CN114269736A - 一种酰胺化合物、药物组合物及其应用 - Google Patents
一种酰胺化合物、药物组合物及其应用 Download PDFInfo
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- CN114269736A CN114269736A CN202180004138.7A CN202180004138A CN114269736A CN 114269736 A CN114269736 A CN 114269736A CN 202180004138 A CN202180004138 A CN 202180004138A CN 114269736 A CN114269736 A CN 114269736A
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- cancer
- cycloalkyl
- chain alkyl
- amide compound
- heterocycloalkyl
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
本申请提供一种酰胺化合物、其异构体、药学上可接受的盐、药物组合物及其应用,所述酰胺化合物具有式I所示结构。本申请的酰胺化合物具有显著的JAK激酶抑制活性、尤其是JAK1激酶抑制活性,对JAK1激酶的抑制活性比对JAK2激酶的抑制活性高,能够作为高选择性的JAK1激酶抑制剂。因此本申请的酰胺化合物可用于制备治疗JAK1激酶介导的疾病的药物。
Description
相关申请
本申请要求申请号为202011348554.2专利申请的优选权(在先申请的申请日为2020年11月26日,发明名称为“一种酰胺化合物、药物组合物及其应用”),其全部内容通过引用结合在本申请中。
技术领域
本申请属于药物化学技术领域,具体涉及一种酰胺化合物、含有所述酰胺化合物的药物组合物以及所述酰胺化合物或药物组合物在制备药物中的应用。
背景技术
JAKs(Janus-associated kinases)是一种非受体酪氨酸激酶,其中包括四个家族成员:JAK1、JAK2、JAK3和TYK2。JAKs在许多细胞因子和生长因子的信号传导中起关键的作用。当一个细胞因子与其受体结合时,与该受体偶联的JAK发生磷酸化和激活。激活的JAK依次磷酸化细胞因子受体和信号转导子与转录激活子(STAT)蛋白。激活的STAT蛋白形成二聚体,转移至细胞核内,调节基因的表达(“The regulation of JAKs in cytokinesignaling and its breakdown in disease”,Hammaren H.M.等,Cytokine,2019,118,48-63)。
由于JAK/STAT信号通路介导了许多细胞因子的信号传递,JAK/STAT信号通路的失调引起了许多炎症和自身免疫性疾病以及癌症(“The JAK-STAT Pathway:Impact onHuman Disease and Therapeutic Intervention”,O'Shea J.J.等,Annual Review ofMedicine,2015,66,311-328)。这些疾病已经在临床上被证实可以通过抑制JAK激酶来治疗(“Therapeutic targeting of JAKs:from hematology to rheumatology and from thefirst to the second generation of JAK inhibitors”,Bertsias G.,MediterraneanJournal of Rheumatology,2020,31,Supp 1,105-111)。目前,已经有多个非选择性的JAK抑制剂被批准用于治疗炎症和自身免疫性疾病(例如tofacitinib和baricitinib)以及原发性骨髓纤维化(例如ruxolitinib),但这些药物都有剂量限制性毒性,例如贫血和血小板降低的副作用(“Clinical efficacy of launched JAK inhibitors in rheumatoidarthritis”,Taylor P.C.,Rheumatology,2019,58,i17-i26;“Safety and efficacy ofbaricitinib at 24weeks in patients with rheumatoid arthritis who have aninadequate response to methotrexate”,Keystone E.C.等,Annals of the RheumaticDiseases,2015,74,333-340),其原因是这些抑制剂都抑制了JAK2激酶,从而干扰了促红细胞生成素(EPO)和血小板生成素(TPO)的信号(“Selective JAKinibs:Prospects inInfammatory and Autoimmune Diseases”,Virtanen A.T.等,BioDrugs,2019,33,15-32)。
在JAK家族的四个成员中,JAK1是参与细胞因子信号最广的激酶,而且是唯一能够与其它三个JAKs形成配对来调节信号的成员。由于JAK1的这一特点,有选择性地抑制JAK1而不需要抑制其它的JAKs,尤其是JAK2就足以阻断JAK/STAT的信号通路(“SelectiveJAKinibs:Prospects in Infammatory and Autoimmune Diseases”,Virtanen A.T.等,BioDrugs,2019,33,15-32)。因此,有选择性的JAK1抑制剂有可能足以用于治疗与JAK/STAT信号通路失调相关的炎症和自身免疫性疾病以及癌症。目前,已经公开的有选择性的JAK1抑制剂(例如upadacitinib、filgotinib)被批准用于治疗RA,但这些抑制剂对JAK2的选择性都不高,在激酶测试中都小于3倍(“In vitro and in vivo characterization of theJAK1 selectivity of upadacitinib(ABT-494)”,Parmentier J.M.等,BMCRheumatology,2018,2,23;“Preclinical Characterization of GLPG0634,a selectiveinhibitor of JAK1,for the treatment of inflammatory diseases”,Van Rompaey L.等,Journal of Immunology,2013,191,3568-3577;“Triazolopyridines as SelectiveJAK1 Inhibitors:From Hit Identification to GLPG0634”,Menet C.J.等,Journal ofMedicinal Chemistry,2014,57,9323-9342)。
因此,开发一种对JAK2选择性更高、对JAK1抑制作用更显著的化合物,是本领域亟待解决的问题。
发明内容
本申请提供一种酰胺化合物、药物组合物及其应用,其中,所述酰胺化合物具有抑制JAK1激酶活性的作用,以及良好的JAK2选择性。
第一方面,本申请提供一种酰胺化合物,所述酰胺化合物具有如式I所示结构:
式I中,R1选自H、卤素、C1~C6直链或支链烷基,C3~C6环烷基或ORa;所述直链或支链烷基、环烷基无取代或被1~3个(例如1个、2个或3个)R1a取代。
R1a选自D或卤素。
式I中,R2选自H、C1~C6直链或支链烷基、C3~C10环烷基或C2~C10杂环烷基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~3个(例如1个、2个或3个)R2a取代。
R2a选自D、卤素、氰基、未取代或卤代的C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、ORa1、SRa1、NRb1Rc1、CORa1、CONRb1Rc1、COORa1、SO2Ra1、SO2NRb1Rc1、NRb1CORa1、NRd1CONRb1Rc1、NRb1SO2Ra1、NRd1SO2NRb1Rc1或SORa1。
式I中,R3选自H、卤素、氰基、未取代或卤代的C1~C6直链或支链烷基、C2~C6烯基、C2~C6炔基或C3~C6环烷基。
式I中,R4选自SO2Ra2、CORa2、COORa2、C3~C10环烷基或C2~C10杂环烷基;所述环烷基、杂环烷基无取代或被1~5个(例如1个、2个、3个、4个或5个)R4a取代。
R4a选自D、卤素、氰基、C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、ORa3、SRa3、NRb3Rc3、CORa3、CONRb3Rc3、COORa3、SO2Ra3或SO2NRb3Rc3;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个(例如1个、2个、3个、4个或5个)R4b取代。
R4b选自D、卤素、氰基、ORa4或NRb4Rc4。
式I中,R5选自F、氰基、C1~C6直链或支链烷基、ORa5。
Ra、Ra1、Rb1、Rc1、Rd1、Ra2、Ra3、Rb3、Rc3、Ra4、Rb4、Rc4、Ra5各自独立地选自H、C1~C10直链或支链烷基、C2~C10烯基、C2~C10炔基、C3~C10环烷基或C2~C10杂环烷基;所述直链或支链烷基、烯基、炔基、环烷基、杂环烷基无取代或被1~4个(例如1个、2个、3个或4个)R6取代。
R6选自D、卤素、氰基、羟基、未取代或卤代的C1~C6直链或支链烷基、C2~C6烯基、C2~C6炔基、C3~C6环烷基、C2~C6杂环烷基、ORa6、SRa6、NRb6Rc6、CORa6、CONRb6Rc6、COORd6、SO2Ra6、SO2NRb6Rc6、NRb6CORa6、NRd6CONRb6Rc6、NRb6SO2Ra6、NRd6SO2NRb6Rc6或SORa6。
Ra6、Rb6、Rc6、Rd6各自独立地选自H、C1~C10直链或支链烷基、C2~C10烯基、C2~C10炔基、C3~C10环烷基或C2~C10杂环烷基。
式I中,n选自0~3的整数,例如0、1、2或3。
当n≥2时,R5之间不连接或通过化学键连接形成3至6元的碳环或碳杂环,即连接在同一个C原子上的2个取代基R5、连接在相邻两个碳原子上的2个取代基R5彼此不连接,或通过化学键连接成环,该环为3至6元(例如3元、4元、5元或6元)的碳环或碳杂环。
本申请中,连接于同一个N原子上的2个取代基Rb1和Rc1、Rb3和Rc3、Rb4和Rc4、Rb6和Rc6彼此不连接,或通过化学键连接成杂环基(含N杂环)。所述杂环基无取代或被1~3个(例如1个、2个或3个)取代基取代,所述取代基的选择范围与R6相同。
本申请中,所述卤素包括F、Cl、Br或I;下文涉及到相同描述,均具有相同的含义。
本申请中,所述C1~C10直链或支链烷基各自独立地可以为C1、C2、C3、C4、C5、C6、C7、C8、C9或C10的直链或支链烷基,示例性地包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或新戊基等。
所述C3~C10环烷基各自独立地可以为C3、C4、C5、C6、C7、C8、C9或C10的环烷基,示例性地包括但不限于:环丙基、环丁基、环戊基或环己基等。
所述C2~C10杂环烷基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的杂环烷基,其中的杂原子包括O、N、S、P或Si等,示例性地包括但不限于:四氢呋喃环、四氢吡咯环(吡咯啶环)、哌啶环等。
所述C1~C6直链或支链烷基各自独立地可以为C1、C2、C3、C4、C5或C6的直链或支链烷基,示例性地包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基或新戊基等。
所述C3~C6环烷基各自独立地可以为C3、C4、C5或C6的环烷基,示例性地包括但不限于:环丙基、环丁基、环戊基或环己基等。
所述C2~C6杂环烷基各自独立地可以为C2、C3、C4、C5或C6的杂环烷基,其中的杂原子包括O、N、S或P等,示例性地包括但不限于:四氢呋喃环、四氢吡咯环(吡咯啶环)、哌啶环等。
所述C2~C6烯基各自独立地可以为C2、C3、C4、C5或C6的烯烃基,示例性地包括但不限于:乙烯基、丙烯基、烯丙基或1-丁烯基等。
所述C2~C6炔基各自独立地可以为C2、C3、C4、C5或C6的炔烃基,示例性地包括但不限于:乙炔基、丙炔基、炔丙基、1-丁炔基或2-丁炔基等。
所述C2~C10烯基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的烯烃基。
所述C2~C10炔基各自独立地可以为C2、C3、C4、C5、C6、C7、C8、C9或C10的炔烃基。
优选地,所述酰胺化合物具有如式IA所示结构:
式IA中,R3、R4各自独立地具有与式I中相同的限定范围。
式IA中,R5a、R5b各自独立地选自H、F、氰基、C1~C6直链或支链烷基、C3~C6环烷基或ORa5;R5a与R5b不连接或通过化学键连接形成3至6元的碳环或杂碳环。
优选地,所述R3选自H、卤素、C1~C6直链或支链烷基。
优选地,所述Ra2选自C1~C6直链或支链烷基。
优选地,所述Ra5选自C1~C6直链或支链烷基,进一步优选为甲基或乙基。
优选地,所述酰胺化合物具有如式IB所示结构:
式IB中,R3、R5a、R5b各自独立地具有与式IA中相同的限定范围。
式IB中,Y为NR7或O。
R7选自H、C1~C6直链或支链烷基、C3~C6环烷基、C2~6杂环烷基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个(例如1个、2个、3个、4个或5个)R7a取代。
R7a选自D、卤素、氰基、C1~C6(例如C1、C2、C3、C4、C5或C6)直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、羟基、C1~C6直链或支链烷氧基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个(例如1个、2个、3个、4个或5个)R7b取代。
R7b选自D、卤素、氰基、羟基、C1~C6直链或支链烷氧基。
m为1或2,p选自1~3的整数,例如可以为1、2或3。
优选地,所述R3选自H、卤素、甲基。
优选地,所述R5a、R5b各自独立地选自H、F、甲氧基或乙氧基。
优选地,所述R7为H或甲基。
优选地,所述p为2。
优选地,所述酰胺化合物包括如下化合物中的任意一种或至少两种的组合:
第二方面,本申请提供一种如第一方面所述的酰胺化合物的立体异构体、几何异构体、互变异构体或其药学上可接受的盐。
第三方面,本申请提供一种药物组合物,所述药物组合物包括活性成分与至少一种药用载体或赋形剂;所述活性成分包括如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐中的任意一种或至少两种的组合。
第四方面,本申请提供一种如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如第三方面所述的药物组合物在制备用于抑制JAK激酶的药物中的应用。
优选地,所述JAK激酶为JAK1激酶。
第五方面,本申请提供一种如第一方面所述的酰胺化合物、如第二方面所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如第三方面所述的药物组合物在制备用于治疗JAK激酶介导的疾病的药物中的应用。
所述疾病包括自身免疫性疾病、炎症疾病、疼痛病、呼吸道疾病、气道疾病、肺疾病、肺炎症和损伤、肺动脉高压、胃肠道疾病、过敏性疾病、感染疾病、创伤和组织损伤疾病、纤维化疾病、眼疾病、关节疾病、肌肉疾病、骨疾病、皮肤疾病、肾脏疾病、造血系统疾病、肝脏疾病、口腔疾病、代谢疾病、心脏疾病、血管疾病、神经炎性疾病、神经变性疾病、脓毒症、基因疾病或癌症。
优选地,所述疾病包括炎症、自身免疫性疾病或癌症。
优选地,所述炎症、自身免疫性疾病包括系统性红斑狼疮、狼疮性肾炎、关节炎、牛皮癣、克罗恩病、溃疡性结肠炎、特应性皮炎、痛风、脱发秃头症、白癜风、化脓性汗腺炎、I型糖尿病、慢性肾脏病、急性肾脏损伤、慢性阻塞性肺疾病、哮喘、支气管炎或移植物抗宿主病。
优选地,所述癌症包括乳腺癌、肺癌、前列腺癌、胆小管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子宫颈癌、阴道癌、白血病、骨髓纤维化、多发性骨髓瘤或淋巴瘤。
相对于现有技术,本申请具有以下有益效果:
本申请提供一种具有新化学结构的酰胺化合物,其具有显著的抑制JAK激酶的活性、尤其是抑制JAK1激酶的活性,对JAK1激酶的抑制活性比对JAK2激酶的抑制活性高,能够作为高选择性的JAK1激酶抑制剂。本申请酰胺化合物可用于制备治疗JAK1激酶介导的疾病的药物,在JAK1激酶介导的炎症、自身免疫性疾病或癌症等病症中将发挥良好的治疗效果,具有广阔的应用前景。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本申请,不应视为对本申请的具体限制。
本申请的术语“卤基”或“卤素”包括氟、氯、溴、和碘。
术语“直链或支链烷基”是指直链或支链的饱和烃基团。烷基的实例包括甲基(Me)、乙基(Et)、丙基(例如正丙基、异丙基)、丁基(例如正丁基、异丁基、特丁基)、戊基(例如正戊基、异戊基、新戊基)、己基(例如正己基、2-己基、3-己基、2-甲基戊基、3-甲基戊基、2,2-二甲基丁基、3-乙基戊基-1等)、庚基(例如正庚基、2-庚基、3-庚基、4-庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、3-乙基戊基-1等)、辛基(例如1-辛基、2-辛基、2-乙基己基等)、壬基(如1-壬基)、癸基(如正癸基等),以及类似基团。进一步优选的碳原子数为1、2、3、4、5、6的直链或支链的烷基。除非有相反定义,本申请中的所有基团定义如在本文中所定义。
术语“卤代烷基”是指具有一个或多个卤素取代基的烷基基团。其中烷基基团和卤基或卤素的定义如上。卤代烷基基团的实例包括CH2F、CHF2、CF3、C2F5、CCl3,以及类似基团。
术语“烯基”是指具有一个或多个C=C双键的烃基基团。烯基的实例包括乙烯基、丙烯基、烯丙基、1-丁烯基、2-丁烯基、1,3-丁二烯基、1-戊烯基、2-戊烯基、1,3-戊二烯基、1-己烯基、2-己烯基等,以及类似基团。
术语“炔基”是指具有一个或多个C≡C三键的烃基基团。炔基的实例包括乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基等,以及类似基团。
术语“环烷基”是指非芳香碳环,包括环化的烷基、环化的烯基、环化的炔基。环烷基可以为单环或多环(例如具有2、3或4个的稠合环)的环系统,包括螺环。在某些实施方式中,环烷基可具有3、4、5、6、7、8、9、10个碳原子。环烷基可进一步具有0、1、2或3个C=C双键,和/或,0、1或2个C≡C三键。同时被包括在环烷基的定义中的还有那些具有一个或多个稠合于环烷基环的芳香环(例如具有共用的键)的部分,例如戊烷、戊烯、己烷、己烯的苯并衍生物等,以及类似化合物。具有一个或多个稠合芳环的环烷基可以通过芳香部分或非芳香部分连接。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基、金刚烷基、二氢茚基、四氢萘基以及类似基团。
术语“杂环烷基”是指其中一个或多个形成环的原子是如O、N,P或S等杂原子的非芳香杂环。杂环基可包括单环或多环(如具有2、3或4个稠合环)的环系统以及螺环。优选的“杂环烷基”的实例包括但不限于:氮杂环丙烷基、氮杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、吡咯烷基、噁唑烷基、噻唑烷基、咪唑烷基、异噁唑烷基、异噻唑烷基、吡唑烷基、吗啉基、硫代吗啉基、哌嗪基、哌啶基,以及类似基团。同时被包括在杂环烷基的定义中还有那些具有一个或多个稠合于非芳香杂环烷基环的芳香环(例如具有共用的键)的部分,例如2,3-二氢苯并呋喃基、1,3-苯并二氧杂环戊烯基、苯并-1,4-二氧杂环己基、邻苯二甲酰亚胺基、萘二甲酰亚胺基,以及类似基团。具有一个或多个稠合芳环的杂环烷基基团可以通过芳香部分或非芳香部分连接。
术语“酰胺化合物”,如在本文中所使用,是指包括所有的立体异构体、几何异构体、互变异构体、同位素。
本申请所述酰胺化合物可以是非对称的,例如具有一个或多个立体中心。除非有另外的限定,所有的立体异构体,可以是对映异构体和非对映异构体。含有非对称取代的碳原子的本申请的酰胺化合物可以被分离成光学纯或外消旋形式。光学纯形式可以通过外消旋体的拆分来制备,或者通过使用手性合成子(synthon)或手性试剂来制备。
本申请所述酰胺化合物也可以包括互变异构体形式。互变异构体新形式由单键和相邻的双键一起伴随质子的迁移而互换所产生的。
本申请所述酰胺化合物也可以包括存在于中间体或最终化合物中的原子的所有同位素形式。同位素包括具有相同的原子序数但不同的质量数的原子。例如,氢的同位素包括氘和氚。
本申请还包括所述酰胺化合物的药学上可接受的盐。“药学上可接受的盐”是指其中母体化合物通过所存在的碱部分转化成它的盐形式而进行改性的化合物的衍生物,或者其中母体化合物通过所存在的酸部分转化成它的盐形式而进行改性的化合物的衍生物。药学上可接受的盐的实例包括但不限于:碱性基团(如氨)的无机或有机酸的盐,或者酸性基团(如羧酸)的无机或有机碱的盐。本申请的药学上可接受的盐可以由式I、式IA和式IB的母体化合物通过在溶剂体系中使这些化合物的游离碱形式与1~4当量适当的酸反应而合成。合适的盐在Remington's Pharmaceutical Sciences,17th ed.,Mack PublishingCompany,Easton Pa.,1985,1418和Journal of Pharmaceutical Science,66,2,1977中列出。
本申请所述酰胺化合物、及其药学上可接受的盐还包括溶剂化物形式或水合物形式。一般而言,溶剂化物形式或水合物形式与非溶剂化物形式或非水合物形式是等同的,均包括在本申请的范围内。本申请的一些酰胺化合物可以多种晶型形式或非晶型形式存在。总体而言,化合物的所有的物理形式都包括在本申请的范围内。
本申请还包括所述酰胺化合物的前药。前药是一种由母体药物衍生的药理学物质(即药物)。一旦给药之后,前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备。关于前药的制备和使用可以在“Pro-drugs as NovelDelivery Systems”,T.Higuchi and V.Stella,Vol.14of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design,ed.Edward B.Roche,AmericanPharmaceutical Association and Pergamon Press,1987中找到。
在一个具体实施方式中,所述酰胺化合物包括如下化合物:
(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(乙磺酰基)吡咯啶-2-甲酰胺;
(S)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺;
(S)-N-(3-(5-氯-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺;
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4R)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-4-甲氧基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-4-甲氧基-1-(哌啶-4-基)吡咯啶-2-甲酰胺;
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4S)-4-乙氧基-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4S)-4-甲氧基-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(R)-N-(3-(5-氯-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺;
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R,4S)-4-氟-N-(3(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R)-4,4-二氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-4,4-二氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-((R)-四氢呋喃-3-基)吡咯啶-2-甲酰胺;
(R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)-1-((S)-四氢呋喃-3-基)吡咯啶-2-甲酰胺;
(2R,3'R)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S)-4,4-二氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'R,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;
(2R,3'S,4S)-4-氟-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺;和
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺。
本申请提供了一种药物组合物,由所述酰胺化合物或其N-氧化物衍生物、单独的异构体、或其异构体的混合物,以及药学上可接受的盐与药学上可接受的载体或赋形剂组成。本申请的药物组合物可以通过口服给药、胃肠外给药(注射给药)、喷雾吸入、局部给药、经直肠给药、经鼻腔给药、阴道给药、腹膜内给药或经由植入的储库给药。
本申请的另一方面,所述酰胺化合物和药学上可接受的盐可与一个或多个其它药物联合使用。联合用药时,本申请所述酰胺化合物与联合使用的药物可能起到叠加的作用或协同的作用。联合使用的药物可以是小分子药物、单体克隆药物、融合蛋白药物或抗感DNA药物。
在一个具体实施方式中,所述酰胺化合物可通过如下制备路线1或制备路线2获得:
制备路线1
制备路线2
上述制备路线中,NH2-pyrazole代表R1、R2、R3、R4、R5、n各自独立地具有与式I中相同的限定范围;Ts、Boc、SEM为氨基保护基;Bzl代表苄基,为羧酸保护基;Y为离去基团,例如Cl。具体合成方法在实施例中进行详细描述。
制备例1
制备中间体1:3-甲氧基-1-甲基-4-氨基-1H-吡唑,具体步骤如下:
(1)合成3-甲氧基-1H-吡唑-4-甲酸甲酯
于一1L圆底烧瓶中,加入2-(甲氧基亚甲基)马来酸二甲酯(25.0g,143.7mmol)、盐酸肼(20.0g,292.0mmol)和乙醇(EtOH,500mL),然后加热回流反应16h。反应完成后,减压浓缩除掉乙醇,余物分散于乙酸乙酯(EtOAc,500mL),搅拌30min后过滤,滤渣以EtOAc洗涤。滤液浓缩除去溶剂得10.0g产物。产率45%。LCMS(ESI):m/z=157(M+H)+。
(2)合成3-甲氧基-1H-吡唑
于一100mL圆底烧瓶中,3-甲氧基-1H-吡唑-4-甲酸甲酯(10.0g,64.1mmol)溶于盐酸(6M,30mL),然后加热到90℃反应16h。反应完成后,加水稀释,以NaHCO3固体中和。所得水相以EtOAc萃取,酯相以无水Na2SO4干燥,过滤后浓缩得6.0g产物。产率95%。LCMS(ESI):m/z=99(M+H)+。
(3)合成3-甲氧基-4-硝基-1H-吡唑
冰水浴下,3-甲氧基-1H-吡唑(6.0g,61.2mmol)溶于浓硫酸(36mL),向溶液中分批加入硝酸钾固体(6.2g,61.2mmol),维持温度反应30min。反应完成后,将反应液倒入冰水中,以NaHCO3固体中和。水相以EtOAc萃取,酯相以无水Na2SO4干燥,过滤后浓缩得4.2g产物。产率48%。LCMS(ESI):m/z=144(M+H)+。
(4)合成3-甲氧基-1-甲基-4-硝基-1H-吡唑
于一100mL圆底烧瓶中,3-甲氧基-4-硝基-1H-吡唑(4.2g,29.4mmol)溶于二甲基甲酰胺(DMF,40mL),向溶液中加入K2CO3(6.1g,44.1mmol),室温反应30min后加入碘甲烷(12.5g,88.2mmol),室温反应16h。反应完成后,加水稀释,以EtOAc萃取,酯相以无水Na2SO4干燥,过滤后浓缩得3.8g产物。产率82%。LCMS(ESI):m/z=158(M+H)+。
(5)合成3-甲氧基-1-甲基-4-氨基-1H-吡唑
往3-甲氧基-1-甲基-4-硝基-1H-吡唑(3.8g,24.2mmol)的EtOAc/EtOH(40mL/10mL)溶液中,加入钯炭(10%Pd/C,55%水,1.0g)和水合肼(8mL),室温反应16h。反应完成后,过滤,滤渣以EtOAc洗涤。合并滤液,减压浓缩,所得余物溶于EtOAc,快速搅拌下滴入HCl/EtOAc至沉淀析出完全。过滤,滤渣以EtOAc和乙腈(MeCN)洗涤,得到产物的盐酸盐3.5g。产率89%。LCMS(ESI):m/z=128(M+H)+。
制备例2
制备中间体2:7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-(4-甲基苯磺酰基)-1H-吲哚,具体步骤如下:
(1)合成7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
于一1000mL圆底烧瓶中,7-硝基-1H-吲哚(16.2g,100.0mmol)和四丁基溴化铵(3.2g,10.0mmol)溶于CH2Cl2(300mL),置于冰水浴冷却。向上述溶液滴入NaOH水溶液(10M,40mL),维持温度反应30min,然后加入4-甲基苯磺酰氯(28.5g,150.0mmol)。反应体系可自然升室温反应16h。反应完成后,加CH2Cl2稀释,有机相依次以水、10%K2CO3水溶液、水、1M稀盐酸、饱和NaCl水溶液洗涤,无水Na2SO4干燥,过滤后浓缩得产物30.0g。产率95%。LCMS(ESI):m/z=317(M+H)+。
(2)合成3-溴-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
冰水浴下,7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(31.6g,100.0mmol)溶于CH2Cl2/CCl4(250mL/250mL),然后缓慢滴入Br2(24.0g,150.0mmol)的CCl4溶液(100mL),滴完后自然升室温反应16h。反应完成后,减压浓缩除去溶剂,加入EtOAc(500mL),加热回流1h,然后冷至室温,过滤,滤渣以EtOAc洗涤,干燥得到淡黄色固体25g。产率63%。
(3)合成7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-(4-甲基苯磺酰基)-1H-吲哚
N2保护下,于一500mL圆底烧瓶中,加入3-溴-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(10.0g,31.6mmol),联硼酸频哪醇酯(16.0g,63.2mmol),钯催化剂Pd(dppf)Cl2(2.3g,3.2mmol),乙酸钾(AcOK,9.3g,94.8mmol)和二氧六环(300mL),加热到100℃反应16h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩至50mL,然后加入石油醚300mL,快速搅拌1min后迅速过滤。滤液置于冰水浴中冷却析出固体,过滤。滤渣以石油醚,冷乙醇洗涤得淡黄色固体7.5g。产率54%。LCMS(ESI):m/z=443(M+H)+。
制备例3
制备中间体3:3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-胺,具体步骤如下:
(1)合成3-(2-氯嘧啶-4-基)-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚
N2保护下,于一100mL圆底烧瓶中,加入中间体2(2.0g,4.5mmol),2,4-二氯嘧啶(666mg,4.5mmol),Pd(dppf)Cl2(366mg,0.5mmol),四丁基氟化铵(131mg,0.5mmol),Na2CO3(1.4g,13.5mmol)和DMSO(30mL),置于预加热到120℃的油浴锅中反应2h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与甲醇MeOH体积比为20:1的混合液),得产物1.5g。产率78%。LCMS(ESI):m/z=429(M+H)+。
(2)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺
N2保护下,于一100mL圆底烧瓶中,加入3-(2-氯嘧啶-4-基)-7-硝基-1-(4-甲基苯磺酰基)-1H-吲哚(1.5g,3.5mmol),3-甲氧基-1-甲基-1H-吡唑-4-胺盐酸盐(570mg,3.5mmol),钯催化剂Pd(dba)2(230mg,0.4mmol),联萘二苯磷(BINAP,249mg,0.4mmol),Cs2CO3(4.5g,14.0mmol)和二氧六环(30mL),加热到110℃反应2h。反应体系冷至室温,加入NaOH水溶液(3M,10mL),室温反应1h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比为10:1的混合液),得产物1.0g。产率78%。LCMS(ESI):m/z=366(M+H)+。
(3)合成3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-胺
冰水浴下,N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(1.0g,2.7mmol)溶于EtOH(20mL),然后加入乙酸(AcOH,1.6g,27mmol)和锌粉(864mg,13.5mmol),自然升室温反应1h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩得产物850mg。产率94%。LCMS(ESI):m/z=336(M+H)+。
按照制备例3中的中间体3的合成路线合成中间体4-5,具体结构及产物质谱信息如表1所示。
表1
制备例4
制备中间体6:3-(2((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-胺,具体步骤如下:
(1)合成3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1H-吲哚
N2保护下,于一100mL圆底烧瓶中,中间体2(2.0g,4.5mmol),2,4-二氯-5-甲基嘧啶(734mg,4.5mmol),Pd(dppf)Cl2(366mg,0.5mmol),四丁基氟化铵(131mg,0.5mmol),Na2CO3(1.4g,13.5mmol)和DMSO(30mL),置于预加热到120℃的油浴锅中反应2h。反应体系冷至室温,加入NaOH水溶液(3M,10mL),室温反应1h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比为10:1的混合液)得产物1.0g。产率77%。LCMS(ESI):m/z=289(M+H)+。
(2)合成3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1-((2-(三甲硅基)乙氧基)甲基)-1H-吲哚
冰水浴下,3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1H-吲哚(2.0g,6.9mmol)分散于四氢呋喃(THF,30mL)。向上述混合物加入NaH(556mg,60%,13.9mmol),维持温度反应30min。然后滴入2-(三甲基硅烷基)乙氧甲基氯(SEMCl,1.7g,10.4mmol),反应1h。反应完成后,将反应液小心倒入冰水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为5:1的混合液)得产物2.6g。产率90%。LCMS(ESI):m/z=419(M+H)+。
(3)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲哚-3-基)嘧啶-2-胺
N2保护下,于一100mL圆底烧瓶中,加入3-(2-氯-5-甲基嘧啶-4-基)-7-硝基-1-((2-(三甲硅基)乙氧基)甲基)-1H-吲哚(2.6g,6.2mmol),3-甲氧基-1-甲基-1H-吡唑-4-胺盐酸盐(1.0g,6.2mmol),Pd(dba)2(345mg,0.6mmol),BINAP(373mg,0.6mmol),Cs2CO3(6.0g,18.6mmol)和二氧六环(50mL),加热到110℃反应2h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为3:1的混合液),得产物2.3g。产率73%。LCMS(ESI):m/z=510(M+H)+。
(4)合成N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺
冰水浴下,N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吲哚-3-基)嘧啶-2-胺(2.3g,4.5mmol)溶于CH2Cl2(15mL),加入三氟乙酸(TFA,15mL),自然升室温反应1h。减压浓缩除去TFA,余物溶于MeOH(15mL),冰水浴冷却,加入氨水(25%,15mL),升室温反应6h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相CH2Cl2与MeOH体积比为20:1),得产物1.4g。产率为82%。LCMS(ESI):m/z=380(M+H)+。
(5)合成3-(2((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-胺
冰水浴下,N-(3-甲氧基-1-甲基-1H-吡唑-4-基)-5-甲基-4-(7-硝基-1H-吲哚-3-基)嘧啶-2-胺(1.4g,3.7mmol)溶于EtOH(20mL),然后加入AcOH(2.2g,37mmol)和锌粉(1.2g,18.5mmol),升室温反应1h。反应完成后,将反应液倒入水中,以EtOAc萃取。酯相以无水Na2SO4干燥,过滤后浓缩得产物1.2g。产率93%。LCMS(ESI):m/z=350(M+H)+。
制备例5
制备中间体7:(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺
于一100mL圆底烧瓶中,加入中间体4(1.2g,3.4mmol)和N-Boc-L-脯氨酸(731mg,3.4mmol)溶于CH2Cl2(30mL),然后加入N,N-二异丙基乙胺(DIEA,877mg,6.8mmol)和缩合试剂HATU(1.9g,5.1mmol),室温反应8h。反应完成后,加CH2Cl2稀释。有机相以水洗,无水Na2SO4干燥,过滤后浓缩。上所得余物溶于CH2Cl2(10mL),加入TFA(10mL),室温反应1h。反应完成后,加水,水相以EtOAc萃取,分液去掉有机相。水相以饱和Na2CO3溶液调碱,以CH2Cl2萃取。有机相以无水Na2SO4干燥,过滤后浓缩,得产物1.0g。产率65%。LCMS(ESI):m/z=451(M+H)+。
按照制备例5中间体7的合成路线依次合成中间体8-12,具体结构及产物质谱信息如表2所示。
表2
制备例6
制备中间体13:(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺,具体步骤如下:
(1)合成叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)胺甲酰基)吡咯啶-1-甲酸酯
于一100mL圆底烧瓶中,中间体6(1.2g,3.4mmol)和(2R,4S)-N-Boc-4-氟脯氨酸(792mg,3.4mmol)溶于吡啶(10mL),然后加入丙基磷酸三环酸酐(50%,溶剂为EtOAc,10.8g,17.0mmol),室温反应18h。反应完成后,加EtOAc稀释,以4M盐酸中和。有机相水洗,无水Na2SO4干燥,过滤后浓缩。所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比20:1混合液)得产物650mg。产率34%。LCMS(ESI):m/z=565(M+H)+。
(2)合成(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)吡咯啶-2-甲酰胺
叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)-5-甲基嘧啶-4-基)-1H-吲哚-7-基)胺甲酰基)吡咯啶-1-甲酸酯(650mg,1.2mmol)溶于CH2Cl2(10mL),加入TFA(10mL),室温反应1h。反应完成后,加水,水相以EtOAc萃取,分液去掉有机相。水相以饱和Na2CO3溶液调碱,以CH2Cl2萃取。有机相无水Na2SO4干燥,过滤后浓缩,得产物460mg。产率83%。LCMS(ESI):m/z=465(M+H)+。
按照制备例6中间体13的合成路线分别合成中间体14-19,具体结构及产物质谱信息如表3所示。
表3
实施例1
(S)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(甲磺酰基)吡咯啶-2-甲酰胺
冰水浴下,于一25mL圆底烧瓶中,中间体7(45mg,0.1mmol)和三乙胺(Et3N,30mg,0.3mmol)溶于CH2Cl2(2mL),然后加入甲烷磺酰氯(14mg,0.12mmol),反应10min。反应完成后,减压浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比10:1的混合液),得产物36mg。产率68%。LCMS(ESI):m/z=529(M+H)+。
1H-NMR(400MHz,CDCl3):δ11.61(s,1H),10.05(s,1H),8.50(d,J=8.1Hz,1H),8.18(d,J=3.7Hz,1H),8.07(t,J=2.8Hz,1H),7.75(s,1H),7.15(t,J=7.8Hz,1H),6.82(d,J=7.5Hz,1H),6.56(s,1H),4.38(dd,J=8.6,3.5Hz,1H),3.97(s,3H),3.80-3.62(m,4H),3.53-3.36(m,1H),2.98(s,3H),2.62-2.46(m,1H),2.28-2.17(m,1H),2.15-2.00(m,2H)。
以下表4所示的实施例2-4根据实施例1中的方法制备得到。
表4
实施例5
(R)-N-(3-(5-氟-2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(哌啶-4-基)吡咯啶-2-甲酰胺
冰水浴下,于一25mL圆底烧瓶中,加入中间体8(90mg,0.2mmol),N-叔丁氧羰基-4-哌啶酮(80mg,0.4mmol),CH2Cl2(3mL)和MeOH(2mL)。往上反应液加入氰基硼氢化钠(19mg,0.3mmol),反应30min。然后,小心加入TFA(5mL),室温反应1h。反应完成后,加水,水相以EtOAc萃取,分液去掉有机相。水相以饱和Na2CO3溶液调碱,以CH2Cl2萃取。有机相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比为10:1,0.1%Et3N),得产物64mg。产率60%。LCMS(ESI):m/z=534(M+H)+。
1H-NMR(400MHz,CDCl3):δ11.61(s,1H),10.05(s,1H),8.50(d,J=8.1Hz,1H),8.18(d,J=3.7Hz,1H),8.07(t,J=2.8Hz,1H),7.75(s,1H),7.15(t,J=7.8Hz,1H),6.82(d,J=7.5Hz,1H),6.56(s,1H),3.98(s,3H),3.76(s,3H),3.56-3.46(m,1H),3.29(t,J=7.3Hz,1H),3.22-3.05(m,2H),2.71-2.52(m,4H),2.31-2.05(m,2H),2.02-1.72(m,4H),1.64-1.45(m,2H)。
以下表5所示的实施例6-17根据实施例5中的方法制备得到。
表5
实施例18和实施例19
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(实施例18)和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(实施例19)
(1)合成2-苄基1-(叔丁基)(2R,4S)-4-氟吡咯啶-1,2-二甲酸酯
于一250mL圆底烧瓶中,加入(2R,4S)-1-(叔丁氧羰基)-4-氟吡咯啶-2-羧酸(7.0g,30.0mmol)、碳酸铯(14.6g,45.0mmol)和MeCN(100mL),室温搅拌反应1h。向上述反应体系加入苄溴(7.7g,45.0mmol),然后加热至60℃反应2h。反应完成后,过滤,滤渣以EtOAc洗涤。滤液浓缩除去溶剂,得8.5g产物,产率88%。LCMS(ESI):m/z=324(M+H)+。
(2)合成苄基(2R,4S)-4-氟吡咯啶-2-甲酸酯
2-苄基1-(叔丁基)(2R,4S)-4-氟吡咯啶-1,2-二甲酸酯(8.5g,26.3mmol)溶于MeOH(40mL),置于冰水浴冷却,然后加入浓盐酸(12M,20mL),自然升室温反应1h。反应完成后,减压浓缩除去甲醇,余物溶于水,水相以EtOAc萃取,分液去掉有机相。水相以饱和Na2CO3溶液调碱,以CH2Cl2萃取。有机相以无水Na2SO4干燥,过滤后浓缩,得产物5.2g。产率89%。LCMS(ESI):m/z=224(M+H)+。
(3)合成2-苄基1'-(叔丁基)(2R,4S)-4-氟-[1,3'-联吡咯啶]-1',2-二甲酸酯
冰水浴下,于一100mL圆底烧瓶中,加入苄基(2R,4S)-4-氟吡咯啶-2-甲酸酯(5.2g,23.3mmol),N-Boc-3-吡咯烷酮(6.6g,35.6mmol)和MeOH(50mL)。向上述反应液加入氰基硼氢化钠(2.2g,35.6mmol),反应20h。反应完成后,加水,减压浓缩除去甲醇,水相以EtOAc萃取。有机相以无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为PE与EtOAc体积比为10:1的混合液),得产物7.6g。产率83%。LCMS(ESI):m/z=393(M+H)+。
(4)合成(2R,4S)-1'-(叔丁氧羰基)-4-氟-[1,3'-联吡咯啶]-2-甲酸
于一250mL装有氢气球的三口圆底烧瓶中,2-苄基1'-(叔丁基)(2R,4S)-4-氟-[1,3'-联吡咯啶]-1',2-二甲酸酯(7.6g,19.4mmol)溶于MeOH(40mL),然后加入Pd/C(2.0g,10%,55wt%水),室温反应20h。反应完成后,过滤,滤渣以甲醇洗涤。滤液减压浓缩得产物4.9g。产率85%。LCMS(ESI):m/z=303(M+H)+。
(5)合成叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)氨甲酰基)-[1,3'-联吡咯啶]-1'-甲酸酯
于一50mL圆底烧瓶中,中间体3(191mg,0.57mmol)和(2R,4S)-1'-(叔丁氧羰基)-4-氟-[1,3'-联吡咯啶]-2-甲酸(172mg,0.57mmol)溶于DMF(5mL),然后加入DIEA(219mg,1.7mmol)、HATU(260mg,0.68mmol),室温反应1h。反应完成后,加CH2Cl2稀释。有机相以水洗,无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比为30:1的混合液),得产物254mg。产率72%。LCMS(ESI):m/z=620(M+H)+。
(6)合成(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺
于一50mL圆底烧瓶中,叔丁基(2R,4S)-4-氟-2-((3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)氨甲酰基)-[1,3'-联吡咯啶]-1'-甲酸酯(127mg,0.21mmol)溶于CH2Cl2(5mL),置于冰水浴冷却。然后往上溶液加入TFA(2.0mL),室温反应1h。反应完成后,减压浓缩除去TFA和溶剂。余物以手性色谱柱(chiral ND(2)SU 250×21.1mm;流动相为乙醇、异丙醇、甲醇和正己烷,体积比为35:30:10:15的混合液(含0.3%三乙胺);流速12mL/min)分离。第一个洗脱出来的组分42mg,为实施例18,产率38%。LCMS(ESI):m/z=520(M+H)+。1H-NMR(400MHz,CDCl3):δ12.05(s,1H),10.05(s,1H),8.30(d,J=5.3Hz,1H),8.23(d,J=8.0Hz,1H),7.85(s,1H),7.82(s,1H),7.32–7.25(m,1H),7.19(t,J=7.8Hz,1H),6.97(d,J=5.3Hz,1H),6.62(s,1H),5.21(d,J=53.1Hz,1H),3.98(s,3H),3.85–3.70(m,5H),3.60–3.51(m,1H),3.49–3.32(m,1H),3.29–3.19(m,2H),3.18–3.07(m,2H),3.06–2.97(m,1H),2.86–2.69(m,1H),2.29–2.07(m,1H),2.06–1.98(m,2H);第二个洗脱出来的组分36mg,为实施例19,产率33%。LCMS(ESI):m/z=520(M+H)+。1H-NMR(400MHz,CDCl3):δ12.35(s,1H),9.68(s,1H),8.30(d,J=5.3Hz,1H),8.23(d,J=8.0Hz,1H),7.83(s,1H),7.81(s,1H),7.32–7.25(m,1H),7.19(t,J=7.8Hz,1H),6.97(d,J=5.3Hz,1H),6.62(s,1H),5.21(d,J=53.1Hz,1H),3.96(s,3H),3.85–3.70(m,5H),3.60–3.51(m,1H),3.49–3.32(m,1H),3.29–3.19(m,2H),3.18–3.07(m,2H),3.06–2.97(m,1H),2.86–2.69(m,1H),2.29–2.07(m,1H),2.06–1.98(m,2H).
实施例20和实施例21
(2R,3'R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺(实施例20)和(2R,3'S,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1'-甲基-[1,3'-联吡咯啶]-2-甲酰胺(实施例21)
冰水浴下,于一50mL圆底烧瓶中,加入(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-[1,3'-联吡咯啶]-2-甲酰胺(127mg,0.21mmol),40%甲醛水溶液(47mg,0.63mmol)和MeOH(10mL)。向上述反应液加入氰基硼氢化钠(2.2g,35.6mmol),反应1h。反应完成后,加水,减压浓缩除去甲醇,水相以EtOAc萃取。有机相以无水Na2SO4干燥,过滤后浓缩,余物以手性色谱柱(chiral ND(2)SU 250×21.1mm;流动相为乙醇、异丙醇、甲醇和正己烷,体积比为35:30:10:15的混合液(含0.3%三乙胺);流速12mL/min)分离。第一个洗脱出来的组分37mg,为实施例20,产率33%。LCMS(ESI):m/z=534(M+H)+。1H-NMR(400MHz,CDCl3):δ11.50(s,1H),9.96(s,1H),8.31(d,J=5.3Hz,1H),8.22(d,J=8.0Hz,1H),7.86(s,1H),7.83(s,1H),7.31–7.24(m,1H),7.20(t,J=7.8Hz,1H),6.99(d,J=5.3Hz,1H),6.62(s,1H),5.20(d,J=53.0Hz,1H),3.98(s,3H),3.84–3.72(m,4H),3.63–3.53(m,1H),3.50–3.31(m,1H),3.25–3.08(m,2H),3.03–2.92(m,1H),2.87–2.70(m,4H),2.42–2.27(m,2H),2.26–2.15(m,1H),2.11–1.93(m,2H)。第二个洗脱出来的组分30mg,为实施例21,产率27%。LCMS(ESI):m/z=534(M+H)+。1H-NMR(400MHz,CDCl3):δ11.30(s,1H),9.86(s,1H),8.31(d,J=5.3Hz,1H),8.21(d,J=8.0Hz,1H),7.86(s,1H),7.84(s,1H),7.31–7.24(m,1H),7.20(t,J=7.8Hz,1H),6.99(d,J=5.3Hz,1H),6.62(s,1H),5.20(d,J=53.0Hz,1H),3.97(s,3H),3.84–3.72(m,4H),3.63–3.53(m,1H),3.50–3.31(m,1H),3.25–3.08(m,2H),3.03–2.92(m,1H),2.87–2.70(m,4H),2.42–2.27(m,2H),2.26–2.15(m,1H),2.11–1.93(m,2H)。
以下表6所示的实施例22-39根据实施例18和19、实施例20和21中的方法制备得到。
表6
实施例40
(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺
(1)合成甲基(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸酯
冰水浴下,于一100mL圆底烧瓶中,1-(叔丁基)2-甲基(2R,4S)-4-氟吡咯啶-1,2-二羧酸酯(1.0g,4.0mmol)溶于CH2Cl2(50mL)。往上溶液加入TFA(10mL),室温反应2h。反应完成后减压浓缩除去TFA和溶剂。余物溶于MeOH(50mL),置于冰水浴中冷却,然后加入N-甲基-哌啶-4-酮(678mg,6.0mmol)和氰基硼氢化钠(378mg,6.0mmol),反应20h。反应完成后,以硅藻土过滤,甲醇洗涤,收集滤液,减压浓缩除去甲醇,所得余物直接用于下一步反应。得产物1.2g。LCMS(ESI):m/z=245(M+H)+。
(2)合成(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸盐酸盐
于一100mL圆底烧瓶中,加入甲基(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸酯(1.2g,4.9mmol)和6M盐酸(50mL),加热回流6h。反应完成后,减压浓缩除去溶剂。余物加到异丙醇(150mL)中,搅拌加热至100℃至完全溶解,再反应30min,逐渐析出固体,继续反应2h。然后自然冷至室温,搅拌10h。过滤,滤渣以异丙醇洗涤,干燥得目标产物850mg,两步总产率70%。LCMS(ESI):m/z=231(M+H)+。
(3)合成(2R,4S)-4-氟-N-(3-(2-((3-甲氧基-1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1H-吲哚-7-基)-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酰胺
于一50mL圆底烧瓶中,中间体3(191mg,0.57mmol)和(2R,4S)-4-氟-1-(1-甲基哌啶-4-基)吡咯啶-2-甲酸盐酸盐(172mg,0.57mmol)溶于DMF(5mL),然后加入DIEA(294mg,2.3mmol)、HATU(260mg,0.68mmol),室温反应1h。反应完成后,加CH2Cl2稀释。有机相以水洗,无水Na2SO4干燥,过滤后浓缩,所得余物以硅胶柱层析分离纯化(流动相为CH2Cl2与MeOH体积比为10:1的混合液),得产物245mg。产率78%。LCMS(ESI):m/z=548(M+H)+。1H-NMR(400MHz,CDCl3):δ11.30(s,1H),9.74(s,1H),8.34–8.26(m,2H),7.88(d,J=2.8Hz,1H),7.83(s,1H),7.14(t,J=7.8Hz,1H),6.98(d,J=5.4Hz,1H),6.77(d,J=7.5Hz,1H),6.63(s,1H),5.20(d,J=53.6Hz,1H),3.99(s,3H),3.94–3.84(m,1H),3.76(s,3H),3.53–3.35(m,1H),3.32–3.16(m,1H),2.98–2.85(m,2H),2.80(s,1H),2.77–2.55(m,2H),2.26(s,3H),2.17–2.01(m,1H),2.01–1.87(m,3H),1.76–1.60(m,2H)。
测试例1
对以上实施例提供的酰胺化合物进行JAK1和JAK2激酶抑制活性的测试,方法如下:
用Mobility Shift Assay方法检测所述酰胺化合物对激酶JAK1和JAK2在1mM ATP下的抑制活性(IC50)。JAK1激酶购自Carna公司(目录号:08-144,批号:11CBS-0144V),JAK2激酶购自Carna公司(目录号:08-045,批号:10CBS-0289R)。JAK1 Peptide购自GL公司(目录号:758318,批号:P191104-TL758318),Kinase substrate22购自GL公司(目录号:112393,批号:P200403-CL112393)。使用的阳性对照化合物是baricitinib。具体步骤如下:
1、配制1×Kinase buffer。
2、化合物浓度梯度的配制:受试化合物起始浓度为10000nM(JAK1)或30000nM(JAK2),在384孔板中稀释成100倍终浓度的100%DMSO溶液,3倍稀释化合物,10个浓度。使用分液器Echo 550向目的板转移250nL 100倍终浓度的化合物。
3、用1×Kinase buffer配制2.5倍终浓度的激酶溶液。
4、在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer。
5、1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。
6、用1×Kinase buffer配制5/3倍终浓度的ATP(ATP终浓度=1mM)和Kinasesubstrate的混合溶液。
7、加入15μL的5/3倍终浓度的ATP和底物的混合溶液,起始反应。
8、将384孔板1000rpm离心30秒,振荡混匀后室温分别孵育相应的时间。
9、加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。
10、用Caliper EZ Reader读取转化率,计算半数抑制浓度的IC50,数据如表7所示。
表7
根据表7的测试数据可知,本申请提供的酰胺化合物在1mM ATP浓度下,能够有效地抑制JAK1激酶。而且,本申请所述酰胺化合物对抑制JAK1激酶的活性比对抑制JAK2激酶的活性都高,具有高的JAK1选择性。跟两个JAK1抑制剂abrocitinib和AZD4205相比,本申请大多数化合物对抑制JAK1激酶比对抑制JAK2激酶的选择性更高。
测试例2
细胞因子IFNα可以通过JAK1/TYK2信号通路诱导STAT3磷酸化(pSTAT3)。本申请用小鼠全血实验来测试本申请实施例30和实施例32提供的化合物对INFα诱导的pSTAT3的抑制,同时测试两个选择性的JAK1抑制剂abrocitinib和AZD4205作为比较。使用的IFNα是Recombinant mouse IFNα(Miltenyi#130-093-131),使用的pSTAT3抗体是Alexa Fluor488anti-STAT3 Phospho(Tyr705)Antibody(Biolegend#651106),使用的CD3抗体是Brilliant Violet 421anti-mouse CD3 Antibody(Biolegend#100228)。细胞因子稀释缓冲液为:PBS+0.1%BSA,过滤并在-4℃储存。FACS缓冲液为:PBS+0.2%BSA+1mM EDTA。具体步骤如下:
1、将C57BL/6J小鼠血液以每孔90μL加入96孔板。
2、每孔加入5μL的化合物(19X)并混匀,培养箱中37℃60min。
3、每孔加入5μL 20X的IFNα(工作浓度为20000IU/mL)刺激因子并混匀,37℃30min。
4、将血液转移到96深孔板,每孔加入1mL Lyse fix buffer(1X)并混匀,37℃10min。
5、600g 5min离心,弃上清。每孔加入1mL PBS,600g 5min离心,弃上清,重复两遍。每孔加入100μL anti-mCD3 antibody(用细胞因子稀释缓冲液80倍稀释)并混匀,4℃30min。
6、每孔加入1mL PBS,600g 5min离心,弃上清,重复两遍。每孔加入1000μL PermIII,混匀,4℃30min。
7、600g 5min离心,弃上清。每孔加入1mL PBS,600g 5min离心,弃上清,重复两遍。
8、每孔加入100μL anti-pSTAT3 antibody(用FACS缓冲液50倍稀释)并混匀,25℃40min。
9、每孔加入1mL FACS缓冲液,600g 5min离心,弃上清。每孔加入200μL FACS缓冲液并重悬,将所有样品转移到96孔尖底板中并上机。
10、收集数据并分析。其50%抑制率(IC50)列于表8。
表8
从表8的测试结果可以看出,本申请化合物在小鼠全血实验中能有效地抑制JAK1/TYK2的信号通路,实施例30和实施例32对抑制IFNα诱导的pSTAT3表达的IC50分别为127nM和121nM,而且比两个JAK1选择性的抑制剂abrocitinib和AZD4205的抑制活性还高。申请人声明,本申请通过上述实施例来说明本申请的酰胺化合物、药物组合物及其应用,但本申请并不局限于上述实施例,即不意味着本申请必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本申请的任何改进,对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本申请的保护范围和公开范围之内。
Claims (12)
1.一种酰胺化合物,其具有如式I所示结构:
其中,R1选自H、卤素、C1~C6直链或支链烷基、C3~C6环烷基或ORa;所述直链或支链烷基、环烷基无取代或被1~3个R1a取代;
R1a选自D或卤素;
R2选自H、C1~C6直链或支链烷基、C3~C10环烷基或C2~C10杂环烷基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~3个R2a取代;
R2a选自D、卤素、氰基、未取代或卤代的C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、ORa1、SRa1、NRb1Rc1、CORa1、CONRb1Rc1、COORa1、SO2Ra1、SO2NRb1Rc1、NRb1CORa1、NRd1CONRb1Rc1、NRb1SO2Ra1、NRd1SO2NRb1Rc1或SORa1;
R3选自H、卤素、氰基、未取代或卤代的C1~C6直链或支链烷基、C2~C6烯基、C2~C6炔基或C3~C6环烷基;
R4选自SO2Ra2、CORa2、COORa2、C3~C10环烷基或C2~C10杂环烷基;所述环烷基、杂环烷基无取代或被1~5个R4a取代;
R4a选自D、卤素、氰基、C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、ORa3、SRa3、NRb3Rc3、CORa3、CONRb3Rc3、COORa3、SO2Ra3或SO2NRb3Rc3;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个R4b取代;
R4b选自D、卤素、氰基、ORa4或NRb4Rc4;
R5选自F、氰基、C1~C6直链或支链烷基、C3~C6环烷基或ORa5;
Ra、Ra1、Rb1、Rc1、Rd1、Ra2、Ra3、Rb3、Rc3、Ra4、Rb4、Rc4、Ra5各自独立地选自H、C1~C10直链或支链烷基、C2~C10烯基、C2~C10炔基、C3~C10环烷基或C2~C10杂环烷基;所述直链或支链烷基、烯基、炔基、环烷基、杂环烷基无取代或被1~4个R6取代;
R6选自D、卤素、氰基、羟基、未取代或卤代的C1~C6直链或支链烷基、C2~C6烯基、C2~C6炔基、C3~C6环烷基、C2~C6杂环烷基、ORa6、SRa6、NRb6Rc6、CORa6、CONRb6Rc6、COORd6、SO2Ra6、SO2NRb6Rc6、NRb6CORa6、NRd6CONRb6Rc6、NRb6SO2Ra6、NRd6SO2NRb6Rc6或SORa6;
Ra6、Rb6、Rc6、Rd6各自独立地选自H、C1~C10直链或支链烷基、C2~C10烯基、C2~C10炔基、C3~C10环烷基或C2~C10杂环烷基;以及
n选自0~3的整数,当n≥2时,R5之间不连接或通过化学键连接形成3至6元的碳环或碳杂环。
3.根据权利要求2所述的酰胺化合物,其中,所述R3选自H、卤素、C1~C6直链或支链烷基。
4.根据权利要求2所述的酰胺化合物,其中,所述R4选自SO2Ra2、无取代或R4a取代的C2~C10杂环烷基;
任选地,所述Ra2选自C1~C6直链或支链烷基;
任选地,所述R4a选自C1~C6直链或支链烷基;
任选地,所述Ra5选自C1~C6直链或支链烷基。
5.根据权利要求2-4任一项所述的酰胺化合物,其中,所述酰胺化合物具有如式IB所示结构:
其中,R3、R5a、R5b各自独立地具有与式IA中相同的限定范围;
Y为NR7或O;
R7选自H、C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个R7a取代;
R7a选自D、卤素、氰基、C1~C6直链或支链烷基、C3~C6环烷基、C2~C6杂环烷基、羟基、C1~C6直链或支链烷氧基;所述直链或支链烷基、环烷基、杂环烷基无取代或被1~5个R7b取代;
R7b选自D、卤素、氰基、羟基、C1~C6直链或支链烷氧基;以及
m为1或2,p选自1~3的整数。
6.根据权利要求5所述的酰胺化合物,其中,所述R3选自H、卤素或甲基;
任选地,所述R5a、R5b各自独立地选自H、F、甲氧基或乙氧基。
7.根据权利要求5所述的酰胺化合物,其中,所述R7为H或甲基;
任选地,所述p为2。
9.一种如权利要求1-8任一项所述的酰胺化合物的立体异构体、几何异构体、互变异构体或其药学上可接受的盐。
10.一种药物组合物,其包括活性成分与至少一种药用载体或赋形剂;所述活性成分包括如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐中的任意一种或至少两种的组合。
11.一种如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如权利要求10所述的药物组合物在制备用于抑制JAK激酶的药物中的应用;
任选地,所述JAK激酶为JAK1激酶。
12.一种如权利要求1-8任一项所述的酰胺化合物、如权利要求9所述的立体异构体、几何异构体、互变异构体或其药学上可接受的盐、如权利要求10所述的药物组合物在制备用于治疗JAK激酶介导的疾病的药物中的应用;
任选地,所述疾病包括炎症、自身免疫性疾病或癌症;
任选地,所述炎症、自身免疫性疾病包括系统性红斑狼疮、狼疮性肾炎、关节炎、牛皮癣、克罗恩病、溃疡性结肠炎、特应性皮炎、痛风、脱发秃头症、白癜风、化脓性汗腺炎、I型糖尿病、慢性肾脏病、急性肾脏损伤、慢性阻塞性肺疾病、哮喘、支气管炎或移植物抗宿主病;
任选地,所述癌症包括乳腺癌、肺癌、前列腺癌、胆小管癌、骨癌、膀胱癌、头颈癌、肾癌、肝癌、胃肠组织癌、食道癌、卵巢癌、胰腺癌、皮肤癌、睾丸癌、甲状腺癌、子宫癌、子宫颈癌、阴道癌、白血病、骨髓纤维化、多发性骨髓瘤或淋巴瘤。
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WO2024009215A1 (en) * | 2022-07-05 | 2024-01-11 | Dong-A St Co., Ltd. | Novel compounds as gcn2 inhibitors, pharmaceutical compositions and uses thereof |
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