CN115806553A - 杂环并内酰胺类衍生物、其制备方法及含有该衍生物的药物组合物在医药上的应用 - Google Patents
杂环并内酰胺类衍生物、其制备方法及含有该衍生物的药物组合物在医药上的应用 Download PDFInfo
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Abstract
本发明涉及一种杂环并内酰胺类衍生物、其制备方法及含有该衍生物的药物组合物在医药上的应用。具体而言,本发明涉及一种通式(I)所示的取代的杂环并内酰胺类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是HPK1抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
技术领域
本发明涉及一种杂环并内酰胺类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为HPK1抑制剂的用途。
背景技术
造血祖细胞激酶(HPK1,又称MAP4K1)是一种哺乳动物Ste20样丝氨酸/苏氨酸激酶,作为基因MAP4K1的表达产物,主要在造血干细胞中,属于有丝分裂原活化蛋白激酶激酶激酶激酶家族(MAP4K),目前发现该家族还包括另外5个成员MAP4K2,MAP4K3,MAP4K4,MAP4K5,MAP4K6。HPK1是一个相对分子量为97kDa的蛋白质,主要分为3个区域,N端的Ste20样激酶区,C端激酶区和中间段4个富含脯氨酸的区域(P1、P2、P3和P4),该中间区域通常与含有SH2/SH3区的接头蛋白相互作用,激活一系列信号通路的转导。
当HPK1受到各种上游信号因子的激活,包括表皮生长因子、前列腺素E2、肿瘤生长因子、红细胞生成素、T细胞受体、B细胞受体等,就会触发一系列生物级联反应。HPK1也可以与下游信号通路中的接头蛋白SLP-76家族、CARD11、GRB2家族、CRK家族等相互作用,活化造血干细胞的JNK/SAPK信号途径,从而对T细胞通路进行反向调节。所以说,HPK1参与调控细胞增殖和细胞凋亡,在免疫抑制方面也发挥着重要作用。
HPK1作为一种调节免疫抑制的激酶,是T细胞受体的反向调节剂,当T细胞受体被激活后,细胞质内的HPK1招募聚集到细胞膜附近,活化的HPK1磷酸化接头蛋白SLP76,激活的SLP76作为T细胞调节抑制蛋白14-3-3的停靠位点,多种蛋白结合形成SLP76复合物,SLP76复合物会引发泛素化降解,最终导致T细胞受体信号复合物的不稳定,从而下调T细胞信号通路和T细胞增殖。
然而T细胞参与抗肿瘤免疫的重要过程,通过T细胞的抗原受体识别肿瘤细胞上的特异性抗体,直接杀死肿瘤细胞;或者通过激活巨噬细胞和分泌其它淋巴因子,从而间接性杀死肿瘤细胞。因此,HPK1的抑制能够使T细胞增殖并活化T细胞信号通路,进一步增强对肿瘤的杀伤作用,抑制肿瘤生长。由于HPK1在免疫调节方面具有重要作用,HPK1可以作为治疗炎症反应、自身免疫疾病(如系统性红斑狼疮、银屑病)和恶性肿瘤(如急性髓性白血病、膀胱上皮癌、结肠癌、胰腺癌)的研究方向。
即使针对HPK1靶点的抑制剂,目前只有两款化合物进入临床,分别是Treadwell公司的CFI-402411(二期)和百济神州的BGB-15025(一期),但是面对肿瘤这场恶战,医药工作者都不甘落后,如今越来越多的医药公司已经加入到这一战役中,例如NimbusTherapeutics和阿诺医药。HPK1抑制剂作为比较前沿的研究方向,治疗肿瘤的同时必将会带来与T细胞相关的免疫反应,因此需要找到更加安全有效的HPK1抑制剂,降低治疗过程中的风险,减少患者的痛苦。
发明内容
针对上述的技术问题,本发明提供一种通式(I)所示的杂环并内酰胺类衍生物或其立体异构体、互变异构体或其可药用的盐:
其中:
X选自N或CRA;
RA选自氢原子、卤素、羟基、氰基、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;RA优选为氢原子;
环A选自5~10元杂芳基或6~11元稠合环;
条件是:当X选自CRA时,环A不选自吡啶基或嘧啶基;
R1和R2相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5的取代基所取代;
R3选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R3优选为氢原子;
R4相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、稠合环、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个RB取代;
RB相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5的取代基所取代;
R5各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
m选自0、1、2或3;
r选自0、1或2;
本发明的优选方案,一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
RC相同或不同,各自独立地选自氢原子或烷基;其中所述烷基优选为甲基;
n各自独立地选自0、1或2;
环A、R1、R2、R3、RB和X的定义如通式(I)1中所述。
本发明的优选方案,一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中X为N。
本发明的优选方案,一种通式(I)、(II)或(III)述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
X为N;
环A选自以下基团:
本发明的优选方案,一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
X选为CRA;
RA选自氢原子或烷基,优选为氢原子。
本发明的优选方案,一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
X选为CRA;
RA选自氢原子或烷基,优选为氢原子;
环A选自:
本发明的优选方案,一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R1选自-NR6R7;
R6和R7各自独立地选自烷基,优选为甲基或异丙基。
本发明的优选方案,一种通式(I)、(II)或(III)述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自-NR6R7或烷基;其中所述的烷基任选进一步被一个或多个-NR6R7所取代;
优选地,R2选自-CH2NR6R7;
R6和R7各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
本发明的优选方案,一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R3为氢原子。
本发明的优选方案,一种通式(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
RB相同或不同,各自独立地选自氢原子、烷基、卤代烷基或环烷基;其中所述烷基优选为异丙基。
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。
更进一步,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
本发明提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备HPK1抑制剂中的用途。
本发明还提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由HPK1介导的疾病的药物中的用途,其中所述的由HPK1介导的疾病优选为炎症、自身免疫疾病或肿瘤,其中所述的自身免疫疾病优选为系统性红斑狼疮或银屑病;其中所述的肿瘤优选恶性血液肿瘤或恶性实体肿瘤;其中所述的肿瘤优选选自急性髓性白血病、膀胱上皮癌、结肠癌、直肠癌、胰腺癌、肺癌、小细胞肺癌、非小细胞肺癌、淋巴瘤、母细胞瘤、视网膜母细胞瘤、肉瘤、前列腺癌、胆管癌、食管癌、胃癌、肝癌、胶质细胞瘤、宫颈癌、卵巢癌、头颈部癌或多发性骨髓瘤。
本发明进一步提供一种通式(I)、(II)或(III)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗炎症、自身免疫疾病或肿瘤疾病药物中的用途,其中所述的自身免疫疾病优选为系统性红斑狼疮或银屑病;其中所述的肿瘤优选恶性血液肿瘤或恶性实体肿瘤;其中所述的肿瘤优选为急性髓性白血病、膀胱上皮癌、结肠癌、直肠癌、胰腺癌、肺癌、小细胞肺癌、非小细胞肺癌、淋巴瘤、母细胞瘤、视网膜母细胞瘤、肉瘤、前列腺癌、胆管癌、食管癌、胃癌、肝癌、胶质细胞瘤、宫颈癌、卵巢癌、头颈部癌或多发性骨髓瘤。
本发明的药物制剂可以经局部、口服、经皮、经直肠、经阴道、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
本发明的制剂适合以单位计量的形式存在,并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合,从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。
用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合,并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。
当本发明的化合物以药物的形式对人类及动物进行给药时,所述化合物可进行单独提供或者以药物组合物的形式提供,所述药物组合物含有与药学上可接受的载剂进行组合的活性成分,例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分。
药学上可接受的载剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸盐缓冲溶液;(21)环糊精,例如连接于纳米粒子的靶向配体,例如AccurinsTM;及(22)用于药物制剂中的其它无毒兼容物质,例如聚合物基组合物。
药学上可接受的抗氧化剂的实例包括但不限于:(1)水溶性抗氧化剂,例如抗坏血酸、半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物;及(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂,例如柠檬酸钠或者磷酸二钙,和/或以下任意其中之一:(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸;(2)黏合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或阿拉伯胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收加速剂,例如四级铵化合物;(7)湿润剂,例如十六醇及甘油单硬脂酸酯;(8)吸收剂,例如高岭土及膨润土;(9)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外,液体剂型可含有通常用于本技术领域中的惰性稀释剂,例如水或其它溶剂;增溶剂及乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。
除活性化合物之外,悬浮液也可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。
除活性化合物之外,软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂,例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。
除活性化合物之外,粉末及喷雾剂也可以含有赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂,例如氯氟烃、以及挥发性的未被取代的烃,例如丁烷及丙烷。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“键”是指标示的取代基不存在,该取代基的两端部分直接连接成键。
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。烯基可以是任选取代的或未取代的。
“炔基”是指含有一个碳碳三键的脂肪烃基团,可为直链也可以带有支链。优先选择的是C2-C10的炔基,更优选C2-C6炔基,最优选C2-C4炔基。炔基基团的实施例包括,但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“亚烷基”是二价烷基。优选为C1-C10亚烷基,更优选为C1-C6亚烷基,特别优选为C1-C4亚烷基。亚烷基基团的实施例包括但不限于亚甲基、亚乙基、-CH(CH3)2亚正丙基等。亚烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此公用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环o[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环烷基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双环或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。
“单环杂环基”的实例包括但不限于吗啉基、氧杂环丁烷基、硫代吗啉基、四氢呋喃基、四氢吡喃基、1,1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮、哌嗪基、六氢嘧啶基或单环杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内可以含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基、5-氧杂螺[2.4]庚基。
螺杂环基可以是取代或未取代的。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元、5元/6元或5元/7元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基、八氢苯并[b][1,4]二噁英(dioxine)。
稠杂环基可以是取代或未取代的。
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香系统,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基、8-氧杂-3-氮杂-双环[3.2.1]辛基、2-氮杂二环[3.3.2]癸基。
桥杂环基可以是取代或未取代。
“芳基”是指含有一个或者两个环的碳环芳香系统,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基,比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基,更优选芳基为苯基和萘基,最优选为萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至7元单环或8至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,三唑基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基、苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基、苯并异噁唑基、
杂芳基可以是取代或未取代的。
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团,一个或多个环可以含有一个或多个双键,但至少一个环不具有完全共轭的π电子的芳香系统,同时,至少一个环具有完全共轭的π电子的芳香系统,其中0个、一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。当稠合环为三环或三环以上的稠合环时,其中的两个环任选地彼此共用一个或多个原子,且至少有两个环彼此共用一对原子。稠合环优选包括双环或三环的稠合环,其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环,三环稠合环优选为芳基或杂芳基与双环螺杂环基或双环桥杂环基的稠合环。“稠合环”优选为6至14元,更优选为8至12元。“稠合环”的实施例包括但不限于:
稠合环可以是取代或未取代的。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基,其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“TFA”指三氟醋酸。
“Ts”指对甲苯磺酰基。
“Tf”指对三氟甲基苯磺酰基。
“X-PHOS Pd G2”指氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)。
“RuPhos Pd G3”指甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)。
“离去基团(leaving group)”,或称离去基,在化学反应中从一较大分子中脱离的原子或官能基,是亲核取代反应与消除反应中应用的术语。在亲核取代反应中,被亲核试剂进攻的反应物称为底物(substrate),而从底物分子中带着一对电子断裂出去的原子或原子团称为离去基团。易接受电子、承受负电荷能力强的基团是好的离去基团。当离去基团共轭酸的pKa越小,离去基团越容易从其他分子中脱离。原因是因为当其共轭酸的pKa越小,相应离去基团不需和其他原子结合,以阴离子(或电中性离去基团)的形式存在的趋势也就增强。常见的离去基团包括但不限于卤素、甲磺酰基、-OTs、-OTf或-OH。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
r选自0、1或2;
本发明化合物可以含有不对称中心或手性中心,因此以不同的立体异构体形式存在。所预期的是,本发明化合物的所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物,如外消旋体混合物,均在本发明的范围内。
除非另外指出,本发明描述的结构还包括此结构的所有异构体(如,非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式;例如,各不对称中心的R和S构型,(Z)和(E)双键异构体,以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明提供了一种通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法包括:
通式(IA)化合物和通式(IB)化合物在铜催化剂及碱性试剂的作用下进行Ullmann偶联反应,任选进一步脱去保护基,得到通式(I)化合物;
其中:
X1为卤素,优选为溴;
R1~R4、X和m的定义如通式(I)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1HNMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于上海皓鸿生物医药科技有限公司,上海韶远试剂有限公司,上海毕得医药科技有限公司,萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用硅胶柱层析法和反相柱层析法,其中洗脱剂体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:乙酸乙酯和甲醇体系;D:碳酸氢铵水溶液和甲醇体系;E:三氟乙酸水溶液和乙腈体系;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行调节,如醋酸或三乙胺等。
室温:20℃~30℃。
实施例1
6-(isopropyl(methyl)amino)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-4-((甲基氨基)甲基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮
第一步
tert-butyl((6-(isopropyl(methyl)amino)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)methyl)(methyl)carbamate
((6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯
将((6-(异丙基(甲基)氨基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯1a(50mg,143.50μmol,根据公开专利WO 2020100027制备)和4-溴-2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑1b(78.39mg,286.99μmol,根据公开专利WO2019134680制备)溶于1,4-二氧六环(5mL)中,加入碘化亚铜(27.33mg,143.50μmol),N,N’-二甲基乙二胺(25.30mg,286.99μmol)和碳酸钾(59.50mg,430.49μmol),氩气保护,升温至100℃反应24小时。反应液降至室温,减压浓缩,所得残余物用硅胶柱层析(洗脱剂:A体系)分离纯化,得到((6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯1c(60mg,110.97μmol),产率77.33%。
MS m/z(ESI):541.0[M+H]+
第二步
6-(isopropyl(methyl)amino)-2-(2-(4-isopropyl-4H-1,2,4-triazol-3-yl)thiazol-4-yl)-4-((methylamino)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one
6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-4-((甲基氨基)甲基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮
((6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-1-氧代-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)甲基)(甲基)氨基甲酸叔丁酯1c(60mg,110.97μmol)溶于二氯甲烷(4mL)中,加入盐酸的1,4-二氧六环溶液(4M,274.27mL),室温下搅拌3小时。反应液减压浓缩,所得残余物用反相柱层析法(洗脱剂:E体系)分离纯化,得到6-(异丙基(甲基)氨基)-2-(2-(4-异丙基-4H-1,2,4-三唑-3-基)噻唑-4-基)-4-((甲基氨基)甲基)-2,3-二氢-1H-吡咯并[3,4-c]吡啶-1-酮1(20mg,35.53μmol),产率32.02%。
MS m/z(ESI):441.0[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.13(s,1H),6.89(s,1H),5.49–5.37(m,1H),5.13(s,2H),5.09–4.98(m,1H),4.35(s,2H),2.92(s,3H),2.73(s,3H),1.58(d,J=6.7Hz,6H),1.16(d,J=6.6Hz,6H)ppm.
生物学评价
测试例1、本发明化合物对HPK1激酶抑制活性的测试
以下方法用于测定本发明化合物在体外条件下对重组人源HPK1激酶活性的抑制程度。本方法使用Promega公司的ADP-GloTM Kinase Assay试剂盒(货号V9102)。上述试剂盒是一种发光法激酶检测试剂盒,用于检测激酶反应产生的ADP含量,ADP的含量与激酶活性正相关,通过测定ADP的含量,反映化合物对HPK1激酶活性的抑制强弱。详细实验操作可参考试剂盒说明书。
将实验流程简述如下:受试化合物首先溶解于DMSO中制备为贮存液,随后按照试剂说明书中提供的缓冲液配方配置缓冲液(20mM MgCl2,50uM DTT,0.1mg/ml BSA,40mMTris,pH7.4),使用该缓冲液进行梯度稀释,受试化合物在反应体系中的终浓度范围为1000nM~0.02nM。反应在384孔微孔板中进行,首先向孔中加入化合物和重组人源HPK1蛋白(终浓度1ng/uL,购自Signalchem,货号M23-11G-10),并在室温下孵育5分钟,随后向反应液中加入ATP溶液(终浓度10uM)及底物MBP(终浓度为0.2ug/uL,购自Signalchem,货号M42-51N),并在室温下振荡孵育60分钟。随后向反应体系中加入5μL ADP-Glo Reagent,并在室温下继续振荡孵育40分钟。之后向反应体系中加入10μL Kinase Detection Reagent,并在室温下继续振荡孵育30分钟。孵育结束后,在酶标仪以Luminescence模式测定各孔的化学发光强度值。通过与对照组(0.1%DMSO)的发光强度比值进行比较计算化合物在各浓度下的百分比抑制率,并通过GraphPad Prism 5软件以化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值,见表1。
表1本发明化合物对HPK1激酶抑制活性
化合物编号 | IC<sub>50</sub>(nM) |
1 | 30.13 |
结论:本发明化合物对于HPK1激酶具有较好的抑制活性。
测试例2、本发明化合物在人肝微粒体中代谢稳定性研究
1.实验目的
本实验研究的目的是对本发明化合物1在人肝微粒体中代谢稳定性进行研究。
2.试剂信息(见表2)
表2实验所用试剂信息
3.实验方案
将受试化合物与人的肝微粒体进行共孵育,加入辅酶NADPH启动反应。在0、5、15、30和60分钟取出20μL孵育液并转移至200μL含有内标的乙腈中终止反应。蛋白沉淀后,3,700rpm离心10分钟,取上清。上清液加水1:1稀释后由LC-MS/MS方法分析。根据受试化合物在孵育体系中的清除半衰期算出体外内在清除率。咪达唑仑作为内部参考化合物,均平行孵育2份。孵育条件总结如下表3:
表3孵育条件
4.数据分析
分析物/内标峰面积之比(Aanalyte/AIS)将由仪器得出,剩余百分比(%Control)由非零时间点样品与零时刻样品中Aanalyte/AIS之比计算出。将Ln(%Control)对孵育时间作图并进行线性拟合。受试化合物清除常数(k,min-1)和清除半衰期(T1/2,min)由以下方程式计算得到。
k=-slope
T1/2=0.693/k
5、实验结果(见表4)
表4本发明化合物在人肝微粒体中代谢稳定性
化合物编号 | 半衰期/(T<sub>1/2</sub>,min,人) |
1 | 137.94 |
结论:本发明的化合物,半衰期时间长,人肝微粒体稳定性高。
Claims (17)
1.一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
X选自N或CRA;
RA选自氢原子、卤素、羟基、氰基、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;RA优选为氢原子;
环A选自5~10元杂芳基或6~11元稠合环;
条件是:当X选自CRA时,环A不选自吡啶基或嘧啶基;
R1和R2相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5的取代基所取代;
R3选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R3优选为氢原子;
R4相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、稠合环、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、环烷基、杂环基、芳基、杂芳基或稠合环任选进一步被一个或多个RB取代;
RB相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7或-S(O)rR5的取代基所取代;
R5各自独立地选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
m选自0、1、2或3;
r选自0、1或2;
3.根据权利要求1~2中所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中X为N。
5.根据权利要求1~2中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
X选为CRA;
RA选自氢原子或烷基,优选为氢原子。
7.根据权利要求1~6中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R1选自-NR6R7;
R6和R7各自独立地选自烷基,优选为甲基或异丙基。
8.根据权利要求1~7中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自-NR6R7或烷基;其中所述的烷基任选进一步被一个或多个-NR6R7所取代;
优选地,R2选自-CH2NR6R7;
R6和R7各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
9.根据权利要求1~8中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R3为氢原子。
10.根据权利要求2中所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
RB相同或不同,各自独立地选自氢原子、烷基、卤代烷基或环烷基;其中所述烷基优选为异丙基。
12.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~11中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合物。
13.根据权利要求1~11中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求12所述的药物组合物在制备HPK1抑制剂中的用途。
14.根据权利要求1~11中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求12所述的药物组合物在制备治疗由HPK1介导的疾病的药物中的用途,其中所述的由HPK1介导的疾病优选为炎症、自身免疫疾病或肿瘤,其中所述的自身免疫疾病优选为系统性红斑狼疮或银屑病;其中所述的肿瘤优选恶性血液肿瘤或恶性实体肿瘤。
15.根据权利要求14所述的用途,其中所述的肿瘤选自急性髓性白血病、膀胱上皮癌、结肠癌、直肠癌、胰腺癌、肺癌、小细胞肺癌、非小细胞肺癌、淋巴瘤、母细胞瘤、视网膜母细胞瘤、肉瘤、前列腺癌、胆管癌、食管癌、胃癌、肝癌、胶质细胞瘤、宫颈癌、卵巢癌、头颈部癌或多发性骨髓瘤。
16.根据权利要求1~11中任一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求12所述的药物组合物在制备治疗炎症、自身免疫疾病或肿瘤药物中的用途,其中所述的自身免疫疾病优选为系统性红斑狼疮或银屑病;其中所述的肿瘤优选恶性血液肿瘤或恶性实体肿瘤。
17.根据权利要求16所述的用途,其中所述的肿瘤选自急性髓性白血病、膀胱上皮癌、结肠癌、直肠癌、胰腺癌、肺癌、小细胞肺癌、非小细胞肺癌、淋巴瘤、母细胞瘤、视网膜母细胞瘤、肉瘤、前列腺癌、胆管癌、食管癌、胃癌、肝癌、胶质细胞瘤、宫颈癌、卵巢癌、头颈部癌或多发性骨髓瘤。
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