CN114437077A - 用作激酶抑制剂的化合物及其应用 - Google Patents
用作激酶抑制剂的化合物及其应用 Download PDFInfo
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- CN114437077A CN114437077A CN202011216420.5A CN202011216420A CN114437077A CN 114437077 A CN114437077 A CN 114437077A CN 202011216420 A CN202011216420 A CN 202011216420A CN 114437077 A CN114437077 A CN 114437077A
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
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Abstract
本发明公开了一种用作激酶抑制剂的化合物及其应用,具体公开了一种式Ⅰ所示的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药。本发明的式Ⅰ所示化合物可用作激酶抑制剂,用于制备治疗ROS1、NTRK、ALK等激酶介导的疾病的药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及用作激酶抑制剂的化合物,其制备方法,以及在制备用于治疗ROS1、NTRK、ALK等激酶介导的疾病的药物方面的应用。
背景技术
ROS1(c-ros oncogene 1receptor kinase)是一种人体内由ROS1原癌基因编码的酪氨酸蛋白激酶,定位于6q22.1染色体,属于酪氨酸激酶胰岛素受体基因,由胞内酪氨酸激酶活性区、跨膜区及胞外区3部分组成,编码具有酪氨酸激酶活性的嵌合蛋白。基本结构由胞外N-末端配体结合区(氨基酸1-1861)、跨膜区(氨基酸1862-1882)及胞内C-末端464个氨基酸构成的酪氨酸激酶活性区(氨基酸1883-2347)组成。ROS1基因发生重排时丢失细胞外区域,保留跨膜区和胞内酪氨酸激酶区域,重排位点主要发生在ROS1基因的32~36外显子。ROS1基因突变主要发生在肺癌患者中,患者比例为1%-2%。在NSCLC中ROS1基因主要与SLC34A2、CD74发生融合,并持续激活ROS1酪氨酸激酶区及下游JAK/STAT、PI3K/AKT、RAS/MAPK等信号通路,进而引起肿瘤的发生。在大量地文献和临床上均已经证实,通过抑制突变的ROS1激酶的活性,就可以达到治疗由ROS1过度激活所导致的疾病,尤其是癌症。目前上市的用于ROS1阳性非小细胞肺癌的治疗药物有克唑替尼和恩曲替尼,他们均属于第一代的小分子ROS1抑制剂。但是,在服用克唑替尼或恩曲替尼的治疗过程中,大约在15个月左右会产生耐药,发生疾病进展。在发生耐药的患者中,最为常见的耐药突变就是G2032R等溶剂前沿突变,对于耐药的患者,目前还没有治疗药物上市。所以目前急需研发针对ROS1的新抑制剂,尤其是针对使用克唑替尼或恩曲替尼等一代ROS1抑制剂产生耐药的新的ROS1抑制剂药物用于临床的治疗。
原肌球蛋白受体激酶(TRK)家族属于跨膜受体酪氨酸激酶(RTKs),参与调节哺乳动物神经系统的突触生长与功能维持、记忆的发生发展以及保护神经元免受损伤等。TRK激酶是一类神经生长因子受体,其家族由高度同源性的原肌球蛋白相关激酶A(Tropomyosin-related kinase A,TRKA)、原肌球蛋白相关激酶B(Tropomyosin-related kinase B,TRKB)、原肌球蛋白相关激酶C(Tropomyosin-related kinase C,TRKC)组成,分别有NTRK1、NTRK2和NTRK3基因编码。完整的TRK激酶包括胞外区、跨膜区和胞内区三个部分,和其他的RTKs一样,TRK激酶的胞外区与相应的配体结合之后,形成二聚体,能够引起TRK激酶的胞内区发生自体磷酸化从而激活自身的激酶活性,进一步激活下游的信号转导通路。TRK激酶通过Ras/MAPK、PI3K/AKT和PLCγ等下游通路影响细胞的增殖、分化、代谢和凋亡。当NTRKs基因发生融合或突变后,会改变或消除胞外区受体(Greco,A.et.al,Mol.Cell.Biol.1995,15,6118;Oncogene 1998,16,809),而融合或突变的TRK蛋白在不需要配体结合的情况下,自身处于高度活化的激酶活性状态,从而能够持续性的激活下游的信号转导通路,可导致TRK激酶下游信号通路调控失常,诱导细胞的增殖,促进肿瘤的发生和发展。NTRKs基因融合出现在多种成人和儿童实体瘤中,包括乳腺癌、结直肠癌、非小细胞肺癌、乳头状甲状腺癌、Spitz样黑色素瘤、神经胶质瘤以及各种肉瘤等。在常见的癌症中,如非小细胞肺癌、结直肠癌等中,NTRK基因融合的发生率较低,大致为1%-3%,但在一些罕见的癌症中,如婴儿纤维肉瘤、乳腺分泌型癌等,NTRK基因融合的发生率可达90%以上。最早的TPM3-TRKA融合蛋白是在结肠癌细胞中发现的。后来在不同的临床肿瘤病人样本如乳腺癌、非小细胞肺癌、乳头状甲状腺癌、Spitz样黑色素瘤、神经胶质瘤等中发现了更多类型的NTRK融合蛋白,如CD74-NTRKA、MPRIP-NTEKA、QKI-NTRKB、ETV6-NTRKC、BTB1-NTRKC等。因此,近年来,NTRK融合蛋白成为了一个有效的抗癌靶点,成为了抗癌药物研发的一个热点。随着近年来人们对TRK激酶的进一步的深入了解,发现了更多的TRK融合蛋白类型及突变类型(Russo,M.et.al CancerDiscovery,2016,6,36;Drilon,A.et.al,Annals of Oncology,2016,27,920),所以临床上急需开发活性更好,作用更广泛的新型NTRK抑制剂,从而解决这些NTRK蛋白融合或突变所引起的肿瘤的治疗问题。
NSCLC中有2-5%的病例为间变性淋巴瘤激酶(ALK)重排型,间变性淋巴瘤激酶是胰岛素受体超家族的一个受体型蛋白质酪氨酸磷酸激酶。最初人们是在间变性大细胞淋巴瘤中以一种激活的融合癌基因的形式发现了ALK,随后连续的研究在多种癌症中发现了ALK的融合形式,其中包括系统性组织异常增生、炎性肌纤维细胞癌、非小细胞肺癌等。ALK在多种癌症中的突变和异常的活性,已经使其成为一个治疗ALK阳性癌症的药物靶点。目前上市了多个ALK激酶抑制剂,随着这些药物在临床上的应用,患者都会发生耐药突变,如果G1202R等耐药突变,导致这些药物失去疗效。
随着近年来人们对ROS1、NTRK、ALK等激酶的进一步的深入了解,以及临床耐药患者的增多,所以临床上急需开发活性更好,作用更广泛的新型酪氨酸激酶抑制剂,从而解决这些由ROS1、NTRK、ALK等激酶蛋白融合或突变所引起的肿瘤的治疗问题。
发明内容
本发明的第一方面,提供一种式Ⅰ所示的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,
式中,
*为R或S构型;
Z1、Z2、Z3各自独立地选自:N或CR13;
X选自下组:NR6、O、CR1R2、S、S(O)或S(O)2;
R1、R2、R3、R4、R5、R6和R13各自独立地选自取代或未取代的下组基团:H、卤素、氨基、氰基、硝基、羟基、酰基、酯基、C1-C6烷基、C3-C8环烷基、3-8元杂环基、C1-C6烷氧基、C6-C14芳基、5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R7、R8、R9、R10、R11和R'11各自独立地选自取代或未取代的下组基团:氢原子、氰基、C1-C6烷基、C3-C8环烷基、C6-C14芳基和5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R12选自:C1-C6烷基或羟基取代的C1-C6烷基;
R选自:氘、卤素、氨基、氰基、硝基、羟基、酰基、酯基、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、C3-C8卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C6-C14芳基和5-14元杂芳基。
其中,所述的取代是指被选自下组的一个或多个基团取代:卤素、氰基、硝基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式II所示的结构:
式中,
*为R或S构型;
Z1、Z2、Z3、R1、R2、R3、R4、R5、R6和A的定义如上所述。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式III或IV所示的结构:
式中,
*为R或S构型;
Z1、Z2、Z3、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11的定义如上所述。
在另一优选例中,Z1为CR13,优选地为CH。
在另一优选例中,Z2为CR13,优选地为CH。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式V或VI所示的结构:
式中,
*为R或S构型;
R4选自:H、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
Z3、R1、R2、R3、R5、R6、R7、R8、R9、R10和R11的定义如上所述。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其中,R1、R2和R3各自独立的选自:氢、卤素或氨基;
R4选自:氢、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
R5选自:氢、卤素;
R6选自:氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷胺基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C1-C6烷胺基、卤代C3-C6环烷基;
R7、R8、R9、R10和R11各自独立地选自:氢、取代或未取代的C1-C6烷基;其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、氨基、氰基、羟基、酰基、酯基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C6-C10芳基和5-10元杂芳基。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其具有式VII或VIII所示的结构:
式中,
*为R或S构型;
Z3、R1、R2、R3、R4、R6、R7、R8、R9、R10和R11的定义如上所述。
在另一优选例中,R6选自:卤素、卤代C1-C3烷氧基、卤代C1-C6烷胺基。
在另一优选例中,式I中,R5为F。
在另一优选例中,R7、R8、R9、R10各自独立地选自:氢、C1-C3烷基和卤代C1-C3烷基。
在另一优选例中,式I中,Z1、Z2、Z3、R1、R2、R3、R4、R5、R6、X和A的为实施例各具体化合物所对应基团。
在另一优选例中,所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其中,所述化合物选自下组:
本发明第二方面,提供一种药物组合物,所述药物组合物含有i)治疗有效量的第一方面所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和ii)一种或多种药学上可以接受的载体、稀释剂或赋形剂。
在另一优选例中,所述药物组合物还包括选自下组的药物:PD-1抑制剂(如纳武单抗、派姆单抗、pidilizumab、cemiplimab、JS-001、SHR-120、BGB-A317、IBI-308、GLS-010、GB-226、STW204、HX008、HLX10、BAT1306、AK105、LZM 009或上述药物的生物类似药等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗、阿维鲁单抗(avelumab)、CS1001、KN035、HLX20、SHR-1316、BGB-A333、JS003、CS1003、KL-A167、F 520、GR1405、MSB2311或上述药物的生物类似药等)、CD20抗体(如利妥昔单抗、奥滨尤妥珠单抗、奥法木单抗、veltuzumab、托西莫单抗、131I-托西莫单抗、替伊莫单抗、90Y-替伊莫单抗、90In-替伊莫单抗、替伊莫单抗(ibritumomab tiuxetan)等)、CD47抗体(如Hu5F9-G4、CC-90002、TTI-621、TTI-622、OSE-172、SRF-231、ALX-148、NI-1701、SHR-1603、IBI188、IMM01)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、PI3K抑制剂(如艾代拉里斯、Duvelisib、Dactolisib、Taselisib、Bimiralisib、Omipalisib、Buparlisib等)、BTK抑制剂(如依鲁替尼、Tirabrutinib、阿卡替尼、赞布替尼、Vecabrutinib等)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、埃克替尼、卡奈替尼、沙普替尼、Naquotinib、吡咯替尼、罗乐替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、司曲替尼、Ningetinib、卡博替尼、舒尼替尼、多纳非尼等)、HDAC抑制剂(如Givinostat、Tucidinostat、伏立诺他、Fimepinostat、Droxinostat、恩替诺特、达西司特、Quisinostat、泰克地那林等)、CDK抑制剂(如帕博西尼、瑞博西尼、Abemaciclib等)、MEK抑制剂(如司美替尼(AZD6244)、曲美替尼(GSK1120212)、PD0325901、U0126、Pimasertib(AS-703026)、PD184352(CI-1040)等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068、TNO155等),或其组合。
本发明第三方面,提供一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述第一方面所述的化合物或其立体异构体或光学异构体、药学上可接受的盐、前药或溶剂化物进行混合,从而形成药物组合物。
在另一优选例中,本发明化合物可以制备成散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂等。
本发明第四方面,提供一种第一方面所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的用途,用于制备预防和/或治疗ROS1、NTRK或ALK介导的病理学特征的疾病的药物。
在另一优选例中,所述ROS1、NTRK或ALK介导的病理学特征的疾病包括癌症、肉瘤和疼痛。
在另一优选例中,所述的癌症选自下组:乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、腹膜肿瘤、黑色素瘤、神经胶质瘤、神经胶母细胞瘤、头颈癌、乳突肾性瘤、白血病、淋巴瘤、骨髓瘤和甲状腺瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
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具体实施方式
本申请发明人经过广泛而深入的研究,意外发现一种新的化合物,这些化合物对ROS1、NTRK和ALK及它们的耐药突变具有优异的抑制活性,尤其是针对耐药突变具有较好的抑制活性,且具有更好的药效学、药代动力学性能和更低的毒副作用,非常有潜力开发成目前临床急需的用于耐药病人的有效药物。
术语
除非特别说明,否则在本申请(包括说明书和权利要求书)所用的以下术语具有下面所给出的定义。
“烷基”(单独或作为其它基团的一部分)指的是仅由碳和氢原子组成的单价直链或支链饱和烃基团。其中,“C1-C6烷基”是指含有1至6个碳原子的烷基基团,优选为C1-C4烷基。烷基基团的实例包括但不限于:甲基、乙基、丙基、异丙基、异丁基、仲丁基、叔丁基、戊基、正己基、辛基、十二烷基等。在本发明中,烷基还意在包括氘代烷基,氘代烷基实例包括但不限于CD3、CD2CD3、CD2CD2CD3。
“亚烷基”(单独或作为其它基团的一部分)是指如上所述的烷基去掉一个氢原子后所得的基团,如亚甲基(-CH2-)、亚乙基(-CH2CH2-)等。
“烷氧基”(单独或作为其它基团的一部分)指的是式-OR或-R'-OR基团,其中,R为本文所定义的烷基基团,R'为亚烷基。烷氧基基团的实例包括但不限于:甲氧基、乙氧基、异丙氧基、叔丁氧基、-CH2O-CH3、-CH2CH2-O-CH3、-CH2-O-CH2CH3等。
“卤素(卤代)”(单独或作为其它基团的一部分)是指氟、氯、溴或碘。
“卤代烷基”(单独或作为其它基团的一部分)指的是如上所述的烷基中的一个或多个氢被相同或不同的卤素取代后所得的基团。其中,“卤代C1-C6烷基”优选地为卤代C1-C4烷基,卤代烷基的实例包括但不限于:-CH2Cl、-CH2CF3、-CH2CCl3、全氟烷基(例如,-CF3-、-CF2CF3)等。
“卤代烷氧基”(单独或作为其它基团的一部分)指的是式-OR基团,其中,R为本文所定义的卤代烷基基团。卤代烷氧基基团的实例包括但不限于:三氟甲氧基、二氟甲氧基、2,2,2-三氟乙氧基等。
“环烷基”(单独或作为其它基团的一部分)指的是仅由碳和氢原子组成的单-或二环组成的单价饱和碳环基团,其中,“C3-C8环烷基”是指含有3至8个碳原子的饱和碳环基团,优选为C3-C6环烷基。环烷基的实例包括但不限于:环丙基、环丁基、环戊基、环己基等。环烷基可以任选地被一个或多个取代基所取代,其中,各取代基独立地为羟基、烷基、烷氧基、卤素、卤代烷基、氨基、单烷基氨基或二烷基氨基。环烷基基团的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。
“环烷氧基”(单独或作为其它基团的一部分)指的是式-OR基团,其中,R为如本文所定义的环烷基。示例性的环烷基氧基包括环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。
“酰基”指的是式-C(O)R基团,其中,R为如本文所定义的烷基或烷氨基。“酰基”优选地为-C(O)C1-C6烷基、-C(O)NH2、-C(O)NHC1-C6烷基、-C(O)N(C1-C6烷基)2,更优选地为-C(O)C1-C3烷基、-C(O)NH2、-C(O)NHC1-C3烷基、-C(O)N(C1-C3烷基)2,示例性的酰基包括乙酰基、正丙酰基、异丙酰基、正丁酰基、异丁酰基、叔丁酰基、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2等。
“烷氨基”(单独或作为其它基团的一部分)指的是式-NRaRb基团,其中,Ra和Rb相同或不同,且各自独立地为H或如本文所定义的烷基。
酯基是指式-C(O)OR的基团,其中R为如本文所定义的烷基。酯基优选地为-C(O)OC1-C6烷基,更优选地为-C(O)OC1-C4烷基,示例性的酯基包括-C(O)OMe、-C(O)OEt、-C(O)O-C(CH3)3等。
磺酰基是指式-S(O)2-R,其中,R为如本文所定义的烷基。磺酰基优选地为-S(O)2-C1-C6烷基,示例性地包括-S(O)2-Me、-S(O)2-Et等。
亚磺酰基指式-SO-R,其中,R为如本文所定义的烷基。亚磺酰基优选地为-SO-C1-C6烷基,示例性地包括-SO-Me、-SO-Et等。
“烷硫基”指的是式-SRa基团,其中Ra为H或如本文所定义的烷基。
“环烷氨基”指的是式-NRaRb基团,其中Ra为H、如本文所定义的烷基或如本文所定义的环烷基,Rb为如本文所定义的环烷基。
“杂环基”(单独或作为其它基团的一部分)是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环,6-11元双环,或8-16元三环系统),其中,至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环带有1、2、3或4个选自氮原子、氧原子或硫原子的杂原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环烷烃(基)是指完全饱和的杂环(基)。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。其中,“3-8元杂环基”是指具有3-8个环成员的基团。典型的单环杂环包括但不限于:氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。
“芳基”(单独或作为其它基团的一部分)是指芳香环状烃类化合物基团,具有1-5个环,尤其指单环和双环基团,凡含有两个或两个以上芳香环(双环等),芳基基团的芳香环可由单键联接(如联苯),或稠合(如萘、蒽等等)。其中,“C6-C12芳基”是指包含6、7、8、9、10、11或12个环碳原子的芳香环状烃类化合物基团。芳基(尤其指单环和双环基团)的实例包括但不限于苯基、联苯基或萘基。芳基可以与杂环基通过单键或者任意两个相邻的环C原子稠合,例如:苯并四氢呋喃基、苯并四氢吡喃基、苯并二氧六环基、等。
“杂芳基”(单独或作为其它基团的一部分)杂环芳基基,其中,“5-12元杂环基”指的是5至12个环原子的单环、二环或三环基团,其含有至少1个(如1、2或3个)选自N、O或S的环杂原子、剩余的环原子是C的芳环,应当清楚地是,杂芳基的连接点应当位于杂芳环上。杂芳基优选具体5-8个环原子(5-8元),更优选具有5-6个环原子(5-6元)。杂芳基基团的实例包括但不限于:咪唑基、唑基、异唑基、噻唑基、异噻唑基、二唑基、噻二唑基、吡嗪基、噻吩基、呋喃基、吡喃基、吡啶基、吡咯基、吡唑基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、、苯并噻吩基、苯并噻喃基、苯并咪唑基、苯并唑基、苯并二唑基、苯并噻唑基、苯并噻二唑基、苯并吡喃基、吲哚基、异吲哚基、三唑基、三嗪基、喹喔啉基、嘌呤基、喹唑啉基、喹嗪基、萘啶基、蝶啶基、咔唑基、氮杂基、二氮杂基、吖啶基等。
“多取代”是指包括两个或两个以上的取代。
本发明中,所述烷基、环烷基、杂环基、芳基、杂芳基等基团,在未特别说明的情况下包括取代的烷基、环烷基、杂环基、芳基、杂芳基等,所述取代基例如(但并不限于):卤素、羟基、氰基、酰基、磺酰基、酯基、亚磺酰基、烷基、环烷基、杂环基、芳基、杂芳基、酰基、酯基等。
“氘代物”指的是化合物中一个氢原子(H)或多个氢原子(H)被氘原子(D)取代后所得到的化合物。
活性成分
如本文所用,术语“本发明的化合物”或“本发明的活性成分”可互换使用,指式I化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药。
式I化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,具有如下结构,
其中,
*为R或S构型;
A、Z1、Z2、Z3、R1、R2、R3、R4、R5、R6和X的定义如上所述。
优选地,所述式I化合物具有式II所示的结构:
式中,
*为R或S构型;
Z1、Z2、Z3、R1、R2、R3、R4、R5、R6和A的定义如上所述。
优选地,所述式I化合物具有式III或IV所示的结构:
式中,
*为R或S构型;
Z1、Z2、Z3、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11的定义如上所述。
优选地,式I化合物具有式V或VI所示的结构:
式中,
*为R或S构型;
R4选自:H、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
Z3、R1、R2、R3、R5、R6、R7、R8、R9、R10和R11的定义如上所述。
优选地其具有式VII或VIII所示的结构:
式中,
*为R或S构型;
Z3、R1、R2、R3、R4、R6、R7、R8、R9、R10和R11的定义如上所述。
优选地,式I-VIII中,R6选自:卤素、卤代C1-C3烷氧基、卤代C1-C6烷胺基。
优选地,式I-VIII中,R1、R2和R3各自独立的选自:氢、卤素或氨基;
R4选自:氢、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
R5选自:氢、卤素;
R6选自:氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷胺基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C1-C6烷胺基、卤代C3-C6环烷基。
优选地,式III-VIII中,R7、R8、R9、R10各自独立地选自:氢、C1-C3烷基和卤代C1-C3烷基。
优选地,式I-IV中,Z1为CR13,优选地为CH。
优选地,式I-IV中,Z2为CR13,优选地为CH。
优选地,式III-VIII中,R1、R2和R3各自独立的选自:氢、卤素或氨基;
R4选自:氢、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
R5选自:氢、卤素;
R6选自:氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷胺基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C1-C6烷胺基、卤代C3-C6环烷基;
R7、R8、R9、R10和R11各自独立地选自:氢、取代或未取代的C1-C6烷基;其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、氨基、氰基、羟基、酰基、酯基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C6-C10芳基和5-10元杂芳基。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机酸盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、羟乙磺酸盐、苯磺酸盐、水杨酸盐、苦味酸盐、谷氨酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐等等。
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如,硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物,如水合物。
本发明中的化合物、盐或溶剂合物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University ScienceBooks,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢,碳,氮,氧,磷,硫,氟和氯同位素,分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
制备方法
本发明化合物可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
通常,在制备流程中,各反应通常在惰性溶剂中,在-60℃~100℃,优选-60℃~80℃下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
优选的合成路线如下:
路线1:
(1)在惰性溶剂(如乙醇、甲醇)中,化合物1和化合物2在碱(如碳酸钠、碳酸钾、氢氧化钠、三乙胺、吡啶等)的存在下,发生亲核取代反应,生成化合物3;
(2)在惰性溶剂(如乙醇、甲醇)中,化合物3经过还原后,生成化合物4;
(3)在惰性溶剂(如1,2-二氯乙烷和/或四氢呋喃)中,化合物4与硫羰基二咪唑和氨基醇原料发生反应,得到化合物5;
(4)在惰性溶剂(如1,2-二氯乙烷和/或四氢呋喃)中,化合物5在碱的作用下,生成最终式I所示化合物;
路线2:
(1)在惰性溶剂(如乙醇、甲醇)中,化合物1和化合物2在碱(如碳酸钠、碳酸钾、氢氧化钠、三乙胺、吡啶等)的存在下,发生亲核取代反应,生成化合物3;
(2)在惰性溶剂(如乙醇、甲醇)中,化合物3经过还原后,生成化合物4;
(3)在惰性溶剂(如1,2-二氯乙烷和/或四氢呋喃)中,化合物4在碱的存在下,生成最终式I所示化合物
路线3:
(1)在惰性溶剂(如乙醇或甲醇)中,化合物1和化合物2在碱(例如叔丁醇钠、叔丁醇钾、氢化钠、氢化钾、碳酸钾、碳酸铯、磷酸钾、氢氧化钾、氢氧化钠等)的存在下,发生亲核取代反应,生成化合物3;
(2)在惰性溶剂(如乙醇)中,酸性条件下,生成化合物4;
(3)在惰性溶剂(如甲苯或二甲苯)中,酸催化下,化合物4与氨基酸原料反应,得到最终式I所示化合物
路线4:
(1)在惰性溶剂(如乙醇或甲醇)中,化合物1和化合物2在碱(例如叔丁醇钠、叔丁醇钾、氢化钠、氢化钾、碳酸钾、碳酸铯、磷酸钾、氢氧化钾、氢氧化钠等)的存在下,发生亲核取代反应,生成化合物3;
(2)在惰性溶剂(如乙醇)中,碱性条件下,化合物3与盐酸羟胺反应,生成化合物4;
(3)在惰性溶剂(如甲苯或二甲苯)中,化合物4与相应原料反应,得到最终式I所示化合物
式中,
Z1、Z2、Z3、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、X的定义如上所述。
本发明的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。
药物组合物和施用方法
本发明所述的药物组合物用于预防和/或治疗以下疾病:炎症、癌症、心血管疾病、感染、免疫性疾病、代谢性疾病。
本发明所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用本发明的化合物。当本发明化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和本发明化合物的药用组合物。药物联用也包括在重叠的时间段服用本发明化合物与其它一种或几种已知药物。当本发明化合物与其它一种或几种药物进行药物联用时,本发明化合物或已知药物的剂量可能比它们单独用药的剂量低。
本发明所述药物组合物的剂型包括(但并不限于):注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1-2000mg,优选10-1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明还提供了一种药物组合物的制备方法,包括步骤:将药学上可接受的载体与本发明所述化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药进行混合,从而形成药物组合物。
本发明还提供了一种治疗方法,它包括步骤:给需要治疗的对象施用本发明中所述化合物,或其药学上可接受的盐、立体异构体、溶剂化物或前药,或施用本发明所述的药物组合物,用于选择性地抑制ROS1、NTRK、ALK等的融合突变及其耐药突变。
本发明具有以下主要优点:
(1)本发明化合物对ROS1、NTRK、ALK激酶均有很好的抑制能力,尤其是对这些靶点耐药突变的活性非常出色;
(2)本发明化合物具有更好的药效学、药代动力学性能和更低的毒副作用;
(3)本发明化合物非常有潜力开发成目前临床急需的用于耐药病人的有效药物。
下面对本发明的技术方案作进一步的说明,但本发明的保护范围不限于此。
下面列举一些具体实施例进行说明。
实施例1
合成路线:
反应步骤:
(1)化合物2的合成
将化合物1(1g,1eq)溶于EtOH:THF=24ml:6ml的混合溶剂中,加入5-chloro-3-nitropyrazolo[1,5-a]pyrimidine(1.01g,1.05eq)和DIEA(1.9g,3eq),N2保护下55℃反应4h,反应完毕后拌样过柱的1.5g化合物2。
(2)化合物3的合成
将化合物2(1.5g,1eq)加入到45mlEtOH中,加入Fe粉(0.76g,3eq)和NH4Cl(0.7g,3eq),N2保护下85℃反应3h,反应完毕,过滤旋出EtOH,加水EA萃取旋干,得到1.4g化合物3,直接用于下一步。
(3)化合物4的合成
N2保护、-10℃下,将硫羰基二咪唑(0.065g,1.1eq)溶于1.5mlTHF中,再加入化合物3(0.1g,1eq)的THF1.5ml溶液,保温反应5min,将2-amino-2-methylpropan-1-ol(0.04g,1.3eq)的0.5ml溶液滴入反应体系,室温反应过夜,反应完毕,拌样过柱得到0.15g化合物4
(4)实施例1:化合物T-01(化合物5)的合成
将化合物4(0.15g,1eq)加入到5mlTHF中,加入NaOH(0.09g,6eq),随后加入TosCl(0.06g,0.9eq),N2保护下室温反应3h,反应完毕,加水EA萃取旋干,得到0.18g化合物5。化合物实施例1的合成:称取化合物7(0.411g),加入二甲氧基缩丙酮(0.457g,4eq)、1,2-二氯乙烷(15mL)、冰醋酸(7.5mL),80℃下搅拌4小时,TLC监测反应完全,直接旋干溶剂,加入水和二氯甲烷,干燥,旋干,过柱,得到170mg最终产品。1H NMR(400MHz,CDCl3)δ8.25–8.12(m,2H),7.05(dd,J=9.1,8.2Hz,1H),6.80(dd,J=9.1,4.0Hz,1H),6.08(t,J=30.1Hz,4H),3.91(s,2H),1.58(t,J=5.8Hz,8H),[M+H]+=399.2。
实施例2
合成路线:
反应步骤:
(1)化合物2的合成:
向2.04g化合物1(1.0eq)中加入20ml无水乙醇,随后分别加入INT-2(1.9g,1.0eq)与DIPEA(6.34ml,4.0eq),置换氮气后于60℃反应4h,TLC监控反应完毕,旋干乙醇,然后向反应体系中加入水后,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱,得到1.75g化合物3。
(2)化合物3的合成:
向1.75化合物2(1.0eq)中加入乙醇(40ml)和水(60ml),然后加入铁粉(0.87g,3.0eq)与氯化铵(0.83g,3.0eq),升温至85℃反应2h,TLC监控反应完毕,旋干乙醇,向反应体系中加入水,然后加入EA(50mlX3)萃取,收集EA相,加入无水硫酸钠干燥后过滤,旋干得到1.5g化合物3。
(3)化合物4的合成:
将0.7g硫羰基二咪唑(1.1eq)溶于THF,然后降温至-10℃,搅拌加入化合物3(1.1g,1.0eq)的THF溶液,搅拌5min后加入2-氨基-2-甲基-1-丙醇(0.41g,1.3eq)的THF溶液,自然升至室温过夜。TLC监控反应完毕,向反应体系中加入水后,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱,得到1.5g化合物4。
(4)实施例2:化合物T-02的合成:
将1.5g化合物4(1.0eq)溶于THF,然后加入TosCl(588mg,0.9eq),NaOH(820.8mg,6eq),室温搅拌过夜。TLC监控反应完毕,向反应体系中加入水后,加入EA(30mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱,得到0.7g T-02,[M+H]+=405.2。
实施例3
合成路线:
反应步骤:
(1)化合物2的合成:
向36.4g化合物1(1.0eq)中加入盐酸二氧六环(30ml),室温反应2h,TLC监控反应完全,旋干溶剂,加入PE打浆,过滤收集滤饼旋干得到26.2g化合物2。
(2)化合物3的合成:
向20g化合物2(1.0eq)中加入ml无水乙醇,随后分别加入INT-1(16.8g,1.0eq)与DIPEA(46.2ml,4.0eq),置换氮气后于60℃反应4h,TLC监控反应完毕,旋干乙醇,然后向反应体系中加入水后有固体析出,过滤,旋干过柱,得到26.6g化合物3。
(3)化合物4的合成:
向10.6g化合物3(1.0eq)中加入无水乙醇(100ml)与1,4-二氧六环(100ml),然后加入盐酸羟胺(13.9g,6.0eq)与碳酸钾(55.4g,12.0eq),置换氮气,80℃反应16h,TLC监控反应完全,过滤,旋干直接过柱,得到8.3g化合物4。
(4)化合物5的合成:
将3.3g化合物4(1.0eq)溶于DMSO,然后加入溴乙缩醛(3.7g,2.0eq)和KOH(2.48g,4.0eq),升温至60℃反应6h,TLC监控反应完毕,向反应体系中加入水后有固体析出,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱,得到1.9g化合物5。
(5)实施例3:化合物T-05的合成:
将1.9g化合物5(1.0eq)溶于DCE(20ml),然后加入TFA(2ml),80℃下反应1h后,TLC监控原料消失,之后降温分批加入氰基硼氢化钠(1.02g,4.0eq),加毕,升温至80℃反应过夜。反应完毕后,降温,向反应体系中加入碳酸氢钠水溶液,调PH至7-8,之后加入DCM(50mlX3)萃取,合并DCM相,加入无水硫酸钠干燥,过滤,旋干过柱,得到400mg T-05,[M+H]+=377.2。
实施例4
合成路线:
反应步骤:
(1)化合物2的合成
N2保护、0℃下,将化合物1(2g,1eq)溶于40mlTHF中,再加入N-羟基邻苯二甲酰亚胺(4.53g,1eq)和PPh3(8.7g,1.2eq),然后滴加DEAD(5.8g,1.2eq)到反应体系,逐步升到室温反应过夜,反应完毕,拌样过柱,得到4.4g化合物2。
(2)化合物3的合成
0℃下,将化合物2(3.7g,1eq)溶于氯乙腈(3.23ml,3eq)和乙酸(3ml,3eq)的混合溶剂中,然后缓慢滴加98%H2SO4(3.5ml,2eq)到反应体系,滴加过程中放热,室温反应1.5h,反应完毕,缓慢加冰水EA萃取,拌样过柱得到2g化合物3。
(3)化合物4的合成
将化合物3(2g,1eq)加入到6N HCl(40ml)中,回流反应1.5h,反应完毕,直接旋干,再用水溶解,MTBE洗两次,水相旋干,EtOH打浆,得到0.3g化合物4。
(4)化合物6的合成
将化合物5(0.3g,1eq)加入到6N盐酸乙醇(2ml)中,室温反应过夜。然后加入K2CO3(0.7g,3eq),搅拌1个小时,过滤,旋干,得到0.2g化合物5,直接用于下一步。
(5)实施例4:化合物T-07的合成
将化合物6(0.2g,1eq)加入2ml乙酸,然后加入化合物4(0.2g,3eq),N2保护下100℃反应,待反应完毕,NaHCO3水溶液调碱,EA萃取旋干,制备得0.3g最终化合物T-07,[M+H]+=405.2。
实施例5
合成路线:
反应步骤:
(1)化合物2的合成:100ml单口瓶,氮气保护,称取化合物1有0.6g(1.65mmol),加入6mlTHF,3ml甲醇,1ml水,再加入氢氧化锂0.35g(8.25mmol,5eq),室温搅拌过夜。次日,处理,过柱,得到0.38g产品,收率68%。
(2)化合物3的合成:250ml单口瓶,氮气保护。称取化合物2有1.425g(4.24mmol),加入二氯甲烷80ml,加2-氨基-2-甲基1-丙醇1.34g(12.73mmol,3eq),DIEA1.095g(8.48mmol,2eq),PyBop2.65g(5.09mmol,1.2eq)。室温搅拌4小时,点板,反应完毕,处理,多次过柱,得到1.61g的白色固体产品。
(3)化合物4的合成:100ml单口瓶中,加入化合物3有0.284g,EA30ml。氮气保护,加入IBX0.39g先室温搅拌10min,之后升温到85℃,反应4小时,处理,过柱,得到0.255g白色固体产品。
(4)实施例5:化合物T-09的合成
100ml单口瓶,加入化合物4有0.2g,加入单盐酸肼33.8mg(1eq),氢氧化钠固体19.76mg(1eq),无水乙醇20ml,先室温搅拌20min,滴入一滴HOAc,80℃反应过夜,点板,处理,过柱,得到130mg产品,[M+H]+=402.2。
实施例6
合成路线:
反应步骤:
(1)化合物2的合成:
将化合物1(1g,4.14mmol,1eq)和INT-1(0.75g,4.23mmol,1.02eq),加入到乙醇中,随后加入三乙胺(1.25g,12.44mmol,3eq),升温至55℃反应2小时,TLC监控,原料反应完后,降温,向反应体系中加入大量的水,有固体析出,过滤,滤饼用石油醚洗,干燥,得到1.2g化合物2。
(2)化合物3的合成:
将化合物2(1.2g,3.45mmol,1eq)溶于EtOH/HCl(50ml)中,室温搅拌过夜。TLC监控反应完全,旋干乙醇,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到0.75g化合物3。
(3)实施例6:化合物T-12的合成
将化合物3(0.75g,1.90mmol,1eq)溶于二甲苯(10ml),然后加入2-氨基异丁酸乙酯(0.75g,5.72mmol,3eq)与乙酸2-3滴催化,置换氮气,升温至130℃反应6h,TLC监控反应完全,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到169mg T-12,[M+H]+=433.2。
实施例7
合成路线:
反应步骤:
(1)化合物2的合成:
向4.6g化合物1(1.0eq)中加入50ml无水乙醇,随后分别加入INT-1(4.0g,1.0eq)与DIPEA(11.7ml,4.0eq),置换氮气后于60℃反应4h,TLC监控反应完毕,旋干乙醇,然后向反应体系中加入水后有固体析出,收集滤饼旋干得到3.5g化合物2。
(2)化合物3的合成:
将3.5g化合物2(1.0eq)溶于EtOH/HCl(50ml)中,室温搅拌过夜。TLC监控反应完全,旋干乙醇,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA
(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到3.7g化合物3。
(3)实施例7:化合物T-17的合成
将1.7g化合物3(1.0eq)溶于二甲苯(17ml),然后加入2-氨基异丁酸乙酯(1.87g,3eq)与乙酸(0.002g,0.006eq),置换氮气,升温至130℃反应6h,TLC监控反应完全,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到320mg T-17,[M+H]+=397.2。
实施例8
合成路线:
反应步骤:
(1)化合物2的合成:
将化合物1(5g,20.7mmol,1eq)和INT-1(3.75g,21.15mmol,1.02eq),加入到乙醇中,随后加入三乙胺(6.25g,62.2mmol,3eq),升温至55℃反应2小时,TLC监控,原料反应完后,降温,向反应体系中加入大量的水,有固体析出,过滤,滤饼用石油醚洗,干燥,得到5.6g化合物2。
(2)化合物3的合成:
将化合物2(4g,12.6mmol,1eq)溶于EtOH/HCl(100ml,溶解度较差)中,室温搅拌过夜。TLC监控反应完全,旋干乙醇,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到2.4g化合物3。
(3)实施例8:化合物T-36的合成
将化合物3(1.2g,3.3mmol,1eq)溶于二甲苯(20ml),然后加入2-氨基异丁酸乙酯(1..29g,9.91mmol,3eq)与乙酸0.1mL催化,置换氮气,升温至130℃反应6h,TLC监控反应完全,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到520mg T-36,[M+H]+=403.1。
实施例9
合成路线:
反应步骤:
(1)化合物2的合成:
将化合物1(1g,4.14mmol,1eq)和INT-1(0.75g,4.23mmol,1.02eq),加入到乙醇中,随后加入三乙胺(1.25g,12.44mmol,3eq),升温至55℃反应2小时,TLC监控,原料反应完后,降温,向反应体系中加入大量的水,有固体析出,过滤,滤饼用石油醚洗,干燥,得到1.2g化合物2。
(2)化合物3的合成:
将化合物2(1.2g,3.45mmol,1eq)中加入到无水乙醇(10ml)与1,4-二氧六环(10ml)中,然后加入盐酸羟胺(1.9g,27.6mmol,8eq)与碳酸钾(3.8g,27.6mmol,8eq),置换氮气,80℃反应16h,TLC监控反应完全,过滤,旋干直接过柱,得到670mg化合物3。
(3)化合物4的合成:
将化合物3(0.67g,1.76mmol,1eq)溶于DMSO中,然后加入溴乙缩醛(0.69g,3.52mmol,2eq)和KOH(0.39g,7.05mmol,4eq),升温至60℃反应6h,TLC监控反应完毕,向反应体系中加入水后有固体析出,加入EA(10mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱,得到0.48g化合物4。
(4)实施例9:化合物T-37的合成
将化合物4(0.48g,0.96mmol,1eq)溶于DCE(5ml),然后加入TFA(0.2ml),80℃下反应1h后,TLC监控原料消失,之后降温分批加入氰基硼氢化钠(0.24g,3.87mmol,4eq),加毕,升温至80℃反应过夜。反应完毕后,降温,向反应体系中加入碳酸氢钠水溶液,调PH至7-8,之后加入DCM(10mlX3)萃取,合并DCM相,加入无水硫酸钠干燥,过滤,旋干过柱,得到90mgT-37,[M+H]+=407.1。
实施例10
合成路线:
反应步骤:
(1)化合物2的合成:
向1.85g化合物1(1.0eq)中加入20ml无水乙醇,随后分别加入INT-1(1.6g,1.0eq)与DIPEA(4.68ml,4.0eq),置换氮气后于60℃反应4h,TLC监控反应完毕,旋干乙醇,然后向反应体系中加入水后有固体析出,收集滤饼旋干得到1.12g化合物2。
(2)化合物3的合成:
将1.12g化合物2(1.0eq)溶于EtOH/HCl(20ml)中,室温搅拌过夜。TLC监控反应完全,旋干乙醇,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到1.5g化合物3。
(3)实施例10:化合物T-42的合成
将1.5g化合物3溶于二甲苯(15ml),然后加入2-氨基异丁酸乙酯(1.65g,3.0eq)与乙酸(1.85mg,0.006eq),置换氮气,升温至130℃反应6h,TLC监控反应完全,降温,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到680mg T-42,[M+H]+=398.2。
实施例11
合成路线:
反应步骤:
(1)化合物2的合成:
将化合物1(2g,12.6mmol,1eq)溶于EtOH/HCl(50ml,溶解度较差)中,室温搅拌过夜。TLC监控反应完全,旋干乙醇,然后向体系中加入NaHCO3水溶液调PH值至7~8,加入EA(50mlX3)萃取,合并EA相,加入无水硫酸钠干燥,过滤,旋干过柱得到1.3g化合物2。
(2)化合物3的合成:
将化合物2(1.3g)加入到50mL氨气的乙醇溶液中,然后加热到50度过夜搅拌反应。将反应直接旋干,过柱得到0.8g的化合物3,[M+H]+=335.1。
(3)将化合物3(0.8g,2.4mmol)加入到50mL的二氯甲烷中,然后加入三乙胺(3.0eq,7.2mmol),0℃下滴加氯甲酸正丙酯(1.2eq,2.9mmol),加毕缓慢升温到室温过夜,反应液加入饱和食盐水洗涤,然后干燥,旋干过柱得325mg最终产物T-11,[M+H]+=421.1。
同时,参照以上实施例,合成了实施例12-28,具体见表1。
表1
生物活性测试例
测试例1:本发明化合物对ROS1、NTRK和ALK及它们的耐药激酶的抑制活性
化合物对蛋白激酶的活性抑制实验在Reaction Biology Corporation放射性标记的HotSpot激酶实验平台开展。制备含相应底物的新鲜反应液(20mM HEPESpH 7.5,10mMMgCl2,1mM EGTA,0.02%Brij35,0.02mg/mL BSA,0.1mM Na3VO4,2mM DTT,1%DMSO),加入所需辅因子和待测激酶至上述溶液并轻轻混匀,使用Echo550移液系统向每孔加入待测化合物DMSO溶液(空白对照组加入相应体积DMSO),加入33P-ATP(最终比活度0.01μCi/μL)以开始反应,反应液于室温孵育120分钟。将孵育后的反应液转移至P81离子交换层析纸(Whatman#3698-915)上,用0.75%的磷酸溶液洗脱,检测层析纸上剩余含放射性的磷酸化底物的量。
表2给出了本发明化合物对ROS1、NTRK和ALK及它们的耐药激酶的抑制活性IC50值,A<0.5nM,0.5nM≤B≤5.0nM,5.0nM<C<50nM,50nM≤D≤500nM,E>500nM。
表2
经激酶活性测试,发现本发明的系列化合物对ROS1、NTRK和ALK及它们的耐药突变有很好的抑制活性,尤其是对耐药突变的抑制更出色。
本发明化合物对ROS1、NTRK和ALK及它们的耐药突变中的一种或多种的活性均比目前在临床上的药物LOXO-101有更好的抑制剂活性。
本发明大部分化合物对ROS1、NTRK和ALK及它们的耐药突变的一种或多种活性优于或与LOXO-195和TPX-0005相当。
本发明化合物非常有潜力应用于由ROS1、NTRK和ALK等所介导的疾病的治疗。
测试例2:化合物对细胞的增殖抑制
化合物对细胞的增殖抑制实验在合肥中科普瑞昇生物医药科技有限公司开展。稳定转染不同激酶基因的Ba/F3工程细胞株复苏后采用RPMI 1640培养基(BiologicalIndustries,Israel)+10%胎牛血清(Biological Industries,Israel)+1%双抗(Penicillin Streptomycin solution,Coring,USA)培养两代,取对数生长期细胞悬液,以2000细胞/孔,接种于96孔白色细胞培养板(Corning 3917,NY,USA),每孔体积为95μL。取5μL20×待测化合物DMSO溶液加入上述含95μL细胞悬液的培养板中,空白对照组加入相应体积DMSO,混匀,于37℃、5%CO2培养箱中孵育72小时,采用CellTiter-Glo检测细胞活力。
表3给出了本发明化合物对ROS1、NTRK和ALK或它们的耐药突变的Ba/F3工程细胞株的抑制活性IC50值。
表3
经细胞活性测试,发现本发明的系列化合物对ROS1、NTRK和ALK及它们的耐药突变的Ba/F3工程细胞株有很好的抑制活性,尤其是对耐药突变的抑制更出色。本发明的化合物对ROS1、NTRK和ALK及它们的耐药突变的Ba/F3工程细胞株活性均很好的抑制剂活性,且本发明大部分化合物对ROS1、NTRK和ALK及它们的耐药突变的Ba/F3工程细胞株活性也非常优异,非常有潜力应用于由ROS1、NTRK和ALK等所介导的疾病的治疗。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.式Ⅰ所示的化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,
式中,
*为R或S构型;
Z1、Z2、Z3各自独立地选自:N或CR13;
X选自下组:NR6、O、CR1R2、S、S(O)或S(O)2;
R1、R2、R3、R4、R5、R6和R13各自独立地选自取代或未取代的下组基团:H、卤素、氨基、氰基、硝基、羟基、酰基、酯基、C1-C6烷基、C3-C8环烷基、3-8元杂环基、C1-C6烷氧基、C6-C14芳基、5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R7、R8、R9、R10、R11和R'11各自独立地选自取代或未取代的下组基团:氢原子、氰基、C1-C6烷基、C3-C8环烷基、C6-C14芳基和5-14元杂芳基;其中,所述取代是指被一个或多个R取代;
R12选自:C1-C6烷基或羟基取代的C1-C6烷基;
R选自:氘、卤素、氨基、氰基、硝基、羟基、酰基、酯基、C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基、C3-C8卤代环烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C6-C14芳基和5-14元杂芳基。
5.如权利要求1所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药,其特征在于,R1、R2和R3各自独立的选自:氢、卤素或氨基;
R4选自:氢、C1-C6烷基、C3-C6环烷基、C1-C6卤代烷基;
R5选自:氢、卤素;
R6选自:氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、C1-C6烷胺基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C1-C6烷胺基、卤代C3-C6环烷基;
R7、R8、R9、R10和R11各自独立地选自:氢、取代或未取代的C1-C6烷基;其中,所述取代是指被选自下组的一个或多个基团取代:氘、卤素、氨基、氰基、羟基、酰基、酯基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C6-C10芳基和5-10元杂芳基。
8.一种药物组合物,其特征在于,所述药物组合物含有i)治疗有效量的权利要求1所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药;和ii)一种或多种药学上可以接受的载体、稀释剂或赋形剂。
9.如权利要求1所述的式Ⅰ化合物、其立体异构体、互变异构体、晶型、药学上可接受的盐、水合物、溶剂合物或前药的用途,其特征在于,用于制备预防和/或治疗ROS1、NTRK或ALK介导的病理学特征的疾病的药物。
10.如权利要求9所述的用途,其特征在于,所述ROS1、NTRK或ALK介导的病理学特征的疾病包括癌症、肉瘤和疼痛。
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WO2007025540A2 (de) * | 2005-09-02 | 2007-03-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte imidazo[1,2b]pyridazine als kinase-inhibitoren, deren herstellung und verwendung als arzneimittel |
WO2011006074A1 (en) * | 2009-07-09 | 2011-01-13 | Array Biopharma Inc. | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
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WO2011006074A1 (en) * | 2009-07-09 | 2011-01-13 | Array Biopharma Inc. | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
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CN111718349A (zh) * | 2019-03-19 | 2020-09-29 | 华中师范大学 | 含氟吡唑并嘧啶化合物和药物组合物及其应用 |
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