(如卤代烷基或卤代甲基),应理解,所讨论的基团被一个或多个独立地选自氟基、氯基、溴基和碘基的卤基取代。典型地,卤基取代基的最大数目仅受不含卤基前缀的相应基团上可用于取代的氢原子数的限制。举例来说,卤代甲基可含有一个、两个或三个卤基取代基。卤代乙基或卤代苯基可含有一个、两个、三个、四个或五个卤基取代基。类似地,除非另外陈述,否则当基团以特定卤基为前缀时,应理解,所讨论的基团被一个或多个特定卤基取代。举例来说,术语“氟甲基”是指被一个、两个或三个氟基团取代的甲基。
除非另外陈述,否则当称基团为“卤基取代的”时,应理解,所讨论的基团被一个或多个独立地选自氟基、氯基、溴基和碘基的卤基取代。典型地,卤基取代基的最大数目仅受被称为卤基取代的基团上可用于取代的氢原子数的限制。举例来说,卤基取代的甲基可含有一个、两个或三个卤基取代基。卤基取代的乙基或卤基取代的苯基可含有一个、两个、三个、四个或五个卤基取代基。
除非另外陈述,否则任何提到一种元素的地方应被视为提到所述元素的所有同位素。因此,例如,除非另外陈述,否则任何提到氢的地方应被视为涵盖氢的所有同位素,包括氘和氚。
在本说明书的背景下,除非另外陈述,否则Cx-Cy基团定义为含有x至y个碳原子的基团。举例来说,C1-C4烷基定义为含有1至4个碳原子的烷基。在计算被任选取代基取代和/或含有任选部分的母体基团中的碳原子总数时,不将任选取代基和部分考虑在内。为免生疑问,在计算Cx-Cy基团中的碳原子数时,不将替代杂原子(例如N、O或S)计数为碳原子。举例来说,将吗啉基视为C6杂环基而非C4杂环基。
出于本说明书的目的,在陈述第一原子或基团“直接连接”至第二原子或基团时,应理解,第一原子或基团共价键合至第二原子或基团并且不存在一个或多个间插原子或基团。因此例如,对于基团(C=O)N(CH3)2,每个甲基的碳原子直接连接至氮原子并且羰基的碳原子直接连接至氮原子,但羰基的碳原子不直接连接至任一甲基的碳原子。
本发明的第二方面提供一种选自由以下组成的组的化合物:
本发明的第三方面提供本发明第一方面或第二方面的任一化合物的药学上可接受的盐、溶剂合物或前药。
本发明的化合物可以其游离碱形式和其酸加成盐形式使用。出于本发明的目的,本发明化合物的“盐”包括酸加成盐。酸加成盐优选为与合适酸的药学上可接受的无毒加成盐,所述酸包括但不限于无机酸,如氢卤酸(例如氢氟酸、盐酸、氢溴酸或氢碘酸)或其他无机酸(例如硝酸、高氯酸、硫酸或磷酸);或有机酸,如有机羧酸(例如丙酸、丁酸、羟乙酸、乳酸、扁桃酸、柠檬酸、乙酸、苯甲酸、水杨酸、琥珀酸、苹果酸或羟基琥珀酸、酒石酸、富马酸、马来酸、羟基马来酸、粘酸或半乳糖二酸、葡萄糖酸、泛酸或扑酸)、有机磺酸(例如甲烷磺酸、三氟甲烷磺酸、乙烷磺酸、2-羟基乙烷磺酸、苯磺酸、对甲苯磺酸、萘-2-磺酸或樟脑磺酸)或氨基酸(例如鸟氨酸、谷氨酸或天冬氨酸)。酸加成盐可为单酸、二酸、三酸或多酸加成盐。优选盐为氢卤酸、硫酸、磷酸或有机酸加成盐。优选盐为盐酸加成盐。
当本发明的化合物包括季铵基团时,典型地化合物以其盐形式使用。季铵基团的反离子可为任何药学上可接受的无毒反离子。合适反离子的实例包括上文所论述与酸加成盐相关的质子酸的共轭碱。
本发明的化合物还可以其游离酸形式和其盐形式使用。出于本发明的目的,本发明化合物的“盐”包括在本发明化合物的质子酸官能团(如羧酸基团)与合适阳离子之间形成的盐。合适阳离子包括但不限于锂、钠、钾、镁、钙和铵。盐可为单盐、二盐、三盐或多盐。优选地,盐为单锂盐、单钠盐、单钾盐、单镁盐、单钙盐或单铵盐或者二锂盐、二钠盐、二钾盐、二镁盐、二钙盐或二铵盐。更优选地,盐为单钠盐或二钠盐或者单钾盐或二钾盐。
优选地,任一盐为药学上可接受的无毒盐。然而,除药学上可接受的盐之外,本发明中还包括其他盐,因为它们可用作纯化或制备其他(例如)药学上可接受的盐的中间体,或可用于鉴定、表征或纯化游离酸或碱。
本发明的化合物和/或盐可为无水的或呈水合物(例如半水合物、单水合物、二水合物或三水合物)或其他溶剂合物形式。此类其他溶剂合物可使用常用有机溶剂来形成,所述常用有机溶剂包括但不限于醇溶剂,例如甲醇、乙醇或异丙醇。
在本发明的一些实施方案中,提供治疗上无活性的前药。前药为在向受试者(如人)施用时整体或部分转化成本发明化合物的化合物。在大多数实施方案中,前药为药理学惰性的化学衍生物,所述化学衍生物可在体内转化成活性药物分子以发挥治疗作用。可以前药形式施用本文所述的任一化合物以增加化合物的活性、生物利用度或稳定性或以其他方式改变化合物的特性。前药的典型实例包括在活性化合物的功能部分上具有生物不稳定保护基团的化合物。前药包括但不限于可氧化、还原、胺化、去胺、羟基化、去羟基化、水解、脱水、烷基化、去烷基化、酰化、去酰化、磷酸化和/或去磷酸化以产生活性化合物的化合物。本发明还涵盖如上文所述的此类前药的盐和溶剂合物。
本发明的化合物、盐、溶剂合物和前药可含有至少一个手性中心。因此,所述化合物、盐、溶剂合物和前药可以至少两种异构形式存在。本发明涵盖本发明的化合物、盐、溶剂合物和前药以及对映体富集的和基本上光学纯的异构体的外消旋混合物。出于本发明的目的,化合物的“大体上光学纯”的异构体包含相同化合物的以重量计小于5%的其他异构体,更典型地小于2%,并且最典型地小于0.5%。
本发明的化合物、盐、溶剂合物和前药可含有任何稳定同位素,包括但不限于12C、13C、1H、2H(D)、14N、15N、16O、17O、18O、19F和127I;以及任何放射性同位素,包括但不限于11C、14C、3H(T)、13N、15O、18F、123I、124I、125I和131I。
本发明的化合物、盐、溶剂合物和前药可呈任何多晶形或无定形形式。
本发明的第四方面提供一种药物组合物,所述药物组合物包含本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药,和药学上可接受的赋形剂。
例如“Aulton’s Pharmaceutics-The Design and Manufacture of Medicines”,M.E.Aulton and K.M.G.Taylor,Churchill Livingstone Elsevier,第4版,2013中描述了选择和制备合适药物制剂的常规程序。
可用于本发明药物组合物中的药学上可接受的赋形剂(包括佐剂、稀释剂或载体)为常用于药物配制领域的那些药学上可接受的赋形剂,并且包括但不限于糖、糖醇、淀粉、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(例如磷酸盐)、甘油、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
在一个实施方案中,本发明第四方面的药物组合物另外包含一种或多种其他活性剂。
在另一个实施方案中,本发明第四方面的药物组合物可作为多部分药盒的一部分来提供,其中所述多部分药盒包含本发明第四方面的药物组合物和一种或多种其他药物组合物,其中所述一种或多种其他药物组合物各自包含药学上可接受的赋形剂和一种或多种其他活性剂。
本发明的第五方面提供本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物,所述化合物、所述药学上可接受的盐、溶剂合物或前药、所述药物组合物用于医学中,和/或用于疾病、病症或疾患的治疗或预防中。典型地,所述使用包括向受试者施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,所述使用包括共同施用一种或多种其他活性剂。
如本文所用的术语“治疗”同等地指治愈性疗法和改善或姑息性疗法。所述术语包括获得有益或期望的生理学结果,所述结果可为或可不为临床上确定的。有益或期望的临床结果包括但不限于可检测或不可检测的症状缓和、症状预防、疾病程度减轻、疾患稳定(即不加剧)、疾患/症状进展/加剧的延迟或减慢、疾患/症状改善或缓解和减退(无论部分还是全部)。如本文所用的术语“缓解”及其变化形式意指与不施用本发明的化合物、盐、溶剂合物、前药或药物组合物相比,减轻生理学疾患或症状的程度和/或不希望的表现和/或减慢或延长进展的时程。如本文所用与疾病、病症或疾患相关的术语“预防”是指预防性(prophylactic)或防预性(preventative)疗法以及降低发展疾病、病症或疾患的风险的疗法。术语“预防”包括避免疾病、病症或疾患的发生与延迟疾病、病症或疾患的发作两者。如通过受控临床试验测量的任何统计学显著(p≤0.05)的发生避免、发作延迟或风险降低均可被视为疾病、病症或疾患的预防。适合预防的受试者包括如通过遗传或生物化学标记物所鉴定疾病、病症或疾患的风险加重的那些受试者。典型地,遗传或生物化学标记物适用于所考虑的疾病、病症或疾患并且可包括(例如)炎症性生物标记物,如C反应蛋白(CRP)和单核细胞趋化蛋白1(MCP-1),在炎症的情况下;总胆固醇、甘油三酯、胰岛素抗性和C肽,在NAFLD和NASH的情况下;和更一般地IL-1β和IL-18,在对NLRP3抑制有响应的疾病、病症或疾患的情况下。
本发明的第六方面提供第一方面或第二方面的化合物、或第三方面的药学上有效的盐、溶剂合物或前药在制造用于治疗或预防疾病、病症或疾患的药剂中的用途。典型地,治疗或预防包括向受试者施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,治疗或预防包括共同施用一种或多种其他活性剂。
本发明的第七方面提供一种治疗或预防疾病、病症或疾患的方法,所述方法包括以下步骤:施用有效量的第一方面或第二方面的化合物、或第三方面的药学上可接受的盐、溶剂合物或前药、或第四方面的药物组合物,由此治疗或预防疾病、病症或疾患。在一个实施方案中,所述方法还包括共同施用有效量的一种或多种其他活性剂的步骤。典型地,施用是针对有需要的受试者。
本发明的第八方面提供本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物,所述化合物、所述药学上可接受的盐、溶剂合物或前药、所述药物组合物用于个体的疾病、病症或疾患的治疗或预防中,其中个体具有NLRP3的种系或体细胞非沉默突变。突变可以是例如功能获得型突变或使NLRP3活性增加的其他突变。典型地,所述使用包括向个体施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,所述使用包括共同施用一种或多种其他活性剂。所述使用还可包括诊断具有NLRP3的种系或体细胞非沉默突变的个体,其中化合物、盐、溶剂合物、前药或药物组合物是基于突变的阳性诊断而向个体施用。典型地,可通过任何合适遗传或生物化学方法来进行个体中NLRP3突变的鉴定。
本发明的第九方面提供第一方面或第二方面的化合物、或第三方面的药学上有效的盐、溶剂合物或前药在制造用于治疗或预防个体的疾病、病症或疾患的药剂中的用途,其中个体具有NLRP3的种系或体细胞非沉默突变。突变可以是例如功能获得型突变或使NLRP3活性增加的其他突变。典型地,所述治疗或预防包括向个体施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,所述治疗或预防包括共同施用一种或多种其他活性剂。所述治疗或预防还可包括诊断具有NLRP3的种系或体细胞非沉默突变的个体,其中化合物、盐、溶剂合物、前药或药剂是基于突变的阳性诊断而向个体施用。典型地,可通过任何合适遗传或生物化学方法来进行个体中NLRP3突变的鉴定。
本发明的第十方面提供一种治疗或预防疾病、病症或疾患的方法,所述方法包括以下步骤:诊断具有NLRP3的种系或体细胞非沉默突变的个体,以及向阳性诊断的个体施用有效量的第一方面或第二方面的化合物、或第三方面的药学上可接受的盐、溶剂合物或前药、或第四方面的药物组合物,由此治疗或预防疾病、病症或疾患。在一个实施方案中,所述方法还包括共同施用有效量的一种或多种其他活性剂的步骤。典型地,施用是针对有需要的受试者。
在一般实施方案中,疾病、病症或疾患可以是免疫系统、心血管系统、内分泌系统、胃肠道、肾系统、肝系统、代谢系统、呼吸系统、中枢神经系统的疾病、病症或疾患,可以是癌症或其他恶性肿瘤,和/或可由病原体引起或与病原体相关。
应了解,根据广泛类别的疾病、病症和疾患定义的这些一般实施方案并不互斥。就这一点而言,任何特定疾病、病症或疾患均可根据上述一般实施方案中的超过一者加以分类。非限制性实例为I型糖尿病,I型糖尿病是自身免疫性疾病和内分泌系统疾病。
在本发明第五、第六、第七、第八、第九或第十方面的一个实施方案中,疾病、病症或疾患对NLRP3抑制有响应。如本文所用,术语“NLRP3抑制”是指完全或部分降低NLRP3的活性水平并且包括例如抑制活性NLRP3和/或抑制NLRP3的活化。
有证据表明,NLRP3诱导的IL-1和IL-18在与多种不同病症相关或由多种不同病症引起的炎症应答中发挥作用(Menu等人,Clinical and Experimental Immunology,166:1–15,2011;Strowig等人,Nature,481:278-286,2012)。
已显现NLRP3作用的遗传性疾病包括镰状细胞病(Vogel等人,Blood,130(Suppl1):2234,2017)和含缬酪肽蛋白病(Valosin Containing Protein disease)(Nalbandian等人,Inflammation,40(1):21-41,2017)。
NLRP3已参与多种自身炎症性疾病,包括家族性地中海热(FMF)、TNF受体相关的周期性综合征(TRAPS)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、化脓性关节炎、坏疽性脓皮病和痤疮(PAPA)、斯威特氏综合征(Sweet's syndrome)、慢性非细菌性骨髓炎(CNO)和寻常性痤疮(Cook等人,Eur.J.Immunol.,40:595-653,2010)。具体来说,已发现NLRP3突变负责一组罕见的自身炎症性疾病,称为CAPS(Ozaki等人,J.Inflammation Research,8:15-27,2015;Schroder等人,Cell,140:821-832,2010;以及Menu等人,Clinical andExperimental Immunology,166:1-15,2011)。CAPS是以回归热和炎症为特征的可遗传疾病并且包含三种形成临床连续体的自身炎症性病症。这些疾病按严重程度递增的顺序为家族性寒冷型自身炎症性综合征(FCAS)、穆-韦二氏综合征(MWS)和慢性婴儿型皮肤神经关节综合征(CINCA;也称为新生儿发作型多系统炎症性疾病,NOMID),并且已显示所有这些疾病都由NLRP3基因的功能获得型突变引起,这些突变使得IL-1β的分泌增加。
已显示多种自身免疫性疾病涉及NLRP3,具体来说包括多发性硬化、1型糖尿病(T1D)、牛皮癣、类风湿性关节炎(RA)、白塞氏病(Behcet's disease)、薛尼兹勒氏综合征(Schnitzler’s syndrome)、巨噬细胞活化综合征(Masters,Clin Immunol,147(3):223-228,2013;Braddock等人,Nat Rev Drug Disc,3:1-10,2004;Inoue等人,Immunology,139:11-18,2013;Coll等人,Nat Med,21(3):248-55,2015;Scott等人,Clin Exp Rheumatol,34(1):88-93,2016;和Guo等人,Clin Exp Immunol,194(2):231-243,2018);系统性红斑狼疮(Lu等人,J Immunol,198(3):1119-29,2017),包括狼疮性肾炎(Zhao等人,Arthritis andRheumatism,65(12):3176-3185,2013)、多发性硬化(Xu等人,J Cell Biochem,120(4):5160-5168,2019)和系统性硬化(Artlett等人,Arthritis Rheum,63(11):3563-74,2011)。
还已显示NLRP3在多种肺病中起作用,所述肺病包括慢性阻塞性肺病(COPD)、哮喘(包括类固醇抗性哮喘和嗜酸细胞性哮喘)、石棉肺和硅肺(De Nardo等人,Am J Pathol,184:42-54,2014;Lv等人,J Biol Chem,293(48):18454,2018;和Kim等人,Am J RespirCrit Care Med,196(3):283-97,2017)。
还已表明NLRP3在多种中枢神经系统疾患中起作用,所述疾患包括帕金森氏病(Parkinson's disease,PD)、阿兹海默氏病(AD)、痴呆、亨廷顿氏病(Huntington'sdisease)、脑型疟疾、来自肺炎球菌脑膜炎的脑损伤(Walsh等人,Nature Reviews,15:84-97,2014和Dempsey等人,Brain Behav Immun,61:306-316,2017)、颅内动脉瘤(Zhang等人,J Stroke&Cerebrovascular Dis,24(5):972-979,2015)、脑内出血(ICH)(Ren等人,Stroke,49(1):184-192,2018)、脑缺血再灌注损伤(Fauzia等人,Front Pharmacol,9:1034,2018;Hong等人,Neural Plasticity,2018:8,2018;Ye等人,ExperimentalNeurology,292:46-55,2017)、全身麻醉神经炎症(Fan等人,Front Cell Neurosci,12:426,2018)、败血症相关性脑病(SAE)(Fu等人,Inflammation,42(1):306-318,2019)、术后认知功能障碍(POCD)(Fan等人,Front Cell Neurosci,12:426,2018)、早期脑损伤(蛛网膜下腔出血SAH)(Luo等人,Brain Res Bull,146:320-326,2019)和创伤性脑损伤(Ismael等人,J Neurotrauma,35(11):1294-1303,2018)。
还已显示NRLP3活性参与多种代谢疾病,包括2型糖尿病(T2D)、动脉粥样硬化、肥胖症、痛风、假性痛风、代谢综合征(Wen等人,Nature Immunology,13:352-357,2012;Duewell等人,Nature,464:1357-1361,2010;Strowig等人,Nature,481:278-286,2012)和非酒精性脂肪性肝炎(NASH)(Mridha等人,J Hepatol,66(5):1037-46,2017)。
动脉粥样硬化、心肌梗塞(van Hout等人,Eur Heart J,38(11):828-36,2017)、心血管疾病(Janoudi等人,European Heart Journal,37(25):1959-1967,2016)、心脏肥大和纤维化(Gan等人,Biochim Biophys Acta,1864(1):1-10,2018)、心力衰竭(Sano等人,J AmColl Cardiol,71(8):875-66,2018)、主动脉瘤和剥离(Wu等人,Arterioscler ThrombVasc Biol,37(4):694-706,2017)、代谢功能障碍引起的心脏损伤(Pavillard等人,Oncotarget,8(59):99740-99756,2017)、心房纤颤(Yao等人,Circulation,138(20):2227-2242,2018)、高血压(Gan等人,Biochim Biophys Acta,1864(1):1-10,2018)以及其他心血管事件(Ridker等人,N Engl J Med,doi:10.1056/NEJMoa1707914,2017)中也已显露NLRP3借助IL-1β的作用。
已显示NLRP3参与的其他疾病包括:
-眼病,如湿式与干式年龄相关性黄斑变性两者(Doyle等人,Nature Medicine,18:791-798,2012;和Tarallo等人,Cell,149(4):847-59,2012)、糖尿病性视网膜病变(Loukovaara等人,Acta Ophthalmol,95(8):803-808,2017)和视神经损伤(Puyang等人,Sci Rep,6:20998,2016年2月19日);
-肝病,包括非酒精性脂肪性肝炎(NASH)(Henao-Meija等人,Nature,482:179-185,2012)、肝脏缺血再灌注损伤(Yu等人,Transplantation,103(2):353-362,2019)、暴发性肝炎(Pourcet等人,Gastroenterology,154(5):1449-1464,e20,2018)、肝纤维化(Zhang等人,Parasit Vectors,12(1):29,2019)和肝衰竭(包括急性肝衰竭)(Wang等人,HepatolRes,48(3):E194-E202,2018);
-肾病,包括肾钙质沉着症(Anders等人,Kidney Int,93(3):656-669,2018)、肾纤维化(包括慢性结晶肾病变)(Ludwig-Portugall等人,Kidney Int,90(3):525-39,2016)和肾性高血压(Krishnan等人,Br J Pharmacol,173(4):752-65,2016;Krishnan等人,Cardiovasc Res,115(4):776-787,2019;Dinh等人,Aging,9(6):1595-1606,2017);
-与糖尿病相关的疾患,包括糖尿病性脑病(Zhai等人,Molecules,23(3):522,2018)、糖尿病性视网膜病变(Zhang等人,Cell Death Dis,8(7):e2941,2017)和糖尿病性低脂联素血症(Zhang等人,Biochimica et Biophysica Acta(BBA)-Molecular Basis ofDisease,1863(6):1556-1567,2017);
-肺和皮肤中的炎症反应(Primiano等人,J Immunol,197(6):2421-33,2016),包括肺缺血再灌注损伤(Xu等人,Biochemical and Biophysical ResearchCommunications,503(4):3031-3037,2018)、上皮细胞向间充质细胞转化(EMT)(Li等人,Experimental Cell Research,362(2):489-497,2018)、接触性超敏反应(如大疱性类天疱疮(Fang等人,J Dermatol Sci,83(2):116-23,2016))、特应性皮炎(Niebuhr等人,Allergy,69(8):1058-67,2014)、化脓性汗腺炎(Alikhan等人,J Am Acad Dermatol,60(4):539-61,2009)、寻常性痤疮(Qin等人,J Invest Dermatol,134(2):381-88,2014)和结节病(Jager等人,Am J Respir Crit Care Med,191:A5816,2015);
-关节中的炎症反应(Braddock等人,Nat Rev Drug Disc,3:1-10,2004)和骨关节炎(Jin等人,PNAS,108(36):14867-14872,2011);
-肌萎缩性脊髓侧索硬化症(Gugliandolo等人,Inflammation,41(1):93-103,2018);
-囊性纤维化(Iannitti等人,Nat Commun,7:10791,2016);
-中风(Walsh等人,Nature Reviews,15:84-97,2014;Ye等人,ExperimentalNeurology,292:46-55,2017);
-慢性肾病(Granata等人,PLoS One,10(3):e0122272,2015);
-镰状细胞病(Vogel等人,Blood,130(Suppl 1):2234,2017);以及
-结肠炎和炎症性肠病,包括溃疡性结肠炎和克罗恩氏病(Braddock等人,Nat RevDrug Disc,3:1-10,2004;Neudecker等人,J Exp Med,214(6):1737-52,2017;Wu等人,Mediators Inflamm,2018:3048532,2018;和Lazaridis等人,Dig Dis Sci,62(9):2348-56,2017)和败血症(肠上皮破裂)(Zhang等人,Dig Dis Sci,63(1):81-91,2018)。
已显示NLRP3的基因消融可预防HSD(高糖饮食)、HFD(高脂饮食)和HSFD诱导的肥胖症(Pavillard等人,Oncotarget,8(59):99740-99756,2017)。
已发现NLRP3炎性体响应于氧化压力、晒伤(Hasegawa等人,Biochemical andBiophysical Research Communications,477(3):329-335,2016)和UVB辐射(Schroder等人,Science,327:296-300,2010)而活化。
还已显示NLRP3参与炎症性痛觉过敏(Dolunay等人,Inflammation,40:366-386,2017)、伤口愈合(Ito等人,Exp Dermatol,27(1):80-86,2018)、疼痛(包括多发性硬化相关的神经性疼痛)(Khan等人,Inflammopharmacology,26(1):77-86,2018)和早产相关的羊膜内炎症/感染(Faro等人,Biol Reprod,100(5):1290-1305,2019;和Gomez-Lopez等人,BiolReprod,100(5):1306-1318,2019)。
还已提出炎性体、且特别是NLRP3是由包括以下的各种病原体调节的靶标:细菌病原体,如金黄色葡萄球菌(Cohen等人,Cell Reports,22(9):2431-2441,2018)、蜡状芽孢杆菌(Mathur等人,Nat Microbiol,4:362-374,2019)、鼠伤寒沙门氏菌(Diamond等人,SciRep,7(1):6861,2017)和A群链球菌(LaRock等人,Science Immunology,1(2):eaah3539,2016);病毒,如DNA病毒(Amsler等人,Future Virol,8(4):357-370,2013)、甲型流感病毒(Coates等人,Front Immunol,8:782,2017)、基孔肯雅病病毒(chikungunya virus)、罗氏河病毒(Ross River virus)和α病毒(Chen等人,Nat Microbiol,2(10):1435-1445,2017);真菌病原体,如白色念珠菌(Tucey等人,mSphere,1(3),pii:e00074-16,2016);以及其他病原体,如刚地弓形虫(T.gondii)(Gov等人,J Immunol,199(8):2855-2864,2017)、蠕虫(Alhallaf等人,Cell Reports,23(4):1085-1098,2018)、利什曼原虫(Novais等人,PLoSPathogens,13(2):e1006196,2017)和疟原虫(Strangward等人,PNAS,115(28):7404-7409,2018)。已显示NLRP3为有效控制病毒、细菌、真菌和蠕虫病原体感染所必需的(Strowig等人,Nature,481:278-286,2012)。
NLRP3还参与许多癌症的发病机制(Menu等人,Clinical and ExperimentalImmunology,166:1-15,2011;和Masters,Clin Immunol,147(3):223-228,2013)。举例来说,若干先前研究已表明IL-1β在癌症侵袭、生长和转移中的作用,并且已显示在随机化、双盲、安慰剂对照试验中用卡那单抗抑制IL-1β可降低肺癌的发病率和总癌症死亡率(Ridker等人,Lancet,S0140-6736(17)32247-X,2017)。还已显示抑制NLRP3炎性体或IL-1β会抑制体外肺癌细胞的增殖和迁移(Wang等人,Oncol Rep,35(4):2053-64,2016)。NLRP3炎性体的作用在骨髓增生异常综合征(Basiorka等人,Blood,128(25):2960-2975,2016)以及包括以下各项的各种其他癌症的致癌作用:神经胶质瘤(Li等人,Am J Cancer Res,5(1):442-449,2015)、结肠癌(Allen等人,J Exp Med,207(5):1045-56,2010)、黑素瘤(Dunn等人,Cancer Lett,314(1):24-33,2012)、乳腺癌(Guo等人,Scientific Reports,6:36107,2016)、炎症诱导的肿瘤(Allen等人,J Exp Med,207(5):1045-56,2010;和Hu等人,PNAS,107(50):21635-40,2010)、多发性骨髓瘤(Li等人,Hematology,21(3):144-51,2016)和头颈部鳞状细胞癌(Huang等人,J Exp Clin Cancer Res,36(1):116,2017)。还已显示NLRP3炎性体活化介导肿瘤细胞对5-氟尿嘧啶的化学抗性(Feng等人,J Exp Clin Cancer Res,36(1):81,2017),并且周围神经中NLRP3炎性体的活化导致化学疗法诱发的神经性疼痛(Jia等人,Mol Pain,13:1-11,2017)。
因此,可对NLRP3抑制有响应并且可根据本发明的第五、第六、第七、第八、第九或第十方面治疗或预防的疾病、病症或疾患的实例包括:
(i)炎症,包括由炎症性病症(例如自身炎症性疾病)引起的炎症、作为非炎症性病症的症状出现的炎症、由感染引起的炎症或继发于创伤、损伤或自身免疫性的炎症;
(ii)自身免疫性疾病,例如急性播散性脑炎、艾迪生氏病(Addison's disease)、强直性脊柱炎、抗磷脂抗体综合征(APS)、抗合成酶综合征、再生不良性贫血、自身免疫性肾上腺炎、自身免疫性肝炎、自身免疫性卵巢炎、自身免疫性多腺体衰竭、自身免疫性甲状腺炎、乳糜泻、克罗恩氏病、1型糖尿病(T1D)、古巴士德氏综合征(Goodpasture's syndrome)、格雷氏病(Graves'disease)、格林-巴利综合征(Guillain-Barrésyndrome,GBS)、桥本氏病(Hashimoto's disease)、特发性血小板减少性紫癜、川崎病(Kawasaki's disease)、红斑狼疮(包括系统性红斑狼疮(SLE))、多发性硬化(MS)(包括原发性进展性多发性硬化(PPMS))、继发性进展性多发性硬化(SPMS)和复发性缓解型多发性硬化(RRMS)、重症肌无力、眼阵挛肌阵挛综合征(OMS)、视神经炎、奥德氏甲状腺炎(Ord's thyroiditis)、天疱疮、恶性贫血、多发性关节炎、原发性胆汁性肝硬化、类风湿性关节炎(RA)、牛皮癣关节炎、幼年特发性关节炎或史迪尔氏病(Still's disease)、难治性痛风性关节炎、莱特氏综合征(Reiter's syndrome)、舍格伦氏综合征(syndrome)、全身性硬化、全身性结缔组织病症、高安氏动脉炎(Takayasu's arteritis)、颞动脉炎、温抗体型自身免疫性溶血性贫血、韦格纳氏肉芽肿(Wegener's granulomatosis)、普秃、白塞氏病、查加斯氏病(Chagas’disease)、自主神经障碍、子宫内膜异位症、化脓性汗腺炎(HS)、间质性膀胱炎、神经性肌强直、牛皮癣、结节病、硬皮症、溃疡性结肠炎、薛尼兹勒氏综合征、巨噬细胞活化综合征、布劳综合征(Blau syndrome)、白斑病或外阴痛症;
(iii)癌症,包括肺癌、胰腺癌、胃癌、骨髓增生异常综合征、白血病(包括急性淋巴细胞性白血病(ALL)和急性骨髓性白血病(AML))、肾上腺癌、肛门癌、基底和鳞状细胞皮肤癌、头颈部鳞状上皮细胞癌、胆管癌、膀胱癌、骨癌、脑和脊髓肿瘤、乳腺癌、子宫颈癌、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓单核细胞性白血病(CMML)、结肠直肠癌、子宫内膜癌、食管癌、尤恩氏肿瘤家族(Ewing family of tumours)、眼癌、胆囊癌、胃肠类癌瘤、胃肠基质瘤(GIST)、妊娠滋养细胞疾病、神经胶质瘤、霍奇金氏淋巴瘤、卡波西肉瘤(Kaposi sarcoma)、肾癌、喉和下咽癌、肝癌、肺类癌瘤、淋巴瘤(包括皮肤T细胞淋巴瘤)、恶性间皮瘤、黑素瘤皮肤癌、默克细胞皮肤癌(Merkel cell skin cancer)、多发性骨髓瘤、鼻腔和副鼻窦癌、鼻咽癌、神经胚细胞瘤、非霍奇金氏淋巴瘤、非小细胞肺癌、口腔和口咽癌、骨肉瘤、卵巢癌、阴茎癌、垂体瘤、前列腺癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、胃癌、睪丸癌、胸腺癌、甲状腺癌(包括甲状腺未分化癌)、子宫肉瘤、阴道癌、外阴癌、华氏巨球蛋白血症(Waldenstrommacroglobulinemia)和威尔姆氏瘤(Wilms tumour);
(iv)感染,包括病毒感染(例如来自流感病毒、人免疫缺陷病毒(HIV)、α病毒(如基孔肯雅病病毒和罗氏河病毒)、黄病毒(如登革热病毒(Dengue virus)和兹卡病毒(Zikavirus))、疱疹病毒(如爱波斯坦-巴尔病毒(Epstein Barr Virus)、巨细胞病毒、水痘带状疱疹病毒和KSHV)、痘病毒(如痘苗病毒(改良的痘苗病毒安卡拉(Ankara))和粘液瘤病毒)、腺病毒(如腺病毒5)或乳头瘤病毒);细菌性感染(例如来自金黄色葡萄球菌(Staphylococcus aureus)、幽门螺旋杆菌(Helicobacter pylori)、炭疽杆菌(Bacillusanthracis)、蜡状芽孢杆菌(Bacillus cereus)、百日咳博德氏菌(Bordatellapertussis)、类鼻疽伯克氏菌(Burkholderia pseudomallei)、白喉棒状杆菌(Corynebacterium diptheriae)、破伤风梭菌(Clostridium tetani)、肉毒杆菌(Clostridium botulinum)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、单核细胞增多性李斯特菌(Listeria monocytogenes)、流感嗜血杆菌(Hemophilus influenzae)、败血性巴氏杆菌(Pasteurella multicida)、痢疾志贺杆菌(Shigella dysenteriae)、结核分枝杆菌(Mycobacterium tuberculosis)、麻疯分枝杆菌(Mycobacterium leprae)、肺炎霉浆菌(Mycoplasma pneumoniae)、人霉浆菌(Mycoplasma hominis)、脑膜炎双球菌(Neisseria meningitidis)、淋病双球菌(Neisseria gonorrhoeae)、立氏立克次体(Rickettsia rickettsii)、嗜肺军团菌(Legionella pneumophila)、克雷伯氏肺炎菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、痤疮丙酸杆菌(Propionibacterium acnes)、梅毒密螺旋体(Treponema pallidum)、沙眼披衣菌(Chlamydia trachomatis)、霍乱弧菌(Vibriocholerae)、鼠伤寒沙门杆菌(Salmonella typhimurium)、伤寒沙门杆菌(Salmonellatyphi)、伯氏疏螺旋体(Borrelia burgdorferi)、尿道致病性大肠杆菌(Uropathogenic Escherichia coli,UPEC)或鼠疫耶尔辛氏菌(Yersinia pestis));真菌感染(例如来自念珠菌(Candida)种或曲霉(Aspergillus)种);原生动物感染(例如来自疟原虫属(Plasmodium)、焦虫属(Babesia)、梨形鞭毛虫属(Giardia)、阿米巴属(Entamoeba)、利什曼原虫属(Leishmania)或锥虫);蠕虫感染(例如来自住血吸虫属(schistosoma)、蛔虫、绦虫或吸虫)和普里昂蛋白(prion)感染;
(v)中枢神经系统疾病,如帕金森氏病、阿兹海默氏病、痴呆、运动神经元疾病、亨廷顿氏病、脑型疟疾、来自肺炎球菌脑膜炎的脑损伤、颅内动脉瘤、脑内出血、败血症相关性脑病、术后认知功能障碍、早期脑损伤、脑外伤、脑缺血再灌注损伤、中风、全身麻醉神经炎症和肌萎缩性脊髓侧索硬化症;
(vi)代谢疾病,如2型糖尿病(T2D)、动脉粥样硬化、肥胖症、痛风和假性痛风;
(vii)心血管疾病,如高血压、缺血、再灌注损伤(包括MI后缺血性再灌注损伤)、中风(包括缺血性中风)、短暂性脑缺血发作、心肌梗塞(包括复发性心肌梗塞)、心力衰竭(包括充血性心力衰竭和射血分数保留型心力衰竭)、心脏肥大和纤维化、栓塞、动脉瘤(包括腹部主动脉瘤)和心包炎(包括德雷斯勒综合征(Dressler's syndrome));
(viii)呼吸疾病,包括慢性阻塞性肺病(COPD)、哮喘(如过敏性哮喘、嗜酸细胞性哮喘和类固醇抗性哮喘)、石棉肺、硅肺、纳米粒子诱导的炎症、囊性纤维化和特发性肺纤维化;
(ix)肝病,包括非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)(包括F3和F4期晚期纤维化)、酒精性脂肪肝病(AFLD)、酒精性脂肪性肝炎(ASH)、肝脏缺血再灌注损伤、暴发性肝炎、肝纤维化和肝功能衰竭(包括急性肝功能衰竭);
(x)肾病,包括慢性肾病、草酸性肾病变、肾钙质沉着症、肾小球性肾炎、糖尿病性肾病变、肾纤维化(包括慢性结晶肾病变)和肾性高血压;
(xi)眼部疾病,包括眼上皮疾病、年龄相关性黄斑变性(AMD)(干式和湿式)、舍格伦氏综合征、眼色素层炎、角膜感染、糖尿病性视网膜病变、视神经损伤、干眼和青光眼;
(xii)皮肤病,包括皮炎(如接触性皮炎和特应性皮炎)、接触性过敏、牛皮癣、晒伤、皮肤病灶、化脓性汗腺炎(HS)、其他包囊引起的皮肤病、坏疽性脓皮病和寻常性痤疮(包括聚合性痤疮);
(xiii)淋巴疾患,如淋巴管炎和卡所门氏病(Castleman's disease);
(xiv)心理障碍,如抑郁症和心理压力;
(xv)移植物抗宿主病;
(xvi)触感痛,包括机械性触感痛;
(xvii)与糖尿病相关的疾患,包括糖尿病性脑病、糖尿病性视网膜病变和糖尿病性低脂联素血症;以及
(xviii)已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
在一个实施方案中,疾病、病症或疾患选自:
(i)癌症;
(ii)感染;
(iii)中枢神经系统疾病;
(iv)心血管疾病;
(v)肝病;
(vi)眼病;或
(vii)皮肤病。
更典型地,疾病、病症或疾患选自:
(i)癌症;
(ii)感染;
(iii)中枢神经系统疾病;或
(iv)心血管疾病。
在一个实施方案中,疾病、病症或疾患选自:
(i)聚合性痤疮;
(ii)特应性皮炎;
(iii)阿兹海默氏病;
(iv)肌萎缩性脊髓侧索硬化症;
(v)年龄相关性黄斑变性(AMD);
(vi)甲状腺未分化癌;
(vii)冷炎素相关周期性综合征(CAPS);
(viii)接触性皮炎;
(ix)囊性纤维化;
(x)充血性心力衰竭;
(xi)慢性肾病;
(xii)克罗恩氏病;
(xiii)家族性寒冷型自身炎症性综合征(FCAS);
(xiv)亨廷顿氏病;
(xv)心力衰竭;
(xvi)射血分数保留型心力衰竭;
(xvii)缺血性再灌注损伤;
(xviii)幼年特发性关节炎;
(xix)心肌梗塞;
(xx)巨噬细胞活化综合征;
(xxi)骨髓增生异常综合征;
(xxii)多发性骨髓瘤;
(xxiii)运动神经元疾病;
(xxiv)多发性硬化;
(xxv)穆-韦二氏综合征;
(xxvi)非酒精性脂肪性肝炎(NASH);
(xxvii)新生儿发作型多系统炎症性疾病(NOMID);
(xxviii)帕金森氏病;
(xxix)镰状细胞病;
(xxx)全身性幼年特发性关节炎;
(xxxi)系统性红斑狼疮;
(xxxii)创伤性脑损伤;
(xxxiii)短暂性脑缺血发作;
(xxxiv)溃疡性结肠炎;或
(xxxv)含缬酪肽蛋白病。
在本发明的另一典型实施方案中,疾病、病症或疾患为炎症。可根据本发明的第五、第六、第七、第八、第九或第十方面治疗或预防的炎症的实例包括与以下各项相关或由以下各项引起的炎症应答:
(i)皮肤疾患,如接触性过敏、大疱性类天疱疮、晒伤、牛皮癣、局部皮炎、接触性皮炎、过敏性接触性皮炎、脂溢性皮炎、扁平苔藓、硬皮症、天疱疮、大疱性表皮松解、荨麻疹、红斑或脱发;
(ii)关节疾患,如骨关节炎、全身性幼年特发性关节炎、成年发作型斯蒂尔氏病、复发性多发性软骨炎、类风湿性关节炎、青少年慢性关节炎、痛风或血清阴性脊椎关节病(例如强直性脊柱炎、牛皮癣关节炎或莱特氏病);
(iii)肌肉疾患,如多发性肌炎或重症肌无力;
(iv)胃肠道疾患,如炎症性肠病(包括克罗恩氏病和溃疡性结肠炎)、胃溃疡、乳糜泻、直肠炎、胰腺炎、嗜酸细胞性肠胃炎、肥大细胞增多症、抗磷脂质综合征或可影响肠远端的食物相关的过敏症(例如偏头痛、鼻炎或湿疹);
(v)呼吸系统疾患,如慢性阻塞性肺病(COPD)、哮喘(包括嗜酸细胞性、支气管性、过敏性、内因性、外因性或尘埃性哮喘,且特别是慢性或顽固性哮喘,如迟发型哮喘和气道高反应性)、支气管炎、鼻炎(包括急性鼻炎、过敏性鼻炎、萎缩性鼻炎、慢性鼻炎、干酪状鼻炎、肥厚性鼻炎、玉米粉样鼻炎、干性鼻炎、药物性鼻炎、膜性鼻炎、季节性鼻炎(例如花粉热)和血管舒缩鼻炎)、窦炎、特发性肺纤维化(IPF)、结节病、农夫肺、硅肺、石棉肺、成人呼吸窘迫综合征、过敏性肺炎或特发性间质性肺炎;
(vi)血管疾患,如动脉粥样硬化、白塞氏病、血管炎或韦格纳氏肉芽肿;
(vii)自身免疫性疾患,如系统性红斑狼疮、舍格伦氏综合征、全身性硬化、桥本氏甲状腺炎、I型糖尿病、特发性血小板减少性紫癜或格雷氏病;
(viii)眼部疾患,如眼色素层炎、过敏性结膜炎或春季结膜炎;
(ix)神经疾患,如多发性硬化或脑脊髓炎;
(x)感染或感染相关疾患,如后天性免疫缺陷综合征(AIDS)、急性或慢性细菌性感染、急性或慢性寄生虫感染、急性或慢性病毒感染、急性或慢性真菌感染、脑膜炎、肝炎(甲型、乙型或丙型或其他病毒性肝炎)、腹膜炎、肺炎、会厌炎、疟疾、登格出血热、利什曼体病、链球菌肌炎、结核分枝杆菌、鸟胞内分枝杆菌、卡氏肺囊虫肺炎、睪丸炎/附睪炎、军团菌属(legionella)、莱姆病(Lyme disease)、甲型流感、爱泼斯坦-巴尔病毒感染、病毒脑炎/无菌性脑膜炎或骨盆炎症性疾病;
(xi)肾疾患,如系膜增生性肾小球性肾炎、肾病综合征、肾炎、肾小球肾炎、急性肾衰竭、尿毒症、肾病综合征、肾纤维化(包括慢性结晶肾病变)或肾性高血压;
(xii)淋巴疾患,如卡所门氏病;
(xiii)免疫系统或涉及免疫系统的疾患,如高IgE综合征、瘤型麻风、家族性嗜血性淋巴组织细胞增生症或移植物抗宿主病;
(xiv)肝疾患,如慢性活动性肝炎、非酒精性脂肪性肝炎(NASH)、酒精诱导的肝炎、非酒精性脂肪肝病(NAFLD)、酒精性脂肪肝病(AFLD)、酒精性脂肪性肝炎(ASH)、原发性胆汁性肝硬化、暴发性肝炎、肝纤维化或肝衰竭;
(xv)癌症,包括上文所列出的那些癌症;
(xvi)烧伤、伤口、创伤、出血或中风;
(xvii)辐射暴露;
(xviii)肥胖症;和/或
(xix)疼痛,如炎症性痛觉过敏。
在本发明第五、第六、第七、第八、第九或第十方面的一个实施方案中,疾病、病症或疾患为自身炎症性疾病,如冷炎素相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)、家族性地中海热(FMF)、新生儿发作型多系统炎症性疾病(NOMID)、肿瘤坏死因子(TNF)受体相关的周期性综合征(TRAPS)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、白介素1受体拮抗剂缺乏(DIRA)、马吉德综合征(Majeedsyndrome)、化脓性关节炎、坏疽性脓皮症和痤疮综合征(PAPA)、成年发作型斯蒂尔氏病(AOSD)、A20单倍剂量不足(HA20)、小儿肉芽肿关节炎(PGA)、PLCG2相关的抗体缺乏和免疫失调(PLAID)、自身炎症性的PLCG2相关的抗体缺乏和免疫失调(APLAID)或伴有B细胞免疫缺陷的含铁母细胞性贫血、周期性发热和发育迟缓(SIFD)。
上文列出了可对NLRP3抑制有响应并且可根据本发明的第五、第六、第七、第八、第九或第十方面治疗或预防的疾病、病症或疾患的实例。这些疾病、病症或疾患中的一些基本上或完全由NLRP3炎性体活性和NLRP3诱导的IL-1β和/或IL-18介导。因此,此类疾病、病症或疾患可特别对NLRP3抑制有响应并且可特别适合于根据本发明的第五、第六、第七、第八、第九或第十方面进行治疗或预防。此类疾病、病症或疾患的实例包括冷炎素相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)、新生儿发作型多系统炎症性疾病(NOMID)、家族性地中海热(FMF)、化脓性关节炎、坏疽性脓皮症和痤疮综合征(PAPA)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、肿瘤坏死因子(TNF)受体相关的周期性综合征(TRAPS)、全身性幼年特发性关节炎、成年发作型斯蒂尔氏病(AOSD)、复发性多发性软骨炎、施尼兹勒氏综合征、斯威特氏综合征、白塞氏病、抗合成酶综合征、白介素1受体拮抗剂缺乏(DIRA)和A20单倍剂量不足(HA20)。
此外,上文所提到的一些疾病、病症或疾患因NLRP3突变、具体而言使NLRP3活性增加的突变而出现。因此,此类疾病、病症或疾患可特别对NLRP3抑制有响应并且可特别适合于根据本发明的第五、第六、第七、第八、第九或第十方面进行治疗或预防。此类疾病、病症或疾患的实例包括冷炎素相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷型自身炎症性综合征(FCAS)和新生儿发作型多系统炎症性疾病(NOMID)。
本发明的第十一方面提供一种抑制NLRP3的方法,所述方法包括使用本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物来抑制NLRP3。
在本发明第十一方面的一个实施方案中,所述方法包括将本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物与一种或多种其他活性剂组合使用。
在本发明第十一方面的一个实施方案中,离体或在体外实施所述方法,例如以分析NLRP3抑制对细胞的效应。
在本发明第十一方面的另一个实施方案中,在体内实施所述方法。举例来说,所述方法可包括以下步骤:施用有效量的第一方面或第二方面的化合物、或第三方面的药学上可接受的盐、溶剂合物或前药、或第四方面的药物组合物,由此抑制NLRP3。在一个实施方案中,所述方法还包括共同施用有效量的一种或多种其他活性剂的步骤。典型地,施用是针对有需要的受试者。
或者,本发明第十一方面的方法可为抑制非人动物受试者的NLRP3的方法,所述方法包括以下步骤:向非人动物受试者施用化合物、盐、溶剂合物、前药或药物组合物,以及任选地随后将非人动物受试者断肢或处死。典型地,这种方法还包括以下步骤:分析一个或多个来自任选地断肢或处死的非人动物受试者的组织或流体样品。在一个实施方案中,所述方法还包括共同施用有效量的一种或多种其他活性剂的步骤。
本发明的第十二方面提供本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物,所述化合物、所述药学上可接受的盐、溶剂合物或前药、所述药物组合物用于NLRP3的抑制中。典型地,所述使用包括向受试者施用化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,将化合物、盐、溶剂合物、前药或药物组合物与一种或多种其他活性剂共同施用。
本发明的第十三方面提供本发明第一方面或第二方面的化合物、或本发明第三方面的药学上有效的盐、溶剂合物或前药在制造用于抑制NLRP3的药剂中的用途。典型地,抑制包括向受试者施用化合物、盐、溶剂合物、前药或药剂。在一个实施方案中,将化合物、盐、溶剂合物、前药或药剂与一种或多种其他活性剂共同施用。
在包括使用或共同施用一种或多种其他活性剂的本发明第五至第十三方面中任一者的任一个实施方案中,一种或多种其他活性剂可包含例如一种、两种或三种不同的其他活性剂。
一种或多种其他活性剂可在彼此和/或本发明第一方面或第二方面的化合物、本发明第三方面的药学上可接受的盐、溶剂合物或前药、或本发明第四方面的药物组合物之前、与其同时、与其依序或在其之后使用或施用。当一种或多种其他活性剂与本发明第一方面或第二方面的化合物、或本发明第三方面的药学上可接受的盐、溶剂合物或前药同时施用时,可施用本发明第四方面的药物组合物,其中药物组合物另外包含一种或多种其他活性剂。
在包括使用或共同施用一种或多种其他活性剂的本发明第五至第十三方面中任一者的一个实施方案中,一种或多种其他活性剂选自:
(i)化疗剂;
(ii)抗体;
(iii)烷基化剂;
(iv)抗代谢物;
(v)抗血管生成剂;
(vi)植物生物碱和/或萜类化合物;
(vii)拓扑异构酶抑制剂;
(viii)mTOR抑制剂;
(ix)芪类化合物;
(x)STING激动剂;
(xi)癌症疫苗;
(xii)免疫调节剂;
(xiii)抗生素;
(xiv)抗真菌剂;
(xv)驱虫剂;和/或
(xvi)其他活性剂。
应了解,根据广泛类别的活性剂定义的这些一般实施方案并不互斥。就这一点而言,任何特定活性剂均可根据上述一般实施方案中的超过一者加以分类。非限制性实例为乌瑞鲁单抗(urelumab),乌瑞鲁单抗为用于治疗癌症的免疫调节剂的抗体。
在一些实施方案中,一种或多种化学治疗剂选自乙酸阿比特龙(abirateroneacetate)、六甲蜜胺(altretamine)、安吖啶(amsacrine)、无水长春碱(anhydrovinblastine)、奥里斯他汀(auristatin)、硫唑嘌呤(azathioprine)、阿德力霉素(adriamycin)、贝沙罗汀(bexarotene)、比卡鲁胺(bicalutamide)、BMS 184476、博来霉素(bleomycin)、N,N-二甲基-L-缬氨酰基-L-缬氨酰基-N-甲基-L-缬氨酰基-L-丙基-L-脯氨酸-叔丁基酰胺、顺铂(cisplatin)、卡铂(carboplatin)、卡铂环磷酰胺(carboplatincyclophosphamide)、氮芥苯丁酸(chlorambucil)、恶液质素(cachectin)、西马多丁(cemadotin)、环磷酰胺(cyclophosphamide)、卡莫司汀(carmustine)、念珠藻素(cryptophycin)、阿糖胞苷(cytarabine)、多西他赛(docetaxel)、多西紫杉醇(doxetaxel)、多柔比星(doxorubicin)、达卡巴嗪(dacarbazine,DTIC)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、地西他滨(decitabine)、尾海兔素(dolastatin)、依托泊苷(etoposide)、磷酸依托泊苷、恩杂鲁胺(enzalutamide,MDV3100)、5-氟尿嘧啶(5-fluorouracil)、氟达拉滨(fludarabine)、氟他胺(flutamide)、吉西他滨(gemcitabine)、羟基脲和羟基脲紫杉烷(hydroxyureataxanes)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊立替康(irinotecan)、甲酰四氢叶酸(leucovorin)、氯尼达明(lonidamine)、洛莫司汀(lomustine,CCNU)、拉洛他赛(larotaxel,RPR109881)、二氯甲基二乙胺(mechlorethamine)、巯嘌呤(mercaptopurine)、氨甲喋呤(methotrexate)、丝裂霉素C(mitomycin C)、米托蒽醌(mitoxantrone)、美法仑(melphalan)、米伏布林(mivobulin)、3',4'-二脱氢-4'-脱氧-8'-去甲-长春花碱(3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine)、尼鲁米特(nilutamide)、奥沙利铂(oxaliplatin)、奥那司酮(onapristone)、泼尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、太平洋紫杉醇(paclitaxel)、含铂抗癌剂、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺、泼尼莫司汀(prednimustine)、丙卡巴肼、利索新(rhizoxin)、色替纳弗(sertenef)、链脲霉素(streptozocin)、磷酸雌莫司汀(stramustine phosphate)、维A酸(tretinoin)、他索那敏(tasonermin)、紫杉醇(taxol)、托泊替康(topotecan)、他莫昔芬(tamoxifen)、替尼泊苷(teniposide)、紫杉烷(taxane)、替加氟(tegafur)/尿嘧啶、长春新碱(vincristine)、长春碱(vinblastine)、长春瑞滨(vinorelbine)、长春地辛(vindesine)、硫酸长春地辛和/或长春氟宁(vinflunine)。
或者或另外,一种或多种化学治疗剂可选自CD59补体片段、纤连蛋白片段、gro-β(CXCL2)、肝素酶、肝素六糖片段、人绒毛膜促性腺激素(hCG)、干扰素α、干扰素β、干扰素γ、干扰素诱导蛋白(IP-10)、白介素-12、kringle 5(纤维蛋白溶酶原片段)、金属蛋白酶抑制剂(TIMP)、2-甲氧基雌二醇、胎盘核糖核酸酶抑制剂、纤维蛋白溶酶原活化剂抑制剂、血小板因子-4(PF4)、泌乳素16kD片段、增殖素相关蛋白(PRP)、各种类视色素、四氢皮质醇-S、凝血酶敏感蛋白-1(TSP-1)、转化生长因子-β(TGF-β)、血管抑制素(vasculostatin)、血管形成抑制素(vasostatin)(钙网蛋白片段)和/或细胞因子(包括白介素,例如白介素-2(IL-2)或IL-10)。
在一些实施方案中,一种或多种抗体可包含一种或多种单克隆抗体。在一些实施方案中,一种或多种抗体选自阿昔单抗(abciximab)、阿达木单抗(adalimumab)、阿伦单抗(alemtuzumab)、阿利珠单抗(atlizumab)、巴利昔单抗(basiliximab)、贝利木单抗(belimumab)、贝伐珠单抗(bevacizumab)、本妥昔单抗维多汀(bretuximab vedotin)、卡那单抗(canakinumab)、西妥昔单抗(cetuximab)、聚乙二醇结合赛妥珠单抗(ceertolizumabpegol)、达克珠单抗(daclizumab)、地诺单抗(denosumab)、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、吉妥珠单抗(gemtuzumab)、戈利木单抗(golimumab)、替伊莫单抗(ibritumomab tiuxetan)、英利昔单抗(infliximab)、伊匹单抗(ipilimumab)、莫罗单抗-CD3(muromonab-CD3)、那他珠单抗(natalizumab)、奥法木单抗(ofatumumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕尼单抗(panitumuab)、兰尼单抗(ranibizumab)、利妥昔单抗(rituximab)、托珠单抗(tocilizumab)、托西莫单抗(tositumomab)和/或曲妥珠单抗(trastuzumab)。
在一些实施方案中,一种或多种烷基化剂可包含能够在细胞(包括例如癌细胞)中存在的条件下将亲核官能团烷基化的剂。在一些实施方案中,一种或多种烷基化剂选自顺铂、卡铂、二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、异环磷酰胺和/或奥沙利铂。在一些实施方案中,烷基化剂可通过在生物重要分子中与氨基、羧基、硫氢基和/或磷酸基团形成共价键损害细胞功能来发挥作用。在一些实施方案中,烷基化剂可通过修饰细胞的DNA发挥作用。
在一些实施方案中,一种或多种抗代谢物可包含能够影响或防止RNA或DNA合成的剂。在一些实施方案中,一种或多种抗代谢物选自硫唑嘌呤和/或巯嘌呤。
在一些实施方案中,一种或多种抗血管生成剂选自内皮抑素、血管生成素抑制剂、血管抑素、血管生成素样蛋白、血管抑素(纤维蛋白溶酶原片段)、基底膜胶原源性抗血管生成因子(肿瘤抑素、血管能抑素或抑制蛋白)、抗血管生成抗凝血酶III和/或软骨源性抑制剂(CDI)。
在一些实施方案中,一种或多种植物碱和/或萜类化合物可防止微管功能。在一些实施方案中,一种或多种植物碱和/或萜类化合物选自长春花生物碱(vinca alkaloid)、鬼臼毒素(podophyllotoxin)和/或紫杉烷。在一些实施方案中,一种或多种长春花生物碱可来源于马达加斯加长春花(Madagascar periwinkle)、长春花(Catharanthus roseus,之前称为日日春(Vinca rosea)),并且可选自长春新碱、长春碱、长春瑞滨和/或长春地辛。在一些实施方案中,一种或多种紫杉烷选自紫杉醇、太平洋紫杉醇、多西他赛和/或奥他赛。在一些实施方案中,一种或多种鬼臼毒素选自依托泊苷和/或替尼泊苷。
在一些实施方案中,一种或多种拓朴异构酶抑制剂选自I型拓朴异构酶抑制剂和/或II型拓朴异构酶抑制剂,并且可通过干扰DNA超螺旋化来干扰DNA的转录和/或复制。在一些实施方案中,一种或多种I型拓朴异构酶抑制剂可包含喜树碱(camptothecin),所述物质可选自依喜替康(exatecan)、伊立替康、勒托替康(lurtotecan)、托泊替康、BNP 1350、CKD602、DB 67(AR67)和/或ST 1481。在一些实施方案中,一种或多种II型拓朴异构酶抑制剂可包含表鬼臼毒素,所述物质可选自安吖啶、依托泊苷、磷酸依托泊苷和/或替尼泊苷。
在一些实施方案中,一种或多种mTOR(雷帕霉素(rapamycin)的哺乳动物靶标,也称为雷帕霉素的机能靶)抑制剂选自雷帕霉素、依维莫司(everolimus)、替西罗莫司(temsirolimus)和/或地伏莫司(deforolimus)。
在一些实施方案中,一种或多种芪类化合物选自白藜芦醇(resveratrol)、白皮杉醇(piceatannol)、赤松素(pinosylvin)、紫檀芪(pterostilbene)、α-葡萄素(viniferin)、白蔹素(ampelopsin)A、白蔹素E、白藜芦醇寡聚体C、白藜芦醇寡聚体F、ε-葡萄素、香茅醇(flexuosol)A、麻藤素(gnetin)H、崖爬藤醇(hemsleyanol)D、坡垒醇(hopeaphenol)、反式白藜芦醇寡聚体B、曲札芪苷(astringin)、云杉新苷(piceid)和/或白藜芦醇寡聚体A。
在一些实施方案中,一种或多种STING(干扰素基因的刺激物,也称为跨膜蛋白(TMEM)173)激动剂可包含环状二核苷酸(如cAMP、cGMP和cGAMP)和/或修饰的环状二核苷酸,所述修饰的环状二核苷酸可包括以下修饰特征中的一者或多者:2'-O/3'-O键联、硫代磷酸酯键联、腺嘌呤和/或鸟嘌呤类似物和/或2'-OH修饰(例如用甲基保护2'-OH或用-F或-N3替代2'-OH)。
在一些实施方案中,一种或多种癌症疫苗选自HPV疫苗、乙型肝炎疫苗、Oncophage和/或Provenge。
在一些实施方案中,一种或多种免疫调节剂可包含免疫检查点抑制剂。免疫检查点抑制剂可靶向包含例如以下的免疫检查点受体或受体的组合:CTLA-4、PD-1、PD-L1、PD-L2、T细胞免疫球蛋白和粘蛋白3(TIM3或HAVCR2)、半乳糖凝集素9、磷酯酰丝氨酸、淋巴细胞活化基因3蛋白(LAG3)、I类MHC、II类MHC、4-1BB、4-1BBL、OX40、OX40L、GITR、GITRL、CD27、CD70、TNFRSF25、TL1A、CD40、CD40L、HVEM、LIGHT、BTLA、CD160、CD80、CD244、CD48、ICOS、ICOSL、B7-H3、B7-H4、VISTA、TMIGD2、HHLA2、TMIGD2、嗜乳脂蛋白(butyrophilin,包括BTNL2)、唾液酸结合性免疫球蛋白样凝集素(Siglec)家族成员、TIGIT、PVR、杀手细胞免疫球蛋白样受体、ILT、白细胞免疫球蛋白样受体、NKG2D、NKG2A、MICA、MICB、CD28、CD86、SIRPA、CD47、VEGF、神经纤毛蛋白、CD30、CD39、CD73、CXCR4和/或CXCL12。
在一些实施方案中,免疫检查点抑制剂选自乌瑞鲁单抗、PF-05082566、MEDI6469、TRX518、瓦利珠单抗(varlilumab)、CP-870893、派姆单抗(pembrolizumab)(PD1)、尼沃鲁单抗(nivolumab)(PD1)、阿特珠单抗(atezolizumab,之前称为MPDL3280A)(PD-L1)、MEDI4736(PD-L1)、阿维鲁单抗(avelumab)(PD-L1)、PDR001(PD1)、BMS-986016、MGA271、利鲁单抗(lirilumab)、IPH2201、依麻特珠单抗(emactuzumab)、INCB024360、盖伦塞替(galunisertib)、乌鲁普单抗(ulocuplumab)、BKT140、巴维昔单抗(bavituximab)、CC-90002、贝伐珠单抗(bevacizumab)和/或MNRP1685A。
在一些实施方案中,一种或多种抗生素选自阿米卡星(amikacin)、庆大霉素(gentamicin)、康霉素(kanamycin)、新霉素(neomycin)、奈替霉素(netilmicin)、妥布霉素(tobramycin)、巴龙霉素(paromomycin)、链霉素(streptomycin)、大观霉素(spectinomycin)、格尔德霉素(geldanamycin)、除莠霉素(herbimycin)、利福昔明(rifaximin)、洛拉卡比(loracarbef)、厄他培南(ertapenem)、多尼培南(doripenem)、亚胺培南(imipenem)、西司他丁(cilastatin)、美罗培南(meropenem)、头孢羟胺苄(cefadroxil)、头孢唑啉(cefazolin)、头孢噻吩(cefalotin)、头孢类新(cefalothin)、头孢胺苄(cefalexin)、头孢克洛(cefaclor)、头孢孟多(cefamandole)、头孢西丁(cefoxitin)、头孢丙烯(cefprozil)、头孢呋辛(cefuroxime)、头孢克肟(cefixime)、头孢地尼(cefdinir)、头孢妥仑(cefditoren)、头孢哌酮(cefoperazone)、头孢噻肟(cefotaxime)、头孢泊肟(cefpodoxime)、头孢他啶(ceftazidime)、头孢布烯(ceftibuten)、头孢唑肟(ceftizoxime)、头孢曲松(ceftriaxone)、头孢吡肟(cefepime)、头孢洛林酯(ceftaroline fosamil)、头孢比普(ceftobiprole)、替考拉宁(teicoplanin)、万古霉素(vancomycin)、替拉万星(telavancin)、达巴万星(dalbavancin)、奥利万星(oritavancin)、克林达霉素(clindamycin)、林可霉素(lincomycin)、达托霉素(daptomycin)、阿奇霉素(azithromycin)、克拉霉素(clarithromycin)、地红霉素(dirithromycin)、红霉素(erythromycin)、罗红霉素(roxithromycin)、醋竹桃霉素(troleandomycin)、泰利霉素(telithromycin)、螺旋霉素(spiramycin)、氨曲南(aztreonam)、呋喃唑酮(furazolidone)、硝基呋喃妥因(nitrofurantoin)、利奈唑胺(linezolid)、泼斯唑来(posizolid)、雷得唑来(radezolid)、特地唑胺(torezolid)、阿莫西林(amoxicillin)、氨比西林(ampicillin)、阿洛西林(azlocillin)、卡本西林(carbenicillin)、氯唑西林(cloxacillin)、二氯唑西林(dicloxacillin)、氟氯西林(flucloxacillin)、美洛西林(mezlocillin)、甲氧西林(methicillin)、萘夫西林(nafcillin)、苯唑西林(oxacillin)、盘尼西林G(penicillin G)、盘尼西林V、哌拉西林(piperacillin)、替莫西林(temocillin)、替卡西林(ticarcillin)、克拉维酸(calvulanate)、氨比西林、舒巴坦(subbactam)、三唑巴坦(tazobactam)、替卡西林(ticarcillin)、克拉维酸、杆菌肽(bacitracin)、粘杆菌素(colistin)、多粘菌素B(polymyxin B)、环丙沙星(ciprofloxacin)、依诺沙星(enoxacin)、加替沙星(gatifloxacin)、吉米沙星(gemifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、莫西沙星(moxifloxacin)、萘啶酮酸(nalidixic acid)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、曲氟沙星(trovafloxacin)、格帕沙星(grepafloxacin)、司帕沙星(sparfloxacin)、替马沙星(temafloxacin)、磺胺米隆(mafenide)、磺乙酰胺(sulfacetamide)、磺胺嘧啶(sulfadiazine)、磺胺嘧啶银(silversulfadiazine)、磺胺地索辛(sulfadimethoxine)、磺胺甲噁唑(sulfamethoxazole)、磺胺(sulfanamide)、磺胺塞拉金(sulfasalazine)、磺胺异噁唑(sulfisoxazole)、甲氧苄啶-磺胺甲噁唑(trimethoprim-sulfamet hoxazole)、磺胺柯衣定(sulfonamideochrysoidine)、地美环素(demeclocycline)、米诺环素(minocycline)、土霉素(oytetracycline)、四环素(tetracycline)、氯法齐明(clofazimine)、氨苯砜(dapsone)、卷曲霉素(dapreomycin)、环丝氨酸(cycloserine)、乙胺丁醇(ethambutol)、乙硫异烟胺(ethionamide)、异烟肼(isoniazid)、吡嗪酰胺(pyrazinamide)、利福平(rifampicin)、利福布汀(rifabutin)、利福喷丁(rifapentine)、链霉素(streptomycin)、胂凡纳明(arsphenamine)、氯霉素(chloramphenicol)、磷霉素(fosfomycin)、夫西地酸(fusidic acid)、甲硝唑(metronidazole)、莫匹罗星(mupirocin)、平板霉素(platensimycin)、奎奴普汀(quinupristin)、达福普汀(dalopristin)、甲砜霉素(thiamphenicol)、替加环素(tigecycyline)、替硝唑(tinidazole)、甲氧苄啶和/或泰斯巴汀(teixobactin)。
在一些实施方案中,一种或多种抗生素可包含一种或多种细胞毒性抗生素。在一些实施方案中,一种或多种细胞毒性抗生素选自放线菌素、蒽二酮、蒽环、沙利度胺(thalidomide)、二氯乙酸、烟碱酸、2-脱氧葡萄糖和/或氯法齐明(chlofazimine)。在一些实施方案中,一种或多种放线菌素选自放线菌素D、杆菌肽、粘杆菌素(多粘杆菌素E)和/或多粘杆菌素B。在一些实施方案中,一种或多种蒽二酮选自米托蒽醌和/或匹杉琼(pixantrone)。在一些实施方案中,一种或多种蒽环选自博来霉素、多柔比星(阿德力霉素)、道诺霉素(柔红霉素(daunomycin))、表柔比星(epirubicin)、伊达比星、丝裂霉素、普卡霉素(plicamycin)和/或戊柔比星(valrubicin)。
在一些实施方案中,一种或多种抗真菌剂选自联苯苄唑(bifonazole)、布康唑(butoconazole)、克霉唑(clotrimazole)、益康唑(econazole)、酮康唑(ketoconazole)、鲁利康唑(luliconazole)、咪康唑(miconazole)、奥莫康唑(omoconazole)、奥昔康唑(oxiconazole)、舍他康唑(sertaconazole)、硫康唑(sulconazole)、噻康唑(tioconazole)、阿巴康唑(albaconazole)、艾氟康唑(efinaconazole)、艾坡康唑(epoziconazole)、氟康唑(fluconazole)、艾沙康唑(isavuconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、丙环唑(propiconazole)、拉夫康唑(ravusconazole)、特康唑(terconazole)、伏立康唑(voriconazole)、阿巴芬净(abafungin)、阿莫罗芬(amorolfin)、布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)、阿尼芬净(anidulafungin)、卡泊芬净(caspofungin)、米卡芬净(micafungin)、苯甲酸(benzoic acid)、环吡酮(ciclopirox)、氟胞嘧啶(flucytosine)、5-氟胞嘧啶、灰黄霉素(griseofulvin)、卤普罗近(haloprogin)、托奈福特(tolnaflate)、十一烯酸和/或秘鲁香脂(balsam of Peru)。
在一些实施方案中,一种或多种驱虫剂选自苯并咪唑(包括阿苯达唑(albendazole)、甲苯达唑(mebendazole)、噻苯咪唑(thiabendazole)、芬苯达唑(fenbendazole)、三氯苯达唑(triclabendazole)和氟苯达唑(flubendazole))、阿巴汀(abamectin)、二乙基乙胺嗪(diethylcarbamazine)、伊维菌素(ivermectin)、苏拉明(suramin)、双羟萘酸噻嘧啶(pyrantel pamoate)、左旋咪唑(levamisole)、柳酰苯胺(包括氯硝柳胺(niclosamide)和羟氯扎胺(oxyclozanide))和/或硝唑尼特(nitazoxanide)。
在一些实施方案中,其他活性剂选自生长抑制剂、消炎剂(包括非类固醇消炎剂)、抗牛皮癣剂(包括蒽林(anthralin)及其衍生物)、维生素和维生素衍生物(包括视黄醇和VDR受体配体)、皮质类固醇、离子通道阻断剂(包括钾通道阻断剂)、免疫系统调节剂(包括环孢菌素、FK 506和糖皮质激素)、黄体生成激素释放激素激动剂(如亮脯瑞林(leuprolidine)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、组氨瑞林(histrelin)、比卡鲁胺、氟他胺和/或尼鲁米特)和/或激素(包括雌激素)。
除非另外陈述,否则在本发明第五至第十三方面中的任一者中,受试者可为任何人或其他动物。典型地,受试者为哺乳动物,更典型地为人或家养哺乳动物,如牛、猪、羔羊、绵羊、山羊、马、猫、狗、兔、小鼠等。最典型地,受试者为人。
可通过经口、肠胃外(包括静脉内、皮下、肌内、真皮内、气管内、腹膜内、关节内、颅内和硬膜外)、经气道(气溶胶)、经直肠、经阴道、经眼部或局部(包括透皮、经颊、经粘膜、舌下和局部眼部)施用来施用用于本发明中的任一药剂。
典型地,所选施用模式为最适合于待治疗或预防的病症、疾病或疾患的施用模式。在施用一种或多种其他活性剂时,施用模式可与本发明的化合物、盐、溶剂合物、前药或药物组合物的施用模式相同或不同。
对于经口施用,通常将以下列形式提供本发明的化合物、盐、溶剂合物或前药:片剂、胶囊、硬或软明胶胶囊、囊片、含片或锭剂、粉末或颗粒或者水溶液、悬浮液或分散液。
用于经口使用的片剂可包括与药学上可接受的赋形剂(如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂)混合的活性成分。合适惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙和乳糖。玉米淀粉和海藻酸为合适的崩解剂。粘合剂可包括淀粉和明胶。润滑剂(如果存在)可为硬脂酸镁、硬脂酸或滑石。如果需要,可用材料(如甘油单硬脂酸酯或甘油二硬脂酸酯)给片剂包覆包衣,以延迟胃肠道中的吸收。片剂还可为泡腾片和/或溶解片。
用于经口使用的胶囊包括其中活性成分与固体稀释剂混合的硬明胶胶囊和其中活性成分与水或油(如花生油、液体石蜡或橄榄油)混合的软明胶胶囊。
用于经口使用的粉末或颗粒可提供于小药囊或管中。可通过将水添加至粉末、颗粒或片剂中来制备水溶液、悬浮液或分散液。
适于经口施用的任一形式可任选地包括甜味剂,如糖、调味剂、着色剂和/或防腐剂。
用于经直肠施用的制剂可呈现为含有合适基质(包含例如可可脂或水杨酸盐)的栓剂。
适于经阴道施用的制剂可呈现为除活性成分外含有例如本领域中已知合适的载体的阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾制剂。
对于肠胃外使用,通常将以缓冲至适当pH值并且等渗的无菌水溶液或悬浮液形式提供本发明的化合物、盐、溶剂合物或前药。合适水性媒介物包括林格氏溶液(Ringer’ssolution)和等渗氯化钠或葡萄糖。根据本发明的水性悬浮液可包括悬浮剂(如纤维素衍生物、海藻酸钠、聚乙烯吡咯烷酮和黄蓍胶)和润湿剂(如卵磷脂)。适于水性悬浮液的防腐剂包括对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯。本发明的化合物还可呈现为脂质体制剂。
对于经眼部施用,通常将以适于局部施用的形式(例如以滴眼剂形式)提供本发明的化合物、盐、溶剂合物或前药。合适形式可包括眼部溶液、凝胶形成溶液、供复原用的无菌粉末、眼部悬浮液、眼部软膏剂、眼部乳液、眼部凝胶和眼部插入物。或者,可以适于其他类型的眼部施用的形式、例如以下列形式提供本发明的化合物、盐、溶剂合物或前药:眼内制剂(包括冲洗溶液、眼内、玻璃体内或巩膜旁注射制剂或玻璃体内植入物)、填塞物或角膜隔离罩、前房内、结膜下或眼球后注射制剂或离子导入制剂。
对于经皮和其他局部施用,通常将以下列形式提供本发明的化合物、盐、溶剂合物或前药:软膏剂、泥罨剂(泥敷剂)、糊剂、粉末、敷料、乳膏、硬膏剂或贴剂。
合适悬浮液和溶液可于吸入器中用于经气道(气溶胶)施用。
当然,本发明的化合物、盐、溶剂合物或前药的剂量将随着待治疗或预防的疾病、病症或疾患而变化。一般来讲,合适剂量将在每天每千克体重接受者0.01至500mg范围内。可以适当间隔呈现所需剂量,如每隔一天一次、每天一次、每天两次、每天三次或每天四次。可以例如每单位剂型含有1mg至50g活性成分的单位剂型来施用所需剂量。
为免生疑问,在可实践范围内,可将本发明给定方面的任一实施方案与本发明同一方面的任何其他实施方案组合。另外,在可实践范围内应理解,本发明任一方面的任何优选、典型或任选实施方案还应被视为本发明任何其他方面的优选、典型或任选实施方案。
实施例-化合物合成
除非另外陈述,否则所有溶剂、试剂和化合物均为购买的并且未经进一步纯化即使用。
缩写
2-MeTHF 2-甲基四氢呋喃
Ac2O 乙酸酐
AcOH 乙酸
AIBN 偶氮二异丁腈
aq 水溶液
Boc 叔丁基氧基羰基
br 宽峰
Cbz 羧基苄基
CDI 1,1-羰基-二咪唑
conc 浓
d 双峰
DABCO 1,4-二氮杂双环[2.2.2]辛烷
DCE 1,2-二氯乙烷,也称为二氯化乙烯
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺,也称为许尼希氏碱(Hünig’s base)
DMA 二甲基乙酰胺
DMAP 4-二甲氨基吡啶,也称为N,N-二甲基吡啶-4-胺
DME 二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
EDC或EDCI N-(3-二甲氨基丙基)-N′-乙基碳二亚胺,也称为1-乙基-3-(3-二甲氨基丙基)碳二亚胺
Eq或equiv 当量
(ES+) 电喷雾电离,正模式
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
HATU 1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧六氟磷酸盐
HPLC 高效液相色谱法
KOtBu 叔丁醇钾
LC 液相色谱法
m 多重峰
m-CPBA 3-氯过氧苯甲酸
Me 甲基
MeCN 乙腈
MeOH 甲醇
(M+H)+ 质子化分子离子
MHz 兆赫
min 分钟
MS 质谱法
Ms 甲磺酰基,也称为甲烷磺酰基
MsCl 甲磺酰氯,也称为甲烷磺酰氯
MTBE 甲基叔丁基醚,也称为叔丁基甲醚
m/z 质荷比
NaOtBu 叔丁醇钠
NBS 1-溴吡咯烷-2,5-二酮,也称为N-溴琥珀酰亚胺
NCS 1-氯吡咯烷-2,5-二酮,也称为N-氯琥珀酰亚胺
NMP N-甲基吡咯烷
NMR 核磁共振(光谱法)
Pd(巴豆 氯(巴豆基)(2-二环己基膦基-2',4',6'-三异丙基联苯)钯(II)基)(XPhos)Cl
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(dba)2 双(二亚苄基丙酮)钯(0)
Pd(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(dppf)Cl2 [1,1'-双(二苯基膦基)二茂铁]二氯钯(II)
PE 石油醚
Ph 苯基
PMB 对甲氧基苄基,也称为4-甲氧基苄基
prep-HPLC 制备型高效液相色谱法
prep-TLC 制备型薄层色谱法
PTSA 对甲苯磺酸
q 四重峰
RP 反相
RT 室温
s 单峰
sat 饱和
SCX 固体支撑的阳离子交换(树脂)
sept 七重峰
t 三重峰
T3P 丙基膦酸酐
TBME 叔丁基甲醚,也称为甲基叔丁基醚
TEA 三乙胺
TFA 2,2,2-三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
TMSCl 三甲基甲硅烷基氯
wt% 重量百分比或以重量计的百分比
实验方法
核磁共振
在300、400或500MHz下记录NMR光谱。除非另外指示,否则在298K下测量光谱,并且相对于溶剂共振来提及。以百万分率报告化学位移。使用以下机器中的一者记录光谱:
-配备有BBO 5mm液体探针的Bruker Avance III 400MHz光谱仪,
-使用ICON-NMR的在TopSpin程序控制下的Bruker 400MHz光谱仪,
-配备有Bruker 5mm SmartProbeTM的Bruker Avance III HD 500MHz光谱仪,
-Agilent VNMRS 300仪器,配备有来自Oxford instruments的7.05特斯拉磁铁(Tesla magnet)、间接检测探针和包括PFG模块的直接驱动控制台,或
-Agilent MercuryPlus 300仪器,配备有来自Oxford instruments的7.05特斯拉磁铁、4个核可自动切换探针和Mercury plus控制台。
LC-MS
LC-MS方法:使用SHIMADZU LCMS-2020、Agilent 1200LC/G1956AMSD和Agilent1200\G6110A、Agilent 1200LC以及Agilent 6110MSD。流动相:A:0.025%NH3·H2O水溶液(v/v);B:乙腈。柱:Kinetex EVO C18 2.1X30 mm,5μm。
LCMS分析方法的反相HPLC条件
方法1a和1b:Waters Xselect CSH C18 XP柱(4.6x30mm,2.5μm),在40℃下;流速2.5-4.5mL min-1,用含有0.1%v/v甲酸(方法1a)或10mM NH4HCO3水溶液(方法1b)的H2O-MeCN梯度洗脱,历时4min,采用254nm UV检测。梯度信息:0-3.00min,从95%水-5%乙腈渐升至5%水-95%乙腈;3.00-3.01min,保持在5%水-95%乙腈下,流速增加至4.5mL min-1;3.01-3.50min,保持在5%水-95%乙腈下;3.50-3.60min,回到95%水-5%乙腈,流速减小至3.50mL min-1;3.60-3.90min,保持在95%水-5%乙腈下;3.90-4.00min,保持在95%水-5%乙腈下,流速减小至2.5mL min-1。
方法1a'和1b':使用维持在40℃的Waters Acquity CSH C18或BEH C18柱(2.1x30mm),并使用适于化合物亲脂性的线性乙腈梯度在3或10分钟内以0.77ml/min的恒定流速洗脱进行UPLC/MS分析。流动相的水相部分为0.1%v/v甲酸(CSH C18柱)(方法1a')或10mM碳酸氢铵(BEH C18柱)(方法1b’)。使用Waters Acquity PDA检测器在210与400nm之间记录LC-UV色谱图。使用Waters Acquity QDa检测器记录质谱,在正负离子模式之间进行电喷雾电离切换。调整样品浓度以提供足够的UV响应。
方法1c:具有UV检测器和HP 6130MSD质量检测器的Agilent 1290系列,使用Waters XBridge BEH C18 XP柱(2.1x50mm,2.5μm),在35℃下;流速0.6mL/min;流动相A:乙酸铵(10mM);水/MeOH/乙腈(900:60:40);流动相B:乙酸铵(10mM);水/MeOH/乙腈(100:540:360);历时4min,采用215和238nm UV检测。梯度信息:0-0.5min,保持在80%A-20%B下;0.5-2.0min,从80%A-20%B渐升至100%B。
制备型反相HPLC一般方法
方法1(碱性制备):Waters X-Bridge制备型柱C18,5μm(19x50mm),流速28mL min-1,用10mM NH4HCO3/MeCN梯度洗脱,历时6.5min,使用254nm UV检测。梯度信息:0.0-0.2min,10%MeCN;0.2-5.5min,从10%MeCN渐升至40%MeCN;5.5-5.6min,从40%MeCN渐升至95%MeCN;5.6-6.5min,保持在95%MeCN下。
方法2:Revelis C18反相12g管柱[碳负载18%;表面积568m2/g;孔径65埃;pH(5%浆液)5.1;平均粒径40μm],流速=30mL/min,用水/甲醇梯度洗脱,历时35分钟,使用215、235、254和280nm UV检测。梯度信息:0-5min,保持在0%甲醇下;5-30min,从0%渐升至70%甲醇;30-30.1min,从70%渐升至100%甲醇;30.1-35min,保持在100%甲醇下。
方法3:XSelect CSH Prep C18 OBD,5μm(100x30mm),用10mM乙酸铵/MeCN梯度洗脱,历时12min。梯度信息:0-2.5min,15%MeCN;2.5-10min,从15%渐升至35%MeCN;10-10.1min,从35%渐升至95%MeCN;10.1-12min,保持在95%MeCN下。
方法4(酸性制备):Waters X-Select CSH柱C18,5μm(19x50mm),流速28mL min-1,用含有0.1%v/v甲酸的H2O-MeCN梯度洗脱,历时6.5min,使用254nm UV检测。梯度信息:0.0-0.2min,25%MeCN;0.2-5.5min,从25%MeCN渐升至55%MeCN;5.5-5.6min,从55%MeCN渐升至95%MeCN;5.6-6.5min,保持在95%MeCN下。
中间体的合成
中间体L1:4-(2-羟基丙-2-基)-2-甲基苯磺酰胺
将3-甲基-4-氨磺酰基苯甲酸甲酯(486mg,2.12mmol)在THF(20mL)中搅拌并且逐滴添加甲基溴化镁在Et2O(3M,4mL,12mmol)中的溶液。将混合物在室温下搅拌2天,并倒入饱和NaHCO3水溶液(水溶液,20mL)中,部分浓缩(除去THF)并过滤。使用EtOAc(20mL)洗涤残余固体并萃取滤液。分离有机相,干燥(Na2SO4),过滤并浓缩,得到呈黄色固体状的标题化合物(0.48g,99%)。
1H NMR(300MHz,甲醇-d4)δ7.89(d,1H),7.47(s,1H),7.45–7.39(d,1H),2.66(s,3H),1.52(s,6H)。
中间体L2:1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺
步骤A:N,N-双(4-甲氧基苄基)-1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺
向N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)(200mg,0.52mmol)在二甲基甲酰胺(2mL)中的溶液中添加K2CO3(100mg,0.72mmol)和2-碘丙烷-d7(110mg,0.62mmol)。将混合物在黑暗中于室温下搅拌7天。将反应混合物倒入水(10mL)中,并用乙酸乙酯萃取水层。用水(4次)和盐水洗涤有机层。将有机层干燥(硫酸钠),过滤并蒸发。将残余物使用乙酸乙酯/庚烷(1:1)作为洗脱剂经二氧化硅纯化,得到呈无色油状物的标题化合物(140mg,62%)。
1H NMR(300MHz,CDCl3)δ7.46(s,1H),7.08(d,4H),6.78(d,4H),6.68(d,1H),4.33(s,4H),3.80(s,6H)。
步骤B:1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺
将N,N-双(4-甲氧基苄基)-1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺(140mg,0.32mmol)溶解在二氯甲烷(5mL)中。添加三氟乙酸(1mL)并将反应物在室温下搅拌3天。蒸发溶剂,并用水研磨残余物。过滤水层并冻干,得到呈白色固体状的标题化合物(67mg,100%)。
1H NMR(300MHz,D2O)δ7.73(d,1H),7.67(d,1H)。
中间体L3:3-氨磺酰基-1H-吡唑-1-羧酸叔丁酯
向1H-吡唑-3-磺酰胺(103mg,0.69mmol)和Et3N(0.14mL,1.05mmol)在无水DCM(2mL)中的悬浮液中添加二碳酸二叔丁酯(188mg,0.83mmol),并将反应混合物在室温下搅拌过夜。将饱和NaHCO3水溶液添加至该混合物中,并用DCM萃取水相。用水洗涤有机层,并经Na2SO4干燥。在减压下浓缩,得到呈黄色油状物的标题化合物(170mg,98%),将其不经进一步纯化即使用。
1H NMR(CD3OD)δ7.74(d,1H),6.70(d,1H),1.51(s,9H)。
中间体L4:1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐
步骤A:1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
向N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)(58mg,0.15mmol,1.25eq)在乙腈(3mL)中的溶液中添加3-(丁-3-炔-1-基)-3-(2-碘乙基)-3H-双吖丙啶(30mg,0.12mol,1eq)和碳酸钾(62mg,0.45mmol,3.75eq)。将反应混合物用铝箔覆盖,接着在室温下搅拌。搅拌过夜后,向反应混合物中额外添加含N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)(23mg,0.06mmol,0.5eq)的乙腈(0.5mL)。搅拌3小时后,将反应混合物用水稀释,接着用二氯甲烷萃取两次。合并有机层,经硫酸钠干燥,过滤,接着在真空中浓缩。将粗产物在硅胶上、使用庚烷和乙酸乙酯作为洗脱剂进行正相纯化,得到标题化合物(24mg,47μmol,39%)。
1H NMR(CDCl3)δ7.49(d,1H),7.07(d,4H),6.77(d,4H),6.65(d,1H),4.30(s,4H),4.02(t,2H),3.78(s,6H),2.04(t,2H),2.01–1.96(m,1H),1.93(dd,2H),1.57–1.47(m,2H)。
步骤B:1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐
将1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(24mg,47μmol,1eq)在三氟乙酸(1.0mL,13.05mmol,277eq)中的溶液在室温下搅拌。四小时后,向反应混合物中添加甲苯,接着将混合物在真空中浓缩,得到标题化合物(17mg,47μmol,定量收率),将其原样用于下一反应。
1H NMR(CD3OD)δ7.78(d,1H),6.66(d,1H),4.13(t,2H),2.32–2.22(m,1H),2.05–1.90(m,4H),1.52(t,2H)。
中间体L5:1-(2-(双(甲基-d3)氨基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐
步骤A:1-(2-羟乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
向N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)(1.5g,3.9mmol,1eq)在乙腈(20mL)中的溶液中添加2-溴乙-1-醇(0.57mL,7.7mmol,2eq)、碘化钾(64mg,0.39mmol,0.1eq)和碳酸钾(1.6g,12.0mmol,3eq)。将反应混合物加热至60℃。搅拌过夜后,额外添加2-溴乙-1-醇(0.14mL,1.95mmol,0.5eq)。再搅拌4小时后,将反应混合物冷却至室温,接着用水稀释。将混合物用二氯甲烷萃取。将有机层用盐水洗涤,经硫酸钠干燥,过滤,接着在真空中浓缩。将粗物质使用庚烷和乙酸乙酯作为洗脱剂进行正相快速色谱法,得到标题化合物(1.08g,2.50mmol,65%)。
1H NMR(CDCl3)δ7.56–7.44(m,1H),7.07(dd,4H),6.85–6.73(m,4H),6.70–6.54(m,1H),4.36–4.20(m,6H),4.02–3.88(m,2H),3.78(s,6H),2.21(s,1H)。
步骤B:甲磺酸2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)乙酯
在室温下,向1-(2-羟乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(780mg,1.81mmol,1eq)和N,N-二异丙基乙胺(0.44mL,2.53mmol,1.4eq)在二氯甲烷(25mL)中的溶液中逐滴添加甲磺酰氯(0.16mL,2.17mmol,1.2eq)。搅拌40分钟后,将反应混合物用二氯甲烷(50mL)稀释,接着用饱和碳酸氢钠水溶液洗涤两次,用盐水洗涤一次,经硫酸钠干燥,过滤并在真空中浓缩,得到标题化合物(921mg,1.81mmol,定量收率),将其原样用于下一反应。
1H NMR(CDCl3)δ7.54(q,1H),7.12–7.00(m,4H),6.84–6.69(m,4H),6.65(q,1H),4.65–4.46(m,4H),4.31(s,4H),3.78(s,6H),2.92(s,3H)。
步骤C:1-(2-(双(甲基-d3)氨基)乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
在微波小瓶中装入甲磺酸2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)乙酯(922mg,1.81mmol,1eq)、双(甲基-d3)胺盐酸盐(634mg,7.24mmol,4eq)、碘化钾(601mg,3.62mmol,2eq)、N,N-二异丙基乙胺(3.2mL,18.1mmol,10eq)和乙腈(15mL)。将微波小瓶盖好,接着在设定为100℃的沙浴中加热。1小时后,将反应混合物冷却至室温,接着添加水。将混合物用二氯甲烷萃取。将有机层用盐水洗涤,经硫酸钠干燥,过滤,接着在真空中浓缩。将粗产物使用二氯甲烷和甲醇作为洗脱剂进行正相快速色谱法,得到标题化合物(541mg,1.16mmol,64%)。
1H NMR(CDCl3)δ7.53(d,1H),7.11–7.00(m,4H),6.82–6.70(m,4H),6.62(d,1H),4.30(s,4H),4.26(t,2H),3.78(s,6H),2.74(t,2H)。
步骤D:1-(2-(双(甲基-d3)氨基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐
向1-(2-(双(甲基-d3)氨基)乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(541mg,1.16mmol,1eq)在二氯甲烷(5mL)中的溶液中添加三氟乙酸(5.0mL,64.9mmol,56eq)。在室温下搅拌反应混合物。搅拌过夜后,将混合物在真空中浓缩。将粗产物悬浮在甲醇中,过滤,并用甲醇洗涤残余物。合并滤液并在真空中浓缩,得到为三氟乙酸盐的标题化合物(394mg,1.16mmol,定量收率),将其原样用于下一反应。
1H NMR(CD3OD)δ7.85(d,1H),6.75(d,1H),4.72–4.61(m,2H),3.76–3.61(m,2H)。
中间体L6:1-异丙基-1H-吡唑-3-亚磺酰胺
步骤A:1-异丙基-3-硝基-1H-吡唑
在0℃在氮气下,向3-硝基-1H-吡唑(75g,663.3mmol,1eq)在无水DMF(500mL)中的溶液中添加NaH(29g,729.6mmol,60%纯度/矿物油,1.1eq)。将反应混合物搅拌30分钟。添加2-溴丙烷(98g,795.9mmol,1.2eq)。在氮气下于0℃继续搅拌30分钟。移除冰浴并将反应混合物在20℃下搅拌15小时。将所得混合物用水(500mL)淬灭并用乙酸乙酯(2L)萃取。将有机层用水(2x500mL)和盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,50:1至5:1)纯化,得到呈白色固体状的标题化合物(60g,58%)。
1H NMR(400MHz,CDCl3)δ7.49(d,1H),6.82(d,1H),4.59-4.46(m,1H)和1.51(d,6H)。
步骤B:1-异丙基-1H-吡唑-3-胺
在60℃下,向1-异丙基-3-硝基-1H-吡唑(50g,322.26mmol,1eq)和NH4Cl(86g,1.61mol,5eq)在EtOH(500mL)和H2O(300mL)中的溶液中分批添加呈粉末状的Fe(36g,644.52mmol,2eq)。将反应混合物在60℃下搅拌16小时,接着在减压下浓缩以去除EtOH。将残余物用H2O(1L)稀释并用EtOAc(3x1L)萃取。将合并的有机层用盐水(2x500mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩,得到呈蓝色油状物的标题化合物(39g,粗物质),将其直接用于下一步骤。
1H NMR(CDCl3)δ7.15(d,1H),5.55(d,1H),4.31-4.20(m,1H),3.60(br s,2H)和1.43(d,6H)。
LCMS:m/z 126.2(M+H)+(ES+)。
步骤C:1-异丙基-1H-吡唑-3-磺酰氯
在0℃下,将1-异丙基-1H-吡唑-3-胺(23g,183.75mmol,1eq)在MeCN(500mL)中的溶液先后用浓HCl(50mL,36wt%于H2O中)在H2O(50mL)中的溶液和NaNO2(15.2g,220.50mmol,1.2eq)在H2O(50mL)中的水溶液处理。将所得混合物在0℃下搅拌40分钟。添加AcOH(50mL)、CuCl2(12.4g,91.87mmol,0.5eq)和CuCl(909mg,9.19mmol,0.05eq)。接着在0℃下将SO2气体(15psi)鼓泡至该混合物中,持续20分钟。将反应混合物在0℃下搅拌1小时,接着在减压下浓缩以去除大部分MeCN和AcOH。将残余物用H2O(500mL)稀释并用EtOAc(3x500mL)萃取。将合并的有机层用盐水(2x300mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,30:1至10:1)纯化,得到呈黄色油状物的标题化合物(16.5g,43%)。
1H NMR(400MHz,CDCl3)δ7.59-7.57(m,1H),6.87-6.85(m,1H),4.70-4.59(m,1H)和1.57(dd,6H)。
步骤D:1-异丙基-1H-吡唑-3-亚磺酸钠
将Na2SO3(4.35g,34.50mmol,2eq)在H2O(12mL)中的溶液在20℃下搅拌10分钟。接着添加Na2CO3(3.66g,34.50mmol,2eq)。将所得混合物在50℃下搅拌10分钟。逐滴添加1-异丙基-1H-吡唑-3-磺酰氯(3.6g,17.25mmol,1eq)。将所得混合物在50℃下搅拌2小时,接着在真空中蒸发。将残余物用EtOH(24mL)处理。将悬浮液在20℃下搅拌10分钟。过滤悬浮液并蒸发滤液,得到白色固体。将白色固体用乙酸乙酯(20mL)处理10分钟,接着过滤混合物。收集滤饼并干燥,得到呈白色固体状的标题化合物(2.4g,67%收率,95%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.58(s,1H),6.17(s,1H),4.46-4.43(m,1H)和1.37(d,6H)。
LCMS:m/z 197(M+H)+(ES+)。
步骤E:1-异丙基-1H-吡唑-3-亚磺酰胺
在0℃下,向1-异丙基-1H-吡唑-3-亚磺酸钠(2.4g,12.23mmol,1eq)在THF(15mL)中的溶液中逐滴添加草酰二氯化物(3.11g,24.46mmol,2eq)。在20℃下搅拌1小时后,在0℃下将反应混合物添加至NH3.H2O(15mL,25wt%于H2O中)中,接着在20℃下搅拌1小时。在减压下浓缩反应混合物。将残余物用DCM(20mL)处理。将混合物在20℃下搅拌20小时,接着过滤。在减压下浓缩滤液,得到呈黄色油状物的标题化合物(1.2g,51%收率,90%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.87(d,1H),6.55(d,1H),6.26(s,2H),4.58-4.51(m,1H)和1.42(d,6H)。
LCMS:m/z 196(M+Na)+(ES+)。
中间体L7:3-氨亚磺酰基氮杂环丁烷-1-羧酸叔丁酯
步骤A:3-((甲基磺酰基)氧基)氮杂环丁烷-1-羧酸叔丁酯
在0℃下,向3-羟基氮杂环丁烷-1-甲酸叔丁酯(50g,288.67mmol,1eq)和TEA(87.63g,866.01mmol,3eq)在THF(500mL)中的溶液中添加甲磺酰氯(40g,346.40mmol,1.2eq)。将反应混合物在25℃搅拌12小时,接着用乙酸乙酯(2L)稀释。将有机层用水(3x1.5L)、盐水(3x1.5L)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈黄色油状物的标题化合物(70g,97%)。
1H NMR(400MHz,CDCl3)δ5.23-5.19(m,1H),4.30-4.26(m,2H),4.13-4.11(m,2H),3.08(s,3H)和1.45(s,9H)。
步骤B:3-(乙酰基硫基)氮杂环丁烷-1-羧酸叔丁酯
向3-((甲基磺酰基)氧基)氮杂环丁烷-1-羧酸叔丁酯(35g,139.28mmol,1eq)在DMF(360mL)中的溶液中添加乙硫醇钾(19g,167.13mmol,1.2eq)。将反应混合物在80℃搅拌12小时,接着用乙酸乙酯(1.5L)稀释。将有机层用饱和NH4Cl水溶液(3x1L)、盐水(3x1L)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到粗产物。将粗产物通过柱色谱法(SiO2,石油醚:乙酸乙酯,100:1至20:1)纯化,得到呈黄色油状物的标题化合物(26g,81%)。
1H NMR(400MHz,CDCl3)δ4.30(t,2H),4.11-4.07(m,1H),3.76-3.72(m,2H),2.27(s,3H)和1.36(s,9H)。
步骤C:3-巯基氮杂环丁烷-1-羧酸叔丁酯
向3-(乙酰基硫基)氮杂环丁烷-1-羧酸叔丁酯(20g,86.46mmol,1eq)在MeOH(80mL)、THF(80mL)和H2O(40mL)中的溶液中添加LiOH.H2O(3.63g,86.46mmol,1eq)。将反应混合物在70℃下搅拌2小时,倒入水(200mL)中,并用乙酸乙酯(3x200mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,得到呈黄色油状物的标题化合物(14g,86%)。
1H NMR(400MHz,CDCl3)δ4.37-4.32(m,2H),3.82-3.77(m,2H),3.70-3.59(m,1H)和1.44(s,9H)。
步骤D:3-(甲氧基亚磺酰基)氮杂环丁烷-1-羧酸叔丁酯
向3-巯基氮杂环丁烷-1-羧酸叔丁酯(6.5g,34.34mmol,1eq)在MeOH(130mL)中的溶液中添加NBS(12.2g,68.68mmol,2eq)。将反应混合物在25℃下搅拌10分钟,用饱和Na2SO3水溶液(200mL)淬灭,并用乙酸乙酯(3x200mL)萃取。将合并的有机层经无水Na2SO4干燥,过滤并浓缩,得到粗产物。将粗产物通过柱色谱法(SiO2,石油醚:乙酸乙酯,10:1至5:1)纯化,得到呈黄色油状物的标题化合物(5g,62%)。
1H NMR(400MHz,CDCl3)δ4.33-4.29(m,1H),4.14-4.08(m,3H),3.83(s,3H),3.66-3.62(m,1H)和1.45(s,9H)。
LCMS:m/z 258.1(M+Na)+(ES+)。
步骤E:1-(叔丁氧基羰基)氮杂环丁烷-3-亚磺酸钠
向3-(甲氧基亚磺酰基)氮杂环丁烷-1-羧酸叔丁酯(5g,21.25mmol,1eq)在MeOH(50mL)中的溶液中添加NaOH(1M,31.87mL,1.5eq)。将反应混合物在25℃下搅拌1小时,用1NHCl水溶液调节至pH=7,并在真空中浓缩以去除MeOH。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:1至0:1)纯化,得到呈白色固体状的标题化合物(5g,97%)。
1H NMR(400MHz,DMSO-d6)δ3.82-3.80(m,2H),3.66-3.64(m,2H),2.72-2.65(m,1H)和1.36(s,9H)。
步骤F:3-氨亚磺酰基氮杂环丁烷-1-羧酸叔丁酯
向1-(叔丁氧基羰基)氮杂环丁烷-3-亚磺酸钠(5g,20.55mmol,1eq)在THF(350mL)中的溶液中添加(COCl)2(5.2g,41.11mmol,2eq)。将反应混合物在25℃下搅拌2小时。在另一个容器中,在-78℃下将NH3(15psi)鼓泡至THF(20mL)中,持续10分钟。接着在-78℃下将上述反应混合物添加至NH3/THF(200mL)中。将所得反应反应混合物在25℃下再搅拌50分钟。过滤反应混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:1至0:1)纯化,得到呈无色油状物的标题化合物(2.5g,55%)。
1H NMR(400MHz,DMSO-d6)δ5.84(s,2H),4.08-3.99(m,3H),3.77-3.75(m,1H),3.63-3.58(m,1H)和1.38(s,9H)。
中间体L8:1-异丙基-1H-吡唑-3-磺酰胺
在0℃下,将NH3气体(15psi)鼓泡至1-异丙基-1H-吡唑-3-磺酰氯(中间体L6,步骤C)(20g,47.9mmol,1eq)在THF(300mL)中的溶液中,持续15分钟。将反应混合物在0℃下搅拌30分钟,接着使其升温至20℃并再搅拌2小时。过滤所得混合物,并在减压下浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,5:1至1:1)纯化,得到呈黄色固体状的标题化合物(6.7g,74%)。
1H NMR(400MHz,DMSO-d6)δ7.91(d,1H),7.35(s,2H),6.57(d,1H),4.63-4.52(m,1H)和1.43(d,6H)。
LCMS:m/z 190(M+H)+(ES+)。
中间体L9:2-(2-羟基丙-2-基)噻唑-5-磺酰胺
步骤A:2-(1,1-二甲氧基乙基)噻唑
在25℃下,向1-(噻唑-2-基)乙酮(25g,196.60mmol,1eq)在MeOH(350mL)中的溶液中添加三甲氧基甲烷(121g,1.14mol,5.80eq)和4-甲基苯磺酸(35.55g,206.43mmol,1.05eq)。接着将反应混合物在50℃下搅拌12小时,倒入H2O(400mL)中,并在真空中浓缩以去除MeOH。将残余物用饱和Na2CO3水溶液(200mL)淬灭,并将混合物用EtOAc(3x100mL)萃取。将合并的有机层用盐水(2x200mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈红色油状物的标题化合物(27g,粗物质)。
1H NMR(400MHz,CDCl3)δ7.84(d,1H),7.33(d,1H),3.27(s,6H)和1.75(s,3H)。
步骤B:5-溴-2-(1,1-二甲氧基乙基)噻唑
在N2下于-78℃下,向2-(1,1-二甲氧基乙基)噻唑(54g,311.72mmol,1eq)在THF(1000mL)中的溶液中逐滴添加n-BuLi(2.5M,137.16mL,1.1eq)。将反应混合物在-78℃下搅拌0.5小时。接着在10分钟内逐滴添加CBr4(113.71g,342.89mmol,1.1eq)在THF(250mL)中的溶液。过滤反应混合物,并将滤液倒入饱和NH4Cl水溶液(200mL)和水(200mL)中。用乙酸乙酯(2x200mL)萃取水相。将合并的有机相用盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至10:1)纯化,得到呈黄色油状物的标题化合物(70g,83%收率,90%纯度,经1H NMR测得)。
1H NMR(400MHz,CDCl3)δ7.70(s,1H),3.25(s,6H)和1.70(s,3H)。
步骤C:1-(5-溴噻唑-2-基)乙酮
在25℃下,向5-溴-2-(1,1-二甲氧基乙基)噻唑(70g,277.64mmol,1eq)在DCM(500mL)中的溶液中添加TFA(462g,4.05mol,14.59eq)和H2O(10g,555.08mmol,2.0eq)。接着将反应混合物在25℃下搅拌12小时,并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至15:1)纯化,得到呈红色固体状的标题化合物(51g,89%)。
1H NMR(400MHz,DMSO-d6)δ8.23(s,1H)和2.60(s,3H)。
步骤D:1-(5-苄基磺酰基噻唑-2-基)乙酮
在25℃下,向1-(5-溴噻唑-2-基)乙酮(20g,97.06mmol,1eq)、苯甲硫醇(13.26g,106.76mmol,1.1eq)、DIPEA(25.09g,194.12mmol,2eq)和(2.81g,4.85mmol,0.05eq)在二噁烷(200mL)中的溶液中添加Pd(dba)2(2.79g,4.85mmol,0.05eq)。在N2下将反应混合物在100℃下搅拌12小时,接着在25℃下搅拌30分钟。过滤反应混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至30:1)纯化,得到呈黄色固体状的标题化合物(20g,67%收率,81.5%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.46-7.27(m,5H),4.30(s,2H)和2.56(s,3H)。
LCMS:m/z 250.0(M+H)+(ES+)。
步骤E:2-乙酰基噻唑-5-磺酰氯
在0℃下,将Cl2气体(15psi)鼓泡至1-(5-苄基磺酰基噻唑-2-基)乙酮(20g,80.21mmol,1eq)在AcOH(360mL)和H2O(40mL)中的溶液中,持续45分钟。将反应混合物在0℃下搅拌1小时,接着倒入水(500mL)中。用乙酸乙酯(2x200mL)萃取水相。将合并的有机相用盐水(2x200mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈黄色油状物的标题化合物(18g,粗物质),将其直接用于下一步骤。
步骤F:2-乙酰基噻唑-5-磺酰胺
在-78℃下将NH3(15psi)鼓泡至THF(300mL)中,持续15分钟。接着在-78℃下将2-乙酰基噻唑-5-磺酰氯(18g,79.76mmol,1eq)在THF(50mL)中的溶液逐滴添加至NH3/THF溶液中。将反应混合物在25℃下搅拌30分钟,接着在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,10:1至1:1)纯化,得到呈黄色固体状的标题化合物(6.8g,41%)。
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.17(br s,2H)和2.65(s,3H)。
LCMS:m/z 206.9(M+H)+(ES+)。
步骤G:2-(2-羟基丙-2-基)噻唑-5-磺酰胺
在N2下于-10℃下,向2-乙酰基噻唑-5-磺酰胺(8.6g,41.70mmol,1eq)在THF(200mL)中的溶液中添加MeMgBr(3M,55.60mL,4eq)。将反应混合物在0℃下搅拌30分钟,接着在20℃下搅拌2小时。将反应混合物倒入NH4Cl水溶液中(500mL)中。用乙酸乙酯(2x100mL)萃取水相。将合并的有机相用盐水(2x200mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,10:1至1:1)纯化,得到呈黄色固体状的标题化合物(3.5g,38%)。
1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.81(br s,2H),6.29(br s,1H)和1.51(s,6H)。
LCMS:m/z 223.0(M+H)+(ES+)。
中间体L10:5-(2-羟基丙-2-基)噻唑-2-磺酰胺
步骤A:2-巯基噻唑-5-羧酸甲酯
将2-溴噻唑-5-羧酸甲酯(10g,45.03mmol,1eq)和NaHS(7.21g,90.07mmol,70wt%纯度(含30%H2O),2eq)在EtOH(100mL)中的溶液在80℃下搅拌2小时。将混合物倒入冰水(300mL)中并用乙酸乙酯(2x300mL)萃取。将合并的有机层用盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈浅黄色固体状的标题化合物(7.82g,90%收率,91%纯度,经LCMS测得),将其不经进一步纯化即用于下一步骤。
1H NMR(400MHz,DMSO-d6)δ13.83(br s,1H),8.12(s,1H)和3.77(s,3H)。
LCMS:m/z 176.6(M+H)+(ES+)。
步骤B:2-(氯磺酰基)噻唑-5-羧酸甲酯
在0℃下,向2-巯基噻唑-5-羧酸甲酯(5.5g,28.56mmol,1eq)在DCM(60mL)中的溶液中添加NCS(11.44g,85.69mmol,3eq)。将反应混合物在25℃下搅拌1小时,接着倒入冰水(100mL)中并用DCM(2x70mL)萃取。将合并的有机层用盐水(2x100mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈浅黄色油状物的标题化合物(6.90g,粗物质),将其不经进一步纯化即用于下一步骤。
步骤C:2-氨磺酰基噻唑-5-羧酸甲酯
在0℃下,向2-(氯磺酰基)噻唑-5-甲酸甲酯(6.90g,28.55mmol,1eq)在THF(80mL)中的搅拌溶液中鼓入NH3气体(15psi),持续0.25小时。将反应混合物在25℃下搅拌0.5小时,接着过滤。在真空下浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,5:1至3:1)纯化,得到呈浅黄色固体状的标题化合物(1.1g,16%收率,92%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.38(s,2H)和3.89(s,3H)。
LCMS:m/z 223.5(M+H)+(ES+)。
步骤D:5-(2-羟基丙-2-基)噻唑-2-磺酰胺
在N2下于-10℃下,向2-氨磺酰基噻唑-5-羧酸甲酯(1g,4.50mmol,1eq)在THF(20mL)中的溶液中逐滴添加MeMgBr(3M,6.75mL,4.5eq)。将反应混合物在0℃下搅拌0.5小时,接着升温至25℃并搅拌15小时。用饱和NH4Cl水溶液(50mL)缓慢淬灭反应混合物,并用EtOAc(2x50mL)萃取。将合并的有机层用盐水(2x70mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,10:1至3:1)纯化,得到呈浅黄色固体状的标题化合物(0.37g,35%收率,95%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.99(s,2H),7.81(s,1H),5.92(s,1H)和1.55(s,6H)。
LCMS:m/z 223.5(M+H)+(ES+)。
中间体L11:1-环丙基-1H-吡唑-3-磺酰氯
步骤A:1-环丙基-3-硝基-1H-吡唑
在25℃下,向环丙基硼酸(36.77g,428.04mmol,1.1eq)在DCE(500mL)中的溶液中添加3-硝基-1H-吡唑(44g,389.12mmol,1eq)、2,2-联吡啶(60.77g,389.12mmol,1eq)和Na2CO3(64.59g,609.44mmol,1.57eq)。将反应混合物在25℃下搅拌30分钟。接着添加Cu(OAc)2(70.68g,389.12mmol,1eq)。将所得反应混合物加热至70℃,搅拌15.5小时,并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,30:1至3:1)纯化,得到不纯的产物(26.7g)。将不纯的产物溶解在吡咯烷(10mL)中。将所得混合物在70℃下搅拌2小时,接着在减压下浓缩以去除吡咯烷。将残余物用H2O(33mL)稀释,并用1M HCl水溶液调节至pH=5-6。用EtOAc(3x50mL)萃取混合物。将合并的有机层用盐水(2x33mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩,得到呈黄色油状物的标题化合物(17.7g,30%)。
1H NMR(400MHz,CDCl3)δ7.54(d,1H),6.84(d,1H),3.73-3.67(m,1H),1.24-1.22(m,2H)和1.13-1.07(m,2H)。
步骤B:1-环丙基-1H-吡唑-3-胺
向1-环丙基-3-硝基-1H-吡唑(36g,235.08mmol,1eq)在EtOH(400mL)中的溶液中添加NH4Cl(62.87g,1.18mol,5eq)在H2O(150mL)中的溶液。接着将反应混合物加热至60℃,并分批添加铁粉(39.38g,705.24mmol,3eq)。将反应混合物在60℃下搅拌16小时,接着在减压下浓缩。将残余物用H2O(500mL)稀释,并将混合物用EtOAc(3x500mL)萃取。将合并的有机层用盐水(2x250mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,30:1至1:1)纯化,得到呈黄色油状物的标题化合物(20g,69%)。
1H NMR(400MHz,CDCl3)δ7.14(d,1H),5.11(d,1H),3.57(br s,2H),3.38-3.32(m,1H),0.99-0.95(m,2H)和0.90-0.87(m,2H)。
LCMS:m/z 124.2(M+H)+(ES+)。
步骤C:1-环丙基-1H-吡唑-3-磺酰氯
在0℃下,向1-环丙基-1H-吡唑-3-胺(19g,154.28mmol,1eq)在MeCN(500mL)和H2O(50mL)中的溶液中添加浓HCl溶液(50mL,36wt%于H2O中)。接着缓慢添加NaNO2(12.77g,185.13mmol,1.2eq)在H2O(50mL)中的水溶液。将所得混合物在0℃下搅拌40分钟。添加AcOH(50mL)、CuCl2(10.37g,77.14mmol,0.5eq)和CuCl(763mg,7.71mmol,0.05eq)。接着在0℃下将SO2气体(15psi)鼓泡至所得混合物中,持续20分钟。将反应混合物在0℃下搅拌1小时,接着在减压下浓缩。将残余物用H2O(250mL)稀释并用EtOAc(3x250mL)萃取。将合并的有机层用盐水(2x150mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,100:0至1:1)纯化,得到呈黄色油状物的标题化合物(14g,44%)。
1H NMR(400MHz,CDCl3)δ7.62(d,1H),6.83(d,1H),3.78-3.72(m,1H),1.28-1.24(m,2H)和1.16-1.12(m,2H)。
中间体L12:5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
步骤A:1-甲基-1H-吡唑-3-磺酰氯
在0℃下,将1-甲基-1H-吡唑-3-胺(20g,205.93mmol,1eq)在MeCN(500mL)中的溶液先后用HCl水溶液(1N,50mL)和NaNO2(17.05g,247.12mmol,1.2eq)在H2O(50mL)中的水溶液处理。将所得溶液在0℃下搅拌40分钟。接着添加AcOH(50mL)、CuCl2(13.84g,102.97mmol,0.5eq)和CuCl(1.02g,10.30mmol,0.05eq)。在0℃下将SO2气体(15psi)鼓泡至该混合物中,持续20分钟。将反应混合物在0℃下搅拌1小时,接着在减压下浓缩。将残余物用H2O(400mL)稀释并用乙酸乙酯(3x400mL)萃取。将合并的有机层用盐水(2x200mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,30:1至1:1)纯化,得到呈黄色油状物的标题化合物(12g,32%)。
1H NMR(400MHz,CDCl3)δ7.53(d,1H),6.86(d,1H)和4.05(s,3H)。
步骤B:N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺
向双(4-甲氧基苄基)胺(60g,233.17mmol,0.7eq)在THF(600mL)中的溶液中添加TEA(67.23g,664.41mmol,2eq)和1-甲基-1H-吡唑-3-磺酰氯(60g,332.20mmol,1eq)。将反应混合物在25℃下搅拌1小时,接着用H2O(1L)稀释。用HCl水溶液(1N)将pH调节至pH=5-6。用EtOAc(3x1L)萃取混合物。将合并的有机层用盐水(2x300mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物用EtOAc(200mL)研磨,得到呈白色固体状的标题化合物(50g,34%收率,90%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ7.41(d,1H),7.07-7.04(m,4H),6.78-6.75(m,4H),6.62(d,1H),4.31(s,4H),3.96(s,3H)和3.78(s,6H)。
LCMS:m/z 402.2(M+H)+(ES+)。
步骤C:3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸
在-70℃下,向N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺(100g,249.08mmol,1eq)在THF(1.35L)中的溶液中逐滴添加n-BuLi(2.5M,104.61mL,1.05eq)。将反应混合物在-70℃下搅拌1小时。接着将CO2气体(15psi)鼓泡至反应混合物中,持续15分钟。将所得混合物在-70℃下再搅拌1小时,用H2O(1.2L)淬灭,用HCl水溶液(1N)调节至pH=3,并用EtOAc(2×1L)萃取。将合并的有机相用盐水(2x1L)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物用石油醚和乙酸乙酯的混合物(300mL,石油醚:乙酸乙酯,1:1)研磨,得到呈白色固体状的标题化合物(94g,84%收率,99%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ6.98-7.16(m,5H),6.82(d,4H),4.25(s,4H),4.15(s,3H)和3.72(s,6H)。
LCMS:m/z 468.2(M+Na)+(ES+)。
步骤D:3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯
在N2下于0℃下,向3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸(42.75g,95.96mmol,1eq)和DMF(701mg,9.60mmol,0.1eq)在DCM(500mL)中的溶液中添加(COCl)2(37g,287.89mmol,3eq)。将反应混合物在25℃下搅拌0.5小时,接着在0℃下逐滴添加至EtOH(100mL)中。将所得混合物在25℃下搅拌1.5小时,接着在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,15:1至10:1)纯化,得到呈白色固体状的标题化合物(37.5g,80%收率,97.4%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.08(s,1H),7.06(d,4H),6.80(d,4H),4.35-4.29(m,2H),4.26(s,4H),4.15(s,3H),3.71(s,6H)和1.32(t,3H)。
LCMS:m/z 496.1(M+Na)+(ES+)。
步骤E:1-甲基-3-氨磺酰基-1H-吡唑-5-羧酸乙酯
将3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯(35.9g,75.81mmol,1eq)在DCM(200mL)和TFA(100mL)中的溶液在25℃下搅拌15小时。将反应混合物在25℃下在真空中浓缩。将残余物用MeOH(200mL)处理,其中一些固体不溶解。过滤混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯:DCM,10:1:1至1:1:1)纯化,得到呈白色固体状的标题化合物(14.5g,81%收率,98.7%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.58(s,2H),7.09(s,1H),4.32(q,2H),4.14(s,3H)和1.32(t,3H)。
LCMS:m/z 233.9(M+H)+(ES+)。
步骤F:5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
在N2下于-10℃历时0.5小时向1-甲基-3-氨磺酰基-1H-吡唑-5-羧酸乙酯(13.5g,57.88mmol,1eq)在THF(400mL)中的混合物中逐滴添加甲基溴化镁(3M,96.47mL,5eq)。将反应混合物在0℃下搅拌0.5小时,接着升温至25℃并搅拌15小时。用饱和NH4Cl水溶液(300mL)缓慢淬灭反应混合物,并用EtOAc(2x300mL)萃取。将合并的有机层用盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,2:1至0:1)纯化,得到呈无色油状物的标题化合物(5.52g,43%收率,98.7%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.32(s,2H),6.40(s,1H),5.47(s,1H),4.01(s,3H)和1.50(s,6H)。
LCMS:m/z 220.1(M+H)+(ES+)。
中间体L13:4-((二甲氨基)甲基)苯磺酰胺
步骤A:4-(溴甲基)苯磺酰胺
在20℃下,向4-甲基苯磺酰胺(2g,11.68mmol,1eq)和NBS(2.2g,12.27mmol,1.05eq)在四氯化碳(20mL)中的溶液中添加AIBN(192mg,1.17mmol,0.1eq)。将反应混合物在80℃下搅拌2小时,冷却至室温并倒入冰水(20mL)中。用乙酸乙酯(3x20mL)萃取水相。将合并的有机层用盐水(20mL)洗涤,经无水硫酸钠干燥,过滤并在真空中浓缩,得到呈黄色固体状的标题化合物(3g,粗物质)。
1H NMR(400MHz,CD3OD)δ7.87(d,2H),7.59(d,2H)和4.62(s,2H)。
步骤B:4-((二甲氨基)甲基)苯磺酰胺
将4-(溴甲基)苯磺酰胺(1.5g,6.00mmol,1eq)和二甲胺(10mL,33wt%于H2O中,10eq)在THF(5mL)中的混合物在20℃下搅拌12小时,接着在真空中浓缩。将残余物通过反相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈黄色固体状的标题化合物(0.6g,47%)。
1H NMR(400MHz,CD3OD)δ7.87(d,2H),7.49(d,2H),3.55(s,2H)和2.25(s,6H)。
LCMS:m/z 215.1(M+H)+(ES+)。
中间体L14:5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
步骤A:3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯
将3-(氯磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯(9.2g,36.4mmol)逐滴添加至双(4-甲氧基苄基)胺(9.4g,36.5mmol)和三乙胺(10mL,71.7mmol)在DCM(200mL)中的溶液中,于冰浴中冷却。将所得混合物搅拌30分钟,升温至室温并搅拌90分钟,之后用水(200mL)、盐酸水溶液(1M,200mL)、水(200mL)洗涤,干燥(MgSO4),过滤并蒸发,得到黄色油状物。将其通过硅胶色谱法(220g柱,0-60%乙酸乙酯/异己烷)纯化,得到呈白色固体状的标题化合物(15.9g,91%)。
1H NMR(DMSO-d6)δ7.19-7.00(m,5H),6.85-6.77(m,4H),4.33(q,2H),4.25(s,4H),4.15(s,3H),3.71(s,6H)和1.33(t,3H)。
LCMS m/z 496.4(M+Na)+(ES+)。
步骤B:5-(2-羟基丙-2-基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺
将3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯(1.4g,2.96mmol)溶解在无水THF(50mL)中,并在干冰/丙酮浴中冷却至-78℃。在15分钟内经由注射器缓慢添加氯化甲基镁(3M于THF中,5mL,15.0mmol)。使反应混合物达到室温并搅拌过夜,之后在冰浴中冷却,并用部分氯化铵水溶液(20mL)缓慢淬灭。将混合物萃取到乙酸乙酯(3x50mL)中,并将合并的有机萃取物用盐水(10mL)洗涤,干燥(Na2SO4),过滤并在真空中浓缩,得到无色油状物。将粗产物通过硅胶色谱法(40g柱,0-50%乙酸乙酯/异己烷)纯化,得到呈粘稠无色油状物的标题化合物(1.11g,67%)。
1H NMR(DMSO-d6)δ7.09-7.03(m,4H),6.85-6.80(m,4H),6.41(s,1H),4.21(s,4H),4.04(s,3H),3.72(s,6H)和1.50(s,6H)。未观察到一个可交换质子。
LCMS m/z 460(M+H)+(ES+);458(M-H)-(ES-)。
步骤C:N,N-双-(4-甲氧基苄基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
在氮气气氛下,将5-(2-羟基丙-2-基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺(2.5g,5.33mmol)溶解在无水DMF(50mL)中。在冰浴中冷却后,按单份添加氢化钠(60%于矿物油中,0.25g,6.25mmol),并将浑浊的黄色混合物搅拌30分钟。按单份添加碘甲烷(1.5mL,24.1mmol),并将混合物再搅拌2小时,同时升温至室温。通过缓慢添加饱和氯化铵水溶液(10mL)来淬灭反应混合物,接着在乙酸乙酯(100mL)与水(50mL)之间分配。用乙酸乙酯(4x50mL)萃取水相。将合并的有机部分用盐水(20mL)洗涤,干燥(Na2SO4),过滤并在真空中浓缩,得到黄色油状物。将粗产物通过硅色谱法(40g柱,0-100%乙酸乙酯/异己烷)纯化,在真空中干燥后,得到呈无色固体状的标题化合物(2.41g,94%)。
1H NMR(DMSO-d6)δ7.10-7.04(m,4H),6.85-6.80(m,4H),6.48(s,1H),4.23(s,4H),3.97(s,3H),3.72(s,6H),2.97(s,3H)和1.50(s,6H)。
LCMS m/z 474(M+H)+(ES+);472(M-H)-(ES-)。
步骤D:5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
将N,N-双-(4-甲氧基苄基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(2.4g,5.02mmol)溶解在乙腈(40mL)中。按单份添加硝酸铈铵(15g,27.4mmol)在水(10mL)中的溶液,并将暗红色反应混合物在室温下搅拌4小时。添加水(10mL)和DCM(250mL),分离有机相,通过疏水性玻璃料干燥,并在真空中浓缩,得到橙色油状物(约2.5g)。通过硅胶色谱法(40g柱,0-20%甲醇/二氯甲烷)纯化粗产物,得到橙色油状物。将该物质在TBME(10mL)和异己烷(5mL)中研磨,得到棕褐色沉淀物,将其通过硅胶色谱法(24g,20%-100%乙酸乙酯/己烷)进一步纯化,得到呈黄色固体状的标题化合物(383mg,31%)。
1H NMR(CDCl3)δ6.57(s,1H),5.08(s,2H),4.06(s,3H),3.08(s,3H)和1.57(s,6H)。
中间体L15:1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺
步骤A:1-(2,2,2-三氟乙基)-1H-吡唑-4-胺
将4-硝基-1-(2,2,2-三氟乙基)-1H-吡唑(1g,5.13mmol)和10%Pd/C(湿)87L型(27mg,0.256)用MeOH(12.8mL)和EtOAc(12.8mL)悬浮。用N2吹扫容器三次,接着用H2吹扫三次。将反应混合物在5巴H2下在室温下搅拌18小时。将反应混合物过滤通过硅藻土垫。用EtOAc(2x5mL)洗涤滤饼,并将合并的滤液在真空中蒸发,得到呈红色油状物的标题化合物(0.85g,100%)。
1H NMR(氯仿-d)δ7.25(d,J=0.9Hz,1H),7.09(d,J=0.8Hz,1H),4.57(q,J=8.4Hz,2H),2.43(br s,2H)。
19F NMR(氯仿-d)δ-71.88(t,J=8.4Hz)。
LCMS m/z 166.0(M+H)+(ES+)。
步骤B:1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰氯
将浓HCl(1.9mL)在水(1.3mL)和乙腈(6.5mL)中的混合物冷却至-10℃(丙酮/干冰浴),并用亚硝酸钠(426mg,6.18mmol)在水(0.7mL)中的溶液逐滴处理,维持内部温度低于0℃。形成黄色溶液,将其搅拌10分钟,接着在0℃下在15分钟内用1-(2,2,2-三氟乙基)-1H-吡唑-4-胺(850mg,5.15mmol)在MeCN(6.5mL)中的溶液处理,将其预冷却至0℃。将所得反应混合物在0℃下搅拌45分钟。将冷乙酸(2.6mL)、氯化铜(II)(346mg,2.57mmol)和氯化铜(I)(25.5mg,0.257mmol)依序添加至反应混合物中。接着在0℃下将反应混合物用二氧化硫气体吹扫70分钟。将反应混合物用水(15mL)稀释,并用EtOAc(3x30mL)萃取,接着干燥(MgSO4),过滤并浓缩至干,得到棕色糊状物。将粗产物通过硅胶色谱法(40g柱,0-50%DCM/异己烷)纯化,得到呈澄清黄色油状物的标题化合物(420mg,16%)。
1H NMR(氯仿-d)δ8.20(s,1H),8.06(s,1H),4.81(q,J=8.1Hz,2H)。
步骤C:1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺
将1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰氯(420mg,0.845mmol)(50wt%纯度)在THF(1.4mL)中的溶液用NH3(0.5M/二噁烷,5mL)处理。接着将反应混合物在室温下搅拌17小时。在真空中去除溶剂,并将残余物在水(5mL)与DCM(15mL)之间分配。分离有机相,并用DCM(2x15mL)萃取水层。将合并的有机层干燥(MgSO4),在真空中浓缩,得到橙色油状物,将其与3:1异己烷/DCM共蒸发两次,直至干燥的混合物固化。接着将固体产物溶解在DCM(3mL)中,并添加异己烷(9mL)。倾析出上清液,并用3:1异己烷/DCM(1x3mL)和异己烷(2x3mL)洗涤固体。收集固体并在真空中干燥,得到呈橙色粉末状的标题化合物(159mg,78%)。
1H NMR(DMSO-d6)δ8.32(d,J=0.7Hz,1H),7.87(d,J=0.7Hz,1H),7.42(s,2H),5.24(q,J=9.0Hz,2H)。
19F NMR(DMSO-d6)δ-70.16(t,J=9.0Hz)。
LCMS m/z 227.9/228.9(M-H)-(ES-)。
中间体L16:1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰胺
步骤A:1-(2,2,2-三氟乙基)-1H-吡唑-3-胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-胺(中间体L15,步骤A)的一般程序由3-硝基-1-(2,2,2-三氟乙基)-1H-吡唑进行制备,得到呈黄色固体状的标题化合物(420mg,98%)。
1H NMR(氯仿-d)δ7.23(d,J=2.4Hz,1H),5.72(d,J=2.4Hz,1H),4.47(q,J=8.4Hz,2H),2.96-2.27(br s,2H)。
LCMS m/z 166.0(M+H)+(ES+)。
步骤B:1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰氯
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰氯(中间体L15,步骤B)的一般程序由1-(2,2,2-三氟乙基)-1H-吡唑-3-胺进行制备,得到呈澄清橙色油状物的标题化合物(756mg,50%)。
1H NMR(氯仿-d)δ7.69(d,J=2.5Hz,1H),7.00(d,J=2.5Hz,1H),4.86(q,J=8.1Hz,2H)。
19F NMR(氯仿-d)δ-71.16(t,J=8.1Hz)。
LCMS m/z 246.8(M-H)-(ES-)。
步骤C:1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15,步骤C)的一般程序由1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰氯进行制备,得到呈白色粉末状的标题化合物(394mg,67%)。
1H NMR(DMSO-d6)δ8.00(d,J=2.4Hz,1H),7.55(s,2H),6.70(d,J=2.4Hz,1H),5.26(q,J=9.1Hz,2H)。
19F NMR(DMSO-d6)δ-70.08(t,J=9.2Hz)。
LCMS m/z 229.1(M+H)+(ES+);227.9(M-H)-(ES-)。
中间体L17:1-异丙基-3-甲基-1H-吡唑-4-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15,步骤C)的一般程序由1-异丙基-3-甲基-1H-吡唑-4-磺酰氯进行制备,得到呈白色结晶固体状的标题化合物(541mg,59%)。
1H NMR(DMSO-d6)δ8.06(s,1H),7.15(s,2H),4.46(sept,J=6.6Hz,1H),2.29(s,3H),1.38(d,J=6.7Hz,6H)。
LCMS m/z 204.0(M+H)+(ES+)。
中间体L18:1-(环丙基甲基)-1H-吡唑-4-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15,步骤C)的一般程序由1-(环丙基甲基)-1H-吡唑-4-磺酰氯进行制备,得到呈桃红色固体状的标题化合物(153mg,66%)。
1H NMR(DMSO-d6)δ8.21(d,J=0.7Hz,1H),7.71(d,J=0.8Hz,1H),7.25(s,2H),4.00(d,J=7.2Hz,2H),δ1.33-1.17(m,1H),0.63-0.49(m,2H),0.41-0.36(m,2H)。
LCMS m/z 202.0(M+H)+(ES+)。
中间体L19:1-乙基-1H-吡唑-3-磺酰胺
步骤A:1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-亚磺酸锂
将BuLi(100mL,250mmol,2.5M/己烷)缓慢添加至1-(四氢-2H-吡喃-2-基)-1H-吡唑(36.2g,238mmol)在THF(500mL)中的溶液中,维持温度低于-65℃。将混合物搅拌1.5小时,接着使二氧化硫鼓泡通过,持续10分钟。将混合物升温至室温,蒸发溶剂,并将残余物用TBME(300mL)研磨且过滤。用TBME和异己烷洗涤固体,干燥,得到粗标题化合物(54.9g,99%)。
1H NMR(DMSO-d6)δ7.26(d,J=1.6Hz,1H),6.10(d,J=1.7Hz,1H),5.99(dd,J=10.0,2.5Hz,1H),3.92-3.87(m,1H),3.56-3.49(m,1H),2.25-2.15(m,1H),2.00-1.91(m,1H),1.75-1.69(m,1H),1.66-1.46(m,3H)。
LCMS m/z 215(M-H)-(ES-)。
步骤B:N,N-双(4-甲氧基苄基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-磺酰胺
将NCS(12.0g,90mmol)添加至1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-亚磺酸锂(20g,90mmol)在DCM(250mL)中的悬浮液中,在冰浴中冷却。将混合物搅拌4小时,用水(100mL)淬灭,接着在DCM(300mL)与水(200mL)之间分配。将有机相用水(200mL)洗涤,干燥(MgSO4),并蒸发至约50mL。将溶液添加至双(4-甲氧基苄基)胺(24g,93mmol)和三乙胺(40mL,287mmol)在DCM(300mL)中的混合物中,在冰浴中冷却。搅拌1小时后,将混合物升温至室温,并在DCM(300mL)与水(250mL)之间分配。将有机层用水(250mL)、1M HCl水溶液(2x250mL)、水(250mL)洗涤,干燥(MgSO4)并蒸发,得到呈棕色油状物的标题化合物(41.0g,97%)。
LCMS m/z 494.2(M+Na)+(ES+)。
步骤C:N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
将N,N-双(4-甲氧基苄基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-磺酰胺(41g,87mmol)和1M HCl水溶液(30mL)在THF(300mL)和MeOH(50mL)中的混合物在室温下搅拌18小时。蒸发溶剂并将残余物在EtOAc(400mL)与1M HCl水溶液(200mL)之间分配。将有机层用10%盐水(200mL)洗涤,干燥(MgSO4)并蒸发。将残余物用TBME研磨,过滤并干燥,得到呈灰白色固体状的标题化合物(24.9g,69%)。
1H NMR(CDCl3)δ7.88(d,J=2.4Hz,1H),7.06-7.02(m,4H),6.79-6.75(m,4H),6.63(d,J=2.4Hz,1H),4.31(s,4H),3.78(s,6H)。未观察到一个可交换质子。
LCMS m/z 388(M+H)+(ES+);386(M-H)-(ES-)。
步骤D:1-乙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
在氮气下,添加N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(0.347g,0.896mmol)溶解在无水MeCN(10mL)和K2CO3(0.619g,4.48mmol)。按单份添加溴乙烷(0.267mL,3.58mmol),并将混浊的混合物加热至60℃保持30小时。将混合物用水(5mL)稀释并用EtOAc(3x25mL)萃取。将有机相干燥(MgSO4)并在真空中浓缩。将粗产物通过硅胶色谱法(40g柱,0-100%EtOAc/异己烷)纯化,得到呈无色油状物的标题化合物(280mg,69%)。
LCMS m/z 416(M+H)+(ES+)。
步骤E:1-乙基-1H-吡唑-3-磺酰胺
将1-乙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(280mg,0.674mmol)溶解在DCM(1mL)中,并且添加水(0.5mL)和TFA(2mL)。将反应混合物在室温下搅拌15小时。将溶液在真空中浓缩,并将残余物通过RP快速C18反相色谱法(12g柱,1%-30%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(102mg,83%)。
1H NMR(DMSO-d6)δ7.88(d,J=2.3Hz,1H),7.36(br s,2H),6.57(d,J=2.3Hz,1H),4.20(q,J=7.3Hz,2H),1.40(t,J=7.3Hz,3H)。
中间体L20:1-异丙基-1H-1,2,4-三唑-3-磺酰胺
步骤A:3-(苄硫基)-1-异丙基-1H-1,2,4-三唑
将2-碘丙烷(3.00mL,30.0mmol)添加至3-(苄硫基)-1H-1,2,4-三唑(8.2g,30.0mmol)和K2CO3(8.30g,60.0mmol)在DMF(100mL)中的混合物中,在冰浴中冷却。将混合物搅拌2小时,接着升温至室温并搅拌20小时。将混合物在EtOAc(200mL)与水(100mL)之间分配,将有机层用水(2x100mL)洗涤,干燥(MgSO4)并蒸发。将残余物通过硅胶色谱法(80g柱,0-50%EtOAc/异己烷)纯化,得到呈油状物的标题化合物(2.8g,40%)。
1H NMR(DMSO-d6)δ8.53(s,1H),7.41-7.35(m,2H),7.33-7.19(m,3H),4.54(sept,J=6.8Hz,1H),4.31(s,2H),1.42(d,J=6.6Hz,6H)。
LCMS m/z 234.4(M+H)+(ES+)。
步骤B:1-异丙基-1H-1,2,4-三唑-3-磺酰氯
将NCS(5.59g,41.8mmol)添加至3-(苄硫基)-1-异丙基-1H-1,2,4-三唑(2g,10.46mmol)在AcOH(40mL)和水(20mL)中的溶液中。将混合物搅拌2小时,接着在EtOAc(200mL)与水(200mL)之间分配。将有机层用饱和NaHCO3水溶液(100mL)、盐水(50mL)洗涤,干燥(MgSO4),过滤并蒸发。向残余物中添加TBME(20mL),滤出固体并蒸发滤液,得到呈黄色油状物的标题化合物(1.80g),将其不经纯化即用于下一步骤。
步骤C:1-异丙基-1H-1,2,4-三唑-3-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15,步骤C)的一般程序由1-异丙基-1H-1,2,4-三唑-3-磺酰氯进行制备,得到呈无色固体状的标题化合物(770mg,37%收率,经2个步骤)。
1H NMR(DMSO-d6)δ8.76(s,1H),7.71(s,2H),4.69(sept,J=6.7Hz,1H),1.47(d,J=6.7Hz,6H)。
中间体L21:(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺
将1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(712mg,3.76mmol)在MeCN(4.4mL)中的溶液用N,N-二甲基吡啶-4-胺(919mg,7.53mmol)处理,并将反应混合物在室温下搅拌,直至磺酰胺溶解。添加碳酸二苯酯(887mg,4.14mmol),并将反应混合物在室温下放置16小时。通过过滤分离所得沉淀物,用MTBE洗涤并干燥,得到呈白色固体状的标题化合物(776mg,61%),将其不经进一步纯化即使用。
1H NMR(CDCl3)δ8.95(d,J=7.5Hz,2H),7.35(d,J=2.3Hz,1H),6.83(d,J=2.3Hz,1H),6.62(d,J=7.5Hz,2H),4.58–4.43(m,1H),3.24(s,6H),1.42(d,J=6.7Hz,6H)。
中间体L22:1-异丙基-1H-1,2,3-三唑-5-磺酰胺
步骤A:4-(苄硫基)-1H-1,2,3-三唑
将苄基溴(24mL,202mmol)逐滴添加至1H-1,2,3-三唑-4-硫醇钠(25g,203mmol)在EtOH(300mL)中的悬浮液中,在冰浴中冷却。将混合物搅拌48小时,接着蒸发溶剂。将残余物在EtOAc(500mL)与水(300mL)之间分配,将有机层用盐水(200mL)洗涤,干燥(MgSO4)并蒸发。将残余物用TBME/异己烷研磨,得到呈白色固体状的标题化合物(35.1g,88%)。
1H NMR(CDCl3)δ7.40-7.24(m,7H),4.16(s,2H)。
LCMS m/z 192(M+H)+(ES+);190(M-H)-(ES-)。
步骤B:5-(苄硫基)-1-异丙基-1H-1,2,3-三唑
将2-碘丙烷(7mL,70.1mmol)添加至4-(苄硫基)-1H-1,2,3-三唑(12g,62.7mmol)和K2CO3(18g,130mmol)在DMF(150mL)中的混合物中,在冰浴中冷却。将混合物搅拌2小时,接着升温至室温并搅拌20小时。将混合物在EtOAc(400mL)与水(400mL)之间分配。将有机层用水(2x300mL)洗涤,干燥(MgSO4),并在真空中蒸发。将残余物通过硅胶色谱法(220g柱,0-50%EtOAc/异己烷)纯化,得到呈油状物的标题化合物(1.95g,13%)。
1H NMR(CDCl3)δ7.62(s,1H),7.32-7.26(m,3H),7.14-7.10(m,2H),4.64(sept,J=6.7Hz,1H),3.94(s,2H),1.41(d,J=6.7Hz,6H)。
4-(苄硫基)-1-异丙基-1H-1,2,3-三唑(2.39g,16%)和4-(苄硫基)-2-异丙基-2H-1,2,3-三唑(9.16g,61%)也从此反应中分离出来。
步骤C:1-异丙基-1H--1,2,3-三唑-5-磺酰氯
根据1-异丙基-1H1,2,4-三唑-3-磺酰氯(中间体L20,步骤B)的一般程序由5-(苄硫基)-1-异丙基-1H-1,2,3-三唑进行制备得到油状物,将其不经纯化即用于下一步骤。
步骤D:1-异丙基-1H-1,2,3-三唑-5-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中级L15,步骤C)的一般程序由1-异丙基-1H-1,2,3-三唑-5-磺酰氯进行制备,得到呈灰白色固体状的标题化合物(757mg,65%)。
1H NMR(DMSO-d6)δ8.32(br s,2H),8.04(s,1H),5.15(sept,J=6.6Hz,1H),1.56(d,J=6.6Hz,6H)。
中间体L23:2-异丙基-2H-1,2,3-三唑-4-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中级L15,步骤C)的一般程序由2-异丙基-2H-1,2,3-三唑-4-磺酰氯进行制备,得到呈白色固体状的标题化合物(1.17g,71%)。
1H NMR(CDCl3)δ7.97(s,1H),5.18(br s,2H),4.92(sept,J=6.7Hz,1H),1.64(d,J=6.7Hz,6H)。
中间体L24:5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺
步骤A:1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
根据3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯(中间体L14,步骤A)的一般程序由1-异丙基-1H-吡唑-3-磺酰氯(中间体L6,步骤C)进行制备,得到呈白色固体状的标题化合物(16.6g,80%)。
1H NMR(DMSO-d6)δ8.00(d,J=2.4Hz,1H),7.07-6.96(m,4H),6.85-6.76(m,4H),6.70(d,J=2.4Hz,1H),4.61(sept,J=6.7Hz,1H),4.20(s,4H),3.71(s,6H),1.44(d,J=6.7Hz,6H)。
LCMS m/z 452.2(M+Na)+(ES+)。
步骤B:5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
将1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(2.5g,5.82mmol)在THF(30mL)中的溶液冷却至-78℃并经由注射器缓慢添加BuLi(2.5M于THF中,2.4mL,6.00mmol)。添加完成后,将混合物在-78℃下搅拌1小时,之后经由注射器缓慢添加丙-2-酮(0.52mL,7.08mmol)。将混合物升温至室温并搅拌1小时。将反应物用饱和NH4Cl水溶液(25mL)淬灭并用EtOAc(3x75mL)萃取。将合并的有机萃取物用盐水(50mL)洗涤,干燥(相分离器)并蒸发,得到黄色油状物。将粗产物通过硅胶色谱法(80g柱,0-100%EtOAc/异己烷)纯化,得到呈澄清黄色油状物的标题化合物(2.80g,49%),其缓慢固化。
LCMS m/z 510.5(M+Na)+(ES+)。
步骤C:5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺
根据5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14,步骤D)的一般程序由5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈淡黄色固体状的标题化合物(72.5mg,28%)。
1H NMR(DMSO-d6)δ7.32(s,2H),6.34(s,1H),5.51(s,1H),5.27(sept,J=6.6Hz,1H),1.51(s,6H),1.39(d,J=6.6Hz,6H)。
LCMS m/z 248.4(M+H)+(ES+)。
中间体L25:5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺
步骤A:5-(1-羟基环丁基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺
根据5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤B)的一般程序由N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L12,步骤B)和环丁酮进行制备,得到标题化合物(1.09g,61%)和起始物质的3:2混合物。
LCMS m/z 472.5(M+H)+(ES+)。
步骤B:N,N-双(4-甲氧基苄基)-5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺
根据N,N-双-(4-甲氧基苄基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14,步骤C)的一般程序由5-(1-羟基环丁基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈无色油状物的标题化合物(0.41g,91%)。
1H NMR(DMSO-d6)δ=7.09-7.04(m,4H),6.85-6.79(m,4H),6.75(s,1H),4.24(s,4H),3.81(s,3H),3.71(s,6H),2.85(s,3H),2.44-2.25(m,4H),1.89-1.76(m,1H),1.62-1.49(m,1H)。
LCMS m/z 508.5(M+Na)+,486.5(M+H)+(ES+)。
步骤C:5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由N,N-双(4-甲氧基苄基)-5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈淡棕色固体状的标题化合物(0.198g,89%)。
LCMS m/z 245.8(M+H)+(ES+)。
中间体L26:5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺
步骤A:5-(1-羟基环戊基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺
根据5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤B)的一般程序由N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L12,步骤B)和环戊酮进行制备,得到起始物质和呈乳白色固体状的标题化合物(1.96g,55%)的63:37混合物(经HPLC测得)。
LCMS m/z 486.2(M+H)+(ES+)。
步骤B:N,N-双(4-甲氧基苄基)-5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺
根据N,N-双-(4-甲氧基苄基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14,步骤C)的一般方法由5-(1-羟基环戊基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈无色油状物的标题化合物(0.61g,93%)。
LCMS m/z 500.2(M+H)+(ES+)。
步骤C:5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺
根据5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14,步骤D)的一般方法由N,N-双(4-甲氧基苄基)-5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈橙色固体状的标题化合物(0.22g,35%)。
LCMS m/z 260.3(M+H)+(ES+)。
中间体L27:5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺
步骤A:5-(1-羟乙基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺
根据5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤B)的一般程序由N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L12,步骤B)和乙醛进行制备,得到呈粘稠无色油状物的标题化合物(2.12g,60%)。
1H NMR(DMSO-d6)δ7.09-7.01(m,4H),6.86-6.77(m,4H),6.54(s,1H),5.51(d,J=5.7Hz,1H),4.86(p,J=6.4Hz,1H),4.20(s,4H),3.91(s,3H),3.72(s,6H),1.43(d,J=6.5Hz,3H)。
LCMS m/z 446(M+H)+(ES+)。
步骤B:N,N-双(4-甲氧基苄基)-5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺
根据N,N-双-(4-甲氧基苄基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14,步骤C)的一般程序由5-(1-羟乙基)-N,N-双(4-甲氧基苄基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈油状物的标题化合物(858mg,99%)。
1H NMR(CDCl3)δ7.12-7.08(m,4H),6.81-6.76(m,4H),6.51(s,1H),4.53(q,J=6.6Hz,1H),4.34(s,4H),3.95(s,3H),3.80(s,6H),3.29(s,3H),1.53(d,J=6.6Hz,3H)。
LCMS m/z 460.1(M+H)+(ES+)。
步骤C:5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由N,N-双(4-甲氧基苄基)-5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺进行制备,得到呈棕色固体状的标题化合物(395mg,93%)。
1H NMR(DMSO-d6)δ7.37(s,2H),6.53(s,1H),4.64(q,J=6.5Hz,1H),3.87(s,3H),3.22(s,3H),1.43(d,J=6.5Hz,3H)。
LCMS m/z 220.2(M+H)+(ES+)。
中间体L28:5-(1-羟乙基)-1-异丙基-1H-吡唑-3-磺酰胺
步骤A:5-(1-羟乙基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
根据5-(2-羟基丙-2-基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤B)的一般程序由1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤A)和乙醛进行制备,得到呈白色固体状的标题化合物(2.14g,65%)。
1H NMR(DMSO-d6)δ7.07-6.99(m,4H),6.84-6.78(m,4H),6.51(s,1H),5.49(d,J=6.0Hz,1H),4.96-4.76(m,2H),4.19(s,4H),3.72(s,6H),1.44(d,J=6.5Hz,3H),1.39(appt,J=6.4Hz,6H)。
LCMS m/z 496.4(M+Na)+(ES+)。
步骤B:5-(1-羟乙基)-1-异丙基-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由5-(1-羟乙基)-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈白色固体状的标题化合物(0.09g,36%)。
LCMS 234.3(M+H)+(ES+)。
中间体L29:4-氟-1-异丙基-1H-吡唑-3-磺酰胺
在室温下将(2.81g,7.93mmol)分批添加至1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(0.5g,2.64mmol)在无水乙腈(8mL)中的溶液中,接着将溶液在66℃下搅拌24小时。添加另一部分的(2.81g,7.93mmol),并将反应物在66℃下再搅拌24小时。将反应物用MeOH(50mL)稀释,过滤并在减压下浓缩。将残余物溶解于无水MeCN(10mL)中,分批添加(4.68g,13.2mmol),并将反应物在66℃下搅拌24小时,冷却至室温,溶解于MeOH(50mL)中,过滤并在减压下浓缩。将残余物溶解于无水MeCN(20mL)中,另外分批添加(3.7g,10.6mmol),并将反应物在66℃下再搅拌18小时。在减压下去除挥发物并且将残余物溶解于DCM/水(1:1,150mL)中。分离有机相,将水相进一步用EtOAc(70mL)萃取,并将合并的有机相干燥(MgSO4),过滤并在减压下浓缩。将残余物通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(36mg,6%)。
LCMS m/z 208.0(M+H)+(ES+)。
中间体L30:1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-1H-吡唑-3-磺酰胺
步骤A:2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)-2-甲基丙酸甲酯
根据1-乙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤D)的一般程序由N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)和2-溴-2-甲基丙酸甲酯进行制备,得到呈澄清无色油状物的标题化合物(2.45g,94%)。
1H NMR(DMSO-d6)δ8.18(d,J=2.5Hz,1H),7.05-6.95(m,4H),6.85-6.78(m,4H),6.78(d,J=2.5Hz,1H),4.18(s,4H),3.72(s,6H),3.65(s,3H),1.81(s,6H)。
LCMS m/z 511(M+Na)+(ES+)。
步骤B:2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)-2-甲基丙酸
将2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)-2-甲基丙酸甲酯(2.4g,4.92mmol)和2M NaOH水溶液(5mL,10mmol)在THF(5mL)和MeOH(3mL)中的混合物在室温下搅拌20小时。将混合物在EtOAc(100mL)与1M HCl水溶液(100mL)之间分配,将有机层用盐水(50mL)洗涤,干燥(MgSO4)并蒸发,得到呈胶状物的标题化合物(2.38g,95%),其在静置后固化。
1H NMR(CDCl3)δ7.64(d,J=2.5Hz,1H),7.09-7.05(m,4H),6.80-6.77(m,4H),6.73(d,J=2.5Hz,1H),4.32(s,4H),3.80(s,6H),1.91(s,6H)。未观察到一个可交换质子。
LCMS m/z 472(M-H)-(ES-)。
步骤C:1-(1-(氮杂环丁-1-基)-2-甲基-1-氧代丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
将2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)-2-甲基丙酸(1.15g,2.23mmol)、许尼希氏碱(1.56mL,8.91mmol)和HATU(0.921g,2.42mmol)在DMF(6.5mL)中的混合物在0-5℃下搅拌10分钟。接着添加氮杂环丁烷盐酸盐(0.272g,2.90mmol)。将混合物升温至室温并搅拌20小时。添加另外的HATU(0.263g,1.12mmol),随后添加另外的许尼希氏碱(0.390mL,2.23mmol)。将混合物冷却至0-5℃保持10分钟,接着添加另外的氮杂环丁烷盐酸盐(0.064g,1.12mmol)。将混合物升温至室温,再搅拌1小时,接着在TBME(75mL)和水(40mL)之间分配。将有机层用1M HCl水溶液(40mL)、水(25mL)洗涤,干燥(MgSO4),蒸发并通过硅胶色谱法(120g柱,0-100%TBME/异己烷)纯化,得到呈透明胶状物的标题化合物(615mg,51%)。
1H NMR(CDCl3)δ7.56(d,J=2.4Hz,1H),7.13-7.09(m,4H),6.80-6.76(m,5H),4.32(s,4H),3.99(t,J=7.8Hz,2H),3.79(s,6H),3.23(t,J=7.7Hz,2H),2.08-2.01(m,2H),1.78(s,6H)。
LCMS m/z 513.1(M+H)+(ES+)。
步骤D:1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
将BH3.THF(1M于THF中,21.5mL,21.5mmol)添加至1-(1-(氮杂环丁-1-基)-2-甲基-1-氧代丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(3.15g,6.15mmol)在THF(26.3mL)中的溶液中。将混合物搅拌3分钟,接着在整个周末加热回流。将反应物冷却至室温,之后将其置于冰浴中。逐滴添加MeOH(50mL),并将混合物在60℃加热3小时,接着冷却至室温过夜。将混合物在真空中浓缩,并上样到SCX(30g)柱/MeOH(50mL)上。用MeOH(100mL)、含0.7M氨的MeOH(100mL)洗涤柱,并用含7M氨的MeOH(100mL)洗脱产物。将所得混合物在真空中浓缩,得到呈无色粘稠油状物的标题化合物(2.89g,85%)。
1H NMR(DMSO-d6)δ7.98(d,J=2.5Hz,1H),7.07-7.02(m,4H),6.84-6.79(m,4H),6.69(d,J=2.4Hz,1H),4.19(s,4H),3.72(s,6H),2.92(t,J=7.0Hz,4H),2.68(s,2H),1.84(p,J=7.0Hz,2H),1.48(s,6H)。
LCMS m/z 499.2(M+H)+(ES+)。
步骤E:1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈白色固体状的标题化合物(1.06g,69%)。
1H NMR(DMSO-d6)δ7.89(d,J=2.5Hz,1H),7.34(s,2H),6.54(d,J=2.4Hz,1H),2.94(t,J=7.0Hz,4H),2.68(s,2H),1.84(p,J=7.0Hz,2H),1.47(s,6H)。
LCMS m/z 259.1(M+H)+(ES+)。
中间体L31:3-((二甲氨基)甲基)-5-甲基苯磺酰胺
步骤A:3-溴-N,N-双(4-甲氧基苄基)-5-甲基苯磺酰胺
根据3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1-甲基-1H-吡唑-5-羧酸乙酯(中间体L14,步骤A)的一般程序由3-溴-5-甲基苯-1-磺酰氯进行制备,得到呈淡橙色油状物的标题化合物(1.56g,77%),其在静置后固化。
1H NMR(氯仿-d)δ7.70-7.65(m,1H),7.53-7.49(m,1H),7.49-7.45(m,1H),7.10-7.02(m,4H),6.86-6.78(m,4H),4.29(s,4H),3.81(s,6H),2.38(s,3H)。
步骤B:3-((二甲氨基)甲基)-N,N-双(4-甲氧基苄基)-5-甲基苯磺酰胺
将3-溴-N,N-双(4-甲氧基苄基)-5-甲基苯磺酰胺(290mg,0.591mmol)、(N,N-二甲氨基甲基)三氟硼酸钾(117mg,0.710mmol)和碳酸铯(578mg,1.77mmol)在THF(10mL)和水(1mL)中的溶液用氮气脱气5分钟。添加Pd(巴豆基)(XPhos)Cl(20mg,0.030mmol),并将反应混合物搅拌回流21小时。将反应混合物冷却至室温,并添加更多的(N,N-二甲氨基甲基)三氟硼酸钾(117mg,0.710mmol)和Pd(巴豆基)(XPhos)Cl(20mg,0.030mmol)。将反应混合物再搅拌回流3小时。此时间之后,将反应混合物在EtOAc(20mL)与饱和NH4Cl水溶液(20mL)之间分配。分离水层并用EtOAc(2x20mL)萃取。将合并的有机物用盐水(30mL)洗涤,干燥(MgSO4)并在真空中浓缩,得到橙色油状物(322mg)。将粗产物上样到SCX(2g)柱/MeOH上。用MeOH洗涤柱,并用含0.7M氨的MeOH洗脱产物。将所得混合物在真空中浓缩,得到呈粘性橙色油状物的标题化合物(118mg,38%)。
1H NMR(氯仿-d)δ7.57-7.48(m,3H),7.03-6.97(m,4H),6.81-6.75(m,4H),4.28(s,4H),3.80(s,6H),3.54(s,2H),2.42(s,3H),2.33(s,6H)。
LCMS m/z 469.5(M+H)+(ES+)。
步骤C:3-((二甲氨基)甲基)-5-甲基苯磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由3-((二甲氨基)甲基)-N,N-双(4-甲氧基苄基)-5-甲基苯磺酰胺进行制备,得到呈橙色胶状物的标题化合物(45mg,64%)。
1H NMR(DMSO-d6)δ7.60-7.51(m,2H),7.32(s,1H),7.28(s,2H),3.43(s,2H),2.38(s,3H),2.17(s,6H)。
LCMS m/z 229.1(M+H)+(ES+)。
中间体L32:1-(2,2-二氟乙基)-1H-吡唑-4-磺酰胺
根据1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15,步骤C)的一般程序由1-(2,2-二氟乙基)-1H-吡唑-4-磺酰氯进行制备,得到呈淡黄色固体状的标题化合物(422mg,92%)。
1H NMR(DMSO-d6)δ8.24(d,J=0.7Hz,1H),7.80(d,J=0.7Hz,1H),7.33(s,2H),6.40(tt,J=54.6,3.6Hz,1H),4.71(td,J=15.2,3.6Hz,2H)。
19F NMR(DMSO-d6)δ-123.15(dt,J=54.5,15.1Hz)。
LCMS m/z 212.0(M+H)+(ES+)。
中间体L33:1-环丁基-1H-吡唑-3-磺酰胺
步骤A:1-环丁基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
将N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)(5g,12.9mmol)在DMF(60mL)中的溶液冷却至0℃,之后添加NaH(60wt%于矿物油中,0.671g,16.8mmol)。将混合物升温至室温并搅拌30分钟,之后经由注射器缓慢添加溴环丁烷(1.3mL,13.8mmol)。将所得混合物在50℃下搅拌整个周末。用EtOAc(100mL)稀释混合物。添加水(100mL),并分离各层。将水层用EtOAc(2x100mL)萃取。将合并的有机萃取物用盐水(3x80mL)洗涤,干燥(相分离器)并在真空中浓缩。将残余物上样到二氧化硅上并通过硅胶色谱法(80g柱,0-100%EtOAc/异己烷)纯化,得到呈淡黄色油状物的标题化合物(4.72g,75%)。
1H NMR(DMSO-d6)δ8.03(d,J=2.4Hz,1H),7.04(d,J=8.6Hz,4H),6.81(d,J=8.6Hz,4H),6.71(d,J=2.3Hz,1H),4.94(p,J=8.4Hz,1H),4.22(s,4H),3.72(s,6H),2.49-2.38(m,4H),1.87-1.77(m,2H)。
LCMS m/z 464.2(M+Na)+(ES+)。
步骤B:1-环丁基-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由1-环丁基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈淡白色固体状的标题化合物(1.5g,66%)。
1H NMR(DMSO-d6)δ7.96(d,J=2.4Hz,1H),7.39(s,2H),6.59(d,J=2.4Hz,1H),4.96-4.86(m,1H),2.50-2.44(m,2H),2.44-2.36(m,2H),1.85-1.77(m,2H)。
LCMS m/z 202.0(M+H)+(ES+)。
中间体L34:1-(1-((二甲氨基)甲基)环丁基)-1H-吡唑-3-磺酰胺
步骤A:1-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-羧酸乙酯和1-(5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-甲酸乙酯
根据1-环丁基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L33,步骤A)的一般程序由N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)和1-溴环丁烷羧酸乙酯进行制备,得到标题化合物(1.26g,23%),其为呈澄清黄色油状物的区域异构体混合物(3:1比率的1-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-羧酸乙酯:1-(5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-羧酸乙酯)。
LCMS m/z 536.2(M+Na)+(ES+)。
步骤B:1-(1-(羟甲基)环丁基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
在0℃下,向1-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-羧酸乙酯和1-(5-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)环丁烷-1-羧酸乙酯的3:1混合物(710mg,1.04mmol)在THF(20mL)中的溶液中缓慢添加LiAlH4(2M于THF中,2.1mL,4.20mmol)。接着使混合物升温至室温并搅拌过夜。将反应物依序用H2O(0.2mL)、2MNaOH水溶液(0.5mL)和H2O(1mL)淬灭。添加Na2SO4,将混合物搅拌30分钟,接着过滤通过硅藻土垫,用EtOAc冲洗。蒸发滤液,并将残余物上样到二氧化硅上且通过色谱法(40g柱,15%-100%EtOAc/异己烷)纯化,得到呈澄清无色油状物的标题化合物(410mg,83%)。
1H NMR(DMSO-d6)δ7.89(d,J=2.4Hz,1H),7.01(d,J=8.7Hz,4H),6.82(d,J=8.7Hz,4H),6.70(d,J=2.4Hz,1H),5.20(t,J=5.6Hz,1H),4.20(s,4H),3.75(d,J=5.6Hz,2H),3.72(s,6H),2.48-2.39(m,2H),2.39-2.27(m,2H),1.95-1.80(m,2H)。
LCMS m/z 494.0(M+Na)+(ES+)。
步骤C:1-(1-((二甲氨基)甲基)环丁基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
向1-(1-(羟甲基)环丁基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(472mg,1.00mmol)和Et3N(0.3mL,2.15mmol)在DCM(1mL)中的冰冷溶液中添加MsCl(0.1mL,1.28mmol)。将反应物升温至室温并搅拌1小时,之后用DCM(10mL)稀释,用NaHCO3(10mL)和盐水(10mL)洗涤,干燥(相分离器)并在真空中浓缩。将残余物溶解在THF(1mL)中,并添加二甲胺(5.00mL,10.0mmol)。整个周末在密封的小瓶中将反应物加热至80℃。将二甲胺(5.00mL,10.0mmol)和KI(166mg,1.00mmol)添加至反应混合物中,将其在85℃下搅拌过夜。将另一份二乙胺(5.00mL,10.0mmol)添加至反应混合物中,并将其在80℃下加热过夜。将反应混合物冷却至室温,并添加水(30mL)和EtOAc(30mL)。分离有机相并用EtOAc(3x20mL)萃取水相。合并有机相,干燥(相分离器)并在真空中浓缩。将粗产物上样到SCX(约10g)柱/MeOH上。用MeOH(50mL)洗涤柱,并用含0.7M氨的MeOH(50mL)洗脱产物。将所得混合物在真空中浓缩,得到呈澄清黄色油状物的标题化合物(187mg,36%)。
LCMS m/z 499.3(M+H)+(ES+)。
步骤D:1-(1-((二甲氨基)甲基)环丁基)-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由1-(1-((二甲氨基)甲基)环丁基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈粘性黄色油状物的标题化合物(65mg,64%)。
LCMS m/z 259.1(M+H)+(ES+)。
中间体L35:5-氟-1-异丙基-1H-吡唑-3-磺酰胺
步骤A:5-氟-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
在N2下于-78℃下,在15分钟内向1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L24,步骤A)(0.500g,1.16mmol)在THF(8mL)中的搅拌溶液中逐滴添加n-BuLi(2.5M/己烷,0.500mL,1.25mmol)。将所得混合物在-78℃下搅拌1小时,接着在15分钟内逐滴添加含N-氟-N-(苯磺酰基)苯磺酰胺(NFSI)(0.394g,1.25mmol)的THF(2mL)。将所得反应混合物在-78℃下搅拌2小时,接着在室温下搅拌过夜。通过添加水(20mL)将反应混合物淬灭并用DCM(3x20mL)萃取。将合并的有机物用饱和NaHCO3水溶液(30mL)、盐水(30mL)洗涤,干燥(相分离器)并在真空中浓缩,得到黄色油状物。将粗产物通过硅胶色谱法(40g柱,0-30%EtOAc/异己烷)纯化,得到呈黄色油状物的标题化合物和4,5-二氟-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺的1.6:1混合物(124mg),其在静置后固化。
1H NMR(DMSO-d6)δ7.08-7.02(m,4H),6.87-6.80(m,4H),6.53(d,J=5.6Hz,1H),4.69-4.57(m,1H),4.23(s,4H),3.73(s,6H),1.41(d,J=6.7Hz,6H)。
LCMS m/z 470.3(M+Na)+(ES+),62%和488.2(M+Na)+(ES+)。
步骤B:5-氟-1-异丙基-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由5-氟-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺和4,5-二氟-1-异丙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺的1.6:1混合物进行制备,得到呈白色固体状的标题化合物(39mg,16%,经2个步骤)。
1H NMR(DMSO-d6)δ7.52(s,2H),6.36(d,J=5.7Hz,1H),4.67-4.57(m,1H),1.41(d,J=6.7Hz,6H)。
LCMS m/z 208.2(M+H)+(ES+)。
还分离出呈白色固体状的4,5-二氟-1-异丙基-1H-吡唑-3-磺酰胺(18mg,6%,经2个步骤)。
中间体L36:((1-(2,2-二氟乙基)-1H-吡唑-3-基)磺酰基)(4-(二甲氨基)吡啶-1-鎓-1-羰基)酰胺
步骤A:1-(2,2-二氟乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺
根据1-乙基-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤D)的一般程序由N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L19,步骤C)和1,1-二氟-2-碘乙烷进行制备,得到呈澄清无色油状物的标题化合物(775mg,57%),其在静置后固化。
1H NMR(DMSO-d6)δ8.02(d,J=2.4Hz,1H),7.04-6.98(m,4H),6.85-6.75(m,5H),6.55-6.29(m,1H),4.85-4.74(m,2H),4.21(s,4H),3.72(s,6H)。
LCMS m/z 474.3(M+Na)+(ES+)。
步骤B:1-(2,2-二氟乙基)-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由1-(2,2-二氟乙基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺进行制备,得到呈白色固体状的标题化合物(360mg,99%)。
1H NMR(DMSO-d6)δ7.93(d,J=2.4Hz,1H),7.49(s,2H),6.66(d,J=2.4Hz,1H),6.40(tt,J=54.6,3.6Hz,1H),4.73(td,J=15.3,3.6Hz,2H)。
步骤C:((1-(2,2-二氟乙基)-1H-吡唑-3-基)磺酰基)(4-(二甲氨基)吡啶-1-鎓-1-羰基)酰胺
根据(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺(中间体L21)的一般程序由1-(2,2-二氟乙基)-1H-吡唑-3-磺酰胺进行制备,得到呈白色固体状的标题化合物(83mg,11%)。将粗产物不经进一步纯化或分析即使用。
中间体L37:1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺
步骤A:N,N-双(4-甲氧基苄基)-1-(2-甲基-1-氧代-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺
根据1-(1-(氮杂环丁-1-基)-2-甲基-1-氧代丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L30,步骤C)的一般程序由2-(3-(N,N-双(4-甲氧基苄基)氨磺酰基)-1H-吡唑-1-基)-2-甲基丙酸(中间体L30,步骤B)和吡咯烷进行制备,得到呈淡白色固体状的标题化合物(862mg,73%)。
1H NMR(DMSO-d6)δ8.16(d,J=2.5Hz,1H),7.06(d,J=8.6Hz,4H),6.85(d,J=2.5Hz,1H),6.82(d,J=8.7Hz,4H),4.17(s,4H),3.72(s,6H),3.37-3.33(m,2H),2.38-2.32(m,2H),1.73(s,6H),1.59(br s,4H)。
步骤B:N,N-双(4-甲氧基苄基)-1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺
根据1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-N,N-双(4-甲氧基苄基)-1H-吡唑-3-磺酰胺(中间体L30,步骤D)的一般程序由N,N-双(4-甲氧基苄基)-1-(2-甲基-1-氧代-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺进行制备,得到标题化合物(388mg,42%)。
1H NMR(DMSO-d6)δ8.01(d,J=2.5Hz,1H),7.05(d,J=8.6Hz,4H),6.82(d,J=8.6Hz,4H),6.71(d,J=2.4Hz,1H),4.18(s,4H),3.72(s,6H),2.81(s,2H),2.24-2.15(m,4H),1.55(s,6H),1.54-1.51(m,4H)。
LCMS m/z 513.0(M+H)+(ES+)。
步骤C:1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺
根据1-乙基-1H-吡唑-3-磺酰胺(中间体L19,步骤E)的一般程序由N,N-双(4-甲氧基苄基)-1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺进行制备,得到呈粘性无色油状物的标题化合物(136mg,59%)。
LCMS m/z 273.1(M+H)+(ES+)。
中间体L38:((1-环丙基-1H-吡唑-3-基)磺酰基)(4-(二甲氨基)吡啶-1-鎓-1-羰基)酰胺
根据(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺(中间体L21)的一般程序由1-环丙基-1H-吡唑-3-磺酰胺进行制备,得到呈固体状的标题化合物(1.57g,55%)。
1H NMR(DMSO-d6)δ8.82-8.63(m,2H),7.81(d,J=2.3Hz,1H),7.04-6.86(m,2H),6.57(d,J=2.4Hz,1H),3.76(m,1H),3.25(s,6H),1.07-1.01(m,2H),1.00-0.95(m,2H)。
中间体R1:4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯
在环境温度下,向光气(4.45mL,20重量%于甲苯中,8.4mmol)在乙酸乙酯(90mL)中的溶液中逐滴添加1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(589mg,3.4mmol)在乙酸乙酯(45mL)中的溶液。接着将所得反应混合物加热回流3小时,冷却后过滤并在真空中浓缩,得到呈棕色油状物的标题化合物(756mg,100%)。将粗产物不经进一步纯化直接用于下一步骤。
1H NMR(300MHz,CDCl3)δ6.8(s,1H),2.89(m,8H)和2.09(m,4H)。
中间体R2:8-异氰酸基-1,2,3,5-四氢-s-茚并四烯
步骤A:1,2,3,7-四氢-s-茚并四烯-4-胺
向8-硝基-1,2,3,5-四氢-s-茚并四烯(Salla等人,ACS Med Chem Lett,2016,第7(12)卷,第1034-1038页)(700mg,3.48mmol)在二噁烷/乙醇/水(10ml/6mL/4mL)的混合物的溶液中添加铁粉(1.17g,20.9mmol)和氯化铵(0.93g,17.4mmol)。将混合物回流15分钟。添加乙酸乙酯(50mL),并将混合物经硅藻土过滤。用乙酸乙酯洗涤固体。蒸发合并的乙酸乙酯层。使用乙酸乙酯作为洗脱剂,在二氧化硅上过滤粗产物,得到呈棕色油状物的标题化合物(97%),其在静置后固化。
1H NMR(300MHz,CDCl3)δ6.88(s,1H),6.85(m,1H),6.39(m,1H),3.68(s,br,2H)3.36(s,2H),2.93(t,2H),2.75(t,2H),2.14(m,2H)。
步骤B:8-异氰酸基-1,2,3,5-四氢-s-茚并四烯
在环境温度下,向光气(0.23mL,20重量%于甲苯中,0.44mmol)在乙酸乙酯(5mL)中的溶液中逐滴添加1,2,3,7-四氢-s-茚并四烯-4-胺(30mg,0.18mmol)在乙酸乙酯(5mL)中的溶液。接着将所得反应混合物加热回流2小时。将混合物过滤并在真空中浓缩,得到呈棕色油状物的标题化合物(35mg,100%),其在静置后固化。将粗产物不经进一步纯化直接用于下一步骤。
1H NMR(CDCl3)δ7.12(s,1H),6.80(m,1H),6.51(m,1H),3.35(q,2H),2.96(m,4H),2.14(p,2H)。
中间体R3:4-异氰酸基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮
在10分钟内将4-氨基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮(Salla等人,ACS MedChem Lett,2016,第7(12)卷,第1034-1038页)(40mg,0.21mmol)在乙酸乙酯(5mL)中的溶液中逐滴添加光气(20%于甲苯中,0.5mL,0.54mmol)在乙酸乙酯(5mL)中的溶液。将混合物搅拌回流1小时。接着浓缩混合物,得到呈油状物的标题化合物(45mg,100%),将其原样用于下一步骤。
中间体R4:8-异氰酸基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮
向8-氨基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮(57mg,0.30mmol)在甲苯中的溶液中添加光气溶液(20%于甲苯中,0.39mL,0.75mmol),并将混合物回流30分钟。在减压下浓缩得到呈绿色油状物的标题化合物(64.6mg,99%),将其不经进一步纯化即使用。
1H NMR(CDCl3)δ7.10(s,1H),3.03(m,2H),2.96(t,2H),2.89(t,2H),2.71(m,2H),2.12(p,2H)。
中间体R5:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰氯
步骤A:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙烯酸叔丁酯
将4-(2-溴-5-氟-3-异丙基苯基)-2-甲氧基吡啶(0.9g,3mmol)和丙烯酸叔丁酯(1g,3eq,8mmol)在DMF(10ml)中的溶液用氮气吹扫。添加碳酸钾(0.8g,6mmol)、三苯基膦(0.1g,0.6mmol)和乙酸钯(67mg,0.30mmol)。将混合物在120℃下搅拌18小时。将混合物冷却,并添加乙酸乙酯。将有机层用水(4次)和盐水洗涤,干燥(硫酸钠),过滤并蒸发。将残余物使用乙酸乙酯/庚烷作为洗脱剂经二氧化硅纯化,得到呈淡红色油状物的标题化合物(0.6g,58%)。
1H NMR(300MHz,CDCl3)δ8.14(d,1H),7.58(d,1H),7.07(dd,1H),6.85(dd,1H),6.75(dd,1H),6.66(s,1H),5.58(d,1H),3.98(s,3H),3.24(m,1H),1.44(s,9H),1.25(d,6H)。
步骤B:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酸叔丁酯
在氢气气氛(气球)下,将3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙烯酸叔丁酯(0.6g,1.6mmol)和Pd/C(10%,50mg)在乙酸乙酯中的混合物搅拌18小时。将混合物过滤(硅藻土)并蒸发,得到呈油状物的标题化合物(0.6g,定量收率)。
1H NMR(300MHz,CDCl3)δ8.20(d,1H),7.02(dd,1H),6.80(d,1H),6.70(dd,1H),6.64(s,1H),3.98(s,3H),3.21(m,1H),2.81(t,2H),2.20(t,2H),1.37(s,9H),1.27(d,6H)。
步骤C:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酸
向3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酸叔丁酯(0.60g,1.6mmol)在二氯甲烷(5mL)中的溶液中添加TFA(5mL)。将混合物在室温下搅拌18小时。蒸发溶剂,得到为TFA盐的呈无色油状物的标题化合物(0.63g,100%)。
1H NMR(300MHz,CDCl3)δ8.44(d,1H),7.29(d,1H),7.15(dd,1H),7.11(s,1H),6.73(dd,1H),4.21(s,3H),3.16(m,1H),2.90(t,2H),2.41(t,2H),1.30(d,6H)。
步骤D:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰氯
将3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酸(285mg,62wt%,0.56mmol)在DCM(10mL)中搅拌并添加一滴DMF,随后逐滴添加草酰氯(0.24mL,2.8mmol)。将溶液在室温下搅拌4小时并充分浓缩,得到呈黄色油状物的标题化合物(190mg,99%)。
1H NMR(300MHz,氯仿-d)δ8.45(d,1H),7.34(d,1H),7.17–7.07(m,2H),6.72(dd,1H),4.38(s,3H),3.19(dd,1H),2.96–2.82(m,2H),2.41(d,2H),1.28(d,6H)。
中间体R6:6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-碳酰氯
步骤A:2-(4-氟-2-(丙-1-烯-2-基)苯基)乙酸与2,3-二甲基丁烷-2,3-二醇(1:1)混合物
将碳酸钾(120g,0.89mol)溶解在水(100mL)中,并添加至2-(2-溴-4-氟苯基)乙酸(69g,1eq,0.30mol)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二杂氧戊硼烷(50g,1eq,0.30mol)在1,4-二噁烷(100mL)中的溶液中。将混合物置于N2气氛下并添加PdCl2(dppf)-CH2Cl2加合物(4.9g,6.0mmol),之后将混合物回流48小时。将混合物冷却至室温。添加水直至所有盐溶解。分离各层并用乙酸乙酯(2x100mL)萃取水层。将合并的有机层经硫酸钠干燥,并通过旋转蒸发去除溶剂,得到呈棕色油状物的产物(87g,94%)。
1H NMR(CDCl3)δ7.22(dd,1H),6.95(dd,1H),6.88(dd,1H),5.23(s,1H),4.84(s,1H),3.68(s,2H),2.00(s,3H),1.24(s,6H),1.21(s,6H)。
LCMS:m/z 193(M-H)-(ES-)。
步骤B:2-(4-氟-2-异丙基苯基)乙酸
将2-(4-氟-2-(丙-1-烯-2-基)苯基)乙酸与2,3-二甲基丁烷-2,3-二醇的(1:1)混合物(80g,0.26mol)和铂(IV)氧化物(1g,4mmol)溶解在乙醇(200mL)中,并在3巴H2压力下搅拌过夜。添加另外的铂(IV)氧化物(0.1g,0.4mmol),并将混合物在3巴H2下再搅拌5小时。将混合物经硅藻土过滤,并通过旋转蒸发去除乙醇。对所得油状物进行降膜蒸馏以去除频哪醇。将残余物溶解于DCM(200mL)中,并用0.5M HCl水溶液(100mL)洗涤。将有机层经硫酸钠干燥,并用SiO2(d=10cm,h=5cm)堵住。用DCM(2L)冲洗SiO2。对收集的洗脱液进行旋转蒸发,得到呈浅橙色固体状的产物(45g,90%)。
1H NMR(CDCl3)δ7.18(dd,1H),7.00(dd,1H),6.82(dt,1H),3.67(s,2H),3.07(m,1H),1.20(d,6H)。
LCMS:m/z 195(M-H)-(ES-)。
步骤C:2-(4-氟-2-异丙基苯基)乙酸乙酯
在N2气氛下,将2-(4-氟-2-异丙基苯基)乙酸(1.8g,9.2mmol)溶解在乙醇(25mL)中并冷却至0℃。逐滴添加亚硫酰氯(1.6g,14mmol),并将混合物在室温下搅拌过夜。将混合物蒸发至干,得到呈澄清油状物的标题化合物(2.1g,100%)。
1H NMR(CDCl3)δ7.18(dd,1H),6.99(dd,1H),6.82(dt,1H),4.15(q,2H),3.62(s,2H),3.09(m,1H),1.24(t,3H),1.21(d,6H)。
步骤D:2-(4-氟-2-异丙基苯基)-5-甲基己-4-烯酸乙酯
在N2气氛下,将2-(4-氟-2-异丙基苯基)乙酸乙酯(1.6g,7.1mmol)溶解在THF(10mL)中并冷却至-78℃。添加LiHMDS(1.3g,8mL,7.8mmol),并将混合物在-78℃下搅拌15分钟。添加1-溴-3-甲基丁-2-烯(1.2g,7.8mmol),并使混合物经过周末达到室温。将混合物蒸发至接近干燥,并添加1M HCl(20mL)和乙酸乙酯(20mL)。分离各层并用乙酸乙酯(2x20mL)萃取水层。将合并的有机层经硫酸钠干燥并蒸发至干,得到呈澄清油状物的标题化合物(2.0g,96%)。
1H NMR(CDCl3)δ7.32(dd,1H),6.95(dd,1H),6.82(dt,1H),5.02(t,1H),4.10(q,2H),3.82(t,1H),3.22(m,1H),2.75(m,1H),2.38(m,1H),1.62(s,3H),1.56(s,3H),1.23(t,3H),1.20(d,6H)。
LCMS:m/z 293(M+H)+(ES+)。
步骤E:6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-羧酸乙酯
在N2气氛下,将2-(4-氟-2-异丙基苯基)-5-甲基己-4-烯酸乙酯(2.0g,7mmol)溶解在二氯乙烷(40mL)中。添加三氟甲磺酸铋(III)(0.2g,0.3mmol),并将混合物回流2小时。将混合物经硅藻土过滤,蒸发至干,并进行二氧化硅柱色谱法(庚烷/乙酸乙酯梯度为0至15%),得到呈无色油状物的标题产物(1.0g,48%)。
1H NMR(CDCl3)δ6.91(dd,1H),6.80(dd,1H),4.12(q,2H),3.92(m,1H),2.93(m,1H),2.14(m,1H),2.04(m,1H),1.75(m,1H),1.58(m,1H),1.35(s,3H),1.28(s,3H),1.22(t,3H),1.18(d,6H)。
步骤F:6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-羧酸
将6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-羧酸乙酯(0.8g,3mmol)溶解在甲醇(20mL)中。添加含氢氧化锂(1.0g,42mmol)的水(10mL),并将混合物回流过夜。通过旋转蒸发浓缩反应混合物,并在TBME(20mL)与水(20mL)之间分配。将水相用5N HCl酸化至pH 1并用DCM(2x20mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,得到呈白色固体状的标题产物(254mg,35%)。
1H NMR(CDCl3)δ6.91(dd,1H),6.80(dd,1H),3.97(m,1H),2.97(m,1H),2.20(m,1H),2.04(m,1H),1.72(dt,1H),1.58(m,1H),1.32(s,3H),1.23(s,3H),1.18(dd,6H)。
LCMS:m/z 263(M-H)-(ES-)。
步骤G:6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-碳酰氯
将6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-羧酸(100mg,0.38mmol)在DCM(10mL)中搅拌并添加一滴DMF,随后逐滴添加草酰氯(0.17mL,1.89mmol)。将溶液在室温下搅拌4小时并充分浓缩,得到呈黄色油状物的标题化合物(107mg,99%)。
1H NMR(300MHz,氯仿-d)δ6.91(dd,1H),6.84(dd,1H),4.31(dd,1H),2.96–2.82(m,1H),2.56–2.39(m,1H),2.27–2.05(m,1H),1.72–1.62(m,2H),1.32(d,6H),1.26–1.19(m,6H)。
中间体R7:5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-碳酰氯
步骤A:3-(4-氟-2-异丙基苯基)-5,5-二甲基二氢呋喃-2(3H)-酮
经由注射器将n-BuLi溶液(2.5M/己烷,0.69mL,4.3mL,11mmol)添加至二异丙胺(1.1g,1.5mL,11mmol)在THF(15mL)中的冷却(-20℃)溶液中。将反应混合物在-20℃下搅拌20分钟,接着冷却至-78℃,并且经由套管添加3-(4-氟-2-异丙基苯基)-4,4-二甲基二氢呋喃-2(3H)-酮(1g,5.1mmol)在THF(5mL)中的溶液。将反应混合物在-78℃下搅拌20分钟,接着升温至室温并搅拌2小时。接着将反应混合物冷却至0℃,并经由注射器添加纯净的2,2-二甲基环氧乙烷(0.37mmol,0.45mL,5.1mmol),得到澄清的黄色溶液,将其在室温下搅拌12小时。将水(7mL)添加至反应混合物中。将反应混合物加热1小时至回流,接着冷却。通过浓缩去除大部分THF。接着将反应混合物用TBME(2次)洗涤。将水相用EtOH(12mL)处理,用37%HCl水溶液(3.1mL)酸化,搅拌回流3小时,接着静置过夜。用CHCl3(3x25mL)萃取反应混合物。将合并的有机相用饱和NaHCO3水溶液(2x15mL)洗涤,接着干燥(Na2SO4),过滤并浓缩,得到油状物(1.2g),其在静置后部分结晶。将该物质在TBME:庚烷(6:1)中搅拌30分钟,过滤并干燥(430mg)。将滤液浓缩成油状物,得到稍纯的物质(530mg)。合并该物质得到呈黄色油状物的标题化合物(0.96g,75%)。
1H NMR(300MHz,氯仿-d)δ7.11(dd,1H),6.99(dd,1H),6.89(td,1H),4.23(dd,1H),3.13–2.93(m,1H),2.55(dd,1H),2.08(t,1H),1.61–1.45(m,6H),1.34–1.17(m,6H)。
步骤B:5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-羧酸
将3-(4-氟-2-异丙基苯基)-5,5-二甲基二氢呋喃-2(3H)-酮(430mg,1.72mmol)溶解在1,2-二氯乙烷(2mL)中,并在1小时内将其逐滴添加至AlCl3(458mg,3.44mmol)在1,2-二氯乙烷(2mL)中的冰冷溶液中。将混合物搅拌2小时并倒入冰/水(10mL)中。使用CHCl3(10-15mL)冲洗反应容器。经硅藻土过滤反应混合物,并分离各层。将有机相经无水硫酸钠干燥,过滤并浓缩溶液,得到呈黄色油状物的标题化合物(0.43g,99%)。
1H NMR(300MHz,氯仿-d)δ6.82(dd,1H),6.68(dd,1H),4.07(dd,1H),2.98–2.77(m,1H),2.48–2.20(m,2H),1.29(m,6H),1.25–1.11(m,6H)。
步骤C:5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-碳酰氯
将5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-羧酸(65mg,0.26mmol)在DCM(10mL)中搅拌并添加一滴DMF,随后逐滴添加草酰氯(0.11mL,1.3mmol)。将溶液在室温下搅拌3小时并充分浓缩,得到呈黄色油状物的标题化合物(70mg,99%)。
1H NMR(300MHz,氯仿-d)δ6.84(dd,1H),6.69(dd,1H),4.45(ddd,1H),2.78(pd,1H),2.57–2.34(m,2H),1.36–1.23(m,9H),1.19(d,3H)。
中间体R8:4-(4-异氰酸基-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶
步骤A:4-硝基-2,3-二氢-1H-茚
在0℃下历时3.5小时向2,3-二氢-1H-茚(60g,507.72mmol,1eq)在浓H2SO4(30mL)中的混合物中逐滴添加HNO3(50mL,69wt%于水溶液中)在浓H2SO4(50mL)中的溶液。将反应混合物在0℃下搅拌0.5小时,接着倒入冰水(600mL)中,并用乙酸乙酯(2x400mL)萃取。将合并的有机层用水(500mL)、饱和NaHCO3水溶液(500mL)和盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至100:1)纯化,得到呈无色油状物的标题化合物(55g,含有另一种区域异构体)。
1H NMR(400MHz,CDCl3)δ7.98(d,1H),7.51(d,1H),7.30(t,1H),3.41(t,2H),302(t,2H)和2.22-2.20(m,2H)。
步骤B:2,3-二氢-1H-茚-4-胺
在N2下,向4-硝基-2,3-二氢-1H-茚(55g,含有另一种区域异构体)在MeOH(500mL)中的溶液中添加Pd/C(5g,10wt%载量/活性炭)。将悬浮液在真空中脱气,并用H2吹扫几次。将反应混合物在H2(50psi)下于20℃搅拌12小时。过滤反应混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至100:4)纯化,得到呈棕色油状物的标题化合物(19.82g,43%收率,96.4%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ7.01(t,1H),6.71(d,1H),6.51(d,1H),3.57(br s,2H),2.93(t,2H),2.75(t,2H)和2.16-2.08(m,2H)。
LCMS:m/z 134.2(M+H)+(ES+)。
步骤C:N-(2,3-二氢-1H-茚-4-基)乙酰胺
在0℃下历时0.1小时向2,3-二氢-1H-茚-4-胺(19.8g,148.66mmol,1eq)和TEA(19.56g,193.26mmol,1.3eq)在DCM(300mL)中的溶液中逐滴添加Ac2O(17.45g,170.96mmol,1.15eq)。接着将反应混合物升温至16℃,搅拌1.4小时,倒入水(500mL)中,并用DCM(2x300mL)萃取。将合并的有机相用盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩,得到呈白色固体状的标题化合物(25.74g,收率96%,96.7%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ7.70(d,1H),7.15(t,1H),7.02(d,1H),2.95(t,2H),2.81(t,2H),2.18(s,3H)和2.15-2.08(m,2H)。
LCMS:m/z 176.2(M+H)+(ES+)。
步骤D:N-(5-溴-2,3-二氢-1H-茚-4-基)乙酰胺
将N-(2,3-二氢-1H-茚-4-基)乙酰胺(34.6g,197.46mmol,1eq)、4-甲基苯磺酸(18.70g,108.60mmol,0.55eq)和Pd(OAc)2(2.22g,9.87mmol,0.05eq)的混合物悬浮在甲苯(400mL)中,并在空气气氛下于20℃搅拌0.5小时。添加NBS(38.66g,217.20mmol,1.1eq)。将所得反应混合物在20℃下搅拌2小时,倒入水(500mL)中,并用乙酸乙酯(2x500mL)萃取。将合并的有机相用盐水(2x500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,10:1至2:1)纯化,得到呈白色固体状的标题化合物(13.9g,27%收率,98.1%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ7.33(d,1H),7.16(s,1H),6.98(d,1H),2.92-2.83(m,4H),2.21(s,3H)和2.10-2.02(m,2H)。
LCMS:m/z 254.1(M+H)+(ES+)。
步骤E:5-溴-2,3-二氢-1H-茚-4-胺盐酸盐
将N-(5-溴-2,3-二氢-1H-茚-4-基)乙酰胺(45.68g,179.76mmol,1eq)在EtOH(200mL)和浓HCl(300mL,36wt%)中的混合物在80℃下搅拌36小时。将反应混合物在冰浴中冷却至0℃,并沉淀出一些固体。过滤悬浮液。将滤饼用冰水(50mL)洗涤,在真空中干燥,得到呈灰色固体状的标题化合物(34.1g,收率72%,94.1%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.67(br s,2H),7.24(d,1H),6.69(d,1H),2.85(t,2H),2.79(t,2H)和2.04-1.96(m,2H)。
LCMS:m/z 212.0(M+H)+(ES+)。
步骤F:5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-胺
将(2-甲氧基吡啶-4-基)硼酸(25.11g,164.15mmol,1.2eq)、5-溴-2,3-二氢-1H-茚-4-胺盐酸盐(34g,136.80mmol,1eq)和K2CO3(60.50g,437.74mmol,3.2eq)在二噁烷(500mL)和H2O(100mL)中的混合物用氮气脱气15分钟。添加Pd(dppf)Cl2.CH2Cl2(6g,7.35mmol,0.053eq)。在氮气下,将反应混合物加热至80℃保持12小时,倒入水(500mL)中,并用乙酸乙酯(2x500mL)萃取。将合并的有机相用盐水(2x700mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,0:1至1:10)纯化,得到呈白色固体状的标题化合物(27.4g,79%收率,95%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.22(d,1H),7.03-7.00(m,1H),6.99(d,1H),6.87(s,1H),6.77(d,1H),3.99(s,3H),3.77(br s,2H),2.97(t,2H),2.77(t,2H)和2.21-2.13(m,2H)。
LCMS:m/z 241.2(M+H)+(ES+)。
步骤G:4-(4-异氰酸基-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶
在0℃下,向5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-胺(11g,45.78mmol,1eq)和TEA(5.10g,50.35mmol,1.1eq)在THF(275mL)中的溶液中分批添加碳酸双(三氯甲基)酯(4.93g,16.61mmol,0.36eq)。将反应混合物在16℃下搅拌0.5小时。将反应混合物过滤通过硅胶垫,并用THF(2L)洗涤滤饼。将滤液在真空中浓缩,得到呈浅黄色固体状的标题化合物(9.04g,74%)。
1H NMR(400MHz,CDCl3)δ8.28(d,1H),7.20-7.16(m,3H),7.02(s,1H),4.16(s,3H),3.04-2.99(m,4H)和2.23-2.15(m,2H)。
中间体R9:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰氯
步骤A:3-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮
在N2气氛下,将AlCl3(225.67g,1.69mol,1eq)在DCM(1L)中的悬浮液冷却至-10℃。接着逐滴添加2,3-二氢-1H-茚(200g,1.69mol,1eq)和3-氯丙酰氯(214.88g,1.69mol,1eq)在DCM(400mL)中的混合物。将反应混合物升温至27℃并搅拌2小时。接着在低于10℃下将反应混合物缓慢添加至HCl水溶液(2N,2.8L)中。分离各层并用DCM(1L)萃取水层。将合并的有机层用水(1L)、饱和NaHCO3水溶液(1L)和盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物用石油醚(500mL)研磨,得到呈白色固体状的标题化合物(260.44g,74%)。
1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.79-7.76(m,1H),7.33(d,1H),3.94(t,2H),3.45(t,2H),2.98(t,4H),2.18-2.11(m,2H)。
LCMS:m/z 209.1(M+H)+(ES+)。
步骤B:2,3,6,7-四氢-s-茚并四烯-1(5H)-酮
向浓H2SO4溶液(1.84kg,18.39mol,98wt%于水溶液中,37.25eq)中添加至3-氯-1-(2,3-二氢-1H-茚-5-基)丙-1-酮(103g,493.57mmol,1eq)。将反应混合物在70℃下搅拌12小时,倒入冰水(4.5L)中并过滤。将滤饼溶解在EtOAc(500mL)中,并添加饱和Na2CO3水溶液(500mL)。分离有机相,并用EtOAc(3x200mL)萃取水层。将合并的有机层在真空中浓缩,得到呈黄色固体状的标题化合物(60g,69%收率,98%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.30(s,1H),3.08-2.96(m,2H),2.95-2.91(m,4H),2.70(t,2H)和2.15-2.05(m,2H)。
LCMS:m/z 173.2(M+H)+(ES+)。
步骤C:1,2,3,5,6,7-六氢-s-茚并四烯
向2,3,6,7-四氢-s-茚并四烯-1(5H)-酮(15g,87.10mmol,1eq)在MeOH(200mL)中的溶液中添加MeSO3H(16.94g,176.22mmol,2.02eq)和Pd(OH)2/C(3.2g,20wt%载量/活性炭)。将反应混合物脱气并用H2吹扫三次。在H2(15psi)下,将所得混合物在25℃下搅拌12小时。过滤反应混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,仅用石油醚洗脱)纯化,得到呈白色固体状的标题化合物(12g,85%)。
1H NMR(400MHz,CDCl3)δ7.14(s,2H),3.00-2.85(m,8H)和2.16-2.09(m,4H)。
步骤D:4-溴-1,2,3,5,6,7-六氢-s-茚并四烯
向1,2,3,5,6,7-六氢-s-茚并四茚(11.5g,72.67mmol,1eq)在CCl4(200mL)中的溶液中添加I2(922mg,3.63mmol,0.05eq)。接着在0℃下逐滴添加Br2(12.19g,76.31mmol,1.05eq)在CCl4(50mL)中的溶液。将所得混合物在0℃下搅拌2小时,用饱和NH4Cl水溶液(100mL)淬灭,并用DCM(3x200mL)萃取。将合并的有机层经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,仅用石油醚洗脱)纯化,得到呈红色油状物的标题化合物(15g,87%)。
1H NMR(400MHz,CDCl3)δ7.00(s,1H),3.10-2.83(m,8H)和2.11(m,4H)。
步骤E:(2-(叔丁氧基)-2-氧乙基)溴化锌(II)
将Zn(80g)在HCl(1M,308mL)中的混合物在25℃下搅拌30分钟。接着将混合物过滤并将滤饼在真空中干燥。在N2下于20℃下,向此Zn(55g,841.11mmol,2.98eq)在THF(550mL)中的混合物中添加TMSCl(3.06g,28.20mmol,0.1eq)和1,2-二溴乙烷(5.30g,28.20mmol,0.1eq)。接着在N2下于50℃下添加2-溴乙酸叔丁酯(55g,281.97mmol,1eq)。将反应混合物在50℃下搅拌2小时。将混合物(理论量:0.5M,550mL,于THF溶液中)冷却并不经进一步纯化即用于下一步骤。
步骤F:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酸叔丁酯
在0℃下,向4-溴-1,2,3,5,6,7-六氢-s-茚并四烯(20g,84.34mmol,1eq)、Pd2(dba)3(3.86g,4.22mmol,0.05eq)和(4.02g,8.43mmol,0.1eq)在THF(1mL)中的溶液中添加(2-(叔丁氧基)-2-氧乙基)溴化锌(II)(168.68mmol,500mL,0.5M,于THF中,2eq)。接着将反应混合物在70℃下搅拌12小时,用饱和NH4Cl水溶液(500mL)淬灭,并用乙酸乙酯(3x500mL)萃取。将合并的有机层经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,仅用石油醚洗脱)纯化,得到呈黄色油状物的标题化合物(20g,87%)。
1H NMR(400MHz,CDCl3)δ7.02(s,1H),3.51(s,2H),2.90-2.84(m,8H),2.11-2.04(m,4H)和1.44(s,9H)。
步骤G:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酸
向2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酸叔丁酯(20g,73.43mmol,1eq)在DCM(200mL)中的溶液中添加TFA(308g,2.70mol,36.79eq)。将反应混合物在25℃下搅拌1小时,接着在真空中浓缩。将残余物溶解在DCM(300mL)中,并用NaOH水溶液(2N)将混合物调节至pH=9。分离水相,并用HCl水溶液(1N)调节至pH=2-3。形成大的白色固体,过滤混合物。将收集的固体干燥,得到呈白色固体状的标题化合物(12g,76%)。
1H NMR(400MHz,DMSO-d6)δ12.20(s,1H),6.95(s,1H),3.70(s,2H),2.82-2.70(m,8H)和2.03-1.94(m,4H)。
步骤H:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰氯
将2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酸(500mg,2.31mmol,1eq)在SOCl2(10mL)中的溶液加热至80℃保持1小时。将反应混合物在真空中浓缩,得到呈黄色油状物的标题化合物(542.6mg,100%),将其直接用于下一步骤。
中间体R10:2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酸
步骤A:4-(4-溴-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶
在0℃下,向5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-胺(中间体R8,步骤F)(28g,116.52mmol,1eq)在MeCN(300mL)中的混合物中添加亚硝酸异戊酯(16.38g,139.83mmol,1.2eq)。在N2下,将反应混合物在0℃下搅拌30分钟。在0℃下添加CuBr(17.05g,118.85mmol,1.02eq),并将所得混合物在60℃下搅拌1小时。过滤反应混合物,并在真空中浓缩滤液。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至20:1)纯化,得到呈黄色固体状的标题化合物(15g,37%收率,87.7%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.20(d,1H),7.21(d,1H),7.06(d,1H),6.94(dd,1H),6.78(s,1H),3.99(s,3H),3.08(t,2H),3.03(t,2H)和2.20-2.10(m,2H)。
LCMS:m/z 304.0(M+H)+(ES+)。
步骤B:2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酸叔丁酯
在N2下于20℃下,向4-(4-溴-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶(15g,49.31mmol,1eq)、(2.35g,4.93mmol,0.1eq)和Pd2(dba)3(2.26g,2.47mmol,0.05eq)在THF(50mL)中的溶液中添加(2-(叔丁氧基)-2-氧代乙基)溴化锌(II)(中间体R9,步骤E)在THF(0.5M,296mL,3eq)中的溶液。在N2下,将反应混合物在70℃下搅拌12小时。将混合物倒入饱和NH4Cl水溶液中(200mL)中。用乙酸乙酯(3x200mL)萃取水相。将合并的有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至20:1)纯化,得到呈黄色油状物的标题化合物(15g,83%收率,92.9%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.17(dd,1H),7.20(d,1H),7.04(d,1H),6.86(dd,1H),6.72(s,1H),3.98(s,3H),3.47(s,2H),3.01(t,2H),2.90(t,2H),2.18-2.10(m,2H)和1.43(s,9H)。
LCMS:m/z 340.1(M+H)+(ES+)。
步骤C:2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酸
在20℃下,向2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酸叔丁酯(16g,47.14mmol,1eq)在DCM(100mL)中的溶液中添加TFA(154g,1.35mol,28.65eq)。将反应混合物在20℃下搅拌12小时,接着在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,20:1至5:1)纯化,得到呈黄色固体状的标题化合物(12g,87%收率,97%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.89(br s,1H),8.35(d,1H),7.25(s,1H),7.11(d,1H),7.05(d,1H),6.98(s,1H),4.05(s,3H),3.58(s,2H),3.00(t,2H),2.92(t,2H)和2.19-2.10(m,2H)。
LCMS:m/z 284.1(M+H)+(ES+)。
中间体R11:2-(4-氟-2,6-二异丙基苯基)乙酸
步骤A:4-氟-2,6-二(丙-1-烯-2-基)苯胺
在减压下将2,6-二溴-4-氟苯胺(10g,1eq)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼烷(16.67g,2.67eq)、Cs2CO3(36.35g,3eq)和Pd(dppf)Cl2(2.72g,3.72mmol,0.1eq)在二噁烷(100mL)和H2O(10mL)中的溶液脱气。接着在氮气下将反应混合物加热至100℃保持3小时。通过添加H2O(200mL)来淬灭反应混合物,并用EtOAc(150mL)稀释。用EtOAc(2x150mL)萃取混合物。将合并的有机层用盐水(2x200mL)洗涤,经无水Na2SO4干燥,过滤并在减压下浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,1:0至100:1)纯化,得到呈黄色油状物的标题化合物(8g,89%收率,78.9%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ6.68(d,2H),5.32-5.31(m,2H),5.08(d,2H),3.84(s,2H)和2.07(d,6H)。
LCMS:m/z 192.2(M+H)+(ES+)。
步骤B:4-氟-2,6-二异丙基苯胺
向4-氟-2,6-二(丙-1-烯-2-基)苯胺(8g,1eq)在MeOH(150mL)中的溶液中添加Pd/C(624mg,10wt%载量/活性炭)。将混合物脱气并用H2(20psi)吹扫。将反应混合物在H2(20psi)下于25℃搅拌12小时,接着过滤。在真空下浓缩滤液。将残余物通过柱色谱法(SiO2,仅用石油醚洗脱)纯化,得到呈无色油状物的标题化合物(4g,63%收率,100%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ6.76(d,2H),3.56(s,2H),2.99-2.89(m,2H)和1.26(d,12H)。
LCMS:m/z 196.2(M+H)+(ES+)。
步骤C:2-溴-5-氟-1,3-二异丙基苯
向4-氟-2,6-二异丙基苯胺(3.7g,18.95mmol,1eq)在MeCN(180mL)中的溶液中添加CuBr(4.08g,1.5eq)。接着在0℃下逐滴添加亚硝酸叔丁酯(2.93g,1.5eq)。将所得混合物在60℃下搅拌1.5小时,接着在真空中浓缩。将残余物通过柱色谱法(SiO2,仅用石油醚洗脱)纯化,得到呈白色固体状的标题化合物(2.02g,41%)。
1H NMR(400MHz,CDCl3)δ6.85(d,2H),3.55-3.48(m,2H)和1.24(d,12H)。
步骤D:2-(4-氟-2,6-二异丙基苯基)乙酸叔丁酯
将2-溴-5-氟-1,3-二异丙基苯(16g,61.74mmol,1eq)在THF(100mL)中的溶液冷却至0℃。接着添加Pd2(dba)3(2.83g,3.09mmol,0.05eq)、(2.94g,6.17mmol,0.1eq)和(2-(叔丁氧基)-2-氧乙基)溴化锌(II)(中间体R9,步骤E)(0.5M,246.95mL,于THF溶液中,2eq)。将反应混合物在70℃下搅拌12小时,接着在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,100:0至10:1)纯化,得到呈红色油状物的标题化合物(12g,59%收率,90%纯度,经1H NMR测得)。
1H NMR(400MHz,CDCl3)δ6.83(d,2H),3.66(s,2H),3.21-3.14(m,2H),1.43(s,9H)和1.21(d,12H)。
步骤E:2-(4-氟-2,6-二异丙基苯基)乙酸
向2-(4-氟-2,6-二异丙基苯基)乙酸叔丁酯(12g,40.76mmol,1eq)在DCM(120mL)中的溶液中添加TFA(184.80g,39.76eq)。将反应混合物在25℃下搅拌3小时。在减压下蒸发大部分溶剂。将残余物用H2O(300mL)稀释,并用2M NaOH水溶液将混合物调节至pH=10。用EtOAc(3x500mL)洗涤混合物,并弃去有机相。接着用1M HCl水溶液将水层调节至pH=3并用EtOAc(3x500mL)萃取。将合并的有机层用盐水(2x200mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩,得到呈黄色固体状的标题化合物(8g,82%)。
1H NMR(400MHz,DMSO-d6)δ12.24(br s,1H),6.91(d,2H),3.78(s,2H),3.16-3.06(m,2H)和1.18(d,12H)。
中间体R12:7-氯-5-异丙基-2,3-二氢-1H-茚-4-胺
步骤A:5-溴-7-氯-2,3-二氢-1H-茚-4-胺
将7-氯-2,3-二氢-1H-茚-4-胺盐酸盐(1.00g,4.90mmol)(J Med Chem,2015,第58(2)卷,第878-887页)溶解在水(20mL)中。添加饱和NaHCO3水溶液(10mL)以中和溶液。用EtOAc(4x30mL)萃取混合物并将合并的有机物用盐水(30mL)洗涤,干燥(MgSO4)并在真空中浓缩。将残余物溶解在DCM(10mL)中并冷却至0℃。添加NBS(959mg,5.39mmol),并将混合物在0℃下搅拌2小时。滤出沉淀物,并用1N NaOH(2x20mL)洗涤滤液,干燥(MgSO4)且在真空中浓缩。将残余物通过硅胶色谱法(40g柱,0-5%MeOH/DCM)纯化,得到呈棕色油状物的标题化合物(895mg,67%)。
LCMS m/z 246/248(M+H)+(ES+)。
步骤B:7-氯-5-(丙-1-烯-2-基)-2,3-二氢-1H-茚-4-胺
将5-溴-7-氯-2,3-二氢-1H-茚-4-胺(440mg,1.78mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二杂氧戊硼烷(900mg,5.35mmol)、磷酸氢二钾(933mg,5.35mmol)、二环己基(2',6'-二甲氧基-[1,1'-联苯]-2-基)膦(88mg,0.214mmol)、Pd2(dba)3(49.0mg,0.054mmol)和水(0.5mL)添加至脱气的甲苯(10mL)中。在N2下将溶液回流16小时,接着冷却至室温。用EtOAc(10mL)稀释反应物,并将有机相用饱和NaHCO3水溶液(2x10mL)洗涤,干燥(MgSO4)并在真空中浓缩。将产物通过硅胶色谱法(40g柱,10%-30%EtOAc/异己烷)纯化,得到呈无色油状物的标题化合物(80mg,20%)。
LCMS m/z 208/210(M+H)+(ES+)。
步骤C:7-氯-5-异丙基-2,3-二氢-1H-茚-4-胺
将7-氯-5-(丙-1-烯-2-基)-2,3-二氢-1H-茚-4-胺(50mg,0.241mmol)和5%Pd/C(50重量%,87L型,5.1mg,0.024mmol)在乙醇(5mL)中的混合物氢化(5巴)16小时。将反应混合物过滤通过硅藻土,并将滤液在真空中浓缩。将残余物通过硅胶色谱法(40g柱,5%-20%乙酸乙酯/异己烷)纯化,得到呈无色油状物的标题化合物(20mg,37%)。
1H NMR(CDCl3)δ6.88(s,1H),2.91-2.80(m,3H),2.76(t,J=7.0Hz,2H),2.05(tt,J=8.2,7.0Hz,2H),1.17(d,J=6.8Hz,6H)。未观察到两个可交换质子。
LCMS m/z 210/212(M+H)+(ES+)。
中间体R13:4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯
将三光气(141mg,0.476mmol)添加至8-溴-1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(182mg,0.722mmol)和Et3N(302μL,2.16mmol)在THF(8mL)中的混合物中。将反应混合物加热回流2小时,接着在真空中浓缩并与甲苯(3x1mL)共沸干燥。将残余物溶解于甲苯中,并过滤通过二氧化硅塞,用甲苯洗涤。浓缩滤液,得到呈无色固体状的标题化合物(197mg,97%)。
LCMS m/z 365/367(M+H)+(ES+)。
中间体R14:8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯-4-甲腈
根据4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R13)的一般程序由8-氨基-1,2,3,5,6,7-六氢-s-茚并四烯-4-甲腈(如WO 2017/184623中所述制备)进行制备,得到呈无色固体状的标题化合物(101mg,87%)。
LCMS m/z 312.1(M+H)+(ES+)。
中间体R15:5-氯-2-异氰酸基-1,3-二异丙基苯
根据4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R13)的一般程序由4-氯-2,6-二异丙基苯胺进行制备,得到呈淡橙色油状物的标题化合物(1.05g,94%)。
LCMS m/z 325(M+H)+(ES+);323(M-H)-(ES-)。
中间体R16:5-氟-2-异氰酸基-1,3-二异丙基苯
根据4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R13)的一般程序由4-氟-2,6-二异丙基苯胺(中间体R11,步骤B)进行制备,得到呈澄清无色油状物的标题化合物(1.04g,92%)。
1H NMR(DMSO-d6)δ7.01(d,J=9.7Hz,2H),3.21-3.08(m,2H),1.20(d,J=6.9Hz,12H)。
LCMS m/z 309.4(M+Na)+(ES+)。
中间体R17:8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-胺
步骤A:N-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰胺
在0℃下,将乙酸酐(6.00mL,63.5mmol)逐滴添加至1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(10g,57.7mmol)和Et3N(9.65mL,69.3mmol)在DCM(140mL)中的溶液中。将溶液在室温下搅拌过夜。添加水(100mL),并通过过滤收集固体,用水洗涤并在真空中干燥,得到呈灰白色固体状的标题化合物(9.63g,77%)。
1H NMR(DMSO-d6)δ9.31(s,1H),6.94(s,1H),2.81(t,J=7.4Hz,4H),2.67(t,J=7.4Hz,4H),2.00(s,3H),1.96(p,J=7.4Hz,4H)。
步骤B:N-(8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰胺
将N-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰胺(4.0g,18.6mmol)和HF-吡啶(20mL,222mmol)在DCM(13mL)中的溶液在冰浴中冷却。逐滴添加PhI(OCOCF3)2(12g,27.9mmol)在DCM(13mL)中的溶液,并将反应物在冰浴中搅拌1小时。用饱和氢氧化钙水溶液淬灭反应混合物,并分离各相。使有机物通过疏水性玻璃料,并在真空中去除溶剂。将粗产物分成2批,并通过硅胶色谱法(220g和120g柱,0-100%EtOAc/异己烷)纯化,得到呈淡黄色固体状的标题化合物(747mg,16%)。
1H NMR(DMSO-d6)δ9.32(br s,1H),2.84(t,J=7.5Hz,4H),2.71(t,J=7.5Hz,4H),2.03(p,J=7.5Hz,4H),1.99(3H,s)。
19F NMR(DMSO-d6)δ-125.83。
步骤C:8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-胺
将N-(8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰胺(0.350g,1.50mmol)在EtOH(6.5mL)和浓HCl(6.5mL)中的溶液加热回流4天。将溶液冷却至室温并添加2M NaOH(20mL)。将产物萃取到DCM(3x50mL)中,并使有机萃取物通过疏水性玻璃料且在真空中蒸发。将粗产物通过硅胶色谱法(24g柱,0-50%EtOAc/异己烷)纯化,得到呈淡棕色固体状的标题化合物(240mg,79%)。
1H NMR(CDCl3)δ3.83(br s,2H),2.90(t,J=7.4Hz,4H),2.73(t,J=7.4Hz,4H),2.23-2.04(m,4H)。
LCMS m/z 192.1(M+H)+(ES+)。
实施例的制备
实施例1:5-氟-N-((4-(2-羟基丙-2-基)-2-甲基苯基)磺酰基)-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-甲酰胺
将4-(2-羟基丙-2-基)-2-甲基苯磺酰胺(中间体L1)(36mg,0.16mmol)和5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-羧酸(中间体R7,步骤B)(39mg,0.16mmol)在DCM(6mL)中搅拌。将EDC(60mg,0.31mmol)和DMAP(38mg,0.31mmol)添加至反应混合物中。将混合物在室温下搅拌过夜,用DCM(5mL)稀释,并用1M HCl水溶液(3mL)洗涤。浓缩有机相。将残余物溶解在DMSO(0.5mL)中,并添加KOtBu(52mg,0.47mmol)。将混合物通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(12mg,17%)。
1H NMR(300MHz,甲醇-d4)δ7.95(d,1H),7.36(s,1H),7.31(d,1H),6.69–6.60(m,1H),6.60–6.51(m,1H),3.96(s,1H),2.71(s,4H),2.27(dd,1H),2.05(dd,1H),1.49(d,6H),1.24(s,3H),1.14(s,3H),1.04(d,3H),0.80(d,3H)。
LCMS:m/z 462(M+H)+(ES+);460(M-H)-(ES-)。
实施例2:2-(4-氟-2,6-二异丙基苯基)-N-((4-(2-羟基丙-2-基)-2-甲基苯基)磺酰基)乙酰胺钾盐
将4-(2-羟基丙-2-基)-2-甲基苯磺酰胺(中间体L1)(50mg,0.17mmol)和2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(42mg,0.17mmol)在DCM(6mL)中搅拌。将EDC(67mg,0.35mmol)和DMAP(43mg,0.35mmol)添加至反应混合物中。将混合物搅拌过夜,用DCM(5mL)稀释,并用1M HCl水溶液(mL)洗涤。浓缩有机相。将残余物溶解在DMSO(0.5mL)中,并添加KOtBu(59mg,0.52mmol)。将混合物通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(41mg,52%)。
1H NMR(300MHz,甲醇-d4)δ7.90(d,1H),7.34(d,1H),7.28(dd,1H),6.69(d,2H),3.64(s,2H),3.19–2.98(m,2H),2.68(s,3H),1.48(d,6H),1.07(d,12H)。
LCMS:m/z 450(M+H)+(ES+);448(M-H)-(ES-)。
实施例3:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)-N-((4-(2-羟基丙-2-基)-2-甲基苯基)磺酰基)丙酰胺
将4-(2-羟基丙-2-基)-2-甲基苯磺酰胺(中间体L1)(85mg,0.37mmol)和Et3N(38mg,0.37mmol)在DCM(6mL)中搅拌。接着逐滴添加含3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰氯(中间体R5)(63mg,0.19mmol)的DCM(1mL)并搅拌过夜。将EDC(36mg,0.19mmol)和DMAP(23mg,0.35mmol)添加至反应混合物中。将混合物搅拌过夜,用DCM(5mL)稀释,并用1M HCl水溶液(3mL)洗涤。浓缩有机相。将残余物溶解在DMSO(0.5mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(22mg,22%)。
1H NMR(300MHz,甲醇-d4)δ8.14–8.09(m,1H),7.87(d,1H),7.34(d,2H),7.10–7.00(m,1H),6.83(dd,1H),6.72–6.61(m,2H),3.92(s,3H),3.23(q,1H),2.83–2.66(m,2H),2.54(s,3H),2.22(dd,2H),1.51(s,6H),1.22(d,6H)。
LCMS:m/z 529(M+H)+(ES+);527(M-H)-(ES-)。
实施例4:N-((4-((二甲氨基)甲基)苯基)磺酰基)-3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰胺钾盐
将4-((二甲氨基)甲基)苯磺酰胺(中间体L13)(80mg,0.37mmol)和KOtBu(63mg,0.56mmol)在THF(6mL)中搅拌。接着逐滴添加含3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰氯(中间体R5)(63mg,0.19mmol)的THF(1mL)并搅拌过夜。将EDC(36mg,0.19mmol)和DMAP(23mg,0.35mmol)添加至反应混合物中。将混合物搅拌2小时并浓缩。将残余物溶解在DMSO(0.5mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(19mg,20%)。
1H NMR(300MHz,甲醇-d4)δ8.11(d,1H),7.81(d,2H),7.38(d,2H),7.03(dd,1H),6.86(d,1H),6.65(m,2H),3.93(s,3H),3.54(s,2H),3.30(m,1H),2.78–2.63(m,2H),2.25(s,6H),2.23–2.13(m,2H),1.22(d,6H)。
LCMS:m/z 514(M+H)+(ES+);512(M-H)-(ES-)。
实施例5:3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)-N-((4-(2-羟基丙-2-基)噻吩-2-基)磺酰基)丙酰胺
将4-(2-羟基丙-2-基)噻吩-2-磺酰胺(120mg,0.55mmol)和Et3N(55mg,0.55mmol)在DCM(6mL)中搅拌。接着逐滴添加含3-(4-氟-2-异丙基-6-(2-甲氧基吡啶-4-基)苯基)丙酰氯(中间体R5)(90mg,0.27mmol)的DCM(1mL)。将混合物搅拌过夜并浓缩。将残余物通过反相制备型HPLC方法3纯化,得到呈白色固体状的标题化合物(5mg,4%)。
1H NMR(300MHz,甲醇-d4)δ8.18–8.10(m,1H),7.77(d,1H),7.66(d,1H),7.09(dd,1H),6.88(dd,1H),6.78–6.68(m,2H),3.96(s,3H),3.17(m,1H),2.89–2.70(m,2H),2.36–2.22(m,2H),1.52(s,6H),1.24(d,6H)。
LCMS:m/z 521(M+H)+(ES+);519(M-H)-(ES-)。
实施例6:N-((1-环丙基-1H-吡唑-3-基)磺酰基)-6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-甲酰胺
将1-环丙基-1H-吡唑-3-磺酰胺(70mg,0.37mmol)和Et3N(38mg,0.37mmol)在DCM(6mL)中搅拌。接着逐滴添加含6-氟-8-异丙基-4,4-二甲基-1,2,3,4-四氢萘-1-碳酰氯(中间体R6)(53mg,0.19mmol)的DCM(1mL)。将混合物搅拌过夜。将DMAP(23mg,0.19mmol)添加至反应混合物中。将混合物再搅拌一天,接着浓缩。将残余物通过反相制备型HPLC方法3纯化,得到呈白色固体状的标题化合物(8mg,10%)。
1H NMR(300MHz,甲醇-d4)δ7.76(d,1H),6.90(dd,1H),6.75(m,2H),3.88(t,1H),3.77(tt,1H),2.82–2.65(m,1H),2.07(dt,2H),1.73–1.58(m,1H),1.58–1.39(m,1H),1.24(d,6H),1.20–1.01(m,6H),0.89(d,4H)。
LCMS:m/z 434(M+H)+(ES+);432(M-H)-(ES-)。
实施例7:N-((1-环丙基-1H-吡唑-4-基)磺酰基)-5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-甲酰胺
将5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-羧酸(中间体R7,步骤B)(60mg,0.24mmol)、DIPEA(93mg,0.72mmol)和HATU(110mg,0.29mmol)在DCM(6mL)中搅拌50分钟。接着添加1-环丙基-1H-吡唑-4-磺酰胺(45mg,0.24mmol)。将混合物搅拌过夜,用DCM稀释并用水洗涤。浓缩有机相。将残余物通过反相制备型HPLC方法3纯化,得到呈白色固体状的标题化合物(主旋转异构体)(5mg,5%)。
1H NMR(300MHz,甲醇-d4)δ8.25(s,1H),7.83(s,1H),6.81–6.61(m,2H),4.01–3.89(m,1H),3.71(dt,1H),2.47(dt,1H),2.31(dd,1H),2.06–1.92(m,1H),1.21(d,6H),1.11–1.00(m,6H),0.89(d,4H)。
LCMS:m/z 420(M+H)+(ES+);418(M-H)-(ES-)。
实施例8:5-氟-N-((4-(2-羟基丙-2-基)噻吩-2-基)磺酰基)-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-甲酰胺钾盐(旋转异构体P1)和
实施例9:5-氟-N-((4-(2-羟基丙-2-基)噻吩-2-基)磺酰基)-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-甲酰胺钾盐(旋转异构体P2)
将4-(2-羟基丙-2-基)噻吩-2-磺酰胺(110mg,0.48mmol)和KOtBu(54mg,0.48mmol)在THF(6mL)中搅拌。接着逐滴添加含5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-碳酰氯(中间体R7)(65mg,0.24mmol)的THF(1mL)。将反应混合物搅拌过夜并浓缩。将残余物通过反相制备型HPLC方法3纯化,得到为单独的旋转异构体的标题化合物。旋转异构体P1是第一洗脱旋转异构体(10mg,9%),旋转异构体P2是第二洗脱旋转异构体(2mg,2%),两者均呈白色固体状。
旋转异构体P1:
1H NMR(300MHz,甲醇-d4)δ7.80(d,1H),7.64(d,1H),6.75(dd,1H),6.67(dd,1H),3.97(ddd,1H),2.62–2.44(m,1H),2.32(dd,1H),1.98(dd,1H),1.50(s,6H),1.21(d,6H),1.08(d,3H),0.94(d,3H)。
LCMS:m/z 454(M+H)+(ES+);452(M-H)-(ES-)。
旋转异构体P2:
LCMS:m/z 454(M+H)+(ES+);452(M-H)-(ES-)。
实施例10:5-氟-7-异丙基-N-((1-异丙基-1H-吡唑-3-基)磺酰基)-3,3-二甲基-2,3-二氢-1H-茚-1-甲酰胺钾盐(旋转异构体P2)
将1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(91mg,0.48mmol)和KOtBu(81mg,0.72mmol)在THF(6mL)中搅拌。接着逐滴添加含5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-碳酰氯(中间体R7)(65mg,0.24mmol)的THF(1mL)。将反应混合物搅拌过夜并浓缩。通过反相制备型HPLC方法3纯化残余物。分离出呈白色固体状的标题化合物,其为第二洗脱旋转异构体(3mg,3%)。
1H NMR(300MHz,甲醇-d4)δ7.79(d,1H),7.03(d,1H),6.85–6.75(m,2H),4.69–4.54(m,1H),4.00(t,1H),3.13(p,1H),2.27–2.03(m,2H),1.54–1.44(m,6H),1.29(s,3H),1.25–1.13(m,9H)。
LCMS:m/z 422(M+H)+(ES+);418(M-H)-(ES-)。
实施例11:3-(N-(5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-羰基)氨磺酰基)-N,N,1-三甲基-1H-吡唑-5-甲酰胺
将N,N,1-三甲基-3-氨磺酰基-1H-吡唑-5-甲酰胺(120mg,0.52mmol)和Et3N(110mg,1mmol)在DCM(6mL)中搅拌。接着逐滴添加含5-氟-7-异丙基-3,3-二甲基-2,3-二氢-1H-茚-1-碳酰氯(中间体R7)(70mg,0.26mmol)的DCM(1mL)。将混合物搅拌过夜,接着浓缩。将残余物通过反相制备型HPLC方法3纯化,得到呈白色固体状的标题化合物(4mg,3%)。
1H NMR(300MHz,甲醇-d4)δ6.95(s,1H),6.73(dd,1H),6.64(dd,1H),3.96(s,3H),3.95(m,1H),3.09(d,6H),2.80–2.66(m,1H),2.31(dd,1H),2.05(dd,1H),1.21(d,6H),1.10(d,3H),0.99(d,3H)。
LCMS:m/z 465(M+H)+(ES+);463(M-H)-(ES-)。
实施例12:1-(2-(双(甲基-d3)氨基)乙基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
将1-(2-(双(甲基-d3)氨基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐(中间体L5)(367mg,1.08mmol)和KOtBu(365mg,3.25mmol)在THF(6mL)中搅拌。接着逐滴添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(230mg,1.08mmol)的THF(1mL)。将混合物搅拌过夜并浓缩。将残余物溶解在DMSO(1mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(114mg,25%)。
1H NMR(300MHz,甲醇-d4)δ7.67(d,1H),6.85(s,1H),6.63(d,1H),4.29(t,2H),2.80(td,6H),2.71(t,4H),1.98(p,4H)。
LCMS:m/z 424(M+H)+(ES+);422(M-H)-(ES-)。
实施例13:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
向3-氨磺酰基-1H-吡唑-1-羧酸叔丁酯(中间体L3)(62mg,0.25mmol)在THF(1mL)中的溶液中添加KOtBu(28mg,0.25mmol)。将形成的悬浮液搅拌1小时,接着添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(50mg,0.25mmol)的THF(1mL)。将所得反应混合物在室温下搅拌过夜。在减压下浓缩混合物,并通过HPLC分析残余物,观察到标题化合物和BOC保护的衍生物的混合物。将粗产物溶解在DMSO(0.5mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(17mg,20%)。
1H NMR(CD3OD)δ7.60(s,1H),6.85(d,1H),6.69(t,1H),2.81(t,4H),2.71(t,4H),1.98(m,4H)。
LCMS:m/z 347(M+H)+(ES+);346(M-H)-(ES)。
实施例14:N-((1,2,3,5-四氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
向3-氨磺酰基-1H-吡唑-1-羧酸叔丁酯(中间体L3)(41mg,0.17mmol)在THF(1mL)中的溶液中添加KOtBu(19mg,0.17mmol)。将形成的悬浮液搅拌1小时,接着添加含8-异氰酸基-1,2,3,5-四氢-s-茚并四烯(中间体R2)(33mg,0.17mmol)的THF(0.8mL)。将所得反应混合物在室温下搅拌过夜。在减压下浓缩混合物,并通过HPLC分析残余物,观察到标题化合物和BOC保护的衍生物的混合物。将粗产物溶解在DMSO(0.5mL)中,并通过反相柱色谱法进行纯化,得到呈白色固体状的标题化合物(13mg,22%)。
1H NMR(CD3OD)δ7.61(s,1H),7.04(s,1H),6.73(m,2H),6.41(s,1H),2.85(dt,6H),2.03(m,2H)。
LCMS:m/z 345(M+H)+(ES+);343(M-H)-(ES-)。
实施例15:1-异丙基-N-((3-氧代-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
向1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(57mg,0.30mmol)在THF(1mL)中的溶液中添加KOtBu(34mg,0.30mmol)。将形成的悬浮液搅拌1小时,接着添加含8-异氰酸基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮(中间体R4)(64mg,0.30mmol)的THF(1mL)。将所得反应混合物在室温下搅拌过夜。将反应混合物在减压下浓缩。将残余物溶解在DMSO(1mL)中,并通过反相柱色谱法进行纯化,得到呈白色固体状的标题化合物(25mg,20%)。
1H NMR(CD3OD)δ7.61(d,1H),7.00(s,1H),6.66(d,1H),4.53(p,1H),3.00(m,2H),2.88(t,2H),2.77(t,2H),2.64(m,2H),1.96(p,2H),1.47(d,6H)。
LCMS:m/z 403(M+H)+(ES+);401(M-H)-(ES-)。
实施例16:1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
将1-(2-(3-(丁-3-炔-1-基)-3H-双吖丙啶-3-基)乙基)-1H-吡唑-3-磺酰胺2,2,2-三氟乙酸盐(中间体L4)(12mg,0.047mmol)和KOtBu(8mg,0.071mmol)在THF(3mL)中搅拌。接着逐滴添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(9mg,0.047mmol)的THF(1mL)。将所得反应混合物搅拌过夜并浓缩。将残余物溶解在DMSO(1mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(10mg,45%)。
1H NMR(300MHz,甲醇-d4)δ6.85(s,1H),6.67(d,1H),4.07(t,2H),3.72(s,1H),2.76(dt,9H),1.96(ddt,8H),1.47(t,2H)。
LCMS:m/z 467(M+H)+(ES+);465(M-H)-(ES-)。
实施例17:4-((2-(氨基甲基)-3-氟烯丙基)氧基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)苯磺酰胺2,2,2-三氟乙酸盐
将叔丁基-(3-氟-2-((4-(N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)氨磺酰基)苯氧基)甲基)烯丙基)氨基甲酸酯钾盐(实施例18)(7mg,0.013mmol)溶解在DCM(0.3mL)和TFA(0.3mL)中。将混合物在室温下搅拌4小时并浓缩。将残余物溶解于水中并冷冻干燥,得到呈白色固体状的标题化合物(3mg,43%)。
1H NMR(300MHz,甲醇-d4)δ7.86(m,2H),7.13(m,1H),7.02(m,2H),6.85(m,1H),4.68–4.51(m,2H),3.61–3.43(m,2H),2.87–2.61(m,8H),1.97(p,4H)。
LCMS:m/z 460(M+H)+(ES+);458(M-H)-(ES-)。
实施例18:叔丁基-(3-氟-2-((4-(N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)氨磺酰基)苯氧基)甲基)烯丙基)氨基甲酸酯钾盐
将叔丁基-(3-氟-2-((4-氨磺酰基苯氧基)甲基)烯丙基)氨基羧酸酯(如WO 2013/163675中所述制备,95mg,0.26mmol)和KOtBu(30mg,0.26mmol)在THF(3mL)中搅拌。接着逐滴添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(52mg,0.26mmol)的THF(1mL)。将混合物搅拌过夜并浓缩。将残余物溶解在DMSO(1mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(9mg,6%)。
1H NMR(300MHz,甲醇-d4)δ7.87(d,2H),7.07–6.93(m,3H),6.79(d,1H),4.55–4.46(m,1H),3.92(s,1H),2.80(t,4H),2.75–2.60(m,6H),1.98(q,4H),1.39(s,9H)。
LCMS:m/z 560(M+H)+(ES+);558(M-H)-(ES-)。
实施例19:1-乙基-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-1,2,3-三唑-4-磺酰胺钾盐
将1-乙基-1H-1,2,3-三唑-4-磺酰胺(Chemspace,49mg,0.28mmol)和KOtBu(31mg,0.28mmol)在THF(6mL)中搅拌。接着逐滴添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(55mg,0.28mmol)的THF(1mL)。将混合物搅拌过夜并浓缩。将残余物溶解在DMSO(1mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(65mg,63%)。
1H NMR(300MHz,甲醇-d4)δ8.29(s,1H),6.87(s,1H),4.47(q,2H),2.77(m,8H),2.00(m,4H),1.54(t,3H)。
LCMS:m/z 376(M+H)+(ES+);374(M-H)-(ES-)。
实施例20:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺钾盐
将1-(丙-2-基-d7)-1H-吡唑-3-磺酰胺(中间体L2)(146mg,0.47mmol)和KOtBu(106mg,0.94mmol)在THF(6mL)中搅拌。接着逐滴添加含4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(100mg,0.47mmol)的THF(1mL)。将混合物搅拌过夜并浓缩。将残余物溶解在DMSO(1mL)中并通过反相制备型HPLC方法2纯化,得到呈白色固体状的标题化合物(112mg,60%)。
1H NMR(300MHz,甲醇-d4)δ7.65(t,1H),6.84(s,1H),6.63(d,1H),2.75(m,8H),2.19–1.79(m,4H)。
LCMS:m/z 396(M+H)+(ES+);394(M-H)-(ES-)。
实施例21:N-((1-羟基-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
步骤A:1-异丙基-N-((1-氧代-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺
将1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(45mg,0.22mmol)在THF(4mL)中的溶液冷却至0℃。接着添加KOtBu(27mg,0.24mmol),并将混合物在21℃下搅拌30分钟。接下来,添加4-异氰酸基-3,5,6,7-四氢-s-茚并四烯-1(2H)-酮(中间体R3)(46mg,0.24mmol)在THF(4mL)中的溶液,并将混合物在21℃下搅拌18小时。过滤混合物,得到呈白色固体状的标题化合物(70mg,80%)。
LCMS:m/z 403(M+H)+(ES+);401(M-H)-(ES-)。
步骤B:N-((1-羟基-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
将含1-异丙基-N-((1-氧代-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺(70mg,0.17mmol)的甲醇(4mL)冷却至0℃。接下来添加硼氢化钠(66mg,1.74mmol),并将混合物在室温下搅拌18小时。添加水(2mL),并蒸发混合物。将残余物通过反相制备型HPLC方法3纯化,得到呈白色固体状的标题化合物(64mg,91%)。
1H NMR(300MHz,D2O)δ7.65(d,1H),7.08(s,1H),6.59(d,1H),5.10(t,1H),4.49(m,1H),2.80(t,2H),2.71(m,1H),2.60(t,2H),2.52(m,1H),2.33(m,1H),1.93(m,2H),1.81(m,1H),1.39(d,6H)。
LCMS:m/z 463(M+59)+(ES+);403(M-H)-(ES-)。
实施例22:
1-异丙基-N-((1,2,3,7-四氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐和1-异丙基-N-((1,2,3,5-四氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钾盐
在0℃下,向1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(31mg,0.16mmol)在THF(4mL)中的溶液中添加KOtBu(18mg,0.16mmol)。将混合物在21℃下搅拌1小时。接着添加含8-异氰酸基-1,2,3,5-四氢-s-茚并四烯(中间体R2)(35mg,0.18mmol)的THF(3mL),并将混合物在21℃下搅拌18小时。蒸发溶剂,并将残余物通过反相柱色谱法纯化,得到呈白色固体状的标题化合物(65mg,100%)。
1H NMR(300MHz,D2O),两种异构体的混合物,比率3/2,δ7.65(d,1H),7.22和7.16(s,1H),6.77和6.68(d,J=32.6,5.6Hz,1H),6.59(d,J=2.4Hz,1H),6.55–6.37(m,1H),4.49(dt,J=13.4,6.6Hz,1H),3.31和3.16(s,2H),2.74(dt,J=54.3,7.4Hz,4H),1.95(m,J=7.5Hz,2H),1.39(d,J=6.7Hz,7H)。
LCMS:m/z 387(M+H)+(ES+);385(M-H)-(ES-)。
实施例23:1-异丙基-N-((5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酰基)-1H-吡唑-3-亚磺酰胺
向1-异丙基-1H-吡唑-3-亚磺酰胺(中间体L6)(0.1g,577.25μmol,1eq)在THF(2mL)中的溶液中添加t-BuONa(56mg,577.25μmol,1eq)。将混合物在25℃下搅拌30分钟。接着添加4-(4-异氰酸基-2,3-二氢-1H-茚-5-基)-2-甲氧基吡啶(中间体R8)(150mg,563.29μmol,0.98eq)。将所得混合物在25℃下搅拌1小时,接着在真空中浓缩。将残余物通过制备型HPLC(柱:Waters Xbridge C18,150mm x 25mm x 5μm;流动相:[A:水(0.05%氢氧化铵v/v),B:MeCN];B%:20%-50%,10min)纯化,得到呈白色固体状的标题化合物(81.42mg,31%收率,98%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ8.15(d,1H),7.92(s,1H),7.22-7.19(m,1H),7.14-7.11(m,1H),6.95(d,1H),6.77(s,1H),6.59(s,1H),4.60-4.53(m,1H),3.87(s,3H),2.94(t,2H),2.82(t,2H),2.04-2.00(m,2H)和1.44(d,6H)。
LCMS:m/z 440.2(M+H)+(ES+)。
实施例24:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)-N-(1-异丙基-1H-吡唑-3-磺酰亚氨基)乙酰胺
步骤A:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)-N-((1-异丙基-1H-吡唑-3-基)亚磺酰基)乙酰胺
在-70℃下,向1-异丙基-1H-吡唑-3-亚磺酰胺(中间体L6)(400mg,2.31mmol,1eq)在THF(20mL)中的溶液中添加n-BuLi(2M,1.27mL,1.1eq)。将反应混合物搅拌30分钟。在20℃下,向此反应混合物中添加2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)乙酰氯(中间体R9)(542mg,2.31mmol,1eq)在THF(1mL)中的溶液。将反应混合物在-70℃下搅拌2.5小时,倒入水(50mL)中,并用EtOAc(2x50mL)萃取。将合并的有机层经Na2SO4干燥,过滤并在真空中浓缩。将残余物通过反相快速色谱法(0.01%TFA-MeCN)纯化,得到呈黄色固体状的标题化合物(170mg,20%)。
1H NMR(400MHz,DMSO-d6)δ11.31(br s,1H),8.05(d,1H),6.97(s,1H),6.75(d,1H),4.65-4.58(m,1H),3.62(s,2H),2.83-2.74(m,8H),2.02-1.94(m,4H)和1.46(m,6H)。
LCMS:m/z 372.1(M+H)+(ES+)。
步骤B:2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)-N-(1-异丙基-1H-吡唑-3-磺酰亚氨基)乙酰胺
向2-(1,2,3,5,6,7-六氢-s-茚并四烯-4-基)-N-((1-异丙基-1H-吡唑-3-基)亚磺酰基)乙酰胺(150mg,403.77μmol,1eq)在THF(5mL)中的溶液中添加1-氯-1H-苯并[d][1,2,3]三唑(68mg,444.15μmol,1.1eq)。将反应混合物在20℃下搅拌0.5小时。在-70℃下将所得混合物逐滴添加至NH3在THF中的溶液中,所述溶液是通过在-70℃下将NH3(15psi)鼓泡至THF(20mL)中持续10分钟制得的。将反应混合物在20℃下搅拌2小时,接着在真空中浓缩。将残余物用EtOAc(100mL)稀释并用水(2x50mL)提取。将有机层经Na2SO4干燥,过滤并在真空中浓缩。将残留物通过制备型TLC(SiO2,石油醚:乙酸乙酯,2:1)纯化,接着通过制备型HPLC(柱:Phenomenex Gemini C18,150mm x 25mm x 10μm;流动相:[A:水(10mM NH4HCO3);B:MeCN];B%:25%-55%,10min),得到呈黄色油状物的标题化合物(28.28mg,17%收率,95.2%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ7.45(d,1H),7.01(s,1H),6.54(d,1H),6.19(br s,1H),4.60-4.50(m,1H),3.71(s,2H),2.90-2.80(m,8H),2.09-2.02(m,4H)和1.53(d,6H)。
LCMS:m/z 387.1(M+H)+(ES+)。
实施例25:N-(1-异丙基氮杂环丁烷-3-磺酰亚氨基)-2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰胺
步骤A:3-(N-(2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰基)氨亚磺酰基)氮杂环丁烷-1-羧酸叔丁酯
向2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酸(中间体R10)(600mg,2.12mmol,1eq)在THF(10mL)中的溶液(A)中添加CDI(343mg,2.12mmol,1eq),并将反应混合物在70℃下搅拌1小时。在-70℃下,向3-氨亚磺酰基氮杂环丁烷-1-羧酸叔丁酯(中间体L7)(560mg,2.54mmol,1.2eq)在THF(10mL)中的另一溶液(B)中添加n-BuLi(2.5M,1.02mL,1.2eq),并将反应混合物在-70℃下搅拌0.5小时。在-70℃下,将溶液(A)添加至溶液(B)中。将所得混合物加热至20℃并再搅拌1小时。将反应混合物用水(80mL)淬灭并用乙酸乙酯(100mL)萃取。将有机层用盐水(60mL)洗涤,经Na2SO4干燥,过滤并在真空中浓缩。将残余物通过反相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈黄色油状物的标题化合物(400mg,39%)。
1H NMR(400MHz,DMSO-d6)δ10.82(br s,1H),8.18(d,1H),7.23(d,1H),7.03(d,1H),6.87-6.85(m,1H),6.66(s,1H),4.13-4.11(m,3H),3.88(s,3H),3.87-3.84(m,1H),3.75-3.70(m,1H),3.54-3.47(m,2H),2.94(t,2H),2.79(t,2H),2.07-2.02(m,2H)和1.39(s,9H)。
LCMS:m/z 486.2(M+H)+(ES+)。
步骤B:3-(N-(2-(5-(2-(甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰基)磺酰亚氨基)氮杂环丁烷)-1-羧酸叔丁酯
向3-(N-(2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰基)氨亚磺酰基)氮杂环丁烷-1-羧酸叔丁酯(380mg,782.55μmol,1eq)在THF(10mL)中的溶液中添加1-氯-1H-苯并[d][1,2,3]三唑(132mg,860.80μmol,1.1eq)。将反应混合物在20℃下搅拌0.5小时。在-70℃下将所得混合物逐滴添加至NH3在THF中的溶液中,所述溶液是通过在-70℃下将NH3(15psi)鼓泡至THF(30mL)中持续10分钟制得的。将反应混合物在20℃下搅拌2小时,接着在真空中浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,5:1至1:1)纯化,得到呈黄色油状物的标题化合物(102mg,21%收率,80.1%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.10-8.08(m,1H),7.17-7.08(m,1H),6.96-6.93(m,1H),6.79-6.72(m,1H),6.63-6.55(m,1H),4.12-4.01(m,5H),3.89(s,3H),3.52-3.48(m,2H),2.92-2.79(m,4H),2.07-2.01(m,2H)和1.36(s,9H)。
LCMS:m/z 501.1(M+H)+(ES+)。
步骤C:N-(氮杂环丁烷-3-磺酰亚氨基)-2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰胺
向3-(N-(2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰基)磺酰亚氨基)氮杂环丁烷-1-羧酸叔丁酯(90mg,179.78μmol,1eq)在DCM(8mL)中的溶液中添加TFA(0.8mL)。将反应混合物在25℃下搅拌1小时。将N2鼓泡通过反应混合物以去除溶剂,并将残余物通过反相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈黄色油状物的标题化合物(30mg,42%)。
1H NMR(400MHz,DMSO-d6)δ8.19-8.16(m,1H),7.19(dd,1H),7.04-7.00(m,1H),6.90(dd,1H),6.72(d,1H),4.56-4.48(m,1H),3.91(s,3H),3.89-3.51(m,4H),3.49(d,2H),2.93-2.90(m,2H),2.81-2.78(m,2H)和2.08-2.00(m,2H)。
LCMS:m/z 401.2(M+H)+(ES+)。
步骤D:N-(1-异丙基氮杂环丁烷-3-磺酰亚氨基)-2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰胺
向N-(氮杂环丁烷-3-磺酰亚氨基)-2-(5-(2-甲氧基吡啶-4-基)-2,3-二氢-1H-茚-4-基)乙酰胺(26mg,64.92μmol,1eq)在DMSO(0.5mL)中的溶液中添加DIPEA(17mg,129.84μmol,2eq)和2-碘丙烷(22mg,129.84μmol,2eq)。将反应混合物在30℃下搅拌21小时。将反应混合物直接通过反相快速色谱法(0.1%TFA/水-MeCN)纯化。将产物通过制备型HPLC(柱:Phenomenex Gemini C18,150mm x 25mm x 10μm;流动相:[A:水(0.04%NH3.H2O+10mM NH4HCO3),B:MeCN];B%:20%-64%,43min)进一步纯化;得到呈白色固体状的标题化合物(3mg,10%)。
1H NMR(400MHz,CD3Cl)δ8.17(d,1H),7.20(d,1H),7.04(d,1H),6.88(dd,1H),6.73(s,1H),4.20-4.15(m,1H),3.98(s,3H),3.62(s,2H),3.59-3.53(m,2H),3.46-3.42(m,2H),2.99(t,2H),2.89(t,2H),2.36-2.34(m,1H),2.15-2.11(m,2H)和0.92(d,6H)。
LCMS:m/z 443.2(M+H)+(ES+)。
实施例26:2-(4-氟-2,6-二异丙基苯基)-N-((1-异丙基-1H-吡唑-3-基)磺酰基)乙酰胺
向1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(50mg,264.22μmol,1eq)在DMF(1.5mL)和DCM(1.5mL)中的溶液中添加EDCI(101mg,528.44μmol,2eq)、DMAP(64mg,528.44μmol,2eq)和2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(62mg,264.22μmol,1eq)。将反应混合物在25℃下搅拌2小时,用水(5mL)稀释并用DCM(3x5mL)萃取。将合并的有机层用1NHCl水溶液洗涤直至其pH为7。接着将有机层用Na2SO4干燥,过滤并在减压下浓缩。将残余物通过制备型HPLC(柱:Phenomenex Luna C18,150mm x 25mm x 10μm;流动相:[A:水(0.1%TFA),B:MeCN],B%:50%-78%,10min)纯化,得到呈白色固体状的标题化合物(24.15mg,22%收率,99%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),7.96(d,1H),6.87(d,2H),6.71(d,1H),4.63-4.55(m,1H),3.75(s,2H),2.92-2.85(m,2H),1.41(d,6H)和1.03(d,12H)。
LCMS:m/z 410.3(M+H)+(ES+)。
实施例27:2-(4-氟-2,6-二异丙基苯基)-N-((2-(2-羟基丙-2-基)噻唑-5-基)磺酰基)乙酰胺
在25℃下,向2-(2-羟基丙-2-基)噻唑-5-磺酰胺(中间体L9)(80mg,359.90μmol,1eq)、2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(94mg,395.89μmol,1.1eq)和DMAP(65mg,539.85μmol,1.5eq)在DMF(2mL)中的溶液中添加EDCI(103mg,539.85μmol,1.5eq)。将反应混合物在25℃下搅拌1小时,接着在真空中浓缩。将残余物通过制备型HPLC(柱:Phenomenex Luna C18,150mm x 25mm x 10μm;流动相:[A:水(0.1%TFA),B:MeCN],B%:42%-72%,10min)纯化,得到呈白色固体状的标题化合物(65.13mg,41%收率,100%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ12.73(br s,1H),8.25(s,1H),6.89(dd,2H),3.77(s,2H),2.89-2.85(m,2H),1.46(s,6H)和1.00(d,12H)。
LCMS:m/z 443.1(M+H)+(ES+)。
实施例28:N-((5-溴-2-((1-甲基-1H-四唑-5-基)硫代)苯基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
将(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺(中间体L21)(30mg,88.92μmol,1eq)和5-溴-2-((1-甲基-1H-四唑-5-基)硫代)苯胺(28mg,97.81μmol,1.1eq)在MeCN(1mL)中的溶液在70℃下搅拌1小时,接着在真空中浓缩。将残余物通过制备型HPLC(柱:Phenomenex Gemini C18,150mm x 25mm x 10μm;流动相:[A:水(0.05%氢氧化铵v/v),B:MeCN];B%:10%-40%,12min)纯化,得到呈白色固体状的标题化合物(13.34mg,29%收率,96.1%纯度,经LCMS测得)。
LCMS:m/z 502.9(M+H)+(ES+)。
实施例29:2-(4-氟-2,6-二异丙基苯基)-N-((5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-基)磺酰基)乙酰胺
向5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺(中间体L24)(100mg,404.34μmol,1eq)、2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(106mg,444.78μmol,1.1eq)和DMAP(74mg,606.52μmol,1.5eq)在DMF(2mL)中的溶液中添加EDCI(116mg,606.52μmol,1.5eq)。将反应混合物在25℃下搅拌1小时,接着在真空中浓缩。将残余物通过制备型HPLC(柱:Phenomenex Synergi C18,150mm x 25mm x 10μm;流动相:[A:水(0.1%TFA),B:MeCN],B%:49%-79%,10min)纯化,得到呈黄色固体状的标题化合物(38.27mg,20%收率,100%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ12.30(br s,1H),6.87(d,2H),6.46(s,1H),5.54(s,1H),5.31-5.27(m,1H),3.76(s,2H),2.91-2.87(m,2H),1.47(s,6H),1.38(d,6H)和1.04(d,12H)。
LCMS:m/z 468.2(M+H)+(ES+)。
实施例30:2-(4-氟-2,6-二异丙基苯基)-N-((5-(2-羟基丙-2-基)噻唑-2-基)磺酰基)乙酰胺
在25℃下,向5-(2-羟基丙-2-基)噻唑-2-磺酰胺(中间体L10)(80mg,359.90μmol,1eq)、2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(94mg,395.89μmol,1.1eq)和DMAP(66mg,539.85μmol,1.5eq)在DMF(1.5mL)中的溶液中添加EDCI(104mg,539.85μmol,1.5eq)。将反应混合物在25℃下搅拌1小时。将反应混合物直接通过制备型HPLC(柱:Phenomenex Luna C18,150mm x 25mm x 5μm;流动相:[A:水(0.075%TFA v/v),B:MeCN];B%:50%-80%,9min)纯化,得到呈白色固体状的标题化合物(95mg,59%收率,99.4%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ12.97(br s,1H),7.89(s,1H),6.86(d,2H),6.00(s,1H),3.78(s,2H),2.92-2.85(m,2H),1.50(s,6H)和1.02(d,12H)。
LCMS:m/z 443.1(M+H)+(ES+)。
实施例31:1-异丙基-N-((1-氧代-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钠盐
根据N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺钠盐(实施例61)的一般程序由(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺(中间体L21)和4-氨基-2,3,6,7-四氢-s-茚并四烯-1(5H)-酮进行制备,得到呈白色固体状的标题化合物(46mg,40%)。
1H NMR(DMSO-d6)δ7.90(s,1H),7.71(d,J=2.3Hz,1H),7.17(s,1H),6.40(d,J=2.3Hz,1H),4.50(sept,J=6.7Hz,1H),2.92-2.88(m,2H),2.85(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H),2.55-2.52(m,2H),1.96(p,J=7.5Hz,2H),1.40(d,J=6.7Hz,6H)。未观察到一个可交换质子。
LCMS m/z 403.2(M+H)+(ES+);401.1(M-H)-(ES-)。
实施例32:2-(4-氟-2,6-二异丙基苯基)-N-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)磺酰基)乙酰胺铵盐
向5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L12)(80mg,364.86μmol,1eq)、2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(96mg,401.35μmol,1.1eq)和DMAP(67mg,547.29μmol,1.5eq)在DMF(2mL)中的溶液中添加EDCI(105mg,547.29μmol,1.5eq)。将反应混合物在25℃下搅拌1小时。过滤反应混合物,并将滤液通过制备型HPLC(柱:Waters Xbridge C18,150mm x 25mm x 5μm;流动相:[A:水(0.05%氢氧化铵v/v),B:MeCN];B%:5%-35%,10min)纯化,得到呈白色固体状的标题化合物(38.5mg,23%收率,100%纯度,经LCMS测得)。
1H NMR(400MHz,DMSO-d6)δ12.4(br s,1H),7.07(br s.1H),6.84(d,2H),6.39(s,1H),5.42(s,1H),3.98(s,3H),3.66(s,2H),3.02-2.99(m,2H),1.45(s,6H)和1.05(d,12H)。
LCMS:m/z 440.2(M+H)+(ES+)。
实施例33:N-((4-((二甲氨基)甲基)苯基)磺酰基)-2-(4-氟-2,6-二异丙基苯基)乙酰胺2,2,2-三氟乙酸盐
在20℃下,向2-(4-氟-2,6-二异丙基苯基)乙酸(中间体R11)(222mg,933.34μmol,1eq)在DMF(2mL)中的溶液中添加CDI(166mg,1.03mmol,1.1eq)。在0℃下将反应混合物搅拌30分钟,接着添加至NaH(56mg,1.40mmol,60wt%于矿物油中,1.5eq)和4-((二甲氨基)甲基)苯磺酰胺(中间体L13)(200mg,933.34μmol,1eq)在DMF(2mL)中的溶液中。将所得混合物在20℃下搅拌2小时。接着将反应混合物倒入冰水(30mL)中,搅拌10分钟并用乙酸乙酯(3x15mL)萃取。将合并的有机层用盐水(10mL)洗涤、经无水硫酸钠干燥、过滤并在真空中浓缩。将残余物通过制备型HPLC(柱:Phenomenex Synergi C18,150mm x 25mm x 10μm;流动相:[A:水(0.1%TFA),B:MeCN],B%:24%-54%,10min)纯化,得到呈白色固体状的标题化合物(38.9mg,8%收率,100%纯度,经LCMS测得)。
1H NMR(400MHz,CDCl3)δ8.08(d,2H),7.66(d,2H),6.83(d,2H),4.26(s,2H),3.76(s,2H),2.89-2.83(m,2H),2.81(s,6H)和1.09(d,12H)。
LCMS:m/z 435.2(M+H)+(ES+)。
实施例34:N-((7-氯-5-异丙基-2,3-二氢-1H-茚-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
将三光气(22.6mg,0.076mmol)添加至含7-氯-5-异丙基-2,3-二氢-1H-茚-4-胺(中间体R12)(20mg,0.095mmol)和Et3N(0.016mL,0.114mmol)的THF(2mL)中。将混合物在室温下搅拌15小时。添加另一部分的三光气(22.6mg,0.076mmol),并将混合物再搅拌2小时。将混合物在真空中浓缩并与甲苯(3x1mL)共沸干燥。将THF(2mL)添加至残余物中,随后添加1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(18.1mg,0.095mmol)。30分钟后,添加NaH(60wt%于矿物油中,9.54mg,0.238mmol),并将混合物在60℃加热15小时。冷却至室温后,添加饱和NH4Cl水溶液(10mL),并将混合物用EtOAc(3x10mL)萃取。将有机层用盐水(5mL)洗涤,干燥(MgSO4),并在真空中蒸发。将残余物通过硅胶色谱法(25g柱,5-100%EtOAc/异己烷)纯化,得到呈白色固体状的标题化合物(7.5mg,18%)。
1H NMR(DMSO-d6)δ10.98(br s,1H),7.98-7.95(m,2H),7.07–7.04(m,1H),6.70(s,1H),4.62-4.59(m,1H),2.97-2.95(m,1H),2.85(t,J=7.5Hz,2H),2.66-2.64(m,2H),1.97-1.95(m,2H),1.44(d,J=6.7Hz,6H),1.30-0.82(m,6H)。
LCMS m/z 425/427(M+H)+(ES+)。
实施例35:N-((8-氯-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
将三光气(42mg,0.142mmol)添加至8-氯-1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(48mg,0.231mmol)和Et3N(0.088mL,0.634mmol)在THF(2mL)中的混合物中。将混合物加热回流4小时,在真空中浓缩并与甲苯(3x1mL)共沸干燥,得到4-氯-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯。
将1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(40mg,0.211mmol)溶解在THF(2mL)中并添加NaH(60wt%于矿物油中,10mg,0.250mmol)。将反应物在室温下搅拌30分钟,并添加含粗4-氯-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯的THF(2mL)。将反应物在室温下搅拌2天。添加饱和NH4Cl水溶液(10mL)并用EtOAc(3x10mL)萃取混合物。将有机相用盐水(5mL)洗涤,干燥(MgSO4)并在真空中浓缩。通过硅胶色谱法(25g柱,5%-100%EtOAc/异己烷)纯化产物。将分离的产物用MTBE(10mL)研磨并过滤,得到呈无色固体状的标题化合物(17mg,18%)。
1H NMR(DMSO-d6)δ10.91(s,1H),8.09(s,1H),7.98(d,J=2.4Hz,1H),6.73(d,J=2.4Hz,1H),4.62(sept,J=6.7Hz,1H),2.84(t,J=7.4Hz,4H),2.68(t,J=7.5Hz,4H),1.99(p,J=7.5Hz,4H),1.44(d,J=6.7Hz,6H)。
LCMS m/z 423.0/425.0(M+H)+(ES+)。
实施例36:N-((8-溴-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-4-磺酰胺
将1-异丙基-1H-吡唑-4-磺酰胺(38mg,0.201mmol)溶解在THF(2mL)中并添加NaH(60wt%于矿物油中,10mg,0.250mmol)。将反应混合物在室温下搅拌30分钟。添加含4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R13)(62mg,0.22mmol)的THF(2mL),并将反应混合物在室温下搅拌过夜,之后用水(2mL)稀释并在真空中浓缩。将粗产物通过RP快速C18反相色谱法(12g柱,5%-40%MeCN/10mM碳酸氢铵)纯化,得到呈无色固体状的标题化合物(18mg,18%)。
1H NMR(DMSO-d6)δ10.65(s,1H),8.44(s,1H),8.14(s,1H),7.86(s,1H),4.61(sept,J=6.7Hz,1H),2.82(t,J=7.4Hz,4H),2.70(t,J=7.5Hz,4H),1.98(p,J=7.5Hz,4H),1.42(d,J=6.6Hz,6H)。
LCMS m/z 467/469(M+H)+(ES+)。
实施例37:N-((8-氰基-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
将1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)(28mg,0.148mmol)溶解在THF(2mL)中并添加NaH(60wt%于矿物油中,8mg,0.200mmol)。将反应物在室温下搅拌30分钟,接着添加含8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯-4-甲腈(中间体R14)(37mg,0.165mmol)的THF(2mL)。将反应混合物在室温下搅拌4小时,用水(2mL)稀释并在真空中浓缩。将水(1.5mL)添加至残余物中,并将残余物用MTBE(2x3mL)洗涤。将水层过滤通过注射器过滤器,并通过RP快速C18反相色谱法(12g柱,5%-40%MeCN/10mM碳酸氢铵)纯化,得到呈无色固体状的标题化合物(45mg,73%)。
1H NMR(DMSO-d6)δ11.06(s,1H),8.43(s,1H),7.98(d,J=2.4Hz,1H),6.74(d,J=2.4Hz,1H),4.61(sept,J=6.8Hz,1H),2.95(t,J=7.4Hz,4H),2.66(t,J=7.4Hz,4H),2.03(p,J=7.5Hz,4H),1.43(d,J=6.7Hz,6H)。
LCMS m/z 414.4(M+H)+(ES+)。
实施例38:N-((8-溴-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
根据N-((8-溴-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-4-磺酰胺(实施例36)的一般程序由1-异丙基-1H-吡唑-3-磺酰胺(中间体L8)和4-溴-8-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R13)进行制备,得到呈无色固体状的标题化合物(57mg,55%)。
1H NMR(DMSO-d6)δ10.91(s,1H),8.08(s,1H),7.97(d,J=2.4Hz,1H),6.72(d,J=2.4Hz,1H),4.69-4.49(m,1H),2.81(t,J=7.4Hz,4H),2.71(t,J=7.5Hz,4H),2.04-1.91(m,4H),1.43(d,J=6.7Hz,6H)。
LCMS m/z 467/469(M+H)+(ES+)。
实施例39:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺
将三光气(11mg,0.037mmol)添加至1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(11mg,0.063mmol)和Et3N(24μL,0.172mmol)在THF(2mL)中的混合物中。将反应混合物搅拌15小时,在真空中蒸发,并与甲苯(3x1mL)共沸。添加THF(2mL),并过滤混合物。将滤液添加至5-(2-甲氧基丙-2-基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L14)(50mg,0.054mmol)和NaH(60wt%于矿物油中,6mg,0.150mmol)在THF(2mL)中的混合物中。将反应物在室温下搅拌20小时,之后用水(2mL)淬灭。在真空中蒸发THF,并将残余物用TBME(2x3mL)洗涤,用磷酸二氢钠(73.1mg)缓冲且通过RP快速C18反相色谱法(12g柱,5%-50%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(5mg,21%)。
1H NMR(DMSO-d6)δ10.81(s,1H),8.02(s,1H),6.94(s,1H),6.68(s,1H),3.99(s,3H),3.00(s,3H),2.79(t,J=7.4,Hz,4H),2.58(t,J=7.4Hz,4H),1.94(p,J=7.5Hz,4H),1.53(s,6H)。
LCMS m/z 433.5(M+H)+(ES+);431.3(M-H)-(ES-)。
实施例40:N-((4-氯-2,6-二异丙基苯基)氨基甲酰基)-1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺
将NaH(60wt%于矿物油中,20.14mg,0.504mmol)添加至含1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15)(55.4mg,0.242mmol)的THF(2mL)中,并将反应混合物在室温下搅拌30分钟。添加5-氯-2-异氰酸基-1,3-二异丙基苯(中间体R15)。将反应混合物在60℃下加热15小时并用水(2mL)淬灭。在真空中蒸发THF。将含水残余物用TBME(2x3mL)洗涤并通过RP快速C18反相色谱法(12g柱,0-50%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(15.5mg,16%)。
1H NMR(DMSO-d6)δ8.14(br s,1H),7.72(s,1H),7.46(s,1H),7.03(s,2H),5.15-5.11(m,2H),3.08-3.05(m,2H),1.02(d,J=6.9Hz,12H)。未观察到一个可交换质子。
LCMS m/z 467/469(M+H)+(ES+)。
实施例41:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺钠盐
将NaH(60wt%于矿物油中,7.85mg,0.196mmol)添加至含1-(2,2,2-三氟乙基)-1H-吡唑-4-磺酰胺(中间体L15)(30mg,0.131mmol)的THF(5mL)中,并将反应混合物在室温下搅拌1小时。添加4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(26.1mg,0.131mmol),并将反应混合物在室温下搅拌15小时。将悬浮液过滤并用THF(1mL)洗涤。将收集的固体用EtOAc(10mL)研磨并在真空中干燥,得到呈白色固体状的标题化合物(44mg,73%)。
1H NMR(DMSO-d6)δ8.05(s,1H),7.67(s,1H),7.33(s,1H),6.76(s,1H),5.14-5.11(m,2H),2.75(t,J=7.4Hz,4H),2.66(t,J=7.2Hz,4H),1.92-1.89(m,4H)。
LCMS m/z 429(M+H)+(ES+)。
实施例42:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰胺
将NaH(60wt%于矿物油中,7.85mg,0.196mmol)添加至含1-(2,2,2-三氟乙基)-1H-吡唑-3-磺酰胺(中间体L16)(30mg,0.131mmol)的THF(5mL)中,并将反应混合物在室温下搅拌1小时。添加4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(26.1mg,0.131mmol),并将反应混合物在室温下搅拌15小时。用水(2mL)淬灭反应物,并通过在真空中蒸发来去除THF。将含水残余物用TBME(2x3mL)洗涤并通过RP快速C18反相色谱法(12g柱,0-50%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(7.2mg,13%)。
1H NMR(DMSO-d6)δ7.75(d,J=2.4Hz,1H),7.50(s,1H),6.76(s,1H),6.50(d,J=2.4Hz,1H),5.14-5.11(m,2H),2.74(t,J=7.4Hz,4H),2.64(t,J=7.4Hz,4H),1.90-1.88(m,4H)。未观察到一个可交换质子。
LCMS m/z 429(M+H)+(ES+)。
实施例43:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐
将NaOtBu(2M于THF中,0.101mL,0.201mmol)添加至含1-异丙基-3-甲基-1H-吡唑-4-磺酰胺(中间体L17)(39mg,0.192mmol)的THF(3mL)中。将反应物在室温下搅拌1小时。添加4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)(38.2mg,0.192mmol)。将反应混合物在室温下搅拌15小时并过滤,用THF(1mL)洗涤。将收集的固体用EtOAc(5mL)研磨并在真空中干燥,得到呈白色固体状的标题化合物(48mg,58%)。
1H NMR(DMSO-d6)δ7.75(s,1H),7.46(s,1H),6.76(s,1H),4.38-4.31(m,1H),2.74(t,J=7.3Hz,4H),2.63(t,J=7.4Hz,4H),2.24(s,3H),1.93-1.85(m,4H),1.35(d,J=6.6Hz,6H)。
LCMS m/z 403(M+H)+(ES+)。
实施例44:1-(环丙基甲基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-4-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-(环丙基甲基)-1H-吡唑-4-磺酰胺(中间体L18)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备,得到呈白色固体状的标题化合物(60mg,75%)。
1H NMR(DMSO-d6)δ7.94(d,J=0.7Hz,1H),7.53(d,J=0.7Hz,1H),7.34(s,1H),6.76(s,1H),3.92(d,J=7.1Hz,2H),2.75(t,J=7.4Hz,4H),2.67(t,J=7.3Hz,4H),1.90(p,J=7.4Hz,4H),1.27-1.13(m,1H),0.57-0.45(m,2H),0.38-0.32(m,2H)。
LCMS m/z 401(M+H)+(ES+)。
实施例45:1-乙基-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-乙基-1H-吡唑-3-磺酰胺(中间体L19)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备,得到呈白色固体状的标题化合物(40.1mg,28%)。
1H NMR(DMSO-d6)δ7.66(d,J=2.2Hz,1H),7.52(s,1H),6.77(s,1H),6.36(d,J=2.2Hz,1H),4.11(q,J=7.3Hz,2H),2.75(t,J=7.3Hz,4H),2.65(t,J=7.4Hz,4H),1.90(p,J=7.4Hz,4H),1.36(t,J=7.3Hz,3H)。
LCMS m/z 375(M+H)+(ES+)。
实施例46:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-1,2,4-三唑-3-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-异丙基-1H-1,2,4-三唑-3-磺酰胺(中间体L20)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备,得到呈无色固体状的标题化合物(83mg,76%)。
1H NMR(DMSO-d6)δ8.49(s,1H),7.62(s,1H),6.77(s,1H),4.59(sept,J=6.7Hz,1H),2.75(t,J=7.4Hz,4H),2.64(t,J=7.3Hz,4H),1.97-1.81(m,4H),1.44(d,J=6.7Hz,6H)。
LCMS m/z 390.4(M+H)+(ES+)。
实施例47:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-1,2,3-三唑-5-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-异丙基-1H-1,2,3-三唑-5-磺酰胺(中间体L22)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈无色固体状的标题化合物(15mg,14%)。
1H NMR(400MHz,DMSO-d6)δ7.89(s,1H),7.82(s,1H),6.84(s,1H),5.38(sept,J=6.7Hz,1H),2.76(t,J=7.4Hz,4H),2.61(t,J=7.4Hz,4H),1.91(p,J=7.4Hz,4H),1.51(d,J=6.7Hz,6H)。未观察到一个可交换质子。
LCMS m/z 390(M+H)+(ES+);388(M-H)-(ES-)。
实施例48:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-2-异丙基-2H-1,2,3-三唑-4-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由2-异丙基-2H-1,2,3-三唑-4-磺酰胺(中间体L23)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈无色固体状的标题化合物(15.5mg,15%)。
1H NMR(DMSO-d6)δ11.25(s,1H),8.20(s,1H),8.06(s,1H),6.92(s,1H),4.91(sept,J=6.7Hz,1H),2.78(t,J=7.3Hz,4H),2.57(t,J=7.4Hz,4H),1.93(p,J=7.4Hz,4H),1.51(d,J=6.7Hz,6H)。
LCMS m/z 390(M+H)+(ES+);388(M-H)-(ES-)。
实施例49:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺(中间体L24)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-50%MeCN/10mM碳酸氢铵)纯化,得到呈澄清无色固体状的标题化合物(27.1mg,30%)。
1H NMR(DMSO-d6)δ10.82(s,1H),8.01(s,1H),6.94(s,1H),6.50(s,1H),5.57(s,1H),5.31(sept,J=6.6Hz,1H),2.78(t,J=7.4Hz,4H),2.59(t,J=7.4Hz,4H),1.93(p,J=7.4Hz,4H),1.51(s,6H),1.39(d,J=6.6Hz,6H)。
LCMS m/z 447.5(M+H)+(ES+)。
实施例50:N-((4-氟-2,6-二异丙基苯基)氨基甲酰基)-5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(2-羟基丙-2-基)-1-异丙基-1H-吡唑-3-磺酰胺(中间体L24)和5-氟-2-异氰酸基-1,3-二异丙基苯(中间体R16)进行制备并通过RP快速C18反相色谱法(12g柱,5%-50%MeCN/10mM碳酸氢铵)纯化,得到呈澄清无色固体状的标题化合物(7.5mg,8%)。
1H NMR(DMSO-d6)δ11.03(s,1H),7.79(s,1H),6.91(d,J=9.9Hz,2H),6.45(s,1H),5.52(s,1H),5.29(sept,J=6.6Hz,1H),3.03-2.92(m,2H),1.49(s,6H),1.40(d,J=6.5Hz,6H),1.05(app br s,12H)。
LCMS m/z 469.5(M+H)+(ES+)。
实施例51:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(1-甲氧基环丁基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L25)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-100%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(31mg,28%)。
1H NMR(DMSO-d6)δ7.97(s,1H),6.90(s,1H),6.85(s,1H),3.80(s,3H),2.87(s,3H),2.77(t,J=7.4,4H),2.58(t,J=7.4,4H),2.45-2.27(m,4H),1.91(p,J=7.5,4H),1.87-1.77(m,1H),1.66-1.51(m,1H)。未观察到一个可交换质子。
LCMS m/z 445.4(M+H)+(ES+)。
实施例52:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(1-甲氧基环戊基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L26)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-100%MeCN/10mM碳酸氢铵)纯化,得到呈乳白色固体状的标题化合物(9mg,12%)。
1H NMR(DMSO-d6)δ7.99(s,1H),6.91(s,1H),6.70(s,1H),3.94(s,3H),2.89(s,3H),2.78(t,J=7.4Hz,4H),2.57(t,J=7.4Hz,4H),2.23-2.14(m,2H),1.98-1.83(m,6H),1.76-1.62(m,4H)。未观察到一个可交换质子。
LCMS m/z 459.5(M+H)+(ES+)。
实施例53:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(1-甲氧基乙基)-1-甲基-1H-吡唑-3-磺酰胺(中间体L27)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(33mg,24%)。
1H NMR(DMSO-d6)δ10.81(s,1H),8.01(s,1H),6.93(s,1H),6.69(s,1H),4.65(q,J=6.5Hz,1H),3.89(s,3H),3.20(s,3H),2.78(t,J=7.4Hz,4H),2.59(t,J=7.4Hz,4H),1.94(p,J=7.4Hz,4H),1.42(d,J=6.5Hz,3H)。
LCMS m/z 419.4(M+H)+(ES+)。
实施例54:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-(1-羟乙基)-1-异丙基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-(1-羟乙基)-1-异丙基-1H-吡唑-3-磺酰胺(中间体L28)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-100%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的标题化合物(18mg,10%)。
1H NMR(DMSO-d6)δ10.84(br s,1H),7.97(s,1H),6.92(s,1H),6.57(s,1H),5.49(d,J=6.1Hz,1H),4.92-4.79(m,2H),2.79(t,J=7.4Hz,4H),2.61(t,J=7.4Hz,4H),1.94(p,J=7.4Hz,4H),1.49-1.34(m,9H)。
LMCS m/z 433.4(M+H)+(ES+)。
实施例55:4-氟-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由4-氟-1-异丙基-1H-吡唑-3-磺酰胺(中间体L29)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(23mg,34%)。
1H NMR(DMSO-d6)δ11.09(s,1H),8.12(s,1H),7.93(s,1H),6.91(s,1H),4.48(app.p,J=6.7Hz,1H),2.78(t,J=7.4Hz,4H),2.59(t,J=7.4Hz,4H),1.93(p,J=7.4Hz,4H),1.40(d,J=6.7Hz,6H)。
LCMS m/z 407.7,429.1(M+H,M+Na)+(ES+)。
实施例56:1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-(1-(氮杂环丁-1-基)-2-甲基丙-2-基)-1H-吡唑-3-磺酰胺(中间体L30)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(23mg,34%)。
1H NMR(DMSO-d6)δ10.71(s,1H),7.95–7.94(m,2H),6.92(s,1H),6.69(d,J=2.4Hz,1H),2.96(app br s,4H),2.80-2.70(m,6H),2.61(t,J=7.4Hz,4H),1.94(p,J=7.5Hz,4H),1.78(p,J=7.1Hz,2H),1.50(s,6H)。
LCMS m/z 458.4(M+H)+(ES+);456.3(M-H)-(ES-)。
实施例57:3-((二甲氨基)甲基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-5-甲基苯磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由3-((二甲氨基)甲基)-5-甲基苯磺酰胺(中间体L31)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备,得到呈白色固体状的标题化合物(40mg,44%)。
1H NMR(DMSO-d6)δ7.51-7.44(m,3H),7.10(s,1H),6.76(s,1H),3.34(s,2H),2.74(t,J=7.4Hz,4H),2.64(t,J=7.4Hz,4H),2.31(s,3H),2.14(s,6H),1.94-1.84(m,4H)。
LCMS m/z 428.3(M+H)+(ES+)。
实施例58:1-(2,2-二氟乙基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-4-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-(2,2-二氟乙基)-1H-吡唑-4-磺酰胺(中间体L32)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备,得到呈白色固体状的标题化合物(42mg,40%)。
1H NMR(DMSO-d6)δ7.98(s,1H),7.64(s,1H),7.34(s,1H),6.76(s,1H),6.49-6.17(m,1H),4.68-4.51(m,2H),2.75(t,J=7.4Hz,4H),2.66(t,J=7.5Hz,4H),1.97-1.82(m,4H)。
LCMS m/z 411.6(M+H)+(ES+)。
实施例59:1-环丁基-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-环丁基-1H-吡唑-3-磺酰胺(中间体L33)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(33mg,34%)。
1H NMR(DMSO-d6)δ10.86(s,1H),8.02(d,J=2.4Hz,1H),6.94(s,1H),6.74(d,J=2.4Hz,1H),4.95(p,J=8.4Hz,1H),2.79(t,J=7.4Hz,4H),2.58(t,J=7.4Hz,4H),2.48-2.35(m,4H),1.94(p,J=7.4Hz,4H),1.86-1.76(m,2H)。未观察到一个可交换质子。
LCMS m/z 401.3(M+H)+(ES+)。
实施例60:1-(1-((二甲氨基)甲基)环丁基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-(1-((二甲氨基)甲基)环丁基)-1H-吡唑-3-磺酰胺(中间体L34)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈白色固体状的标题化合物(3mg,4%)。
1H NMR(DMSO-d6)δ7.92(app s,2H),6.91(s,1H),6.70(app s,1H),2.81-2.75(m,6H),2.60(t,J=7.4Hz,4H),2.49-2.44(m,2H),2.35-2.28(m,2H),1.97-1.92(m,4H),1.91(s,6H),1.89-1.82(m,2H)。未观察到一个可交换质子。
LCMS m/z 458.2(M+H)+(ES+);456.3(M-H)-(ES-)。
实施例61:N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺钠盐
步骤A:将8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-胺(中间体R17)(80mg,0.418mmol)和(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)胺(中间体L21)(141mg,0.418mmol)在MeCN(5mL)中的溶液在50℃下搅拌1.5小时。在真空中去除溶剂,并通过反相制备型HPLC方法1纯化粗产物,得到呈淡黄色固体状的N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺(88mg)。
LCMS m/z 407.0(M+H)+(ES+);405.2(M-H)-(ES-)。
步骤B:将N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺(85mg,0.21mmol)溶解在含有2滴THF的NaOH水溶液(0.1M,2.2mL,0.22mmol)中并冷冻干燥,得到呈白色固体的标题化合物(94mg,52%)。
1H NMR(DMSO-d6)δ7.71(d,J=2.3Hz,1H),7.54(br s,1H),6.38(d,J=2.3Hz,1H),4.50(sept,J=6.7Hz,1H),2.78(t,J=7.5Hz,4H),2.68(t,J=7.5Hz,4H),1.95(p,J=7.5Hz,4H),1.40(d,J=6.7Hz,6H)。
LCMS m/z 407.5(M+H)+(ES+);405.2(M-H)-(ES-)。
实施例62:5-氟-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由5-氟-1-异丙基-1H-吡唑-3-磺酰胺(中间体L35)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过反相制备型HPLC方法1纯化,得到呈固体状的5-氟-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺(9.85mg)。添加NaOH水溶液(0.1M,0.24mL),并将溶液冷冻干燥,得到呈固体状的标题化合物(10.3mg,12%)。
1H NMR(DMSO-d6)δ7.89(s,1H),6.89(s,1H),6.40(s,1H),4.67-4.57(m,1H),2.78(t,J=7.4Hz,4H),2.62(t,J=7.4Hz,4H),1.93(p,J=7.4Hz,4H),1.40(d,J=6.7Hz,6H)。
LCMS m/z 407.2(M+H)+(ES+)。
实施例63:1-(2,2-二氟乙基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钠盐
根据N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺钠盐(实施例61)的一般程序由((1-(2,2-二氟乙基)-1H-吡唑-3-基)磺酰基)(4-(二甲氨基)吡啶-1-鎓-1-羰基)酰胺(中间体L36)和1,2,3,5,6,7-六氢-s-茚并四烯-4-酰胺进行制备,得到呈固体状的标题化合物(13.8mg,14%)。
1H NMR(DMSO-d6)δ7.92-7.86(m,2H),6.89(s,1H),6.73-6.69(m,1H),6.52-6.23(m,1H),4.77-4.66(m,2H),2.78(t,J=7.4Hz,4H),2.61(t,J=7.4Hz,4H),1.93(p,J=7.4Hz,4H)。
LCMS m/z 411.2(M+H)+(ES+)。
实施例64:1-异丙基-N-((3,5,6,7-四氢-2H-茚并[5,6-b]呋喃-8-基)氨基甲酰基)-1H-吡唑-3-磺酰胺钠盐
根据N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺钠盐(实施例61)的一般程序由(4-(二甲氨基)吡啶-1-鎓-1-羰基)((1-异丙基-1H-吡唑-3-基)磺酰基)酰胺(中间体L21)和3,5,6,7-四氢-2H-茚并[5,6-b]呋喃-8-酰胺进行制备,得到呈白色固体状的标题化合物(18mg,79%)。
1H NMR(DMSO-d6)δ7.70(d,J=2.3Hz,1H),7.19(s,1H),6.76(s,1H),6.38(d,J=2.3Hz,1H),4.56-4.38(m,3H),3.08(t,J=8.6Hz,2H),2.71(t,J=7.3Hz,2H),2.61(t,J=7.4Hz,2H),1.87(p,J=7.4Hz,2H),1.40(d,J=6.7Hz,6H)。
LCMS m/z 391.3(M+H)+(ES+)。
实施例65:N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺(中间体L37)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-50%MeCN/10mM碳酸氢铵)纯化,得到呈白色固体状的N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-(2-甲基-1-(吡咯烷-1-基)丙-2-基)-1H-吡唑-3-磺酰胺(46.4mg)。将获得的粗产物溶解在NaOH水溶液(0.1M,0.980mL,0.098mmol)中并冷冻干燥,得到呈白色粉末状的标题化合物(44mg,38%)。
1H NMR(DMSO-d6)δ7.68(d,J=2.4Hz,1H),7.52(br s,1H),6.75(s,1H),6.37(d,J=2.3Hz,1H),2.82-2.69(m,6H),2.64(t,J=7.4Hz,4H),2.29-2.17(m,4H),1.88(p,J=7.4Hz,4H),1.54-1.41(m,10H)。
LCMS m/z 472.3(M+H)+(ES+);470.1(M-H)-(ES-)。
实施例66:4-((二甲氨基)甲基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)苯磺酰胺钠盐
根据N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-3-甲基-1H-吡唑-4-磺酰胺钠盐(实施例43)的一般程序由4-((二甲氨基)甲基)苯磺酰胺(中间体L13)和4-异氰酸基-1,2,3,5,6,7-六氢-s-茚并四烯(中间体R1)进行制备并通过RP快速C18反相色谱法(12g柱,5%-50%MeCN/10mM碳酸氢铵)纯化,得到呈白色粉末状的4-((二甲氨基)甲基)-N-((1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)苯磺酰胺(51.6mg)。将获得的粗产物溶解在NaOH水溶液(0.1M,1.25mL,0.125mmol)中并冷冻干燥,得到呈白色固体状的标题化合物(51mg,35%)。
1H NMR(DMSO-d6)δ7.76-7.60(m,2H),7.41(s,1H),7.31-7.21(m,2H),6.75(s,1H),3.38(s,2H),2.73(t,J=7.4Hz,4H),2.61(t,J=7.4Hz,4H),2.13(s,6H),1.87(p,J=7.4Hz,4H)。
LCMS m/z 414.3(M+H)+(ES+);412.2(M-H)-(ES-)。
实施例67:1-环丙基-N-((3,5,6,7-四氢-2H-茚并[5,6-b]呋喃-4-基)氨基甲酰基)-1H-吡唑-3-磺酰胺
根据N-((8-氟-1,2,3,5,6,7-六氢-s-茚并四烯-4-基)氨基甲酰基)-1-异丙基-1H-吡唑-3-磺酰胺(实施例61,步骤A)的一般程序由((1-环丙基-1H-吡唑-3-基)磺酰基)(4-(二甲氨基)吡啶-1-鎓-1-羰基)酰胺(中间体L38)和3,5,6,7-四氢-2H-茚并[5,6-b]呋喃-4-酰胺进行制备,得到呈白色固体状的标题化合物(19mg,26%)。
1H NMR(DMSO-d6)δ8.00(s,1H),7.90(app.t,J=2.0Hz,1H),6.62(app.t,J=2.0Hz,1H),6.44(s,1H),4.44(t,J=8.6Hz,2H),3.85-3.78(m,1H),2.94(t,J=8.6Hz,2H),2.75(t,J=7.5Hz,2H),2.59(t,J=7.3Hz,2H),1.94(p,J=7.4Hz,2H),1.07-0.98(m,4H)。不能观察到一个可交换质子。
LCMS m/z 389.2(M+H)+(ES+)。
通过与上文和下文所概述的方法类似的方法合成实施例68-97的化合物。
表1:1H NMR和MS数据
实施例98:2-(3,5-双(三氟甲基)苯基)-N-((4-(2-羟基-丙-2-基)呋喃-2-基)磺酰基)乙酰胺
向2-(3,5-双(三氟甲基)苯基)乙酸(0.1mmol)在DMF(0.33mL)中的溶液中添加4-(2-羟基丙-2-基)呋喃-2-磺酰胺(0.021g,0.100mmol)、DMAP(0.024g,0.200mmol)和EDC(0.038g,0.200mmol)在DMF(1mL)中的溶液。将所得混合物在96孔板中在室温下摇动16小时。将粗产物通过反相制备型HPLC方法4纯化,得到呈白色固体状的标题化合物(0.9mg,2%)。
LCMS m/z 482.2(M+Na)+(ES+)。
实施例-生物学研究
NLRP3和细胞焦亡
已充分确认,NLRP3的活化导致细胞焦亡并且此特征在临床疾病的表现中起重要作用(Yan-gang Liu等人,Cell Death&Disease,2017,8(2),e2579;Alexander Wree等人,Hepatology,2014,59(3),898-910;Alex Baldwin等人,Journal of MedicinalChemistry,2016,59(5),1691-1710;Ema Ozaki等人,Journal of InflammationResearch,2015,8,15-27;Zhen Xie和Gang Zhao,Neuroimmunology Neuroinflammation,2014,1(2),60-65;Mattia Cocco等人,Journal of Medicinal Chemistry,2014,57(24),10366-10382;T.Satoh等人,Cell Death&Disease,2013,4,e644)。因此,预期NLRP3的抑制剂将阻断细胞焦亡,以及从细胞释放促炎细胞因子(例如IL-1β)。
THP-1细胞:培养和制备
使THP-1细胞(ATCC编号TIB-202)生长于含有L-谷氨酰胺的RPMI(Gibco编号11835)中,其中补充有含1mM丙酮酸钠(Sigma编号S8636)和盘尼西林(100单位/毫升)/链霉素(0.1mg/ml)(Sigma编号P4333)的10%胎牛血清(FBS)(Sigma编号F0804)。使细胞以常规方式传代并且生长至汇合(约106个细胞/毫升)。在实验当天,收获THP-1细胞并再悬浮于RPMI培养基(不含FBS)中。接着对细胞计数并且通过台盼蓝(Trypan blue)(Sigma编号T8154)检查存活率(>90%)。制备适当稀释物以获得625,000个细胞/毫升的浓度。向此稀释的细胞溶液中添加LPS(Sigma编号L4524)以获得1μg/ml最终测定浓度(FAC)。将40μl最终制剂等分至96孔板的每个孔中。将由此制备的板用于化合物筛选。
THP-1细胞焦亡测定
化合物筛选遵循以下逐步测定方法。
1.将含有THP-1细胞(25,000个细胞/孔)的1.0μg/ml LPS接种于用聚D-赖氨酸(VWR编号734-0317)包被的96孔黑壁透明底细胞培养板中的40μl RPMI培养基(不含FBS)中
2.将5μl化合物(8点半对数稀释,使用10μM最高剂量)或媒介物(DMSO 0.1%FAC)添加至适当孔中
3.在37℃、5%CO2下孵育3小时
4.将5μl尼日利亚菌素(nigericin)(Sigma编号N7143)(FAC 5μM)添加至所有孔中
5.在37℃、5%CO2下孵育1小时
6.在孵育时段结束时,将板在300xg下离心3min并去除上清液
7.接着添加50μl刃天青(resazurin)(Sigma编号R7017)(含FAC 100μM刃天青的不含FBS的RPMI培养基)并将板在37℃和5%CO2下再孵育1-2小时
8.在Envision读数器中在Ex 560nm和Em 590nm下读取板
9.将IC50数据拟合至非线性回归方程(抑制剂对数对比反应-可变斜率4参数)
96孔板图谱
所进行的细胞焦亡测定的结果以THP IC50形式汇总于下表2中。
人全血IL-1β释放测定
对于全身性递送,当化合物存在于血流内时抑制NLRP3的能力至关重要。为此,根据以下方案研究多种化合物在人全血中的NLRP3抑制活性。
从来自志愿者供体组的健康供体获得肝素锂管中的人全血。
1.将80μl含有全血的1μg/ml LPS涂铺在96孔透明底细胞培养板(Corning编号3585)中
2.将10μl化合物(8点半对数稀释,使用10μM最高剂量)或媒介物(DMSO 0.1%FAC)添加至适当孔中
3.在37℃、5%CO2下孵育3小时
4.将10μl尼日利亚菌素(Sigma编号N7143)(10μM FAC)添加至所有孔中
5.在37℃、5%CO2下孵育1小时
6.在孵育时段结束时,将板在300xg下离心5min以使细胞沉淀并去除20μl上清液并且添加至96孔v形底板中用于IL-1β分析(注意:可将这些含有上清液的板储存在-80℃下以供日后分析)
7.根据制造商的方案(Perkin Elmer-AlphaLisa IL-1试剂盒AL220F-5000)测量IL-1β
8.将IC50数据拟合至非线性回归方程(抑制剂对数对比反应-可变斜率4参数)
人全血测定的结果以HWB IC50的形式汇总于下表2中。
表2:NLRP3抑制活性(≤0.25μM=‘++++++’,≤0.5μM=‘+++++’,≤1μM=‘++++’,≤5μM=‘+++’,≤10μM=‘++’,>10μM=‘+’,未测定=‘ND’)。
PK方案
在雄性史-道二氏大鼠(Sprague Dawley rat)(Charles River,UK,250-300g;或中国北京维塔河实验动物科技有限公司(Vital River Laboratory Animal TechnologyCo Ltd,Beijing,China),7-9周龄)中测定药代动力学参数。将动物在研究期间单独圈养并且维持在12h光照/黑暗循环下。动物可自由获得食物和水,除了经口给药的动物在研究之前禁食过夜。
对于静脉内施用,将化合物配制成以2mL/kg给药体积的于DMSO:PBS[10:90]中的溶液并且经由尾部静脉施用。对于经口施用,将化合物配制成以5mL/kg给药体积的于DMSO:水[10:90]中的溶液并且经口施用。
在给药后8个时间点(0.083、0.25、0.5、1、2、4、8和24h)中的每个时间点从每只动物采集系列血液样品(约200-230μL)。使样品在冰上保持不长于30分钟,之后离心(10,000rpm(8,385g)持续3分钟;或5,696rpm(3,000g)持续15分钟)以产生血浆。将血浆在干冰上冷冻,之后进行生物分析。使用Dotmatics或Phoenix WinNonlin 6.3软件根据LC-MS/MS数据生成PK参数。
表3:PK数据(静脉内施用)
表4:PK数据(经口施用)(ND=未测定)
如从表2中呈现的结果显而易见,令人惊奇地,尽管本发明的化合物相对于现有技术化合物具有结构差异,但本发明的化合物在细胞焦亡测定和人全血测定中显示高水平的NLRP3抑制活性。
如从表3和表4中呈现的结果显而易见,与现有技术化合物相比,本发明的化合物显示有利的药代动力学特性,例如半衰期T1/2、曲线下面积AUC、清除率Cl和/或生物利用度。
应理解,上文仅借助实施例阐述本发明。所述实施例并不意欲限制本发明的范围。可在不脱离本发明的范围和精神的情况下形成各种修改和实施方案,本发明的范围和精神仅由权利要求限定。
Claims (17)
11.一种如权利要求1至10中任一项所述的化合物的药学上可接受的盐、溶剂合物或前药。
12.一种药物组合物,所述药物组合物包含如权利要求1至10中任一项所述的化合物、或如权利要求11所述的药学上可接受的盐、溶剂合物或前药,以及药学上可接受的赋形剂。
13.如权利要求1至10中任一项所述的化合物、或如权利要求11所述的药学上可接受的盐、溶剂合物或前药、或如权利要求12所述的药物组合物,所述化合物、所述药学上可接受的盐、溶剂合物或前药、所述药物组合物用于医学中。
14.如权利要求13所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,所述化合物、药学上可接受的盐、溶剂合物、前药或药物组合物用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患对NLRP3抑制有响应。
15.如权利要求13或14所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,所述化合物、药学上可接受的盐、溶剂合物、前药或药物组合物用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患选自:
(i)炎症;
(ii)自身免疫性疾病;
(iii)癌症;
(iv)感染;
(v)中枢神经系统疾病;
(vi)代谢疾病;
(vii)心血管疾病;
(viii)呼吸疾病;
(ix)肝病;
(x)肾病;
(xi)眼病;
(xii)皮肤病;
(xiii)淋巴疾患;
(xiv)心理障碍;
(xv)移植物抗宿主病;
(xvi)触感痛;
(xvii)与糖尿病相关的疾患;和
(xviii)已确定个体携带NLRP3的种系或体细胞非沉默突变的任何疾病。
16.如权利要求13或14所述的化合物、药学上可接受的盐、溶剂合物、前药或药物组合物,所述化合物、药学上可接受的盐、溶剂合物、前药或药物组合物用于治疗或预防疾病、病症或疾患,其中所述疾病、病症或疾患选自:
(i)冷炎素相关周期性综合征(CAPS);
(ii)穆-韦二氏综合征(MWS);
(iii)家族性寒冷型自身炎症性综合征(FCAS);
(iv)新生儿发作型多系统炎症性疾病(NOMID);
(v)家族性地中海热(FMF);
(vi)化脓性关节炎、坏疽性脓皮症和痤疮综合征(PAPA);
(vii)高免疫球蛋白血症D和周期性发热综合征(HIDS);
(viii)肿瘤坏死因子(TNF)受体相关的周期性综合征(TRAPS);
(ix)全身性幼年特发性关节炎;
(x)成年发作型斯蒂尔氏病(AOSD);
(xi)复发性多发性软骨炎;
(xii)施尼兹勒氏综合征;
(xiii)斯威特氏综合征;
(xiv)白塞氏病;
(xv)抗合成酶综合征;
(xvi)白介素1受体拮抗剂缺乏(DIRA);和
(xvii)A20单倍剂量不足(HA20)。
17.一种抑制NLRP3的方法,所述方法包括使用如权利要求1至10中任一项所述的化合物、或如权利要求11所述的药学上可接受的盐、溶剂合物或前药、或如权利要求12所述的药物组合物来抑制NLRP3。
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