CN112888675A - 新型磺酰脲化合物 - Google Patents
新型磺酰脲化合物 Download PDFInfo
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- CN112888675A CN112888675A CN201980067160.9A CN201980067160A CN112888675A CN 112888675 A CN112888675 A CN 112888675A CN 201980067160 A CN201980067160 A CN 201980067160A CN 112888675 A CN112888675 A CN 112888675A
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- alkyl
- haloalkyl
- optionally substituted
- halo
- compound
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
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- C07—ORGANIC CHEMISTRY
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Abstract
Description
发明领域
本发明涉及式(I)的化合物;并且涉及相关盐、溶剂合物、前药和药物组合物。本发明还涉及这类化合物尤其通过抑制NLRP3治疗和预防医学病症和疾病的用途。
背景技术
NOD样受体(NLR)家族含热蛋白结构域的蛋白3(NLRP3)炎症小体是炎性过程的一种组分,并且它的活性异常是遗传病症例如冷吡啉相关周期性综合征(cryopyrin-associated periodic syndrome,CAPS)和复杂疾病例如多发性硬化、2型糖尿病、阿尔茨海默病(Alzheimer′sdisease)和动脉粥样硬化的发病原因。
NLRP3是一种细胞内信号传导分子,它能够感知许多病原体源性、环境和宿主源性的因子。在活化后,NLRP3结合于含有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。接着ASC聚合形成大的聚集体,被称为ASC斑点。聚合的ASC又与半胱氨酸蛋白酶半胱天冬酶-1相互作用,形成被称为炎症小体的复合体。这引起半胱天冬酶-1的活化,使促炎性细胞因子IL-1β和IL-18的前体形式(分别称为前IL-1β和前IL-18)裂解,从而活化这些细胞因子。半胱天冬酶-1还介导一种炎性细胞死亡,被称为细胞焦亡。ASC斑点还可以募集和活化半胱天冬酶-8,半胱天冬酶-8能够加工前IL-1β和前IL-18并触发细胞凋亡式细胞死亡。
半胱天冬酶-1使前IL-1β和前IL-18裂解成其活性形式,从细胞中分泌出。活性半胱天冬酶-1还使消皮素-D(gasdermin-D)裂解,触发细胞焦亡。通过对细胞焦亡式细胞死亡途径的控制,半胱天冬酶-1还介导警报素分子例如IL-33和高迁移率族蛋白1(highmobility group box 1protein,HMGB1)的释放。半胱天冬酶-1还使细胞内IL-1R2裂解,引起其降解并使IL-1α释放。在人细胞中,半胱天冬酶-1还可能控制IL-37的加工和分泌。大量的其它半胱天冬酶-1底物,例如细胞骨架和糖酵解途径的组分,会促进半胱天冬酶-1依赖性炎症。
NLRP3依赖性ASC斑点被释放至细胞外环境中,在这里,它们可以活化半胱天冬酶-1,诱导半胱天冬酶-1底物的加工并传播炎症。
源自于NLRP3炎症小体活化的活性细胞因子是炎症的重要驱动因素,并与其它的细胞因子途径相互作用,从而定型免疫反应进行感染和损伤。举例来说,IL-1β信号传导诱导促炎性细胞因子IL-6和TNF的分泌。IL-1β和IL-18与IL-23协同作用,诱导记忆CD4 Th17细胞和γδT细胞在缺乏T细胞受体参与下产生IL-17。IL-18和IL-12还协同作用,诱导从记忆T细胞和NK细胞产生IFN-γ,驱动Th1反应。
遗传CAPS疾病穆-韦二氏综合征(Muckle-Wells syndrome,MWS)、家族性寒冷性自身炎症性综合征(FCAS)和新生儿发作型多系统炎性疾病(NOMID)是由NLRP3的功能获得型突变引起的,因此界定NLRP3为炎性过程的关键组分。NLRP3与大量复杂疾病,特别是包括代谢病症例如2型糖尿病、动脉粥样硬化、肥胖症和痛风的发病机理相关联。
NLRP3在中枢神经系统疾病中的作用正显露出来,并且还显示肺疾病受NLRP3的影响。此外,NLRP3在肝病、肾病和衰老的发展过程中起作用。使用Nlrp3-/-小鼠界定这些关联中的多个,但还洞察到在这些疾病中NLRP3的特异性活化。在2型糖尿病(T2D)中,胰岛淀粉样多肽在胰腺中的沉积活化NLRP3和IL-1β信号传导,引起细胞死亡和炎症。
已显示几种小分子抑制NLRP3炎症小体。在微摩尔级的浓度下格列本脲(Glyburide)响应于NLRP3而不是NLRC4或NLRP1的活化而抑制IL-1β。其它先前表征的弱NLRP3抑制剂包括小白菊内酯(parthenolide)、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效力并且是非特异性的。
当前针对NLRP3相关疾病的治疗包括靶向IL-1的生物剂。这些是重组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)。这些方法已经证实成功治疗CAPS,并且这些生物剂已经用于其它IL-1β相关疾病的临床试验中。
一些含有二芳基磺酰脲的化合物已经被确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是一类含有二芳基磺酰脲的化合物,其抑制IL-1β的翻译后加工。IL-1β的翻译后加工伴随有半胱天冬酶-1的活化和细胞死亡。CRID抑制活化的单核细胞,使得半胱天冬酶-1保持非活性并且保持质膜潜伏期。
某些含有磺酰脲的化合物也被公开为NLRP3的抑制剂(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)。另外,WO 2017/184604 A1和WO2019/079119 A1公开大量含有磺酰胺的化合物作为NLRP3的抑制剂。某些含有亚磺酰亚胺的化合物也被公开为NLRP3的抑制剂(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/或适合作为已知化合物的替代品的化合物。
定义
在本说明书的上下文中,“烃基”取代基团或取代基团中的烃基部分只包括碳和氢原子,但除非另有说明,否则在其碳骨架中不包括任何杂原子,例如N、O或S。烃基/部分可为饱和或不饱和的(包括芳香族),并且可为直链或支链,或为或包括环状基团,其中除非另有说明,否则环状基团在其碳骨架中不包括任何杂原子,例如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/部分和所有这些基团/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”类似地定义为二价烃基。
“烷基”取代基团或取代基团中的烷基部分可为线性(即直链)或支链。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。除非另有说明,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”类似地定义为二价烷基。
“烷氧基烷基”取代基团或取代基团中的烷氧基烷基部分为(烷基)-O-(亚烷基)-基团。典型地,烷氧基烷基为(C1-C6烷基)-O-(C1-C6亚烷基)-基团。更典型地,烷氧基烷基为(C1-C4烷基)-O-(C1-C6亚烷基)-基团。更典型地,烷氧基烷基为(C1-C3烷基)-O-(C1-C6亚烷基)-基团。烷氧基烷基基团/部分的实例包括甲氧基烷基和乙氧基烷基。甲氧基烷基的实例包括甲氧基-(C1-C6亚烷基)-、甲氧基-(C1-C4亚烷基)-和甲氧基-(C1-C3亚烷基)-。乙氧基烷基的实例包括乙氧基-(C1-C6亚烷基)-、乙氧基-(C1-C4亚烷基)-和乙氧基-(C1-C3亚烷基)-。
“烯基”取代基团或取代基团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。除非另有说明,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”类似地定义为二价烯基。
“炔基”取代基团或取代基团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”类似地定义为二价炔基。
“环状”取代基团或取代基团中的环状部分是指任何烃基环,其中所述烃基环可为饱和或不饱和(包括芳香族)并且可在其碳骨架中包括一个或多个杂原子,例如N、O或S。环状基团的实例包括如以下论述的环烷基、环烯基、杂环基、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,此意味着其含有3至12个环原子。更典型地,环状基团为3至7元单环基团,此意味着其含有3至7个环原子。
“杂环”取代基团或取代基团中的杂环部分是指在环结构中包括一个或多个碳原子和一个或多个(例如一个、两个、三个或四个)杂原子,例如N、O或S的环状基团或部分。杂环基团的实例包括如以下论述的杂芳基和非芳香族杂环基团,例如氮杂环丁烯基、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、硫杂环己烷基、哌嗪基、二噁烷基、吗啉基和硫吗啉基。
“环烷基”取代基团或取代基团中的环烷基部分是指含有例如3至7个碳原子的饱和烃环,其实例包括环丙基、环丁基、环戊基和环己基。除非另有说明,否则环烷基取代基团或部分可包括单环、双环或多环烃环。
“环烯基”取代基团或取代基团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个碳原子的非芳香族不饱和烃环,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。除非另有说明,否则环烯基取代基团或部分可包括单环、双环或多环烃环。
“芳基”取代基团或取代基团中的芳基部分是指芳香族烃环。术语“芳基”包括单环芳香族烃和多环稠环芳香族烃,其中所有稠环系统(排除作为任选的取代基的一部分或由任选的取代基形成的任何环系统)均为芳香族。芳基基团/部分的实例包括苯基、萘基、蒽基和菲基。除非另有说明,否则术语“芳基”不包括“杂芳基”。
“杂芳基”取代基团或取代基团中的杂芳基部分是指芳香族杂环基团或部分。术语“杂芳基”包括单环芳香族杂环和多环稠环芳香族杂环,其中所有稠环系统(排除作为任选的取代基的一部分或由任选的取代基形成的任何环系统)均为芳香族。杂芳基基团/部分的实例包括以下:
其中G=O、S或NH。
出于本说明书的目的,在部分的组合称为一个基团,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的情况下,最后提及的部分含有使所述基团连接于分子其余部分的原子。芳基烷基的一实例为苯甲基。
出于本说明书的目的,在任选取代的基团或部分中:
(i)每个氢原子可任选地被独立地选自以下的单价取代基置换:卤代基;-CN;-NO2;-N3;-Rβ;-OH;-ORβ;-Rα-卤代基;-Rα-CN;-Rα-NO2;-Rα-N3;-Rα-Rβ;-Rα-OH;-Rα-ORβ;-SH;-SRβ;-SORβ;-SO2H;-SO2Rβ;-SO2NH2;-SO2NHRβ;-SO2N(Rβ)2;-Rα-SH;-Rα-SRβ;-Rα-SORβ;-Rα-SO2H;-Rα-SO2Rβ;-Rα-SO2NH2;-Rα-SO2NHRβ;-Rα-SO2N(Rβ)2;-Si(Rβ)3;-O-Si(Rβ)3;-Rα-Si(Rβ)3;-Rα-O-Si(Rβ)3;-NH2;-NHRβ;-N(Rβ)2;-N(O)(Rβ)2;-N+(Rβ)3;-Rα-NH2;-Rα-NHRβ;-Rα-N(Rβ)2;-Rα-N(O)(Rβ)2;-Rα-N+(Rβ)3;-CHO;-CORβ;-COOH;-COORβ;-OCORβ;-Rα-CHO;-Rα-CORβ;-Rα-COOH;-Rα-COORβ;-Rα-OCORβ;-C(=NH)Rβ;-C(=NH)NH2;-C(=NH)NHRβ;-C(=NH)N(Rβ)2;-C(=NRβ)Rβ;-C(=NRβ)NHRβ;-C(=NRβ)N(Rβ)2;-C(=NOH)Rβ;-C(=NORβ)Rβ;-C(N2)Rβ;-Rα-C(=NH)Rβ;-Rα-C(=NH)NH2;-Rα-C(=NH)NHRβ;-Rα-C(=NH)N(Rβ)2;-Rα-C(=NRβ)Rβ;-Rα-C(=NRβ)NHRβ;-Rα-C(=NRβ)N(Rβ)2;-Rα-C(=NOH)Rβ;-Rα-C(=NORβ)Rβ;-Rα-C(N2)Rβ;-NH-CHO;-NRβ-CHO;-NH-CORβ;-NRβ-CORβ;-NH-COORβ;-NRβ-COORβ;-NH-C(=NH)Rβ;-NRβ-C(=NH)Rβ;-NH-C(=NH)NH2;-NRβ-C(=NH)NH2;-NH-C(=NH)NHRβ;-NRβ-C(=NH)NHRβ;-NH-C(=NH)N(Rβ)2;-NRβ-C(=NH)N(Rβ)2;-NH-C(=NRβ)Rβ;-NRβ-C(=NRβ)Rβ;-NH-C(=NRβ)NHRβ;-NRβ-C(=NRβ)NHRβ;-NH-C(=NRβ)N(Rβ)2;-NRβ-C(=NRβ)N(Rβ)2;-NH-C(=NOH)Rβ;-NRβ-C(=NOH)Rβ;-NH-C(=NORβ)Rβ;-NRβ-C(=NORβ)Rβ;-CONH2;-CONHRβ;-CON(Rβ)2;-NH-CONH2;-NRβ-CONH2;-NH-CONHRβ;-NRβ-CONHRβ;-NH-CON(Rβ)2;-NRβ-CON(Rβ)2;-Rα-NH-CHO;-Rα-NRβ-CHO;-Rα-NH-CORβ;-Rα-NRβ-CORβ;-Rα-NH-COORβ;-Rα-NRβ-COORβ;-Rα-NH-C(=NH)Rβ;-Rα-NRβ-C(=NH)Rβ;-Rα-NH-C(=NH)NH2;-Rα-NRβ-C(=NH)NH2;-Rα-NH-C(=NH)NHRβ;-Rα-NRβ-C(=NH)NHRβ;-Rα-NH-C(=NH)N(Rβ)2;-Rα-NRβ-C(=NH)N(Rβ)2;-Rα-NH-C(=NRβ)Rβ;-Rα-NRβ-C(=NRβ)Rβ;-Rα-NH-C(=NRβ)NHRβ;-Rα-NRβ-C(=NRβ)NHRβ;-Rα-NH-C(=NRβ)N(Rβ)2;-Rα-NRβ-C(=NRβ)N(Rβ)2;-Rα-NH-C(=NOH)Rβ;-Rα-NRβ-C(=NOH)Rβ;-Rα-NH-C(=NORβ)Rβ;-Rα-NRβ-C(=NORβ)Rβ;-Rα-CONH2;-Rα-CONHRβ;-Rα-CON(Rβ)2;-Rα-NH-CONH2;-Rα-NRβ-CONH2;-Rα-NH-CONHRβ;-Rα-NRβ-CONHRβ;-Rα-NH-CON(Rβ)2;-Rα-NRβ-CON(Rβ)2;-O-Rα-OH;-O-Rα-ORβ;-O-Rα-NH2;-O-Rα-NHRβ;-O-Rα-N(Rβ)2;-O-Rα-N(O)(Rβ)2;-O-Rα-N+(Rβ)3;-NH-Rα-OH;-NH-Rα-ORβ;-NH-Rα-NH2;-NH-Rα-NHRβ;-NH-Rα-N(Rβ)2;-NH-Rα-N(O)(Rβ)2;-NH-Rα-N+(Rβ)3;-NRβ-Rα-OH;-NRβ-Rα-ORβ;-NRβ-Rα-NH2;-NRβ-Rα-NHRβ;-NRβ-Rα-N(Rβ)2;-NRβ-Rα-N(O)(Rβ)2;-NRβ-Rα-N+(Rβ)3;-N(O)Rβ-Rα-OH;-N(O)Rβ-Rα-ORβ;-N(O)Rβ-Rα-NH2;-N(O)Rβ-Rα-NHRβ;-N(O)Rβ-Rα-N(Rβ)2;-N(O)Rβ-Rα-N(O)(Rβ)2;-N(O)Rβ-Rα-N+(Rβ)3;-N+(Rβ)2-Rα-OH;-N+(Rβ)2-Rα-ORβ;-N+(Rβ)2-Rα-NH2;-N+(Rβ)2-Rα-NHRβ;-N+(Rβ)2-Rα-N(Rβ)2;或-N+(Rβ)2-Rα-N(O)(Rβ)2;和/或
(ii)任两个连接至同一个碳或氮原子的氢原子可任选地被独立地选自以下的以π键键合的取代基置换:氧代基(=O)、=S、=NH或=NRβ;和/或
(iii)任何硫原子可任选地经一个或两个独立地选自以下的以π键键合的取代基取代:氧代基(=O)、=NH或=NRβ;和/或
(iv)任两个连接至相同或不同原子的氢原子在同一个任选地取代的基团或部分内可任选地被独立地选自以下的桥接取代基置换:-O-、-S-、-NH-、-N=N-、-N(Rβ)-、-N(O)(Rβ)-、-N+(Rβ)2-或-Rα-;
其中各-Rα-独立地选自亚烷基、亚烯基或亚炔基,其中所述亚烷基、亚烯基或亚炔基在其主链中含有1至6个原子,其中所述亚烷基、亚烯基或亚炔基的主链内的一个或多个碳原子可任选地被一个或多个杂原子N、O或S置换,其中所述亚烷基、亚烯基或亚炔基的主链内的一个或多个-CH2-基团可任选地被一个或多个-N(O)(Rβ)-或-N+(Rβ)2-基团置换,并且其中所述亚烷基、亚烯基或亚炔基可任选地经一个或多个卤代基和/或-Rβ基团取代;并且
其中各-Rβ独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团,或其中任两个或三个连接至同一个氮原子的-Rβ可连同它们所连接的氮原子一起形成C2-C7环状基团,并且其中任何-Rβ可任选地经一个或多个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)、-CO(C3-C7环烷基)、-CO(C3-C7卤代环烷基)、-COO(C1-C4烷基)、-COO(C1-C4卤代烷基)、-COO(C3-C7环烷基)、-COO(C3-C7卤代环烷基)、卤代基、-OH、-NH2、-CN、-C≡CH、氧代基(=O)、苯基、卤代基苯基或任选地被卤代基取代的4至6元杂环基取代。
典型地,本发明的化合物包含至多一个季铵基团,例如-N+(Rβ)3或-N+(Rβ)2-。
在提及-Rα-C(N2)Rβ基团的情况下,意图为:
典型地,在任选取代的基团或部分中:
(i)每个氢原子可任选地被独立地选自以下的单价取代基置换:卤代基;-CN;-NO2;-N3;-Rβ;-OH;-ORβ;-Rα-卤代基;-Rα-CN;-Rα-NO2;-Rα-N3;-Rα-Rβ;-Rα-OH;-Rα-ORβ;-SH;-SRβ;-SORβ;-SO2H;-SO2Rβ;-SO2NH2;-SO2NHRβ;-SO2N(Rβ)2;-Rα-SH;-Rα-SRβ;-Rα-SORβ;-Rα-SO2H;-Rα-SO2Rβ;-Rα-SO2NH2;-Rα-SO2NHRβ;-Rα-SO2N(Rβ)2;-NH2;-NHRβ;-N(Rβ)2;-N+(Rβ)3;-Rα-NH2;-Rα-NHRβ;-Rα-N(Rβ)2;-Rα-N+(Rβ)3;-CHO;-CORβ;-COOH;-COORβ;-OCORβ;-Rα-CHO;-Rα-CORβ;-Rα-COOH;-Rα-COORβ;或-Rα-OCORβ;和/或
(ii)任两个连接于同一个碳原子的氢原子可任选地被独立地选自以下的以π键键合的取代基置换:氧代基(=O)、=S、=NH或=NRβ;和/或
(iii)任两个连接至相同或不同原子的氢原子在同一个任选地取代的基团或部分内可任选地被独立地选自以下的桥接取代基置换:-O-、-S-、-NH-、-N(Rβ)-、-N+(Rβ)2-或-Rα-;
其中各-Rα-独立地选自亚烷基、亚烯基或亚炔基,其中所述亚烷基、亚烯基或亚炔基在其主链中含有1至6个原子,其中所述亚烷基、亚烯基或亚炔基的主链内的一个或多个碳原子可任选地被一个或多个杂原子N、O或S置换,其中所述亚烷基、亚烯基或亚炔基的主链内的单个-CH2-基团可任选地被-N+(Rβ)2-基团置换,并且其中所述亚烷基、亚烯基或亚炔基可任选地经一个或多个卤代基和/或-Rβ基团取代;并且
其中各-Rβ独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团,或其中任两个或三个连接至同一个氮原子的-Rβ可连同它们所连接的氮原子一起形成C2-C7环状基团,并且其中任何-Rβ可任选地经一个或多个C1-C4烷基、C1-C4卤代烷基、C3-C7环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-O(C3-C7环烷基)、卤代基、-OH、-NH2、-CN、-C≡CH、氧代基(=O)或4至6元杂环基取代。
典型地,在任选取代的基团或部分中:
(i)每个氢原子可任选地被独立地选自以下的单价取代基置换:卤代基;-CN;-NO2;-N3;-Rβ;-OH;-ORβ;-Rα-卤代基;-Rα-CN;-Rα-NO2;-Rα-N3;-Rα-Rβ;-Rα-OH;-Rα-ORβ;-SH;-SRβ;-SORβ;-SO2H;-SO2Rβ;-SO2NH2;-SO2NHRβ;-SO2N(Rβ)2;-Rα-SH;-Rα-SRβ;-Rα-SORβ;-Rα-SO2H;-Rα-SO2Rβ;-Rα-SO2NH2;-Rα-SO2NHRβ;-Rα-SO2N(Rβ)2;-NH2;-NHRβ;-N(Rβ)2;-Rα-NH2;-Rα-NHRβ;-Rα-N(Rβ)2;-CHO;-CORβ;-COOH;-COORβ;-OCORβ;-Rα-CHO;-Rα-CORβ;-Rα-COOH;-Rα-COORβ;或-Rα-OCORβ;和/或
(ii)任两个连接于同一个碳原子的氢原子可任选地被独立地选自以下的以π键键合的取代基置换:氧代基(=O)、=S、=NH或=NRβ;和/或
(iii)任两个连接至相同或不同原子的氢原子在同一个任选地取代的基团或部分内可任选地被独立地选自以下的桥接取代基置换:-O-、-S-、-NH-、-N(Rβ)-或-Rα-;
其中各-Rα-独立地选自亚烷基、亚烯基或亚炔基,其中所述亚烷基、亚烯基或亚炔基在其主链中含有1至6个原子,其中所述亚烷基、亚烯基或亚炔基的主链内的一个或多个碳原子可任选地被一个或多个杂原子N、O或S置换,并且其中所述亚烷基、亚烯基或亚炔基可任选地经一个或多个卤代基和/或-Rβ基团取代;并且
其中各-Rβ独立地选自C1-C6烷基、C2-C6烯基、C2-C6炔基或C2-C6环状基团,或其中任两个连接至同一个氮原子的-Rβ可连同它们所连接的氮原子一起形成C2-C6环状基团,并且其中任何-Rβ可任选地经一个或多个C1-C4烷基、卤代基、-OH或4至6元杂环基取代。
典型地,被取代的基团包含1个、2个、3个或4个取代基,更典型地包含1个、2个或3个取代基,更典型地包含1个或2个取代基,并且更典型地包含1个取代基。
除非另有说明,否则任选取代的基团或部分(例如R1)的任何二价桥接取代基(例如-O-、-S-、-NH-、-N(Rβ)-、-N(O)(Rβ)-、-N+(Rβ)2-或-Rα-)只能连接至指定基团或部分,而不能连接至第二基团或部分(例如R2),即使所述第二基团或部分本身可以任选地被取代。
术语“卤代基”包括氟、氯、溴和碘。
除非另有说明,否则在基团前面有术语“卤代基”,例如卤代烷基或卤代甲基的情况下,应了解所讨论的基团经一个或多个独立地选自氟、氯、溴和碘的卤代基取代。典型地,卤代基取代基的最大数目只受没有卤代基前缀的对应基团上进行取代可利用的氢原子的数目限制。举例来说,卤代甲基可以含有一个、两个或三个卤代基取代基。卤代乙基或卤代苯基可以含有一个、两个、三个、四个或五个卤代基取代基。类似地,除非另有说明,否则在基团前面为特定卤代基的情况下,应了解所讨论的基团经特定卤代基中的一个或多个取代。举例来说,术语“氟甲基”是指经一个、两个或三个氟基取代的甲基。
类似地,除非另有说明,否则在称基团“经卤代基取代”的情况下,应了解所讨论的基团经一个或多个独立地选自氟、氯、溴和碘的卤代基取代。典型地,卤代基取代基的最大数目只受称被卤代基取代的基团上进行取代可利用的氢原子的数目限制。举例来说,被卤代基取代的甲基可以含有一个、两个或三个卤代基取代基。被卤代基取代的乙基或被卤代基取代的苯基可以含有一个、两个、三个、四个或五个卤代基取代基。
除非另有说明,否则对元素的任何提及将被认为是提及所述元素的所有同位素。因此,举例来说,除非另有说明,否则对氢的任何提及被认为涵盖包括氘和氚的所有氢同位素。
除非另有说明,否则对化合物或基团的任何提及将被认为是提及所述化合物或基团的所有互变异构体。
在提及在碳骨架中包括一个或多个杂原子N、O或S的烃基或其它基团的情况下,或在提及烃基或其它基团的碳原子被N、O或S原子置换的情况下,意图:
-CH2-被-NH-、-O-或-S-置换;
-CH3被-NH2、-OH或-SH置换;
-CH=被-N=置换;
CH2=被NH=、O=或S=置换;或
CH≡被N≡置换;
条件是所得到的基团包含至少一个碳原子。举例来说,甲氧基、二甲基氨基和氨基乙基被认为是在其碳骨架中包括一个或多个杂原子N、O或S的烃基。
在提及烃基或其它基团的主链中的-CH2-基团被-N(O)(Rβ)-或-N+(Rβ)2-基团置换的情况下,意图:
在本说明书的上下文中,除非另有说明,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。当计算经任选的取代基取代和/或含有任选的部分的母基团中的碳原子总数时,任选的取代基和部分不计入内。为了避免引起怀疑,当计算Cx-Cy基团中的碳原子数目时,置换杂原子,例如N、O或S,算作是碳原子。举例来说,吗啉基被认为是C6杂环基,不是C4杂环基。
出于本说明书的目的,在说第一原子或基团“直接连接”至第二原子或基团的情况下,应了解第一原子或基团共价键合至第二原子或基团,不存在间插原子或基团。因此,举例来说,对于基团-(C=O)N(CH3)2来说,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甲基的碳原子。
为了避免引起怀疑,在说化合物或基团,例如R1,含有x至y个除氢以外的原子的情况下,应了解包括任何任选取代基的化合物或基团总体上含有x至y个除氢以外的原子。这类化合物或基团可以含有许多氢原子。
发明内容
本发明的第一方面提供了式(I)的化合物:
其中:
A为苯基或5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代;
B为苯基、5或6元杂芳基或4至6元饱和杂环基,其中B任选地被取代;
X为O、NH或N(CN);
Y为O或S;
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R4为单价的,并且在α’位置连接至A,并且选自C1-C4烷基、C3-C6环烷基和苯基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
或R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH=CHCH2-、-CH2CH=CH-、-CH2CH2O-、-OCH2CH2-、-CH2CH2CH2CH2-和-CH=CH-CH=CH-,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)或卤素;
R20为键、-NH-、-NMe-、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
A为苯基或5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置(相对于A与R1-S(X)(O)-NH-CY-NH-的连接点)经R4取代,并且其中A任选地另外被取代。在一个实施方案中,A为苯基或包含一个、两个或三个氮及/或氧及/或硫环原子的5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。在一个实施方案中,A为苯基或包含一个或两个氮及/或氧环原子的5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。在一个实施方案中,A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、噻唑基或异噻唑基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。在一个实施方案中,A为苯基、嘧啶基、吡唑基或咪唑基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。在一个实施方案中,A为苯基或咪唑基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。
A任选地另外被取代。在一个实施方案中,A在γ位置(相对于A与R1-S(X)(O)-NH-CY-NH-的连接点)经卤素或氰基取代。在一个实施方案中,A在γ位置经氟、氯或氰基取代。在一个实施方案中,A在γ位置经氟取代。
B为苯基、5或6元杂芳基或4至6元饱和杂环基,其中B任选地被取代。在一个实施方案中,B为苯基,或包含一个、两个或三个氮及/或氧及/或硫环原子的5或6元杂芳基,或包含一个或两个氮及/或氧及/或硫环原子的4至6元饱和杂环基,其中B任选地被取代。在一个实施方案中,B为苯基,或包含一个或两个氮及/或氧环原子的5或6元杂芳基,或包含一个氮或氧环原子的4至6元饱和杂环基,其中B任选地被取代。在一个实施方案中,B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、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,其中B任选地被取代。在一个实施方案中,B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、三唑基或噁二唑基,其中B任选地被取代。在一个实施方案中,B为苯基、吡啶基、嘧啶基、吡唑基、咪唑基、异噁唑基或噻唑基,其中B任选地被取代。在一个实施方案中,B为苯基、吡啶基、嘧啶基或吡唑基,其中B任选地被取代。在一个实施方案中,B为苯基或吡啶基,其中B任选地被取代。在一个实施方案中,B为任选地被取代的吡啶基。在一个实施方案中,B为任选地被取代的吡啶-4-基。
B任选地被取代。在一个实施方案中,B任选地经R2取代并且任选地另外被取代。在一个实施方案中,R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-O-R10-O(C1-C4卤代烷基)、-R8-NH2、-R8-NH(C1-C4烷基)、-R8-NH(C1-C4卤代烷基)、-R8-N(C1-C4烷基)2、-R8-N(C1-C4烷基)(C1-C4卤代烷基)、-R8-N(C1-C4卤代烷基)2、-R11、-OR11或-O-R10-R11;其中
R8为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R10为C1-C4亚烷基或C1-C4卤代亚烷基;并且
R11为C3-C6环烷基或4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C3-C4环烷基、C2-C4烯基、C2-C4卤代烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-NH2、-NH(C1-C4烷基)、-NH(C1-C4卤代烷基)、-N(C1-C4烷基)2、-N(C1-C4烷基)(C1-C4卤代烷基)和-N(C1-C4卤代烷基)2。
在一个实施方案中,R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-O-R10-O(C1-C4卤代烷基)、-R8-NH2、-R8-NH(C1-C4烷基)、-R8-NH(C1-C4卤代烷基)、-R8-N(C1-C4烷基)2、-R8-N(C1-C4烷基)(C1-C4卤代烷基)、-R8-N(C1-C4卤代烷基)2、-R11、-OR11或-O-R10-R11;其中
R8为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R10为C1-C4亚烷基或C1-C4卤代亚烷基;并且
R11为C3-C6环烷基或包含一个或两个氮及/或氧及/或硫环原子的4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C3-C4环烷基、C2-C4烯基、C2-C4卤代烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-NH2、-NH(C1-C4烷基)、-NH(C1-C4卤代烷基)、-N(C1-C4烷基)2、-N(C1-C4烷基)(C1-C4卤代烷基)和-N(C1-C4卤代烷基)2。
在一个实施方案中,R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-O-R10-O(C1-C4卤代烷基)、-R8-NH2、-R8-NH(C1-C4烷基)、-R8-NH(C1-C4卤代烷基)、-R8-N(C1-C4烷基)2、-R8-N(C1-C4烷基)(C1-C4卤代烷基)、-R8-N(C1-C4卤代烷基)2、-R11、-OR11或-O-R10-R11;其中
R8为键、C1-C3亚烷基或C1-C3卤代亚烷基;
R10为C1-C3亚烷基或C1-C3卤代亚烷基;并且
R11为C3-C6环烷基或包含一个氮或氧环原子的4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C3-C4环烷基、C2-C4烯基、C2-C4卤代烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-NH2、-NH(C1-C4烷基)、-NH(C1-C4卤代烷基)、-N(C1-C4烷基)2、-N(C1-C4烷基)(C1-C4卤代烷基)和-N(C1-C4卤代烷基)2。
在一个实施方案中,R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-R11、-OR11或-O-R10-R11;其中
R8为键或-CH2-;
R10为C1-C3亚烷基;并且
R11为环丙基、环丁基、环戊基、环己基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、C1-C3卤代烷基、C2-C3烯基、C2-C3卤代烯基、苯基、苯甲基、-OH、-O(C1-C3烷基)、-O(C1-C3卤代烷基)、-NH2、-NH(C1-C3烷基)、-NH(C1-C3卤代烷基)、-N(C1-C3烷基)2、-N(C1-C3烷基)(C1-C3卤代烷基)和-N(C1-C3卤代烷基)2。
在一个实施方案中,R2为氢、卤代基、氰基、C1-C3烷基、C1-C3卤代烷基、-R8-OH、-R8-O(C1-C3烷基)、-R8-O(C1-C3卤代烷基)、-O-R10-OH、-O-R10-O(C1-C3烷基)、-R11、-OR11或-O-R10-R11;其中
R8为键或-CH2-;
R10为C1-C3亚烷基;并且
R11为环丙基、环丁基、环戊基、环己基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地经一个或两个独立地选自以下的取代基取代:氟、C1-C3烷基、C2-C3烯基、苯基、苯甲基、-OH、-O(C1-C3烷基)、-NH2、-NH(C1-C3烷基)和-N(C1-C3烷基)2。
在一个实施方案中,R2为氢、卤代基、氰基、C1-C3烷基、C1-C3卤代烷基、-R8-OH、-R8-O(C1-C3烷基)、-R8-O(C1-C3卤代烷基)、-O-R10-OH、-O-R10-O(C1-C3烷基)、-R11、-OR11或-O-R10-R11;其中
R8为键或-CH2-;
R10为C1-C3亚烷基;并且
R11为环丙基、环丁基、环戊基、环己基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地经一个或两个独立地选自以下的取代基取代:氟、甲基、-OH、-OMe、-NHMe和-NMe2。
在一个实施方案中,当R11为吡咯烷基或哌啶基时,吡咯烷基或哌啶基在氮环原子上被取代。
B可在α、β或γ位置(相对于B与A的连接点)经R2取代。在一个实施方案中,B在β或γ位置经R2取代。在一个实施方案中,B在β位置经R2取代。
在一个实施方案中,B为吡啶-4-基,在β位置经R2取代,并且任选地另外被取代。
在一个实施方案中,B任选地经R2取代并任选地进一步经一个或两个独立地选自以下的取代基取代:卤代基、C1-C3烷基、-O(C1-C3烷基)、-OH、-NH2和-CN。在一个实施方案中,B进一步经一个或两个独立地选自以下的取代基取代:氟、氯、甲基、乙基、-OMe、-OEt、-OH、-NH2和-CN。在一个实施方案中,B进一步经甲基取代。
X为O、NH或N(CN)。在一个实施方案中,X为O或NH。在一个实施方案中,X为O。
Y为O或S。在一个实施方案中,Y为O。
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;其中R20为键、-NH-、-NMe-、C1-C4亚烷基或C1-C4卤代亚烷基;R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;其中R20为键、C1-C4亚烷基或C1-C4卤代亚烷基;R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NH(C1-C3烷基)、-N(C1-C3烷基)2或-R20-R21基团,均任选地被卤代基取代;其中R20为键、C1-C3亚烷基或C1-C3卤代亚烷基;R21为C3-C6环烷基或苯基,或包含一个或两个氮及/或氧及/或硫环原子的4至6元饱和杂环基,或包含一个、两个或三个氮及/或氧及/或硫环原子的5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且R23为C3-C6环烷基或包含一个或两个氮及/或氧及/或硫环原子的4至6元饱和杂环基,均任选地被卤代基取代。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2、-NMeEt或-R20-R21基团,均任选地被卤代基取代;其中R20为键或C1-C2亚烷基;R21为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、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、三唑基或噁二唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、-R22-OH、-R22-O(C1-C4烷基)、-R22-NH(C1-C4烷基)、-R22-N(C1-C4烷基)2和-R22-R23;R22为键或C1-C4亚烷基;并且R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt,均任选地被卤代基取代;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、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、三唑基或噁二唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、-R22-OH、-R22-O(C1-C4烷基)、-R22-NH(C1-C4烷基)、-R22-N(C1-C4烷基)2和-R22-R23;其中R22为键或C1-C4亚烷基;并且R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt,均任选地被卤代基取代;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2和-R22-R23;其中R22为键或C1-C4亚烷基;并且R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地经C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2或-R22-R23取代;其中R22为键或C1-C4亚烷基;并且R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在一个实施方案中,R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt;或R1为环丙基、环丁基、环戊基、环己基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地经C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2或-R22-R23取代;其中R22为键或C1-C4亚烷基;并且R23为环丙基、环丁基、环戊基、环己基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在一个实施方案中,R1为甲基、乙基或-NMe2;或R1为环丙基、苯基、呋喃基或吡唑基,均任选地经甲基、乙基、异丙基、CMe2(OH)或环丙基取代。
在一个实施方案中,当R1为吡咯烷基、哌啶基、吡唑基或咪唑基时,吡咯烷基、哌啶基、吡唑基或咪唑基在氮环原子上被取代。
在一个实施方案中,A为苯基,在α位置经B取代,在β位置经R7取代,在α'位置经R4取代,并且任选地另外被取代;并且R1为甲基、乙基或-NMe2,或R1为环丙基、苯基、呋喃基或吡唑基,均任选地经甲基、乙基、异丙基、CMe2(OH)或环丙基取代。
在另一实施方案中,A为咪唑基,在α位置经B取代,在β位置经R7取代,在α'位置经R4取代,并且任选地另外被取代;并且R1为呋喃基或吡唑基,均任选地经甲基、乙基、异丙基、CMe2(OH)或环丙基取代。
在一个实施方案中,R4为单价的,并且在α’位置(相对于A与R1-S(X)(O)-NH-CY-NH-的连接点)连接至A,并且选自C1-C4烷基、C3-C6环烷基和苯基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基(=O)、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基)。在一个实施方案中,R4为单价的,并且在α’位置连接至A,并且选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基和苯基,均任选地被卤代基取代及/或任选地经一个选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基)。在一个实施方案中,R4为单价的,并且在α’位置连接至A,并且选自异丙基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基和苯基,均任选地被卤代基取代。在一个实施方案中,R4为单价的,并且在α’位置连接至A,并且选自异丙基、环戊基、环己基和苯基,均任选地被卤代基取代。在一个实施方案中,R4为单价的,并且在α’位置连接至A,并且选自异丙基、环戊基、环己基和苯基。在一个实施方案中,R4为在α’位置连接至A的异丙基。
在一替代实施方案中,R4为二价的,并且在α’和β’位置(相对于A与R1-S(X)(O)-NH-CY-NH-的连接点)连接至A,并且选自-CH2CH2CH2-、-CH=CHCH2-、-CH2CH=CH-、-CH2CH2O-、-OCH2CH2-、-CH2CH2CH2CH2-和-CH=CH-CH=CH-,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基(=O)、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基)。在一个实施方案中,R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH2CH2O-和-OCH2CH2-,均任选地被卤代基取代及/或任选地经一个选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基)。在一个实施方案中,R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH2CH2O-和-OCH2CH2-,均任选地被卤代基取代。在一个实施方案中,R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH2CH2O-和-OCH2CH2-。在一个实施方案中,R4为在α'和β'位置连接至A的-CH2CH2CH2-基团。
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)或卤素。在一个实施方案中,R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基或卤素。在一个实施方案中,R7为甲基、乙基、卤代甲基、卤代乙基、环丙基、卤代环丙基或卤素。在一个实施方案中,R7为甲基、乙基、三氟甲基、环丙基或氟。在一个实施方案中,R7为甲基、乙基、环丙基或氟。在一个实施方案中,R7为甲基。
本发明的第一方面还提供了式(IA)化合物:
其中:
A为苯基或5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代;
B为苯基、5或6元杂芳基或4至6元饱和杂环基,其中B经R2取代,并且其中B任选地另外被取代;
X为O、NH或N(CN);
Y为O或S;
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-O-R10-O(C1-C4卤代烷基)、-R8-NH2、-R8-NH(C1-C4烷基)、-R8-NH(C1-C4卤代烷基)、-R8-N(C1-C4烷基)2、-R8-N(C1-C4烷基)(C1-C4卤代烷基)、-R8-N(C1-C4卤代烷基)2、-R11、-OR11或-O-R10-R11;
R4为单价的,并且在α’位置连接至A,并且选自C1-C4烷基、C3-C6环烷基和苯基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
或R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH=CHCH2-、-CH2CH=CH-、-CH2CH2O-、-OCH2CH2-、-CH2CH2CH2CH2-和-CH=CH-CH=CH-,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)或卤素;
R8为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R10为C1-C4亚烷基或C1-C4卤代亚烷基;
R11为C3-C6环烷基或4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C3-C4环烷基、C2-C4烯基、C2-C4卤代烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-NH2、-NH(C1-C4烷基)、-NH(C1-C4卤代烷基)、-N(C1-C4烷基)2、-N(C1-C4烷基)(C1-C4卤代烷基)和-N(C1-C4卤代烷基)2;
R20为键、-NH-、-NMe-、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
以上关于式(I)的化合物所述的A、B、X、Y、R1、R2、R4、R7、R8、R10、R11、R20、R21、R22和R23的实施方案同等适用于式(IA)的化合物。
本发明的第一方面还提供了式(II)的化合物:
其中:
X为O、NH或N(CN);
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2a为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;
R3为氢或甲基;
R4a为C1-C4烷基、C3-C6环烷基或苯基,均任选地被卤代基取代;
R5为氢;或
R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-,均任选地被卤代基取代;
R6为氢、卤素或氰基;
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基或卤素;
R9为C3-C6环烷基或4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:C1-C4烷基、C2-C4烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-NH(C1-C4烷基)和-N(C1-C4烷基)2;
R20为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
以上关于式(I)的化合物所述的X、R1、R7、R20、R21、R22和R23的实施方案同等适用于式(II)的化合物。
R2a为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;其中R9为C3-C6环烷基或4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:C1-C4烷基、C2-C4烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-NH(C1-C4烷基)和-N(C1-C4烷基)2。
在一个实施方案中,R2a为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;其中R9为C3-C6环烷基或包含一个或两个氮及/或氧环原子的4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:C1-C4烷基、C2-C4烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-NH(C1-C4烷基)和-N(C1-C4烷基)2。
在一个实施方案中,R2a为氢、氰基、C1-C3烷基、C1-C3卤代烷基、-O(C1-C3烷基)、-O(C1-C3卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;其中R9为C3-C6环烷基或包含一个氮或氧环原子的4至6元饱和杂环基,其中环烷基或杂环基任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-OH、-O(C1-C3烷基)、-NH(C1-C3烷基)和-N(C1-C3烷基)2。
在一个实施方案中,R2a为氢、氰基、C1-C3烷基、C1-C3卤代烷基、-O(C1-C3烷基)、-O(C1-C3卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;其中R9为C3-C6环烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-OH、-O(C1-C3烷基)、-NH(C1-C3烷基)和-N(C1-C3烷基)2。
在一个实施方案中,R2a为氢、氰基、甲基、乙基、正丙基、异丙基、卤代甲基、卤代乙基、-OMe、-OEt、-O-(卤代甲基)、-O-(卤代乙基)、-O-(甲氧基烷基)或-OR9;其中R9为环丙基、环丁基、环戊基、环己基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地经一个选自以下的取代基取代:甲基、乙基、-OH、-OMe、-OEt、-NHMe、-NMe2、-NHEt、-NEt2和-NMeEt。
在一个实施方案中,当R9为吡咯烷基或哌啶基时,吡咯烷基或哌啶基在氮环原子上被取代。
R3为氢或甲基。在一个实施方案中,R3为氢。在一个实施方案中,R3为甲基。
在式(II)的化合物的一个实施方案中,R5为氢并且R4a为C1-C4烷基、C3-C6环烷基或苯基,均任选地被卤代基取代。在一个实施方案中,R4a为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基或苯基,均任选地被卤代基取代。在一个实施方案中,R4a为异丙基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基或苯基,均任选地被卤代基取代。在一个实施方案中,R4a为异丙基、环戊基、环己基或苯基,均任选地被卤代基取代。在一个实施方案中,R4a为异丙基、环戊基、环己基或苯基。在一个实施方案中,R4a为异丙基。
在式(II)的化合物的一替代实施方案中,R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-,均任选地被卤代基取代。在一个实施方案中,R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-。在一个实施方案中,R4a和R5一起形成-CH2CH2CH2-。
R6为氢、卤素或氰基。在一个实施方案中,R6为氢、氟、氯或氰基。在一个实施方案中,R6为氢或氟。
在一个实施方案中,本发明提供了式(II)的化合物,其中:
X为O或NH;
R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt,均任选地被卤代基取代;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2和-R22-R23;
R2a为氢、氰基、C1-C3烷基、C1-C3卤代烷基、-O(C1-C3烷基)、-O(C1-C3卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;
R3为氢或甲基;
R4a为异丙基、环戊基、环己基或苯基;
R5为氢;或
R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-;
R6为氢、卤素或氰基;
R7为甲基、乙基、环丙基或氟;
R9为C3-C6环烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-OH、-O(C1-C3烷基)、-NH(C1-C3烷基)和-N(C1-C3烷基)2;
R22为键或C1-C4亚烷基;并且
R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
本发明的第一方面还提供了式(III)的化合物:
其中:
X为O、NH或N(CN);
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2b为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)或-O(C1-C4卤代烷基);
R3为氢或甲基;
R4b为C1-C4烷基或C1-C4卤代烷基;
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基或卤素;
R20为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
以上关于式(I)的化合物所述的X、R1、R7、R20、R21、R22和R23的实施方案同等适用于式(III)的化合物。
R2b为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)或-O(C1-C4卤代烷基)。在一个实施方案中,R2b为氢、氰基、C1-C3烷基、C1-C3卤代烷基、-O(C1-C3烷基)或-O(C1-C3卤代烷基)。在一个实施方案中,R2b为氢、C1-C3烷基、-O(C1-C3烷基)或-O(C1-C3卤代烷基)。在一个实施方案中,R2b为氢、甲基、三氟甲基或-OMe。在一个实施方案中,R2b为氢或-OMe。
R3为氢或甲基。在一个实施方案中,R3为氢。在一个实施方案中,R3为甲基。
R4b为C1-C4烷基或C1-C4卤代烷基。在一个实施方案中,R4b为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基,均任选地被卤代基取代。在一个实施方案中,R4b为异丙基、仲丁基、异丁基或叔丁基,均任选地被卤代基取代。在一个实施方案中,R4b为任选地被卤代基取代的异丙基。在一个实施方案中,R4b为异丙基。
在一个实施方案中,本发明提供了式(III)的化合物,其中:
X为O或NH;
R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt,均任选地被卤代基取代;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2和-R22-R23;
R2b为氢、氰基、C1-C3烷基、C1-C3卤代烷基、-O(C1-C3烷基)或-O(C1-C3卤代烷基);
R3为氢或甲基;
R4b为C1-C4烷基或C1-C4卤代烷基;
R7为甲基、乙基、环丙基或氟;
R22为键或C1-C4亚烷基;并且
R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
在任一以上实施方案的一方面,R1含有1至30个除氢以外的原子。更典型地,R1含有1至25个除氢以外的原子。更典型地,R1含有1至20个除氢以外的原子。更典型地,R1含有1至16个除氢以外的原子。
在任一以上实施方案的一方面,A、B、R4和R7一起含有11至50个除氢以外的原子。更典型地,A、B、R4和R7一起含有12至45个除氢以外的原子。更典型地,A、B、R4和R7一起含有13至40个除氢以外的原子。最典型地,A、B、R4和R7一起含有14至35个除氢以外的原子。
在任一以上实施方案的一方面,式(I)、(IA)、(II)或(III)的化合物具有250至2,000Da的分子量。典型地,式(I)、(IA)、(II)或(III)的化合物具有300至1,000Da的分子量。典型地,式(I)、(IA)、(II)或(III)的化合物具有310至800Da的分子量。更典型地,式(I)、(IA)、(II)或(III)的化合物具有320至650Da的分子量。
本发明的第二方面提供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的第一或第二方面的任何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。酸加成盐优选为用合适酸形成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,例如氢卤酸(例如氢氟酸、盐酸、氢溴酸或氢碘酸)或其它无机酸(例如硝酸、高氯酸、硫酸或磷酸);或有机酸,例如有机羧酸(例如丙酸、丁酸、乙醇酸、乳酸、扁桃酸、柠檬酸、乙酸、苯甲酸、水杨酸、丁二酸、苹果酸或羟基丁二酸、酒石酸、反丁烯二酸、顺丁烯二酸、羟基顺丁烯二酸、粘酸或半乳糖二酸、葡糖酸、泛酸或双羟萘酸)、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、甲苯-对磺酸、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、二、三或多酸加成盐。优选的盐为氢卤酸、硫酸、磷酸或有机酸加成盐。优选的盐为盐酸加成盐。
在本发明的化合物包括季铵基团的情况下,化合物典型地以其盐形式使用。季铵基团的抗衡离子可以是任何药学上可接受的无毒抗衡离子。合适抗衡离子的实例包括上文关于酸加成盐所论述的质子酸的共轭碱。
本发明的化合物还可以其游离酸形式和其酸加成盐形式两者使用。出于本发明目的,本发明化合物的“盐”包括在本发明化合物的质子酸官能团(例如羧酸基)与合适阳离子之间形成的盐。合适的阳离子包括(但不限于)锂、钠、钾、镁、钙和铵。盐可以是单、二、三或多盐。盐优选为单锂、钠、钾、镁、钙或铵盐或二锂、钠、钾、镁、钙或铵盐。更优选地,盐为单或二钠盐或者单或二钾盐。
优选地,任何盐为药学上可接受的无毒盐。然而,除药学上可接受的盐外,其它盐包括在本发明中,因为其可能在其它例如药学上可接受的盐的纯化或制备中用作中间体,或可用于鉴定、表征或纯化游离酸或碱。
本发明的化合物和/或盐可以是无水的或呈水合物(例如半水合物、单水合物、二水合物或三水合物)或其它溶剂合物形式。这类其它溶剂合物可以用常见的有机溶剂形成,所述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,提供治疗非活性的前药。前药为在向例如人的受试者施用时完全或部分地转化成本发明化合物的化合物。在大部分实施方案中,前药为药理学惰性化学衍生物,其可以在体内转化成活性药物分子,以发挥治疗作用。任何本文所述的化合物可以作为前药施用以增加化合物的活性、生物利用率或稳定性,或以其它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官能部分上具有生物学上不稳定的保护基的化合物。前药包括(但不限于)可以氧化、还原、氨化、脱氨基、羟基化、脱羟基、水解、脱水、烷基化、脱烷基、酰化、脱酰化、磷酸化和/或脱去磷酸以产生活性化合物的化合物。本发明还涵盖如上所述的这类前药的盐和溶剂合物。
本发明的化合物、盐、溶剂合物和前药可以含有至少一个手性中心。因此,化合物、盐、溶剂合物和前药可以以至少两种异构体形式存在。本发明涵盖本发明的化合物、盐、溶剂合物和前药的外消旋混合物以及对映异构性富集和基本上对映异构体纯的异构体。出于本发明的目的,化合物的“基本上对映异构体纯的”异构体包含按重量少于5%的相同化合物的其它异构体,更典型地少于2%,并且最典型地少于0.5%。
本发明的化合物、盐、溶剂合物和前药可以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,和任何放射性同位素,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、溶剂合物和前药可以呈任何多晶型或非晶形式。
本发明的第四方面提供一种药物组合物,其包含本发明的第一或第二方面的化合物,或本发明的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。
用于选择和制备合适的药物制剂的常规程序描述于例如“Aulton’sPharmaceutics-The Design and Manufacture of Medicines”,M.E.Aulton和K.M.G.Taylor,Churchill Livingstone Elsevier,第4版,2013。
可以用于本发明的药物组合物中的包括佐剂、稀释剂或载体的药学上可接受的赋形剂为药物制剂领域中常用的赋形剂,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(例如人血清白蛋白)、缓冲物质(例如磷酸盐)、甘油、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态二氧化硅、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-聚氧化丙烯嵌段聚合物、聚乙二醇和羊毛脂。
在一个实施方案中,本发明的第四方面的药物组合物另外包含一种或多种其它活性剂。
在另一实施方案中,本发明的第四方面的药物组合物可以作为成套部件的一部分提供,其中成套部件包含本发明的第四方面的药物组合物和一种或多种其它药物组合物,其中一种或多种其它药物组合物各包含药学上可接受的赋形剂和一种或多种其它活性剂。
本发明的第五方面提供本发明的第一或第二方面的化合物,或本发明的第三方面的药学上可接受的盐、溶剂合物或前药,或本发明的第四方面的药物组合物,用于医药中和/或用于治疗或预防疾病、病症或疾患。典型地,所述使用包括向受试者施用所述化合物、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它活性剂。
如本文所用,术语“治疗”同等地指治愈性疗法和改善性或姑息性疗法。所述术语包括获得可能或可能未在临床上确立的有益或希望的生理学结果。有益或希望的临床结果包括(但不限于)减轻症状、预防症状、减弱疾病程度、疾患稳定(即不恶化)、延迟或减缓疾患/症状的进展/恶化、改善或缓和疾患/症状和症状缓解(无论部分还是完全),无论可检测还是不可检测。如本文所用,术语“缓和”和其变型意指与未施用本发明的化合物、盐、溶剂合物、前药或药物组合物相比,减轻生理疾患或症状的程度和/或不希望有的表现形式,和/或减缓或延长进展时程。如本文关于疾病、病症或疾患所用,术语“预防”是指防治性或预防性疗法,以及降低显现疾病、病症或疾患的风险的疗法。术语“预防”包括避免疾病、病症或疾患的发生和延迟疾病、病症或疾患的发作。如通过可控临床试验测量的任何统计上显著(p≤0.05)的发生避免、发作延迟或风险降低可以认为疾病、病症或疾患的预防。能够预防的受试者包括如通过遗传或生物化学标记物鉴定,处于增高的疾病、病症或疾患风险下的受试者。典型地,遗传或生物化学标志物适合于所考虑的疾病、病症或疾患,并且可以包括例如炎性生物标志物,例如在炎症情况下C-反应蛋白(CRP)和单核细胞趋化蛋白1(MCP-1);在NAFLD和NASH情况下总胆固醇、甘油三酸酯、胰岛素抗性和C-肽;以及更一般地,在对NLRP3抑制有响应的疾病、病症或疾患情况下IL-1β和IL-18。
本发明的第六方面提供第一或第二方面的化合物或者第三方面的药学上有效的盐、溶剂合物或前药的用途,其用于制造供治疗或预防疾病、病症或疾患用的药物。典型地,治疗或预防包括向受试者施用化合物、盐、溶剂合物、前药或药物。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它活性剂。
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,所述方法包括施用有效量的第一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的步骤,从而治疗或预防所述疾病、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它活性剂的步骤。典型地,施用至有需要的受试者。
本发明的第八方面提供本发明的第一或第二方面的化合物,或本发明的第三方面的药学上可接受的盐、溶剂合物或前药,或本发明的第四方面的药物组合物,其用于治疗或预防个体的疾病、病症或疾患,其中所述个体具有NLRP3的生殖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引起NLRP3活性增加的其它突变。典型地,所述使用包括向所述个体施用所述化合物、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它活性剂。所述使用还可以包括诊断具有NLRP3的生殖系或体细胞非沉默突变的个体,其中基于突变的阳性诊断,向个体施用所述化合物、盐、溶剂合物、前药或药物组合物。典型地,可以通过任何合适的遗传学或生物化学方式鉴定个体中的NLRP3突变。
本发明的第九方面提供第一或第二方面的化合物或者第三方面的药学上有效的盐、溶剂合物或前药的用途,其用于制造供个体的治疗或预防疾病、病症或疾患用的药物,其中所述个体具有NLRP3的生殖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引起NLRP3活性增加的其它突变。典型地,治疗或预防包括向所述个体施用化合物、盐、溶剂合物、前药或药物。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它活性剂。治疗或预防还可以包括诊断具有NLRP3的生殖系或体细胞非沉默突变的个体,其中基于突变的阳性诊断,向个体施用所述化合物、盐、溶剂合物、前药或药物。典型地,可以通过任何合适的遗传学或生物化学方式鉴定个体中的NLRP3突变。
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的生殖系或体细胞非沉默突变的个体;和向经诊断呈阳性的个体施用有效量的第一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,从而治疗或预防所述疾病、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它活性剂的步骤。典型地,施用至有需要的受试者。
在通用实施方案中,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、肾脏系统、肝脏系统、代谢系统、呼吸系统、中枢神经系统的疾病、病症或疾患,可以是癌症或其它恶性病,和/或可以由病原体引起或与病原体相关。
应了解,这些根据疾病、病症和疾患的大类界定的通用实施方案不互斥。关于此,可以根据以上通用实施方案中的不只一个,将任何具体的疾病、病症或疾患分类。一个非限制性实例为I型糖尿病,I型糖尿病为自身免疫性疾病和内分泌系统疾病。
在本发明的第五、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NLRP3的活性水平完全或部分减少,并且包括例如活性NLRP3的抑制和/或NLRP3活化的抑制。
有证据证明NLRP3诱发的IL-1和IL-18在与许多不同病症有关或由许多不同病症引起而发生的炎症反应中起作用(Menu等人,Clinical and Experimental Immunology,166:1-15,2011;Strowig等人,Nature,481:278-286,2012)。
已提出NLRP3起作用的遗传性疾病包括镰状细胞病(Vogel等人,Blood,130(增刊1):2234,2017)和含缬酪肽蛋白病(Valosin Containing Protein disease)(Nalbandian等人,Inflammation,40(1):21-41,2017)。
NLRP3已经与大量自身炎症性疾病相关,包括家族性地中海热(FMF)、TNF受体相关周期性综合征(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)、斯维特综合征(Sweet’s syndrome)、慢性非细菌性骨髓炎(CNO)和寻常痤疮(Cook等人,Eur J Immunol,40:595-653,2010)。具体地说,已经发现NLRP3突变引起一组称为CAPS的罕见自身炎症性疾病(Ozaki等人,J Inflammation Research,8:15-27,2015;Schroder等人,Cell,140:821-832,2010;和Menu等人,Clinical andExperimental Immunology,166:1-15,2011)。CAPS是特征在于回归热和炎症的遗传病并且由形成临床连续体的三种自身炎症性病症构成。这些疾病按严重度增加的次序为家族性寒冷性自身炎症性综合征(FCAS)、穆-韦二氏综合征(MWS)和慢性婴儿神经皮肤关节综合征(CINCA;又称为新生儿发作型多系统炎性疾病,NOMID),并且均显示由NLRP3基因的功能获得型突变引起,这导致IL-1β分泌增加。
大量自身免疫性疾病已经显示涉及NLRP3,具体地说,包括多发性硬化、1型糖尿病(T1D)、牛皮癣、类风湿性关节炎(RA)、白塞病(Behcet’s disease)、施尼茨勒综合征(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和Rheumatism,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)。
NLRP3还显示在大量肺部疾病中起作用,包括慢性阻塞性肺病(COPD)、哮喘(包括类固醇抵抗型哮喘和嗜酸细胞性哮喘)、石棉沉着病和硅肺(De Nardo等人,Am J Pathol,184:42-54,2014;Lv等人,JBiol Chem,293(48):18454,2018;和Kim等人,Am J RespirCrit Care Med,196(3):283-97,2017)。
还提出NLRP3在大量中枢神经系统疾患中起作用,包括帕金森氏病(Parkinson’sdisease,PD)、阿尔茨海默病(AD)、痴呆、亨廷顿病(Huntington’s disease)、脑型疟、由肺炎球菌性脑膜炎引起的脑损伤(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,JStroke&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)、败血症相关脑病(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(蛛网膜下出血SAH)(Luo等人,Brain Res Bull,146:320-326,2019)和创伤性脑损伤(Ismael等人,JNeurotrauma,35(11):1294-1303,2018)。
NRLP3活性还显示与多种代谢疾病有关,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)。
还提出NLRP3在以下中经由IL-1β起作用: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 HeartJournal,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 Am Coll Cardiol,71(8):875-66,2018)、主动脉瘤与剥离(Wu等人,Arterioscler Thromb Vasc Biol,37(4):694-706,2017)、由代谢功能障碍诱发的心脏损伤(Pavillard等人,Oncotarget,8(59):99740-99756,2017)、心房颤动(Yao等人,Circulation,138(20):2227-2242,2018)、高血压(Gan等人,BiochimBiophys Acta,1864(1):1-10,2018)和其它心血管事件(Ridker等人,N Engl J Med,doi:10.1056/NEJMoa1707914,2017)。
已显示涉及NLRP3的其它疾病包括:
-眼病,例如湿性和干性年龄相关的黄斑变性(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(Loukovaara等人,Acta Ophthalmol,95(8):803-808,2017)和视神经损害(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)、暴发型肝炎(Pourcet等人,Gastroenterology,154(5):1449-1464,e20,2018)、肝纤维化(Zhang等人,Parasit Vectors,12(1):29,2019)和肝功能衰竭(Wang等人,Hepatol Res,48(3):E194-E202,2018);
-肾病,包括肾钙质沉着(Anders等人,Kidney Int,93(3):656-669,2018)、肾纤维化(包括慢性晶体肾病)(Ludwig-Portugall等人,Kidney Int,90(3):525-39,2016)和肾性高血压(Krishnan等人,Br JPharmacol,173(4):752-65,2016);
-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(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)、上皮间质转化(EMT)(Li等人,ExperimentalCell Research,362(2):489-497,2018)、接触性超敏反应(例如大疱性类天疱疮(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)、寻常痤疮(Qin等人,J Invest Dermatol,134(2):381-88,2014)和结节病(Jager等人,Am JRespir 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);
-肌萎缩侧索硬化(Gugliandolo等人,Inflammation,41(1):93-103,2018);
-囊肿性纤维化(Iannitti等人,Nat Commun,7:10791,2016);
-中风(Walsh等人,Nature Reviews,15:84-97,2014);
-慢性肾病(Granata等人,PLoS One,10(3):e0122272,2015);
-镰状细胞病(Vogel等人,Blood,130(增刊1):2234,2017);和
-结肠炎和炎症性肠病,包括溃疡性结肠炎和克罗恩病(Crohn’sdisease)(Braddock等人,Nat Rev Drug 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,DigDis 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的基因切除避免HSD(高糖饮食)、HFD(高脂饮食)和HSFD诱发的肥胖症(Pavillard等人,Oncotarget,8(59):99740-99756,2017)。
已经发现NLRP3炎症小体响应于氧化应激、晒伤(Hasegawa等人,Biochemical andBiophysical Research Communications,477(3):329-335,2016)和UVB照射(Schroder等人,Science,327:296-300,2010)而被活化。
还显示NLRP3与以下相关:炎性痛觉过敏(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)和与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,Biol Reprod,100(5):1306-1318,2019)。
还提出炎症小体,特别是NLRP3作为通过多种病原体进行调节的标靶,所述病原体包括细菌性病原体,例如金黄色葡萄球菌(Staphylococcus aureus)(Cohen等人,CellReports,22(9):2431-2441,2018)、蜡状芽孢杆菌(bacillus cereus)(Mathur等人,NatMicrobiol,4:362-374,2019)、鼠伤寒沙门氏菌(salmonella typhimurium)(Diamond等人,Sci Rep,7(1):6861,2017)和A组链球菌(LaRock等人,Science Immunology,1(2):eaah3539,2016);病毒,例如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)、基孔肯雅病毒(chikungunya)、罗斯河病毒(Ross river virus)和α病毒(Chen等人,Nat Microbiol,2(10):1435-1445,2017);真菌病原体,例如白色念珠菌(Candida albicans)(Tucey等人,mSphere,1(3),pii:e00074-16,2016);和其它病原体,例如刚地弓形虫(T.gondii)(Gov等人,J Immunol,199(8):2855-2864,2017)、蠕虫(Alhallaf等人,Cell Reports,23(4):1085-1098,2018)、利什曼虫(Novais等人,PLoS Pathogens,13(2):e1006196,2017)和疟原虫(Strangward等人,PNAS,115(28):7404-7409,2018)。已显示NLRP3是有效控制病毒、细菌、真菌和蠕虫病原体感染所需的(Strowig等人,Nature,481:278-286,2012)。
NLRP3也与许多癌症的发病机理相关(Menu等人,Clinical and ExperimentalImmunology,166:1-15,2011;和Masters,Clin Immunol,147(3):223-228,2013)。举例来说,几个先前的研究已经提出IL-1β在癌症侵袭性、生长和转移中的作用,并且在随机化、双盲、安慰剂对照试验中用卡那单抗(canakinumab)抑制IL-1β显示降低肺癌发生率和总癌死亡率(Ridker等人,Lancet,S0140-6736(17)32247-X,2017)。NLRP3炎症小体或IL-1β的抑制还显示在体外抑制肺癌细胞的增殖和迁移(Wang等人,Oncol Rep,35(4):2053-64,2016)。已经提出NLRP3炎症小体在骨髓增生异常综合征中的作用(Basiorka等人,Blood,128(25):2960-2975,2016)以及在多种其它癌症的癌发生中的作用,包括胶质瘤(Li等人,Am JCancer Res,5(1):442-449,2015)、结肠癌(Allen等人,J Exp Med,207(5):1045-56,2010)、黑色素瘤(Dunn等人,Cancer Lett,314(1):24-33,2012)、乳腺癌(Guo等人,Scientific Reports,6:36107,2016)、炎症诱发的肿瘤(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)和头颈鳞状细胞癌(Huang等人,J Exp Clin CancerRes,36(1):116,2017)。还显示NLRP3炎症小体的活化介导肿瘤细胞对5-氟尿嘧啶(5-fluorouracil)的化学抗性(Feng等人,J Exp Clin Cancer Res,36(1):81,2017),并且NLRP3炎症小体在周围神经中的活化促进了化学疗法诱发的神经性疼痛(Jia等人,MolPain,13:1-11,2017)。
因此,可能对NLRP3抑制有响应并且可以根据本发明的第五、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,包括因炎症性病症而发生的炎症(例如自身炎症性疾病)、因非炎症性病症的症状而发生的炎症、因感染而发生的炎症或继发于外伤、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、再生障碍性贫血、自身免疫性肾上腺炎、自体免疫性肝炎、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、克罗恩病、1型糖尿病(T1D)、古德帕斯彻氏综合征(Goodpa sture's syndrome)、格雷夫斯病(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)(包括原发性进展型多发性硬化(PPMS)、继发性进展型多发性硬化(SPMS)和复发-缓解型多发性硬化(RRMS))、重症肌无力、眼球阵挛-肌阵挛综合征(OMS)、视神经炎、奥德甲状腺炎(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)、牛皮癣性关节炎、幼年特发性关节炎或斯蒂尔病(Still's disease)、难治性痛风性关节炎、莱特尔氏综合征(Reiter's syndrome)、舍格伦综合征( syndrome)、系统性硬化(一种全身结缔组织病症)、高安氏动脉炎(Takayasu's arteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener's granulomatosis)、全身脱毛、白塞病、恰加斯氏病(Chagas'disease)、家族性自主神经异常、子宫内膜异位、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、硬皮病、溃疡性结肠炎、施尼茨勒综合征、巨噬细胞活化综合征、布劳综合征(Blau syndrome)、白斑病或外阴疼痛;
(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、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、食道癌、尤因氏家族肿瘤(Ewing family of tumour)、眼癌、胆囊癌、胃肠道类癌肿瘤、胃肠道间质瘤(GIST)、妊娠滋养细胞疾病、胶质瘤、霍奇金淋巴瘤(Hodgkin lymphoma)、卡波西肉瘤(Kaposi sarcoma)、肾癌、喉和下咽癌、肝癌、肺类癌瘤肿瘤、淋巴瘤(包括皮肤T细胞淋巴瘤)、恶性间皮瘤、黑色素瘤皮肤癌、默克尔细胞皮肤癌(Merkel cell skin cancer)、多发性骨髓瘤、鼻腔和鼻旁窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、口腔和口咽癌、骨肉瘤、卵巢癌、阴茎癌、垂体肿瘤、前列腺癌、成视网膜细胞瘤、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、睾丸癌、胸腺癌、甲状腺癌(包括未分化甲状腺癌)、子宫肉瘤、阴道癌、外阴癌、瓦尔登斯特伦巨球蛋白血症(Waldenstrommacroglobulinemia)和威尔姆斯肿瘤(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)、甲病毒属(例如基孔肯雅病毒和罗斯河病毒)、黄病毒(例如登革热病毒(Dengue virus)和寨卡病毒(Zika virus))、疱疹病毒(例如艾伯斯坦巴尔病毒、巨细胞病毒、水痘-带状疱疹病毒和KSHV)、痘病毒(例如牛痘病毒(改良安卡拉牛痘病毒(Modified vaccinia virus Ankara)和粘液瘤病毒)、腺病毒(例如腺病毒5)或乳头瘤病毒)、细菌感染(例如来自金黄色葡萄球菌、幽门螺旋杆菌(Helicobacter pylori)、炭疽芽孢杆菌(Bacillus anthracis)、百日咳鲍特菌(Bordatella pertussis)、类鼻疽伯克霍尔德菌属(Burkholderia pseudomallei)、白喉棒状杆菌(Corynebacterium diptheriae)、破伤风杆菌(Clostridium tetani)、肉毒梭菌(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氏菌(Listeria monocytogenes)、流感嗜血杆菌(Hemophilus influenzae)、多杀性巴氏杆菌(Pasteurella multicida)、痢疾杆菌(Shigella dysenteriae)、结核分枝杆菌(Mycobacterium tuberculosis)、麻风分枝杆菌(Mycobacterium leprae)、肺炎支原体(Mycoplasma pneumoniae)、人型支原体(Mycoplasma hominis)、脑膜炎奈瑟氏菌(Neisseria meningitidis)、淋病奈瑟氏菌(Neisseria gonorrhoeae)、立氏立克次体(Rickettsia rickettsii)、嗜肺军团菌(Legionella pneumophila)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、绿脓杆菌(Pseudomonas aeruginosa)、痤疮丙酸杆菌(Propionibacterium acnes)、梅毒螺旋体(Treponema pallidum)、沙眼衣原体(Chlamydia trachomatis)、霍乱弧菌(Vibriocholerae)、鼠伤寒沙门氏菌、伤寒沙门氏菌(Salmonella typhi)、伯氏疏螺旋体(Borreliaburgdorferi)或鼠疫耶尔森菌(Yersinia pestis))、真菌感染(例如来自念珠菌属(Candida)或曲霉属(Aspergillus species)物种)、原生动物感染(例如来自疟原虫、巴贝虫属(Babesia)、贾第鞭毛虫属(Giardia)、内阿米巴属(Entamoeba)、利什曼虫或锥体虫)、蠕虫感染(例如来自血吸虫属(schistosoma)、蛔虫、绦虫或吸虫)和朊病毒感染;
(v)中枢神经系统疾病,例如帕金森氏病、阿尔茨海默病、痴呆、运动神经元病、亨廷顿氏病、脑型疟、由肺炎球菌性脑膜炎引起的脑损伤、颅内动脉瘤、脑内出血、败血症相关脑病、术后认知功能障碍、早期脑损伤、创伤性脑损伤和肌萎缩侧索硬化;
(vi)代谢疾病,例如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,例如高血压、局部缺血、再灌注损伤(包括MI后缺血再灌注损伤)、中风(包括缺血性中风)、短暂性缺血性发作、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(例如过敏性哮喘、嗜酸细胞性哮喘和类固醇抵抗型哮喘)、石棉沉着病、硅肺、纳米粒子诱发的炎症、囊肿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),包括晚期纤维化F3和F4期、酒精性脂肪肝病(AFLD)、酒精性脂肪性肝炎(ASH)、肝缺血再灌注损伤、暴发型肝炎、肝纤维化和肝功能衰竭;
(x)肾病,包括慢性肾病、草酸盐肾病、肾钙质沉着、肾小球肾炎、糖尿病肾病、肾纤维化(包括慢性晶体肾病)和肾性高血压;
(xi)眼病,包括眼睛上皮眼病、年龄相关的黄斑变性(AMD)(干性和湿性)、葡萄膜炎、角膜感染、糖尿病性视网膜病、视神经损害、干眼症和青光眼;
(xii)皮肤病,包括皮炎(例如接触性皮炎和特应性皮炎)、接触性超敏反应、晒伤、皮肤病变、化脓性汗腺炎(HS)、其它引起囊肿的皮肤病和聚合性痤疮;
(xiii)淋巴管疾患,例如淋巴管炎和卡斯特曼病(Castleman′s disease);
(xiv)心理病症,例如抑郁症和心理应激;
(xv)移植物抗宿主疾病;
(xvi)触诱发痛,包括机械触诱发痛;
(xvii)与糖尿病相关的疾患,包括糖尿病性脑病、糖尿病性视网膜病和糖尿病性低脂联素血症;以及
(xviii)已经确定个体携带NLRP3的生殖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)阿尔茨海默病;
(iv)肌萎缩侧索硬化;
(v)年龄相关黄斑变性(AMD);
(vi)未分化甲状腺癌;
(vii)冷吡啉相关周期性综合征(CAPS);
(viii)接触性皮炎;
(ix)囊肿性纤维化;
(x)充血性心力衰竭;
(xi)慢性肾病
(xii)克罗恩病;
(xiii)家族性寒冷性自身炎症性综合征(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)短暂性缺血性发作;
(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。可以根据本发明的第五、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相关或由以下引起而出现的炎性反应:
(i)皮肤疾患,例如接触性超敏反应、大疱性类天疱疮、晒伤、牛皮癣、特应性皮炎、接触性皮炎、过敏性接触性皮炎、脂溢性皮炎、扁平苔癣、硬皮病、天疱疮、大疱性表皮松解、荨麻疹、红斑或脱发;
(ii)关节疾患,例如骨关节炎、全身性幼年特发性关节炎、成人发作型斯蒂尔病、复发性多软骨炎、类风湿性关节炎、幼年型慢性关节炎、痛风或血清阴性脊椎关节病(例如强直性脊柱炎、牛皮癣性关节炎或莱特尔氏病);
(iii)肌肉疾患,例如多发性肌炎或重症肌无力;
(iv)胃肠道疾患,例如炎性肠病(包括克罗恩病和溃疡性结肠炎)、结肠炎、胃溃疡、乳糜泻、直肠炎、胰腺炎、嗜酸细胞性胃肠炎、肥大细胞增多症、抗磷脂综合征或可具有远离肠的作用(例如偏头痛、鼻炎或湿疹)的食物相关过敏;
(v)呼吸系统疾患,例如慢性阻塞性肺病(COPD)、哮喘(包括嗜酸细胞性哮喘、支气管性哮喘、过敏性哮喘、内源性哮喘、外因性或尘埃性哮喘和尤其慢性或顽固性哮喘,例如迟发性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、干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎(rhinitis pumlenta)、干性鼻炎、药物性鼻炎、膜性鼻炎、季节性鼻炎(例如枯草热)和血管舒缩性鼻炎)、鼻窦炎、特发性肺纤维化(IPF)、结节病、农民肺(farmer’s lung)、硅肺、石棉沉着病、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,例如动脉粥样硬化、白塞病、血管炎或韦格纳肉芽肿病;
(vii)自身免疫性疾患,例如系统性红斑狼疮、舍格伦综合征、系统性硬化、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夫斯病;
(viii)眼睛疾患,例如葡萄膜炎、过敏性结膜炎或春季结膜炎;
(ix)神经疾患,例如多发性硬化或脑脊髓炎;
(x)感染或感染相关疾患,例如获得性免疫缺陷综合征(AIDS)、急性或慢性细菌感染、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、乙型或丙型或其它病毒性肝炎)、腹膜炎、肺炎、会厌炎、疟疾、登革热出血热、利什曼病、链状球菌性肌炎、结核分枝杆菌、胞内鸟分枝杆菌、卡氏肺囊虫病(pneumocystis cariniipneumonia)、睾丸炎/附睾炎、军团菌属、莱姆病(Lyme disease)、甲型流感、艾司坦-巴尔病毒感染、病毒性脑炎/无菌性脑膜炎或骨盆炎症性疾病;
(xi)肾脏疾患,例如系膜增生性肾小球肾炎、肾病综合征、肾炎、肾小球性肾炎、急性肾功能衰竭、尿毒症、肾脏综合征、包括慢性晶体肾病的肾纤维化或肾性高血压;
(xii)淋巴管疾患,例如卡斯特曼病;
(xiii)免疫系统或涉及免疫系统的疾患,例如高IgE综合征、瘤型麻风、家族性噬血细胞性淋巴组织细胞增生症或移植物抗宿主疾病;
(xiv)肝脏疾患,例如慢性活动型肝炎、非酒精性脂肪肝病(NASH)、酒精诱发的肝炎、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、暴发型肝炎、肝纤维化或肝功能衰竭;
(xv)癌症,包括以上列出的那些癌症;
(xvi)烧伤、伤口、外伤、出血或中风;
(xvii)辐射暴露;
(xviii)肥胖症;和/或
(xix)疼痛,例如炎性痛觉过敏。
在本发明的第五、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,例如冷吡啉相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷性自身炎症性综合征(FCAS)、家族性地中海热(FMF)、新生儿发作型多系统炎性疾病(NOMID)、肿瘤坏死因子(TNF)受体相关周期性综合征(TRAPS)、高免疫球蛋白血症D和周期性发热综合征(HIDS)、白细胞介素1受体拮抗体缺陷(DIRA)、马吉德综合征(Majeed syndrome)、化脓性关节炎、坏疽性脓皮病和痤疮综合征(PAPA)、成人发作型斯蒂尔病(AOSD)、A20单倍剂量不足(HA20)、儿科肉芽肿关节炎(PGA)、PLCG2相关抗体缺陷和免疫失调(PLAID)、PLCG2相关自身炎症性抗体缺陷和免疫失调(APLAID)或伴有B细胞免疫缺陷、周期性发热和发育延迟的铁粒幼红细胞性贫血(SIFD)。
因此,上文列出了可能对NLRP3抑制有响应并且可以根据本发明的第五、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炎症小体活性和NLRP3诱发的IL-1β和/或IL-18介导。因此,这类疾病、病症或疾患可能尤其对NLRP3抑制有响应并且尤其适合于根据本发明的第五、第六、第七、第八、第九或第十方面治疗或预防。这类疾病、病症或疾患的实例包括冷吡啉相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷性自身炎症性综合征(FCAS)、新生儿发作型多系统炎性疾病(NOMID)、家族性地中海热(FMF)、化脓性关节炎、坏疽性脓皮病和痤疮综合征(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)受体相关周期性综合征(TRAPS)、全身性幼年特发性关节炎、成人发作型斯蒂尔病(AOSD)、复发性多软骨炎、施尼茨勒综合征、斯维特综合征、白塞病、抗合成酶综合征、白细胞介素1受体拮抗体缺陷(DIRA)和A20单倍剂量不足(HA20)。
此外,以上提及的一些疾病、病症或疾患因NLRP3的尤其引起NLRP3活性增加的突变而出现。因此,这类疾病、病症或疾患可能尤其对NLRP3抑制有响应并且尤其适合于根据本发明的第五、第六、第七、第八、第九或第十方面治疗或预防。这类疾病、病症或疾患的实例包括冷吡啉相关周期性综合征(CAPS)、穆-韦二氏综合征(MWS)、家族性寒冷性自身炎症性综合征(FCAS)和新生儿发作型多系统炎性疾病(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的第一或第二方面的化合物、或本发明的第三方面的药学上可接受的盐、溶剂合物或前药、或本发明的第四方面的药物组合物来抑制NLRP3。
在本发明的第十一方面的一个实施方案中,所述方法包括与一种或多种其它活性剂组合使用本发明的第一或第二方面的化合物、或本发明的第三方面的药学上可接受的盐、溶剂合物或前药、或本发明的第四方面的药物组合物。
在本发明的第十一方面的一个实施方案中,所述方法离体或在体外执行,例如以分析NLRP3抑制对细胞的作用。
在本发明的第十一方面的另一个实施方案中,所述方法在体内执行。举例来说,所述方法可以包括以下步骤:施用有效量的第一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,从而抑制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它活性剂的步骤。典型地,施用至有需要的受试者。
可替代地,本发明的第十一方面的方法可以是一种在非人动物受试者中抑制NLRP3的方法,所述方法包括以下步骤:向所述非人动物受试者施用所述化合物、盐、溶剂合物、前药或药物组合物,并且任选地随后将所述非人动物受试者断残或处死。典型地,这类方法还包括分析一种或多种来自任选地断残或处死的非人动物受试者的组织或流体样品的步骤。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它活性剂的步骤。
本发明的第十二方面提供本发明的第一或第二方面的化合物,或本发明的第三方面的药学上可接受的盐、溶剂合物或前药,或本发明的第四方面的药物组合物,用于抑制NLRP3。典型地,所述使用包括向受试者施用所述化合物、盐、溶剂合物、前药或药物组合物。在一个实施方案中,化合物、盐、溶剂合物、前药或药物组合物与一种或多种其它活性剂共同施用。
本发明的第十三方面提供本发明的第一或第二方面的化合物、或本发明的第三方面的药学上有效的盐、溶剂合物或前药的用途,其用于制造用于抑制NLRP3用的药物。典型地,所述抑制包括向受试者施用所述化合物、盐、溶剂合物、前药或药物。在一个实施方案中,化合物、盐、溶剂合物、前药或药物与一种或多种其它活性剂共同施用。
在包括使用或共同施用一种或多种其它活性剂的本发明的第五至第十三方面中的任一方面的任何实施方案中,一种或多种其它活性剂可以包括例如一种、两种或三种不同的其它活性剂。
一种或多种其它活性剂可以在彼此和/或本发明的第一或第二方面的化合物、本发明的第三方面的药学上可接受的盐、溶剂合物或前药、或本发明的第四方面的药物组合物之前、同时、相继或之后使用或施用。在一种或多种其它活性剂与本发明的第一或第二方面的化合物或者本发明的第三方面的药学上可接受的盐、溶剂合物或前药同时施用的情况下,可以施用本发明的第四方面的药物组合物,其中所述药物组合物另外包含一种或多种其它活性剂。
在包括使用或共同施用一种或多种其它活性剂的本发明的第五至第十三方面中的任一方面的一个实施方案中,一种或多种其它活性剂选自:
(i)化学治疗剂;
(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)抗肠虫剂;和/或
(xvi)其它活性剂。
应了解,这些根据活性剂大类界定的通用实施方案不互斥。关于此,可以根据以上通用实施方案中的不只一个,将任何具体的活性剂分类。一个非限制性实例为乌瑞鲁单抗(urelumab),其为作为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阿比特龙乙酸盐(abirateroneacetate)、六甲蜜胺(altretamine)、安吖啶(amsacrine)、脱水长春碱(anhydrovinblastine)、奥利司他汀(auristatin)、咪唑硫嘌呤(azathioprine)、阿霉素(adriamycin)、贝沙罗汀(bexarotene)、比卡米特(bicalutamide)、BMS 184476、博莱霉素(bleomycin)、N,N-二甲基-L-缬氨酰-L-缬氨酰-N-甲基-L-缬氨酰-L-脯氨酰-L-脯胺酸-叔丁酰胺、顺铂(cisplatin)、卡铂(carboplatin)、卡铂环磷酰胺(carboplatincyclophosphamide)、苯丁酸氮芥(chlorambucil)、恶病质素(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)、多烯紫杉醇(doxetaxel)、多柔比星(doxorubicin)、达卡巴嗪(dacarbazine,DTIC)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地西他滨(decitabine)、多拉司他汀(dolastatin)、依托泊苷(etoposide)、依托泊苷磷酸盐(etoposide phosphate)、恩杂鲁胺(enzalutamide,MDV3100)、5-氟尿嘧啶(5-fluorouracil)、氟达拉滨(fludarabine)、氟他米特(flutamide)、吉西他滨(gemcitabine)、羟基脲(hydroxyurea)和羟脲紫杉烷(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)、洛他赛(larotaxel,RPR109881)、氮芥(mechlorethamine)、巯基嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、丝裂霉素C(mitomycin C)、米托蒽醌(mitoxantrone)、美法仑(melphalan)、米伏布林(mivobulin)、3',4'-双脱氢-4'-脱氧-8'-异-长春花碱、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)、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(procarbazine)、根霉素(rhizoxin)、sertenef、链脲霉素(streptozocin)、雌莫司汀磷酸盐(stramustine phosphate)、维甲酸(tretinoin)、他索纳明(tasonermin)、紫杉醇(taxol)、拓扑替康(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)、长春花碱(vinblastine)、长春瑞滨(vinorelbine)、长春地辛(vindesine)、长春地辛硫酸盐和/或长春氟宁(vinflunine)。
可替代地或另外,一种或多种化学治疗剂可以选自CD59补体片段、纤连蛋白片段、gro-β(CXCL2)、肝素酶、肝素多聚己糖片段、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)、白细胞介素-12、kringle 5(血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子抑制剂、血小板因子-4(PF4)、催乳激素16kD片段、多育曲菌素相关蛋白(proliferin-related protein,PRP)、多种类视色素、四氢皮质醇-S、凝血栓蛋白-1(TSP-1)、转化生长因子-β(TGF-β)、血管抑制素、血管抑制因子(钙网蛋白片段)和/或细胞因子(包括白细胞介素,例如白细胞介素-2(IL-2)或IL-10)。
在一些实施方案中,一种或多种抗体可以包括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)、阿仑单抗(alemtuzumab)、阿特利珠单抗(atlizumab)、巴利昔单抗(basiliximab)、贝利单抗(belimumab)、贝伐单抗(bevacizumab)、维布妥昔单抗(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)、达利珠单抗(daclizumab)、地诺单抗(denosumab)、依库珠单抗(eculizumab)、依法珠单抗(efalizumab)、吉妥珠单抗(gemtuzumab)、戈利木单抗(golimumab)、替伊莫单抗(ibritumomab tiuxetan)、英夫利昔单抗(infliximab)、伊匹单抗(ipilimumab)、莫罗莫那-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以包括能够在包括例如癌细胞的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、氮芥、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,烷基化剂可以通过与生物重要分子中的氨基、羧基、巯基和/或磷酸基形成共价键而削弱细胞功能来起作用。在一些实施方案中,烷基化剂可以通过修饰细胞的DNA来起作用。
在一些实施方案中,一种或多种抗代谢物可以包括能够影响或防止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咪唑硫嘌呤和/或巯基嘌呤。
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、血管抑制蛋白、血管抑素(血纤维蛋白溶酶原片段)、基底膜胶原蛋白源性抗血管生成因子(肿瘤抑素、血管能抑制素或抑制蛋白)、抗血管生成抗凝血酶III和/或软骨源性抑制因子(CDI)。
在一些实施方案中,一种或多种植物碱和/或萜类化合物可以阻止微管功能。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、足叶草毒素和/或紫杉烷。在一些实施方案中,一种或多种长春花生物碱可以源自于长春花(Madagascarperiwinkle)、常春花(Catharanthus roseus)(原来称为日日春),并且可以选自长春新碱、长春花碱、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他克唑(taxol)、紫杉醇、多西他赛和/或沃塔紫杉醇(ortataxel)。在一些实施方案中,一种或多种足叶草毒素选自依托泊苷和/或替尼泊苷。
在一些实施方案中,一种或多种拓扑异构酶抑制剂选自I型拓扑异构酶抑制剂和/或II型拓扑异构酶抑制剂,并且可能通过干扰DNA超螺旋而干扰DNA的转录和/或复制。在一些实施方案中,一种或多种I型拓扑异构酶抑制剂可以包括喜树碱,其可以选自依沙替康(exatecan)、伊立替康、勒托替康(lurtotecan)、拓扑替康、BNP 1350、CKD 602、DB 67(AR67)和/或ST 1481。在一些实施方案中,一种或多种II型拓扑异构酶抑制剂可以包括表鬼臼毒素,其可以选自安吖啶、鬼臼乙叉苷(etoposid)、依托泊苷磷酸盐和/或替尼泊苷。
在一些实施方案中,一种或多种mTOR(雷帕霉素的靶蛋白,亦称雷帕霉素的机制性标靶)抑制剂选自雷帕霉素、依维莫司(everolimus)、替西罗莫司(temsirolimus)和/或地磷莫司(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(alpha-viniferin)、白蔹素A(ampelopsin A)、白蔹素E(ampelopsin E)、diptoindonesin C、diptoindonesin F、ε-威夫素(epsilon-vinferin)、弯曲素A(flexuosol A)、精奈素(gnetin H)、海丝藜醇D(hemsleyanol D)、霍毕酚(hopeaphenol)、反式-diptoindonesinB、白皮杉醇葡萄糖苷(astringin)、云杉新甙(piceid)和/或diptoindonesin A。
在一些实施方案中,一种或多种STING(干扰素基因刺激蛋白,亦称跨膜蛋白(TMEM)173)激动剂可以包含环状二核苷酸,例如cAMP、cGMP和cGAMP,和/或经修饰的环状二核苷酸,所述经修饰的环状二核苷酸可以包括以下修饰特征中的一种或多种: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以包括免疫检查点抑制剂。免疫检查点抑制剂可以靶向包括例如以下的免疫检查点受体或受体组合: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、磷脂酰丝氨酸、淋巴细胞活化基因3蛋白(LAG3)、MHC I类、MHC II类、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(包括BTNL2)、Siglec家族成员、TIGIT、PVR、杀伤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、伐立鲁单抗(varlilumab)、CP-870893、派姆单抗(PD1)、纳武单抗(PD1)、阿特珠单抗(原来为MPDL3280A)(PD-L1)、MEDI4736(PD-L1)、阿维鲁单抗(PD-L1)、PDR001(PD1)、BMS-986016、MGA271、利瑞鲁单抗、IPH2201、艾马妥组单抗(emactuzumab)、INCB024360、格鲁索替(galunisertib)、乌洛鲁单抗(ulocuplumab)、BKT140、巴维昔单抗(bavituximab)、CC-90002、贝伐单抗和/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)、卡那霉素(kanamycin)、新霉素(neomycin)、奈替米星(netilmicin)、托普霉素(tobramycin)、巴龙霉素(paromomycin)、链霉素(streptomycin)、壮观霉素(spectinomycin)、格尔德霉素(geldanamycin)、除莠霉素(herbimycin)、利福昔明(rifaximin)、氯拉卡比(loracarbef)、厄他培南(ertapenem)、多尼培南(doripenem)、亚胺培南(imipenem)、西拉司丁(cilastatin)、美罗培南(meropenem)、头孢羟氨苄(cefadroxil)、头孢若林(cefazolin)、头孢娄新(cefalotin)、头孢噻啶(cefalothin)、头孢氨苄(cefalexin)、头孢克洛(cefaclor)、头孢孟多(cefamandole)、头孢噻吩(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(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)、克林霉素(clindamycin)、林肯霉素(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)、三乙酰夹竹桃霉素(troleandomycin)、泰利霉素(telithromycin)、螺旋霉素(spiramycin)、氨曲南(aztreonam)、呋喃唑酮(furazolidone)、硝化呋喃托英(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)、安比西林(ampicillin)、阿洛西林(azlocillin)、羧苄青霉素(carbenicillin)、氯唑西林(cloxacillin)、双氯西林(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)、青霉素G(penicillin G)、青霉素V(penicillin V)、哌拉西林(piperacillin)、替莫西林(temocillin)、替卡西林(ticarcillin)、卡拉维酸钾盐(calvulanate)、安比西林(ampicillin)、舒巴坦匹酯(subbactam)、他唑巴坦(tazobactam)、替卡西林(ticarcillin)、克拉维酸盐(clavulanate)、杆菌肽(bacitracin)、粘菌素(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)、司氟沙星(sparfloxacin)、替马沙星(temafloxacin)、磺胺米隆(mafenide)、磺胺醋酰(sulfacetamide)、磺胺嘧啶(sulfadiazine)、磺胺嘧啶银(silver sulfadiazine)、磺胺二甲氧啶(sulfadimethoxine)、磺胺甲基异噁唑sulfamethoxazole)、磺胺二甲异噁唑(sulfanamide)、柳氮磺胺吡啶(sulfasalazine)、磺胺异噁唑唑(sulfisoxazole)、甲氧苄啶-磺胺甲基异噁唑(trimethoprim-sulfamethoxazole)、磺酰胺柯衣定(sulfonamideochrysoidine)、地美环素(demeclocycline)、米诺环素(minocycline)、土霉素(oytetracycline)、四环素(tetracycline)、氯苯吩嗪(clofazimine)、达普松(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)、利福布丁(rifabutin)、利福喷丁(rifapentine)、链霉素(streptomycin)、胂凡纳明(arsphenamine)、氯霉素(chloramphenicol)、磷霉素(fosfomycin)、梭链孢酸(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)、甲砜氯霉素(thiamphenicol)、替加环素(tigecycyline)、替硝唑(tinidazole)、甲氧苄啶(trimethoprim)和/或泰斯巴汀(teixobactin)。
在一些实施方案中,一种或多种抗生素可以包括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、蒽环霉素、沙利度胺(thalidomide)、二氯乙酸、烟酸、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、粘菌素(多粘菌素E)和/或多粘菌素B。在一些实施方案中,一种或多种蒽二酮选自米托蒽醌(mitoxantrone)和/或匹杉琼(pixantrone)。在一些实施方案中,一种或多种蒽环霉素选自博莱霉素、多柔比星(阿霉素)、柔红霉素(道诺霉素(daunomycin))、表柔比星(epirubicin)、伊达比星、丝裂霉素(mitomycin)、光神霉素(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)、卢立康唑(luliconazole)、霉康唑(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)、依普康唑(epoziconazole)、氟康唑(fluconazole)、艾沙康唑(isavuconazole)、伊曲康唑(itraconazole)、泊沙康唑(posaconazole)、丙环唑(propiconazole)、拉维康唑(ravusconazole)、特康唑(terconazole)、伏立康唑(voriconazole)、阿巴芬净(abafungin)、阿莫洛芬(amorolfin)、布替萘芬(butenafine)、奈替芬(naftifine)、特比奈芬(terbinafine)、阿尼芬净(anidulafungin)、卡泊芬净(caspofungin)、米卡芬净(micafungin)、苯甲酸、环吡司(ciclopirox)、氟胞嘧啶(flucytosine)、5-氟胞嘧啶(5-fluorocytosine)、灰黄霉素(griseofulvin)、氯酚醚(haloprogin)、托萘酯(tolnaflate)、十一碳烯酸和/或秘鲁香脂(balsam of Peru)。
在一些实施方案中,一种或多种抗肠虫剂选自苯并咪唑(包括阿苯达唑(albendazole)、甲苯咪唑(mebendazole)、噻苯咪唑(thiabendazole)、芬苯达唑(fenbendazole)、三氯苯咪唑(triclabendazole)和氟苯达唑(flubendazole))、阿维菌素(abamectin)、乙胺嗪(diethylcarbamazine)、伊维菌素(ivermectin)、苏拉明(suramin)、双羟萘酸喹嘧啶(pyrantel pamoate)、左旋四咪唑(levamisole)、水杨酰替苯胺(salicylanilide)(包括贝螺杀(niclosamide)和羟氯扎胺(oxyclozanide))和/或硝唑尼特(nitazoxanide)。
在一些实施方案中,其它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)和其衍生物)、维生素和维生素衍生物(包括视黄酸类和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(cyclosporin)、FK 506和糖皮质素)、促黄体生成激素释放激素激动剂(例如亮丙瑞林(leuprolidine)、戈舍瑞林(goserelin)、曲普瑞林(triptorelin)、组氨瑞林(histrelin)、比卡鲁胺(bicalutamide)、氟他米特(flutamide)和/或尼鲁米特(nilutamide))和/或激素(包括雌激素)。
除非另有说明,否则在本发明的第五至第十三方面中的任一方面中,受试者可以是任何人或其它动物。典型地,受试者为哺乳动物,更典型地是人或驯养哺乳动物,例如母牛、猪、羊羔、绵羊、山羊、马、猫、犬、兔、小鼠等。最典型地,受试者为人。
本发明中采用的任何药物都可以通过口腔、肠胃外(包括静脉内、皮下、肌肉内、皮内、气管内、腹膜内、关节内、颅内和硬膜外)、气道(气溶胶)、直肠、阴道、眼睛或表面(包括经皮、经颊、粘膜、舌下和眼睛表面)施用来施用。
典型地,所选施用模式为最适合于有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它活性剂的情况下,施用模式可以与本发明的化合物、盐、溶剂合物、前药或药物组合物的施用模式相同或不同。
对于口服施用来说,本发明的化合物、盐、溶剂合物或前药一般以片剂、胶囊、硬或软明胶胶囊、囊片、糖锭或含片形式、呈粉剂或颗粒或呈水溶液、悬浮液或分散液提供。
口服片剂可以包括与药学上可接受的赋形剂混合的活性成分,所述赋形剂例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂。合适的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙以及乳糖。玉米淀粉和海藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶。润滑剂如果存在,那么可以是硬脂酸镁、硬脂酸或滑石。必要时,片剂可以用例如单硬脂酸甘油酯或二硬脂酸甘油酯的材料包衣,以延迟在胃肠道中的吸收。片剂还可以是泡腾片和/或速溶片(dissolving tablet)。
口服胶囊包括硬明胶胶囊,其中活性成分与固体稀释剂混合;和软明胶胶囊,其中活性成分与水或油例如花生油、液体石蜡或橄榄油混合。
口服粉剂或颗粒可以提供于小袋或盆中。可以通过将水加入至粉剂、颗粒或片剂中来制备水溶液、悬浮液或分散液。
任何适合于口服施用的形式可以任选地包括甜味剂,例如糖、调味剂、着色剂和/或防腐剂。
用于直肠施用的制剂可以呈现为具有合适基质栓剂包括,所述合适的基质包括例如可可脂或水杨酸盐。
适合于阴道施用的制剂可以呈现为子宫托、棉塞、乳膏、凝胶剂、糊剂、泡沫或喷雾制剂,其除活性成分外还含有如所属领域中已知的适当的载体。
对于肠胃外使用,本发明的化合物、盐、溶剂合物或前药一般以无菌水溶液或悬浮液提供,被缓冲至适当pH和等渗性。合适的水性媒介物包括林格氏溶液(Ringer’ssolution)和等张氯化钠或葡萄糖。根据本发明的水性悬浮液可以包括悬浮剂,例如纤维素衍生物、海藻酸钠、聚乙烯吡咯烷酮和黄蓍胶,和润湿剂,例如卵磷脂。适用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。本发明的化合物也可以呈现为脂质体制剂。
对于眼部施用,本发明的化合物、盐、溶剂合物或前药一般以适合于表面施用的形式提供,例如呈滴眼剂。合适的形式可以包括眼用溶液、形成凝胶的溶液、用于复原的无菌粉剂、眼用悬浮液、眼用软膏、眼用乳液、眼用凝胶和眼用插入物。可替代地,本发明的化合物、盐、溶剂合物或前药可以适合于其它类型眼部施用的形式提供,例如呈眼内制剂(包括呈灌洗液,呈眼内、玻璃体内或近巩膜注射制剂,或呈玻璃体内植入物),呈包装或角膜防护罩,呈前房内、结膜下或眼球后注射制剂,或呈离子电渗制剂。
对于经皮和其它表面施用,本发明的化合物、盐、溶剂合物或前药一般以软膏、泥敷剂(泥罨剂)、糊剂、粉剂、敷料、乳膏、膏药或贴片形式提供。
合适的悬浮液和溶液可以用于吸入器中供气道(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有待治疗或预防的疾病、病症或疾患而变。一般说来,合适的剂量将在每天每公斤接受者体重0.01至500mg范围内。所需剂量可以适当时间间隔提供,例如每隔一天一次、一天一次、一天两次、一天三次或一天四次。所希望的剂量可以例如每个单位剂型含有1mg至50g活性成分的单位剂型施用。
为了避免引起怀疑,在可行的范围内,本发明的给定方面的任何实施方案可以与本发明的相同方面的任何其它实施方案组合存在。另外,在可行的范围内,应了解,本发明的任何方面的任何优选、典型或任选的实施方案也应被认为是本发明的任何其它方面的优选、典型或任选的实施方案。
实施例-化合物合成
除非另有说明,否则所有的溶剂、试剂和化合物都是购买的并且在没有进一步纯化下使用。
缩写
2-MeTHF 2-甲基四氢呋喃
Ac2O 乙酸酐
AcOH 乙酸
aq 水溶液
B2Pin2 双(频哪醇合)二硼,也称作4,4,4',4',5,5,5',5'-八甲基
-2,2'-联(1,3,2-二氧杂戊硼烷)
Boc 叔丁氧羰基
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,也称作二氯化乙烯
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺,也称作亨氏碱(Hünig′s base)
DMA 二甲基乙酰胺
DMAP 4-二甲基氨基吡啶,也称作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 1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺
eq或equiv 当量
(ES+) 电喷雾电离,正离子模式
Et 乙基
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]
吡啶鎓3-氧化物六氟磷酸盐
HPLC 高效液相色谱法
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,也称作甲烷磺酰基
MsCl 甲磺酰氯,也称作甲烷磺酰氯
MTBE 甲基叔丁基醚,也称作叔丁基甲醚
m/z 质荷比
NaOtBu 叔丁醇钠
NBS 1-溴吡咯烷-2,5-二酮,也称作N-溴代丁二酰亚胺
NCS 1-氯吡咯烷-2,5-二酮,也称作N-氯代丁二酰亚胺
NMP N-甲基吡咯烷
NMR 核磁共振(光谱学)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
PdCl2(dppf) [[1,1′-双(二苯基膦基)二茂铁]二氯钯(II),也称作Pd(dppf)Cl2
PE 石油醚
Ph 苯基
PMB 对甲氧苯甲基,也称作4-甲氧苯甲基
制备型HPLC 制备型高效液相色谱法
制备型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 丙基磷酸酐
TBME 叔丁基甲醚,也称作甲基叔丁基醚
TEA 三乙胺
TFA 2,2,2-三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
wt% 重量百分比或按重量计的百分比
Xphos 2-二环己基膦基-2′,4′,6′-三异丙基联苯
实验方法
核磁共振
NMR谱是在300、400或500MHz下记录。除非另外指示,否则光谱在298K下测量,并且相对于溶剂共振提及。化学位移以百万分率报告。光谱是使用以下机器中的一种记录:
-Bruker Avance III分光光度计,在400MHz下,装有BBO 5mm液体探针,
-Bruker 400MHz分光光度计,使用ICON-NMR,在TopSpin程序控制下,
-Bruker Avance III HD分光光度计,在500MHz下,装备Bruker5mm SmartProbeTM,
-Agilent VNMRS 300仪器,装有来自Oxford instruments的7.05Tesla磁体、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,装有来自Oxford instruments的7.05Tesla磁体、4核自身可变换探针和Mercury plus控制台。
LC-MS
LC-MS方法:使用SHIMADZU LCMS-2020、Agilent 1200LC/G1956A MSD和Agilent1200\G6110A、Agilent 1200LC和Agilent6110MSD。流动相:A:水中0.025%NH3·H2O(v/v);B:乙腈。柱:Kinetex EVO C18 2.1×30mm,5μm。
制备型反相HPLC通用方法
酸性制备型HPLC(水中x-y%MeCN):Waters X-Select CSH柱C18,5μm(19×50mm),流速28mL min-1,经6.5分钟,用含有0.1%v/v甲酸的H2O-MeCN梯度洗脱,使用254nm下UV检测。梯度信息:0.0-0.2分钟,x%MeCN;0.2-5.5分钟,从x%MeCN匀变至y%MeCN;5.5-5.6分钟,从y%MeCN匀变至95%MeCN;5.6-6.5分钟,保持在95%MeCN下。
酸性制备型HPLC(水中x-y%MeOH):Waters X-Select CSH柱C18,5μm(19×50mm),流速28mL min-1,经7.5分钟,用10mM甲酸水溶液-MeOH梯度洗脱,使用254nm下UV检测。梯度信息:0.0-1.5分钟,x%MeOH;1.5-6.8分钟,从x%MeOH匀变至y%MeOH;6.8-6.9分钟,从y%MeOH匀变至95%MeOH;6.9-7.5分钟,保持在95%MeOH下。
碱性制备型HPLC(水中x-y%MeCN):Waters X-Bridge Prep柱C18,5μm(19×50mm),流速28mL min-1,经6.5分钟,用10mM NH4HCO3-MeCN梯度洗脱,使用254nm下UV检测。梯度信息:0.0-0.2分钟,x%MeCN;0.2-5.5分钟,从x%MeCN匀变至y%MeCN;5.5-5.6分钟,从y%MeCN匀变至95%MeCN;5.6-6.5分钟,保持在95%MeCN下。
合成中间体
中间体L1:(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(甲基磺酰基)酰胺
将甲烷磺酰胺(1.7g,17.87mmol)和DMAP(4.37g,35.7mmol)于MeCN(25mL)中的溶液在室温下搅拌10分钟。接着加入碳酸二苯酯(4.21g,19.66mmol)并将反应在室温下搅拌5天。滤出沉淀,用MTBE洗涤并真空干燥,得到呈白色固体状的标题化合物(1.67g,38%)。
1H NMR(CDCl3)δ9.07(d,J=7.4Hz,2H),6.74(d,J=7.5Hz,2H),3.35(s,6H),3.20(s,3H)。
以下中间体根据中间体L1的通用程序制备:
中间体L7:4-(2-羟基丙-2-基)呋喃-2-磺酰胺
步骤A:呋喃-3-羧酸乙酯
在25℃下向呋喃-3-羧酸(50g,446.10mmol,1当量)于EtOH(500mL)中的混合物逐滴加入H2SO4(89.29g,892.20mmol,溶液中98%纯度,2当量)。然后将反应混合物加热至75℃并搅拌2.5小时。将混合物倾倒至冰水(200mL)中并用EtOAc(3×200mL)萃取。将有机相用20%NaHCO3水溶液(2×200mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到呈黄色油状物的标题化合物(50g,80%)。
1H NMR(400MHz,CDCl3)δ8.01(d,1H),7.43(t,1H),6.75(t,1H),4.31(q,2H)和1.35(s,3H)。
步骤B:4-(乙氧羰基)呋喃-2-磺酸
在N2下在-10℃下向呋喃-3-羧酸乙酯(45g,321.12mmol,1当量)于DCM(500mL)中的混合物逐滴加入氯磺酸(46.77g,401.39mmol,1.25当量)。在15分钟后,将反应混合物在20℃下搅拌24小时。然后将反应混合物过滤并且将滤饼真空干燥,得到呈白色固体状的标题化合物(55g,78%)。
1H NMR(400MHz,D2O)δ8.19(s,1H),7.10(s,1H),4.27(q,2H)和1.27(t,3H)。
步骤C:5-(氯磺酰基)呋喃-3-羧酸乙酯
在N2下在-10℃下向4-(乙氧羰基)呋喃-2-磺酸(55g,249.77mmol,1当量)于DCM(350mL)中的混合物逐滴加入吡啶(20.74g,262.26mmol,1.05当量)。在15分钟后,加入PCl5(54.61g,262.26mmol,1.05当量)并将所得混合物再搅拌15分钟。然后使反应混合物升温至20℃并搅拌12小时。将混合物用水(200mL)淬灭并用DCM(2×200mL)萃取。然后将合并的有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到呈黄色油状物的标题化合物(35g,59%),其未经进一步纯化直接用于下一步中。
步骤D:5-氨磺酰基呋喃-3-羧酸乙酯
在0℃下使NH3(15psi)鼓泡至5-(氯磺酰基)呋喃-3-羧酸乙酯(35g,146.66mmol,1当量)于DCM(300mL)中的溶液中,历时15分钟。然后将反应混合物在20℃下搅拌45分钟。将混合物过滤并真空浓缩滤液。将残余物通过用DCM(200mL)湿磨纯化。将混合物过滤并且将滤饼真空干燥,得到呈白色固体状的标题化合物(24g,75%)。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.93(s,2H),7.12(s,1H),4.27(q,2H)和1.28(t,3H)。
步骤E:4-(2-羟基丙-2-基)呋喃-2-磺酰胺
在-10℃下在N2下经30分钟的时间向5-氨磺酰基呋喃-3-羧酸乙酯(24g,109.48mmol,1当量)于THF(500mL)中的混合物逐滴加入MeMgBr(3M,164.22mL,4.5当量)。将混合物在0℃下搅拌30分钟,然后升温至20℃并搅拌12小时。将混合物缓慢倾倒至冰水(300mL)中并用EtOAc(2×300mL)萃取。将有机相用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过用正己烷:EtOAc(v:v 20:1,300mL)的混合物湿磨纯化。将混合物过滤并且将滤饼真空干燥,得到呈白色固体状的标题化合物(22g,97%产率,LCMS上99.3%纯度)。
1H NMR(400MHz,DMSO-d6)δ7.68(s,1H),7.65(br s,2H),6.94(s,1H),和1.38(s,6H)。
中间体L8:1-环丙基-1H-吡唑-3-磺酰胺
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,1.1当量)于DCE(500mL)中的溶液中加入3-硝基-1H-吡唑(44g,389.12mmol,1当量)、2,2-联吡啶(60.77g,389.12mmol,1当量)和Na2CO3(64.59g,609.44mmol,1.57当量)。将混合物在25℃下搅拌30分钟。然后加入Cu(OAc)2(70.68g,389.12mmol,1当量),并将反应混合物加热至70℃并搅拌15.5小时。将反应混合物减压浓缩。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)。使不纯的产物溶于吡咯烷(10mL)中,并将所得混合物在70℃下搅拌2小时。将反应混合物减压浓缩以去除吡咯烷。将残余物用H2O(33mL)稀释并用1M HCl水溶液将pH调至5-6。将混合物用EtOAc(3×50mL)萃取。将合并的有机层用盐水(2×33mL)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,1当量)于EtOH(400mL)中的溶液中加入NH4Cl(62.87g,1.18mol,5当量)于H2O(150mL)中的溶液。然后将反应混合物加热至60℃并分批加入铁粉(39.38g,705.24mmol,3当量)。将反应混合物在60℃下搅拌16小时。然后将反应混合物减压浓缩。将残余物用H2O(500mL)稀释,并将混合物用EtOAc(3×500mL)萃取。将合并的有机层用盐水(2×250mL)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,1当量)于MeCN(500mL)和H2O(50mL)中的溶液中加入浓HCl溶液(50mL,36wt%水溶液)。然后缓慢加入NaNO2(12.77g,185.13mmol,1.2当量)于H2O(50mL)中的溶液。将所得溶液在0℃下搅拌40分钟。加入AcOH(50mL)、CuCl2(10.37g,77.14mmol,0.5当量)和CuCl(763mg,7.71mmol,0.05当量)。然后在0℃下使SO2气体(15psi)鼓泡至所得混合物中,历时20分钟。将所得反应混合物在0℃下搅拌1小时。将反应混合物减压浓缩。将残余物用H2O(250mL)稀释并用EtOAc(3×250mL)萃取。将合并的有机层用盐水(2×150mL)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,1:0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)。
步骤D:1-环丙基-N,N-双(4-甲氧基苯甲基)-1H-吡唑-3-磺酰胺
向1-环丙基-1H-吡唑-3-磺酰氯(28g,135.49mmol,1当量)于THF(300mL)中的溶液中加入TEA(27.42g,270.99mmol,2当量)和双(4-甲氧基苯甲基)胺(34.87g,135.49mmol,1当量)。将反应混合物在25℃下搅拌1小时,用H2O(500mL)稀释并用EtOAc(3×500mL)萃取。将合并的有机层用盐水(2×500mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将残余物通过逆相快速色谱法(0.5%NH3.H2O-MeCN)纯化并将所收集的洗脱溶液减压浓缩以去除大部分MeCN。然后将混合物用EtOAc(3×1L)萃取。将合并的有机层用盐水(2×500mL)洗涤,经Na2SO4干燥,过滤并在减压下浓缩,得到标题化合物(30g,52%产率,HPLC上99.8%纯度)。
1H NMR(400MHz,CDCl3)δ7.49(d,1H),7.08-7.06(m,4H),6.79-6.77(m,4H),6.62(d,1H),4.32(s,4H),3.80(s,6H),3.68-3.64(m,1H),1.15-1.13(m,2H)和1.09-1.06(m,2H)。
LCMS:m/z 428.2(M+H)+(ES+)。
步骤E:1-环丙基-1H-吡唑-3-磺酰胺
向1-环丙基-N,N-双(4-甲氧基苯甲基)-1H-吡唑-3-磺酰胺(1g,2.34mmol,1当量)于DCM(10mL)中的混合物加入TFA(15.40g,135.06mmol,57.74当量)。将混合物在25℃下搅拌12小时。大部分溶剂蒸发,并使残余物再溶于MeOH(30mL)中。形成固体并将反应混合物过滤。将滤液真空浓缩,并将残余物用石油醚与EtOAc的混合物(30mL,20:1)湿磨,得到呈白色固体状的标题化合物(430mg,88%产率,LCMS上90%纯度)。
1H NMR(DMSO-d6)δ7.92(s,1H),7.38(br s,2H),6.55(s,1H),3.84-3.78(m,1H)和1.10-0.98(m,4H)。
中间体L9:1-甲基-3-[甲基(氨磺酰基)氨基]吡咯烷
向N,1-二甲基吡咯烷-3-胺(4g,35.03mmol,1当量)于1,2-二甲氧基乙烷(80mL)中的溶液中一次性加入硫酰胺(4.04g,42.04mmol,1.2当量)。将反应混合物加热至90℃并在N2下搅拌12小时。然后将反应混合物真空浓缩。将残余物通过柱色谱法(SiO2,EtOAc:EtOH,20:1至5:1)纯化,得到呈棕色油状物的标题化合物(3.5g,43%产率,LCMS上83%纯度)。
1H NMR(400MHz,DMSO-d6)δ6.65(s,2H),4.31-4.23(m,1H),2.62(s,3H),2.61-2.56(m,2H),2.41-2.36(m,1H),2.20(s,3H),2.18-2.12(m,1H),2.05-1.98(m,1H)和1.78-1.71(m,1H)。
LCMS:m/z 194.0(M+H)+(ES+)。
中间体L10:苯亚磺酰胺
在-78℃下向苯亚磺酸甲酯(500mg,3.20mmol,1当量)于THF(10mL)中的溶液中加入LiHMDS(1M,4.80mL,1.5当量)。将反应混合物在-78℃下搅拌2小时。然后加入NH4Cl(342mg,6.40mmol,2当量)于H2O(5mL)中的溶液,并将所得混合物在25℃下搅拌1小时。将反应混合物用水(20mL)淬灭,并用乙酸乙酯(3×20mL)萃取。将有机层经无水Na2SO4干燥,过滤并浓缩,得到呈白色固体状的标题化合物(400mg,89%)。
1H NMR(400MHz,CDCl3)δ7.78-7.74(m,2H),7.54-7.51(m,3H)和4.36(br s,2H)。
LCMS:m/z 141.9(M+H)+(ES+)。
中间体L11:甲烷亚磺酰胺
在-78℃下使氨气(15psi)鼓泡至THF(10mL)中,历时10分钟。在0℃下在氮气下将草酰氯(39.18mmol,3.4mL,2当量)加入至甲烷亚磺酸钠(2g,19.59mmol,1当量)于THF(20mL)中的溶液。将混合物在0℃下搅拌1小时。然后在0℃下将混合物滴入以上NH3/THF溶液中。将所得混合物在20℃下搅拌12小时。形成固体。反应混合物过滤,并真空浓缩滤液,得到呈黄色固体状的标题化合物(0.9g,粗)。
1H NMR(400MHz,CDCl3)δ4.30(br s,2H)和2.66(s,3H)。
中间体R1:5-溴-6-甲基-2,3-二氢-1H-茚-4-胺
步骤A:N-(6-溴-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺
将硝酸(150mL,2350mmol)缓慢加入至冷却至0℃的硫酸(150mL),同时保持温度低于20℃。将混合物搅拌10分钟并逐滴加入至搅拌的N-(6-溴-2,3-二氢-1H-茚-5-基)乙酰胺(58g,228mmol)于AcOH(300mL)和硫酸(150mL)中的混合物,保持温度低于30℃。将反应混合物在室温下搅拌4小时,然后倾倒至冰/水(4.5L总体积,2.5kg冰)上并在室温下静置18小时。将固体过滤,用水(2.5L)洗涤,并干燥,得到呈赭色粉末状的标题化合物(55g,80%)。
1H NMR(DMSO-d6)δ9.99(s,1H),7.85(s,1H),3.01-2.88(m,4H),2.07(p,J=7.5Hz,2H),2.00(s,3H)。
LCMS m/z 299.0/301.0(M+H)+(ES+)。
步骤B:N-(6-甲基-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺
将N-(6-溴-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺(30g,100mmol)、2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼杂环己烷(14.02mL,100mmol)和K2CO3(34.7g,251mmol)于二噁烷(500mL)和H2O(140mL)中的混合物用N2脱气15分钟。加入PdCl2(dppf)-CH2Cl2加合物(4.10g,5.01mmol)。将反应混合物在100℃下加热16小时,用盐水(300mL)稀释,并用EtOAc(2×800mL)萃取。将有机层干燥(MgSO4)并蒸发。将残余物用EtOAc/异己烷(1:1混合物,400mL)湿磨并将所得固体过滤,用己烷冲洗,并真空干燥,得到呈棕色固体状的标题化合物(15.33g,56%)。
1H NMR(DMSO-d6)δ9.65(s,1H),7.41(s,1H),2.98-2.87(m,4H),2.20(s,3H),2.07-2.03(m,2H),1.99(s,3H)。
LCMS m/z 235.2(M+H)+(ES+)。
步骤C:6-甲基-4-硝基-2,3-二氢-1H-茚-5-胺
使N-(6-甲基-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺(15.33g,65.4mmol)悬浮于EtOH(126mL)与浓HCl水溶液(126mL)的混合物中。将混合物加热至回流,过夜并真空浓缩。将残余物通过逐份加入2MNaOH水溶液(500mL)来碱化。将水层用DCM(5×200mL)萃取,干燥(MgSO4)并真空浓缩,得到呈棕色固体状的标题化合物(15.18g,84%)。
1H NMR(DMSO-d6)δ7.21(s,1H),6.61(s,2H),3.16(t,J=7.5Hz,2H),2.76(t,J=7.6Hz,2H),2.16(s,3H),2.00-1.94(m,2H)。
LCMS m/z 193.4(M+H)+(ES+)。
步骤D:5-溴-6-甲基-4-硝基-2,3-二氢-1H-茚
将6-甲基-4-硝基-2,3-二氢-1H-茚-5-胺(4.9g,20.39mmol)和亚硝酸异戊酯(3mL,22.33mmol)于MeCN(400mL)中的溶液加热至55℃,然后加入CuBr2(4.56g,20.39mmol)。将反应混合物加热至70℃并搅拌1小时。使反应混合物冷却至室温并加入1MHCl(200mL)。将反应混合物用DCM(3×200mL)萃取。将有机相真空浓缩并将粗产物通过快速色谱法(0-20%EtOAc/异己烷)纯化,得到呈浅黄色固体状的标题化合物(3.2g,60%)。
1H NMR(DMSO-d6)δ7.50(s,1H),2.94-2.86(m,4H),2.41(s,3H),2.09(p,J=7.6Hz,2H)。
LCMS m/z 279.2(M+Na)+(ES+)。
步骤E:5-溴-6-甲基-2,3-二氢-1H-茚-4-胺
将搅拌的5-溴-6-甲基-4-硝基-2,3-二氢-1H-茚(8.42g,32.9mmol)、饱和NH4Cl水溶液(50mL)和铁粉(7.34g,132mmol)于EtOH/水(3:2,80mL)中的混合物在80℃下搅拌2小时。在冷却至室温后,将反应用EtOAc(20mL)稀释,并经垫过滤。将滤液用水(10mL)稀释。分离各层并将有机层干燥(MgSO4)并真空浓缩。将残余物通过快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈粉色固体状的标题化合物(6.52g,75%)。
1H NMR(DMSO-d6)δ6.48(s,1H),4.94(br s,2H),2.73(t,J=7.5Hz,2H),2.68(t,J=7.4Hz,2H),2.24(s,3H),2.02-1.95(m,2H)。
LCMS m/z 226/228(M+H)+(ES+)。
中间体R2:2-溴-5-环丙基-4-氟苯胺
步骤A:3-环丙基-4-氟苯胺
将3-溴-4-氟苯胺(5g,26.3mmol)、环丙基硼酸(2.7g,31.4mmol)和K2CO3(11g,80mmol)于二噁烷(100mL)和水(20ml)中的混合物用N2脱气10分钟。加入PdCl2(dppf)(0.96g,1.312mmol)并将反应混合物在80℃下加热16小时。加入另外的环丙基硼酸(2.7g,26.3mmol)和另外的PdCl2(dppf)(0.96g,26.3mmol)并将反应混合物在80℃下加热48小时。然后使反应混合物冷却至室温并于EtOAc(100mL)与水(100mL)之间分配。将有机相用饱和盐水(2×100mL)洗涤,干燥(MgSO4)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈棕色固体状的标题化合物(1.87g,42%)。
1H NMR(DMSO-d6)δ6.79-6.71(m,1H),6.35-6.28(m,1H),6.12(dd,J=7.0,2.7Hz,1H),4.78(s,2H),1.96-1.88(m,1H),0.94-0.86(m,2H),0.61-0.55(m,2H)。
LCMS m/z 152.1(M+H)+(ES+)。
步骤B:2-溴-5-环丙基-4-氟苯胺
将MeCN(20mL)中3-环丙基-4-氟苯胺(1.37g,8.07mmol)和NBS(1.4g,7.87mmol)在室温下搅拌16小时。然后将反应混合物真空浓缩并将粗产物通过硅胶上快速色谱法(0-40%EtOAc/己烷)纯化,得到呈浅棕褐色固体状的标题化合物(1.04g,52%)。
1H NMR(DMSO-d6)δ7.18(d,J=9.7Hz,1H),6.40(d,J=7.4Hz,1H),5.00(s,2H),1.91(tt,J=8.5,5.2Hz,1H),0.97-0.90(m,2H),0.63-0.58(m,2H)。
LCMS m/z 229.9/231.9(M+H)+(ES+)。
中间体R3:2-溴-4-氟-5-(三氟甲氧基)苯胺
将MeCN(50mL)中4-氟-3-(三氟甲氧基)苯胺(1g,5.13mmol)和NBS(1g,5.62mmol)在室温下搅拌3小时。蒸发挥发物。将粗产物用DCM(50mL)稀释,用水(100mL)和饱和Na2S2O3水溶液(100mL)洗涤,干燥(MgSO4)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈棕色油状物的标题化合物(1.25g,88%)。
1H NMR(DMSO-d6)δ7.62(d,J=9.9Hz,1H),6.94-6.87(m,1H),5.53(s,2H)。
LCMS m/z 273/275(M+H)+(ES+)。
中间体R4:2-溴-5-乙基-4-氟苯胺
将MeCN(25mL)中3-乙基-4-氟苯胺(1.06g,7.62mmol)和NBS(1.4g,7.87mmol)在室温下搅拌3小时。蒸发挥发物。将粗产物用DCM(50mL)稀释,用水(100mL)和饱和Na2S2O3水溶液(100mL)洗涤,干燥(MgSO4)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-40%EtOAc/异己烷)纯化,然后通过硅胶上的另一个快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈棕色油状物的标题化合物(1.39g,75%)。
1H NMR(DMSO-d6)δ7.19(d,J=9.4Hz,1H),6.70(d,J=7.3Hz,1H),5.12(s,2H),2.47(q,J=7.4Hz,2H),1.12(t,J=7.5Hz,3H)。
LCMS m/z 218/220(M+H)+(ES+)。
中间体R5:4-溴-3-甲基-2-((1-甲基哌啶-4-基)氧基)吡啶
在室温下将1-甲基哌啶-4-醇(0.67g,5.79mmol)加入至KOtBu(0.89g,7.89mmol)于THF(5mL)中的混合物。将反应混合物搅拌1小时,然后在冰浴中冷却。加入4-溴-2-氟-3-甲基吡啶(1g,5.26mmol)于THF(5mL)中的溶液。使混合物升温至室温,搅拌2天,然后于EtOAc(20mL)与水(20mL)之间分配。将水相用EtOAc(20mL)萃取。将有机相合并,干燥(MgSO4)并真空浓缩。将粗产物通过快速色谱法(0-10%(0.7M氨/MeOH)/DCM)纯化,得到呈无水油状物的标题化合物(1.30g,86%)。
1H NMR(DMSO-d6)δ7.85(dd,J=5.4,0.8Hz,1H),7.19(d,J=5.4Hz,1H),5.02(tt,J=8.1,4.0Hz,1H),2.59-2.52(m,2H),2.26-2.20(m,5H),2.17(s,3H),1.97-1.86(m,2H),1.74-1.62(m,2H)。
LCMS m/z 285.1/287.1(M+H)+(ES+)。
以下中间体根据中间体R5的通用程序制备:
中间体R7:5-溴-6-环丙基-2,3-二氢-1H-茚-4-胺
步骤A:N-(6-环丙基-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺
使N2鼓泡通过搅拌的N-(6-溴-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺(中间体R1,步骤A)(1g,3.34mmol)、环丙基硼酸(0.35g,4.01mmol)和K2CO3(1.39g,10.03mmol)于二噁烷(35ml)和水(10ml)中的混合物,历时10分钟。加入PdCl2(dppf)(0.122g,0.167mmol)。然后将反应混合物在80℃下加热4小时,冷却至室温,并于EtOAc(100mL)与水(100mL)之间分配。将有机层干燥(MgSO4)并蒸发。将粗产物通过硅胶上快速色谱法(0-100%EtOAc/异己烷)纯化,得到呈黄色固体状的标题化合物(120mg,13%)。
1H NMR(DMSO-d6)δ9.76(s,1H),7.09(s,1H),2.98-2.88(m,4H),2.09-1.94(m,6H),1.00-0.89(m,2H),0.68-0.60(m,2H)。
LCMS m/z 261.2(M+H)+(ES+)。
步骤B:6-环丙基-4-硝基-2,3-二氢-1H-茚-5-胺
使N-(6-环丙基-4-硝基-2,3-二氢-1H-茚-5-基)乙酰胺(120mg,0.461mmol)悬浮于H2O(2mL)中。在反应混合物在冰浴中冷却时缓慢加入浓HCl(2mL)。然后将反应混合物在110℃下搅拌16小时并在冰上冷却至0℃。将反应混合物通过逐份加入50wt%NaOH水溶液(以10mL增量加入,约50mL)来碱化。将水性混合物用DCM(5×200mL)萃取。将合并的有机层干燥(MgSO4)并真空浓缩,得到呈棕色固体状的标题化合物(107mg,51%)。
1H NMR(DMSO-d6)δ7.14(s,1H),6.76(s,2H),3.16(t,J=7.3Hz,2H),2.76(t,J=7.6Hz,2H),1.97(p,J=7.4Hz,2H),1.76-1.65(m,1H),0.96-0.90(m,2H),0.59-0.47(m,2H)。
LCMS m/z 219.4M+H)+(ES+)。
步骤C:5-溴-6-环丙基-4-硝基-2,3-二氢-1H-茚
将6-环丙基-4-硝基-2,3-二氢-1H-茚-5-胺(106mg,0.487mmol)和亚硝酸异戊酯(72μL,0.536mmol)于MeCN(7mL)中的溶液加热至55℃。然后加入CuBr2(109mg,0.487mmol),并将反应混合物加热至70℃并搅拌1小时。然后使反应混合物冷却至室温。加入1M HCl(10mL)并将反应混合物用DCM(3×20mL)萃取。将合并的有机相真空浓缩,得到标题化合物,其作为粗物质用于下一步。
步骤D:5-溴-6-环丙基-2,3-二氢-1H-茚-4-胺
将搅拌的5-溴-6-环丙基-4-硝基-2,3-二氢-1H-茚(104mg,0.369mmol)、饱和氯化铵水溶液(0.5mL)和铁粉(82mg,1.474mmol)于EtOH:水(3:2,1mL)中的混合物在80℃下搅拌2小时。然后使反应混合物冷却至室温,用EtOAc(20mL)稀释并通过垫过滤。将滤液用水(10mL)稀释并收集有机层,干燥(MgSO4)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈粉色固体状的标题化合物(17mg,11%)。
LCMS m/z 252/254(M+H)+(ES+)。
中间体R8:6-甲基-5-(吡啶-4-基)-2,3-二氢-1H-茚-4-胺
使N2鼓泡通过搅拌的5-溴-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R1)(200mg,0.885mmol)、吡啶-4-基硼酸(120mg,0.973mmol)和K2CO3(367mg,2.65mmol)于二噁烷(30mL)和水(5mL)中的混合物,历时5分钟。加入PdCl2(dppf)(32.4mg,0.044mmol),并将反应混合物在80℃下加热20小时。然后使反应混合物冷却至室温,并于EtOAc(100mL)与水(50mL)之间分配。将有机层干燥(MgSO4),蒸发并将残余物通过硅胶上快速色谱法(0-40%EtOAc/异己烷)纯化,得到呈黄色油状物的标题化合物(40mg,20%)。
1H NMR(DMSO-d6)δ8.67-8.62(m,2H),7.21-7.17(m,2H),6.47(s,1H),4.14(s,2H),2.79(t,J=7.5Hz,2H),2.65(t,J=7.3Hz,2H),2.00(p,J=7.4Hz,2H),1.87(s,3H)。
LCMS m/z 225.1(M+H)+(ES+)。
以下中间体根据中间体R8的通用程序制备:
中间体R13:5-(2-环丙氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
步骤A:4-溴-2-环丙氧基吡啶
向环丙醇(1g,17.22mmol)和4-溴-2-氟吡啶(1.2ml,11.68mmol)于NMP(13mL)中的混合物逐份加入叔丁醇钾(1.9g,16.93mmol)。将所得混合物在氮气下在室温下搅拌30分钟。然后将反应混合物用EtOAc(50mL)稀释,用水(30mL)和盐水(30mL)洗涤,经无水硫酸钠干燥,过滤并蒸发,得到呈棕色油状物的标题化合物(2.27g,83%)。
1H NMR(DMSO-d6)δ8.12(d,J=5.4Hz,1H),7.28(dd,J=5.4,1.7Hz,1H),7.16(d,J=1.6Hz,1H),4.21(tt,J=6.2,3.0Hz,1H),0.80-0.74(m,2H),0.70-0.66(m,2H)。
LCMS m/z 214/216(M+H)+(ES+)。
步骤B:5-(2-环丙氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
向4-溴-2-环丙氧基吡啶(189mg,0.885mmol)于二噁烷(5mL)中的溶液中加入B2Pin2(247mg,0.973mmol),然后加入乙酸钾(347mg,3.54mmol)和PdCl2(dppf)-CH2Cl2加合物(36mg,0.044mmol)。将反应脱气(N2,5分钟),抽空并且用N2回填(×3)并且在90℃下搅拌2小时。然后使反应混合物冷却至室温。加入5-溴-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R1)(200mg,0.885mmol)于二噁烷(3mL)中的溶液,然后加入碳酸钾(367mg,2.65mmol)于水(1.5mL)中的溶液。将反应混合物在90℃下搅拌16小时,用盐水(10mL)稀释,并用DCM(2×20mL)萃取。将有机层干燥(MgSO4),过滤并蒸发。将粗产物通过快速色谱法(0-60%EtOAc/异己烷)纯化,得到呈黄色油状物的标题化合物(135mg,52%)。
1H NMR(DMSO-d6)δ8.26(d,J=5.1Hz,1H),6.81(dd,J=5.1,1.3Hz,1H),6.63(d,J=1.2Hz,1H),6.45(s,1H),4.22(tt,J=6.3,3.1Hz,1H),4.16(s,2H),2.78(t,J=7.5Hz,2H),2.64(t,J=7.3Hz,2H),2.02-1.95(m,2H),1.88(s,3H),0.81-0.68(m,4H)。
LCMS m/z 281.2(M+H)+(ES+)。
以下中间体根据中间体R13的通用程序制备:
中间体R25:5-(2-甲氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
步骤A:2-甲氧基-4-(6-甲基-4-硝基-2,3-二氢-1H-茚-5-基)吡啶
将5-溴-6-甲基-4-硝基-2,3-二氢-1H-茚(中间体R1,步骤D)(218mg,0.851mmol)、(2-甲氧基吡啶-4-基)硼酸(156mg,1.021mmol)于含二噁烷(2.5ml)和K2CO3(353mg,2.55mmol)的水(0.5mL)中的混合物用N2脱气15分钟。然后加入Pd(dppf)Cl2.DCM(35mg,0.043mmol)。将反应混合物加热至80℃,保持2小时,冷却至室温并于EtOAc(10mL)与水(5mL)之间分配。将有机层用水(10mL)和盐水(10mL)洗涤,干燥(MgSO4)并蒸发,得到标题化合物(186mg,63%),其未经纯化就用于下一步。
1H NMR(DMSO-d6)δ8.24(d,J=5.2Hz,1H),7.50(s,1H),6.88-6.81(m,1H),6.67(d,J=2.0Hz,1H),3.89(s,3H),3.03-2.92(m,4H),2.18-2.03(m,5H)。
LCMS m/z 285.0(M+H)+(ES+)。
步骤B:5-(2-甲氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
将2-甲氧基-4-(6-甲基-4-硝基-2,3-二氢-1H-茚-5-基)吡啶(186mg,0.536mmol)和5%Pd/C(类型87L,58.5%湿度)(55mg,10.72μmol)于EtOH(2mL)中的混合物在1巴(bar)下氢化6小时。然后反应混合物经过滤并蒸发,得到标题化合物(120mg,77%),其未经纯化就使用。
1H NMR(DMSO-d6)δ8.24(d,J=5.2Hz,1H),6.77(dd,J=5.2,1.5Hz,1H),6.58(s,1H),6.45(s,1H),4.16(s,2H),3.89(s,3H),2.78(t,J=7.5Hz,2H),2.64(t,J=7.4Hz,2H),1.99(p,J=7.4Hz,2H),1.88(s,3H)。
LCMS m/z 255.1(M+H)+(ES+)。
以下中间体根据中间体R25的通用程序制备:
中间体R27:4-(4-异硫氰基-6-甲基-2,3-二氢-1H-茚-5-基)-2-((1-甲基哌啶-4-基)氧基)吡啶
将含三光气(0.077g,0.260mmol)的THF(1mL)逐滴加入至冰冷的6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-胺(中间体R26)(0.129g,0.4mmol)和Et3N(0.112mL,0.800mmol)于THF(5mL)中的溶液,并在室温下搅拌3小时。将反应混合物过滤,用THF洗涤,真空浓缩并与甲苯(3×1mL)共沸干燥。粗产物未经进一步纯化就使用。
以下中间体根据中间体R27的通用程序制备:
中间体R29:5-(2-乙氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
步骤A:5-(2-氟吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
将4-溴-2-氟吡啶(1.170g,6.65mmol)、KOAc(2.60g,26.5mmol)、B2Pin2(1.685g,6.63mmol)和PdCl2(dppf)-CH2Cl2加合物(0.271g,0.332mmol)于1,4-二噁烷(20mL)中的溶液在N2下在100℃下加热2小时。然后使反应混合物冷却至室温并加入5-溴-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R1)(1.5g,6.63mmol)于1,4-二噁烷(5mL)中的溶液,然后加入K2CO3(3.67g,26.5mmol)于水(2.5mL)中的溶液。将反应混合物在100℃下加热2小时,用EtOAc(75mL)稀释,并用水(100mL)和盐水(100mL)洗涤。分离有机相,干燥(MgSO4)并真空蒸发。将粗产物通过快速色谱法(0-50%EtOAc/异己烷)纯化,得到呈白色固体状的标题化合物(940mg,55%)。
1H NMR(CDCl3)δ8.32(d,J=5.0Hz,1H),7.12(dt,J=5.2,1.6Hz,1H),6.88(s,1H),6.66(s,1H),3.36(s,2H),2.93(t,J=7.5Hz,2H),2.72(t,J=7.4Hz,2H),2.14(p,J=7.5Hz,2H),2.00(s,3H)。
LCMS m/z 243.2(M+H)+(ES+)。
步骤B:5-(2-乙氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
使5-(2-氟吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺(100mg,0.413mmol)溶于THF(2mL)中。加入EtONa(42mg,0.617mmol),并将反应混合物在室温下搅拌18小时。加入另外的EtONa(42mg,0.617mmol)并将反应混合物搅拌4小时。然后反应混合物于EtOAc(20mL)与水(10mL)之间分配。将有机层分离,用水(10mL)洗涤,干燥(相分离器)并真空浓缩,得到标题化合物(121mg,产率定量)。
1H NMR(DMSO-d6)δ8.21(d,J=5.2Hz,1H),6.74(dd,J=5.2,1.4Hz,1H),6.54(s,1H),6.45(s,1H),4.34(q,J=7.0Hz,2H),4.14(s,2H),2.78(t,J=7.5Hz,2H),2.64(t,J=7.3Hz,2H),1.99(p,J=7.5Hz,2H),1.88(s,3H),1.35(t,J=7.1Hz,3H)。
LCMS m/z 269.2(M+H)+(ES+)。
以下中间体根据中间体R29的通用程序制备:
中间体R31:5-(2-(环己基氧基)吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺
将KOtBu(0.132g,1.176mmol)加入至含环己醇(0.163mL,1.568mmol)的THF(3mL)中。将反应混合物在室温下搅拌1小时,然后冷却至0℃。加入5-(2-氟吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R29,步骤A)(0.200g,0.784mmol)并将反应混合物在室温下搅拌18小时。然后反应混合物于EtOAc(20mL)与水(10mL)之间分配。将有机层用水(10mL)洗涤,干燥(相分离器)并真空浓缩。将粗产物通过快速色谱法(0-25%EtOAc/异己烷)纯化,得到呈稠无水油状物的标题化合物(0.177g,61%)。
1H NMR(DMSO-d6)δ8.19(d,J=5.1Hz,1H),6.71(dd,J=5.1,1.4Hz,1H),6.49(s,1H),6.44(s,1H),5.04-4.96(m,1H),4.12(s,2H),2.77(t,J=7.5Hz,2H),2.64(t,J=7.3Hz,2H),2.04-1.94(m,4H),1.88(s,3H),1.78-1.69(m,2H),1.59-1.52(m,1H),1.51-1.33(m,4H),1.30-1.22(m,1H)。
LCMS m/z 323.3(M+H)+(ES+)。
以下中间体根据中间体R31的通用程序制备:
中间体R33:4-氟-6-异丙基-2-(2-甲氧基吡啶-4-基)-3-甲基苯胺
步骤A:4-氟-5-甲基-2-(丙-1-烯-2-基)苯胺
将2-溴-4-氟-5-甲基苯胺(10.00g,49.0mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂戊硼烷(11mL,58.8mmol)、Pd(OAc)2(440mg,1.960mmol)、三环己基膦(21.2g,76mmol)和K3PO4(28.1g,132mmol)于二噁烷(120mL)和水(30mL)中的混合物用N2脱气。然后将反应混合物在100℃下加热18小时。将溶剂蒸发并且残余物于异己烷(500mL)与水(300mL)之间分配。将有机层用水(200mL)洗涤,干燥(相分离器)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-40%EtOAc/异己烷)纯化,得到呈棕色油状物的标题化合物(9.09g,99%)。
1H NMR(DMSO-d6)δ6.70(d,J=10.6Hz,1H),6.52(d,J=7.3Hz,1H),5.24-5.20(m,1H),5.01-4.98(m,1H),4.59(br s,2H),2.09(s,3H),1.98(s,3H)。
步骤B:4-氟-2-异丙基-5-甲基苯胺
将4-氟-5-甲基-2-(丙-1-烯-2-基)苯胺(13.33g,81mmol)和5%Pd/C(类型87L,58.5%湿度)(1.66g,0.324mmol)于EtOAc(145mL)中的混合物在3巴下氢化16小时。然后反应混合物经过滤并真空浓缩,得到呈深绿色油状物的标题化合物(11.95g,79%)。
1H NMR(DMSO-d6)δ6.74(d,J=11.4Hz,1H),6.50(d,J=7.3Hz,1H),5.07(s,2H),2.92(hept,J=6.7Hz,1H),2.08(s,3H),1.11(d,J=6.8Hz,6H)。
LCMS m/z 168.1(M+H)+(ES+)。
步骤C:2-溴-4-氟-6-异丙基-3-甲基苯胺
将NBS(12.08g,67.9mmol)加入至4-氟-2-异丙基-5-甲基苯胺(11.95g,67.9mmol)于DCM(180mL)中的溶液。将反应混合物在室温下搅拌20分钟,然后用水(200mL)和10%Na2S2O3水溶液(200mL)洗涤,干燥(相分离器)并真空浓缩,得到粗产物(14.6g)。5g粗产物通过硅胶上快速色谱法(0-20%EtOAc/异己烷)纯化,得到呈红橙色油状物的标题化合物(3.26g,19%)。
1H NMR(DMSO-d6)δ6.89(d,J=11.0Hz,1H),4.87(s,2H),3.06(sept,J=6.7Hz,1H),2.20(d,J=2.4Hz,3H),1.14(d,J=6.7Hz,6H)。
LCMS m/z 246.1/248.1(M+H)+(ES+)。
步骤D:4-氟-6-异丙基-2-(2-甲氧基吡啶-4-基)-3-甲基苯胺
使(2-甲氧基吡啶-4-基)硼酸(200mg,1.308mmol)、2-溴-4-氟-6-异丙基-3-甲基苯胺(322mg,1.308mmol)、碳酸钾(723mg,5.23mmol)和PdCl2(dppf).DCM(53mg,0.065mmol)溶于1,4-二噁烷(6mL)和水(3mL)中。将反应混合物脱气(N2,5分钟)并抽空并且用N2回填(×3)。然后将反应混合物在100℃下搅拌3小时。将反应混合物用EtOAc(20mL)稀释并用盐水(2×20mL)洗涤。将有机萃取物干燥(相分离器)并真空浓缩。将粗产物通过硅胶上快速色谱法(0-100%EtOAc/异己烷)纯化,得到呈棕色油状物的标题化合物(276mg,73%)。
1H NMR(DMSO-d6)δ8.28(d,J=5.1Hz,1H),6.88(d,J=11.3Hz,1H),6.81(dd,J=5.2,1.4Hz,1H),6.65(s,1H),3.99(s,2H),3.90(s,3H),3.03-2.96(m,1H),1.79(d,J=2.1Hz,3H),1.15(d,J=6.7Hz,6H)。
LCMS(m/z 275.1(M+H)+(ES+)。
以下中间体根据中间体R33的通用程序制备:
中间体R39:4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺
步骤A:2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑
在0℃下向NaH(9.74g,243.59mmol,矿物油中60wt%,1当量)于DMF(200mL)中的溶液中分批加入2-甲基-1H-咪唑(20g,243.59mmol,1当量)。将反应混合物在0℃下搅拌30分钟。然后加入(2-(氯甲氧基)乙基)三甲基硅烷(48.73g,292.31mmol,1.2当量)。将所得混合物在0℃下搅拌2小时。将反应混合物用冰水(300mL)淬灭,用乙酸乙酯(1L)稀释,并用饱和NH4Cl水溶液(3×300mL)和盐水(3×300mL)洗涤。将有机层经无水Na2SO4干燥,过滤并真空浓缩。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(40g,76%产率,LCMS上98%纯度)。
1H NMR(400MHz,CDCl3)δ6.90(s,2H),5.18(s,2H),3.47(t,2H),2.43(s,3H),0.89(t,2H)和0.01(s,9H)。
LCMS:m/z 213.0(M+H)+(ES+)。
步骤B:4-溴-2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑
在-20℃下向2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(20g,94.18mmol,1当量)于DMF(200mL)中的溶液中加入NBS(16.76g,94.18mmol,1当量)。然后将反应混合物在-20℃下搅拌2小时。将反应混合物用饱和Na2SO3水溶液(100mL)淬灭,用EtOAc(200mL)稀释,并用饱和NH4Cl水溶液(3×100mL)和盐水(3×100mL)洗涤。将有机层经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过柱色谱法(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(13.5g,41%产率,LCMS上84%纯度)。
1H NMR(400MHz,CDCl3)δ6.88(s,1H),5.25(s,2H),3.55(t,2H),2.42(s,3H),0.91(t,2H)和0.02(s,9H)。
LCMS:m/z 292.9(M+H)+(ES+)。
步骤C:2-甲基-4-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑
将4-溴-2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(10g,28.84mmol,1当量)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂戊硼烷(5.33g,31.72mmol,1.1当量)、Pd(dppf)Cl2(1.06g,1.44mmol,0.05当量)和Na2CO3(6.11g,57.68mmol,2当量)于二噁烷(100mL)和H2O(20mL)中的溶液在N2下在100℃下搅拌12小时。将反应混合物用水(100mL)稀释,然后用乙酸乙酯(3×100mL)萃取。将有机层经无水Na2SO4干燥,过滤并真空浓缩。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(7g,96%)。
1H NMR(400MHz,CDCl3)δ6.88(s,1H),5.23(s,2H),5.20(s,1H),5.14(s,1H),3.52(t,2H),2.48(s,3H),2.08(s,3H),0.93(t,2H)和0.01(s,9H)。
LCMS:m/z 253.0(M+H)+(ES+)。
步骤D:4-异丙基-2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑
在N2下向2-甲基-4-(丙-1-烯-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(7.18g,28.44mmol,1当量)于MeOH(100mL)中的溶液中加入Pd/C(700mg,10wt%负载在活性碳上)。将悬浮液真空脱气并用H2净化几次。将混合物在H2(15psi)下在25℃下搅拌12小时。然后将反应混合物过滤并真空浓缩滤液,得到呈黄色油状物的标题化合物(8g,99%产率,LCMS上90%纯度)。
1H NMR(400MHz,CDCl3)δ6.66(s,1H),5.15(s,2H),3.49(t,2H),2.95-2.84(m,1H),2.43(s,3H),1.26(d,6H),0.91(t,2H)和0.02(s,9H)。
LCMS:m/z 255.2(M+H)+(ES+)。
步骤E:4-异丙基-2-甲基-1H-咪唑
在25℃下向4-异丙基-2-甲基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(8g,31.44mmol,1当量)于DCM(80mL)中的溶液中加入TFA(123.20g,1.08mol,34.37当量)。然后将混合物在25℃下搅拌12小时。将反应混合物用冰水(10mL)和饱和NaHCO3水溶液(300mL)淬灭。将混合物用乙酸乙酯(2×100mL)萃取。将合并的有机层用盐水(2×200mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过柱色谱法(SiO2,乙酸乙酯:甲醇,1:0至20:1)纯化,得到呈黄色油状物的标题化合物(3.7g,95%)。
1H NMR(400MHz,CDCl3)δ6.71(s,1H),2.99-2.93(m,1H),2.53(s,3H)和1.27(d,6H)。
LCMS:m/z 125.3(M+H)+(ES+)。
步骤F:4-(4-异丙基-2-甲基-1H-咪唑-1-基)吡啶
向4-异丙基-2-甲基-1H-咪唑(1.4g,11.27mmol,1当量)和4-碘吡啶(1.85g,9.02mmol,0.8当量)于DMF(14mL)中的溶液中加入Cu2O(81mg,563.68μmol,0.05当量)和Cs2CO3(7.35g,22.55mmol,2当量)。将反应混合物在100℃下搅拌15小时。然后将反应混合物用乙酸乙酯(50mL)稀释,并用饱和NH4Cl水溶液(3×30mL)和盐水(3×30mL)洗涤。将有机层经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过柱色谱法(SiO2,石油醚:乙酸乙酯,5:1至0:1)纯化,得到呈黄色固体状的标题化合物(600mg,26%产率,LCMS上97%纯度)。
1H NMR(400MHz,CDCl3)δ8.73(dd,2H),7.27(dd,2H),6.77(s,1H),2.93-2.86(m,1H),2.48(s,3H)和1.29(d,6H)。
LCMS:m/z 202.0(M+H)+(ES+)。
步骤G:4-(4-异丙基-2-甲基-5-硝基-1H-咪唑-1-基)吡啶
在0℃下向4-(4-异丙基-2-甲基-1H-咪唑-1-基)吡啶(400mg,1.93mmol,1当量)于H2SO4(71.33mmol,3.88mL,溶液中98%纯度,37当量)中的溶液中加入HNO3(5.78mmol,400μL,水溶液中65%纯度,3当量)。然后将反应混合物在25℃下搅拌12小时。将反应混合物用冰水(20mL)淬灭,并用饱和NaHCO3水溶液调至pH=8~9。将混合物用乙酸乙酯(3×20mL)萃取。将有机层经无水Na2SO4干燥,过滤并真空浓缩。将黄色固体通过柱色谱法(SiO2,石油醚:乙酸乙酯,2:1至1:1)纯化,得到呈黄色固体状的标题化合物(400mg,84%)。
1H NMR(400MHz,CDCl3)δ8.83(d,2H),7.22(d,2H),3.75-3.69(m,1H),2.25(s,3H)和1.36(d,6H)。
LCMS:m/z 247.1(M+H)+(ES+)。
步骤H:4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺
将4-(4-异丙基-2-甲基-5-硝基-1H-咪唑-1-基)吡啶(400mg,1.62mmol,1当量)和Pd/C(40mg,10wt%负载在活性碳上)于MeOH(20mL)中的混合物在20℃下在H2(15psi)下氢化1小时。然后将反应混合物过滤,并真空浓缩滤液。使残余物溶于THF(10mL)中,并用4MHCl/二噁烷调至pH=3~4。将所得混合物真空浓缩,得到呈黄色固体状的标题化合物(400mg,97%,HCl盐),其未经进一步纯化就用于下一步。
1H NMR(400MHz,DMSO-d6)δ15.02(s,1H),8.99(d,2H),7.90(d,2H),3.25-3.15(m,1H),2.45(s,3H)和1.27(d,6H)。
LCMS:m/z 217.1(M+H)+(ES+)。
中间体R40:4-异丙基-1-(2-甲氧基吡啶-4-基)-2-甲基-1H-咪唑-5-胺
步骤A:4-(4-异丙基-2-甲基-1H-咪唑-1-基)-2-甲氧基吡啶
将4-异丙基-2-甲基-1H-咪唑(中间体R39,步骤E)(1g,6.44mmol,1当量)、4-碘-2-甲氧基吡啶(1.51g,6.44mmol,1当量)、Cu2O(922mg,6.44mmol,1当量)和Cs2CO3(4.20g,12.88mmol,2当量)于DMF(10mL)中的反应混合物在100℃下搅拌12小时。然后将反应混合物过滤。将滤液倾倒至水(20mL)中并用乙酸乙酯(3×30mL)萃取。将有机层经无水Na2SO4干燥,过滤,并真空浓缩。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(700mg,47%)。
1H NMR(400MHz,CD3OD)δ8.25(d,1H),7.03(d,1H),6.98(s,1H),6.84(s,1H),3.96(s,3H),2.87-2.80(m,1H),2.46(s,3H)和1.26(d,6H)。
LCMS:m/z 232.2(M+H)+(ES+)。
步骤B:4-(4-异丙基-2-甲基-5-硝基-1H-咪唑-1-基)-2-甲氧基吡啶
在0℃下向4-(4-异丙基-2-甲基-1H-咪唑-1-基)-2-甲氧基吡啶(0.7g,3.03mmol,1当量)于H2SO4(12.88g,水溶液中98wt%,131.32mmol,43.39当量)中的溶液中加入HNO3(829mg,9.08mmol,水溶液中69wt%,3当量)。然后将反应混合物在25℃下搅拌2小时。将反应混合物倾倒至冰水(40mL)中,并用NaOH固体调至pH=8~9。然后将混合物用乙酸乙酯(3×50mL)萃取。将有机层经无水Na2SO4干燥,过滤,并真空浓缩。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,得到呈黄色固体状的标题化合物(600mg,67%产率,LCMS上94%纯度)。
1H NMR(400MHz,CD3OD)δ8.33(d,1H),6.99(dd,1H),6.90(d,1H),4.00(s,3H),3.76-3.68(m,1H),2.25(s,3H)和1.34(d,6H)。
LCMS:m/z 277.0(M+H)+(ES+)。
步骤C:4-异丙基-1-(2-甲氧基吡啶-4-基)-2-甲基-1H-咪唑-5-胺
在N2气氛下向4-(4-异丙基-2-甲基-5-硝基-1H-咪唑-1-基)-2-甲氧基吡啶(200mg,723.88μmol,1当量)于MeOH(5mL)中的溶液中加入Pd/C(20mg,10wt%负载在活性碳上)。将悬浮液真空脱气并用H2净化几次。将混合物在25℃下在H2(15psi)下搅拌2小时。然后将反应混合物过滤,并真空浓缩滤液,得到呈黄色油状物的标题化合物(178mg,100%),其直接用于下一步。
1H NMR(400MHz,CDCl3)δ8.30(d,1H),6.81(dd,1H),6.65(d,1H),4.01(s,3H),3.65-3.57(m,1H),2.26(s,3H)和1.37(d,6H)。
中间体R41:
(6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酸苯酯
步骤A:4-溴-2-((1-甲基哌啶-4-基)氧基)吡啶
在20℃下向KOtBu(41.13g,366.51mmol,1.5当量)于THF(500mL)中的溶液中加入1-甲基哌啶-4-醇(33.77g,293.20mmol,1.2当量)。将反应混合物搅拌1小时。然后在0℃下加入4-溴-2-氟吡啶(43g,244.34mmol,1当量)。将反应混合物在20℃下搅拌12小时,然后倾倒至水(500mL)中。将水相用乙酸乙酯(2×500mL)萃取。将合并的有机相用盐水(2×500mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过柱色谱法(SiO2,含0.1%NH3.H2O,DCM:甲醇1:0至10:1)纯化,得到呈黄色固体状的标题化合物(61g,92%)。
1H NMR(400MHz,DMSO-d6)δ8.05(d,1H),7.18(dd,1H),7.06(s,1H),4.98-4.93(m,1H),2.62-2.59(m,2H),2.16-2.11(m,5H)1.94-1.91(m,2H)和1.66-1.62(m,2H)。
LCMS:m/z 273.0(M+H)+(ES+)。
步骤B:2-((1-甲基哌啶-4-基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶
在N2下向4-溴-2-((1-甲基哌啶-4-基)氧基)吡啶(20g,73.76mmol,1当量)和4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂戊硼烷(24.35g,95.89mmol,1.3当量)于二噁烷(200mL)中的混合物一次性加入PdCl2(dppf)(3.24g,4.43mmol,0.06当量)和KOAc(34.24g,348.88mmol,4.73当量)。然后将反应混合物加热至100℃,保持2小时。将反应混合物真空浓缩。将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈棕色油状物的标题化合物(22.5g,96%)。
1H NMR(400MHz,DMSO-d6)δ8.17-8.12(m,1H),7.08-7.03(m,1H),6.93-6.88(m,1H),5.05-4.90(m,1H),3.92-3.86(m,2H),2.73-2.66(m,2H),2.22(s,3H),1.95-1.90(m,2H),1.69-1.63(m,2H)和1.06(s,12H)。
LCMS:m/z 319.0(M+H)+(ES+)。
步骤C:
6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-胺
在N2下向5-溴-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R1)(40g,176.90mmol,1当量)和2-((1-甲基哌啶-4-基)氧基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(78.81g,247.66mmol,1.4当量)于二噁烷(500mL)和H2O(100mL)中的混合物一次性加入K2CO3(73.35g,530.71mmol,3当量)和PdCl2(dppf)(7.77g,10.61mmol,0.06当量)。然后将反应混合物在100℃下搅拌12小时。将反应混合物用水(500mL)淬灭并用EtOAc(3×500mL)萃取。将合并的有机相用盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。将残余物用DCM(300mL)稀释并用HCl(3×100mL,3M)萃取。将合并的水相用饱和Na2CO3水溶液调至pH 8,然后用DCM(3×200mL)萃取。将合并的有机相用盐水(200mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。将残余物通过柱色谱法(SiO2,PE:EtOAc 1:0至5:1,然后DCM:MeOH 1:0至10:1,含0.1%NH3.H2O)纯化,得到呈棕色胶状的标题化合物(50g,80%产率,HPLC上95.6%纯度)。
1H NMR(400MHz,DMSO-d6)δ8.20(d,1H),6.72(dd,1H),6.50(s,1H),6.44(s,1H),5.02-4.97(m,1H),4.13(s,2H),2.77(t,2H),2.67-2.61(m,4H),2.17(s,3H),2.16-2.11(m,2H),2.02-1.94(m,4H),1.87(s,3H)和1.72-1.64(m,2H)。
LCMS:m/z 338.2(M+H)+(ES+)。
步骤D:
(6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酸苯酯
在0℃下向6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-胺(1g,2.96mmol,1当量)和氯甲酸苯酯(463mg,2.96mmol,1当量)于DCM(20mL)中的溶液中加入TEA(300mg,2.96mmol,1当量)。然后将反应混合物在25℃下搅拌2小时。将反应混合物真空浓缩。将残余物通过逆相快速色谱法(水中0.1%TFA-MeCN)纯化,得到呈黄色固体状的标题化合物(350mg,20%产率,LCMS上95%纯度,TFA盐)。
1H NMR(400MHz,DMSO-d6)δ9.70-9.60(m,1H),9.19(s,1H),8.25(t,1H),7.36-7.34(m,2H),7.23-7.16(m,2H),6.90-6.81(m,3H),6.68-6.62(m,1H),5.36-5.19(m,1H),3.39-3.14(m,4H),2.97-2.91(m,2H),2.87-2.79(m,5H),2.38-2.33(m,1H),2.27-2.16(m,1H),2.06(d,6H)和1.90-1.78(m,1H)。
LCMS:m/z 458.1(M+H)+(ES+)。
制备实施例
实施例1:N-((6-甲基-5-(2-甲基吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷磺酰胺
将6-甲基-5-(2-甲基吡啶-4-基)-2,3-二氢-1H-茚-4-胺(中间体R9)(35mg,0.147mmol)加入至(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(甲基磺酰基)酰胺(中间体L1)(36mg,0.148mmol)于乙腈(1mL)中的悬浮液。将反应混合物在60℃下搅拌1小时。将挥发物蒸发,并且使粗产物溶于DMSO(1mL)中并过滤。粗产物通过碱性制备型HPLC(水中10-40%MeCN)纯化,得到呈白色固体状的标题化合物(7mg,13%)。
1H NMR(DMSO-d6)δ8.48(d,J=5.1Hz,1H),7.11(s,1H),7.04(s,1H),6.96(d,J=5.1Hz,1H),3.30(s,3H),3.02(s,3H),2.91(t,J=7.4Hz,2H),2.75(t,J=7.3Hz,2H),2.04-1.97(m,5H)。未观察到两个可交换质子。
LCMS m/z 360.2(M+H)+(ES+)。
以下实施例根据实施例1的通用程序制备:
实施例40:N-((5-(2-甲氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷磺酰胺,钠盐
将5-(2-甲氧基吡啶-4-基)-6-甲基-2,3-二氢-1H-茚-4-胺(中间体R25)(148mg,0.582mmol)加入至(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(甲基磺酰基)酰胺(中间体L1)(142mg,0.582mmol)于MeCN(2mL)中的悬浮液。将反应混合物在60℃下搅拌1小时。将挥发物蒸发,并使粗产物溶于DMSO(2mL)中并过滤。粗产物通过碱性制备型HPLC纯化,得到游离酸,将其用0.5M NaOH(474μL,0.237mmol)处理并冷冻干燥,得到呈白色固体状的标题化合物(83mg,87%)。
1H NMR(DMSO-d6)δ8.15(dd,J=5.2,0.7Hz,1H),6.95(s,1H),6.75(dd,J=5.2,1.4Hz,1H),6.63-6.54(m,2H),3.87(s,3H),2.86(t,J=7.4Hz,2H),2.79(t,J=7.5Hz,2H),2.58(s,3H),2.04-1.89(m,5H)。
LCMS m/z 376.2(M+H)+(ES+)。
实施例41:1-(2-(二甲基氨基)乙基)-N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)-1H-吡唑-3-磺酰胺
在室温下向搅拌的1-(2-(二甲基氨基)乙基)-1H-吡唑-3-磺酰胺(22mg,0.1mmol)于THF(2mL)中的溶液中加入于THF中的2M叔丁醇钠(0.055mL,0.11mmol)。将所得混合物在室温下搅拌1小时。然后加入4-(4-异氰酸基-6-甲基-2,3-二氢-1H-茚-5-基)-2-((1-甲基哌啶-4-基)氧基)吡啶(中间体R27)(36.3mg,0.1mmol)于THF(1mL)中的溶液并将反应混合物在室温下搅拌过夜。将挥发物蒸发,并且使粗产物溶于DMSO(1mL)中并通过碱性制备型HPLC(水中10-40%MeCN)纯化,得到呈固体状的标题化合物(5mg,9%)。
1H NMR(DMSO-d6)δ8.13(d,J=5.3Hz,1H),7.79(s,1H),7.25(s,1H),7.02(s,1H),6.67(d,J=5.3Hz,1H),6.53(s,1H),6.47-6.40(m,1H),5.13-5.04(m,1H),4.23(t,J=6.6Hz,2H),2.96-2.89(m,2H),2.85(t,J=7.4Hz,2H),2.66(t,J=6.6Hz,2H),2.62-2.56(m,4H),2.41(s,3H),2.19(s,6H),2.10-2.03(m,2H),1.98(s,3H),1.96-1.90(m,2H),1.87-1.73(m,2H)。未观察到一个可交换质子。
LCMS m/z 582.3(M+H)+(ES+)。
以下实施例根据实施例41的通用程序制备:
实施例46:4-(2-羟基丙-2-基)-N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)呋喃-2-磺酰胺,铵盐
步骤A:((4-(2-羟基丙-2-基)呋喃-2-基)磺酰基)(4-异丙基吡啶-1-鎓-1-羰基)酰胺
将4-(2-羟基丙-2-基)呋喃-2-磺酰胺(中间体L7)(100mg,487.26μmol,1当量)和N,N-二甲基吡啶-4-胺(119mg,974.51μmol,2当量)于MeCN(2mL)中的溶液在25℃下搅拌30分钟。然后加入碳酸二苯酯(115mg,535.98μmol,1.1当量)。将反应混合物在25℃下搅拌12小时。反应混合物,红色溶液(理论量:172.19mg,于2mL MeCN中)直接用于下一步。
步骤B:
4-(2-羟基丙-2-基)-N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)呋喃-2-磺酰胺,铵盐
向4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺(中间体R39)(100mg,395.66μmol,1当量,HCl盐)于MeCN(1mL)中的溶液中加入((4-(2-羟基丙-2-基)呋喃-2-基)磺酰基)(4-异丙基吡啶-1-鎓-1-羰基)酰胺于MeCN(理论量:140mg,1.6mL,395.66μmol,1当量)中的溶液。将反应混合物在70℃下搅拌1小时。然后反应混合物通过逆相制备型HPLC(柱:WatersXBridge C18,150mm×25mm×5μm;流动相[A:水(0.05%氢氧化铵v/v);B:MeCN];B%:1%-20%,10分钟)纯化,得到呈白色固体状的标题化合物(9.52mg,两步5%产率,LCMS上99%纯度,铵盐)。
1H NMR(400MHz,DMSO-d6+D2O)δ8.71(s,2H),7.51-7.40(m,3H),6.72-6.65(s,1H),2.85-2.81(m,1H),2.33(s,3H),1.37(s,6H)和1.17(s,6H)。
LCMS:m/z 448.1(M+H)+(ES+)。
实施例47:1-环丙基-N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)-1H-吡唑-3-磺酰胺
步骤A:((1-环丙基-1H-吡唑-3-基)磺酰基)(4-(二甲基氨基)吡啶-1-鎓-1-羰基)酰胺
将1-环丙基-1H-吡唑-3-磺酰胺(中间体L8)(150mg,801.20μmol,1当量)和N,N-二甲基吡啶-4-胺(196mg,1.60mmol,2当量)于MeCN(3mL)中的混合物在25℃下搅拌30分钟。然后加入碳酸二苯酯(189mg,881.32μmol,1.1当量)。将所得混合物在25℃下搅拌12小时。反应混合物变混浊并且一些固体沉淀出。将悬浮液过滤,并收集滤饼,得到呈灰白色固体状的标题化合物(95mg,35%)。
1H NMR(DMSO-d6)δ8.10(d,2H),7.92(d,1H),6.59-6.56(m,3H),3.84-3.75(m,1H),2.95(s,6H)和1.07-0.99(m,4H)。
步骤B:
1-环丙基-N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)-1H-吡唑-3-磺酰胺
向4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺(中间体R39)(107mg,424.89μmol,1.5当量,HCl盐)于MeCN(4mL)中的溶液中加入((1-环丙基-1H-吡唑-3-基)磺酰基)(4-(二甲基氨基)吡啶-1-鎓-1-羰基)酰胺(95mg,283.26μmol,1当量)。将反应混合物在N2下在70℃下搅拌45分钟。然后将反应混合物真空浓缩。将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,然后通过逆相制备型HPLC(柱:Waters XBridge,150mm×25mm×5μm;流动相[A:水(0.05%氢氧化铵v/v);B:MeCN];B%:1%-20%,10分钟)纯化,得到呈白色固体状的标题化合物(11.61mg,两步9%产率,HPLC上98%纯度)。
1H NMR(400MHz,DMSO-d6)δ8.65-8.62(m,2H),7.89(s,1H),7.79(d,1H),7.34-7.31(m,2H),6.47(s,1H),3.83-3.81(m,1H),2.67-2.64(m,1H),2.20(s,3H)和1.10-1.02(m,10H)。
LCMS:m/z 430.1(M+H)+(ES+)。
实施例48:4-(2-羟基丙-2-基)-N-((4-异丙基-1-(2-甲氧基吡啶-4-基)-2-甲基-1H-咪唑-5-基)氨甲酰基)呋喃-2-磺酰胺
将4-异丙基-1-(2-甲氧基吡啶-4-基)-2-甲基-1H-咪唑-5-胺(中间体R40)(178mg,722.67μmol,1当量)和((4-(2-羟基丙-2-基)呋喃-2-基)磺酰基)(4-异丙基吡啶-1-鎓-1-羰基)酰胺(实施例46,步骤A)(255mg,722.67μmol,1当量)于MeCN(5mL)中的混合物在N2下在70℃下搅拌2小时。反应混合物直接通过逆相快速色谱法(0.1%NH3·H2O-MeCN)纯化,然后通过逆相制备型HPLC(柱:Xtimate C18,150mm×25mm×5μm;流动相[A:水(0.05%氢氧化铵v/v);B:MeCN];B%:0%-24%,10min)进一步纯化,得到呈白色固体状的标题化合物(24.92mg,两步7%产率,LCMS上100%纯度)。
1H NMR(400MHz,DMSO-d6)δ8.27-8.19(m,1H),7.68-7.45(m,1H),7.39(s,1H),7.04-6.77(m,2H),6.65-6.53(m,1H),4.93(s,1H),3.87(s,3H),2.80-2.69(m,1H),2.22(s,3H),1.33(s,6H)和1.10(s,6H)。
LCMS:m/z 478.3(M+H)+(ES+)。
实施例49:1-(5-异丙基-2-甲基-3-(4-吡啶基)咪唑-4-基)-3-(甲基-(1-甲基吡咯烷-3-基)氨磺酰基)脲
步骤A:(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(N-甲基-N-(1-甲基吡咯烷-3-基)氨磺酰基)酰胺
将N,N-二甲基吡啶-4-胺(366mg,3.00mmol,2当量)和1-甲基-3-[甲基(氨磺酰基)氨基]吡咯烷(中间体L9)(0.29g,1.50mmol,1当量)于MeCN(8mL)中的溶液在20℃下搅拌30分钟。然后加入碳酸二苯酯(353mg,1.65mmol,1.1当量)。将所得混合物在20℃下搅拌12小时。混合物(理论量:0.53g,粗)直接用于下一步。
步骤B:1-(5-异丙基-2-甲基-3-(4-吡啶基)咪唑-4-基)-3-(甲基-(1-甲基吡咯烷-3-基)氨磺酰基)脲
向4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺(中间体R39)(0.2g,791.32μmol,1当量,HCl盐)于MeCN(1mL)中的混合物加入(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(N-甲基-N-(1-甲基吡咯烷-3-基)氨磺酰基)酰胺(步骤A的反应混合物)于MeCN(8mL)中的溶液。将所得混合物加热至70℃并在N2下搅拌30分钟。然后将反应混合物真空浓缩。将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,然后通过制备型HPLC进一步纯化(柱:Waters XBridge C18,150mm×25mm×5μm;流动相[A:水(10mM NH4HCO3),B:MeCN];B%:1%-15%,10分钟),得到呈白色固体状的标题化合物(25.13mg,两步7%产率,LCMS上100%纯度)。
1H NMR(400MHz,CD3OD)δ8.70(d,J=6.0Hz,2H),7.50-7.48(m,2H),4.48-4.44(m,1H),3.30-2.92(m,5H),2.74(s,3H),2.63(s,3H),2.29(s,3H),2.15-1.98(m,2H),1.27(d,J=6.8Hz,6H)。2×NH丢失。
LCMS:m/z 436.1(M+H)+(ES+)。
实施例50:N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)苯磺酰胺
步骤A:(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(苯基磺酰基)酰胺
将苯磺酰胺(125mg,795.22μmol,1当量)和N,N-二甲基吡啶-4-胺(194mg,1.59mmol,2当量)于MeCN(3mL)中的溶液在25℃下搅拌30分钟。然后加入碳酸二苯酯(187mg,874.74μmol,1.1当量)。将所得混合物在25℃下搅拌12小时。反应混合物(理论量:242mg,粗)直接用于下一步。
步骤B:N-((4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-基)氨甲酰基)苯磺酰胺
向4-异丙基-2-甲基-1-(吡啶-4-基)-1H-咪唑-5-胺(197mg,780.00μmol,1当量,HCl盐)(中间体R39)于MeCN(2mL)中的溶液中加入(4-(二甲基氨基)吡啶-1-鎓-1-羰基)(苯基磺酰基)酰胺(步骤A的反应混合物)于MeCN(3mL)中的溶液。将所得混合物在N2下在70℃下搅拌45分钟。然后将反应混合物浓缩并将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,然后通过制备型HPLC(柱:Xtimate C18,150mm×25mm×5μm;流动相[A:水(0.05%氢氧化铵v/v),B:MeCN];B%:0%-30%,10分钟)进一步纯化,得到呈白色固体状的标题化合物(17.42mg,两步6%产率,HPLC上99.8%纯度)。
1H NMR(400MHz,DMSO-d6)δ8.60-8.45(m,2H),7.70-7.47(m,6H),7.26-6.90(m,2H),2.68-2.65(m,1H),2.19(s,3H)和1.09(d,6H)。1×NH丢失。
LCMS:m/z 400.1(M+H)+(ES+)。
实施例51:N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)苯亚氨代磺酰胺
步骤A:
N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)苯亚磺酰胺
在25℃下向苯亚磺酰胺(中间体L10)(50mg,354.13μmol,1当量)于THF(1mL)中的溶液中加入t-BuONa(102mg,1.06mmol,3当量)。将反应混合物在25℃下搅拌30分钟。然后加入(6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酸苯酯(中间体R41)(202mg,354.13μmol,1当量,TFA盐)。将所得混合物在25℃下搅拌5小时。然后将反应混合物真空浓缩。将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈白色固体状的标题化合物(120mg,59%产率,LCMS上88%纯度)。
1H NMR(400MHz,DMSO-d6)δ9.57-9.27(m,1H),8.31-8.17(m,1H),7.71-7.42(m,5H),7.24-7.07(m,1H),6.82-6.65(m,1H),6.51(s,1H),5.11-4.93(m,1H),3.48-3.41(m,2H),2.99-2.68(m,5H),2.24-1.96(m,11H)和1.89-1.61(m,2H)。1×NH丢失。
LCMS:m/z 505.3(M+H)+(ES+)。
步骤B:
N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)苯亚氨代磺酰胺
向N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)苯亚磺酰胺(0.1g,198.16μmol,1当量)于THF(1mL)中的溶液中加入1-氯-1H-苯并[d][1,2,3]三唑(27mg,178.34μmol,0.9当量)。将反应混合物在25℃下搅拌30分钟。然后在-70℃下将反应混合物加入至NH3/THF溶液(5mL)中;使NH3鼓泡至THF中,历时5分钟,得到NH3/THF溶液。在加入后,将混合物在-70℃下搅拌30分钟。然后将反应混合物真空浓缩。残余物通过制备型TLC(SiO2,DCM:甲醇,10:1)纯化,然后通过制备型HPLC(柱:Phenomenexluna C18,150mm×25mm×10μm;流动相[A:水(0.1%TFA);B:MeCN];B%:22%-42%,10分钟)进一步纯化,得到呈白色固体状的标题化合物(21.45mg,17%产率,LCMS上100%纯度,TFA盐)。
1H NMR(400MHz,CDCl3)δ8.22-8.10(m,1H),8.02-7.80(m,2H),7.68-7.46(m,3H),7.10(d,1H),6.83-6.62(m,2H),5.45-5.21(m,1H),3.93-3.40(m,2H),3.38-3.01(m,2H),3.00-2.71(m,7H),2.49-2.19(m,4H)和2.17-1.96(m,5H)。3×NHs丢失。
LCMS:m/z 520.1(M+H)+(ES+)。
实施例52:N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷亚氨代磺酰胺
步骤A:N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷亚磺酰胺
在20℃下将叔丁醇钠(134mg,1.40mmol,1.6当量)加入至甲烷亚磺酰胺(中间体L11)(103mg,1.31mmol,1.5当量)于THF(2mL)中的混合物。将反应混合物在20℃下搅拌30分钟。然后在20℃下加入(6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨基甲酸苯酯(中间体R41)(400mg,874.20μmol,1当量)并将所得混合物在20℃下搅拌30分钟。将反应混合物倾倒至冰水(30mL)中。将水相用乙酸乙酯(3×20mL)萃取。将合并的有机相用盐水(20mL)洗涤,经无水硫酸钠干燥,过滤并真空浓缩。将残余物通过逆相快速色谱法(0.1%NH3.H2O-MeCN)纯化,得到呈白色固体状的标题化合物(150mg,26%产率,LCMS上68%纯度)。
1H NMR(400MHz,CDCl3)δ8.17(d,1H),7.14(d,1H),6.71-6.65(m,1H),6.54(d,1H),5.08-5.04(m,1H),2.97(t,2H),2.87(t,2H),2.75-2.73(m,2H),2.64(s,3H),2.33-2.27(m,5H),2.15-2.07(m,7H)和1.86-1.73(m,2H)。2×NHs丢失。
LCMS:m/z 443.4(M+H)+(ES+)。
步骤B:N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷亚氨代磺酰胺
在20℃下向N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷亚磺酰胺(250mg,564.88μmol,1当量)于THF(5mL)中的溶液中加入1-氯-1H-苯并[d][1,2,3]三唑(78mg,508.39μmol,0.9当量)。将反应混合物在20℃下搅拌30分钟。然后在-78℃下将反应混合物加入至NH3/THF溶液;使NH3气体(15psi)鼓泡至THF(5mL)中,历时5分钟,得到NH3/THF溶液。将所得混合物在-78℃下搅拌20分钟,然后升温至20℃并搅拌2小时。然后将反应混合物真空浓缩。将残余物通过制备型HPLC(柱:XtimateC18,150mm×40mm×10μm;流动相[A:水(0.05%氢氧化铵v/v);B:MeCN];B%:19%-49%,10分钟)纯化,得到呈黄色固体状的标题化合物(2.19mg,1%产率,LCMS上99.8%纯度)。
1H NMR(400MHz,CD3OD)δ8.12(d,1H),7.09(s,1H),6.82(d,1H),6.69(s,1H),5.14-5.12(m,1H),3.21(s,3H),3.03-3.01(m,2H),2.95(t,2H),2.88(t,2H),2.83-2.57(m,2H),2.55(s,3H)和2.14-1.92(m,9H)。3×NHs丢失。
LCMS:m/z 458.3(M+H)+(ES+)。
实施例53:1-(N-氰基-S-甲基-亚氨磺酰基)-3-(6-甲基-5-(2-((1-甲基-4-哌啶基)氧基)-4-吡啶基)茚满-4-基)脲
在25℃下向N-((6-甲基-5-(2-((1-甲基哌啶-4-基)氧基)吡啶-4-基)-2,3-二氢-1H-茚-4-基)氨甲酰基)甲烷亚氨代磺酰胺(实施例52)(30mg,65.56μmol,1当量)和三乙胺(27mg,262.24μmol,4当量)于DMF(1mL)中的混合物加入溴化氰(14mg,131.12μmol,2当量)。将反应混合物在25℃下搅拌12小时,然后用水(0.5mL)淬灭并真空浓缩。将残余物通过制备型HPLC(柱:Phenomenex Gemini-NX C18,75mm×30mm×3μm;流动相[A:水(0.1%TFA),B:MeCN];B%:20%-30%,7分钟)纯化,得到呈黄色油状物的标题化合物(21.8mg,54%产率,HPLC上97.6%纯度,TFA盐)。
1H NMR(400MHz,DMSO-d6+D2O)δ8.16(t,1H),7.09(s,1H),6.79(t,1H),6.63(d,1H),5.27-5.13(m,1H),3.48-3.45(m,1H),3.35-3.32(m,1H),3.27-3.12(m,5H),2.88(t,2H),2.81-2.75(m,5H),2.34-2.30(m,1H),2.18-2.13(m,1H),3.05-1.96(m,6H)和1.83-1.75(m,1H)。2×NHs丢失。
LCMS:m/z 483.2(M+H)+(ES+)。
实施例-生物学研究
NLRP3和细胞焦亡
众所周知,NLRP3的活化引起细胞焦亡,并且这个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抑制剂将阻断细胞焦亡以及促炎性细胞因子(例如IL-1β)从细胞释放。
THP-1细胞:培养和制备
使THP-1细胞(ATCC#TIB-202)在含有L-谷氨酰胺的RPMI(Gibco#11835)中生长,所述培养基补充有于10%胎牛血清(FBS)(Sigma#F0804)中的1mM丙酮酸钠(Sigma#S8636)和青霉素(100个单位/毫升)/链霉素(0.1mg/ml)(Sigma#P4333)。使细胞按照惯例进行传代并生长至汇合(约106个细胞/毫升)。实验当天,收获THP-1细胞并且再悬浮至RPMI培养基(无FBS)中。然后对细胞计数并用锥虫蓝(Sigma#T8154)检查活力(>90%)。进行适当稀释,得到625,000个细胞/毫升的浓度。向这个稀释的细胞溶液中加入LPS(Sigma#L4524),得到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。由此制备的平板用于筛选化合物。
THP-1细胞的细胞焦亡测定
以下方法逐步测定之后为化合物筛选。
1.将THP-1细胞(25,000个细胞/孔)在含有1.0μg/ml LPS的40μlRPMI培养基(无FBS)中接种在涂有多聚-D-赖氨酸(VWR#734-0317)的96孔黑壁透明底的细胞培养板中
2.加入5μl化合物(8点半对数稀释,最高剂量为10μM)或媒介物(DMSO 0.1%FAC)至适当孔
3.在37℃、5%CO2下孵育3小时
4.加入5μl尼日利亚菌素(nigericin,Sigma#N7143)(FAC 5μM)至所有孔
5.在37℃、5%CO2下孵育1小时
6.在孵育期结束时,将平板在300×下旋转3分钟并去除上清液
7.然后加入50μl刃天青(Sigma#R7017)(FAC无FBS的RPMI培养基中100μM刃天青)并在37℃和5%CO2下再孵育平板1-2小时
8.在Envision读数器中在Ex 560nm和Em 590nm下读取平板
9.将IC50数据拟合成非线性回归等式(log抑制剂对反应变化斜率4参数)
96孔板图
以下表1中以THP IC50概述细胞焦亡测定的结果。
人全血IL-1β释放测定
对于全身递送,当化合物存在于血流内抑制NLRP3的能力非常重要。为此,根据以下方案研究人全血中大量化合物的NLRP3抑制活性。
从来自志愿者供体小组的健康供体获得人全血于肝素锂管中。
1.将含有1μg/ml LPS的80μl全血涂铺在96孔透明底的细胞培养板(Corning#3585)中
2.加入10μl化合物(8点半对数稀释,最高剂量为10μM)或媒介物(DMSO 0.1%FAC)至适当孔
3.在37℃、5%CO2下孵育3小时
4.加入10μl尼日利亚菌素(Sigma#N7143)(10μM FAC)至所有孔
5.在37℃、5%CO2下孵育1小时
6.在孵育期结束时,将平板在300×g下旋转5分钟以使细胞成团粒,并去除20μl上清液并加入至96孔v形底板中,进行IL-1β分析(注意:这些含有上清液的板可以存储在-80℃下,以供日后分析)
7.根据制造商方案(Perkin Elmer-AlphaLisa IL-1试剂盒AL220F-5000)测量IL-1β
8.将IC50数据拟合成非线性回归等式(log抑制剂对反应变化斜率4参数)
以下表1中以HWB IC50概述人全血测定的结果。
为进行比较,表1中包括三种在权利要求书范围之外的化合物:
表1:NLRP3抑制活性(≤0.25μM=‘++++++’,≤0.5μM=‘+++++’,≤1μM=‘++++’,≤2μM=‘+++’,≤5μM=‘++’,≤10μM=‘+’,>10μM=‘非活性’,未测定=‘ND’)。
如从表1中呈现的结果显而易见,意外地,尽管与现有技术化合物对比存在结构差异,但本发明的化合物在细胞焦亡测定和尤其人全血测定中显示高水平的NLRP3抑制活性。
应了解上文只是借助于实施例来描述本发明。所述实施例不意图限制本发明的范围。在不脱离本发明的范围和精神下可进行多种修改和实施方案,本发明的范围和精神只由以下权利要求书限定。
Claims (25)
1.一种式(I)的化合物:
其中:
A为苯基或5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代;
B为苯基、5或6元杂芳基或4至6元饱和杂环基,其中B任选地被取代;
X为O、NH或N(CN);
Y为O或S;
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R4为单价的,并且在α’位置连接至A,并且选自C1-C4烷基、C3-C6环烷基和苯基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
或R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH=CHCH2-、-CH2CH=CH-、-CH2CH2O-、-OCH2CH2-、-CH2CH2CH2CH2-和-CH=CH-CH=CH-,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)或卤素;
R20为键、-NH-、-NMe-、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
2.如权利要求1所述的化合物,其中B为任选地被取代的吡啶基。
3.如权利要求1或2所述的化合物,其中所述化合物具有式(IA):
其中:
A为苯基或5或6元杂芳基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代;
B为苯基、5或6元杂芳基或4至6元饱和杂环基,其中B经R2取代,并且其中B任选地另外被取代;
X为O、NH或N(CN);
Y为O或S;
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-R8-OH、-R8-O(C1-C4烷基)、-R8-O(C1-C4卤代烷基)、-O-R10-OH、-O-R10-O(C1-C4烷基)、-O-R10-O(C1-C4卤代烷基)、-R8-NH2、-R8-NH(C1-C4烷基)、-R8-NH(C1-C4卤代烷基)、-R8-N(C1-C4烷基)2、-R8-N(C1-C4烷基)(C1-C4卤代烷基)、-R8-N(C1-C4卤代烷基)2、-R11、-OR11或-O-R10-R11;
R4为单价的,并且在α’位置连接至A,并且选自C1-C4烷基、C3-C6环烷基和苯基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
或R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH=CHCH2-、-CH2CH=CH-、-CH2CH2O-、-OCH2CH2-、-CH2CH2CH2CH2-和-CH=CH-CH=CH-,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氧代基、-OH、-O(C1-C4烷基)和-O(C1-C4卤代烷基);
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)或卤素;
R8为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R10为C1-C4亚烷基或C1-C4卤代亚烷基;
R11为C3-C6环烷基或4至6元饱和杂环基,其中所述环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C3-C4环烷基、C2-C4烯基、C2-C4卤代烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-NH2、-NH(C1-C4烷基)、-NH(C1-C4卤代烷基)、-N(C1-C4烷基)2、-N(C1-C4烷基)(C1-C4卤代烷基)和-N(C1-C4卤代烷基)2;
R20为键、-NH-、-NMe-、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
4.如权利要求1至3中任一项所述的化合物,其中B为吡啶基,经R2取代,并且任选地另外被取代。
5.如权利要求1至4中任一项所述的化合物,其中A为苯基或咪唑基,其中A在α位置经B取代,在β位置经R7取代并且在α'位置经R4取代,并且其中A任选地另外被取代。
6.如权利要求1至5中任一项所述的化合物,其中Y为O。
7.如权利要求1至6中任一项所述的化合物,其中
R4为单价的,并且在α’位置连接至A,并且选自异丙基、环戊基、环己基和苯基;
或R4为二价的,并且在α’和β’位置连接至A,并且选自-CH2CH2CH2-、-CH2CH2O-和-OCH2CH2-。
8.如权利要求1至7中任一项所述的化合物,其中所述化合物具有式(II):
其中:
X为O、NH或N(CN);
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2a为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)、-O(C1-C4卤代烷基)、-O-(烷氧基烷基)、-OR9或-OCH2-R9;
R3为氢或甲基;
R4a为C1-C4烷基、C3-C6环烷基或苯基,均任选地被卤代基取代;
R5为氢;或
R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-,均任选地被卤代基取代;
R6为氢、卤素或氰基;
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基或卤素;
R9为C3-C6环烷基或4至6元饱和杂环基,其中所述环烷基或杂环基任选地被卤代基取代及/或任选地经一个、两个或三个独立地选自以下的取代基取代:C1-C4烷基、C2-C4烯基、苯基、苯甲基、-OH、-O(C1-C4烷基)、-NH(C1-C4烷基)和-N(C1-C4烷基)2;
R20为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
9.如权利要求8所述的化合物,其中:
R5为氢并且R4a为异丙基、环戊基、环己基或苯基;
或R4a和R5一起形成-CH2CH2CH2-、-CH2CH2O-或-OCH2CH2-。
10.如权利要求8或9所述的化合物,其中R6为氢或氟。
11.如权利要求1至7中任一项所述的化合物,其中所述化合物具有式(III):
其中:
X为O、NH或N(CN);
R1为C1-C4烷基、C2-C4烯基、-NH(C1-C4烷基)、-N(C1-C4烷基)2或-R20-R21基团,均任选地被卤代基取代;
R2b为氢、卤代基、氰基、C1-C4烷基、C1-C4卤代烷基、-O(C1-C4烷基)或-O(C1-C4卤代烷基);
R3为氢或甲基;
R4b为C1-C4烷基或C1-C4卤代烷基;
R7为C1-C4烷基、C1-C4卤代烷基、C3-C6环烷基、C3-C6卤代环烷基或卤素;
R20为键、C1-C4亚烷基或C1-C4卤代亚烷基;
R21为C3-C6环烷基、苯基、4至6元饱和杂环基或5或6元杂芳基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:氰基、C1-C4烷基、C1-C4卤代烷基、C2-C4烯基、C2-C4卤代烯基、-R22-OH、-R22-O(C1-C4烷基)、-R22-O(C1-C4卤代烷基)、-R22-NH2、-R22-NH(C1-C4烷基)、-R22-NH(C1-C4卤代烷基)、-R22-N(C1-C4烷基)2、-R22-N(C1-C4烷基)(C1-C4卤代烷基)、-R22-N(C1-C4卤代烷基)2和-R22-R23;
R22为键、C1-C4亚烷基或C1-C4卤代亚烷基;并且
R23为C3-C6环烷基或4至6元饱和杂环基,均任选地被卤代基取代。
12.如权利要求11所述的化合物,其中R4b为异丙基、仲丁基、异丁基或叔丁基,均任选地被卤代基取代。
13.如权利要求1至12中任一项所述的化合物,其中X为O。
14.如权利要求1至13中任一项所述的化合物,其中R1为C1-C4烷基、C2-C4烯基、-NHMe、-NMe2、-NHEt、-NEt2或-NMeEt,均任选地被卤代基取代;或R1为C3-C6环烷基、苯基、吡咯烷基、哌啶基、四氢呋喃基、四氢吡喃基、呋喃基、噻吩基、吡唑基或咪唑基,均任选地被卤代基取代及/或任选地经一个或两个独立地选自以下的取代基取代:C1-C3烷基、-R22-OH、-R22-O(C1-C3烷基)、-R22-NH(C1-C3烷基)、-R22-N(C1-C3烷基)2和-R22-R23;其中R22为键或C1-C4亚烷基;并且R23为C3-C6环烷基、氮杂环丁烷基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基。
15.如权利要求3至14中任一项所述的化合物,其中R2为氢、卤代基、氰基、C1-C3烷基、C1-C3卤代烷基、-R8-OH、-R8-O(C1-C3烷基)、-R8-O(C1-C3卤代烷基)、-O-R10-OH、-O-R10-O(C1-C3烷基)、-R11、-OR11或-O-R10-R11;其中
R8为键或-CH2-;
R10为C1-C3亚烷基;并且
R11为环丙基、环丁基、环戊基、环己基、吡咯烷基、哌啶基、四氢呋喃基或四氢吡喃基,均任选地经一个或两个独立地选自以下的取代基取代:氟、C1-C3烷基、C2-C3烯基、苯基、苯甲基、-OH、-O(C1-C3烷基)、-NH2、-NH(C1-C3烷基)和-N(C1-C3烷基)2。
16.如权利要求1至15中任一项所述的化合物,其中R7为甲基、乙基、环丙基或氟。
18.一种权利要求1至17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。
19.一种药物组合物,其包含权利要求1至17中任一项所述的化合物或权利要求18所述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。
20.如权利要求19所述的药物组合物,其中所述药物组合物是口服或局部药物组合物。
21.如权利要求1至17中任一项所述的化合物,或如权利要求18所述的药学上可接受的盐、溶剂合物或前药,或如权利要求19或20所述的药物组合物,其用于医药中。
22.如权利要求21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,其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。
23.如权利要求21或22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,其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)淋巴管疾患;
(xiv)心理病症;
(xv)移植物抗宿主疾病;
(xvi)触诱发痛;和
(xvii)已经确定个体携带NLRP3的生殖系或体细胞非沉默突变的任何疾病。
24.如权利要求21或22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,其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)冷吡啉相关周期性综合征(CAPS);
(ii)穆-韦二氏综合征(MWS);
(iii)家族性寒冷性自身炎症性综合征(FCAS);
(iv)新生儿发作型多系统炎性疾病(NOMID);
(v)家族性地中海热(FMF);
(vi)化脓性关节炎、坏疽性脓皮病和痤疮综合征(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)受体相关周期性综合征(TRAPS);
(ix)全身性幼年特发性关节炎;
(x)成人发作型斯蒂尔病(AOSD);
(xi)复发性多软骨炎;
(xii)施尼茨勒综合征;
(xiii)斯维特综合征;
(xiv)白塞病;
(xv)抗合成酶综合征;
(xvi)白细胞介素1受体拮抗体缺陷(DIRA);和
(xvii)A20单倍剂量不足(HA20)。
25.一种抑制NLRP3的方法,所述方法包括使用如权利要求1至17中任一项所述的化合物、或如权利要求18所述的药学上可接受的盐、溶剂合物或前药、或如权利要求19或20所述的药物组合物以抑制NLRP3。
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US20220106288A1 (en) | 2022-04-07 |
EP3837243A1 (en) | 2021-06-23 |
GB201902327D0 (en) | 2019-04-03 |
WO2020035466A1 (en) | 2020-02-20 |
JP2021535098A (ja) | 2021-12-16 |
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