CN117136186A - Rock1和rock2蛋白激酶的选择性抑制剂及其用途 - Google Patents
Rock1和rock2蛋白激酶的选择性抑制剂及其用途 Download PDFInfo
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- CN117136186A CN117136186A CN202280009230.7A CN202280009230A CN117136186A CN 117136186 A CN117136186 A CN 117136186A CN 202280009230 A CN202280009230 A CN 202280009230A CN 117136186 A CN117136186 A CN 117136186A
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- Prior art keywords
- methyl
- benzamide
- pyrazol
- oxoisoquinolin
- oxo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明涉及可抑制Rho激酶和/或Rho激酶介导的肌球蛋白轻链磷酸根的磷酸化的新颖的经取代的双环衍生物、包含所述衍生物的组合物、用于制备所述衍生物的方法、和使用所述衍生物和/或组合物的方法。
Description
相关申请的交叉引用
本申请要求于2021年1月6日提交的美国临时申请号63/134,458的优先权,该美国临时申请以引用方式并入本文。
技术领域
本发明涉及能够选择性抑制含Rho相关卷曲螺旋的蛋白激酶(Rho-associatedcoiled-coil containing protein kinase,ROCK)的化合物、包含所述化合物的组合物、用于制备所述化合物的方法,以及使用所述化合物或组合物的方法。
背景技术
含Rho相关卷曲螺旋的蛋白激酶(ROCK/Rho激酶/Rho相关激酶)是小GTP酶Rho(RhoA、Rho B、Rho C和Rho E)的下游效应物,并且属于丝氨酸/苏氨酸激酶家族。Rho的活性GTP结合形式通过ROCK的作用介导若干种生物学功能,包括平滑肌收缩、细胞运动和胞质分裂。ROCK蛋白于1996年被鉴定为与Rho GTP酶结合的蛋白质。两种蛋白质被独立地分离为p160和p164。后来,这些蛋白质分别被识别为ROCK-1和ROCK-2,并且是Rho相关激酶的同种型。这两种同种型ROCK-1(ROCK-b/p160)和ROCK-2(ROCK-a/p164)在其氨基酸序列中共享92%的相似性。它们的结构包含位于N末端的催化激酶结构域,之后是包含卷曲螺旋的区域(600个氨基酸),以及在C末端的Rho结合结构域和普列克底物蛋白同源(pleckstrin homology,PH)结构域。它们具有不同的位置,并且已经鉴定出了每一者的不同生理作用。ROCK-1转录物(位于18号染色体上的基因)是遍在性的,在肝脏、肾脏、脾脏、睾丸、胸腺和血球中的表达更为突出,而ROCK-2mRNA(2号染色体)在骨骼肌和脑中的表达更为丰富,表明它们在这些位置具有专门作用。
ROCK抑制剂已被考虑用于多种疾病,诸如脑缺血、高血压、勃起功能障碍、青光眼、骨质疏松症、心脏肥大、糖尿病性心肌病、视网膜病、肺动脉高压和动脉粥样硬化。然而,由于缺乏关于特定ROCK同种型参与的知识,它们的实施受到限制。同种型特异性靶向或联合ROCK抑制是否会提供更好的治疗结果还有待验证。尽管它们对ROCK同种型以及其他丝氨酸/苏氨酸激酶(例如PRK2、PKC、cAMP依赖性蛋白激酶和香橼激酶(citron kinase))的特异性不完全,但一些非特异性ROCK抑制剂在某些病理状态(例如青光眼和高血压)下已经显示出有希望的结果。然而,同种型选择性ROCK抑制剂要进行临床使用还需要进一步的工作,但是一些基于科研的研究已经在一定程度上帮助解决了ROCK-1和ROCK-2特异性功能的模糊性。因此,仍然需要了解特定疾患中每种同种型的各别功能,以帮助解决安全性和特异性问题,并扩大ROCK抑制剂的治疗应用。
发明内容
在一个方面中,本发明提供了由下式(1)表示的新颖化合物,所述新颖化合物能够抑制Rho相关的卷曲螺旋形成蛋白丝氨酸/苏氨酸激酶(ROCK)。
其中A、B、E、X、Y、R1、R2和R3在本发明的以下具体实施方式中定义。
在另一方面中,本发明提供了所述新颖化合物的药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药。又,本发明提供了所述非对映异构体、对映异构体或外消旋体的药学上可接受的盐、水合物或溶剂化物。
在又一方面中,本发明提供了药物组合物,所述药物组合物各自包含所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药,或它们的组合。
在仍又一方面中,本发明提供了通过使用所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或组合物来治疗或减轻某些ROCK介导的疾病或疾患的方法。所述疾病或疾患的非限制性示例包括心血管、肺、炎性、神经性或增殖性疾病或疾患。
在另外的方面中,本发明提供了制备所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物和前药的方法。
具体实施方式
1.化合物
在一个方面中,本发明提供了一种由式(1)表示的化合物、其药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药:
其中:
X是H或卤素;
Y是N或CR4;
A、B和E各自独立地为N或CH;
代表单键或双键;
R1是H、F、Cl、OH、杂芳基、C1-C3烷基、C1-C3烷氧基、C(O)2R5、NHS(O)2R5、S(O)2R5、C(O)NR5R6或NHC(O)R7,其中所述杂芳基、C1-C3烷基或C1-C3烷氧基可任选地被一个或多个合适的取代基,例如卤素、氨基、羟基或烷氧基取代;
R2为H或C1-C3烷基,其中所述C1-C3烷基可任选地且独立地被一个或多个合适的取代基,例如卤素、羟基、C1-C3烷氧基或NR5R6取代;
R3为5-6元杂芳基、杂环烷基或不饱和杂环烷基,其中所述杂芳基、杂环烷基或不饱和杂环烷基可任选地被一个或多个合适的取代基,例如卤素、CN、CHF2、CF3、C1-C3烷基或氨基取代,其中所述5-6元杂芳基、杂环烷基或不饱和杂环烷基具有1-3个选自由以下组成的组的杂原子:氧、氮以及它们的组合;
R4为H、卤素、CN、CF3、C1-C3烷基、C1-C3烷氧基或C2-C6炔基,其中所述C1-C3烷基或C2-C6炔基可以被一个或多个合适的取代基,例如氨基、羟基、C1-C2NR5R6或C1-C3烷氧基取代;
R5为H或C1-C3烷基,其中所述C1-C3烷基可任选地被一个或多个合适的取代基,例如卤素、氨基、羟基或烷氧基取代;
R6为H、CD3、C1-C6烷基、C3-C7环烷基、芳基、杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基、或包含1-2个选自由N、O、S、亚砜基和砜基组成的组的杂原子的4-7元杂环烷基,其中所述C1-C6烷基、C3-C7环烷基、芳基或杂芳基任选地被卤素、NR5R6、芳基、杂芳基、杂环烷基或OR5取代,其中当所述4-7元杂环烷基具有一个氮原子时,所述4-7元杂环烷基任选地在氮原子处被R6、C(O)R5、S(O)2NH2、C(O)OR5、或C(O)NHR5取代;
R7为C1-C6烷基、C3-C7环烷基、包含1-2个选自N或O的杂原子的4-7元杂环烷基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基,或8-10元饱和或部分不饱和双环杂芳基,其中所述C1-C6烷基、C3-C7环烷基、包含1-2个选自N或O的杂原子的4-7元杂环烷基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基或8-10元饱和或部分不饱和双环杂芳基任选地被卤素、C1-C3烷基、OR5、NH2或5-6元杂芳基取代。
在一些实施方式中,
X是H或卤素;
Y是N或CR4;
A、B和E各自独立地为N或CH;
是单键或双键;
R1为H、F、Cl、OH、杂芳基、C1-C3烷氧基、C(O)OR5、NHS(O)2R5、S(O)2R5、C(O)NR5R6或NHC(O)R7,其中所述杂芳基或C1-C3烷氧基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合;
R2为H或C1-C3烷基,其任选地被一个或多个选自由以下组成的组的取代基取代:卤素、羟基、C1-C3烷氧基、NR5R6以及它们的组合;
R3为5-6元杂芳基或杂环,其中所述杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、CN、CHF2、CF3、C1-C3烷基、氨基、以及它们的组合,并且其中所述5-6元杂芳基具有1-3个选自由以下组成的组的杂原子:氧、氮以及它们的组合;
R4为H、卤素、CF3、CN、C1-C3烷基、C1-C3烷氧基、或C2-C6炔基,其中所述C1-C3烷基或C2-C6炔基任选地被一个或多个选自由以下组成的组的取代基取代:OH、NH2、C1-C2氨基、C1-C2羟基、C1-C2NR5R6、C1-C3烷氧基以及它们的组合;
R5为H或C1-C3烷基,其中所述C1-C3烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合;
R6为H、CD3、C1-C6烷基、C3-C7环烷基、芳基、杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基、或包含1-2个选自由N、O、S以及它们的组合组成的组的杂原子的4-7元杂环基,其中所述C1-C6烷基、C3-C7环烷基、芳基或杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、NR5R6、芳基、杂芳基和OR5以及它们的组合,并且其中当所述4-7元杂环基具有一个氮原子时,所述4-7元杂环基在氮原子处任选地被C1-C3烷基、CF3、C(O)R5、S(O)2NH2、OCF3、C(O)OR5或C(O)NHR5取代;并且
R7为C1-C6烷基、C3-C7环烷基、包含1-2个选自由N、O以及它们的组合组成的组的杂原子的4-7元杂环基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基,其中所述C1-C6烷基或C3-C7环烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、C1-C3烷基、OR5、NH2、5-6元杂芳基以及它们的组合。
在一些实施方式中,X可以是H、F或Cl。
在一些实施方式中,R1可为H、F、Cl、OH、甲氧基、杂芳基、C(O)OR5、NHS(O)2R5、S(O)2R5、C(O)NR5R6或NHC(O)R7,其中所述杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合。
在一些实施方式中,R2可为H或C1-C3烷基,其任选地被一个或多个选自由以下组成的组的取代基取代:羟基、甲氧基、乙氧基、NH2、NHMe、NMe2以及它们的组合。
在一些实施方式中,R3可以是以下基团中的一个:
在一些实施方式中,R4可为H、Me、F、Cl、CN、C1-C3烷基或C2-C4炔基,其中所述C1-C3烷基或C2-C4炔基任选地被一个或多个选自由以下组成的组的取代基取代:OH、NH2、NMe2、OMe以及它们的组合。
在一些实施方式中,R5可为H或Me。
在一些实施方式中,R6可为H、CD3、C1-C6烷基、C3-C7环烷基、苯基、杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基、或包含1-2个选自由N、O、S以及它们的组合组成的组的杂原子的4-7元杂环基,其中所述C1-C6烷基、C3-C7环烷基、苯基,或杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、CF3、OH、OMe、NR5R6、芳基、杂芳基以及它们的组合,并且其中当所述4-7元杂环基具有一个氮原子时,所述4-7元杂环基任选地在氮原子处被C1-C3烷基、C(O)R5、S(O)2NH2、OCF3、C(O)OR5或C(O)NHR5取代。
在一些实施方式中,R7可为H、C1-C6烷基、C3-C7环烷基、包含1-2个选自由N、O以及它们的组合组成的组的杂原子的4-7元杂环基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基、或8-10元饱和或部分不饱和双环杂芳基,其中所述C1-C6烷基或C3-C7环烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、C1-C3烷基、OH、OMe、NH2、5-6元杂芳基以及它们的组合。
术语“烷基”,单独使用或作为较大部分(例如“芳基烷基”或“环烷基”)的一部分使用,是指具有1至10个碳原子、或1至8个碳原子、或1-6个碳原子、或1-4个碳原子的直链或支链烃基(除非另有说明),并且包括例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、正己基等。烷基可以是未取代的或被一个或多个合适的取代基取代。
术语“环烷基”是指在烃环中具有3至10个碳原子或3至7个碳原子的单环或多环烃环基团(除非另有说明),并且包括例如环丙基、环庚基、环辛基、环癸基、环丁基、金刚烷基、降蒎烷基(norpinanyl)、十氢化萘基(decalinyl)、降冰片基、环己基、环戊基等。环烷基基团可以是未取代的或被一个或多个合适的取代基取代。
术语“杂”是指用至少一个杂原子(例如氮、硫、亚砜、砜和氧)取代环系中的至少一个碳原子成员。
术语“杂环烷基”意指具有在环中的2至9个碳原子或2至7个碳原子(除非另有说明)和至少一个杂原子,优选地1至4个选自氮、硫(包括氧化硫,例如砜或亚砜)和氧的杂原子的非芳族饱和或非芳族不饱和单环或非芳族饱和或非芳族不饱和多环环。杂环烷基基团的环或环系可以经由碳原子或氮原子(如果此类原子存在的话)连接到化合物的另一部分。杂环烷基基团在环系中可具有总共3-10个、或3-8个、或5-8个原子(除非另有说明)。杂环烷基基团可以在环基团中具有一个或多个碳-碳双键或碳-杂原子双键,只要所述环基团不因它们的存在而变成芳族即可。
杂环烷基基团的示例包括氮杂环丁烷基、氮丙啶基、吡咯烷基、哌啶基、哌嗪基、高哌嗪基(homopiperazinyl)、吗啉代、硫代吗啉代、四氢呋喃基、四氢硫代呋喃基、四氢吡喃基、吡喃基等。杂环烷基基团可以是未取代的或被一个或多个合适的取代基取代。
如本文所用,术语“卤基”包括氟、氯、溴和碘。
如本文所用,术语“烷氧基”是指上面通过氧键合的烷基基团,其示例包括甲氧基、乙氧基、异丙氧基、叔丁氧基等。此外,烷氧基还指聚醚,例如-O-(CH2)2-O-CH3等。烷氧基可以是未取代的或被一个或多个合适的取代基取代。
如本文所用,术语“芳基”是指未取代或取代的芳族单环或多环基团并且包括例如碳环芳族基团(例如苯基、萘基等)以及杂芳族基团(例如吡啶基、呋喃基、苯硫基等)。术语“芳基”还包括与非芳族碳环或杂环环稠合的芳族环(例如苯基或吡啶基环)。术语“芳基”可与“芳基环”、“芳族基团”和“芳族环”可互换地使用。杂芳基基团在杂芳族环中具有4至14个原子,所述原子中的1至9个原子独立地选自由以下组成的组:氧、硫和氮。杂芳基基团在5-8元芳族基团中具有1-3个杂原子。芳基或杂芳基可以是单环或双环芳族基团。典型的芳基和杂芳基基团包括例如苯基、喹啉基、吲唑基、吲哚基、二氢苯并二氧杂环己炔基(dihydrobenzodioxynyl)、3-氯苯基、2,6-二溴苯基、吡啶基、嘧啶基、3-甲基吡啶基、苯并噻吩基、2,4,6-三溴苯基、4-乙基苯并噻吩基、呋喃基、3,4-二乙基呋喃基、萘基、4,7-二氯萘基、吡咯、吡唑、咪唑、噻唑等。芳基或杂芳基可以是未取代的或被一个或多个合适的取代基取代。
如本文所用,术语“羟基(hydroxyl/hydroxy)”是指-OH。
如本文所用,术语“氨基”是指-NH2。
如本文所用,术语“羟烷基”是指烷基基团的任何羟基衍生物。术语“羟烷基”包括一个或多个氢原子被羟基取代的任何烷基基团。
如本文所用,术语“芳基烷基”包括一个或多个氢原子被芳基基团(例如,苄基、苯乙基等)取代的任何烷基基团。
如本文所用,“取代基”是指与感兴趣的分子内的原子共价键合的分子部分。例如,环取代基可以是与作为环成员的原子(优选地碳或氮原子)共价键合的部分,例如卤素、烷基基团、卤代烷基基团或其他基团。芳族基团的取代基通常共价键合至环碳原子。术语“取代”是指用取代基取代分子结构中的氢原子,使得不超过指定原子上的化合价,并且使得从所述取代产生化学稳定的化合物(即,可被分离、表征并测试生物活性的化合物)。
如上所述,某些基团可以是未取代的,或在一个或多个可用位置处被除氢以外的一个或多个合适的取代基取代,通常是在1、2、3、4或5个位置处被一个或多个合适的基团(其可以是相同或不同的)取代。某些基团在被取代时被1、2、3或4个独立选择的取代基取代。合适的取代基包括卤基、烷基、卤代烷基、芳基、羟基、烷氧基、羟烷基、氨基等。
如本文所用,术语“药学上可接受的”是指不消除本文所述化合物的生物活性或性质的材料,例如载体或稀释剂。将此类材料施用于个体,而不会引起非期望的生物学效应或以有害方式与包含所述材料的组合物的组分中的任何组分相互作用。
如本文所用,术语“药学上可接受的盐”是指这样的化合物制剂,所述化合物制剂不会对其所施用于的生物体造成显著刺激并且不会消除本文所述化合物的生物活性和性质。
药学上可接受的盐形式包括药学上可接受的酸式/阴离子或碱式/阳离子盐(UKJournal of Pharmaceutical and Biosciences第2(4)卷,01-04,2014,该文献以引用方式并入本文)。药学上可接受的酸式/阴离子盐包括乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、依地酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐(estolate)、乙磺酸盐、富马酸盐、甘肽酸盐、葡庚糖酸盐(glyceptate)、葡糖酸盐、谷氨酸盐、乙醇酰氨苯胂酸盐(glycollylarsanilate)、己基间苯二酚盐、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、次乙酸盐、琥珀酸盐、硫酸盐、硫酸氢盐、单宁酸盐、酒石酸盐、茶氯酸盐(teoclate)、甲苯磺酸盐和三乙基碘盐。药学上可接受的碱式/阳离子盐包括钠盐、钾盐、钙盐、镁盐、二乙醇胺盐、N-甲基-D-葡糖胺盐、L-赖氨酸盐、L-精氨酸盐、铵盐、乙醇胺盐、哌嗪盐和三乙醇胺盐。
药学上可接受的酸式盐是通过式1化合物的游离碱形式与合适的无机酸或有机酸反应形成的,所述无机酸或有机酸包括但不限于氢溴酸、盐酸、硫酸、硝酸、磷酸、琥珀酸、马来酸、甲酸、乙酸、丙酸、富马酸、柠檬酸、酒石酸、乳酸、苯甲酸、水杨酸、谷氨酸、天冬氨酸、对甲苯磺酸、苯磺酸、甲磺酸、乙磺酸、萘磺酸(例如2-萘磺酸)或己酸。式1化合物的药学上可接受的酸加成盐可以包括或者是例如氢溴酸盐、盐酸盐、硫酸盐、硝酸盐、磷酸盐、琥珀酸盐、马来酸盐、甲酸盐、乙酸盐、丙酸盐、富马酸盐、柠檬酸盐、酒石酸盐、乳酸盐、苯甲酸盐、水杨酸盐、谷氨酸盐、天冬氨酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、萘磺酸盐(例如,2-萘磺酸盐)或己酸盐。
本发明的化合物的游离酸或游离碱形式可通过本领域普通技术人员已知的方法(例如,更多细节参见L.D.Bigley,S.M.Berg,D.C.Monkhouse,“Encyclopedia ofPharmaceutical Technology”.J.Swarbrick和J.C.Boylam编辑,第13卷,Marcel Dekker,Inc.,1995,第453-499页;该文献的全部教导以引用方式并入本文)分别由对应的碱加成盐或酸加成盐形式制备。例如,通过用合适的碱(例如,氢氧化铵溶液、氢氧化钠等)处理,可以将酸加成盐形式的本发明的化合物转换为对应的游离碱形式。通过用合适的酸(例如,盐酸等)处理,可以将碱加成盐形式的本发明的化合物转换成对应的游离酸。
本发明的化合物的前药衍生物可以通过本领域普通技术人员已知的方法制备(例如,关于进一步的细节参见Saulnier等人,Bioorg.Med.Chem.Letters,1994,4,1985;Daniela Hartmann Jornada at.Al.,Molecules 2016,21,42;所述文献的全部教导以引用方式并入本文)。本发明的化合物的受保护衍生物可以通过本领域普通技术人员已知的方法制备。适用于产生保护基团和去除保护基团的技术的详细描述可以在T.W.Greene,“Green's Protective Groups in Organic Chemistry,”第4版,John Wiley and Sons,Inc.,2006中找到,该文献的全部教导以引用方式并入本文。
本发明的化合物可以通过以下方式制备为其单独的立体异构体:使所述化合物的外消旋混合物与光学活性拆分剂反应形成一对非对映异构化合物,分离所述非对映异构体并回收光学纯的对映异构体。对映异构体的拆分可以使用本发明的化合物的共价非对映异构体衍生物,或通过使用可离解的复合物(例如,结晶非对映异构体盐)来进行。非对映异构体具有不同的物理性质(例如,熔点、沸点、溶解度、反应性等),并且可以通过利用这些不同点轻松分离。非对映异构体可通过色谱法,或通过基于溶解度差异的分离/拆分技术分离。然后通过任何不会导致外消旋化的实用方法,回收光学纯的对映异构体以及拆分剂。适用于从化合物的外消旋混合物中拆分化合物的立体异构体的技术的更详细描述可以在JeanJacques,Andre Collet and Samuel H.Wilen,“Enantiomers,Racemates andResolutions,”John Wiley And Sons,Inc.,1981中找到,该文献的全部教导以引用方式并入本文。
如本文所用,术语“溶剂化物”是指由溶质(在本发明中,式1化合物或其药学上可接受的盐)和溶剂形成的可变化学计量的复合物。用于本发明目的的此类溶剂可不干扰溶质的生物活性。合适溶剂的非限制性示例包括水、丙酮、甲醇、乙醇和乙酸。优选地,所使用的溶剂是药学上可接受的溶剂。合适的药学上可接受的溶剂的非限制性示例包括水、乙醇和乙酸。
2.组合物
在另一方面中,本发明提供了一种药物组合物,所述药物组合物包含所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药,或它们的药物组合。所述组合物可进一步包含附加组分。所述附加组分的非限制性示例包括药学上可接受的载体、稀释剂、赋形剂以及它们的组合。
如本文所用,术语“药物组合物”是指本文所述的化合物与其他化学组分(例如载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂)的混合物。
如本文所用,术语“药物组合”意指由多于一种活性成分混合或组合产生的产物。
如本文所用,关于制剂、组合物或成分的术语“可接受的”,意指对进行治疗的受试者的总体健康没有持久的有害影响。
如本文所用,术语“载体”是指有助于将本文所述的化合物掺入细胞或组织中的化合物或试剂。
如本文所用,术语“稀释剂”是指用于在递送之前稀释本文所述的化合物的化合物。稀释剂也可用于稳定化本文所述的化合物。
用于本发明的药物组合物的合适的药学上可接受的载体、稀释剂、佐剂、或赋形剂包括由例如可力酮(collidone)或虫胶、阿拉伯树胶、滑石、二氧化钛或糖制成的片剂(包衣片剂),胶囊剂(明胶),溶液(水溶液或水-乙醇溶液),含有活性物质的糖浆剂,乳液或可吸入粉剂(含各种糖类例如乳糖或葡萄糖、盐以及这些赋形剂与彼此的混合物)和气雾剂(含推进剂或不含推进剂的吸入溶液)。
可使用的赋形剂包括例如水、药学上可接受的有机溶剂例如石蜡(例如,石油馏分)、植物油(例如花生油或芝麻油)、单或多官能醇(例如,乙醇或甘油)、载体例如天然矿物粉末(例如,高岭土、粘土、滑石、白垩)、合成矿物粉末(例如,高度分散的硅酸和硅酸盐)、糖类(例如,蔗糖、乳糖和葡萄糖)、乳化剂(例如,木质素、亚硫酸盐废液、甲基纤维素、淀粉和聚乙烯吡咯烷酮)和润滑剂(例如,硬脂酸镁、滑石、硬脂酸和十二烷基硫酸钠)。
3.使用化合物或组合物的方法
在另一方面中,本发明提供了通过向受试者或患者施用治疗有效量的所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或组合物来治疗或减轻某些蛋白激酶介导的疾病或病症的方法。在一些实施方式中,本发明提供了通过向受试者或患者施用治疗有效量的所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或组合物来治疗或减轻某些ROCK介导的疾病或疾患的方法。在一些实施方式中,本发明提供了治疗或减轻已知ROCK起作用的疾病或疾患的方法。
在又一方面中,本发明提供了通过向受试者或患者施用治疗有效量的所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或组合物来抑制酶活性,特别是ROCK1、ROCK2、PKCδ、PKCθ、PRK1、GSK3、PRK2、NEK1和NEK4激酶活性的方法。
在又一方面中,本发明提供了通过使生物样品与所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或组合物接触来抑制生物样品中的蛋白激酶活性(例如ROCK激酶活性)的方法。
如本文所用,术语“抑制剂”是指抑制一种或多种本文所述的激酶的化合物。例如,术语“ROCK抑制剂”是指抑制ROCK受体或降低信号传导效应的化合物。
如本文所用,术语“蛋白激酶介导的疾病”或“由不适当的蛋白激酶活性介导的疾患或疾病或病症”是指由本文所述的蛋白激酶介导或调节的任何疾病状态。此类疾病状态包括但不限于纤维化疾患;包括囊性和特发性肺纤维化的肺纤维化、辐射诱发的肺损伤、包括肝硬化在内的肝纤维化、包括动脉纤维化在内的心脏纤维化、心内膜心肌纤维化、陈旧性心肌梗死、动脉硬化、动脉粥样硬化、再狭窄、关节纤维化、克罗恩氏病、骨髓纤维化、佩罗尼氏病、肾源性系统性纤维化、进行性大块纤维化、腹膜后腔纤维化、硬皮病/系统性硬化症、纵隔纤维化、瘢痕瘤和增生性瘢痕、神经胶质瘢痕、或肾纤维化;心血管疾病或疾患,例如脑血管痉挛、高血压、动脉粥样硬化、心绞痛、心肌梗塞、缺血/再灌注损伤、中风、支气管哮喘;青光眼、早产、勃起功能障碍,或肾脏疾病,例如慢性肾衰竭、慢性肾炎、糖尿病性肾病和IgA肾病变;神经系统疾病或疾患,例如脊髓损伤、阿尔茨海默氏病、多发性硬化症或神经性疼痛;和增殖性疾患,例如视网膜病变、纤维化或侵袭性/转移性癌症。此类癌症包括腺癌、肾上腺皮质癌;膀胱癌;骨癌;脑癌;乳腺癌;口腔癌;宫颈癌;结肠癌;结直肠癌;子宫内膜癌或子宫癌;表皮样癌;食道癌;眼癌;滤泡癌;胆囊癌;胃肠癌;泌尿生殖道癌;成胶质细胞瘤;毛细胞癌;头颈癌;肝肿瘤;肝细胞癌;霍奇金氏病;角化棘皮瘤;肾癌;大细胞癌;大肠癌;喉癌;肝癌;肺癌,例如肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌;黑素瘤;骨髓增生性疾患;成神经细胞瘤;卵巢癌;乳头状癌;胰腺癌;腹膜癌;前列腺癌;直肠癌;唾液腺癌;肉瘤;鳞状细胞癌;小细胞癌;小肠癌;胃癌;睾丸癌;甲状腺癌;和外阴癌。在特定实施方式中,所治疗的癌症是黑素瘤、乳腺癌、结肠癌或胰腺癌。
如本文所用,术语“治疗(treat/treating/treatment)”是指预防和/或治疗地减轻、缓和或改善疾病或病症症状、预防附加症状、改善或预防症状的潜在代谢原因、抑制疾病或病症、阻止疾病或病症的发展、缓解疾病或病症、导致疾病或病症消退、缓解由疾病或病症引起的病症、或停止疾病或病症的症状的方法。
如本文所用,术语“受试者”或“患者”包括哺乳动物和非哺乳动物。哺乳动物的示例包括但不限于人类、黑猩猩、猿猴、牛、马、绵羊、山羊、猪;兔、狗、猫、大鼠、小鼠、豚鼠等。非哺乳动物的示例包括但不限于鸟类、鱼类等。
如本文所用,术语主题化合物的“施用(administration/administering)”是指向需要治疗的受试者提供本发明的化合物和/或其前药。
如本文所用,术语“有效量”或“治疗有效量”是指施用足够量的本文所述的化合物,所述量的化合物将在一定程度上缓解所治疗的疾病或病症的症状中的一种或多种。结果可以是病征、症状或疾病原因的减少和/或减轻,或生物系统的任何其他所需改变。例如,用于治疗用途的“有效量”是提供疾病症状的临床上显著减少所需的包含如本文所公开的化合物的组合物的量。可以使用例如剂量递增研究的技术来确定任何个案中适当的“有效”量。仅举例来说,本发明的化合物的治疗有效量可在例如约0.01mg/kg/天至约1000mg/kg/天、约0.1mg/kg/天至约500mg/kg/天、约0.1mg(x2)/kg/天至约500mg(x2)/kg/天的范围内。
针对激酶组筛选本发明的化合物并抑制该组上的至少一种激酶的活性。激酶的示例包括但不限于ROCK1和rock2。
本文所述的化合物是ROCK激酶活性的抑制剂并且在治疗与不适当的激酶活性相关联的疾患方面,特别是在治疗和预防由激酶(包括ROCK激酶)介导的疾病状态方面具有治疗益处。因此,本发明提供了调节,特别是抑制激酶起作用的信号转导级联(signaltransduction cascades)的方法。该方法通常涉及向受试者施用有效量的本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药和/或组合物,或使表达激酶的细胞与本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药和/或组合物接触,以调节或抑制信号转导级联。所述方法还用于调节,特别是抑制由特定激酶信号转导级联的激活所引起的下游过程或细胞反应。所述方法还作为针对以激酶依赖性信号转导级联的激活为特征、由其引起或与其相关联的疾病的治疗或预防的治疗途径在体外环境或体内环境中实践。
对于本文提供的化合物,包括式1化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药的治疗用途,将此类化合物以治疗有效量单独或作为药物组合物的一部分施用。因此,本文提供了药物组合物,所述药物组合物包含至少一种本文所提供的化合物,包括至少一种式1化合物、其药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,以及一种或多种药学上可接受的载体、稀释剂、佐剂或赋形剂。
此外,此类化合物和组合物单独或与一种或多种附加治疗剂组合施用。所述附加治疗剂的非限制性示例可包括免疫检查点抑制剂和诱导免疫原性细胞死亡(immunogeniccell death,ICD)的化学治疗剂。免疫检查点抑制剂的非限制性示例可包括PD-1抑制剂、PD-L1抑制剂和CTLA-4抑制剂。诱导免疫原性细胞死亡(ICD)的化学治疗剂的非限制性示例可包括多柔比星、伊达比星、米托蒽醌、互变霉素、海绵诱癌素A、沙鲁胺(salubrinal)、奥沙利铂、博莱霉素和环磷酰胺。此类化合物和组合物的施用方法包括但不限于静脉内施用、吸入施用、口服施用、直肠施用、肠胃外施用、玻璃体内施用、皮下施用、肌内施用、鼻内施用、经真皮施用、局部施用、眼科施用、经颊施用、气管施用、支气管施用、舌下施用或眼部施用。本文所提供的化合物通过已知的药物制剂施用,所述药物制剂包括用于口服施用的片剂、胶囊剂或酏剂,用于直肠施用的栓剂,用于肠胃外或肌内施用的无菌溶液或混悬剂,用于局部施用的洗剂、凝胶剂、软膏剂或乳膏剂,等等。在一些实施方式中,此类药物组合物被配制为片剂、丸剂、胶囊剂、液体剂、吸入剂、鼻喷雾溶液、栓剂、溶液剂、凝胶剂、乳剂、软膏剂、滴眼剂或滴耳剂。
治疗有效量将取决于所指示的疾病、所述疾病的严重程度、受试者的年龄和相对健康、所施用化合物的效力、施用模式和所需治疗等变化。所需剂量也将取决于施用模式、待治疗的具体病症和所需效应而变化。
式1化合物可用于抑制一种或多种蛋白激酶并用于治疗由蛋白激酶介导的疾病和疾患,例如癌症、自身免疫性疾病、纤维化疾患、心血管疾病和神经退行性疾病。
如本文所用,术语“生物样品”意指动物体外样品,并且包括但不限于细胞培养物或其提取物;从动物或其提取物获得的活检材料;和血液、唾液、尿液、粪便、精液、泪液或其他体液或其提取物。抑制生物样品中的激酶活性,特别是ROCK激酶活性可用于本领域技术人员已知的多种目的。此类目的的示例包括但不限于生物样品存储和生物测定。
如本文所用,术语“ROCK介导的疾病”或“病症”意指已知ROCK起作用的任何疾病或其他有害病症。ROCK参与脉管系统中的多种重要生理功能,包括平滑肌收缩;细胞增殖,例如血管平滑肌细胞增殖;和细胞粘附和迁移(参见Hu和Lee,Expert Opin.Ther.Targets,9(4):715-36,2005;Shimokawa和Takeshita,Arterioscler.Thromb.Vase.Biol.25(9):1767-75,2005)。ROCK参与由于白细胞迁移引起的炎症反应,例如自体免疫性疾病和过敏反应(参见Wettschureck等人,J.Mol.Med.80:629-38,2002)。已在中枢神经系统的各种疾患中观察到Rho/ROCK通路的异常激活(参见Mueller等人,Nature Rev.,4:387-98,2005)。此外,ROCK和肿瘤细胞迁移和侵袭((Riento和Ridley,Nature Rev.4:446-56,2004)和骨质疏松症(Ohnaka等人,Biochem.Biophys.,Res.Commun.287(2):337-4,2001)有关系。
具体地,本发明涉及治疗以下疾病或疾患或减轻其严重程度的方法:心血管疾病或疾患,例如脑血管痉挛、高血压、动脉粥样硬化、心绞痛、心肌梗塞、缺血/再灌注损伤、中风、支气管哮喘;青光眼、早产、勃起功能障碍,或肾脏疾病,例如慢性肾衰竭、慢性肾炎、糖尿病性肾病和IgA肾病变;神经系统疾病或疾患,例如脊髓损伤、阿尔茨海默氏病、多发性硬化症或神经性疼痛;和增殖性疾患,例如视网膜病变、纤维化或侵袭性/转移性癌症。此类癌症包括腺癌、肾上腺皮质癌;膀胱癌;骨癌;脑癌;乳腺癌;口腔癌;宫颈癌;结肠癌;结直肠癌;子宫内膜癌或子宫癌;表皮样癌;食道癌;眼癌;滤泡癌;胆囊癌;胃肠癌;泌尿生殖道癌;成胶质细胞瘤;毛细胞癌;头颈癌;肝肿瘤;肝细胞癌;霍奇金氏病;角化棘皮瘤;肾癌;大细胞癌;大肠癌;喉癌;肝癌;肺癌,例如肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌;黑素瘤;骨髓增生性疾患;成神经细胞瘤;卵巢癌;乳头状癌;胰腺癌;腹膜癌;前列腺癌;直肠癌;唾液腺癌;肉瘤;鳞状细胞癌;小细胞癌;小肠癌;胃癌;睾丸癌;甲状腺癌;和外阴癌。在特定实施方式中,所治疗的癌症是黑素瘤、乳腺癌、结肠癌或胰腺癌。
在另一方面中,本发明提供了一种治疗受试者的纤维化疾患的方法,所述方法包括向受试者施用治疗有效量的式I化合物。纤维化疾患的非限制性示例是包括囊性和特发性肺纤维化在内的肺纤维化、辐射诱发的肺损伤、包括肝硬化在内的肝纤维化、包括动脉纤维化在内的心脏纤维化、心内膜心肌纤维化、陈旧性心肌梗死、动脉硬化、动脉粥样硬化、再狭窄、关节纤维化、克罗恩氏病、骨髓纤维化、佩罗尼氏病、肾源性系统性纤维化、进行性大块纤维化、腹膜后腔纤维化、硬皮病/系统性硬化症、纵隔纤维化、瘢痕瘤和增生性瘢痕、神经胶质瘢痕、或肾纤维化。
在一个方面中,本发明提供了治疗细胞增殖性疾病或病症,例如癌症的方法,所述方法包括向需要这种治疗的受试者施用治疗有效量的式1化合物、其药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药,或其药物组合物或药物,其中所述细胞增殖性疾病或病症包括例如淋巴瘤、骨肉瘤、黑素瘤、乳腺癌,肾癌、前列腺癌、结直肠癌、甲状腺癌、卵巢癌、胰腺癌、神经元癌、肺癌、子宫癌或胃肠癌。在一个方面中,本发明提供了用本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或它们的任何组合,或本文所述的组合物来抑制癌细胞生长的方法。
在某些实施方式中,蛋白激酶介导的疾病或病症是炎性疾病或病症、呼吸系统疾病或自身免疫性疾病或病症,例如哮喘、慢性阻塞性肺病(chronic obstructivepulmonary disease,COPD)、成人呼吸窘迫综合征(adult respiratory distresssyndrome,ARDS)、溃疡性结肠炎、克罗恩氏病、支气管炎、皮炎、过敏性鼻炎、牛皮癣、硬皮病、荨麻疹、类风湿性关节炎、多发性硬化症、癌症、乳腺癌、HIV相关的疾病或狼疮。
在另一方面中,本发明提供了通过向受试者施用治疗有效量的本文所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或它们的任何组合,或本文所述的组合物来治疗神经性/神经退行性疾病或病症的方法。在某些实施方式中,此类神经性/神经退行性疾病或病症包括例如阿尔茨海默氏病、脑水肿、脑缺血、多发性硬化症、神经病、帕金森氏病、钝器或手术创伤(包括术后认知功能障碍和脊髓或脑干损伤),以及疾患的神经性方面,例如退变性椎间盘疾病和坐骨神经痛。
在另一方面中,本发明提供了通过向受试者施用治疗有效量的本文所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或它们的任何组合,或本文所述的组合物来治疗心血管疾病的方法。此类心血管疾病影响心脏或血管并且包括例如动脉粥样硬化、心律失常、心绞痛、心肌缺血、心肌梗塞、心脏或血管动脉瘤、脉管炎、中风、肢体、器官或组织的外周阻塞性动脉病、器官或组织缺血后的再灌注损伤、内毒素、手术或创伤性休克、高血压、瓣膜性心脏病、心力衰竭、血压异常、血管收缩、血管异常或炎症。
在另一方面中,本发明提供治疗癌症的方法,所述方法包括向有需要的受试者施用组合物,所述组合物包含治疗有效量的至少一种本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药以及治疗有效量的至少一种免疫检查点抑制剂,其中所述癌症是腺癌、肾上腺皮质癌、膀胱癌、骨癌、脑癌、乳腺癌、口腔癌、宫颈癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、表皮样癌、食道癌、眼癌、滤泡癌、胆囊癌、胃肠癌、泌尿生殖道癌、成胶质细胞瘤、毛细胞癌、头颈癌、肝肿瘤、肝细胞癌、霍奇金氏病、角化棘皮瘤、肾癌、大细胞癌、大肠癌、喉癌、肝癌、肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌、黑素瘤、骨髓增生性疾患、成神经细胞瘤、卵巢癌、乳头状癌、胰腺癌、腹膜癌、前列腺癌、直肠癌、唾液腺癌、肉瘤、鳞状细胞癌、小细胞癌、小肠癌、胃癌、睾丸癌、甲状腺癌、外阴癌,或它们的任何组合。所述检查点抑制剂的示例包括但不限于PD-1抑制剂、PD-L1抑制剂和CTLA-4抑制剂。
在另一方面中,本发明提供治疗癌症的方法,所述方法包括向有需要的受试者施用组合物,所述组合物包含治疗有效量的至少一种本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药以及治疗有效量的至少一种诱导免疫原性细胞死亡(ICD)的化学治疗剂,其中所述癌症是腺癌、肾上腺皮质癌、膀胱癌、骨癌、脑癌、乳腺癌、口腔癌、宫颈癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、表皮样癌、食道癌、眼癌、滤泡癌、胆囊癌、胃肠癌、泌尿生殖道癌、成胶质细胞瘤、毛细胞癌、头颈癌、肝肿瘤、肝细胞癌、霍奇金氏病、角化棘皮瘤、肾癌、大细胞癌、大肠癌、喉癌、肝癌、肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌、黑素瘤、骨髓增生性疾患、成神经细胞瘤、卵巢癌、乳头状癌、胰腺癌、腹膜癌、前列腺癌、直肠癌、唾液腺癌、肉瘤、鳞状细胞癌、小细胞癌、小肠癌、胃癌、睾丸癌、甲状腺癌、外阴癌,或它们的任何组合。诱导免疫原性细胞死亡(ICD)的化学治疗剂的示例包括但不限于多柔比星、伊达比星、米托蒽醌、互变霉素、海绵诱癌素A、沙鲁胺(salubrinal)、奥沙利铂、博莱霉素和环磷酰胺。
在使用本发明的化合物的上述方法中,将本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药施用于包含细胞或组织的系统。在某些实施方式中,将本文所述的化合物、其盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或它们的任何组合施用于人或动物受试者。在又某些实施方式中,将包含所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物、前药或它们的任何组合中的至少一者的药物组合物或药物施用于人或动物受试者。
4.制备化合物的方法
在另外的方面中,本发明提供了制备所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物和前药的方法。在一些实施方式中,所述化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药可通过包括但不限于以下方法中的一种或多种方法的方法制备:
(a)任选地将本发明的化合物转换成药学上可接受的盐;
(b)任选地将本发明的化合物的盐形式转换成非盐形式;
(c)任选地将本发明的化合物的未氧化形式转换成药学上可接受的N-氧化物;
(d)任选地从立体异构体的混合物中拆分出本发明的化合物的个别异构体;
(e)任选地将本发明的非衍生化合物转换成药学上可接受的前药衍生物;以及
(f)任选地将本发明的化合物的前药衍生物转换成其非衍生形式。
在本文中,描述了用于制备本发明的化合物的示例性方法,包括在实施例中,所述实施例将在下面详细描述。本发明的一些实施方式提供了制备本发明的化合物的方法,如在以下方法1至5中所示。
在无机碱(K2CO3、Na2CO3、Cs2CO3)或有机碱(三乙胺、二异丙基乙胺、吡啶)存在下,使双环化合物(2)与苄基溴(3)在有机溶剂(DMF、丙酮、乙腈或二氯甲烷)中于室温(RT)至100℃反应5-16小时以提供苄基双环中间体(4)。使用钯催化剂(Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4或Pd(dppf)Cl2.DCM),用Suzuki反应条件使所得中间体(4)与硼酸(5)或硼酸酯(6)反应,以提供化合物(1)。
在无机碱(K2CO3、Na2CO3或Cs2CO3)或有机碱(三乙胺、二异丙基乙胺或吡啶)存在下,使双环化合物(2)与苄基溴(7)在有机溶剂(DMF、丙酮、乙腈或二氯甲烷)中于RT至100℃反应5-16小时以提供苄基双环中间体(8)。于RT至80℃,使用碱(LiOH、NaOH或KOH)在水与溶剂(MeOH、THF)的混合物中将所得中间体(8)转换成苯甲酸(9)达3-20小时。在碱(三乙胺、二异丙基乙胺)存在下,在溶剂(DMF、THF、DCM)中于RT至60℃使苯甲酸与胺(10)通过偶联剂(EDCI、HATU、HBTU、PyBop或ByBrop)偶联达1-20小时,以得到化合物(11)。在无机碱(K2CO3、Na2CO3或Cs2CO3)存在下,使用钯催化剂(Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4或Pd(dppf)Cl2.DCM),用Suzuki反应条件使所得化合物(11)与硼酸(5)或硼酸酯(6)反应,以提供化合物(12)。
在无机碱(K2CO3、Na2CO3或Cs2CO3)存在下,使用钯催化剂(Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4或Pd(dppf)Cl2.DCM),用Suzuki反应条件使苄基双环酯(8)与硼酸(5)或硼酸酯(6)反应,以提供化合物(13)。于RT至80℃,使用碱(LiOH、NaOH或KOH)在水与溶剂(MeOH或THF)的混合物中将所得化合物(13)转换成其苯甲酸(14)达3-20小时。在碱(三乙胺、二异丙基乙胺)存在下,在溶剂(DMF、THF或DCM)中于RT至60℃使苯甲酸与胺(10)通过偶联剂(EDCI、HOBT、HBTU、PyBop或ByBrop)偶联达1-20小时以得到化合物(12)。
在无机碱(K2CO3、Na2CO3或Cs2CO3)存在下,使用钯催化剂(Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4或Pd(dppf)Cl2.DCM),用Suzuki反应条件使双环化合物(2)与硼酸(5)或硼酸酯(6)反应,以提供化合物15。在无机碱(K2CO3、Na2CO3或Cs2CO3)或有机碱(三乙胺、二异丙基乙胺或吡啶)存在下,使双环Suzuki加合物(15)与苄基溴(7)在有机溶剂(DMF、丙酮、乙腈或二氯甲烷)中于RT至100℃反应5-16小时,以提供苄基双环中间体(13)。
在无机碱(K2CO3、Na2CO3或Cs2CO3)或有机碱(三乙胺、二异丙基乙胺或吡啶)存在下,使双环化合物(2)与硝基苄基溴(16)在有机溶剂(DMF、丙酮、乙腈或二氯甲烷)中于RT至100℃反应5-16小时,以提供苄基双环中间体(17)。通过在溶剂(MeOH、EtOH、i-PrOH或EtOAc)中进行钯催化氢化,将所得中间体(17)转换成其氨基苄基双环(18)。在碱(三乙胺或二异丙基乙胺)存在下,在溶剂(DMF、THF或DCM)中于RT至60℃使所得化合物(18)与酸R7COOH通过偶联剂(EDCI、HOBT、HBTU、PyBop或ByBrop)偶联达1-20小时以得到化合物(19)。在无机碱(K2CO3、Na2CO3或Cs2CO3)存在下,使用钯催化剂(Pd(OAc)2、Pd2(dba)3、Pd(PPh3)4或Pd(dppf)Cl2.DCM),用Suzuki反应条件使所得化合物(19)与硼酸(5)或硼酸酯(6)反应以提供化合物(20)。
本文所述的化合物的非限制性示例可包括:
2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)-3,4-二氢异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-甲基-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-甲基-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(1-(3-羟基苯基)乙基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-甲基异噁唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(1-甲基-1H-吡唑-5-基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-甲基异噁唑-4-基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-羟基苄基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(1-(3-羟基苯基)乙基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(1-甲基-1H-吡唑-5-基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-氟-5-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-氟-5-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(1-(3-甲氧基苯基)乙基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-羟基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(1-(3-羟基苯基)乙基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(吡啶-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(吡啶-4-基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(1-(3-甲氧基苯基)乙基)异喹啉-1(2H)-酮;
3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
N-异丙基-3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-苯基苯甲酰胺;
N-苄基-3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-(甲基磺酰氨基)苄基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-氨磺酰基苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-(三氟甲氧基)苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4-(甲基磺酰氨基)苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(三氟甲氧基)苯基)苯甲酰胺;
N-(6-氟吡啶-3-基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-(1-甲基哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-(2,2-二氟乙基)哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-环丙基-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-甲基哌啶-4-基)甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-(氧杂环丁烷-3-基甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(6-氟吡啶-2-基)乙基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(哌啶-4-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(2-羟乙基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺盐酸盐;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
N-(环丙基甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,3R)-3-羟基环丁基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺盐酸盐;
[3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺盐酸盐;
N-((1-环丙基哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-异丙基哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-(3,3-二氟烯丙基)哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-((1-(2,2二氟乙基)哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异噁唑-3-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异色满-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异色满-7-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(5-异丙基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-异丙基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-7-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-羟乙基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
N-(1-(2,2-二氟乙基)哌啶-4-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-((3-羟基环丁基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基氮杂环丁烷-3-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((2-氟吡啶-4-基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-异丙基哌啶-4-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(二甲基氨基)乙基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-甲氧基乙基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-7-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-氟-N-(1-甲基哌啶-4-基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-环丙基-3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-N-(氧杂环丁烷-3-基甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,3S)-3-羟基环丁基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,3R)-3-羟基环丁基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4R)-4-甲氧基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-甲氧基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-异丙基哌啶-4-基)甲基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-氟-N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(5-异丙基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-7-基)-3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-氟-N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-((3-羟基环丁基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基氮杂环丁烷-3-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-异丙基哌啶-4-基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-(2-(二甲基氨基)乙基)-3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(2-氟吡啶-4-基)乙基)-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-苄基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(萘-2-基甲基)苯甲酰胺;
N-(2-(氨基甲基)苄基)-3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(羟甲基)苄基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-苯乙基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1R,4R)-4-羟基环己基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异色满-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异色满-7-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-环戊基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1H-咪唑-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基-1H-吡唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(1-甲基-1H-吡唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异噁唑-5-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异噁唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(异噁唑-3-基)苯甲酰胺;
N-(异噁唑-5-基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-氟-N-((1S,3S)-3-羟基环丁基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,3R)-3-羟基环丁基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1-甲基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-(2,2-二氟乙基)哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-异丙基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-异丙基哌啶-4-基)甲基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
N-甲基-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((8-氧代-3-(5-(三氟甲基)-1H-吡唑-4-基)-1,7-萘啶-7(8H)-基)甲基)苯甲酰胺;
N-甲基-3-((3-(3-甲基异噁唑-4-基)-8-氧代-1,7-萘啶-7(8H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(2-甲基呋喃-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(5-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-乙基-3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(氧杂环丁烷-3-基甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-甲基哌啶-4-基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1R,4R)-4-羟基环己基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-异丙基苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-(吡啶-3-基)乙基)苯甲酰胺;
3-((6-(3-溴-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-异丙基苯甲酰胺;
3-((6-(3-溴-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-((4-氯-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-d3)-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
N-(甲基-d3)-3-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-5-氟-N-甲基苯甲酰胺;
3-(1-(6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-5-(1-(6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2,5-二氢呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((1-氧代-6-(1H-吡咯-3-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-((4-氯-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-6-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)甲基吡啶酰胺;
N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)烟酰胺;
N-甲基-4-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)甲基吡啶酰胺;
2-氟-N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-氯-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氯-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-氟-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-1,2,3-三唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(6-氧杂-3-氮杂双环[3.1.1]庚-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
(S)-N-甲基-3-((6-(2-甲基吗啉代)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(3-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-氟-5-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(2-氟-5-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)异丁酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)-3-(吡啶-2-基)丙烯酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)烟酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)苯甲酰胺;
N-(3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
4-氟-N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)苯甲酰胺;
N-(3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)甲基吡啶酰胺;
N-(3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟苯基)乙酰胺;
3-(3-甲氧基苄基)-7-(1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(1-甲基-1H-吡唑-5-基)喹唑啉-4(3H)-酮;
7-(3-(二氟甲基)-1H-吡唑-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-(二氟甲基)-1H-吡唑-4-基)-3-(3-氟-5-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-氯-1H-吡唑-4-基)-3-(3-氟-5-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-氯-1H-吡唑-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮;
7-(2-氨基吡啶-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
(R)-7-(2-氨基吡啶-4-基)-3-(1-(3-甲氧基苯基)乙基)喹唑啉-4(3H)-酮;
N-甲基-3-((4-氧代-7-(1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-异丙基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-4-基)乙基)苯甲酰胺;
N-苄基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(吡啶-4-基甲基)苯甲酰胺;
N-(4-(甲基磺酰氨基)苄基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(异噁唑-3-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(1-甲基哌啶-4-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-(氧杂环丁烷-3-基甲基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(2-羟乙基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(4-(甲基磺酰氨基)苯基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-d3)-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-羟乙基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((2-氟吡啶-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(甲基磺酰基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(甲基磺酰氨基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(二甲基氨基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-5-氟-N-(甲基-D3)苯甲酰胺;
5-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基烟酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
N-甲基-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-异丙基-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-3-基)乙基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-氟-N-甲基-5-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-D3)-5-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1R,3R)-3-羟基环丁基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-(2-羟乙基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-甲基-3-((7-(1-甲基-1H-1,2,3-三唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
(R)-N-甲基-3-(1-(7-(5-甲基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(S)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-异丙基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-(吡啶-4-基甲基)苯甲酰胺;
(R)-N-(异噁唑-3-基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
(R)-N-(1-甲基哌啶-4-基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
(R)-N-(氧杂环丁烷-3-基甲基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(2-羟乙基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-氟-N-(甲基-d3)-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-2-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-(D)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-羟乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-5-氟-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-d3)苯甲酰胺;
(S)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(哌啶-4-基甲基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-吗啉代乙基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2,2,2-三氟乙基)苯甲酰胺;
(R)-N-甲基-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((R)-1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
(R)-N-(2-羟乙基)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(3-氯苯基)-2-羟乙基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮;
7-(2-氨基吡啶-4-基)-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
7-(5-氯-1H-吡唑-4-基)-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
7-(5-氯-1H-吡唑-4-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(2-氨基吡啶-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-氯-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-氯-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(2-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(3-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
3-((7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((6-(5-溴-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-溴-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(4-氟苯基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-7-(5-氯-1H-吡唑-4-基)-3-(1-(3-氯苯基)-2-羟乙基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(1-甲基-1H-吡唑-5-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(吡啶-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-甲基异噁唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-7-(5-氯-1H-吡唑-4-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(1-甲基-1H-吡唑-5-基)-2,3-二氢喹唑啉-4(1H)-酮;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1l2-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-环丙基-3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-环丙基-3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟丙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((4-(2-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氟-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氟-1H-吡咯-3-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟丙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-4-(2-(二甲氨基)乙基)-1-氧代异喹啉-2(1H基)乙基)-N-甲基苯甲酰胺;
3-((4-(2-(二甲基氨基)乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(2-(二甲基氨基)乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氟-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-甲氧基-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酰胺;
(R)-(4-(3-(1-(3-(甲基氨基甲酰基)苯基)乙基)-4-氧代-3,4-二氢喹唑啉-7-基)-5-(三氟甲基)-1H-吡唑-1-基)甲基磷酸二氢盐;或者
(R)-(4-(3-(1-(3-(甲基氨基甲酰基)苯基)乙基)-4-氧代-3,4-二氢喹唑啉-7-基)-5-(三氟甲基)-1H-吡唑-1-基)甲基磷酸二钠。
下面是代表本发明的不同方面的实施例。此类实施例不应被解释为限制本公开的范围。对于本领域的技术人员来说,本发明范围内的替代机制路径和类似结构将是显而易见的。实施例中的要素和动作旨在为了简单起见来说明本发明,并且不一定根据任何特定顺序或实施方式来呈现。
实施例
本发明通过以下实施例进一步举例说明。所述实施例仅用于说明目的并且并不旨在限制本发明,也不应被解释为以任何方式限制本发明。本领域的技术人员应理解,可以在不改变本发明的范围的情况下进行变化和修改。
实施例1:化合物的制备
所获得的以下实施例中描述的化合物和本文所述的化合物的核磁共振(nuclearmagnetic resonance,NMR)和质谱(mass spectrometry,MS)光谱与本文所述式的化合物的NMR和MS光谱一致。
液相色谱-质谱(liquid chromatography-mass spectrometry,LC-MS)法:
1.将样品在具有在室温下以1.5mL/分钟的流率运行的Zorbax Eclipse XDB-C18(3.5μ)反相柱(4.6×50mm)的Agilent Technologies6120MSD系统上运行。
2.流动相使用溶剂A(水/0.1%甲酸)和溶剂B(乙腈/0.1%甲酸):95%/5%至0%/100%(A/B)持续5分钟。
3.使用电喷雾电离(electrospray ionization,ESI)记录质谱(m/z)。
4.将电离数据四舍五入为最接近的整数。
质子NMR光谱:
除非另有说明,否则所有1H NMR光谱均在Varian系列Mercury300或400MHz上运行。使用用于指定主峰的常规缩写:例如s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)和brs(宽单态),所有观察到的质子都报告为来自四甲基硅烷的低场的百万分率(ppm)。
化合物1:2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)-3,4-二氢异喹啉-1(2H)-酮
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步骤1:将6-溴-3,4-二氢异喹啉-1(2H)-酮(226mg,1.0mmol)在DMF(1.5mL)中的溶液冷却至0℃,并加入55%NaH(52mg,1.2mmol)。然后将混合物在0℃下搅拌30分钟。在0℃将3-甲氧基苄基溴(240mg,1,2mmol)在DMF(0.5mL)中的溶液缓慢加入到混合物中,然后将所述混合物加温至室温(RT)并振荡1小时。将反应用饱和NH4Cl水溶液猝灭并用EtOAc萃取两次。将合并的有机层依次用水和盐水洗涤,干燥(Na2SO4),过滤,浓缩,并通过硅胶柱色谱法纯化,以提供产率为57%的6-溴-2-(3-甲氧基苄基)-3,4-二氢异喹啉-1(2H)-酮。LC/MS实测值346.0[M+H]+。
步骤2:将6-溴-2-(3-甲氧基苄基)-3,4-二氢异喹啉-1(2H)-酮(180mg,0.52mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(131mg,1.3当量)、Na2CO3(175mg)和Pd(dppf)Cl2·CH2Cl2(18mg)在1,4-二噁烷(1.0mL)和H2O(0.2mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用0-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为60%的呈无色固体的化合物1(103mg)。LC/MS实测值334.1[M+H]+。
一般方案1
化合物2:2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮
方案1
步骤1:将6-溴代异喹啉-1(2H)-酮(223mg,1.00mmol)的DMF(1.5mL)溶液冷却至0℃,并加入55%的NaH(1.2当量)。然后将混合物在0℃下搅拌30分钟。在0℃将3-甲氧基苄基溴(1.2当量)在DMF(0.5mL)中的溶液缓慢加入到所述混合物中,然后将所述混合物加温至RT并振荡1小时。将反应用饱和NH4Cl水溶液猝灭并用EtOAc萃取两次。将合并的有机层依次用水和盐水洗涤,经Na2SO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供产率为80%的6-溴-2-(3-甲氧基苄基)-异喹啉-1(2H)-酮(275mg)。LC/MS实测值344.0[M+H]+。
步骤2:将6-溴-2-(3-甲氧基苄基)-异喹啉-1(2H)-酮(68mg,0.2mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(50mg,1.3当量)、Na2CO3(65mg)和Pd(dppf)Cl2·CH2Cl2(8mg)在1,4-二噁烷(1.0mL)和H2O(0.2mL)中的混合物经由用氩气喷射10分钟脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用0-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为53%的呈无色固体的化合物2(35mg)。LC/MS实测值332.1[M+H]+。
化合物3:2-(3-羟基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮
在0℃向化合物2(20mg,0.06mmol)在DCM(3mL)中的溶液中缓慢加入BBr3(2当量)。将反应混合物在RT下搅拌22小时,倒在H2O上,并用DCM萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用5-30%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为70%的呈无色固体的化合物3(13mg)。LC/MS实测值318.1[M+H]+。
下表1中的化合物4至25通过与上文针对化合物2和化合物3的制备所述的方法相似的方法(一般方案1),使用合适的硼酸和合适的6-溴-2-(3-甲氧基苄基)-异喹啉-1(2H)-酮制备。
表1
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一般方案2
化合物27:(3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺)
步骤1:将6-溴异喹啉-1(2H)-酮(674mg,3.00mmol)、3-(溴甲基)苯甲酸甲酯(1.05g,4.60mmol)、Na2CO3(1.59g,15.0mmol)和NaI(97mg,0.65mmol)在丙酮(30mL)中的混合物在搅拌下加热至回流过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用10-40%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为79%的呈暗黄色固体的中间体1,3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸甲酯(928mg,2.49mmol)。LC/MS实测值372.0[M+H]+。
步骤2:将中间体1(740mg,2.0mmol)、4-吡唑硼酸、频哪醇酯(630mg,3.0mmol)、Na2CO3(700mg,0.66mmol)和Pd(PPh3)2Cl2(57mg,81μmol)在1,4-二噁烷(15mL)和H2O(5mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用CH2Cl2萃取。将有机层用H2O洗涤,用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用1-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为53%的呈白色固体的中间体2(380mg)。LC/MS实测值360.3[M+H]+。
步骤3:将中间体2(380mg,1.1mmol)和LiOH·H2O(480mg,11mmol)在CH3OH(40mL)和H2O(10mL)中的混合物在RT下搅拌过夜。将所述混合物用1N HCl酸化至pH 2。将所得沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为80%的呈白色固体的3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酸(中间体3)(303mg)。LC/MS实测值346.2[M+H]+。
步骤4:将中间体3(35mg,0.1mmol)、HBTU(57.2mg,0.15mmol)、i-Pr2NEt(0.52mL,0.3mmol)和2-(吡啶-2-基)乙-1-胺(0.16mL)的CH2Cl2(3mL)溶液在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用5-30%的MeOH在CH2Cl2中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为90%的呈白色固体的(3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺),化合物27(40.5mg)。LC/MS实测值450.3[M+H]+。
下表2中的化合物28至230是通过与针对化合物27的制备所述的方法相似的方法(一般方案2),使用3-(溴甲基)苯甲酸甲酯、合适的硼酸/酯和合适的胺制备的。
表2
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一般方案3
化合物231:N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺
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步骤1:将6-溴-2,7-萘啶-1(2H)-酮(674mg,3.00mmol)、3-(溴甲基)苯甲酸甲酯(1.05g,4.60mmol)、Na2CO3(1.59g,15.0mmol)和NaI(97mg,0.65mmol)在丙酮(30mL)中的混合物在搅拌下加热至回流过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用10-40%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为95%的呈黄色固体的3-((6-溴-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酸甲酯(1.06g)。LC/MS实测值374.2[M+H]+。
步骤2:将3-((6-溴-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酸甲酯(380mg,1.1mmol)和LiOH·H2O(480mg,11mmol)在CH3OH(40mL)和H2O(10mL)中的混合物在RT下搅拌过夜。将所述混合物用1N HCl酸化至pH 2。将所得沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为85%的呈白色固体的3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酸(336mg)。LC/MS实测值359.2[M+H]+。
步骤3:将3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酸(72mg,0.2mmol)、HBTU(120mg,0.30mmol)、i-Pr2NEt(1.0mL,0.6mmol)和1M甲胺的THF(1mL)溶液在CH2Cl2(3mL)中的混合物在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用0-30%的MeOH在CH2Cl2中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为80%的呈白色固体的3-((6-溴-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺(59.5mg)。LC/MS实测值372.3[M+H]+。
步骤4:将甲基3-((6-溴-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺(37mg,0.1mmol)、42-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯(31mg,0.15mmol)、Na2CO3(32mg,0.3mmol)和Pd(PPh3)2Cl2(6mg)在1,4-二噁烷(2mL)和H2O(0.4mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用CH2Cl2萃取。将有机层用H2O洗涤,用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用0-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为60%的呈白色固体的化合物231(22.3mg)。LC/MS实测值373.3[M+H]+。
下表3中的化合物232至252是通过与针对化合物231的制备所述的方法相似的方法(一般方案3),使用3-(溴甲基)苯甲酸甲酯、合适的硼酸/酯和合适的胺制备的。
表3
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一般方案4
下表4中的化合物253至276是通过与针对化合物27的制备所述的方法相似的方法(一般方案4),使用3-(溴甲基)苯甲酸甲酯、合适的硼酸/酯和合适的胺制备的。
表4
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一般方案5
化合物277:N-甲基-3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺
步骤1:将来自方案2的中间体1(450mg,1.1mmol)和LiOH·H2O(480mg,11mmol)在CH3OH(8mL)和H2O(4mL)中的混合物在RT下搅拌过夜。将所述混合物用1M HCl酸化至pH2。将所得沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为69%的呈淡黄色固体的3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(中间体4)(285mg)。LC/MS实测值358.1[M+H]+。
步骤2:将3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(366mg,1.02mmol)、HBTU(572mg,1.50mmol)、i-Pr2NEt(0.52mL,3.0mmol)和CH3NH2(2.0M的THF溶液,1.0mL,2.0mmol)在CH2Cl2(10mL)中的混合物在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供定量产率的呈白色固体的3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(中间体5)(379mg)。LC/MS实测值370.9[M+H]+。
步骤3:将3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(77mg,0.2mmol)、(3-甲基异噁唑-4-基)硼酸(39mg,0.30mmol)、Na2CO3(70mg,0.66mmol)和PdCl2(PPh3)2(5.7mg,8.1μmol)在1,4-二噁烷(1.5mL)和H2O(0.5mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用10%i-PrOH的CH2Cl2溶液萃取。将合并的有机层依次用H2O和盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用1-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为70%的呈白色固体的化合物277(52.1mg)。LC/MS实测值374.2[M+H]+。使用以下替代方法制备化合物277。
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一般方案6
步骤1:将6-溴异喹啉-1(2H)-酮(4.48g,20mmol)、(3-甲基异噁唑-4-基)硼酸(7.86g,30mmol)、Na2CO3(6.3g,60mmol)和PdCl2(PPh3)2(700mg,1.0mol)在1,4-二噁烷(30mL)和H2O(6.0mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至室温并倒在H2O上以形成沉淀物。所得沉淀物通过过滤收集,用水洗涤,然后用高真空干燥,以提供呈淡黄色固体的6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮(3.34g,73%)。LC/MS实测值227.1[M+H]+。
步骤2:将6-(3-甲基异噁唑-4-基)异喹啉-1(2H)-酮(228.0mg,1.0mmol)、3-(溴甲基)苯甲酸甲酯(0.34g,1.5mmol)、Na2CO3(0.53g,3.0mmol)和NaI(30mg,0.2mmol)在丙酮(10mL)中的混合物在搅拌下加热至回流过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用10-40%EtOAc在庚烷中的梯度的硅胶柱色谱法纯化残余物,以提供产率为90%的呈黄色固体的3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸甲酯(337mg)。LC/MS实测值375.2[M+H]+。
步骤3:将3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸甲酯(337,0.9mmol)和LiOH·H2O(380mg,9.0mmol)在CH3OH(40mL)和H2O(10mL)中的混合物在RT下搅拌过夜。将所述混合物用1N HCl酸化至pH 2。将所得沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为85%的3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(276mg)。LC/MS实测值361.1[M+H]+。
步骤4:将3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(82mg,0.2mmol)、HBTU(108mg,0.30mmol)、i-Pr2NEt(1.0mL,0.6mmol)和1M甲胺的THF(1mL)溶液在CH2Cl2(3mL)中的混合物在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用0-30%的MeOH在CH2Cl2中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为90%的呈白色固体的化合物277,N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉)-2(1H)-基)甲基)苯甲酰胺(100.8mg)。LC/MS实测值374.2.1[M+H]+。
1H NMR(400MHz,DMSO-d6)δ9.30(s,1H),8.42(m,1H),8.27(d,1H,J=8.4Hz),7.84(d,1H,J=1.5Hz),7.78(s,1H),7.72(dt,1H,J=7.3,1.5Hz),7.68(dd,1H,J=8.4,1.8Hz),7.63(d,1H,J=7.3Hz),7.43(m,2H),6.71(d,1H,J=7.4Hz),5.24(s,2H),2.75(d,3H,J=4.5Hz),2.47(s,3H)。
下表5中的化合物278至327是通过上述方法(方案4或5)使用针对化合物277的制备所述的反应条件制备的。
表5
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一般方案7
化合物328:N-甲基-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺
将中间体5(方案5)3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(75mg,0.2mmol)、吗啉(26mg,0.3mmol)、NaOBut(58mg,0.6mmol)、Binap(10mol%)和Pd2(bda)3(5mol%)在甲苯(3mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将合并的有机层用H2O洗涤,用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用1-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为85%的呈白色固体的化合物328(64mg)。LC/MS实测值378.2[M+H]+。
下表6中的化合物329-331是使用中间体5和合适的胺通过针对化合物328的制备描述的Buckwald反应条件制备的。
表6
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一般方案8
化合物332:N-(3-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺
步骤1:从1-(溴甲基)-3-硝基苯(1.2g,5.5mmol)和6-溴异喹啉-1(2H)-酮(1.12g,5mmol)开始并使用中间体1的制备的步骤1,获得了6-溴-2-(3-硝基苄基)异喹啉-1(2H)-酮(1.6g,95%)。LC/MS实测值359.0[M+H]+。
步骤2:将6-溴-2-(3-硝基苄基)异喹啉-1(2H)-酮(530mg,1.48mmol)和SnCl2(839mg,4.5mmol)在EtOH(20mL)中的悬浮液在70℃下振荡3小时。将混合物用冰浴冷却并用水稀释。将混合物在0℃下用1N NaOH溶液中和,然后搅拌30min。将悬浮液过滤,然后将粗产物在CH2Cl2中重悬。将混合物经MgSO4干燥,过滤并浓缩,以提供2-(3-氨基苄基)-6-溴异喹啉-1(2H)-酮。LC/MS实测值329.1[M+H]+。
步骤3:将2-(3-氨基苄基)-6-溴异喹啉-1(2H)-酮(330mg,1.0mmol)、HBTU(572mg,1.50mmol)、i-Pr2NEt(0.52mL,3.0mmol)和乙酸(140mg,2.0mmol)在CH2Cl2(10mL)中的混合物在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为90%的呈白色固体的N-(3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺(340mg)。LC/MS实测值371.5[M+H]+。
步骤4:从N-(3-((6-溴-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺(170mg,0.45mmol)和4,4,5,5-四甲基-2-(2-甲基呋喃-3-基)-1,3,2-二氧杂环戊硼烷开始并使用化合物27的制备的步骤4,合成呈白色固体的化合物332(65mg,35%产率)。LCMS实测值373.2[M+H]+。
下表7中的化合物333至353是通过与针对化合物332的制备所述的方法相似的方法(一般方案8),使用合适的2-(3-氨基苄基)-6-溴异喹啉-1(2H)-酮、合适的硼酸/酯和合适的酸制备的。
表7
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一般方案9
化合物354:3-(3-甲氧基苄基)-7-(1H-吡唑-4-基)喹唑啉-4(3H)-酮
步骤1:将7-溴代喹唑啉-4(3H)-酮(224mg,1.0mmol)、3-甲氧基苄基溴(300mg,1.5mmol)、K2CO3(530mg,5.0mmol)和NaI(30mg,0.20mmol)在丙酮(10mL)中的混合物在搅拌下加热至回流过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用10-50%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为80%的呈白色固体的7-溴-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮(276mg)。LC/MS实测值345.0[M+H]+。
步骤2:将7-溴-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮(41mg,0.12mmol)、4-吡唑硼酸、频哪醇酯(35mg,0.18mmol)、Na2CO3(43mg,0.41mmol)和Pd(dppf)Cl2·CH2Cl2(4.8mg,6.0μmol)在1,4-二噁烷(1.0mL)和H2O(0.2mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用5-10%的CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为54%的呈无色固体的化合物354(21mg)。LC/MS实测值333.1[M+H]+。
下表8中的化合物355至365是通过与针对化合物355的制备所述的方法类似的方法(一般方案9),使用适当的7-溴-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮和适当的硼酸/酯制备的。
表8
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一般方案10
化合物366:N-甲基-3-((4-氧代-7-(1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺
步骤1:向两个40mL的小瓶中各自装填7-溴代喹唑啉-4(3H)-酮(450mg,2.0mmol)、3-(溴甲基)苯甲酸甲酯(687mg,3.0mmol)、碳酸钾(1.38g,10mmol)、碘化钠(45mg,0.30mmol)和丙酮(9.0mL)。将小瓶在45℃下振荡过夜。合并混合物,用EtOAc(250mL)稀释,依次用水和盐水(各自250mL)洗涤,干燥(Na2SO4),用硅胶处理,并减压蒸发。将所得物质通过硅胶柱色谱法纯化,以提供3-((7-溴-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酸甲酯(1.23g,82%产率)。LC/MS实测值373.0[M+H]+。
步骤2:将中间体2(1.23g。3.3mmol)和LiOH·H2O(33mmol)在CH3OH(20mL)和H2O(10mL)中的混合物在RT下搅拌过夜。将所述混合物用1M HCl酸化至pH 2。将所得沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为85%的呈淡黄色固体的3-((7-溴-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酸(1.01g)。LC/MS实测值359.1[M+H]+。
步骤3:将3-((7-溴-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酸(366mg,1.0mmol)、HBTU(572mg,1.5mmol)、i-Pr2NEt(0.52mL,3.0mmol)和CH3NH2(2.0M的THF溶液,1.0mL,2.0mmol)在CH2Cl2(10mL)中的混合物在RT下搅拌过夜。将混合物倒在H2O上,并用CH2Cl2萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%EtOAc在庚烷中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供定量产率的呈白色固体的3-((7-溴-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺(379mg)。LC/MS实测值372.2[M+H]+。
步骤4:将3-((7-溴-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺(74mg,0.20mmol)、4-吡唑硼酸频哪醇酯(57mg,0.30mmol)、Na2CO3(65mg,0.6mmol)和Pd(dppf)Cl2·CH2Cl2(8.0mg,10.0μmol)在1,4-二噁烷(1.0mL)和H2O(0.2mL)中的混合物经由用氩气喷射10分钟进行脱气,然后加热至100℃过夜。将混合物冷却至RT,倒在H2O上,并用EtOAc萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用5-10%CH3OH在CH2Cl2中的梯度的快速柱色谱法纯化残余物,以提供产率为60%的呈无色固体的化合物366,N-甲基-3-((4-氧代-7-(1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺(43mg)。LC/MS实测值360.1[M+H]+。
下表9中的化合物367至439是通过与针对化合物366的制备所述的方法类似的方法(一般方案10),使用适当的硼酸/酯和适当的胺制备的。
表9
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一般方案11
化合物440:(R)-N-甲基-3-(1-(7-(5-甲基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺
步骤1:将2-氨基-4-溴苯甲酸(2.40g,11mmol)、HBTU(4.94g,13mmol)和DIEA(6.8mL)在DMF(30mL)中的混合物在环境温度下振荡30分钟。将所述混合物用(R)-3-(1-氨基乙基)苯甲酸甲酯(1.80g,10mmol)处理并在室温下振荡过夜。将反应混合物用EtOAc和盐水稀释。将有机层分离出,依次用水和盐水洗涤,干燥(MgSO4),浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(2-氨基-4-溴苯甲酰氨基)乙基)苯甲酸甲酯(3.31g,88%产率)。LC/MS实测值377.0[M+H]+。
步骤2:将(R)-3-(1-(2-氨基-4-溴苯甲酰氨基)乙基)苯甲酸酯(3.31g,8.8mmol)和p-TsOH-H2O(23mg,1.3mmol)在纯原甲酸三乙酯(30mL)中的悬浮液在80℃下振荡过夜。将混合物用EtOAc稀释,依次用饱和NaHCO3水溶液和盐水洗涤,干燥(Na2SO4),过滤,浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(4-溴-N-甲基-2-(亚甲基氨基)苯甲酰氨基)乙基)苯甲酸甲酯(2.8g,82%产率)。LC/MS实测值[M+H]+。
步骤3:将2M LiOH水溶液(36mL,72mmol)加入到(R)-3-(1-(4-溴-N-甲基-2-(亚甲基氨基)苯甲酰氨基)乙基)苯甲酸甲酯(2.8g,7.2mmol)在MeOH(70mL)中的悬浮液中,然后将混合物在RT下振荡过夜。将混合物用1N HCl水溶液酸化至pH 2-4,用DCM萃取。将有机层干燥(Na2SO4)、浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(7-溴-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酸(2.06g,77%产率)。LC/MS实测值373.0[M+H]+。
步骤4:将(R)-3-(1-(7-溴-4)-氧代喹唑啉-3(4H)-基)乙基)苯甲酸(373mg,1mmol)、HBTU(1.5当量)和DIEA(2.0当量)在DMF(3mL)中的混合物在环境温度下振荡30分钟。将混合物用2M甲胺(1mL)的THF溶液处理并在室温下振荡过夜。将反应混合物用EtOAc和盐水稀释。将有机层分离出,依次用水和盐水洗涤,经Na2SO4干燥,浓缩,并通过硅胶柱色谱法纯化,以提供甲基(R)-3-(1-(7-溴-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(193mg,50%产率)。LCMS实测值386.1[M+H]+。
步骤5:将(R)-3-(1-(7-溴-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(39mg,0.1mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5-(三氟甲基)-1H-吡唑(39mg,1.5mmol)、2M碳酸钠水溶液(150uL,3.0当量)和PdCl2(PPh3)2(10.5mg,0.1当量)在二噁烷(2mL)中的混合物用氩气吹扫5分钟。将混合物在70℃下振荡过夜。过滤样品,然后将滤液减压蒸发。将该物质通过硅胶柱色谱法纯化,以提供呈淡黄色固体的化合物440,(R)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑)-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺(21.1mg,48%)。LC/MS实测值442.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ13.94(br.s,1H),8.45(m,3H),8.20(d,1H,J=8.30Hz),7.85(m,1H),7.76(d,1H,J=7.7Hz),7.73(d,1H,J=1.6Hz),7.63(dd,1H,J=8.3,1.6Hz),7.56(d,1H,J=7.9Hz),7.46(t,1H,J=7.7Hz),6.13(q,1H,J=7.2Hz),2.77(d,3H,J=4.6Hz),1.88(d,3H,J=7.2Hz)。
下表10中的化合物441至482是通过针对化合物440的制备所述的方法类似的方法(一般方案11),使用3-(1-(6-溴-1-氧代异喹啉-2(1H)-基)乙基)苯甲酸、适当的硼酸/酯和适当的胺制备的。
表10
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一般方案12
化合物483:3-(1-(3-氯苯基)-2-羟乙基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮
步骤1:将2-氨基-4-溴苯甲酸(640mg,3mmol)、2-氨基-2-(3-氯苯基)乙-1-醇(0.56g,3.3mmol)、HBTU(1.45g)和DIEA(0.55mL)在DMF(20mL)中的混合物在环境温度下振荡2小时。将反应混合物用EtOAc和盐水稀释。将有机层分离出,依次用水和盐水洗涤,干燥(MgSO4),浓缩,并通过硅胶柱色谱法纯化,以提供甲基2-氨基-4-溴-N-(1-(3-氯苯基)-2-羟乙基)苯甲酰胺(943mg,85%)。LC/MS实测值369.5[M+H]+。
步骤2:将2-氨基-4-溴-N-(1-(3-氯苯基)-2-羟乙基)苯甲酰胺(900mg,2,4mmol)和p-TsOH-H2O(0.15当量)在纯原甲酸三乙酯(20mL)中的溶液在80℃下振荡过夜。将反应混合物用EtOAc稀释,依次用饱和NaHCO3水溶液和盐水洗涤,用MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供7-溴-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮(684mg,75%)。LC/MS实测值379[M+H]+。
步骤3:将7-溴-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮(80mg,0.2mmol)、吡啶-4-基硼酸(37mg,0.3mmol)、2M碳酸钠水溶液(3.0当量)和PdCl2(PPh3)2(0.1当量)在二噁烷(3mL)中的混合物用氩气吹扫5分钟。将混合物在70℃下振荡过夜。将反应混合物用EtOAc稀释,依次用饱和NaHCO3水溶液和盐水洗涤,用MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供化合物483,3-(1-(3-氯苯基)-2-羟乙基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮(34mg,45%)。LC/MS实测值378.4[M+H]+。
下表11中的化合物484至491是通过针对化合物483的制备所述的方法类似的方法(一般方案12),使用合适的7-溴-(2-羟乙基)喹唑啉-4(3H)-酮和适当的硼酸/酯制备的。
表11
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一般方案13
化合物492:3-(2-氨基-1-(3-氯苯基)乙基)-7-(2-氟吡啶-4-基)喹唑啉-4(3H)-酮
步骤1:将7-溴-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮(381mg,1.0mmol)在DCM(10mL)中的溶液冷却至0℃,然后在0℃将TEA(2.0当量)和甲磺酰氯(1.2当量)加入到混合物中。在0℃下3小时后,将混合物用饱和NH4Cl水溶液猝灭,然后用CH2Cl2萃取两次。将合并的有机层经MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供呈淡褐色固体的2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙基甲磺酸盐(434mg,95%)。LC/MS实测值457.0[M+H]+。
步骤2:将2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙基甲磺酸盐(292mg,0.64mmol)和叠氮化钠(127mg,1.92mmol)在DMF(3mL)中的混合物在RT下振荡3天。将混合物用EtOAc稀释并依次用水和盐水洗涤。将有机层经MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供3-(2-叠氮基-1-(3-氯苯基)乙基)-7-溴代喹唑啉-4(3H)-酮(200mg,61%)。LC/MS实测值404.0[M+H]+。
步骤3:将3-(2-叠氮基-1-(3-氯苯基)乙基)-7-溴代喹唑啉-4(3H)-酮(110mg,0.27mmol)和10%Pd/C(10mg)在甲醇(3mL)中的悬浮液在氢气下于环境温度下振荡过夜。将混合物滤过硅藻土,并将硅藻土用MeOH洗涤。将滤液减压蒸发。将残余物悬浮于CH2Cl2(3mL)中并冷却至0℃。将混合物用TEA(74μL)和Boc2O(68mg,0.32mmol)处理并在0℃下搅拌2小时。将混合物用CH2Cl2和盐水稀释。将有机层分离出,经MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供(2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙基)氨基甲酸叔丁酯(39mg,30%)。LC/MS实测值378.0[M-99(Boc)]+。
步骤4:从(2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙基)氨基甲酸叔丁酯(38mg,0.10mmol)和3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(36mg,0.16mmol)开始并使用Suzuki反应条件,合成了(2-(3-氯苯基)-2-(7-(2-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)氨基甲酸叔丁酯(41mg,83%)。LC/MS实测值395.1[M-99(Boc)]+。
步骤5:向(2-(3-氯苯基)-2-(7-(2-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)氨基甲酸叔丁酯(41mg,0.08mmol)在DCM(3mL)中的溶液中加入4M HCl在二噁烷中的溶液(0.2mL)。在室温下3小时后,去除挥发物,以得到呈浅棕色固体的化合物492,3-(2-氨基-1-(3-氯苯基)乙基)-7-(2-氟吡啶-4-基)喹唑啉-4(3H)-酮盐酸盐。LC/MS实测值395.1[M+H]+。
下表12中的化合物493至504是通过针对化合物492的制备所述的方法类似的方法(一般方案13),使用合适的7-溴-(2-羟乙基)喹唑啉-4(3H)-酮和适当的硼酸/酯制备的。
表12
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一般方案14
化合物505:3-(2-氨基-1-(7-(3-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺
将化合物502,3-(2-氨基-1-(7-(2-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苄腈(12mg,0.03mmol)在MeOH(2mL)中的悬浮液用2N碳酸钾水溶液(0.2当量)和30%H2O2(3.0当量)处理。将混合物在50℃下振荡2小时。将混合物浓缩,重悬于水中,并用DCM萃取两次。将合并的有机层经MgSO4干燥,过滤,浓缩,并通过硅胶柱色谱法纯化,以提供呈透明油状物的化合物505,3-(2-氨基-1-(7-(3-氟苯基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺(4.4mg,35%)。LC/MS实测值404.1[M+H]+。
下表13中的化合物506至508是通过针对化合物505的制备所述的反应条件,分别使用化合物501、503和504制备的。
表13
一般方案15
化合物509:(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺
步骤1:在RT下将4-甲苯磺酰氯(9.38g,53.7mmol)加入到4-溴-1H-吡唑-5-胺(4.35g,26.9mmol)在CH2Cl2(50mL)和吡啶(0.5mL)中的混合物中。在搅拌3小时后,将混合物用DCM稀释并用饱和NH4Cl水溶液洗涤。将合并的有机层经Na2SO4干燥,浓缩,并通过柱色谱法纯化,以提供合成的目标化合物4-溴-1-甲苯磺酰基-1H-吡唑-5-胺(12.02g,69%)。LC/MS实测值316.1/318.1[M+H]+。
步骤2:将4-溴-1-甲苯磺酰基-1H-吡唑-5-胺(5.95g,18.8mmol)、双(频哪醇合)二硼(7.17g,28.2mmol)、乙酸钾(4.62g,47.05mmol)悬浮在无水二噁烷(30mL)中。将混合物抽真空并充入氩气三次。加入二氯[1,1'-双(二苯基膦基)二茂铁]钯(II)CH2Cl2(922.08mg,1.13mmol)。将混合物加热至100℃过夜。将混合物用EtOAc稀释,滤过硅藻土垫,浓缩,并通过硅胶柱纯化,以提供目标化合物(5-氨基-1-甲苯磺酰基-1H-吡唑-4-基)硼酸(2.83g,41%)。LC/MS实测值364.2[M+H]+。
步骤3:将(5-氨基-1-甲苯磺酰基-1H-吡唑-4-基)硼酸(727.8mg,2.59mmol)、(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(500mg,1.3mmol)、2M K2CO3溶液(1.62mL)加入二噁烷(7mL)中。将混合物用氮气吹扫3分钟。向混合物中加入四(三苯基膦)钯(74.8mg,64.7μmol),然后将混合物用氮气吹扫3分钟。在70℃搅拌16小时后,真空去除挥发物。将混合物用CH2Cl2稀释,用盐水洗涤,经Na2SO4干燥,浓缩,然后通过硅胶柱纯化,以提供目标化合物(R)-3-(1-(7-(5-氨基-1-甲苯磺酰基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(81%)。LC/MS实测值543.1[M+H]+。
步骤4:在0℃下将(R)-3-(1-(7-(5-氨基-1-甲苯磺酰基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(500mg,0.9mmol)在乙腈(15mL)中的溶液缓慢添加到亚硝酸叔丁酯(1.84mmol,243μL)和溴化铜(II)(411.6mg,1.8mmol)在乙腈(15mL)中的悬浮液中。将混合物在0℃下搅拌,加温至RT,然后再搅拌40分钟。将混合物滤过硅藻土垫,然后用EtOAc洗涤。将滤液用EtOAc萃取,然后用饱和NaHCO3溶液洗涤。将有机层分离出,用约10%的NH4OH水溶液洗涤,经Na2SO4干燥,浓缩,并通过硅胶柱纯化,以提供合成的目标化合物(R)-3-(1-(7-(5-溴)-1-甲苯磺酰基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(354mg,65%)。LC/MS实测值606.1,608.1[M+H]+。
步骤5:向(R)-3-(1-(7-(5-溴)-1-甲苯磺酰基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(354mg,0.58mmol)在MeOH(8mL)中的悬浮液中加入5NNaOH水溶液(1.2mL,6.0mmol)。在RT下搅拌1小时后,真空去除挥发物。将所得残余物用EtOAc萃取(x2)并用盐水洗涤。将合并的有机层经Na2SO4干燥,浓缩,并通过硅胶柱纯化,以提供呈白色固体的化合物509(183.5mg,69%)。LCMS实测值452.1/454.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.44(br.S,1H),8.45(m,3H),8.18(d,1H,J=8.4Hz),7.97(d,1H,J=1.4Hz),7.84(m,2H),7.76(dt 1H,J=7.8,1.2Hz),7.56(d,1H,7.8Hz),7.46(t,1H,7.7Hz),6.13(q,1H,7.1Hz),2.77(d,3H,J=4.4Hz),1.88(d,3H,J=7.3Hz)。
步骤6:向来自步骤3的(R)-3-(1-(7-(5-氨基-1-甲苯磺酰基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺(39mg,0.1mmol)在MeOH(2mL)中的悬浮液中加入5N NaOH水溶液(0.2mL,1.0mmol)。在RT下搅拌1小时后,真空去除挥发物。将所得残余物用DCM萃取(x2)并用盐水洗涤。将合并的有机层经Na2SO4干燥,浓缩,并通过硅胶柱纯化,以提供呈白色固体的化合物518(31.1mg,82%)。LCMS实测值389.1[M+H]+。
下表14中的化合物510至522是通过针对化合物509的制备所述的方法类似的方法(一般方案15)制备的。
表14
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一般方案16
化合物523:(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮
步骤1:将2-氨基-4-溴苯甲酸(460mg,4mmol)、(S)-2-氨基-2-(3-氯苯基)乙酸(880mg,4.8mmol)、HBTU(2.2g,63mmol)和DIEA(2.0mL)在DMF(20mL)中的混合物在环境温度下振荡3小时。将反应混合物用EtOAc和盐水稀释。将有机层分离出,依次用水和盐水洗涤,经MgSO4干燥,浓缩,并通过硅胶柱色谱法纯化,以提供(S)-2-(2-氨基-4-溴苯甲酰氨基)-2-(3-氯苯基)乙酸(1.46g,95%)。LC/MS实测值383.1[M-H]-。
步骤2:将(S)-2-(2-氨基-4-溴苯甲酰氨基)-2-(3-氯苯基)乙酸(1.46mg,3.8mmol)和p-TsOH-H2O(115mg,0.6mmol)在纯原甲酸三乙酯(30mL)中的悬浮液在80℃下振荡过夜。将反应混合物用EtOAc稀释,依次用饱和NaHCO3水溶液和盐水洗涤,干燥(MgSO4),过滤,浓缩,并通过硅胶柱色谱法纯化,以提供(S)-2-(7-溴-4-氧代喹唑啉)-3(4H)-基)-2-(3-氯苯基)乙酸(1.05g,70%)。LC/MS实测值393.1[M+H]+。
步骤3:将(S)-2-(7-溴-4-氧代喹唑啉)-3(4H)-基)-2-(3-氯苯基)乙酸(1.05g,2.6mmol)在EtOH(10mL)中的悬浮液冷却至0℃,然后用DMF(4-5滴)和草酰氯(2.2mL,10当量)处理。将混合物加温至RT并振荡过夜。将混合物浓缩并通过硅胶柱色谱法纯化,以提供(S)-2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙酸乙酯(0.96g,86%产率)。LC/MS实测值420.8[M+H]+。
步骤4:将(S)-2-(7-溴-4-氧代喹唑啉-3(4H)-基)-2-(3-氯苯基)乙酸乙酯(3.7g)在THF(40mL)中的悬浮液用硼氢化钠(9.3g,10当量)处理,然后在RT下振荡过夜。将混合物用饱和NH4Cl水溶液(约50mL)猝灭并搅拌30分钟。将悬浮液用EtOAc萃取两次,然后将合并的有机层经MgSO4干燥,浓缩,并通过硅胶柱色谱法纯化,以提供(S)-7-溴-3-(1-(3-氯苯基)-2-羟乙基)-2,3-二氢喹唑啉-4(1H)-酮(1.0g,38%)。LC/MS实测值382.1[M+H]+。
步骤5:将(S)-7-溴-3-(1-(3-氯苯基)-2-羟乙基)-2,3-二氢喹唑啉-4(1H)-酮(300mg,0.78mmol)、3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(246mg,1.5当量)、2M碳酸钾水溶液(1.2mL,3.0当量)和Pd(PPh3)4(91mg,0.1当量)在二噁烷(5mL)中的混合物用氩气吹扫5分钟。将混合物在70℃下振荡过夜。过滤反应混合物,并将滤液减压蒸发。将所得物质溶解在CH2Cl2/MeOH中,用硅胶处理,并减压蒸发。将所得物质通过硅胶柱色谱法纯化,以提供呈淡黄色凝胶的化合物523,(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮(175mg,58%)。LC/MS实测值383.0[M+H]+。
下表15中的化合物524至531是通过针对化合物523的制备所述的方法类似的方法(一般方案16),使用合适的硼酸通过Suzuki反应条件制备的。
表15
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一般方案17
化合物532:3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺
步骤1:向6-溴-2H-异喹啉-1-酮(4.48g,20.0mmol)在乙腈(80mL)中的混合物中加入N-碘代琥珀酰亚胺(4.72g,21.0mmol),并将混合物在搅拌下加热至回流7小时。将混合物冷却至RT,倒在冰-H2O上,并搅拌5分钟。加入NaHSO3,并将混合物再搅拌10分钟。将剩余的固体真空过滤,用H2O洗涤,并在真空下干燥过夜,以提供产率为95%的呈棕褐色固体的6-溴-4-碘代异喹啉-1(2H)-酮(6.64g)。LC/MS实测值350.0[M+H]+。
步骤2:向6-溴-4-碘代-2H-异喹啉-1-酮(2.10g,6.0mmol)、碳酸钾(1.66g,12.0mmol)和碘化钠(180mg,1.20mmol))在丙酮(60mL)中的混合物中加入3-(溴甲基)苯甲酸甲酯(1.51g,6.6mmol)。将混合物在搅拌下加热至回流过夜,冷却至RT,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。以82%的产率收集呈浅灰白色固体的粗品3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸甲酯(2.46g,4.94mmol)并且无需进一步纯化即可使用。LC/MS实测值498.0[M+H]+。
步骤3:向3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸甲酯(2.46g,4.94mmol)在甲醇(25mL)中的混合物中加入1MNaOH水溶液(25mL),并将所得混合物在搅拌下加热至60℃达2小时。将混合物冷却至室温,倒在冰-H2O上,并用1M HCl水溶液酸化至约pH 2。将混合物搅拌10分钟。将沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以得到产率为99%的呈白色固体的3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(2.37g,4.9mmol)。LC/MS实测值484.0[M+H]+。
步骤4:将3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酸(2.37g,4.90mmol)、甲胺盐酸盐(666mg,9.86mmol)、HBTU(2.05g,5.41mmol)和三乙胺(4.1mL,29mmol)在THF(50mL)中的混合物在RT下搅拌2小时。将混合物倒在冰-H2O上并搅拌5分钟。将沉淀物真空过滤,用H2O洗涤,并在真空下干燥过夜,以提供产率为96%的呈白色固体的3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(2.34g,4.71mmol)。LC/MS实测值497.0[M+H]+。
步骤5:向3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(500mg,1.01mmol)和双(三苯基膦)氯化钯(II)(14mg,20μmol)在无水乙腈(10mL)中的混合物中加入三乙胺(0.42mL,3.0mmol)和丁基乙烯基醚(0.16mL,1.2mmol)。将混合物经由用N2喷射5分钟进行脱气,然后在搅拌下加热至80℃过夜。将混合物冷却至RT并浓缩。通过使用50-100%的EtOAc在CH2Cl2中的梯度的在SiO2上的快速柱色谱法纯化残余物,以提供产率为50%的呈泡沫状黄色固体的3-((6-溴-4-(1-丁氧基乙烯基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(238mg)。LC/MS实测值469.2[M+H]+。
步骤6:将3-((6-溴-4-(1-丁氧基乙烯基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(70mg,0.15mmol)、[3-(三氟甲基)-1H-吡唑-4-基]硼酸(44mg,0.24mmol)、Na2CO3(34mg,0.32mmol)和PdCl2(PPh3)2(2.4mg,3.4μmol)在1,4-二噁烷(3mL)和H2O(1mL)中的混合物经由用N2喷射10分钟进行脱气,然后在搅拌下加热至100℃过夜。将混合物冷却至室温,倒在H2O上,并用10%i-PrOH的CH2Cl2溶液萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%的EtOAc在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为88%的呈白色固体的3-((4-(1-丁氧基乙烯基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(69mg,0.13mmol)。LC/MS实测值469.2[M+H-BuOH+H2O]+。
步骤7:向3-((4-(1-丁氧基乙烯基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(69mg,0.13mmol)在THF(2mL)中的溶液中加入HCl水溶液(1M,2mL),并将混合物在RT下搅拌1小时。将混合物用NaHCO3水溶液猝灭并用EtOAc萃取。将所收集的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。以60%的产率收集呈白色固体的粗品3-((4-乙酰基-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(37mg,79μmol),并且无需进一步纯化即可使用。LC/MS实测值469.2[M+H]+。
步骤8:向3-((4-乙酰基-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(37mg,79μmol)在CH2Cl2(2mL)和CH3OH(1mL)中的溶液中加入NaBH4(12mg,0.32mmol)。将混合物在RT下搅拌1小时,用NH4Cl水溶液猝灭,然后用EtOAc(x2)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用1-10%的CH3OH在CH2Cl2中的梯度的在SiO2上的柱色谱法纯化残余物,以提供产率为35%的呈白色固体的化合物532(13mg)。LC/MS实测值493.2[M+Na]+,453.2[M+H-H2O]+。
下表17中的化合物533至544是通过针对化合物532的制备所述的方法类似的方法(一般方案17),使用合适的硼酸通过Suzuki反应条件制备的。
表17
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一般方案18
化合物546:3-((4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺
步骤1:将3-((6-溴-4-碘代-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(2.38g,4.8mmol)、2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(1.90g,9.6mmol)、Na2CO3(1.53g,14.4mmol)和PdCl2(PPh3)2(350mg,0.5mmol)在1,4-二噁烷(15mL)和H2O(3mL)中的混合物通过用N2喷射10分钟进行脱气,然后在搅拌下加热至50℃达1小时。将混合物冷却至室温,倒在H2O上,并用EtOAc萃取。将有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%的EtOAc在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为50%的呈白色固体的(3-((6-溴-4-(2-乙氧基乙烯基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(1.06g)。LC/MS实测值441.2[M+H]+。
步骤2:向(3-((6-溴-4-(2-乙氧基乙烯基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺)(1.06g,2.4mmol)在THF(10mL)中的溶液中加入10N HCl水溶液(2.4mL)。在RT下搅拌3小时后,真空去除挥发物。将混合物用DCM(x2)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用50-100%的EtOAc在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供定量产率的呈白色固体的3-((6-溴-1-氧代-4-(2-氧乙基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(0.99g)。LC/MS实测值413.1[M+H]+。
步骤3.1:在室温下向3-((6-溴-1-氧代-4-(2-氧乙基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(0.99g,2.4mmol)在DCM(20mL)中的溶液中加入NaBH4(182mg,4.8mmol)。在RT下搅拌2小时后,将混合物用DCM(x2)萃取。将合并的有机层用1N HCl之后是盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用70-100%的EtOAc在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为85%的呈白色固体的3-((6-溴-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(0.85g)。LC/MS实测值415.1[M+H]+。
步骤3.2:在0℃下向3-((6-溴-1-氧代-4-(2-氧乙基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(415mg,1.0mmol)在THF(5mL)中的溶液中加入3M MeMgCl(0.5mL)的THF溶液。在0℃下搅拌2小时后,将反应通过加入饱和NH4Cl溶液猝灭并用EtOAc(x2)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用0-20%的MeOH在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为70%的呈淡黄色固体的3-((6-溴-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(301.0mg)。LC/MS实测值430.1[M+H]+。
步骤3.3:向3-((6-溴-1-氧代-4-(2-氧乙基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(415mg,1.0mmol)和二甲胺盐酸盐(162mg,2mmol)在CH2Cl2(10mL)中的混合物中加入NaBH(OAc)3(181mg,2,5mmol)。在RT下搅拌16小时后,将反应通过加入饱和NaHCO3溶液猝灭并用DCM(x2)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩。通过使用0-50%的MeOH在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为80%的呈淡黄色固体的3-((6-溴-4-(2-(二甲氨基)乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(353.7mg)。LC/MS实测值443.1[M+H]+。
步骤4.1:将3-((6-溴-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(63mg,0.15mmol)、[3-(三氟甲基)-1H-吡唑-4-基]硼酸(44mg,0.24mmol)、Na2CO3(34mg,0.32mmol)和PdCl2(PPh3)2(2.4mg,3.4μmol)在1,4-二噁烷(3mL)和H2O(1mL)中的混合物经由用N2喷射10分钟进行脱气,然后在搅拌下加热至100℃过夜。将混合物冷却至室温,倒在H2O上,并用CH2Cl2(x2)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥,过滤并浓缩。通过使用5-20%的MeOH在CH2Cl2中的梯度的硅胶柱纯化残余物,以提供产率为65%的呈白色固体的化合物546,3-((4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺(69mg)。LC/MS实测值471.2[M+H]+。
步骤4.2:化合物547是使用3-((6-溴-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺通过与上述步骤4.1的方法类似的方法制备的。LC/MS实测值485.1[M+H]+。
步骤4.3:化合物548是使用3-((6-溴-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺通过与上述步骤4.1的方法类似的方法制备的。LC/MS实测值498.1[M+H]+。
下表18中的化合物549至567是通过针对化合物546至548的制备在方案16中所述的方法类似的方法(一般方案18),使用合适的硼酸/酯通过Suzuki反应条件制备的。
表18
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化合物568:(R)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酰胺
一般方案19
步骤1:将4-氨基-6-溴烟酸(0.85g,4.74mmol)、HBTU(2.52g,6.64mmol)和DIPEA(2.1mL,11.9mmol)在DMF(30mL)中的混合物在环境温度下振荡30分钟。将混合物用(R)-3-(1-氨基乙基)苯甲酸甲酯(0.84g,3.92mmol)处理并在室温下振荡过夜。将反应混合物用EtOAc和盐水稀释,然后将有机层分离出,依次用水和盐水洗涤,干燥(Mg2SO4),浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(4-氨基-6-溴烟酰胺基)乙基)苯甲酸甲酯(1.3g,87%产率)。LC/MS实测值378.1和380.0[M+H]+。
步骤2:将2M LiOH水溶液(13.8mL,27.5mmol)加入到(R)-3-(1-(7-溴-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酸甲酯(1.05g,2.8mmol)在THF(20mL)中的悬浮液中,然后将混合物在室温下振荡过夜。在真空去除THF后,将残余溶液用1N HCl水溶液酸化至pH7,然后用CH2Cl2萃取。将有机层干燥(Na2SO4),过滤,浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(7-溴)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酸(1.2g,95%产率)。LC/MS实测值364.0和366.0[M+H]+。
步骤3:将3-[(1R)-1-[(4-氨基-6-溴-吡啶-3-羰基)氨基]乙基]苯甲酸(1.2g,3.29mmol)、HBTU(1.62g,4.28mmol)和DIPEA(1.72mL,9.88mmol)在DMF(15mL)中的混合物在环境温度下振荡30min。将混合物用2M甲胺(3.29mL,6.59mmol)的THF溶液处理并在室温下振荡过夜。将反应混合物用EtOAc和盐水稀释,然后将有机层分离出,依次用水和盐水洗涤,干燥(Na2SO4),浓缩,并通过硅胶柱色谱法纯化,以提供甲基(R)-3-(1-(7-溴-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺(1.15g,92%产率)。LCMS实测值377.0和379.0[M+H]+。
步骤4:将(R)-3-(1-(4-氨基-6-溴烟酰胺基)乙基)苯甲酸甲酯(500mg,1.33mmol)和对甲苯磺酸一水合物(50mg,265μmol)在纯原甲酸三甲酯(5mL)中的悬浮液在100℃下振荡48h。将反应混合物用EtOAc稀释,依次用饱和NaHCO3水溶液和盐水洗涤,干燥(Na2SO4),过滤,浓缩,并通过硅胶柱色谱法纯化,以提供(R)-3-(1-(7-溴-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酸甲酯(75mg,14%产率)。LC/MS实测值387.0和389.0[M+H]+。
步骤5:将(R)-3-(1-(7-溴-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺(30mg,77μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5-(三氟甲基)-1H-吡唑(35mg,194μmol)、2M碳酸钾水溶液(97uL,194μmol)和四(三苯基膦)钯(0)(4.5mg,3.87μmol)的二噁烷(2mL)溶液用氩气吹扫五分钟。将混合物在70℃下振荡过夜。过滤样品,然后将滤液减压蒸发。将该物质溶解在DCM/MeOH中,用硅胶处理,并减压蒸发。将该物质通过硅胶柱色谱法纯化,以提供呈淡黄色固体的化合物568,(R)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酰胺(17mg,49%)。LC/MS实测值443.2[M+H]+。
下表19中的化合物569至572是通过针对化合物568的制备所述的方法类似的方法(一般方案19),使用(R)-3-(1-(7-溴-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺和合适的硼酸/酯制备的。
表19
化合物573:磷酸二氢[4-[3-[(1R)-1-[3-(甲基氨基甲酰基)苯基]乙基]-4-氧代-喹唑啉-7-基]-3-(三氟甲基)吡唑-1-基]甲基酯
一般方案20
步骤1:将化合物440,N-甲基-3-[(1R)-1-[4-氧代-7-[3-(三氟甲基)-1H-吡唑-4-基]喹唑啉-3-基]乙基]苯甲酰胺(100mg,227μmol)、氯甲基磷酸二叔丁基酯(69μL,295μmol)和碳酸铯(148mg,453μmol)在乙腈(3mL)中的混合物在环境温度下振荡48h。将反应混合物浓缩,用EtOAc和盐水稀释,然后将有机层分离出,依次用水和盐水洗涤,干燥(Mg2SO4),浓缩,并通过硅胶柱色谱法纯化,以提供[4-[3-[(1R)-1-[3-(甲基氨基甲酰基)苯基]乙基]-4-氧代-喹唑啉-7-基]-3-(三氟甲基)吡唑-1-基]甲基二叔丁基磷酸酯(125mg,83%产率)。LC/MS未观察到所需质量的实测值[M+H]+。
步骤2:将三氟乙酸(0.5mL)加入到二叔丁基[4-[3-[(1S)-1-[3-(甲基氨基甲酰基)苯基]乙基]-4-氧代-喹唑啉-7-基]-3-(三氟甲基)吡唑-1-基]甲基磷酸甲酯(1.05g,2.8mmol)在DCM(1.5mL)中的溶液中,然后将混合物在室温下振荡1小时。在真空中去除TFA/DCM后,将残余溶液通过硅胶柱色谱法纯化,以提供化合物573,磷酸二氢[4-[3-[(1R)-1-[3-(甲基氨基甲酰基)苯基]乙基]-4-氧代-喹唑啉-7-基]-3-(三氟甲基)吡唑-1-基]甲基酯(55mg,52%产率)。LC/MS实测值552.2[M+H]+。
化合物574:(R)-(4-(3-(1-(3-(甲基氨基甲酰基)苯基)乙基)-4-氧代-3,4-二氢喹唑啉-7-基)-5-(三氟甲基)-1H-吡唑-1-基)甲基磷酸二钠
在室温下向化合物573(55mg,0.1mmol)在丙酮(2ml)中的溶液中缓慢加入1N氢氧化钠水溶液(0.22mL,0.22mmol)以得到结晶固体。在室温下搅拌1h后,所得固体通过过滤收集,用丙酮冲洗,然后高真空干燥,以提供80%产率的所需化合物574(46.7mg)。LC/MS实测值552.2[M+H]+。
实施例2:ROCK抑制试验
通过基于LANCE Ultra TR-FRET(时间分辨荧光共振能量转移)均相技术方法(Perkin Elmer)的体外试验确定激酶IC50。重组ROCK1(氨基酸1-477)和ROCK2(氨基酸5-554)蛋白质购自Carna Biosciences和SignalChem。通过Envision测量化合物活性并计算IC50。试验在来自Greiner Bio-One的白色LUMITRACTM 200 96孔半面积微孔板中执行。激酶反应缓冲液由50mM HEPES pH 7.5、1mM EGTA、10mM MgCl2、2mM DTT和0.01%Tween-20组成。在1(ROCK1)或4(ROCK2)μM ATP存在下,将激酶与50nM(ULight-CREBtide)底物一起孵育。使激酶反应进行1小时,然后将终止缓冲液加入到LANCE检测缓冲液中的最终10mM EDTA和0.6nM LANCE Ultra Europium抗磷酸化CREB(Ser133)抗体(PerkinElmer TRF0200)中。所有试验孵育均在室温下执行,并且在此期间微孔板用聚酯膜密封。将反应孵育1小时,并在Envision中以TR-FRET模式(在320nm激发,并在615/665nm发射)读取信号。
式1化合物表现出有用的药理学性质。如本文所用,描述抑制活性效力(nM)的方式是50%时的抑制活性值(IC50)。结果显示在下表19中,其中小于10nM的IC50定义为“A”,在11nM与100nM之间的IC50定义为“B”,在101nM与500nM之间的IC50定义为“C”,并且大于501nM的IC50定义为“D”。表19说明了代表性的式1化合物对ROCK1和ROCK2的抑制。
表19.ROCK1和ROCK2的抑制活性
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实施例3:ROCK1/2抑制剂在A7r5细胞中的活性
通过基于细胞的ELISA试验测量ROCK1/2在A7r5细胞中的抑制。将大鼠主动脉平滑肌细胞系A7r5细胞在含有10%胎牛血清的DMEM培养基中维持和处理。将细胞以5,000个细胞/孔接种在96孔板中24小时,随后用测试化合物处理90分钟。然后根据细胞内ELISA比色检测试剂盒手册(In-Cell ELISA Colrimetric Detection Kit manual)(ThermoScientific)固定和处理细胞。在用DMSO对照或测试化合物处理后,使用细胞内ELISA试剂盒测定细胞磷酸肌球蛋白轻链(pMLC2、Thr18/Ser19)水平。
将所得数据应用于以下公式‘[1-(化合物/DMSO)]×100%’以计算抑制率百分比。将从化合物的9点3倍连续稀释获得的pMLC2数据应用于GraphPad Prism软件的非线性回归曲线拟合函数以计算细胞EC50值。一些代表性式1化合物的EC50值显示在下表20中,其中小于100nM的EC50定义为“A”,在101nM与500nM之间的EC50定义为“B”,在501nM与1000nM之间的EC50定义为“C”,并且大于1000nM的EC50定义为“D”。
表20.所选ROCK1/2抑制剂的pMCL2活性
化合物 | pMLC2 | 化合物 | pMLC2 | 化合物 | pMLC2 |
10 | A | 108 | B | 281 | B |
12 | B | 146 | C | 315 | C |
22 | A | 165 | C | 320 | D |
24 | B | 184 | A | 323 | B |
25 | B | 186 | A | 326 | B |
31 | A | 188 | A | 365 | B |
75 | B | 191 | A | 437 | B |
77 | B | 200 | A | 440 | B |
82 | A | 233 | B | 466 | A |
86 | A | 277 | C | 469 | A |
107 | B | 280 | C | 495 | B |
尽管出于清楚理解的目的已经通过说明和举例的方式对本发明进行了一些详细的描述,但是对于本领域的普通技术人员来说根据本发明的教导将显而易见的是,在不脱离所附权利要求的精神或范围的情况下可对本发明进行某些改变和修改。
Claims (21)
1.一种式(1)化合物、其药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药:
其中:
X是H或卤素;
Y是N或CR4;
A、B和E各自独立地为N或CH;
为单键或双键;
R1为H、F、Cl、OH、杂芳基、C1-C3烷氧基、C(O)OR5、NHS(O)2R5、S(O)2R5、C(O)NR5R6或NHC(O)R7,其中所述杂芳基或C1-C3烷氧基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合;
R2为H或C1-C3烷基,其任选地被一个或多个选自由以下组成的组的取代基取代:卤素、羟基、C1-C3烷氧基、NR5R6以及它们的组合;
R3为5-6元杂芳基或杂环,其中所述杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、CN、CHF2、CF3、C1-C3烷基、氨基、以及它们的组合,并且其中所述5-6元杂芳基具有1-3个选自由以下组成的组的杂原子:氧、氮以及它们的组合;
R4为H、卤素、CF3、CN、C1-C3烷基、C1-C3烷氧基、或C2-C6炔基,其中所述C1-C3烷基或C2-C6炔基任选地被一个或多个选自由以下组成的组的取代基取代:OH、NH2、C1-C2氨基、C1-C2羟基、C1-C2NR5R6、C1-C3烷氧基以及它们的组合;
R5为H或C1-C3烷基,其中所述C1-C3烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合;
R6为H、CD3、C1-C6烷基、C3-C7环烷基、芳基、杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基、或包含1-2个选自由N、O、S以及它们的组合组成的组的杂原子的4-7元杂环基,其中所述C1-C6烷基、C3-C7环烷基、芳基或杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、NR5R6、芳基、杂芳基和OR5以及它们的组合,并且其中当所述4-7元杂环基具有一个氮原子时,所述4-7元杂环基在氮原子处任选地被C1-C3烷基、CF3、C(O)R5、S(O)2NH2、OCF3、C(O)OR5或C(O)NHR5取代;并且
R7为C1-C6烷基、C3-C7环烷基、包含1-2个选自由N、O以及它们的组合组成的组的杂原子的4-7元杂环基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基,其中所述C1-C6烷基或C3-C7环烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、C1-C3烷基、OR5、NH2、5-6元杂芳基以及它们的组合。
2.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中X是H、F或Cl。
3.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R1为H、F、Cl、OH、甲氧基、杂芳基、C(O)OR5、NHS(O)2R5、S(O)2R5、C(O)NR5R6或NHC(O)R7,其中所述杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、氨基、羟基、烷氧基以及它们的组合。
4.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R2为H或C1-C3烷基,其中所述C1-C3烷基任选被一个或多个选自由以下组成的组的取代基取代:羟基、甲氧基、乙氧基、NH2、NHMe、NMe2以及它们的组合。
5.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R3选自由以下组成的组:
6.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R4为H、Me、F、Cl、CN、C1-C3烷基或C2-C4炔基,其中所述C1-C3烷基或C2-C4炔基任选地被一个或多个选自由以下组成的组的取代基取代:OH、NH2、NMe2、OMe以及它们的组合。
7.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R5为H或Me。
8.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R6为H、CD3、C1-C6烷基、C3-C7环烷基、苯基、杂芳基、8-10元双环杂芳基、8-10元饱和或部分不饱和双环杂芳基、或包含1-2个选自由N、O、S以及它们的组合组成的组的杂原子的4-7元杂环基,其中所述C1-C6烷基、C3-C7环烷基、苯基,或杂芳基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、CF3、OH、OMe、NR5R6、芳基、杂芳基以及它们的组合,其中当所述4-7元杂环基具有一个氮原子时,所述4-7元杂环基任选地在氮原子处被C1-C3烷基、C(O)R5、S(O)2NH2、OCF3、C(O)OR5或C(O)NHR5取代。
9.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药,其中R7为H、C1-C6烷基、C3-C7环烷基、包含1-2个选自由N、O以及它们的组合组成的组的杂原子的4-7元杂环基、5-6元芳基、5-6元杂芳基、8-10元双环杂芳基、或8-10元饱和或部分不饱和双环杂芳基,其中所述C1-C6烷基或C3-C7环烷基任选地被一个或多个选自由以下组成的组的取代基取代:卤素、C1-C3烷基、OH、OMe、NH2、5-6元杂芳基以及它们的组合。
10.一种药物组合物,所述药物组合物包含根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药和至少一种附加组分,所述至少一种附加组分选自由以下组成的组:药学上可接受的载体、稀释剂、赋形剂、佐剂以及它们的组合。
11.一种由以下列表表示的化合物或其药学上可接受的盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药:
2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)-3,4-二氢异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-甲基-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-甲基-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(1-(3-羟基苯基)乙基)-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(3-甲基异噁唑-4-基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(1-甲基-1H-吡唑-5-基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(3-甲基异噁唑-4-基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-羟基苄基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(1-(3-羟基苯基)乙基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(1-甲基-1H-吡唑-5-基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-(二氟甲基)-1H-吡唑-4-基)-2-(3-氟-5-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-氟-5-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(1-(3-甲氧基苯基)乙基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(3-羟基苄基)异喹啉-1(2H)-酮;
6-(3-氯-1H-吡唑-4-基)-2-(1-(3-羟基苯基)乙基)异喹啉-1(2H)-酮;
2-(3-甲氧基苄基)-6-(吡啶-4-基)异喹啉-1(2H)-酮;
2-(3-羟基苄基)-6-(吡啶-4-基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(3-甲氧基苄基)异喹啉-1(2H)-酮;
6-(2-氨基吡啶-4-基)-2-(1-(3-甲氧基苯基)乙基)异喹啉-1(2H)-酮;
3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
N-异丙基-3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-苯基苯甲酰胺;
N-苄基-3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-(甲基磺酰氨基)苄基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-氨磺酰基苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(3-(三氟甲氧基)苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4-(甲基磺酰氨基)苯基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(三氟甲氧基)苯基)苯甲酰胺;
N-(6-氟吡啶-3-基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-(1-甲基哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-(2,2-二氟乙基)哌啶-4-基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-环丙基-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-甲基哌啶-4-基)甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-(氧杂环丁烷-3-基甲基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(6-氟吡啶-2-基)乙基)-3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(哌啶-4-基甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(2-羟乙基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺盐酸盐;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
N-(环丙基甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,3R)-3-羟基环丁基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺盐酸盐;
[3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-异丙基哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-(3,3-二氟烯丙基)哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-((1-(2,2二氟乙基)哌啶-4-基)甲基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异噁唑-3-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异色满-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(异色满-7-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(5-异丙基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-异丙基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-7-基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-羟乙基)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
N-(1-(2,2-二氟乙基)哌啶-4-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(2,2,2-三氟乙基)哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-(氧杂环丁烷-3-基)哌啶-4-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-((3-羟基环丁基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基氮杂环丁烷-3-基)甲基)苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((2-氟吡啶-4-基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(1-异丙基哌啶-4-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(二甲基氨基)乙基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-甲氧基乙基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-7-基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(4-氨磺酰基苯基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-氟-N-(1-甲基哌啶-4-基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-环丙基-3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-N-(氧杂环丁烷-3-基甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,3S)-3-羟基环丁基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,3R)-3-羟基环丁基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4R)-4-甲氧基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-甲氧基环己基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-异丙基哌啶-4-基)甲基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)苯甲酰胺;
3-氟-N-(5-甲基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(5-异丙基-4,5,6,7-四氢噻唑并[4,5-c]吡啶-2-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
N-(2-环丙基-1,2,3,4-四氢异喹啉-7-基)-3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-氟-N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-((3-羟基环丁基)甲基)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基氮杂环丁烷-3-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-氟-N-((6-氟吡啶-3-基)甲基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-异丙基哌啶-4-基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
N-(2-(二甲基氨基)乙基)-3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-甲基-1H-吡唑-3-基)-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(2-(2-氟吡啶-4-基)乙基)-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-苄基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(萘-2-基甲基)苯甲酰胺;
N-(2-(氨基甲基)苄基)-3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(羟甲基)苄基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-苯乙基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-7-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-甲基-1,2,3,4-四氢异喹啉-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(5-甲基-4,5,6,7-四氢噻唑并[5,4-c]吡啶-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-((1R,4R)-4-羟基环己基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异色满-6-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异色满-7-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-环戊基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1H-咪唑-2-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(1-甲基-1H-吡唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(1-甲基-1H-吡唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异噁唑-5-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(异噁唑-3-基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-(异噁唑-3-基)苯甲酰胺;
N-(异噁唑-5-基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-氟-N-((1S,3S)-3-羟基环丁基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,3R)-3-羟基环丁基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1S,4S)-4-羟基环己基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1-甲基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-(2,2-二氟乙基)哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(2,2,2-三氟乙基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-异丙基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1-异丙基哌啶-4-基)甲基)-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-((1-环丙基哌啶-4-基)甲基)-3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-((1-(氧杂环丁烷-3-基)哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(2-甲基-1H-吡咯-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
N-甲基-3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((8-氧代-3-(5-(三氟甲基)-1H-吡唑-4-基)-1,7-萘啶-7(8H)-基)甲基)苯甲酰胺;
N-甲基-3-((3-(3-甲基异噁唑-4-基)-8-氧代-1,7-萘啶-7(8H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(2-甲基呋喃-3-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(5-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-乙基-3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-氟-5-((6-(3-甲基-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-N-((1-甲基哌啶-4-基)甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(氧杂环丁烷-3-基甲基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(1-甲基哌啶-4-基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-((1R,4R)-4-羟基环己基)-5-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)-2,7-萘啶-2(1H)-基)甲基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1R,4R)-4-羟基环己基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-异丙基苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-(4-甲基哌嗪-1-基)乙基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-氟-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-N-(2-(吡啶-3-基)乙基)苯甲酰胺;
3-((6-(3-溴-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-异丙基苯甲酰胺;
3-((6-(3-溴-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代-2,7-萘啶-2(1H)-基)甲基)-5-氟-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-((4-氯-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-d3)-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
N-(甲基-d3)-3-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-5-氟-N-甲基苯甲酰胺;
3-(1-(6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-氟-5-(1-(6-(5-氟-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2,5-二氢呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((1-氧代-6-(1H-吡咯-3-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-((4-氯-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-6-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)甲基吡啶酰胺;
N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)烟酰胺;
N-甲基-4-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)甲基吡啶酰胺;
2-氟-N-甲基-3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-氯-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-氯-N-甲基-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)乙基)苯甲酰胺;
3-氟-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((1-氧代-6-(吡啶-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-甲基-3-((6-(1-甲基-1H-1,2,3-三唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-甲基-3-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((6-吗啉代-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((6-(6-氧杂-3-氮杂双环[3.1.1]庚-3-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
(S)-N-甲基-3-((6-(2-甲基吗啉代)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-(3-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-氟-5-((6-(2-甲基呋喃-3-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(2-氟-5-((6-(5-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-甲基-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)异丁酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺;
N-(3-((1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)-3-(吡啶-2-基)丙烯酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)烟酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
N-(3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)苯甲酰胺;
N-(3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-氯-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)氧杂环丁烷-3-甲酰胺;
4-氟-N-(3-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)苯甲酰胺;
N-(3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)甲基吡啶酰胺;
N-(3-氟-5-((6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((1-氧代-6-(1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯基)乙酰胺;
N-(3-((6-(2-氨基吡啶-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-5-氟苯基)乙酰胺;
3-(3-甲氧基苄基)-7-(1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(1-甲基-1H-吡唑-5-基)喹唑啉-4(3H)-酮;
7-(3-(二氟甲基)-1H-吡唑-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-(二氟甲基)-1H-吡唑-4-基)-3-(3-氟-5-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-氯-1H-吡唑-4-基)-3-(3-氟-5-甲氧基苄基)喹唑啉-4(3H)-酮;
7-(3-氯-1H-吡唑-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
3-(3-甲氧基苄基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮;
7-(2-氨基吡啶-4-基)-3-(3-甲氧基苄基)喹唑啉-4(3H)-酮;
(R)-7-(2-氨基吡啶-4-基)-3-(1-(3-甲氧基苯基)乙基)喹唑啉-4(3H)-酮;
N-甲基-3-((4-氧代-7-(1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-异丙基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-4-基)乙基)苯甲酰胺;
N-苄基-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(吡啶-4-基甲基)苯甲酰胺;
N-(4-(甲基磺酰氨基)苄基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(1-甲基-1H-吡唑-3-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(异噁唑-3-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
N-(1-(氧杂环丁烷-3-基)哌啶-4-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(1-甲基哌啶-4-基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-(氧杂环丁烷-3-基甲基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1R,4R)-4-羟基环己基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(2-羟乙基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(4-(甲基磺酰氨基)苯基)-3-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-d3)-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
2-氟-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氯-N-甲基-5-((4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-羟乙基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((2-氟吡啶-4-基)甲基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(甲基磺酰基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(甲基磺酰氨基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(3-(二甲基氨基)苄基)苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-5-氟-N-甲基苯甲酰胺;
3-((7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-5-氟-N-(甲基-D3)苯甲酰胺;
5-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基烟酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-D3)苯甲酰胺;
3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1S,4S)-4-羟基环己基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基)苯甲酰胺;
3-((7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
N-甲基-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-d3)-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-异丙基-3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(哌啶-4-基甲基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-3-基)乙基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-吗啉代乙基)苯甲酰胺;
3-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2,2,2-三氟乙基)苯甲酰胺;
3-氟-N-甲基-5-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-氟-N-(甲基-D3)-5-((7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-(甲基-D3)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-甲基-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1R,3R)-3-羟基环丁基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
N-((1S,4S)-4-羟基环己基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
N-(2-羟乙基)-3-((7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-甲基苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
N-甲基-3-((7-(1-甲基-1H-1,2,3-三唑-5-基)-4-氧代喹唑啉-3(4H)-基)甲基)苯甲酰胺;
(R)-N-甲基-3-(1-(7-(5-甲基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(S)-N-甲基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-异丙基-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-(吡啶-4-基甲基)苯甲酰胺;
(R)-N-(异噁唑-3-基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
(R)-N-(1-甲基哌啶-4-基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
(R)-N-(氧杂环丁烷-3-基甲基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(2-羟乙基)-3-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-氟-N-(甲基-d3)-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-2-氟-N-甲基-5-(1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-(D)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-羟乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((四氢-2H-吡喃-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-(二氟甲基)-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-5-氟-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(1-甲基哌啶-4-基)苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-d3)苯甲酰胺;
(S)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((1-甲基哌啶-4-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(哌啶-4-基甲基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2-吗啉代乙基)苯甲酰胺;
(R)-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(2,2,2-三氟乙基)苯甲酰胺;
(R)-N-甲基-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-N-(甲基-d3)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
N-((1S,3S)-3-羟基环丁基)-3-((R)-1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基甲基)苯甲酰胺;
(R)-N-(2-羟乙基)-3-(1-(7-(1-甲基-1H-吡唑-5-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(3-氯苯基)-2-羟乙基)-7-(吡啶-4-基)喹唑啉-4(3H)-酮;
7-(2-氨基吡啶-4-基)-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
7-(5-氯-1H-吡唑-4-基)-3-(1-(3-氯苯基)-2-羟乙基)喹唑啉-4(3H)-酮;
3-(1-(3-氯苯基)-2-羟乙基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
7-(5-氯-1H-吡唑-4-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(2-氨基吡啶-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(5-氯-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-氯苯基)乙基)-7-(3-甲基异噁唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-甲基-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(3-甲氧基苯基)乙基)-7-(5-氯-1H-吡唑-4-基)喹唑啉-4(3H)-酮;
3-(2-氨基-1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(2-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲腈;
3-(2-氨基-1-(7-(3-氟吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(7-(2-氨基吡啶-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(4-氧代-7-(5-(三氟甲基)-1H-吡唑-4-基)喹唑啉-3(4H)-基)乙基)苯甲酰胺;
3-(2-氨基-1-(7-(5-氯-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
3-((7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
3-((6-(5-溴-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-溴-1H-吡唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(甲基-d3)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-溴-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(4-氟苯基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(甲基-D3)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-环丙基苯甲酰胺;
(R)-3-(1-(7-(5-氨基-1H-吡唑-4-基)-4-氧代喹唑啉-3(4H)-基)乙基)-N-((6-氟吡啶-3-基)甲基)苯甲酰胺;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-甲基-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-7-(5-氯-1H-吡唑-4-基)-3-(1-(3-氯苯基)-2-羟乙基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(1-(3-氯苯基)-2-羟乙基)-7-(1-甲基-1H-吡唑-5-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(吡啶-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-(三氟甲基)-1H-吡唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(5-甲基异噁唑-4-基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-7-(5-氯-1H-吡唑-4-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-2,3-二氢喹唑啉-4(1H)-酮;
(S)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-7-(1-甲基-1H-吡唑-5-基)-2,3-二氢喹唑啉-4(1H)-酮;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1l2-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-环丙基-3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-环丙基-3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-1-氧代-6-(3-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-(氧杂环丁烷-3-基)苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-(二氟甲基)-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(四氢-2H-吡喃-4-基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
N-((6-氟吡啶-3-基)甲基)-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
N-苄基-3-((4-(1-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)苯甲酰胺;
3-((4-(1-羟乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(二甲基氨基)乙基)苯甲酰胺;
3-((6-(3-氯-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-(2-(吡啶-2-基)乙基)苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(1-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟丙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-羟乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((4-(2-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-羟乙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氟-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-氟-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氨基吡啶-4-基)-4-(2-羟乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-(二氟甲基)-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(5-氯-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(2-氟-1H-吡咯-3-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((4-(2-羟丙基)-6-(3-甲基异噁唑-4-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(2-羟丙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-(1-(4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(4-(2-(二甲基氨基)乙基)-1-氧代-6-(5-(三氟甲基)-1H-吡唑-4-基)异喹啉-2(1H)-基)乙基)-N-甲基苯甲酰胺;
3-(1-(6-(5-氯-1H-吡唑-4-基)-4-(2-(二甲氨基)乙基)-1-氧代异喹啉-2(1H基)乙基)-N-甲基苯甲酰胺;
3-((4-(2-(二甲基氨基)乙基)-6-(1-甲基-1H-吡唑-5-基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
3-((6-(3-氨基-1H-吡唑-4-基)-4-(2-(二甲基氨基)乙基)-1-氧代异喹啉-2(1H)-基)甲基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氯-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-氟-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-3-(1-(7-(5-甲氧基-1H-吡唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)-N-甲基苯甲酰胺;
(R)-N-甲基-3-(1-(7-(3-甲基异噁唑-4-基)-4-氧代吡啶并[4,3-d]嘧啶-3(4H)-基)乙基)苯甲酰胺;
(R)-(4-(3-(1-(3-(甲基氨基甲酰基)苯基)乙基)-4-氧代-3,4-二氢喹唑啉-7-基)-5-(三氟甲基)-1H-吡唑-1-基)甲基磷酸二氢盐;或者
(R)-(4-(3-(1-(3-(甲基氨基甲酰基)苯基)乙基)-4-氧代-3,4-二氢喹唑啉-7-基)-5-(三氟甲基)-1H-吡唑-1-基)甲基磷酸二钠。
12.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药用于制备用于治疗可通过抑制ROCK酶来治疗的疾病的药物的用途。
13.根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药用于治疗或减轻纤维化疾病或疾患、心血管疾病或疾患、炎性疾病或疾患、神经系统疾病或疾患、或增殖性疾病或疾患的用途。
14.根据权利要求13所述的用途,其中所述纤维化疾病或疾患是选自由囊性和特发性肺纤维化组成的组的肺纤维化、辐射诱发的肺损伤、包括肝硬化在内的肝纤维化、包括动脉纤维化在内的心脏纤维化、心内膜心肌纤维化、陈旧性心肌梗死、动脉硬化、动脉粥样硬化、再狭窄、关节纤维化、克罗恩氏病、骨髓纤维化、佩罗尼氏病、肾源性系统性纤维化、进行性大块纤维化、腹膜后腔纤维化、硬皮病/系统性硬化症、纵隔纤维化、瘢痕瘤和增生性瘢痕、神经胶质瘢痕和肾纤维化。
15.根据权利要求13所述的用途,其中所述心血管疾病或疾患选自由以下组成的组:心绞痛、动脉粥样硬化、脑血管痉挛、脑血管收缩、冠状血管痉挛、内皮功能障碍、勃起功能障碍、青光眼、高血压、缺血/再灌注损伤、心肌肥大,心肌梗塞、外周循环障碍、早产、雷诺氏病、肾病、和中风。
16.根据权利要求13所述的用途,其中所述增殖性疾病或疾患是选自由以下组成的组的侵袭性或转移性癌症:腺癌、肾上腺皮质癌、膀胱癌、骨癌、脑癌、乳腺癌、口腔癌、宫颈癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、表皮样癌、食道癌、眼癌、滤泡癌、胆囊癌、胃肠癌、泌尿生殖道癌、成胶质细胞瘤、毛细胞癌、头颈癌、肝肿瘤、肝细胞癌、霍奇金氏病、角化棘皮瘤、肾癌、大细胞癌、大肠癌、喉癌、肝癌、肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌、黑素瘤、骨髓增生性疾患、成神经细胞瘤、卵巢癌、乳头状癌、胰腺癌、腹膜癌、前列腺癌、直肠癌、唾液腺癌、肉瘤、鳞状细胞癌、小细胞癌、小肠癌、胃癌、睾丸癌、甲状腺癌和外阴癌。
17.根据权利要求13所述的用途,其中所述神经系统疾病或疾患选自由以下组成的组:亨廷顿氏病、帕金森氏病、阿尔茨海默氏病、肌萎缩性脊髓侧索硬化症(ALS)、巴滕病、痴呆、脊髓性肌萎缩症、运动神经元疾病、脊髓小脑共济失调,急性或慢性疼痛、痴呆、神经退变、脊髓损伤、脑血管痉挛和多发性硬化症。
18.一种治疗癌症的方法,所述方法包括向有需要的受试者施用组合物,所述组合物包含治疗有效量的根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药中的至少一者和治疗有效量的至少一种免疫检查点抑制剂,其中所述癌症是腺癌、肾上腺皮质癌、膀胱癌、骨癌、脑癌、乳腺癌、口腔癌、宫颈癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、表皮样癌、食道癌、眼癌、滤泡癌、胆囊癌、胃肠癌、泌尿生殖道癌、成胶质细胞瘤、毛细胞癌、头颈癌、肝肿瘤、肝细胞癌、霍奇金氏病、角化棘皮瘤、肾癌、大细胞癌、大肠癌、喉癌、肝癌、肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌、黑素瘤、骨髓增生性疾患、成神经细胞瘤、卵巢癌、乳头状癌、胰腺癌、腹膜癌、前列腺癌、直肠癌、唾液腺癌、肉瘤、鳞状细胞癌、小细胞癌、小肠癌、胃癌、睾丸癌、甲状腺癌、外阴癌,或它们的任何组合。
19.根据权利要求18所述的方法,其中所述检查点抑制剂是PD-1抑制剂、PD-L1抑制剂、或CTLA-4抑制剂。
20.一种治疗癌症的方法,所述方法包括向有需要的受试者施用组合物,所述组合物包含治疗有效量的根据权利要求1所述的化合物、盐、非对映异构体、对映异构体、外消旋体、水合物、溶剂化物或前药中的至少一者和治疗有效量的至少一种诱导免疫原性细胞死亡(ICD)的化学治疗剂,其中所述癌症是腺癌、肾上腺皮质癌、膀胱癌、骨癌、脑癌、乳腺癌、口腔癌、宫颈癌、结肠癌、结直肠癌、子宫内膜癌或子宫癌、表皮样癌、食道癌、眼癌、滤泡癌、胆囊癌、胃肠癌、泌尿生殖道癌、成胶质细胞瘤、毛细胞癌、头颈癌、肝肿瘤、肝细胞癌、霍奇金氏病、角化棘皮瘤、肾癌、大细胞癌、大肠癌、喉癌、肝癌、肺腺癌、小细胞肺癌、肺鳞癌、非小细胞肺癌、黑素瘤、骨髓增生性疾患、成神经细胞瘤、卵巢癌、乳头状癌、胰腺癌、腹膜癌、前列腺癌、直肠癌、唾液腺癌、肉瘤、鳞状细胞癌、小细胞癌、小肠癌、胃癌、睾丸癌、甲状腺癌、外阴癌,或它们的任何组合。
21.根据权利要求20所述的方法,其中所述诱导免疫原性细胞死亡(ICD)的化学治疗剂是多柔比星、伊达比星、米托蒽醌、互变霉素、花萼海绵诱癌素A、沙鲁胺、奥沙利铂、博莱霉素或环磷酰胺。
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