CN110396088A - Hpk1激酶抑制剂、制备方法及其应用 - Google Patents
Hpk1激酶抑制剂、制备方法及其应用 Download PDFInfo
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- CN110396088A CN110396088A CN201810946081.2A CN201810946081A CN110396088A CN 110396088 A CN110396088 A CN 110396088A CN 201810946081 A CN201810946081 A CN 201810946081A CN 110396088 A CN110396088 A CN 110396088A
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
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Abstract
本发明提供一种通式为Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物及其制备方法,本发明还提供一种通式为Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物或氘代化合物作为HPK1激酶抑制剂在预防和/或治疗癌症中的应用。
Description
技术领域
本发明属于医药领域,涉及一种HPK1激酶抑制剂及其制备方法。
背景技术
HPK1激酶参与很多信号级联反应,包括生长因子信号、MAPK信号、细胞因子信号、凋亡信号、生长因子信号以及抗原受体信号等。HPK1激酶是JNK/SAPK信号通路的关键功能性活化因子,当被激活后,它可以选择性地激活C-Jun N-terminal kinase(JNK)的 MAPK信号通路。
HPK1激酶可作为免疫治疗的靶点,其被淋巴细胞抗原受体激活,并抑制AP-1,而AP-1在肿瘤形成及发展过程中在促进细胞增殖、抑制分化、促进肿瘤细胞的侵袭和转移等过程中发挥作用。而针对性的破坏HPK1激酶的等位基因可以使T细胞在TCR应答中提高Th1细胞因子的产生。
S Sawasdikosol(HPK1as a novel target for cancer immunotherapy,ImmunolRes,54 (2012),pp.262–265)报道HPK1激酶-/-的T细胞增殖相对于单体野生型快很多,并且抵抗前列腺素E2(PGE2)介导的抑制作用。最显著的是,转染过HPK1激酶-/-T细胞的老鼠能抵抗癌肿瘤的生长,而且失去HPK1激酶的树突细胞(DCs)具有很好的抗原能力,作为抗肿瘤疫苗,它能使HPK1激酶-/-的DC具有更好地表现出抗肿瘤免疫应答。用小分子抑制剂消除封闭HPK1激酶的活性可以活化上述两种细胞良好的抗肿瘤活性,最后协同放放大潜在的抗肿瘤能力。同时,转染过的HPK1激酶不能在主要的器官内表达,这预示着HPK1激酶活性的抑制剂可能不会导致任何严重的并发症。
US2016158360A1公开了一种用于增强免疫应答和治疗癌症的组合物和方法,该组合物包含PD-1轴拮抗剂和HPK1拮抗剂,其中HPK1拮抗剂包括抑制HPK1的丝氨酸/苏氨酸激酶活性的化合物。
可见,HPK1激酶在疾病治疗特别是癌症治疗中具有关键作用,HPK1激酶小分子抑制剂的发现是目前的迫切需求。
发明内容
本发明一个目的是提供一种HPK1激酶抑制剂及其制备方法;本发明另一个目的是提供一种HPK1激酶抑制剂在预防和/或治疗癌症中的应用;本发明还一个目的是提供一种HPK1激酶抑制剂在癌症免疫疗法中的应用;本发明还一个目的是提供一种HPK1激酶抑制剂在制备预防和/或治疗癌症的药物中的应用。
本发明提供一种通式为Ⅰ的化合物:
其中:
A选自C或N;B选自C或N。
Ar选自芳香性五元杂环基团、芳香性六元杂环基团或苯基,所述芳香性五元杂环基团选自:呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基或噻唑基,所述芳香性六元杂环基团选自:吡啶基、哒嗪基、嘧啶基或吡嗪基,所述芳香性五元杂环基团、芳香性六元杂环基团或苯基上的H可被以下基团取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、 C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、C3-10环烷基、-O杂环烷基、 -N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基,其中所述烷基部分可被一个或多个以下基团任意取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基;
优选的,所述芳香性五元杂环基团、芳香性六元杂环基团或苯基上至少一个H被下述基团取代:-SO2、-SO2NH2、-NHSO2、-CONH(C0-10烷基)、卤素、-CN、-OCF3、-O杂环烷基、-N杂环烷基、C1-10直链/支链烷基、C3-10环烷基、-OC0-10烷基、-N(C0-10烷基)(C0-10烷基);更优选的,所述芳香性五元杂环基团、芳香性六元杂环基团或苯基上至少一个H 被-O杂环烷基或-N杂环烷基取代。
优选的,所述Ar选自:噻唑基、硒代噻唑基、咪唑基、吡唑基或吡啶基。
在本发明的优选实施方式中,所述Ar选自:
所述Q选自O或S;x和z独立的选自0-6间的整数;y选自0或1。
优选的,x和z独立的选自0-2间的整数,如0、1或2。
在本发明的优选实施方式中,所述化合物的结构为通式Ⅱ:
在本发明中,所述化合物结构式为:
所述R0独立的选自:-H、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基或C3-10环烷基。
优选的,所述R0独立的选自:C1-5直链/支链烷基或-N(C0-10烷基)(C0-10烷基)。
在本发明的优选实施方式中,R0独立的选自:-CH3、-CH2CH3或-NH2。
所述R1选自:-H、-O杂环烷基、-N杂环烷基、C1-10直链/支链烷基、C3-10环烷基、-OC0-10烷基、-N(C0-10烷基)(C0-10烷基)、-SO2(C0-10烷基)、-O(C0-10烷基)、-O-苯基、-S(C0-10烷基)、 -N杂环芳香基、-O杂环芳香基或-S杂环芳香基,其中C原子或杂原子上的H可被C1-3直链烷基、-N(C0-10烷基)(C0-10烷基)、-CF3取代。
优选的,所述R1选自:-O杂环烷基或-N杂环烷基、-SO2(C0-3烷基)、-O-苯基、-S(C0-4烷基)、C3-6环烷基或C3-5直链/支链烷基,其中C原子或杂原子上的H可被-CH3、-NH2、 -CF3取代。
在本发明的优选实施方式中,所述R1选自:
所述R2选自:-H、卤素、-NO2、-CN、C1-5直链/支链烷基、C3-10环烷基、-N(C0-10烷基)(C0-10烷基)、-CF3、-OCF3、-OCHF2、-OCH2F或-OC0-10烷基。
优选的,所述R2选自:-NO2、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基或-OCF3。
在本发明的优选实施方式中,所述R2选自:-NH2或-NO2。
当B为N时,R3不存在;当B为C时,所述R3选自:-H、卤素、-OC0-10烷基、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)或C3-10环烷基。
优选的,所述R3选自:-H、卤素、-OC0-10烷基、C1-10直链/支链烷基。
在本发明的优选实施方式中,所述R3选自:-H、-F或-OCH3。
所述R4选自:-H、卤素、-OC0-10烷基、-CN、C3-10环烷基、-C≡C-R10、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-O杂环烷基或-N杂环烷基。
优选的,所述R4选自:-H、卤素、-OC0-10烷基、-CN、C3-10环烷基或-C≡C-R10。
在本发明的优选实施方式中,所述R4选自:-H、-F、-Cl、-OCH3、-CN、或-C ≡C-R10。
所述R10选自:H、C1-5直链/支链烷基、C3-10环烷基或
所述R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-10直链/支链烷基、-CH= C(C0-10烷基)(C0-10烷基)、-C≡C(C0-10烷基)、C3-10环烷基、芳香性五元环基团或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-8环烷基或含-O、-S的C3-8杂环烷基,C4-9稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C原子上的H可被烷基或卤素取代。
优选的,所述R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-10直链/支链烷基、 -CH=C(C0-10烷基)(C0-10烷基)、C3-10环烷基或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-8环烷基、C4-7稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C原子上的H可被烷基或-F取代。
更优选的,所述R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-5直链/支链烷基、-CH=CH(C0-10烷基)、C3-10环烷基或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-6环烷基、C4-6稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C 原子上的H可被烷基或-F取代。
在本发明的优选实施方式中,所述R11、R12独立的选自:-H、-CF3、-CHF2、-CH2F、 -CH3、-CH2CH3、-CH=CH2、 或R11、R12与R11和R12之间的碳原子形成
R5、R6、R7独立的选自:-H、卤素、-CN、-OC0-10烷基、C1-10直链/支链烷基、含O 或N的杂烷基、-N(C0-10烷基)(C0-10烷基)、C3-10环烷基、-C≡C-R10、-O杂环烷基或-N杂环烷基,或R6、R7与R6和R7之间的碳原子形成C3-8环烷基或含-O-、-S-的C3-8杂环烷基、 -N杂环芳香基、-O杂环芳香基或-S杂环芳香基、苯基,其中C原子上的H可被以下基团取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、C3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、 -O杂环芳香基或-S杂环芳香基。
优选的,所述R5、R6、R7独立的选自:-H、卤素、C3-6环烷基、-OC0-5烷基、C1-5直链/支链烷基、含O或N的C1-5直链/支链烷基,或R6、R7与R6和R7之间的碳原子形成 C3-8环烷基或含-O-、-S-的C3-8杂环烷基,其中C原子上的H可被-F取代。
更优选的,所述R5、R6、R7独立的选自:-H、卤素、-OC0-3烷基、C1-3直链/支链烷基、含N的C1-3直链/支链烷基,或R6、R7与R6和R7之间的碳原子形成C3-8环烷基或含-O-的 C3-8杂环烷基,其中C原子上的H可被-F取代。
在本发明的优选实施方式中,所述R5、R6、R7选自:-H、-F、-Cl、-CH3、-CH2NH2、 -CN、-OCH3,或R6、R7与R6和R7之间的碳原子形成含-O-五元环烷基。
R8和R9独立的选自:-H、卤素、C1-10直链/支链烷基。
优选的,所述R8和R9独立的选自:-H、C1-10直链/支链烷基。
更优选的,所述R8和R9独立的选自:-H、C1-3直链/支链烷基。
在本发明的优选实施方式中,所述R8和R9独立的选自:-H或-CH3。
在本发明具体实施方式中,提供如下的具体化合物:
本发明提供一种通式Ⅰ化合物的制备方法,包括如下步骤:
(1)与发生缩合反应生成R13选自:卤素或R14选自:-OH或-F;
(2)与Ar-R15发生缩合反应生成R15选自:-Br或-SnBu3。
优选的,所述步骤(1)中R13选自:-Br;
优选的,所述步骤(2)中R13选自:-Br或当R13是-Br时,R15为-SnBu3,当R13是时,R15为-Br。
本发明所述的通式为Ⅰ的化合物还包括其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物。
本发明所述的药学上可接受的盐中包括酸加成盐和碱加成盐。
所述的酸加成盐包括但是不限于来自无机酸诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸和膦酸的盐,以及来自有机酸如脂肪族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸、链烷二酸、芳香酸和脂肪族和芳香族磺酸的盐。因此,这些盐包括但是不限于硫酸盐,焦硫酸盐,硫酸氢盐,亚硫酸盐,亚硫酸氢盐,硝酸盐,磷酸,磷酸一氢盐,磷酸二氢盐,偏磷酸盐,焦磷酸盐,盐酸盐,氢溴酸盐,碘酸盐,乙酸盐,丙酸盐,辛酸盐,异丁酸盐,乙二酸盐,丙二酸盐,琥珀酸盐,辛二酸,癸二酸盐,富马酸盐,马来酸盐,苦杏仁酸盐,苯甲酸盐,氯代苯甲酸盐,甲基苯甲酸盐,二硝基苯甲酸盐,酞酸盐,苯磺酸盐,甲苯磺酸盐,苯基乙酸盐,柠檬酸盐,乳酸盐,马来酸盐,酒石酸和甲磺酸盐,还包含氨基酸的盐如精氨酸盐,葡糖酸盐,半乳糖醛酸盐等。酸加成盐可以通过以常规方式使游离碱形式与足够量的所需酸接触形成盐的方式制备。可通过使盐形式与碱接触重新生成游离碱形式,并且以常规方式分离该游离碱。
所述的碱加成盐与金属或者胺形成,诸如碱金属和碱土金属的氢氧化物,或者与有机胺形成。用作阳离子的金属的例子包括但是不限于钠、钾、镁、和钙。适当的胺的例子包括但是不限于N,N′-二苄基乙二胺,氯普鲁卡因,胆碱,二乙醇胺,乙二胺(乙烷-1,2- 二胺),N-甲基葡糖胺和普鲁卡因。碱加成盐可通过以常规方式使游离酸形式与足够量的所需碱接触形成盐的方式制备。可通过使盐形式与酸接触重新生成游离酸形式,并且以常规方式分离游离酸。
本发明所述的立体异构体包括对映体、非对映体和几何异构体的形式存在。本发明的一些化合物具有环烷基,其可在超过一个碳原子上被取代,在这种情况下,其所有的几何形式,包括顺式和反式,及其混合物,都处在本发明的范围内。
本发明所述的溶剂化物是指本发明的化合物与一种或多种溶剂分子的物理结合。该物理结合包括各种程度的离子和共价键合,包括氢键合。在某些情况下,溶剂化物可被分离出来,例如当一个或多个溶剂分子掺入到结晶固体的晶格中。“溶剂化物”包括溶液相的和可分离的溶剂化物。代表性的溶剂化物包括乙醇化物、甲醇化物等。“水合物”是其中一个或多个溶剂分子为H2O的溶剂化物。
本发明所述的前药指适于对患者给药的无过分毒性、刺激性和变态反应等的并且对其应用目的有效的式Ⅰ化合物形式,包括缩醛、酯和两性离子形式。前药在体内转化(例如通过在血液中水解)得到上式的母体化合物。
本发明提供一种药物组合物,所述药物组合物包含通式Ⅰ的化合物,还包括药剂学上可接受的辅料,所述辅料选自:载体、稀释剂、粘合剂、润滑剂、润湿剂。优选地,所述药物组合物包含治疗有效量的通式Ⅰ的化合物。在某些实施方案中,这些药物组合物可用于治疗HPK1激酶介导的病症或病况。本发明所述的HPK1激酶抑制剂也可被结合在还包含可用于治疗癌或者其它的HPK1激酶介导的病症的化合物的药物组合物中。
本发明的化合物可以配制为以下形式的药物组合物:糖浆剂,酏剂,悬浮剂,粉剂,颗粒剂,片剂,胶囊,锭剂,水溶液,霜剂,膏剂,洗液剂,凝胶剂,乳剂等。
药物制剂优选为单位剂型。在这种形式中,该制剂被再分成包含适当的量的活性组分的单位剂量。单位剂型可以是包装好的制剂,该包装含有离散的量的制剂,诸如包装在小瓶或者安瓿中的片剂、胶囊和粉剂。另外,单位剂型可以是胶囊,片剂或者其可以是在包装形式中的适当数目的任何这些剂型。
单位剂量制剂中活性组分的量可从0.1毫克到1000毫克之间改变或调整,根据活性组分的具体应用和效力而定。如果需要,组合物还可包含其它适合的治疗剂。
可药用载体部分地根据给用的具体组合物而定,并根据组合物的具体给药方法而定。因此,本发明的药物组合物存在各种适当的制剂。
本发明的化合物,单独或与其它适当的组分结合,被制成气雾剂(即,它们可被“雾化”) 以经由吸入被给药。气雾剂可被置于可接受的被加压的发射剂诸如二氯二氟己烷、丙烷、氮气等中。
适于非肠胃给药诸如例如通过静脉内、肌内、皮内和皮下途径给药的制剂包括含水和非水的等渗无菌注射液,其可包含抗氧化剂,缓冲剂,抑菌剂,和使制剂与接受者的血液等渗的溶质,以及含水和非水的无菌悬浮剂,其可包含助悬剂,增溶剂,增稠剂,稳定剂和防腐剂。在本发明的实践中,组合物可通过例如静脉输注,经口,局部,腹膜内,膀胱内和鞘内给药。化合物的制剂可存在于单位剂量或者多剂量密封容器诸如安瓿和小瓶中。注射用溶液液和悬浮液可从先前所述类型的无菌粉剂、颗粒和片剂制备。
在本发明的环境下,对对象剂量给用应当足够随着时间在对象体内产生有益的治疗学应答。剂量通过所用的具体化合物的效力和对象的病况、以及待治疗对象的体重或者体表面积而定。剂量的大小将根据在具体对象中伴随具体化合物给药产生的任何不利副作用的存在、性质和程度而定。在正被治疗的病症的治疗或者预防中确定待给药的化合物的有效量中,医师可以评价诸如化合物的循环血浆水平、化合物毒性和/或疾病进程等因素而定。
本发明还提供了通式Ⅰ的化合物及其药学上可接受的盐、立体异构体、酯、前药和溶剂化物在预防和/或治疗癌症中的应用。
本发明还提供了通式Ⅰ的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物在制备预防和/或治疗癌症的药物中的应用。
本发明还提供了通式Ⅰ的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物联合PD-1、PD-L1、CTLA-4、TIM-3、TGF-β及其受体、LAG3拮抗剂或TLR4、TLR7、TLR8、TLR9、STING激动剂在癌症免疫疗法中的应用。
本发明还提供了通式Ⅰ的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物与CAR-T免疫疗法相结合在癌症免疫疗法中的应用。
所述CAR-T免疫疗法是指:嵌合抗原受体T细胞免疫疗法,是目前较为有效的恶性肿瘤的治疗方式之一,其基本原理是利用病人自身的免疫细胞来清除癌细胞,属于一种细胞疗法。
本发明所述的癌症包括淋巴瘤,母细胞瘤,髓母细胞瘤,视网膜母细胞瘤,肉瘤,脂肪肉瘤,滑膜细胞肉瘤,神经内分泌肿瘤,类癌肿瘤,胃泌素瘤,胰岛细胞癌,间皮瘤,神经鞘瘤,听神经瘤,脑膜瘤,腺癌,黑素瘤,白血病或淋巴样恶性肿瘤,鳞状细胞癌,上皮鳞状细胞癌,肺癌,小细胞肺癌,非小细胞肺癌,腺癌肺癌,肺鳞癌,腹膜癌,肝细胞癌,胃癌,肠癌,胰腺癌,成胶质细胞瘤,子宫颈癌,卵巢癌,肝癌,膀胱癌,肝癌,乳腺癌,转移性乳腺癌,结肠癌,直肠癌,结肠直肠癌,子宫癌,唾液腺癌,肾癌,前列腺癌,外阴癌,甲状腺癌,肝癌,肛门癌,阴茎癌,梅克尔细胞癌,食管癌,胆道肿瘤,头颈部癌和血液恶性肿瘤。
本发明提供一种通式为Ⅲ的化合物:
R15选自:-Br或-SnBu3;R0和R1如前所述。
本发明提供一种通式为Ⅳ的化合物:
R13选自:卤素或R2-R9如前所述,
优选的,所述R13选自-Br。
本发明中所述的术语C0-10烷基,C0烷基是指H,因此,C0-10烷基包括H、C1烷基、 C2烷基、C3烷基、C4烷基、C5烷基、C6烷基、C7烷基、C8烷基、C9烷基、C10烷基。
本发明中所述的术语C1-10直链/支链烷基,包括甲基、乙基、C3直链/支链烷基、C4直链/支链烷基、C5直链/支链烷基、C6直链/支链烷基、C7直链/支链烷基、C8直链/支链烷基、 C9直链/支链烷基、C10直链/支链烷基。
本发明中所述的术语C3-10支链烷基,包括异丙基、异丁基、叔丁基、异戊基。
本发明中所述的术语C3-10环烷基,包括C3环烷基、C4环烷基、C5环烷基、C6环烷基、C7环烷基、C8环烷基、C9环烷基、C10环烷基。
本发明中所述的术语C3-8环烷基,包括C3环烷基、C4环烷基、C5环烷基、C6环烷基、C7环烷基、C8环烷基。
本发明中所述的术语C4-8环烷基,包括C4环烷基、C5环烷基、C6环烷基、C7环烷基、 C8环烷基。
本发明中所述的术语C4-6环烷基,包括C4环烷基、C5环烷基、C6环烷基。
本发明所述的术语卤素,包括氟、氯、溴、碘。
本发明所述的术语杂环烷基是指含3-10个环原子,优选5-10个环原子的非芳香的饱和单环或多环环系,其中的一个或多个环原子不是碳原子,而是例如氮、氧或硫原子。优选的杂环烷基含有5-6个环原子。杂环烷基前的前缀氮杂、氧杂或硫杂分别是指至少有一个氮、氧或硫原子作为环原子。
本发明所述的术语杂环芳香基是指含5-14个环原子,优选5-10个环原子的芳香单环或多环环系,其中的一个或多个环原子不是碳原子,而是例如氮、氧或硫原子。优选的杂环芳香基含有5-6个环原子。代表性的杂环芳香基包括吡嗪基、呋喃基、噻吩基、吡啶基、嘧啶基、异噁唑基、异噻唑基、噁唑基、噻唑基、吡唑基、呋咱基、吡咯基、吡唑基、三唑基、1,2,4-硫杂二唑基、吡嗪基、哒嗪基、喹喔啉基、2,3-二氮杂萘基、咪唑并[1,2-a]吡啶、咪唑并[2,1-b]噻唑基、苯并呋咱基、吲哚基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基、噻吩并吡啶基、喹唑啉基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶基、异喹啉基、苯并氮杂吲哚基、1,2,4-三嗪基、苯并噻唑基等。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1化合物的制备
化合物的合成路线如下:
化合物2:将化合物4-氨基硫代羰基四氢吡啶-1(2H)-甲酸叔丁酯(25.0g,102.4mmol) 和氯乙醛(40%的水溶液,30.0g,153.6mmol)依次加入到含300mL丙酮的圆底烧瓶内, 50℃搅拌16h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,5/1,v/v),得到黄色油状液体9.0g,产率:32.9%。1H NMR(400MHz,CDCl3)δppm 1.47(s,9H),1.73(ddd,J=25.0,12.1,4.3Hz,2H),2.09(dt,J=15.5,4.7Hz,2H), 2.86(dd,J=25.4,13.1Hz,2H),3.13–3.21(m,1H),4.14(dd,J=17.4,10.1Hz,2H),7.22(d,J =3.3Hz,1H),7.69(d,J=3.3Hz,1H)。
LCMS:Rt=0.45min,MS Calcd.:268.1,MS Found:212.9[M+H-56]+.
化合物3:将化合物2(9.0g,33.6mmol)加入到含100mL 1,4-二氧六环的圆底烧瓶内,搅拌加入100mL 4N的盐酸二氧六环溶液,室温搅拌5h。LCMS监测,反应完成后,减压浓缩。加入200mL乙醚打浆,抽滤,滤饼用100mL乙醚淋洗,干燥,得到灰色固体 5.2g,产率:75.9%。没有进一步纯化。
LCMS:Rt=0.45min,MS Calcd.:168.1,MS Found:169.0[M+H]+.
化合物4:在250mL圆底烧瓶中,将化合物3(5.2g,25.6mmol)溶于80mL的四氢呋喃,加入三乙胺(2.6g,25.6mmol)和37%的甲醛水溶液(3.1g,38.4mmol),搅拌下加入三乙酰氧基硼氢化钠(8.1g,38.4mmol),室温搅拌16h。LCMS监测,反应完成后,减压浓缩。1N氢氧化钠溶液稀释(50mL),二氯甲烷萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,6/1,v/v)得到3.6g黄色油状液体,产率:77.3%。1H NMR(400MHz,CD3OD) δppm 1.81–1.90(m,2H),2.21–2.67(m,4H),2.34(s,3H),2.98–3.08(m,3H),7.71(d,J=2.6 Hz,1H),7.48(d,J=3.4Hz,1H)。
LCMS:Rt=0.42min,MS Calcd.:182.1,MS Found:183.0[M+H]+.
化合物5:在250mL三口烧瓶中,将化合物4(3.6g,19.7mmol)溶于60mL的四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(2.4M的四氢呋喃溶液,8.2mL,19.7mmol), -78℃搅拌1h,随后滴加三丁基氯化锡(6.4g,19.7mmol),滴加完毕后于-78℃继续搅拌1h。LCMS监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100mL× 3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,得到7.8g深黄色油状液体粗品,可直接用于下一步反应不需要进一步纯化。
LCMS:Rt=1.55min,MS Calcd.:472.2,MS Found:473.0[M+H]+.
化合物7:将化合物5(764mg,1.62mmol),6(500mg,1.62mmol),双三苯基膦二氯化钯(112mg,0.16mmol)和碘化亚铜(91mg,0.48mmol)依次加入到含15mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,6/1,v/v),得到黄色固体250mg,产率: 37.7%。
LCMS:Rt=1.04min,MS Calcd.:411.1,MS Found:411.7[M+H]+.
化合物8:将化合物7(250mg,0.61mmol),还原铁粉(170mg,3.04mmol)和氯化铵(163mg,3.04mmol)依次加入到含10mL乙醇和2mL水的圆底烧瓶内,70℃搅拌3h。 LCMS监测,反应完成后,冷却至室温,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:0-20%ACN),冻干,得到类白色固体115mg,产率:37.7%。1H NMR(400MHz,D2O)δppm 1.93–2.04(m,2H),2.35(d, J=14.7Hz,2H),2.81(s,3H),3.09–3.15(m,2H),3.36–3.39(m,1H),3.53–3.60(m,2H),5.65 (s,2H),7.54(d,J=2.5Hz,1H),7.69(d,J=2.5Hz,1H),7.85(s,1H),8.12(d,J=6.5Hz,2H), 8.75(d,J=6.7Hz,2H)。
LCMS:Rt=0.34min,MS Calcd.:381.1,MS Found:381.9[M+H]+.
实施例2化合物的制备
化合物的合成路线如下:
化合物9:将化合物3-溴-5-羟基吡啶(10g,57.8mmol)在0℃下加入到含100mL浓硫酸的三口瓶中,在0℃搅拌下加入65%浓硝酸(11.1g,114.94mmol),室温条件下搅拌 14h。LCMS监测,反应完成后,将反应液倒入200mL冰水中,乙酸乙酯萃取(500mL× 2),合并萃取液,饱和氯化钠水溶液洗(300mL),无水Na2SO4干燥,减压浓缩得到黄色固体11g,产率87.4%。1H NMR(400MHz,DMSO-d6):δppm 7.85(d,J=2.0Hz,1H),8.17 (d,J=2.0Hz,1H),12.09(s,1H)。
LCMS:Rt=1.43min,MS Calcd.:217.9,219.9,MS Found:218.7,220.8[M+H]+
化合物10:将化合物9(4.4g,20mmol),苯甲醇(2.6g,24mmol),三苯基膦(6.4g,24mmol)依次加入到含有100ml无水四氢呋喃的三口瓶中,氮气保护,在无氧0℃条件下加入偶氮二甲酸二异丙酯(4.85g,24mmol),0℃搅拌4h。LCMS监测,反应完成后,减压浓缩。加入100mL水,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯, 10/1,v/v),得到白色固体3.2g产率:49%。1H NMR(400MHz,DMSO-d6):δppm 5.41(s,2H), 7.37–7.45(m,5H),8.31(d,J=2.0Hz,1H),8.43(d,J=1.6Hz,1H)。
LCMS:Rt=1.73min,MS Calcd.:308.0,310.0,MS Found:308.8,310.8[M+H]+
化合物11:将化合物10(3g,9.7mmol),联硼酸频那醇酯(4.9g,19.4mmol),醋酸钾(2.9g,29.1mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.6g,1.94mmol)依次加入到含100mL二氧六环的250mL圆底烧瓶内,氮气保护,80℃搅拌12h。 LCMS监测,反应完成后,冷却到室温,减压浓缩。柱层析分离(洗脱液:二氯甲烷/甲醇, 50/1-20/1,v/v),得到红色固体5g的粗品。1H NMR(400MHz,DMSO-d6):δppm 1.35(s, 12H),5.42(s,2H),7.36–7.43(m,5H),8.09(d,J=1.2Hz,1H),8.28(d,J=1.2Hz,1H)。
LCMS:Rt=1.51min,MS Calcd.:356.2,MS Found:274.8[M+H-82]+
化合物13:将化合物12(10g,32.4mmol),2-溴噻唑(5.8g,35.6mmol),碳酸钠(10.2g,97.2mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(2.6g,3.2mmol)依次加入到含200mL二氧六环和50mL水的500mL圆底烧瓶内,氮气保护,90℃搅拌3h。 LCMS监测,反应完成后,冷却到室温,减压浓缩。加入200mL水,乙酸乙酯萃取(300 mL×2),合并萃取液,饱和氯化钠水溶液洗(200mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,5/1,v/v),得到黄色油状物7.8g,产率:90.1%。1H NMR(400MHz,CDCl3):δppm1.50(s,9H),2.70–2.73(m,2H),3.66(t,J=5.2Hz,2H), 4.13–4.14(m,2H),6.59(s,1H),7.24(d,J=4.0Hz,1H),7.77(d,J=3.6Hz,1H)。
LCMS:Rt=1.62min,MS Calcd.:266.1,MS Found:266.9[M+H]+
化合物14:将化合物13(7.8g,29.2mmol),10%钯碳(10g),醋酸(10ml)依次加入到含300mL甲醇/100mL四氢呋喃的1L反应釜中,在50℃,0.4MPa氢气环境下搅拌48h。LCMS监测,反应完成后,过滤,滤液减压浓缩。加入100mL水,乙酸乙酯萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩得到黄色油状物6.5g,产率:82.7%。1H NMR(400MHz,CDCl3):δppm:1.46(s,9H), 1.69–1.79(m,2H),2.08–2.11(m,2H),2.88(t,J=12.2Hz,2H),3.12–3.20(m,1H),4.18(br.s, 2H),7.21(d,J=3.6Hz,1H),7.69(d,J=3.2Hz,1H)。
LCMS:Rt=1.58min,MS Calcd.:268.1,MS Found:212.9[M+H-56]+
化合物15:将化合物14(4g,15mmol),N-溴代丁二酰亚胺(5.3g,30mmol)依次加入到含100mL乙腈的250mL圆底烧瓶内,50℃搅拌4h。LCMS监测,反应完成后,用饱和硫代硫酸钠溶液(30mL)淬灭,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:乙酸乙酯 /石油醚,1:10,v/v),得到黄色的油1.5g,产率:39.5%。1H NMR(400MHz,CDCl3):δppm 1.47(s,9H),1.65–1.75(m,2H),2.04–2.08(m,2H),2.87(t,J=12.4Hz,2H),3.06–3.14(m,1H), 4.19(br.s,2H),7.57(s,1H)。
LCMS:Rt=1.79min,MS Calcd.:346.0,348.0,MS Found:290.7,292.7[M+H-56]+
化合物16:将化合物15(1.5g,8.6mmol),化合物5(4g(crude),8.6mmol)碳酸钠(1.3g,12.9mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(708mg,0.86mmol)依次加入到含100mL二氧六环和20mL水的250mL圆底烧瓶内,氮气保护,50℃搅拌14h。LCMS监测,反应完成后,减压浓缩。加入100mL水,二氯甲烷萃取(200mL ×3),合并萃取液,无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:乙酸乙酯/石油醚,1/3,v/v),得到黄色的固体750mg产率:34.9%。1H NMR(400MHz,DMSO-d6):δppm 1.42(s,9H),1.55–1.61(m,2H),2.07–2.10(m,2H),2.94(br.s,2H),4.01–4.06(m,3H),5.47(s, 2H),7.36–7.49(m,5H),8.26(d,J=1.6Hz,1H),8.42(d,J=2.0Hz,1H),8.45(s,1H)。
LCMS:Rt=1.86min,MS Calcd.:496.2,MS Found:440.7[M+H-56]+
化合物17:化合物16(750mg,1.5mmol)加入到含10mL二氯甲烷的100mL圆底烧瓶内,搅拌下加入2mL三氟乙酸。室温搅拌14h。LCMS监测,反应完成后,减压浓缩。加入20mL碳酸氢钠饱和溶液调节pH>7,二氯甲烷萃取(100mL×4),合并萃取液,饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩得到黄色固体580mg。产率: 97.0%。1H NMR(400MHz,DMSO-d6):δppm 1.70–7.76(m,2H),2.05–2.08(m,2H), 2.68–2.77(m,3H),3.10–3.13(m,2H),5.48(s,1H),7.38–7.49(m,5H),8.28(s,1H),8.43(d,J=1.6Hz,1H),8.46(s,1H)。
LCMS:Rt=1.33min,MS Calcd.:396.1,MS Found:396.8[M+H]+
化合物18:将化合物17(580mg,1.46mmol),30%甲醛水溶液(732mg,7.3mmol), 三乙酰氧基硼氢化钠(465mg,2.2mmol),醋酸(4mL)依次加入到含20mL四氢呋喃的 100mL圆底烧瓶内,室温搅拌14h。LCMS监测,反应完成后,减压浓缩。加入20mL 水,二氯甲烷萃取(50mL×3),合并萃取液,无水Na2SO4干燥,减压浓缩得到黄色固体 600mg,产率:100%。
LCMS:Rt=1.33min,MS Calcd.:410.1,MS Found:410.8[M+H]+
化合物19:将化合物18(600mg,1.46mmol),铁粉(408mg,7.3mmol),氯化铵(390mg,7.3mmol)。依次加入到含20mL乙醇和4mL水的100mL圆底烧瓶内,70℃搅拌2h。 LCMS监测,反应完成后,过滤,滤液减压浓缩。加入20mL水,二氯甲烷萃取(50mL× 3),合并萃取液,无水Na2SO4干燥,减压浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:10-40%ACN),冻干,得到黄色粘稠物186mg,产率:33.5%。1H NMR(400MHz,CD3OD):δppm 2.06–2.16(m,2H), 2.41–2.45(m,2H),2.95(s,3H),3.21(td,J=13.0,2.4Hz,2H),3.39–3.46(m,1H),3.66–3.69 (m,2H),5.42(s,2H),7.40–7.47(m,3H),7.55–7.57(m,2H),7.72(br.s,2H),8.04(s,1H)。
LCMS:Rt=1.14min,MS Calcd.:380.2,MS Found:380.8[M+H]+.
实施例3化合物的制备
化合物的合成路线如下:
化合物22:将化合物20(1g,4.3mmol),21(2.15g,12.8mmol),双三苯基膦二氯化钯(302mg,0.43mmol)和碘化亚铜(244mg,1.28mmol)依次加入到含10mL二氧六环和2mL三乙胺的圆底烧瓶内,氮气保护,室温搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,20/1,v/v),得到黄色油状液体1g,产率:83.7%。
LCMS:Rt=1.67min,MS Calcd.:274.2 MS Found:296.9[M+Na]+.
化合物24:将化合物22(1.0g,3.65mmol),23(795mg,3.65mmol)和三苯基膦(1.24g,4.74mmol)依次加入到含30mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(960mg,4.74mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭(50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到类白色固体1.3g,产率:74.0%。1H NMR(400MHz,CDCl3)δppm 1.47–1.69(m,11H), 1.71–1.84(m,1H),3.52–3.58(m,1H),3.98–4.02(m,1H),5.15(dd,J=5.4,3.2Hz,1H),5.22(s, 2H),7.33–7.51(m,4H),7.68(t,J=2.3Hz,1H),8.17(d,J=1.8Hz,1H).
LCMS:Rt=1.92min,MS Calcd.:474.1,476.1MS Found:496.6,498.6[M+Na]+.
化合物25:将化合物24(1.3g,2.7mmol),5(1.3g,2.7mmol),双三苯基膦二氯化钯(190mg,0.27mmol)和碘化亚铜(154mg,0.81mmol)依次加入到含30mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到黄色粘稠物700mg(crude)。
LCMS:Rt=1.47min,MS Calcd.:576.2,MS Found:576.8[M+H]+.
化合物26:将化合物25(600mg,1.04mmol),锌粉(677mg,10.4mmol)和对甲苯磺酸(30mg)依次加入到含10mL冰醋酸的圆底烧瓶内,室温搅拌24h。LCMS监测,反应完成后,过滤,滤液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5 μm,流动相:ACN-H2O(0.1%TFA),梯度:15-30%ACN),冻干,得到类白色固体79.4mg,产率:16.3%。1H NMR(400MHz,DMSO-d6)δppm 1.47(s,6H),1.68–1.74(m,2H),1.98–2.05 (m,4H),2.20(s,3H),2.82–2.95(m,3H),5.22(s,2H),5.47(s,1H),6.07(s,2H),7.34–7.42(m, 3H),7.54(dd,J=3.8,1.9Hz,2H),7.77(d,J=1.9Hz,1H),7.87(s,1H).
LCMS:Rt=1.13min,MS Calcd.:462.2,MS Found:462.6[M+H]+.
实施例4化合物的制备
化合物的合成路线如下:
化合物28:将化合物9(1.0g,4.6mmol),27(560mg,4.6mmol)和三苯基膦(1.45g,5.5mmol)依次加入到含40mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(1.12g,5.5mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭 (50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/2,v/v),得到类白色固体1.4g(粗品含三苯氧膦)。
LCMS:Rt=1.38min,MS Calcd.:323.1,324.1MS Found:323.7,325.7[M+H]+.
化合物29:将化合物28(500mg,1.55mmol),5(730mg,1.55mmol),双三苯基膦二氯化钯(109mg,0.16mmol)和碘化亚铜(89mg,0.47mmol)依次加入到含10mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,3/1,v/v),得到浅黄色固体320mg,产率:48.4%。
LCMS:Rt=1.13min,MS Calcd.:425.1,MS Found:425.7[M+H]+.
化合物30:将化合物29(320mg,0.75mmol),还原铁粉(211mg,3.76mmol)和氯化铵(201mg,3.76mmol)依次加入到含10mL乙醇和2mL水的圆底烧瓶内,70℃搅拌 3h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,高效液相制备分离(色谱柱: Gemini-C18 150x21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:5-25%ACN),冻干,得到黄色固体61mg,产率:20.0%。1H NMR(400MHz,DMSO-d6)δppm 1.67(d,J=6.3 Hz,3H),1.86–1.95(m,2H),2.26(d,J=13.9Hz,2H),2.78–2.82(m,3H),3.06–3.14(m,2H), 3.25–3.31(m,1H),3.54(d,J=12.0Hz,2H),6.09–6.11(m,1H),7.62(s,1H),7.84(s,1H),7.90 (s,2H),8.04(s,1H),8.80(d,J=5.6Hz,2H),9.72(s,1H).
LCMS:Rt=0.92min,MS Calcd.:395.2,MS Found:395.7[M+H]+.
实施例5化合物的制备
化合物的合成路线如下:
化合物31:将化合物9(1.0g,4.6mmol),61(580mg,4.6mmol)和三苯基膦(1.45g,5.5mmol)依次加入到含40mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(1.12g,5.5mmol),室温搅拌3h,LCMS监测,反应完成后,加水淬灭 (50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,3/1,v/v),得到黄色固体1.3g,产率:86.7%。1HNMR(400MHz,CDCl3)δppm 5.23(s,2H),7.06–7.20(m,2H), 7.33–7.52(m,2H),7.71(d,J=1.7Hz,1H),8.18(d,J=1.8Hz,1H).
LCMS:Rt=1.71min,MS Calcd.:326.1,328.1;MS Found:326.7,328.7[M+H]+.
化合物32:将化合物31(500mg,1.55mmol),5(730mg,1.55mmol),双三苯基膦二氯化钯(109mg,0.16mmol)和碘化亚铜(89mg,0.47mmol)依次加入到含10mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得到浅黄色固体280mg,产率:41.9%。
LCMS:Rt=1.31min,MS Calcd.:428.1,MS Found:428.6[M+H]+.
化合物33:将化合物32(280mg,0.65mmol),还原铁粉(183mg,3.27mmol)和氯化铵(175mg,3.27mmol)依次加入到含10mL乙醇和2mL水的圆底烧瓶内,70℃搅拌3h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,高效液相制备分离(色谱柱: Gemini-C18 150x21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:9-20%ACN),冻干,得到浅黄色固体108mg,产率:41.5%。1H NMR(400MHz,DMSO-d6)δppm 1.89–1.97 (m,2H),2.29(d,J=13.1Hz,2H),2.80–2.83(m,3H),3.07–3.16(m,2H),3.28–3.34(m,1H), 3.56(d,J=12.2Hz,2H),5.35(s,2H),7.27(t,J=8.8Hz,2H),7.62(dd,J=8.3,5.7Hz,2H), 7.73(s,1H),7.84(s,1H),8.15(s,1H),9.67(s,1H).
LCMS:Rt=1.17min,MS Calcd.:398.2,MS Found:398.8[M+H]+.
实施例6化合物的制备
化合物的合成路线如下:
化合物35:将化合物41(3g,21.9mmol)加入到含60%氢化钠(1g,26.3mmol)和100mL四氢呋喃的三口烧瓶内,氮气保护,0℃搅拌30min,随后加入化合物34(3.1g,21.9mmol),室温搅拌3h。LCMS监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/1,v/v),得到浅黄色固体2.4g,产率: 42.5%。1H NMR(400MHz,CD3OD)δppm 1.75(s,6H),7.10(dd,J=8.5,1.1Hz,1H),7.33 (dd,J=8.5,4.6Hz,1H),7.51(dd,J=4.7,1.7Hz,2H),7.98(dd,J=4.6,1.1Hz,1H),8.54(dd, J=4.7,1.6Hz,2H).
LCMS:Rt=1.10min,MS Calcd.:259.1MS Found:260.1[M+H]+.
化合物36:将化合物35(2.4g,9.3mmol),还原铁粉(2.6g,46.3mmol)和氯化铵(2.5g,46.3mmol)依次加入到含50mL乙醇和10mL水的圆底烧瓶内,70℃搅拌4h。LCMS 监测,反应完成后,冷却至室温,过滤,滤液用水稀释(50mL),乙酸乙酯萃取(100mL ×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,得到类白色固体1.3g,产率:61.3%。1H NMR(400MHz,CDCl3)δppm 1.75(s,3H),4.79(s,2H), 6.28–6.43(m,2H),7.38(dd,J=4.5,1.6Hz,2H),7.66(dd,J=4.1,2.4Hz,1H),8.64(dd,J= 4.5,1.6Hz,2H).
LCMS:Rt=0.39min,MS Calcd.:229.1MS Found:229.9[M+H]+.
化合物37:将化合物36(1.2g,5.2mmol)加入到含20mL乙腈的圆底烧瓶内,0℃搅拌下加入NBS(980mg,5.5mmol),室温搅拌2h。LCMS监测,反应完成后,滤液用乙酸乙酯稀释(150mL),饱和碳酸氢钠溶液洗(50mL×3),饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/2,v/v),得到类白色固体1.1g,产率:69.2%。1H NMR(400MHz,DMSO-d6)δppm 1.68(s,6H),6.04(s,2H), 6.35(d,J=2.0Hz,1H),7.46(dd,J=4.5,1.6Hz,2H),7.59(d,J=2.0Hz,1H),8.61(dd,J= 4.5,1.6Hz,2H).
LCMS:Rt=1.15min,MS Calcd.:307.0,309.0MS Found:307.9,309.9[M+H]+.
化合物38:将化合物37(0.5g,1.6mmol),二叔丁基二碳酸酯(1.7g,4.9mmol),三乙胺(823mg,8.2mmol)和4-二甲氨基吡啶(20mg,0.16mmol)依次加入到含20mL二氯甲烷的圆底烧瓶内,室温搅拌24h。LCMS监测,反应完成后,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/1,v/v),得到白色固体600mg,产率:69.2%。1H NMR(400 MHz,CD3OD)δppm 1.47(s,18H),1.81(s,6H),6.96(d,J=1.8Hz,1H),7.53(d,J=6.1Hz, 2H),8.14(d,J=1.8Hz,1H),8.62(d,J=6.1Hz,2H).
LCMS:Rt=1.15min,MS Calcd.:507.0,509.0MS Found:507.7,509.7[M+H]+.
化合物39:将化合物38(610mg,1.2mmol),7(625mg,1.32mmol),双三苯基膦二氯化钯(84mg,0.12mmol)和碘化亚铜(69mg,0.36mmol)依次加入到含15mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h,LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到黄色粘稠物330mg,产率:45%。
LCMS:Rt=1.32min,MS Calcd.:609.3,MS Found:609.6[M+H]+.
化合物40:将化合物39(400mg,0.66mmol)和三氟乙酸(3mL)依次加入到含15mL 二氯甲烷的圆底烧瓶内,室温搅拌5h。LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:0-20%ACN),冻干,得到类白色固体160mg,产率:54.5%。1H NMR(400MHz,CD3OD) δppm 1.97(s,6H),1.99–2.10(m,2H),2.36(d,J=13.1Hz,2H),2.93(s,3H),3.15–3.21(m, 2H),3.38–3.42(m,1H),3.65(d,J=12.6Hz,2H),6.91(s,1H),7.72(s,1H),7.79(s,1H),8.07 (d,J=5.5Hz,2H),8.85(s,2H)。
LCMS:Rt=0.95min,MS Calcd.:409.2,MS Found:409.9[M+H]+.
实施例7化合物的制备
化合物的合成路线如下:
化合物41:将化合物9(2g,9.14mmol),4-吡啶甲醇(1.5g,13.7mmol),三苯基膦(3.6g,18.3mmol)依次加入到含有100mL无水四氢呋喃的三口瓶中,氮气保护,在无氧0℃条件下加入偶氮二甲酸二异丙酯(3.7g,18.3mmol)。室温搅拌2h。LCMS监测,反应完成后,减压浓缩。加入100mL水,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1-3/1,v/v),得到黄色固体2.5g(80%纯度含有三苯氧磷)产率:71.4%。
LCMS:Rt=1.21min,MS Calcd.:309.0,311.0,MS Found:309.7,311.7[M+H]+
化合物43:在250mL三口烧瓶中,将化合物42(1g,3.73mmol)溶于30mL的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(2.4M的四氢呋喃溶液,1.5mL,3.73 mmol),-78℃搅拌1h,随后滴加三丁基氯化锡(1.33g,4.1mmol),滴加完毕后于-78℃继续搅拌1h。LCMS监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100 mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:乙酸乙酯/石油醚,1/10,v/v),得到黄色的油1.4g,产率:67.3%。1H NMR(400MHz,CDCl3):δppm0.91(t,J=7.4Hz,9H),1.11–1.15(m,5H),1.26–1.38(m, 8H),1.49(s,9H),1.51–1.61(m,5H),1.78(dq,J=12.4,4.0Hz,2H),2.12–2.15(m,2H),2.91(t, J=12.0Hz,2H),3.19–3.27(m,1H),4.11–4.20(m,2H),7.64(s,1H)。
化合物44:将化合物43(1.1g,1.97mmol),化合物2(600mg,1.97mmol),双三苯基磷二氯化钯(278mg,0.39mmol),四丁基氟化铵(150mg,0.59mmol)依次加入到含50 mL二氧六环100mL圆底烧瓶内,氮气保护,50℃搅拌14h。LCMS监测,反应完成后,冷却到室温,减压浓缩得到2.5g粗品,直接用于下一步反应,没有纯化。
LCMS:Rt=1.35min,MS Calcd.:497.2,MS Found:497.8[M+H]+
化合物45:将化合物44(2.5g粗品),铁粉(1.2g,20.1mmol),氯化铵(1.1g,20.1mmol)。依次加入到含40mL乙醇/10mL水的100mL圆底烧瓶内,50℃搅拌2h。LCMS 监测,反应完成后,过滤,滤液减压浓缩。加入50mL水,乙酸乙酯萃取(100mL×3),合并萃取液,无水Na2SO4干燥,减压浓缩柱,层析分离(洗脱液:石油醚/乙酸乙酯3/1- 甲醇在二氯甲烷里0%-10%,v/v),得到黄色的固体340mg,两步总产率:37.0%。1H NMR (400MHz,DMSO-d6):δppm1.42(s,9H),1.58–1.60(m,2H),2.01–2.05(m,2H),3.18–3.21(m, 2H),3.99–4.06(m,3H),5.29(s,3H),6.20(s,2H),7.37(s,1H),7.57(d,J=5.2Hz,2H),7.80(s, 1H),7.90(s,1H),8.60(d,J=4.8Hz,2H)。
LCMS:Rt=1.31min,MS Calcd.:467.2,MS Found:467.8[M+H]+
化合物46:化合物45(340mg,0.73mmol)加入到含10mL二氯甲烷的100mL圆底烧瓶内,搅拌下加入2mL三氟乙酸。室温搅拌14h。LCMS监测,反应完成后,减压浓缩。高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O(0.1% TFA),梯度:0-20%ACN),冻干得到黄色的固体13.4mg,产率:5.0%。1H NMR(400MHz, CD3OD):δppm 2.04–2.14(m,2H),2.36–2.39(m,2H),3.21(t,J=11.6Hz,2H),3.46–3.53(m, 3H),5.72(s,2H),7.82(s,2H),8.08(s,1H),8.18(br.s,2H),8.88(s,2H)。
LCMS:Rt=0.96min,MS Calcd.:367.1,MS Found:367.8[M+H]+.
实施例8化合物的制备
化合物的合成路线如下:
化合物47:将5-溴-2-硝基吡啶-3-醇(1.00g,4.59mmol),(2-氯吡啶-4-基)甲醇(0.66 g,4.59mmol)和三苯基膦(1.45g,5.51mmol)依次加入到含40mL无水四氢呋喃的三口瓶中,抽充3次氮气,冰浴下搅拌,向混合溶液中滴加偶氮二甲酸二异丙酯(1.11g,5.51mmol)。滴加完毕后室温搅拌2h。LCMS监测,反应完成后,减压浓缩。加入100mL水,二氯甲烷萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到黄色固体1.4g, 产率:89%。
LCMS:Rt=1.63min,MS Calcd.:342.9,344.9,MS Found:343.6,345.6[M+H]+.
化合物48:将化合物47(0.45g,1.31mmol),2-(1-哌啶-4基)-5(三丁基锡烷基) 噻唑(0.62g,1.31mmol),二(三苯基膦)二氯化钯(0.25g,0.26mmol)和碘化亚酮(0.075 g,0.39mmol)依次加入到含20mL二氧六环的单口烧瓶中,氮气保护下,加热至90℃反应3h。LCMS监测,反应完成后静置,抽滤除去滤渣,滤液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到白色固体0.23g,产率:39%。
LCMS:Rt=1.34min,MS Calcd.:445.1,MS Found:445.7[M+H]+.
化合物49:将化合物48(150mg,0.34mmol)加入到乙醇(5mL)和水(1mL)的混合溶剂中,室温搅拌下,依次加入氯化铵(54mg,1.02mol)和铁粉(57mg,1.02mmol)。室温反应5h。LCMS监测,反应完成后,浓缩,加入甲醇30mL搅拌,硅藻土过滤,滤液浓缩,(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O(0.1%FA),梯度: 5-20%ACN),冻干,得到15mg黄色固体,收率11%。1H NMR(400MHz,DMSO-d6):δppm 1.72–1.80(m,2H),2.05(d,J=12Hz,2H),2.21(t,J=11.6Hz,2H),2.29(s,3H),3.00–2.92(m, 3H),5.30(s,2H),6.29(s,2H),7.36(s,1H),7.57(d,J=4.8Hz,1H),7.76(s,1H),7.81(s,1H), 7.89(s,1H),8.22(s,1H),8.43(d,J=5.2Hz,1H)。
LCMS:Rt=1.14min,MS Calcd.:415.1,MS Found:415.7[M+H]+.
实施例9化合物的制备
化合物的合成路线如下:
化合物50:将5-溴-2-硝基吡啶-3-醇(3.00g,13.8mmol),(2-甲氧基吡啶-4-基)甲醇 (1.91g,13.8mmol)和三苯基膦(4.35g,16.6mmol)依次加入到含100ml无水四氢呋喃的三口瓶中,抽充3次氮气,冰浴下搅拌,向混合溶液中滴加偶氮二甲酸二异丙酯(3.35 g,16.6mmol)。滴加完毕后室温搅拌2小时,LCMS监测,反应完成后,减压浓缩。加入 100mL水,二氯甲烷萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(200mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到黄色固体1.4g,产率:30%。1H NMR(400MHz,DMSO-d6):δppm 3.76(s,3H),5.31(s,2H), 6.98(d,J=8.8Hz,2H),7.38(d,J=8.4Hz,2H),8.29(d,J=1.2Hz,1H),8.43(d,J=1.6Hz, 1H)。
化合物51:将化合物50(1.40g,4.14mmol),2-(1-哌啶-4基)-5(三丁基锡烷基)噻唑(1.95g,4.14mmol),二(三苯基膦)二氯化钯(0.40g,0.41mmol)和碘化亚酮(0.24 g,1.24mmol)依次加入到含20mL二氧六环的单口烧瓶中,氮气保护下,加热至90℃反应 2h。LCMS监测,反应完成后静置,抽滤除去滤渣,滤液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,30/1,v/v),得到白色固体0.70g,产率:38%。
LCMS:Rt=1.37min,MS Calcd.:440.2,MS Found:440.9[M+H]+.
化合物52:将化合物51(200mg,0.45mmol)加入到乙醇(5ml)和水(1ml)的混合溶剂中,室温搅拌下,依次加入氯化铵(72mg,1.35mol)和铁粉(76mg,1.35mmol)。室温反应5小时,LCMS监测,反应完成后,浓缩,加入甲醇30ml搅拌,硅藻土过滤,滤液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O (0.1%TFA),梯度:15-30%ACN),冻干,得到70mg黄色固体,收率38%。1H NMR(400 MHz,DMSO-d6):δppm 1.70–1.80(m,2H),2.04(d,J=17.2Hz,2H),2.27(s,2H),2.90–2.98 (m,3H),3.76(s,3H),5.13(s,2H),5.98(s,2H),6.95(d,J=8.8Hz,2H),7.37(s,1H),7.46(d,J =8.4Hz,2H),7.74(s,1H),7.90(s,1H),8.19(s,1H)。
LCMS:Rt=1.20min,MS Calcd.:410.2,MS Found:410.9[M+H]+.
实施例10化合物的制备
化合物(21)的合成路线如下:
化合物55:将化合物53(2g,10.7mmol),54(2.7g,16.0mmol),双三苯基膦二氯化钯(751mg,1.07mmol)和碘化亚铜(611mg,3.21mmol)依次加入到含15mL DMF和5mL 三乙胺的圆底烧瓶内,氮气保护,70℃搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,3/1,v/v),得到黄色油状液体2.3g,产率:78.1%。1H NMR(400MHz,CDCl3)δppm 1.53–1.65(m,10H),1.71–1.96(m,2H),3.22(s,1H), 3.51–3.56(m,1H),3.95–4.01(m,1H),4.74(s,2H),5.15(d,J=3.3Hz,1H),7.24(d,J=5.1Hz, 1H),7.43(s,1H),8.47(d,J=5.1Hz,1H)。
LCMS:Rt=1.67min,MS Calcd.:275.2,MS Found:275.9[M+H]+.
化合物57:将化合物55(1.3g,4.6mmol),56(1g,4.6mmol)和三苯基膦(1.4g,5.5mmol)依次加入到含30mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(1.1g,5.5mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭(50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/1,v/v),得到深棕色粘稠物 1.3g(粗品,含有三苯氧膦)。
LCMS:Rt=1.70min,MS Calcd.:475.1/477.1,MS Found:475.5/477.5[M+H]+.
化合物58:将化合物57(1.3g粗品),5(1.3g,2.7mmol),双三苯基膦二氯化钯(190mg,0.27mmol)和碘化亚铜(154mg,0.81mmol)依次加入到含30mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到黄色粘稠物370mg(粗品)。
LCMS:Rt=1.41min,MS Calcd.:577.2,MS Found:577.9[M+H]+.
化合物59:将化合物58(370mg粗品),铁粉(291mg,5.2mmol)和氯化铵(281mg,5.2mmol)依次加入到含10mL乙醇和2mL水的圆底烧瓶内,70℃搅拌4h。LCMS监测,反应完成后,过滤,滤液用水稀释(10mL),乙酸乙酯萃取(30mL×3),合并萃取液,用饱和氯化钠水溶液洗(10mL),无水Na2SO4干燥,减压浓缩,得到棕色固体200mg(粗品),可直接用于下一步反应不需要进一步纯化。
LCMS:Rt=1.25min,MS Calcd.:547.3,MS Found:547.9[M+H]+.
化合物60:在50mL圆底烧瓶中,将化合物59(200mg粗品)溶于15mL四氢呋喃,加入4N盐酸二氧六环溶液(3mL),室温搅拌3h。LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O(0.1% FA),梯度:0-40%ACN),冻干,得到白色固体25mg,四步总产率:1.2%。1H NMR(400 MHz,DMSO-d6)δppm 1.48(s,6H),1.69–1.78(m,2H),2.01–2.14(m,4H),2.24(s,3H), 2.87–2.97(m,3H),5.28(s,2H),6.24(s,2H),7.33(s,1H),7.54(d,J=4.9Hz,1H),7.60(s,1H), 7.80(s,1H),7.88(s,1H),8.55(d,J=5.0Hz,1H)。
LCMS:Rt=1.07min,MS Calcd.:463.2,MS Found:463.6[M+H]+.
实施例11化合物的制备
化合物的合成路线如下:
化合物63:将化合物62(2g,12.19mmol),N-甲基哌嗪(3.66g,36.58mmol)加入到100mL 的圆底烧瓶内,140℃搅拌1h。LCMS监测,反应完成后,冷却到室温,加50mL水稀释,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/10,v/v),得到1.8g黄色的油,产率81.8%。1HNMR(400MHz,DMSO-d6):δppm 2.22(s,3H),2.41(t,J=5.2Hz,4H), 3.37–3.39(m,4H),6.84(d,J=3.6Hz,1H),7.16(d,J=3.6Hz,1H)。
LCMS:Rt=0.39min,MS Calcd.:183.1,MS Found:183.9[M+H]+
化合物64:在250mL三口烧瓶中,将化合物63(900mg,4.91mmol)溶于40mL的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(2.4M的己烷溶液,2.1mL,4.91mmol), -78℃搅拌1h,随后滴加三丁基氯化锡(1.92g,5.89mmol),滴加完毕后于-78℃继续搅拌1h。LCMS监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/10,v/v),得到黄色的油950mg,产率:40.8%。1H NMR(400 MHz,DMSO-d6):δppm 0.86(t,J=7.2Hz,9H),1.04(t,J=8.0Hz,5H),1.25–1.34(m,7H), 1.48–1.59(m,6H),2.22(s,3H),2.39–2.42(m,4H),3.37–3.40(m,4H),7.06(s,1H)。
LCMS:Rt=1.59min,MS Calcd.:473.2,MS Found:473.8[M+H]+
化合物65:将化合物64(900mg,1.90mmol),化合物41(600mg,1.90mmol),双三苯基磷二氯化钯(268mg,0.38mmol),四丁基氟化铵(148mg,0.52mmol)依次加入到含30mL 二氧六环的100mL圆底烧瓶内,氮气保护,50℃搅拌4h。LCMS监测,反应完成后,冷却到室温,减压浓缩。加入100mL水,乙酸乙酯萃取(100mL×3),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/5,v/v),得到黄色固体250mg,产率:31.9%。1H NMR(400MHz,DMSO-d6):δppm 2.42–2.47(m,5H),3.33(s,3H),3.54(t,J=4.8Hz,3H),5.52(s,2H),7.46(d,J=5.2Hz,2H), 7.98(s,1H),8.06(s,1H),8.28(s,1H),8.64(d,J=5.2Hz,2H)。
LCMS:Rt=1.06min,MS Calcd.:412.1,MS Found:412.8[M+H]+
化合物66:将化合物65(250mg,0.61mmol),铁粉(338mg,6.06mmol),氯化铵(324mg, 6.06mmol)依次加入到含乙醇/水(50mL,4/1,v/v)的100mL圆底烧瓶内,50℃搅拌2h。 LCMS监测,反应完成后,过滤,滤液减压浓缩。高效液相制备分离(色谱柱:Gemini-C18150x 21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:0-20%ACN),冻干得到白色的固体39.5mg,产率:17%。1H NMR(400MHz,CD3OD):δppm 2.38(s,3H),2.60(t,J=4.8 Hz,4H),3.52(t,J=4.8Hz,4H),5.32(s,2H),7.30(d,J=7.2Hz,2H),7.60–7.63(m,3H),8.58 (d,J=4.8Hz,2H)。
LCMS:Rt=0.39min,MS Calcd.:382.2,MS Found:382.9[M+H]+.
实施例12化合物的制备
化合物的合成路线如下:
化合物68:将化合物67(3g,23.23mmol),劳森试剂(4.7g,11.61mmol)加入到含有50mL 无水四氢呋喃的圆底烧瓶内,60℃氮气保护下搅拌14h。LCMS监测,反应完成后,加入100mL饱和碳酸氢钠水溶液淬灭,乙酸乙酯萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇10/1,v/v),得到2g白色的固体,产率59.3%。
1HNMR(400MHz,DMSO-d6):δppm 1.55–1.59(m,2H),1.70–1.81(m,2H),2.68–2.76(m, 1H),3.30–3.34(m,2H),3.86–3.90(m,2H),9.10(s,1H),9.40(s,1H)。
LCMS:Rt=1.01min,MS Calcd.:145.2,MS Found:145.9[M+H]+
化合物69:将化合物68(1.4g,9.64mmol),氯乙醛(40%水溶液,3.8g,19.28mmol)加入到含有20mL丙酮的100mL的圆底烧瓶内,60℃搅拌14h。LCMS监测,反应完成后,加50mL水稀释,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/10,v/v),得到1.1g 棕色的油,产率68.8%。1H NMR(400MHz,DMSO-d6):δppm 1.68–1.78(m,2H),1.96–1.99 (m,2H),3.27–3.35(m,1H),3.45–3.49(m,2H),3.90–3.94(m,2H),7.66(d,J=3.2Hz,1H), 7.78(d,J=3.2Hz,1H)。
LCMS:Rt=1.31min,MS Calcd.:169.2,MS Found:169.9[M+H]+
化合物70:在250mL三口烧瓶中,将化合物69(700mg,4.14mmol)溶于40mL的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(2.4M的己烷溶液,21.8mL,1.14mmol), -78℃搅拌1h,随后滴加三丁基氯化锡(1.62g,4.96mmol),滴加完毕后于-78℃继续搅拌1h。LCMS监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/20,v/v),得到黄色的油600mg,产率:31.6%。
LCMS:Rt=2.82min,MS Calcd.:459.2,MS Found:459.6[M+H]+
化合物71:将化合物70(350mg,0.76mmol),化合物41(237mg,0.76mmol),四三苯基磷钯(177mg,0.15mmol),四丁基氟化铵(60mg,0.23mmol)依次加入到含30mL N-甲基吡咯烷酮的100mL圆底烧瓶内,氮气保护,50℃搅拌4h。LCMS监测,反应完成后,冷却到室温,减压浓缩。加入100mL水,乙酸乙酯萃取(100mL×3),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇 /二氯甲烷,1/5,v/v),得到900mg黄色液体粗品(含有大量N-甲基吡咯烷酮)。
LCMS:Rt=1.36min,MS Calcd.:398.1,MS Found:398.9[M+H]+
化合物72:将化合物71(900mg,粗品),铁粉(420mg,67.53mmol),氯化铵(402mg,7.53 mmol)依次加入到含乙醇/水(50mL,4/1,v/v)的100mL圆底烧瓶内,50℃搅拌2h。 LCMS监测,反应完成后,过滤,滤液减压浓缩。高效液相制备分离(色谱柱:Gemini-C18 150x21.2mm,5μm,流动相:ACN-H2O(0.1%TFA),梯度:0-40%ACN),冻干得到黄色的固体8mg,两步总产率:0.8%。1H NMR(400MHz,CDCl3):δppm 1.93–2.00(m,2H), 2.07–2.10(m,2H),3.23–3.29(m,1H),3.58(t,J=11.6Hz,2H),4.09–4.12(m,2H),5.09(s,2H), 5.20(s,2H),7.07(s,1H),7.38(d,J=4.8Hz,2H),7.67(s,1H),7.91(s,1H),8.70(d,J=4.8Hz, 2H)。
LCMS:Rt=0.96min,MS Calcd.:368.5,MS Found:369.1[M+H]+.
实施例13化合物的制备
化合物的合成路线如下:
化合物73:将5-溴-2-硝基吡啶-3-醇(1g,4.59mmol),4-羟甲基吡啶-2-腈(0.62g,4.59 mmol)和三苯基膦(1.45g,5.51mmol)依次加入到含40mL无水四氢呋喃的三口瓶中,抽充3次氮气,冰浴下搅拌,向混合溶液中滴加偶氮二甲酸二异丙酯(1.11g,5.51mmol)。滴加完毕后室温搅拌2h。LCMS监测,反应完成后,减压浓缩。加入100mL水,二氯甲烷萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,5/1,v/v),得到黄色固体0.55g,产率: 36%。
LCMS:Rt=1.59min,MS Calcd.:334.0,336.0,MS Found:334.7,336.7[M+H]+.
化合物74:将化合物73(0.55g,1.64mmol),2-(1-哌啶-4基)-5-(三丁基锡烷基)噻唑(0.77 g,1.64mmol),二(三苯基膦)二氯化钯(0.318g,0.33mmol),碘化亚酮(0.063g,0.33mmol) 和四丁基氟化铵(0.64g,2.46mmol)依次加入到含10mL 1,4-二氧六环的单口烧瓶中,氮气保护下加热至90℃,反应3h。LCMS监测,反应完成后静置,抽滤除去滤渣,滤液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,10/1,v/v),得到红色油状物0.5g,产率:70%。
LCMS:Rt=1.32min,MS Calcd.:436.1,MS Found:436.8[M+H]+.
化合物75:将化合物74(300mg,0.69mmol)加入到乙醇(5mL)和水(1mL)的混合溶剂中,室温搅拌下,依次加入氯化铵(74mg,1.38mmol)和铁粉(77mg,1.38mmol)。室温反应5h。LCMS监测,反应完成后,浓缩,加入30mL甲醇搅拌,硅藻土过滤,滤液浓缩,粗品于制备色谱分离得到13mg白色固体,收率4.6%。1H NMR(400MHz, DMSO-d6):δppm 1.71–1.79(m,2H),2.04(d,J=15.2Hz,2H),2.16(t,J=10.8Hz,2H),2.26 (s,3H),2.90–2.96(m,3H),5.34(s,2H),6.36(s,2H),7.38(s,1H),7.82(s,1H),7.87(d,J=4.0 Hz,1H),7.90(s,1H),8.22(s,1H),8.36(s,1H),8.77(d,J=4.8Hz,1H)。
LCMS:Rt=1.14min,MS Calcd.:406.2,MS Found:406.9[M+H]+.
实施例14化合物的制备
化合物的合成路线如下:
化合物78:将化合物77(5g,71.4mmol)加入到含100mL四氢呋喃的圆底烧瓶内,随后于0oC下滴加乙炔基溴化镁(285mL,142.8mmol,0.5M四氢呋喃溶液),氮气保护, 0oC搅拌16h。TLC监测,反应完成后,加水(200mL)淬灭,乙醚萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,得到黄色油状液体4.8g,粗品,直接用于下一步反应。
化合物79:将化合物78(4.8g,50.0mmol),4-甲基苯磺酸吡啶盐(50mg)加入到含50mL四氢呋喃的圆底烧瓶内,随后加入3,4-二氢吡喃(4.2g,50.0mmol),氮气保护,室温搅拌16h。TLC监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,50/1,v/v),得到黄色油状液体2.9g,粗品,直接用于下一步反应。
化合物81:将化合物79(1g,5.55mmol),80(1.1g,4.63mmol),双三苯基膦二氯化钯(323mg,0.46mmol)和碘化亚铜(263mg,1.38mmol)依次加入到含10mL二氧六环和2mL三乙胺的圆底烧瓶内,氮气保护,室温搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到黄色油状液体1.1g,产率:82.1。
LCMS:Rt=1.67min,MS Calcd.:286.2,MS Found:308.9[M+Na]+.
化合物82:将化合物81(1.0g,3.5mmol),9(762mg,3.5mmol)和三苯基膦(1.1g,4.2mmol)依次加入到含20mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(849mg,4.2mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭(50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到浅黄色粘稠物1.0g,产率:58.6。
LCMS:Rt=1.90min,MS Calcd.:486.1,488.1,MS Found:508.7,510.8[M+Na]+.
化合物83:将化合物82(950mg,1.95mmol),5(923mg,1.95mmol),双三苯基膦二氯化钯(137mg,0.195mmol)和碘化亚铜(111mg,0.585mmol)依次加入到含15mL 二氧六环的圆底烧瓶内,氮气保护,90oC搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,8/1,v/v),得到黄色固体260mg,粗品,直接用于下一步反应。
LCMS:Rt=1.58min,MS Calcd.:588.2,MS Found:588.9[M+H]+.
化合物84:将化合物83(260mg,粗品),还原铁粉(124mg,2.2mmol)和氯化铵(119mg,2.2mmol)依次加入到含5mL乙醇和1mL水的圆底烧瓶内,70oC搅拌3h。LCMS 监测,反应完成后,过滤,滤液浓缩,得到黄色固体230mg,粗品,直接用于下一步反应。
LCMS:Rt=1.37min,MS Calcd.:558.3,MS Found:558.9[M+H]+.
化合物85:将化合物84(230mg,粗品),加入到含5mL四氢呋喃的圆底烧瓶内,氮气保护下加入4N盐酸二氧六环溶液(1mL),室温搅拌3h。LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相: ACN-H2O(0.05%NH3),梯度:40-90%ACN),冻干,得到浅黄色固体79.2mg,三步总收率:8.6。1H NMR(400MHz,DMSO-d6):δppm 1.67–1.82(m,4H),1.99–2.04(m,4H), 2.19–2.25(m,5H),2.33–2.41(m,2H),2.81–2.94(m,3H),5.23(s,2H),5.89(s,1H),6.08 (s,2H),7.36–7.43(m,3H),7.54–7.58(m,2H),7.77(s,1H),7.88(s,1H)。LCMS:Rt=1.22 min,MS Calcd.:474.2,MS Found:474.9[M+H]+.
实施例15化合物的制备
化合物的合成路线如下:
化合物88:将化合物86(500mg,1.05mmol),87(528mg,1.26mmol),双三苯基膦二氯化钯(74mg,0.105mmol)和碘化亚铜(60mg,0.315mmol)依次加入到含10mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,3/1,v/v),得到类白色固体320mg,产率:58.1%。
化合物89:将化合物88(320mg,0.61mmol),还原铁粉(172mg,3.1mmol)和氯化铵(167mg,3.1mmol)依次加入到含5mL乙醇和1mL水的圆底烧瓶内,70℃搅拌3h。 LCMS监测,反应完成后,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/2,v/v),得到黄色固体240mg,产率:80.3%。
LCMS:Rt=1.71min,MS Calcd.:491.2,MS Found:491.9[M+H]+.
化合物90:将化合物89(240mg,0.49mmol),加入到含5mL四氢呋喃的圆底烧瓶内,氮气保护下加入4N盐酸二氧六环溶液(1mL),室温搅拌3h,LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相: ACN-H2O(0.05%NH3),梯度:40-70%ACN),冻干,得到白色固体56.8mg,产率:28.4%。1H NMR(400MHz,DMSO-d6):δppm 1.34(d,J=6.8Hz,6H),1.47(s,6H),3.22–3.33(m,1H), 5.22(s,2H),5.47(s,1H),6.08(s,2H),7.34–7.42(m,3H),7.54(s,2H),7.77(s,1H),7.86(s, 1H)。
LCMS:Rt=1.43min,MS Calcd.:407.2,MS Found:407.9[M+H]+.
实施例16化合物的制备
化合物的合成路线如下:
化合物93:将化合物91(300mg,0.56mmol),92(139mg,1.12mmol),双三苯基膦二氯化钯(39mg,0.056mmol)和碘化亚铜(32mg,0.17mmol)依次加入到含5mL DMF 和1mL三乙胺的圆底烧瓶内,氮气保护,室温搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,8/1,v/v),得到黄色粘稠物110mg(粗品,含量70%)。
LCMS:Rt=1.32min,MS Calcd.:532.2,MS Found:532.8[M+H]+.
化合物94:将化合物93(110mg,粗品),还原铁粉(58mg,1.03mmol)和氯化铵(55mg,1.03mmol)依次加入到含5mL乙醇和1mL水的圆底烧瓶内,70℃搅拌3h。LCMS 监测,反应完成后,冷却至室温,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150 x 21.2mm,5μm,流动相:ACN-H2O(0.1%FA),梯度:5-30%ACN),冻干,得到类白色固体16mg,两步总收率:5.7%。1H NMR(400MHz,DMSO-d6):δppm 1.23–1.30(m,1H), 1.49–1.68(m,8H),1.85–1.88(m,2H),2.09–2.32(m,4H),3.04(s,3H),3.24–3.30(m,1H), 3.44–3.61(m,4H),4.63(s,2H),5.82(s,2H),7.10(s,1H),7.52–7.61(m,3H),7.64(s,1H),7.69 (s,1H),7.82(s,1H),8.37(s,2H)。
LCMS:Rt=1.02min,MS Calcd.:502.2,MS Found:503.1[M+H]+.
实施例17化合物的制备
化合物的合成路线如下:
化合物98:将化合物96(1.5g,8.0mmol),97(1.2g,12.0mmol),双三苯基膦二氯化钯(562mg,0.8mmol)和碘化亚铜(457mg,2.4mmol)依次加入到含20mL二氧六环和 4mL三乙胺的圆底烧瓶内,氮气保护,50℃搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/1,v/v),得到棕黄色油状液体1.5g,产率:91.2%。1H NMR(400MHz,CDCl3):δppm 0.27(s,9H),4.75(s,2H),7.25(d,J=5.0Hz, 1H),7.49(s,1H),8.48(d,J=5.1Hz,1H)。
LCMS:Rt=1.51min,MS Calcd.:205.1,MS Found:206.0[M+H]+.
化合物100:将化合物98(1.5g,7.3mmol),99(1.4g,6.6mmol)和三苯基膦(2.0g,7.9mmol)依次加入到含30mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(1.6g,7.9mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭(50 mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水 Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,2/1,v/v),得到灰色固体1.2g,产率:45.5%。1HNMR(400MHz,CDCl3):δppm 0.30(s,9H),5.25(s,2H),7.34(d, J=4.9Hz,1H),7.51(s,1H),7.67(s,1H),8.24(s,1H),8.65(d,J=5.0Hz,1H)。
LCMS:Rt=1.70min,MS Calcd.:405.0,407.0,MS Found:405.7,407.7[M+H]+.
化合物102:将化合物100(0.8g,2.0mmol),101(932mg,2.0mmol),双三苯基膦二氯化钯(140mg,0.2mmol)和碘化亚铜(114mg,0.6mmol)依次加入到含15mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到黄色粘稠物160mg(粗品)。
LCMS:Rt=1.46min,MS Calcd.:507.2,MS Found:507.9[M+H]+.
化合物103:将化合物102(160mg,粗品),还原铁粉(88mg,1.6mmol)和氯化铵(85mg,1.6mmol)依次加入到含5mL乙醇和1mL水的圆底烧瓶内,70℃搅拌3h。LCMS 监测,反应完成后,过滤,滤液浓缩,得到黄色固体140mg(粗品),粗品直接用于下一步反应。
LCMS:Rt=1.29min,MS Calcd.:477.2,MS Found:477.9[M+H]+.
化合物104:将化合物103(140mg,粗品)和碳酸钾(122mg,0.88mmol)依次加入到含5mL甲醇的圆底烧瓶内,氮气保护,室温搅拌过夜,LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相:ACN-H2O (0.1%FA),梯度:0-30%ACN),冻干,得到灰色固体12mg,两步总收率:1.5%。1H NMR (400MHz,CD3OD):δppm2.05–2.16(m,2H),2.37(d,J=13.2Hz,2H),2.86(s,3H),3.11(t,J =11.7Hz,2H),3.36(s,1H),3.54(d,J=12.3Hz,2H),3.84(s,1H),5.34(s,2H),7.37(s,1H), 7.61(d,J=5.0Hz,1H),7.76(s,1H),7.80(s,1H),7.87(s,1H),8.47(s,1H),8.55(d,J=5.1Hz, 1H)。
LCMS:Rt=1.13min,MS Calcd.:405.2,MS Found:405.9[M+H]+.
实施例18化合物的制备
化合物的合成路线如下:
化合物114:将化合物106(3g,27.2mmol),对甲苯磺酸(50mg)加入到含50mL 四氢呋喃的圆底烧瓶内,随后加入3,4-二氢吡喃(3g,27.2mmol),氮气保护,室温搅拌 16h。TLC监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,50/1, v/v),得到1.5g黄色油状液体粗品,直接用于下一步反应。
化合物108:将化合物114(1.3g,6.7mmol),107(1.5g,6.7mmol),双三苯基膦二氯化钯(470mg,0.67mmol)和碘化亚铜(383mg,2.01mmol)依次加入到含20mL二氧六环和4mL三乙胺的圆底烧瓶内,氮气保护,室温搅拌16h。LCMS监测,反应完成后,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到黄色油状液体1.3g,产率:64.2%。
LCMS:Rt=1.83min,MS Calcd.:300.2,MS Found:323.1[M+Na]+.
化合物110:将化合物108(1.3g,4.3mmol),109(940mg,4.3mmol)和三苯基膦(1.35g,5.16mmol)依次加入到含30mL四氢呋喃的三口烧瓶内,氮气保护,室温搅拌下加入偶氮二甲酸二异丙酯(1.04mg,5.16mmol),室温搅拌3h。LCMS监测,反应完成后,加水淬灭(50mL),乙酸乙酯萃取(50mL×3),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10/1,v/v),得到浅黄色粘稠物900mg,产率:41.9%。
LCMS:Rt=1.99min,MS Calcd.:500.1,502.1,MS Found:522.8,524.8[M+Na]+.
化合物111:将化合物110(0.5g,1.0mmol),5(472mg,1.0mmol),双三苯基膦二氯化钯(70mg,0.1mmol)和碘化亚铜(57mg,0.3mmol)依次加入到含15mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:二氯甲烷/甲醇,5/1,v/v),得到320mg黄色固体粗品。
LCMS:Rt=1.55min,MS Calcd.:602.3,MS Found:602.9[M+H]+.
化合物112:将化合物111(320mg,粗品),还原铁粉(149mg,2.65mmol)和氯化铵(140mg,2.65mmol)依次加入到含5mL乙醇和1mL水的圆底烧瓶内,70℃搅拌3h。 LCMS监测,反应完成后,过滤,滤液浓缩,得到260mg黄色固体粗品,直接用于下一步反应。
LCMS:Rt=1.37min,MS Calcd.:572.3,MS Found:572.9[M+H]+.
化合物113:将化合物112(260mg,粗品),加入到含5mL四氢呋喃的圆底烧瓶内,氮气保护下加入4N盐酸二氧六环溶液(1mL),室温搅拌3h,LCMS监测,反应完成后,反应液浓缩,高效液相制备分离(色谱柱:Gemini-C18 150x 21.2mm,5μm,流动相: ACN-H2O(0.05%NH4OH),梯度:30-90%ACN),冻干,得到白色固体50.1mg,三步总收率:10.2%。1H NMR(400MHz,DMSO-d6):δppm 1.68–1.76(m,6H),1.84–1.91(m,4H), 1.98–2.04(m,4H),2.19(s,3H),2.81–2.93(m,3H),5.22(s,2H),5.34(s,1H),6.09(s,2H), 7.35–7.42(m,3H),7.52–7.54(m,2H),7.77(s,1H),7.87(s,1H)。
LCMS:Rt=1.15min,MS Calcd.:488.2,MS Found:488.6[M+H]+.
实施例19化合物的制备
化合物的合成路线如下:
化合物116:将化合物115(2g,20.17mmol)加入至含有50mL无水四氢呋喃的三口烧瓶内,降温至-78℃,氮气保护下滴加正丁基锂(8.4mL,20.17mmol,2.4M的己烷溶液, -78℃搅拌1h,随后滴加三丁基氯化锡(7.2g,22.19mmol),滴加完毕后于-78℃继续搅拌1h。TLC监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,得到7.8g 黄色油状物,产率:99.2%。1HNMR(400MHz,CDCl3):δppm 0.90(t,J=7.4Hz,9H), 1.09–1.13(m,5H),1.29–1.36(m,8H),1.52–1.58(m,5H),2.77(s,3H),7.57(s,1H)。
化合物117:将化合物116(1.5g,3.87mmol),化合物41(1g,3.22mmol),双三苯基磷二氯化钯(450mg,0.65mmol),碘化亚铜(180mg,0.97mmol)依次加入到含50mL二氧六环的100mL圆底烧瓶内,氮气保护,90℃搅拌3h。LCMS监测,反应完成后,冷却到室温,过滤,滤液减压浓缩。加入100mL水,乙酸乙酯萃取(100mL×3),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,中压快速制备色谱分离(洗脱液:甲醇/二氯甲烷,1/10,v/v),得到黄色固体830mg,产率:78.2%。
LCMS:Rt=1.31min,MS Calcd.:328.1,MS Found:328.8[M+H]+
化合物118:将化合物117(730mg,2.22mmol),铁粉(1.24g,22.23mmol),氯化铵(1.19mg,22.23mmol)依次加入到含乙醇/水(50mL,4/1,v/v)的100mL圆底烧瓶内, 70℃搅拌2h。LCMS监测,反应完成后,过滤,滤液减压浓缩。中压快速制备色谱分离 (洗脱液:甲醇/二氯甲烷,1/10,v/v),冻干得到黄色的固体125mg,产率:18.8%。1H NMR (400MHz,DMSO-d6):δppm 2.64(s,3H),5.29(s,2H),6.20(s,2H),7.37(s,1H),7.57(d,J= 4.8Hz,2H),7.76(s,1H),7.85(s,1H),8.60(d,J=4.0Hz,2H)。
LCMS:Rt=0.78min,MS Calcd.:298.1,MS Found:299.0[M+H]+.
实施例20化合物的制备
化合物的合成路线如下:
化合物120:将化合物119(10g,0.11mol),劳森试剂(24g,0.06mol)加入到含有150mL无水四氢呋喃的圆底烧瓶内,氮气保护下70℃搅拌16h。LCMS监测,反应完成后,加入200mL饱和碳酸氢钠水溶液淬灭,乙酸乙酯萃取(400mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:乙酸乙酯/石油醚,1/3,v/v),得到5g黄色固体,产率42.4%。1H NMR(400MHz,CDCl3):δppm 1.29(d,J=6.8Hz,6H),2.84–2.97(m,1H),6.95(s,1H),7.73(s,1H)。
LCMS:Rt=0.82min,MS Calcd.:103.0,MS Found:104.2[M+H]+
化合物121:将化合物120(2.5g,24mmol),氯乙醛(5.7g,72mmol)加入到含有45 mL丙酮的100mL的圆底烧瓶内,60℃搅拌16h。LCMS监测,反应完成后,减压浓缩,柱层析分离(洗脱液:乙酸乙酯/石油醚,1/2,v/v),得到0.6g黄色固体,产率19.5%。1H NMR (400MHz,CDCl3):δppm 1.44(d,J=7.2Hz,6H),3.30–3.44(m,1H),7.21(d,J=3.2Hz,1H), 7.70(d,J=3.2Hz,1H)。
LCMS:Rt=1.19min,MS Calcd.:127.0,MS Found:128.2[M+H]+
化合物122:在100mL三口烧瓶中,将化合物121(600mg,4.72mmol)溶于25mL 的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(2.2mL,5.2mmol,2.4M的己烷溶液),-78℃搅拌1h,随后滴加三丁基氯化锡(1.61g,5.00mmol),滴加完毕后于-78℃继续搅拌1h。LCMS监测,反应完成后,饱和氯化铵淬灭(20mL),乙酸乙酯萃取(100 mL×2),合并萃取液,用饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,得到黄色的固体1.5g,产率:76.1%。
LCMS:Rt=1.94min,MS Calcd.:417.2,MS Found:418.0[M+H]+
化合物123:将化合物122(800mg,1.93mmol),化合物41(400mg,1.29mmol),双三苯基膦二氯化钯(180mg,0.26mmol),碘化亚铜(73mg,0.39mmol)依次加入到含25mL 1,4-二氧六环的100mL圆底烧瓶内,氮气保护,90℃搅拌3h。LCMS监测,反应完成后,冷却到室温,减压浓缩。中压快速制备色谱分离
(洗脱液:甲醇/二氯甲烷,1/20,v/v),得到灰色固体160mg,产率:34.8%。1H NMR(400MHz,DMSO-d6):δppm 1.39(d,J=6.8Hz,6H),3.34–3.41(m,1H),5.55(s,2H), 7.44–7.57(m,2H),8.23(s,1H),8.43(s,1H),8.47(s,1H),8.55–8.97(m,2H)。
LCMS:Rt=1.45min,MS Calcd.:356.1,MS Found:356.8[M+H]+
化合物124:将化合物123(160mg,0.45mmol),铁粉(126mg,2.25mmol),氯化铵(120mg,2.25mmol)依次加入到含乙醇/水(25mL,4/1,v/v)的100mL圆底烧瓶内,70℃搅拌2h。LCMS监测,反应完成后,过滤,滤液减压浓缩。中压快速制备色谱分离(洗脱液:甲醇/二氯甲烷,1/20,v/v),得到黄色固体60mg,产率:41.9%。1H NMR(400MHz, DMSO-d6):δppm1.34(d,J=6.8Hz,6H),3.21–3.30(m,1H),5.29(s,2H),6.20(s,2H),7.37(s, 1H),7.57(d,J=4.8Hz,2H),7.80(s,1H),7.87(s,1H),8.60(d,J=3.6Hz,2H)。
LCMS:Rt=0.99min,MS Calcd.:326.1,MS Found:327.1[M+H]+.
实施例21化合物的制备
化合物的合成路线如下:
化合物126:将化合物125(6.5g,51.4mmol),劳森试剂(10.3g,25.6mmol)加入到含有150mL无水四氢呋喃的圆底烧瓶内,氮气保护下50℃搅拌14h。LCMS监测,反应完成后,加入100mL碳酸氢钠的饱和溶液淬灭,乙酸乙酯萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,10:1–5:1,v/v),得到2.9g白色固体,产率:39.7%。1H NMR(400MHz, DMSO-d6):δppm 1.11–1.28(m,4H),1.44–1.50(m,2H),1.62–1.74(m,5H),9.01(s,1H),9.27 (s,1H)。
LCMS:Rt=1.44min,MS Calcd.:143.1,MS Found:144.0[M+H]+
化合物127:将化合物126(2.9g,20.24mmol),氯乙醛(3.2g,40.49mmol),醋酸(4mL)加入到含有50mL丙酮的250mL的圆底烧瓶内,50℃搅拌14h。LCMS监测,反应完成后,减压浓缩,加50mL水稀释,乙酸乙酯萃取(100mL×2),合并萃取液,饱和氯化钠水溶液洗(50mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:乙酸乙酯/ 石油醚,1/3,v/v),得到2.4g黄色油状物,产率75%。1HNMR(400MHz,CDCl3):δppm 1.25–1.61(m,6H),1.85–1.88(m,2H),2.15–2.18(m,2H),3.00–3.07(m,1H),7.20(d,J=3.6 Hz,1H),7.70(d,J=3.2Hz,1H)。
LCMS:Rt=1.67min,MS Calcd.:167.1,MS Found:168.0[M+H]+
化合物128:在250mL三口烧瓶中,将化合物127(2.3g,13.75mmol)溶于100mL 的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(5.7mL,13.75mmol,2.4M的己烷溶液),-78℃搅拌1h,随后滴加三丁基氯化锡(4.9g,15.13mmol),滴加完毕后于 -78℃继续搅拌1h。TLC监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100 mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,得到6.2g黄色油状物,产率:98.4%。1H NMR(400MHz,CDCl3):δppm 0.89–0.93(m,9H), 1.10–1.14(m,4H),1.27–1.38(m,12H),1.53–1.59(m,8H),1.85–1.88(m,2H),2.16–2.19(m, 2H),3.03–3.11(m,1H),7.61(s,1H)。
化合物129:将化合物128(1.7g,3.87mmol),化合物41(1g,3.22mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(450mg,0.64mmol),碘化亚铜(184mg,0.97mmol)依次加入到含50mL二氧六环的100mL圆底烧瓶内,氮气保护,90℃搅拌4h。 LCMS监测,反应完成后,冷却到室温,减压浓缩。加入100mL水,乙酸乙酯萃取(100 mL×3),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,中压快速制备色谱分离(洗脱液:甲醇/二氯甲烷,1/50–1/10,v/v),得到580mg黄色固体,产率:56.6%。1H NMR(400MHz,DMSO-d6):δppm 1.25–1.28(m,2H),1.38–1.54(m,4H), 1.79–1.82(m,2H),2.09–2.12(m,2H),3.05–3.10(m,1H),5.55(s,2H),7.47(s,2H),8.22(s, 1H),8.43(s,1H),8.47(s,1H),8.66(br.s,2H)。
LCMS:Rt=1.62min,MS Calcd.:396.1,MS Found:396.9[M+H]+
化合物130:将化合物129(530mg,1.34mmol),铁粉(746mg,13.37mmol),氯化铵(715mg,13.37mmol)依次加入到含乙醇/水(50mL,4/1,v/v)的100mL圆底烧瓶内, 70℃搅拌2h。LCMS监测,反应完成后,过滤,滤液减压浓缩。中压快速制备色谱分离 (洗脱液:甲醇/二氯甲烷,1/10,v/v),冻干得到棕色的固体290mg,产率:17%。1H NMR (400MHz,CD3OD):δppm1.32–1.39(m,2H),1.44–1.62(m,2H),1.88–1.91(m,2H), 2.12–2.15(m,2H),2.98–3.03(m,1H),5.35(s,2H),7.37(s,1H),7.62(d,J=4.8Hz,2H),7.78 (s,2H),8.59(br.s,2H)。
LCMS:Rt=1.35min,MS Calcd.:366.2,MS Found:366.9[M+H]+.
实施例22化合物的制备
化合物的合成路线如下:
化合物133:将化合物131(10g,49.26mmol),化合物132(12g,54.19mmol),碳酸钠(15.7g,147.79mmol),[1,1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(4.0g,9.86mmol)依次加入到含300mL二氧六环和60mL水的500mL圆底烧瓶内,氮气保护,90℃搅拌3h。LCMS监测,反应完成后,冷却到室温,过滤,滤液减压浓缩。加入200mL水,二氯甲烷萃取(300mL×2),合并萃取液,饱和氯化钠水溶液洗(200mL),无水Na2SO4干燥,减压浓缩,柱层析分离(洗脱液:甲醇/二氯甲烷,1/100,v/v),得到棕色固体7.8g,产率:72.2%。1H NMR(400MHz,DMSO-d6):δppm 2.30(s,3H),2.57–2.60(m,4H),3.09(br. s,2H),6.59(s,1H),8.21–8.29(m,2H),8.77(s,3H)。
LCMS:Rt=0.54min,MS Calcd.:219.1,MS Found:220.0[M+H]+
化合物134:将化合物133(7.8g,35.6mmol),10%钯碳(7g),醋酸(4ml)依次加入到含300mL甲醇和100mL四氢呋喃的1L反应釜中,在40℃,0.4MPa氢气环境下搅拌16h。LCMS监测,反应完成后,过滤,滤液减压浓缩。加入100mL水稀释,二氯甲烷萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩得到黄色油状物7g,产率:97.1%。
LCMS:Rt=0.30min,MS Calcd.:191.1,MS Found:192.0[M+H]+
化合物135:在500mL三口烧瓶中,将化合物134(7g,36.60mmol)溶于80mL氢溴酸的水溶液中,降温至-10℃,氮气保护下滴加亚硝酸钠(3.8g,54.89mmol)的水溶液, -10℃搅拌1h,随后滴加溴化钠水溶液(5.7g,54.89mmol),滴加完毕后于室温继续搅拌 16h。LCMS监测,反应完成后,碳酸钠水溶液调节pH>7,二氯甲烷萃取(200mL×2),合并萃取液,饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,中压快速制备色谱分离(洗脱液:甲醇/二氯甲烷,1/10-1/5,v/v),得到黄色固体700mg,产率:7.4%。1H NMR(400MHz,DMSO-d6):δppm1.83–1.91(m,2H),2.00–2.03(m,2H),2.79(s,3H), 2.87–2.92(m,1H),3.01–3.07(m,2H),3.46–3.48(m,2H),7.65(s,2H),8.33(s,1H)。
LCMS:Rt=1.10min,MS Calcd.:254.0,256.0,MS Found:254.9,256.8[M+H]+
化合物136:在250mL三口烧瓶中,将化合物135(440mg,1.7mmol)溶于100mL 的无水四氢呋喃,降温至-78℃,氮气保护下滴加正丁基锂(0.86mL,2.4M的己烷溶液), -78℃搅拌1h,随后滴加三丁基氯化锡(673mg,2.1mmol),滴加完毕后于-78℃继续搅拌1h。TLC监测,反应完成后,饱和氯化铵淬灭(50mL),乙酸乙酯萃取(100mL×3),合并萃取液,用饱和氯化钠水溶液洗(100mL),无水Na2SO4干燥,减压浓缩,得到黄色油状物800mg,产率:98.2%。
LCMS:Rt=1.18min,MS Calcd.:466.2,MS Found:467.2[M+H]+
化合物137:将化合物136(800mg,1.72mmol),化合物41(300mg,0.97mmol),双三苯基膦二氯化钯(136mg,0.19mmol),碘化亚铜(56mg,0.29mmol)依次加入到含50mL 二氧六环的100mL圆底烧瓶内,氮气保护,60℃搅拌6h。LCMS监测,反应完成后,冷却到室温,减压浓缩。加入100mL水,二氯甲烷萃取(100mL×3),合并萃取液,饱和氯化钠水溶液洗(20mL),无水Na2SO4干燥,减压浓缩,中压快速制备色谱分离(洗脱液:甲醇/二氯甲烷,1/10-1/1,v/v),得到黄色固体120mg,率:30.5%。
LCMS:Rt=1.15min,MS Calcd.:405.2,MS Found:405.9[M+H]+
化合物138:将化合物137(120mg,0.30mmol),铁粉(165mg,2.96mmol),氯化铵(158mg,2.96mmol)。依次加入到含40mL乙醇和10mL水的100mL圆底烧瓶内,50℃搅拌2h。LCMS监测,反应完成后,过滤,滤液减压浓缩。高效液相制备分离(色谱柱: Gemini-C18150x 21.2mm,5μm,流动相:ACN-H2O(0.1%FA),梯度:0-20%ACN),冻干得到黄色油状物30mg,产率:27%。1H NMR(400MHz,CD3OD):δppm 1.98–2.08(m,2H), 2.16–2.19(m,2H),2.94(s,3H),2.97–3.03(m,1H),3.16–3.22(m,2H),3.62–3.65(m,2H),5.39 (s,2H),7.63(d,J=4.4Hz,2H),7.75(s,1H),7.78(s,2H),8.19(s,1H),8.50(s,1H),8.59(s, 2H)。
LCMS:Rt=0.40min,MS Calcd.:375.2,MS Found:375.9[M+H]+.
实施例23化合物的制备
化合物的合成路线如下:
化合物141:将化合物139(2.0g,4.2mmol),140(2.81g,5.04mmol),双三苯基膦二氯化钯(295mg,0.42mmol)和碘化亚铜(240mg,1.26mmol)依次加入到含40mL二氧六环的圆底烧瓶内,氮气保护,90℃搅拌6h。LCMS监测,反应完成后,冷却至室温,反应液浓缩,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/1,v/v),得到浅棕色固体2.6g,产率:92.8%。
LCMS:Rt=2.06min,MS Calcd.:662.3,MS Found:685.1[M+Na]+.
化合物142:将化合物141(2.5g,3.77mmol),还原铁粉(1.05g,18.9mmol)和氯化铵(1.02g,18.9mmol)依次加入到含40mL乙醇和10mL水的圆底烧瓶内,70℃搅拌3h。 LCMS监测,反应完成后,柱层析分离(洗脱液:石油醚/乙酸乙酯,1/2,v/v),得到类白色固体1.7g,产率:71.6%。
LCMS:Rt=1.82min,MS Calcd.:632.3,MS Found:632.8[M+H]+.
化合物143:将化合物142(1.0g,1.58mmol)加入到含30mL四氢呋喃的圆底烧瓶内,氮气保护下加入4N盐酸二氧六环溶液(10mL),室温搅拌3h。LCMS监测,反应完成后,加水稀释(50mL),乙酸乙酯萃取(30mL×3),水相用2N氢氧化钠水溶液调pH值到10,有大量沉淀析出,过滤,滤饼用水洗涤,真空干燥,得到类白色固体530mg,产率:75.9%。1H NMR(400MHz,CD3OD):δppm 1.58(s,6H),1.71–1.80(m,2H),2.11(d,J=12.3Hz,2H), 2.75(t,J=12.3Hz,2H),3.15(d,J=12.0Hz,3H),5.22(s,2H),7.34(s,1H),7.38–7.41(m,2H), 7.48–7.51(m,1H),7.56(s,1H),7.76(s,1H),7.79(s,1H)。
LCMS:Rt=1.20min,MS Calcd.:448.2,MS Found:448.9[M+H]+.
实施例24 HPK1ADP-Glo酶活实验
酶活实验使用的缓冲液含有5mM MOPS(PH=7.2),2.5mMβ-Glycerol Phosphate,0.4mM EDTA,1mM EGTA,0.05mM DTT,5mM MgCl2。化合物溶于100%DMSO,母液浓度为10mM。测试起始浓度为5uM,三倍梯度稀释,十个数据点,每个点重复两次。 HPK1蛋白购买自Thermo(货号:PV6355),稀释至2X母液,浓度为10nM(酶活测定最终蛋白浓度为5nM)。2.5μl2X HPK1蛋白分别加至含有待测化合物的平板各孔中, 1000rpm离心30秒,然后在25℃孵育15分钟。MBP蛋白购买自Millipore(货号: 13-110),ATP购买自Sigma(货号:A7699-5G),将二者配成2X工作液,浓度为4uM和 80uM。加入2.5μl 2X MBP和ATP的混合物,1000rpm离心30秒,然后在25℃孵育90分钟。之后加入5ul ADP-GloTM(Promega,货号:V9102)到实验平板中,1000rpm 离心30秒25℃孵育60分钟。最后,加入10ul激酶检测试剂(Promega,货号:V9102)到实验平板中,1000rpm离心30秒25℃孵育60分钟,测定最终的荧光读数。依据该读数,计算化合物的IC50。实验结果如下表所示:
表1 HPK1 ADP-Glo酶活实验
实施例25 Jurkat E6-1 pSLP-76(Ser376)HTRF实验
Jurkat E6-1细胞购买自ATCC(货号:TIB-152TM),使用含0.5%FBS的RPMI 1640 培养过夜,之后加入20μL(浓度为10^7个/mL)细胞至实验平板。将化合物三倍稀释,准备10个不同浓度,分别加入5μl至含有细胞的实验平板中,之后在37℃含5%CO2的培养箱中孵育4小时。然后加入5ul 6X抗人CD3抗体(Biolegend,货号:300432),在37℃含5%CO2的培养箱中孵育20分钟。最后使用Cisbio Phospho-SLP-76和SLP-76 HTRF检测试剂盒(货号分别为:63ADK076PEH和63ADK077PEH)检测Phospho-SLP-76 和SLP-76含量。依据Phospho-SLP-76含量读数,计算化合的IC50。实验结果如下表所示:
表2 Jurkat E6-1 pSLP-76(Ser376)HTRF实验
Claims (15)
1.一种通式为Ⅰ的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,
其中:
A选自C或N;B选自C或N;
Ar选自芳香性五元杂环基团、芳香性六元杂环基团或苯基,所述芳香性五元杂环基团选自:呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基、噻唑基或硒代噻唑基,所述芳香性六元杂环基团选自:吡啶基、哒嗪基、嘧啶基或吡嗪基,任选的所述芳香性五元杂环基、芳香性六元杂环基团或苯基上的H可被以下基团取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、C3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基,其中所述烷基部分可被一个或多个以下基团任意取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基;
所述R2选自:-H、卤素、-NO2、-CN、C1-5直链/支链烷基、C3-10环烷基、-N(C0-10烷基)(C0-10烷基)、-CF3、-OCF3、-OCHF2、-OCH2F或-OC0-10烷基;
当B为N时,R3不存在;当B为C时,所述R3选自:-H、卤素、-OC0-10烷基、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)或C3-10环烷基;
所述R4选自:-H、卤素、-OC0-10烷基、-CN、C3-10环烷基、-C≡C-R10、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-O杂环烷基或-N杂环烷基;
所述R5、R6、R7独立的选自:-H、卤素、-CN、-OC0-10烷基、C1-10直链/支链烷基、含O或N的杂烷基、-N(C0-10烷基)(C0-10烷基)、C3-10环烷基、-C≡C-R10、-O杂环烷基或-N杂环烷基,或R6、R7与R6和R7之间的碳原子形成C3-8环烷基或含-O、-S的C3-8杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基、苯基,其中C原子上的H可被以下基团取代:-SO2、-SO2N(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)SO2(C0-10烷基)、-CON(C0-10烷基)(C0-10烷基)、-N(C0-10烷基)CO(C0-10烷基)、-N(C0-10烷基)COO(C0-10烷基)、-OCON(C0-10烷基)(C0-10烷基)、卤素、-CN、-OCH2F、-OCHF2、-OCF3、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、C3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基;
所述R8和R9独立的选自:-H、卤素、C1-10直链/支链烷基;
其中,所述R10选自H、C1-5直链/支链烷基、C3-10环烷基、R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-10直链/支链烷基、-CH=C(C0-10烷基)(C0-10烷基)、-C≡C(C0-10烷基)、C3-10环烷基、芳香性五元环基团或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-8环烷基或含-O-、-S-的C3-8杂环烷基,C4-9稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C原子上的H可被烷基或卤素取代;
Q选自O或S;x和z独立的选自0-6间的整数;y选自0或1。
2.根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,其通式为Ⅱ,
3.根据权利要求2所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述Ar选自:噻唑基、硒代噻唑基、咪唑基、吡唑基或吡啶基,所述噻唑基、任选的,所述咪唑基、吡唑基或吡啶基上的H可被以下基团取代:-SO2NH2、-NHSO2、-CONH(C0-10烷基)、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基、C3-10环烷基、-O杂环烷基、-N杂环烷基、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基;
所述R2选自:-NO2、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基或-OCF3;
当B为N时,R3不存在;当B为C时,所述R3选自:-H、卤素、-OC0-10烷基、C1-10直链/支链烷基;
所述R4选自:-H、卤素、-OC0-10烷基、-CN、C3-10环烷基或-C≡C-R10;
所述R5、R6、R7独立的选自:-H、卤素、C3-6环烷基、-OC0-5烷基、C1-5直链/支链烷基、含O或N的C1-5直链/支链烷基,或R6、R7与R6和R7之间的碳原子形成C3-8环烷基或含-O-、-S-的C3-8杂环烷基,其中C原子上的H可被-F取代;
所述R8和R9独立的选自:-H、C1-10直链/支链烷基;
所述R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-10直链/支链烷基、-CH=C(C0-10烷基)(C0-10烷基)、C3-10环烷基或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-8环烷基、C4-7稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C原子上的H可被烷基或-F取代。
4.根据权利要求1-3任一所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述Ar上至少一个H被-O杂环烷基或-N杂环烷基取代。
5.根据权利要求2所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述Ar选自: 其中R0独立的选自:-H、C1-10直链/支链烷基、-N(C0-10烷基)(C0-10烷基)、-OC0-10烷基或C3-10环烷基;所述R1选自:-O杂环烷基、-N杂环烷基、C1-10直链/支链烷基、C3-10环烷基、-OC0-10烷基、-N(C0-10烷基)(C0-10烷基)、-SO2(C0-10烷基)、-O(C0-10烷基)、-O-苯基、-S(C0-10烷基)、-N杂环芳香基、-O杂环芳香基或-S杂环芳香基,其中C原子或杂原子上的H可被C1-3直链烷基、-N(C0-10烷基)(C0-10烷基)或-CF3、-CF2H取代。
6.根据权利要求5所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述R0独立的选自:C1-5直链/支链烷基或-N(C0-10烷基)(C0-10烷基);
所述R1选自:-O杂环烷基或-N杂环烷基、-SO2(C0-3烷基)、-O-苯基、-S(C0-4烷基)、C3-7环烷基或C3-5直链/支链烷基,其中C原子或杂原子上的H可被C3-5直链/支链烷基、-NH2、-CF2H、-CF3或C3-7环烷基、-O杂环烷基或-N杂环烷基取代;
所述R2选自:-NH2或-NO2;
当B为N时,R3不存在;当B为C时,所述R3选自:-H、-F或-OCH3;
所述R4选自:-H、-F、-Cl、-OCH3、-CN、或-C≡C-R10;
所述R5、R6、R7独立的选自:-H、卤素、-OC0-3烷基、C1-3直链/支链烷基、含N的C1-3直链/支链烷基,或R6、R7与R6和R7之间的碳原子形成C3-8环烷基或含-O-的C3-8杂环烷基,其中C原子上的H可被-F取代;
所述R8和R9独立的选自:-H、C1-3直链/支链烷基;
所述R11、R12独立的选自:-H、-CF3、-CHF2H、-CH2F、C1-5直链/支链烷基、-CH=CH(C0-10烷基)、C3-10环烷基或芳香性六元环基团,或R11、R12与R11和R12之间的碳原子形成C3-6环烷基、C4-6稠环烷基、C3-7环内酰胺、C3-7环内酯、C3-7环酮,其中C原子上的H可被烷基或-F取代。
7.根据权利要求6所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述R0独立的选自:-CH3、-CH2CH3或-NH2;
所述R1选自:-CH3、
所述R5、R6、R7选自:-H、-F、-Cl、-CH3、-CH2-NH2、-CN、-OCH3,或R6、R7与R6和R7之间的碳原子形成含-O-五元环烷基;
所述R8和R9独立的选自:-H或-CH3;
所述R11、R12独立的选自:-H、-CF3、-CHF2、-CH2F、-CH3、-CH2CH3、-CH=CH2、或R11、R12与R11和R12之间的碳原子形成
8.根据权利要求2所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,其特征在于,所述的化合物为如下结构:
9.制备权利要求2所述的化合物或其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物的方法,包括如下步骤:
(1)发生缩合反应生成
(2)与Ar-R15发生缩合反应生成
其中R13选自:卤素或R14选自:-OH或卤素,R15选自:卤素或-SnBu3。
10.一种药物组合物,所述药物组合物包含权利要求1所述的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物,还包括药剂学上可接受的辅料。
11.权利要求1所述的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物在预防和/或治疗癌症中的应用。
12.权利要求1所述的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物在制备预防和/或治疗癌症的药物中的应用。
13.权利要求1所述的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物联合PD-1、PD-L1、CTLA-4、TIM-3、TGF-β及其受体、LAG3拮抗剂或TLR4、TLR7、TLR8、TLR9、STING激动剂在癌症免疫疗法中的应用。
14.权利要求1所述的化合物及其药学上可接受的盐、立体异构体、酯、前药、溶剂化物和氘代化合物与CAR-T免疫疗法相结合在癌症免疫疗法中的应用。
15.权利要求11-14任一所述的应用,所述的癌症包括:淋巴瘤,母细胞瘤,髓母细胞瘤,视网膜母细胞瘤,肉瘤,脂肪肉瘤,滑膜细胞肉瘤,神经内分泌肿瘤,类癌肿瘤,胃泌素瘤,胰岛细胞癌,间皮瘤,神经鞘瘤,听神经瘤,脑膜瘤,腺癌,黑素瘤,白血病或淋巴样恶性肿瘤,鳞状细胞癌,上皮鳞状细胞癌,肺癌,小细胞肺癌,非小细胞肺癌,腺癌肺癌,肺鳞癌,腹膜癌,肝细胞癌,胃癌,肠癌,胰腺癌,成胶质细胞瘤,子宫颈癌,卵巢癌,肝癌,膀胱癌,肝癌,乳腺癌,转移性乳腺癌,结肠癌,直肠癌,结肠直肠癌,子宫癌,唾液腺癌,肾癌,前列腺癌,外阴癌,甲状腺癌,肝癌,肛门癌,阴茎癌,梅克尔细胞癌,食管癌,胆道肿瘤,头颈部癌和血液恶性肿瘤。
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- 2019-04-19 ES ES19791794T patent/ES2927346T3/es active Active
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WO2022228489A1 (zh) * | 2021-04-29 | 2022-11-03 | 贝达药业股份有限公司 | Hpk1抑制剂及其在医药上的应用 |
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KR20210005668A (ko) | 2021-01-14 |
EP3781563A4 (en) | 2021-02-24 |
AU2019260159A1 (en) | 2020-11-26 |
IL278036B2 (en) | 2024-02-01 |
JP7212142B2 (ja) | 2023-01-24 |
CN110396088B (zh) | 2024-03-12 |
BR112020021862A2 (pt) | 2021-01-26 |
US20210276994A1 (en) | 2021-09-09 |
JP2021519827A (ja) | 2021-08-12 |
EP3781563A1 (en) | 2021-02-24 |
PL3781563T3 (pl) | 2022-10-03 |
IL278036A (en) | 2020-11-30 |
EP3781563B1 (en) | 2022-06-29 |
ES2927346T3 (es) | 2022-11-04 |
CA3097949C (en) | 2024-04-23 |
IL278036B1 (en) | 2023-10-01 |
CN110396087A (zh) | 2019-11-01 |
CA3097949A1 (en) | 2019-10-31 |
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