CN112574189B - 一种ep300/cbp抑制剂 - Google Patents
一种ep300/cbp抑制剂 Download PDFInfo
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- CN112574189B CN112574189B CN202011003637.8A CN202011003637A CN112574189B CN 112574189 B CN112574189 B CN 112574189B CN 202011003637 A CN202011003637 A CN 202011003637A CN 112574189 B CN112574189 B CN 112574189B
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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- RMGYQBHKEWWTOY-UHFFFAOYSA-N (3,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C(F)=C1 RMGYQBHKEWWTOY-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
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- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 23
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- 239000011777 magnesium Substances 0.000 description 22
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
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- 125000000623 heterocyclic group Chemical group 0.000 description 18
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 18
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 15
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- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 12
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- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 7
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- CMJQIHGBUKZEHP-UHFFFAOYSA-N (4-chloro-3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C(F)=C1 CMJQIHGBUKZEHP-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明公开了一种EP300/CBP抑制剂,具体提供了式I所示的化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物。该化合物对EP300/CBP具有高度选择性,并且能够有效抑制EP300/CBP的活性;而且,该化合物对包括***癌细胞、白血病细胞、乳腺癌细胞、多发性骨髓瘤细胞在内的多种肿瘤细胞均具有优异的抑制作用。因此,本发明化合物在制备EP300/CBP抑制剂,以及预防和/或***、髓系造血干/祖细胞恶性疾病,调控调节性T细胞的药物中具有广阔的应用前景。
Description
技术领域
本发明属于药物合成工领域,具体涉及一种结构新颖的EP300/CBP抑制剂及其制药用途。
背景技术
组蛋白乙酰转移酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)可以影响组蛋白的乙酰化,HAT和HDAC的募集和正常功能的发挥是基因表达和细胞周期的关键调控步骤,这些酶的功能性缺陷可能导致包括肿瘤在内的多种疾病。
由高度同源的腺病毒E1A相关的300kDa蛋白(EP300)和环磷酸腺苷反应元件结合蛋白(CREB)的结合蛋白(CBP)组成的EP300/CBP家族是组蛋白乙酰转移酶(HAT)家族主要成员之一。研究发现,EP300和CBP通过它们的溴结构域(bromodomain,BRD)与染色质结合,参与细胞周期进展和细胞的生长、分化和发展,是一类非常重要的辅激活因子,可以调节多种关键转录调节因子的功能。研究表明,EP300/CBP在多种不同的肿瘤中高度表达和激活,EP300/CBP与多种肿瘤疾病密切相关,是一个极具应用前景的肿瘤治疗靶标。因此EP300/CBP抑制剂越来越受到研究者的关注。
Zhou的团队和Hewings的团队公开了如下1a、2a、3a所示的代表性EP300/CBP抑制剂,其亲和力达微摩尔级别,其中1a的CBP:Kd=19.6μmol.L-1,2a的CBP:Kd=19μmol.L-1,3a的CBP:IC50=28.1μmol.L-1)。
牛津大学结构基因组学协会(Structural GenomicsConsortium,SGC)的研究人员首先设计并合成了苯并咪唑类化合物9a,但9a对CBP和BRD4的选择性不高(CBP:IC50=4μmol·L-1,BRD4:IC50=6.3μmol·L-1)。然后通过进一步优化得到了化合物10a(CBP:IC50=0.12μmol·L-1,BRD4:IC50=2.4μmol·L-1)与11a(SGC-CBP30,CBP:IC50=69nmol.L-1、Kd=21nmol.L-1,p300:Kd=32nmol.L-1)。
但是,目前已经报道的EP300/CBP抑制剂仍然不能满足临床的需求,因此,研究出更多结构新颖、选择性更高、抑制活性更好的EP300/CBP抑制剂具有非常重要的意义。
发明内容
本发明的目的在于提供一种结构新颖的高活性EP300/CBP抑制剂。
本发明提供了一种式I所示的化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物:
其中,R1选自被0~4个R7取代的以下基团:5~6元饱和或不饱和环烷基、5~6元饱和或不饱和杂环基,R7各自独立地选自C1~5烷基或其氘代物、=O、C1~5烷氧基或其氘代物、卤素、羟基、氰基;
R2选自被0~4个R5取代的以下基团:5~6元饱和环烷基、5~6元饱和杂环基,R5各自独立地选自C1~5烷基或其氘代物、C1~5卤代烷基、=O、C1~5烷氧基或其氘代物、卤素、羟基、氰基、R6为C1~5烷基;
R3选自被0~4个R4取代的以下基团:3~7元饱和或不饱和环烷基、3~7元饱和或不饱和杂环基,R4各自独立地选自=O、=S、SO2、氰基、C1~5烷基或其氘代物、C1~5烷氧基或其氘代物、羟基、卤素、或者,两个R4连接成3~4元环;其中,R8为C1~3烷基或卤素,n为0~4的整数。
进一步地,R1选自被1~3个R7取代的以下基团:5~6元饱和或不饱和环烷基、5~6元饱和或不饱和杂环基,其中,所述杂环基上的杂原子选自O、N、S;R7各自独立地选自C1~3烷基或其氘代物、=O;
R2选自被1~3个R5取代的以下基团:5~6元饱和环烷基、5~6元饱和杂环基,所述杂环基上的杂原子为选自O、N、S;R5各自独立地选自C1~3烷基或其氘代物、C1~5卤代烷基、=O、C1~3烷氧基或其氘代物、卤素、羟基、氰基、R6为C1~3烷基;
R3选自被0~4个R4取代的以下基团:3~7元饱和或不饱和环烷基、3~7元饱和或不饱和杂环基,所述杂环基中的杂原子选自O、S、N中的一种或两种以上;R4各自独立地选自=O、=S、SO2、氰基、C1~3烷基或其氘代物、C1~3烷氧基或其氘代物、羟基、卤素、或者,两个R4连接成3~4元饱和碳环或3~4元饱和杂环;其中,R8为卤素,n为1~3的整数。
进一步地,所述化合物的结构如式II-1所示:
R5选自C1~3烷基或其氘代物、C1~5卤代烷基、C1~3烷氧基或其氘代物、卤素、羟基;m为1或2;
R1、R3如上所述;
或,所述化合物的结构如式II-2所示:
R5选C1~3烷基或其氘代物、C1~5卤代烷基、C1~3烷氧基或其氘代物、卤素、羟基、R6为C1~3烷基;
R1、R3如上所述;
或,所述化合物的结构如式II-3所示:
R5选C1~3烷基或其氘代物、C1~5卤代烷基、C1~3烷氧基或其氘代物、卤素、羟基、R6为C1~3烷基;
R1、R3如上所述;
或,所述化合物的结构如式II-4所示:
R1、R3如上所述。
进一步地,R1选自
和/或,R3选自 其中R4选自/> R9选自烷基或卤代烷基。
进一步地,所述化合物为以下化合物之一:
本发明还提供了式I’所示的化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物:
其中,R1’选自取代或未取代的以下基团:5~6元饱和或不饱和环烷基、5~6元饱和或不饱和杂环基、C1~5烷基、C2~6烯烃、氨基、酰氨基、羧酸酯基、脲基、卤素、羟基、氰基;其中,R1’上的取代基为1个或多个,所述取代基各自独立的选自氘、氘代或未氘代的C1~4烷基、氘代或未氘代的C1~4烷氧基、环烷基、杂环基、CONR2aR2b、COOR2c、COR2d、COL1NR2fR2g、SO2R2e、=O、=S;R2a、R2b、R2c、R2d、R2e、R2f、R2g各自独立的选自卤代或未卤代的C1~4烷基,L1选自无或C1~2亚烷基;
L0选自无或C1~2亚烷基;
A环为被0个、1个或多个R3’取代的5~7元饱和或不饱和环烷基、5~7元饱和或不饱和杂环基;其中,R3’各自独立的选自氘、=O、=S、C1~4烷基、C1~4烷氧基、氰基、被0~4个R3a取代的芳基、被0~4个R3a取代的杂芳基,或者2个R3’连接成环;R3a各自独立的选自卤素、氨基保护基团、C1~4烷基、C1~4烷氧基、氰基;
n1为0~2的整数,n2为0~2的整数;
X为CH、N、O或S;
Rx选自无、氢、氘、氘代或未氘代的C1~4烷基、氘代或未氘代的C1~4烷氧基、CORx1;Rx1为氘代或未氘代的C1~3烷基。
进一步地,所述化合物的结构如式II’所示:
其中,R1a、R1b各自独立的选自氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基;
L0选自无或亚甲基;
A环为被0个、1个或多个R3’取代的5~7元饱和或不饱和环烷基、5~7元饱和或不饱和杂环基;其中,R3’各自独立的选自氘、=O、=S、C1~4烷基、C1~4烷氧基、氰基、被0~4个R3a取代的芳基、被0~4个R3a取代的杂芳基,或者2个R3’连接成环;R3a各自独立的选自卤素、氨基保护基团、C1~4烷基、C1~4烷氧基、氰基;
n1为0或1,n2为0或1;
X为CH、N、O或S;
Rx选自无、氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基、CORx1;Rx1为氘代或未氘代的C1~2烷基;
所述盐为药学上可接受的盐。
进一步地,所述化合物的结构如式III-1或式III-2所示:
其中,R1a、R1b各自独立的选自氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基;
n1为0或1,优选为1;n2为0或1,优选为1;
m1为0或1;m2为0或1,优选为1;
Y1为O或S;
Y2为O、S、CRY1RY2、NRY3;RY1、RY2、RY3各自独立的选自氢、氘、C1~3烷基、C1~3烷氧基;
Rx选自氢、氘、氘代或未氘代的C1~2烷基、氘代或未氘代的C1~2烷氧基、CORx1;Rx1为氘代或未氘代的C1~2烷基;
R3’选自被0~3个R3a取代的苯基或杂芳基,优选为被2~3个R3a取代的苯基;R3a为卤素,所述卤素优选为氟、氯或溴。
进一步地,所述式III-1所示化合物的结构如式III-3所示:
其中,R1a、R1b各自独立的选自氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基;
Rx选自氢、氘、氘代或未氘代的C1~2烷基、氘代或未氘代的C1~2烷氧基;
n3为2或3,优选为2;
R3a为卤素,所述卤素优选为氟、氯或溴。
进一步地,所述化合物的结构如式IV所示:
其中,R1a、R1b各自独立的选自氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基;
n1为0或1,优选为1;n2为0或1,优选为1;
Rx选自无、氢、氘、氘代或未氘代的C1~3烷基、氘代或未氘代的C1~3烷氧基、CORx1;Rx1为氘代或未氘代的C1~2烷基;
Y3为CH或N;
m3为0~3的整数,优选为2或3;
R4各自独立的选自氰基、C1~3烷基、C1~3烷氧基、取代或未取代的苯基;所述苯基上的取代基选自卤素、C1~3烷基或C1~3烷氧基。
进一步地,所述化合物选自以下化合物之一:
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本发明还提供了上述化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物在制备EP300抑制剂、CBP抑制剂或EP300/CBP抑制剂中的用途。
进一步地,所述EP300/CBP抑制剂为预防和/或***、髓系造血干/祖细胞恶性疾病,调控调节性T细胞的药物;
优选的,所述肿瘤选自血液恶性肿瘤、胃癌、肠癌、***、膀胱癌、喉癌、肝癌、肺癌、乳腺癌、卵巢癌、***癌、淋巴瘤或多发性骨髓瘤,所述髓系造血干/祖细胞恶性疾病为白血病;
更优选的,所述淋巴瘤为非霍奇金淋巴瘤、漫大B细胞淋巴瘤,所述白血病为急性髓细胞白血病。
本发明还提供了一种治疗疾病的药物,所述药物是以上述化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物为活性成分,加上药学上可接受的辅料制得的制剂。
本发明还提供了一种联合用药,它含有相同或不同规格单位制剂的用于同时或者分别给药的上述化合物、或其氘代物、或其盐、或其构象异构体、或其晶型、或其溶剂合物,和其他具有抗肿瘤作用的药物,以及药学上可接受的载体。
进一步地,所述其他具有抗肿瘤作用的药物为化疗药物或放疗药物,优选地,所述化疗药物为靶向药物。
进一步地,所述其他具有抗肿瘤作用的药物选自CDK4/6抑制剂、PARP抑制剂、雄激素受体抑制剂、免疫检查点抑制剂中的一种或两种以上,所述CDK4/6抑制剂优选为palbociclib。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“EP300/CBP抑制剂”指能够同时抑制EP300和CBP活性的抑制剂。
“EP300”即“P300”,“EP300/CBP抑制剂”即“P300/CBP抑制剂”。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表示任何含“a”至“b”个碳原子的烷基。例如,C1~5烷基是指包含1~5个碳原子的直链或支链的烷基。
类似的,C1~5烷氧基是指包含1~5个碳原子的直链或支链的烷氧基。
本文“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换,包括该分子中同位原子或异位原子上的1个、2个或多个取代。
环烷基指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“5~6元饱和或不饱和环烷基”指环碳原子数为5~6的饱和或不饱和的环烷基。
杂环基指饱和或不饱和的环状烃取代基,环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N)。例如,“5~6元饱和或不饱和杂环基”指环原子数为5~6的饱和或不饱和的杂环基。
芳基指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
杂芳基指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
“盐”是将化合物或其立体异构体,与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
“其溶剂合物”指本发明化合物与溶剂形成溶剂合物,其中,所述溶剂包括(但并不限于):水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
“其氘代物”指本发明化合物中的1个或多个氢原子被氘替换后所得的化合物。
本发明式I’所示化合物中,“L0选自无或C1~2亚烷基”表示L0为无或C1~2亚烷基;其中,当L0为无时,式I’所示化合物结构为
实验结果表明,本发明提供的化合物对EP300/CBP具有高度选择性,并且能够有效抑制EP300/CBP的活性;而且,本发明化合物对包括***癌细胞、白血病细胞、乳腺癌细胞、多发性骨髓瘤细胞在内的多种肿瘤细胞均具有优异的抑制作用。因此,本发明化合物在制备EP300/CBP抑制剂,以及预防和/或***、髓系造血干/祖细胞恶性疾病,调控调节性T细胞的药物中具有广阔的应用前景。
本发明化合物还可以与其他抗肿瘤的药物(比如CDK4/6抑制剂)联用,以制备预防和/或***的联合用药物,具有非常好的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。以下为中间体化合物的合成方法:
1、中间体4-溴-N-((反式)-4-甲氧基环己基)-2-硝基苯胺(中间体1)的合成:
将4-溴-1-氟-2-硝基苯(3.38g,15.4mmol),(反式)-4-甲氧基环已基-1-胺(2g,15.4mmol)以及碳酸钾(5.34g,38.6mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入200mL水,过滤,水洗,滤饼经柱层析得到4.5g固体(中间体1),收率88.9%。
2、中间体4-溴N1-((反式)-4-甲氧基环己基)苯-1,2-二胺(中间体2)的合成:
将中间体1(4.5g,13.7mmol),氨水(10mL),溶于150mL四氢呋喃和150mL水中,加入连二亚硫酸钠(38g,185mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到3.5g固体(中间体2),收率85.6%。
3、中间体4-(3,5-二甲基异恶唑-4-基)-N1-((反式)-4-甲氧基环己基)苯-1,2-二胺(中间体3)的合成:
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将中间体2(3.5g,11.7mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.87g,12.8mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.12mmol),碳酸钾(3.23g,23.4mmol)溶于60mL二氧六环和10mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到2.5g固体(中间体3),收率68%。
4、中间体4-溴-N-((反式)-4-羟基环己基)-2-硝基苯胺(中间体4)的合成:
将4-溴-1-氟-2-硝基苯(3.38g,15.4mmol),(反式)-4-羟基环已基-1-胺(1.77g,15.4mmol)以及碳酸钾(5.34g,38.6mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入200mL水,过滤,水洗,滤饼经柱层析得到4.1g固体(中间体4),收率84.9%。
5、中间体4-溴-N-(((反式)-4-(甲氧基-d3)环己基)-2-硝基苯胺(中间体5)的合成:
将中间体4(4g,12.7mmol),氢化钠(0.6g,25.4mmol)溶于40mL四氢呋喃中,冰浴下,滴加氘代碘甲烷(2.8g,19mmol),反应过夜。倒入冰水中,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到2.8g产品(中间体5),收率66%。
6、中间体4-溴N1-((反式)-4-(甲氧基-d3)环己基)苯-1,2-二胺(中间体6)的合成:
将中间体5(4.5g,13.7mmol),氨水(10mL),溶于150mL四氢呋喃和150mL水中,加入连二亚硫酸钠(38g,185mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到3.4g固体(中间体6),收率83%。
7、中间体4-(3,5-二甲基异恶唑-4-基)-N1-((反式)-4-(甲氧基-d3)环己基)苯-1,2-二胺(中间体7)的合成:
将中间体6(3.5g,11.7mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.87g,12.8mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.12mmol),碳酸钾(3.23g,23.4mmol)溶于60mL二氧六环和10mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到2.4g固体(中间体7),收率66%。
8、中间体N-(叔丁氧羰基)-O-(叔丁基二甲基甲硅烷基)-L-高丝氨酸(中间体8)的合成:
向N-Boc高丝氨酸(15g,68mmol),咪唑(11.6g,170mmol),的150mL二氯甲烷溶液中,冰浴下滴加叔丁基二甲基氯硅烷(22.6g,150mmol)的二氯甲烷溶液,反应过夜。水洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩。残余物中加入30mL甲醇,30mL四氢呋喃,30mL水,15g碳酸钾。室温搅拌过夜,浓缩掉大部分甲醇和四氢呋喃。调pH至3-4,乙酸乙酯萃取,无水硫酸钠干燥,浓缩得22g产品(中间体8),直接用于下一步反应。
9、中间体N-(叔丁氧羰基)-O-(叔丁基二甲基甲硅烷基)-L-高丝氨酸甲酯(中间体9)的合成:
将中间体8(22g,66mmol),碳酸钾(26g,188mmol)溶于N,N-二甲基甲酰胺(100mL)中。室温下,向上述溶液滴加碘甲烷(22.4g,158mmol),反应过夜。加入200mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到16g产品(中间体9),两步收率:67.5%。
10、中间体(S)-(4-((叔丁基二甲基甲硅烷基)氧基)-1-氧丁烷-2-基)氨基甲酸叔丁酯(中间体10)的合成:
将中间体9(9g,26mmol)溶于甲苯(50mL)中,氮气氛,-78℃下,滴加DIBAL-H(31mL,1.5M),滴完反应1小时。滴加3mL甲醇淬灭反应。搅拌10分钟后,冰浴下,将反应液倒入1N盐酸中,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化得到7.2g产品(中间体10),收率:87.8%。
以下为本发明具体目标化合物的合成方法:
实施例100化合物(1S,4S,5R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((1r,4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-酮(化合物100)的合成:
(1R,2S,5S)-3-叔丁基-2-甲基-6,6-二甲基-4-氧代-3-氮杂双环[3.1.0]己烷-2,3-二羧酸酯(化合物100-2)的合成:
将原料100-1(269mg,1mmol),高碘酸钠(850mg,4mmol)溶于8mL乙腈和8mL水中。冰水浴冷却下,加入5毫克三氯化钌,反应5小时。倒入水中,EA萃取,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析得到112mg产品(中间体100-2),收率40%。
Ms:284(M+H+)
(1R,2S,5S)-6,6-二甲基-4-氧代-3-氮杂双环[3.1.0]己-2-羧酸甲酯(中间体100-3)的合成:
将中间体100-2(283mg,1mmol)溶于二氯甲烷,向其中加入2M HCl的乙酸异丙酯溶液,室温反应一个小时。浓缩,得到165mg产品(中间体100-3),收率90%。Ms:184(M+H+)
(1R,2S,5S)-3-(3,4-二氟苯基)-6,6-二甲基-4-氧代-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯(中间体100-4)的合成:
将中间体100-3(183mg,1mmol),3,4-二氟苯硼酸(632mg,4mmol),一水醋酸铜(300mg,1.5mmol),三乙胺(150mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到148mg产品(中间体100-4),收率50%。Ms:296(M+H+),
(1S,4S,5R)-3-(3,4-二氟苯基)-4-(羟甲基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-酮(中间体100-5)的合成:
将中间体100-4(295mg,1mmol),溶于10mL甲醇中,滴入硼氢化锂的四氢呋喃溶液,室温反应过夜。倒入水中,萃取,饱和食盐水洗,无水硫酸钠干燥,浓缩,得到260mg粗产品(中间体100-5),收率90%。Ms:268(M+H+)
(1R,2S,5S)-3-(3,4-二氟苯基)-6,6-二甲基-4-氧代-3-氮杂双环[3.1.0]己烷-2-甲醛(中间体100-6)的合成:
将中间体100-5(267mg,1mmol),溶于10mL二氯甲烷中,加入Dess-Martin(2167mg,5mmol),室温反应过夜。过滤,滤液浓缩,得到250mg粗产品(中间体100-6),收率90%。Ms:266(M+H+)(1S,4S,5R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((1r,4S)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-酮(化合物100)的合成:
将中间体100-6(290mg,1.1mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入中间体3(315mg,1mmol)以及焦亚硫酸钠(360mg,1.9mmol),80度下反应5小时。加入80mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到392mg产品(化合物100),收率:70%。
Ms:561(M+H+).
1HNMR(400MHz,CDCl3)δ7.71(m,3H),7.28(m,1H),7.12(m,2H),5.78(s,1H),4.60(s,1H),3.42(s,3H),3.33(s,1H),2.42-2.28(m,9H),2.09-1.00(m,13H).
实施例101化合物2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(101)的合成:
4-(2-羟乙基)-1,3,2-二氧硫代烷-2,2-二氧化物(中间体101-1)的合成:
将1,2,4-三丁醇(10.0g,94.2mmol)加入吡啶(15.2mL)和乙腈(100mL)中,0℃条件下滴加二氯亚砜(34.4mL),反应液在室温下继续搅拌反应15h。反应完成后,加入乙酸乙酯(20mL)和0.1M盐酸溶液(10mL),并用乙酸乙酯萃取(10mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到油状物14.5g。
将上述14.5g油状物溶于乙腈(200mL)和水(40mL)中,并加入高碘酸钠(19.6g)和氯化钌水合物(172mg),室温搅拌反应15h。反应完成后,减压蒸馏除去乙腈,并用乙酸乙酯萃取(100mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到13.8g油状物(中间体101-1),收率78.4%。
2-(2-氯乙基)-1-((二苯基亚甲基)氨基)环丙烷羧酸乙酯(中间体101-2)的合成:
将2-((二苯基亚甲基)氨基)乙酰乙酸乙酯(10.7g,40mmol)加入四氢呋喃(50mL)中,0℃条件下加入氢化钠(3.2g,80mmol),反应液在室温下搅拌反应1h,滴加中间体101-1(7.5g,40mmol)的四氢呋喃溶液(20mL)。反应液在室温下搅拌反应1h后,将反应液温度升高到40℃,继续搅拌反应2h。待反应液冷却到室温后,倒入水(100mL)中,并用乙酸乙酯萃取(50mL×2),有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到11.6g油状物(中间体101-2),收率81.5%。
2-氮杂双环[3.1.0]正己烷-1-羧酸乙酯-2-羧酸叔丁酯(中间体101-3)的合成:
将中间体101-2(10.7g,30mmol)加入四氢呋喃(50mL)和1M盐酸(100mL)中,反应液在40℃下搅拌反应3h。反应完成后,减压蒸馏除去溶剂,得到油状物。
将上述油状物溶于乙醇(50mL)中,加入碳酸钾(27.6g,0.2mol),反应液在室温下搅拌反应4h后,加入(Boc)2O(7.8g,36mmol),继续搅拌反应6h。反应完成后,减压蒸馏除去溶剂,加入乙酸乙酯(50mL)和水(30mL),并用乙酸乙酯萃取(30mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到6.6g油状物(中间体101-3),收率85.2%。
3-氧代-2-氮杂双环[3.1.0]正己烷-1-羧酸乙酯-2-羧酸叔丁酯(中间体101-4)的合成:
将中间体101-3(7.7g,30mmol)油状物溶于乙腈(50mL)和水(10mL)中,并加入高碘酸钠(6.6g)和氯化钌水合物(58mg),室温搅拌反应15h。反应完成后,减压蒸馏除去乙腈,并用乙酸乙酯萃取(30mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到2.1g(中间体101-4),收率25.5%。
1-(羟甲基)-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体101-5)的合成:
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将中间体101-4(1.3g,5mmol)溶于甲醇(10mL)中,并加入硼氢化锂(219mg,10mmol),反应液在40℃下搅拌反应3h。反应完成后,加入乙酸乙酯(30mL)和水(10mL),并用乙酸乙酯萃取(20mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到1.02g(中间体101-5),收率89.5%。
1-甲酰基-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体101-6)的合成:
将中间体101-5(909mg,4mmol)溶于二氯甲烷(10mL)中,并加入戴斯马丁试剂(2.5g,6mmol),反应液在室温下搅拌反应3h。反应完成后,过滤除去不溶物,滤液经减压蒸馏除去溶剂,柱层析得到785mg(中间体101-6),收率87.2%。
1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体101-7)的合成:
将中间体3(535mg,1.7mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体101-6(428mg,1.9mmol)以及焦亚硫酸钠(720mg,3.8mmol),80℃下反应5h。加入水(40mL),乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到604mg产品(中间体101-7),收率:68.2%。
1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(中间体101-8)的合成:
将中间体101-7(521mg,1mmol)溶于二氯甲烷(4mL)中,加入三氟乙酸(2mL)后,在室温下搅拌反应3h,反应完成后,减压蒸馏除去溶剂,得到粗品,未经纯化直接用于下一步反应。
2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(化合物101)的合成:
将中间体101-8(84mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到51mg产品(化合物101),收率47.7%。Ms:533(M+H+),1H NMR:(400MHz,d6-DMSO)δ7.77(d,J=8.5Hz,1H),7.68-7.56(m,2H),7.47-7.33(m,2H),7.16(d,J=7.4Hz,1H),4.25(t,J=11.8Hz,1H),3.29(s,3H),2.79(d,J=18.7Hz,1H),2.37(s,3H),2.29-2.12(m,8H),2.07(dd,J=13.7,7.8Hz,1H),1.88(s,1H),1.50-1.14(m,6H).
实施例102化合物(1S,5S)-2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(102)的合成:
(S)-4-(2-羟乙基)-1,3,2-二氧硫代烷-2,2-二氧化物(中间体102-1)的合成:
将(S)-1,2,4-三丁醇(10.0g,94.2mmol)加入吡啶(15.2mL)和乙腈(100mL)中,0℃条件下滴加二氯亚砜(34.4mL),反应液在室温下继续搅拌反应15h。反应完成后,加入乙酸乙酯(20mL)和0.1M盐酸溶液(10mL),并用乙酸乙酯萃取(10mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到油状物14.2g。
将上述14.2g油状物溶于乙腈(200mL)和水(40mL)中,并加入高碘酸钠(19.2g)和氯化钌水合物(168mg),室温搅拌反应15h。反应完成后,减压蒸馏除去乙腈,并用乙酸乙酯萃取(100mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到13.2g油状物(中间体102-1),收率75%。
(1S)-2-(2-氯乙基)-1-((二苯基亚甲基)氨基)环丙烷羧酸乙酯(中间体102-2)的合成:
将2-((二苯基亚甲基)氨基)乙酰乙酸乙酯(10.7g,40mmol)加入四氢呋喃(50mL)中,0℃条件下加入NaH(3.2g,80mmol),反应液在室温下搅拌反应1h,滴加中间体102-1(7.5g,40mmol)的四氢呋喃溶液(20mL)。反应液在室温下搅拌反应1h后,将反应液温度升高到40℃,继续搅拌反应2h。待反应液冷却到室温后,倒入水(100mL)中,并用乙酸乙酯萃取(50mL×2),有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,得到11.5g油状物(中间体102-2),收率80.5%。
(1S,5R)-2-氮杂双环[3.1.0]正己烷-1-羧酸乙酯-2-羧酸叔丁酯(中间体102-3)的合成:
将中间体102-2(10.7g,30mmol)加入四氢呋喃(50mL)和1M盐酸(100mL)中,反应液在40℃下搅拌反应3h。反应完成后,减压蒸馏除去溶剂,得到油状物。
将上述油状物溶于乙醇(50mL)中,加入碳酸钾(27.6g,0.2mol),反应液在室温下搅拌反应4h后,加入(Boc)2O(7.8g,36mmol),继续搅拌反应6h。反应完成后,减压蒸馏除去溶剂,加入乙酸乙酯(50mL)和水(30mL),并用乙酸乙酯萃取(30mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到6.4g油状物(中间体102-3),收率82.6%。
(1S,5R)-3-氧代-2-氮杂双环[3.1.0]正己烷-1-羧酸乙酯-2-羧酸叔丁酯(中间体102-4)的合成:
将中间体102-3(7.7g,30mmol)油状物溶于乙腈(50mL)和水(10mL)中,并加入高碘酸钠(6.6g)和氯化钌水合物(58mg),室温搅拌反应15h。反应完成后,减压蒸馏除去乙腈,并用乙酸乙酯萃取(30mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到2.3g(中间体102-4),收率27.5%。
(1S,5R)-1-(羟甲基)-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体102-5)的合成:
将中间体102-4(1.3g,5mmol)溶于甲醇(10mL)中,并加入硼氢化锂(219mg,10mmol),反应液在40℃下搅拌反应3h。反应完成后,加入乙酸乙酯(30mL)和水(10mL),并用乙酸乙酯萃取(20mL×2)。有机相用饱和的食盐水(20mL)洗涤一次,经无水硫酸钠干燥,过滤得到滤液。滤液经减压蒸馏除去溶剂,柱层析得到1.04g(中间体102-5),收率91.5%。
(1S,5S)-1-甲酰基-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体102-6)的合成:
将中间体102-5(909mg,4mmol)溶于二氯甲烷(10mL)中,并加入戴斯马丁试剂(2.5g,6mmol),反应液在室温下搅拌反应3h。反应完成后,过滤除去不溶物,滤液经减压蒸馏除去溶剂,柱层析得到761mg(中间体102-6),收率84.5%。
(1S,5S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体102-7)的合成:
将中间体7(541mg,1.7mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体102-6(428mg,1.9mmol)以及焦亚硫酸钠(720mg,3.8mmol),80℃下反应5h。加入水(40mL),乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到609mg产品(中间体102-7),收率:68.8%。
(1S,5S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(中间体102-8)的合成:
将中间体102-7(524mg,1mmol)溶于二氯甲烷(4mL)中,加入三氟乙酸(2mL)后,在室温下搅拌反应3h,反应完成后,减压蒸馏除去溶剂,得到粗品,未经纯化直接用于下一步反应。
(1S,5S)-2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(化合物102)的合成:
将中间体102-8(85mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到49mg产品(化合物102),收率46.2%。Ms:536(M+H+),1H NMR:(400MHz,d6-DMSO)δ7.77(d,J=8.5Hz,1H),7.66(s,1H),7.59(d,J=10.1Hz,1H),7.51-7.30(m,2H),7.16(d,J=8.2Hz,1H),4.25(s,1H),2.79(d,J=18.7Hz,1H),2.37(s,3H),2.30-2.09(m,8H),2.09-2.00(m,1H),1.88(s,1H),1.57-1.09(m,6H)
实施例103化合物(1S,5S)-2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(103)的合成:
(1S,5S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-氧代-2-氮杂双环[3.1.0]正己烷-2-羧酸叔丁酯(中间体103-1)的合成:
将中间体3(535mg,1.7mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体102-6(428mg,1.9mmol)以及焦亚硫酸钠(720mg,3.8mmol),80℃下反应5h。加入水(40mL),乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到589mg产品(中间体103-1),收率:66.5%。
(1R,5R)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(中间体103-2)的合成:
将中间体103-1(521mg,1mmol)溶于二氯甲烷(4mL)中,加入三氟乙酸(2mL)后,在室温下搅拌反应3h,反应完成后,减压蒸馏除去溶剂,得到粗品,未经纯化直接用于下一步反应。
(1S,5S)-2-(3,4-二氟苯基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氮杂双环[3.1.0]己烷-3-酮(化合物103)的合成:
将中间体103-2(84mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到51mg产品(化合物103),收率47.5%。Ms:533(M+H+),1H NMR:(400MHz,d6-DMSO)δ7.77(d,J=8.5Hz,1H),7.66(d,J=1.3Hz,1H),7.60(ddd,J=12.1,7.2,2.3Hz,1H),7.41(dt,J=17.5,9.0Hz,2H),7.16(dd,J=8.5,1.5Hz,1H),4.25(t,J=12.3Hz,1H),3.29(s,3H),2.79(d,J=18.7Hz,1H),2.37(s,3H),2.29-2.12(m,8H),2.05(dd,J=8.5,5.8Hz,1H),1.88(s,1H),1.44(dd,J=16.9,11.3Hz,2H),1.35-1.19(m,4H).
实施例104化合物(R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-酮(104)的合成:
(R)-叔丁基4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2,2-二甲基恶唑烷-3-羧酸酯(104-2)的合成:
将化合物104-1(230mg,1mmol),中间体3(315mg,1mmol),偏重亚硫酸钠(380mg,2mmol)溶于N,N-二甲基甲酰胺(4mL)中,反应加热到80℃反应3~4个小时,反应完毕后加入水,用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析后得300mg(104-2),收率:57%
(R)-2-氨基-2-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)乙醇盐酸盐(104-3)的合成:
将化合物104-2(300mg,1mmol),溶于甲醇(2mL)和浓盐酸(2mL)中,反应过夜,反应完毕后浓缩得230mg(104-3),收率:96%
(R)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-硫酮(中间体104-4)
将中间体104-3(130mg,0.34mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,冰浴下,分批加入硫光气(20mg,0.17mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体104-4)85mg,收率:60%。
(R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-酮(化合物104)的合成:
将中间体104-4(83mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到50mg产品(化合物104),收率48.9%。Ms:539(M+H+),1H NMR(400MHz,d6-DMSO)δ7.8-7.7(m,2H),7.65-7.61(m,1H),7.55-7.48(m,2H),7.4-7.3(m,1H),5.75-5.73(m,1H),5.47-5.45(m,1H),4.71-4.65(m,1H),4.58-4.55(m,1H),3.25(s,3H),2.41(s,3H),2.35-2.30(m,2H),2.25(s,3H),2.15-2.1(m,2H),2.01-1.95(m,1H),1.80-1.75(m,1H),1.55-1.5(m,1H),1.37-1.22(m,2H).
实施例105化合物(R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-酮(105)的合成:
(R)-4-(5-(3,5-二甲基异恶唑-4-基)-1-(反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-酮(中间体105-1)
将中间体104-3(130mg,0.34mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,冰浴下,分批加入三光气(48.3mg,0.17mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体105-1)85mg,收率:60%。
(R)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)恶唑烷-2-酮(化合物105)的合成:
将中间体105-1(83mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到50mg产品(化合物105),收率48.9%。Ms:523(M+H+),1H NMR(400MHz,d6-DMSO)δ7.72(d,J=8.5Hz,1H),7.53-7.58(m,2H),7.36-7.16(m,1H),7.00-7.08(m,2H),6.21(d,J=5.9Hz,1H),4.71(t,J=8.4Hz,1H),4.37(m,2H),3.31(s,1H),3.17(s,3H),2.23(s,3H),2.15(d,J=12.3Hz,2H),2.06(s,3H),2.01(d,J=9.3Hz,2H),1.80(d,J=13.2Hz,1H),1.55(d,J=12.3Hz,1H),1.37-1.22(m,2H).
实施例106化合物(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-(反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,4-氧代氮杂烷-3-酮(106)的合成:
叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体106-1)的合成:
将中间体10(600mg,1.9mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入中间体3(535mg,1.7mmol)以及焦亚硫酸钠(720mg,3.8mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到720mg产品(中间体106-1),收率:70.6%。
叔丁基(S)-3-羟基-1-(1-((反式)-4-甲氧基环己基)-5-(3-甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-氨基甲酸丙基)(中间体106-2)的合成:
将中间体106-1(500mg,0.82mmol),氟氢化钾(320mg,4.1mmol)溶于甲醇(20mL)和水(4mL)中,30度反应过夜。浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,得到356mg产品(中间体106-2),收率:90%。
叔丁基2-((S)-3-(叔丁氧羰基氨基)-3-(1-(反式)-4-甲氧基环己基)-5-(3-甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-基)丙氧基)乙酸酯(化合物106-3)的合成:
将中间体106-2(300mg,0.62mmol)溶于无水的四氢呋喃(5mL)中,在冰浴下分批加入氢化钠(62mg,1.55mmol),加入完毕后撤去冰浴,常温反应半个小时,在加入溴乙酸叔丁酯(157mg,0.81mmol),反应大约2-3个小时,加入氯化铵水溶液,用乙酸乙酯萃取,无水硫酸钠干燥,浓缩柱层析后得105mg产品(中间体106-3),收率:28%。
2-((S)-3-氨基-3-(1-(反式)-4-甲氧基环己基)-5-(3-甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-酰基)丙氧基)乙酸盐酸盐(化合物106-4)的合成:
向中间体106-3(105mg,0.18mmol)加入浓盐酸(2mL),室温搅拌3个小时,反应完毕后旋去溶剂得产品80mg(中间体106-4),收率:93%。
(S)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,4-氧代氮杂烷-3-酮(中间体106-5)的合成:
将中间体106-4(80mg,0.17mmol),二异丙基乙基胺(71mg,0.55mmol)溶于N,N-二甲基甲酰胺中,搅拌下加入HATU(97mg,0.26mmol),反应常温搅拌过夜,反应完毕后加入水,用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后制备板纯化后的得48mg产品(中间体106-5),收率:65%。
(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-(反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,4-氧代氮杂烷-3-酮(产品106)的合成:
将中间体106-5(30mg,0.07mmol),3,4-二氟苯硼酸(44mg,0.28mmol),一水醋酸铜(22mg,0.11mmol),三乙胺(14mg,0.14mmol)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,制备板纯化后得到21mg产品(化合物106),收率56%。Ms:551(M+H+),1H NMR(400MHz,d6-DMSO)δ7.86(d,J=8.5Hz,1H),7.72(d,J=1.2Hz,1H),7.40(dd,J=19.6,9.1Hz,1H),7.34-7.23(m,1H),7.23-7.11(m,1H),6.95(d,J=8.6Hz,1H),5.70(s,1H),4.83(d,J=15.1Hz,1H),4.37(d,J=15.0Hz,2H),3.98(d,J=12.2Hz,1H),3.40(d,J=11.3Hz,2H),3.27(s,3H),2.85-2.60(m,1H),2.42(s,3H),2.37-2.20(m,6H),2.17-2.07(m,1H),2.03(d,J=12.2Hz,1H),1.82(d,J=11.2Hz,1H),1.50(d,J=12.5Hz,1H),1.42-1.27(m,2H)。
实施例107化合物4-(2-((((2S,5S)-2-(3,4-二氟苯基)-5-甲基吡咯烷-1-基)甲基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(107)的合成:
2-((2S,5S)-2-(3,4-二氟苯基)-5-甲基吡咯烷-1-基)乙酸叔丁酯(中间体107-2)的合成:
将化合物107-1100mg,0.51mmol),溴乙酸叔丁酯(119mg,0.61mmol)溶于乙腈(3mL),向反应液中加入碳酸钾(176mg,1.3mmol),反应常温搅拌过夜,反应完毕后加入水,用乙酸乙酯萃取三次,合并,无水硫酸钠干燥,浓缩,得155mg粗品(107-2),收率:97%。
2-((2S,5S)-2-(3,4-二氟苯基)-5-甲基吡咯烷-1-基)乙酸(中间体107-3)的合成:
将粗品107-2(155mg,0.5mmol)加入到浓盐酸(3mL)中,反应搅拌过夜,反应完毕浓缩得粗品103mg(107-3),收率:71%。
2-((2S,5S)-2-(3,4-二氟苯基)-5-甲基吡咯烷-1-基)-N-(5-(3,5-二甲基异恶唑-4-基)-2-((反式)-4-甲氧基环己基氨基)苯基)乙酰胺(中间体107-4)的合成:
将化合物107-3(30mg,0.1mmol),中间体3(36mg,0.11mmol),二异丙基乙基胺(52mg,0.4mmol)溶于N,N-二甲基甲酰胺(2mL),搅拌下加入HATU(57mg,0.15mmol)。反应搅拌过夜,反应完成后加入水,乙酸乙酯萃取三次,合并,无水硫酸钠干燥,浓缩,制备板纯化后得21mg产品(中间体107-4),收率:38%。
4-(2-((((2S,5S)-2-(3,4-二氟苯基)-5-甲基吡咯烷-1-基)甲基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(107)的合成:
将中间体107-4(21mg,0.04mmol)溶于醋酸(3mL)中,加热到60℃,反应过夜,反应完毕后用碳酸钾水溶液调节pH~9-10,用乙酸乙酯萃取三次,合并,无水硫酸钠干燥,浓缩后制备板纯化得8mg产品(107),收率:37%。Ms:535(M+H+),1H NMR(400MHz,d6-DMSO)δ7.72(d,J=8.5Hz,1H),7.51(d,J=1.3Hz,1H),7.42-7.31(m,1H),7.30-7.14(m,2H),7.10(dd,J=8.5,1.5Hz,1H),4.20(t,J=12.2Hz,1H),3.82(s,2H),3.75(t,J=7.5Hz,1H),3.43-3.30(m,4H),3.00(dd,J=12.9,6.6Hz,1H),2.39(s,3H),2.24-1.91(m,10H),1.74-1.48(m,3H),1.38-1.28(m,1H),0.95(dd,J=23.6,9.7Hz,1H),0.82(d,J=6.0Hz,3H)。
实施例108化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1-甲基四氢嘧啶-2(1H)-酮(108)的合成:
((S)-3-((叔丁基二甲基硅基)氧基)-1-(5-(3,5-二甲基异噁唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)丙基)氨基甲酸叔丁酯(108-1)的合成
将中间体10(380mg,1.2mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入中间体7(318mg,1mmol)以及偏重亚硫酸钠(379mg,2mmol),80℃下反应5小时。加入25mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到中间体108-1(460mg,0.75mmol),收率:75%。
(S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-3-羟丙基)氨基甲酸叔丁酯(中间体108-2)的合成:
将中间体108-1(460mg,0.75mmol)溶于甲醇(4mL)和水(1mL)中,再加入KHF2(117mg,1.5mmol),30℃反应过夜。浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到245mg中间体108-2,收率:81.5%。
(S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-3-氧丙基)氨基甲酸叔丁酯(中间体108-3)的合成:
将中间体108-2(502mg,1mmol)溶于二氯甲烷(10mL)中,并加入戴斯马丁(625mg,1.5mmol),反应液在室温下搅拌反应3h。反应完成后,过滤除去不溶物,滤液经减压蒸馏除去溶剂,柱层析得到475mg(中间体108-3),收率95.1%。
(S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-3-(甲氨基)丙基)氨基甲酸叔丁酯(中间体108-4)的合成:
将中间体108-3(400mg,0.8mmol)溶于甲醇(5mL)中,并加甲胺(25mg,0.8mmol)的醇溶液和醋酸硼氢化钠(170mg,0.8mmol),反应液在室温下搅拌反应5h。反应完成后,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到371mg(中间体108-4),收率90.2%。
(S)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-N3-甲基丙烷-1,3-二胺(中间体108-5)的合成:
将中间体108-4(309mg,0.6mmol)溶于甲醇(5mL)中,加入3mL浓盐酸,30℃反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到228mg产品(中间体108-5),收率:92.5%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1-甲基四氢嘧啶-2(1H)-酮(中间体108-6)的合成:
将中间体108-5(137mg,0.33mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,冰浴下,分批加入三光气(48.3mg,0.17mmol),反应30min。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到86mg产品(中间体108-6),收率:59.5%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1-甲基四氢嘧啶-2(1H)-酮(化合物108)的合成:
将中间体108-6(88mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到45mg产品(化合物108),收率40.7%。Ms:553(M+H+)
实施例109化合物(S)-3-(4-氯-3-氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1-甲基四氢嘧啶-2(1H)-酮(109)的合成:
将中间体108-6(88mg,0.2mmol),4-氯-3-氟苯硼酸(140mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到47mg产品(化合物109),收率41.5%。Ms:569(M+H+)
实施例110化合物(S)-1-(3,4-二氟苯基)-6-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-甲基二氢嘧啶-2,4(1H,3H)-二酮(110)的合成:
(S)-N-(5-(3,5-二甲基异恶唑-4-基)-2-(((((反式)-4-甲氧基环己基)氨基)苯基)-1-甲基-2,6-二氧六氢嘧啶-4-羧酰胺(中间体110-1)的合成:
将中间体3(630mg,2mmol),(S)-1-甲基-2,6-二氧六氢嘧啶-4-羧酸(340mg,2mmol),HATU(910mg,2.4mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入三乙胺(400mg,4mmol)常温下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到620mg产品(中间体110-1),收率:66.1%。
(S)-6-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-甲基二氢嘧啶-2,4(1H,3H)-二酮(中间体110-2)的合成:
将中间体110-1(620mg,1.3mmol)溶于乙酸(20mL)中,50度反应过夜。浓缩,加入水(20ml),二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到180mg产品(中间体110-2),收率:29.8%。
(S)-1-(3,4-二氟苯基)-6-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-甲基二氢嘧啶-2,4(1H,3H)-二酮(化合物110)的合成:
将中间体110-2(90mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到35mg产品(化合物110),收率31.4%。Ms:564(M+H+),1H NMR(400MHz,d6-DMSO)δ7.82(d,J=8.5Hz,1H),7.64(d,J=1.5Hz,1H),7.48(ddd,J=26.0,13.5,5.8Hz,2H),7.17(dt,J=5.7,2.8Hz,1H),7.14-7.07(m,1H),5.86(d,J=5.0Hz,1H),4.17(t,J=12.0Hz,1H),3.69(dd,J=16.5,6.9Hz,1H),3.37(dd,J=11.4,7.3Hz,1H),3.26(s,3H),3.11(s,3H),2.89(dt,J=16.5,8.1Hz,1H),2.39(s,3H),2.27-2.14(m,4H),2.14-1.93(m,2H),1.81(d,J=12.1Hz,1H),1.38-1.18(m,4H).
实施例111化合物(R)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)吗啉-3-酮(111)的合成:
2-氯-N-((R)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-羟乙基)乙酰胺(中间体111-1)的合成:
将中间体104-3(100mg,0.24mmol),二异丙基乙基胺(93mg,0.72mmol),溶于二氯甲烷(3mL)中,冰浴下滴加氯乙酰氯(30mg,0.26mmol),滴加完毕后撤去冰浴,反应完毕后加入水,用二氯甲烷萃取,无水硫酸钠干燥,浓缩后柱层析得63mg(111-1),收率:57%。
(R)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)吗啉-3-酮的(中间体111-2)合成:
将中间体111-1(63mg,0.14mmol)溶于无水四氢呋喃(3mL)中,在冰浴下分批加入氢化钠(16mg,0.41mmol),加完后撤去冰浴常温反应,反应完毕后加入氯化铵水溶液,用乙酸乙酯萃取,无水硫酸钠干燥,浓缩后制备板纯化得35mg(111-2),收率:59%。
(R)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)吗啉-3-酮(化合物111)的合成:
将中间体111-2(35mg,0.08mmol),3,4-二氟苯硼酸(51mg,0.32mmol),一水醋酸铜(24mg,0.12mmol),三乙胺(20mg)溶于4mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到21mg产品(化合物111),收率48%。Ms:537(M+H+),1H NMR(400MHz,d6-DMSO)δ7.81(d,J=8.5Hz,1H),7.68(d,J=1.3Hz,1H),7.52(ddd,J=11.9,7.4,2.3Hz,1H),7.40(dd,J=19.6,9.1Hz,1H),7.15(dd,J=8.5,1.5Hz,2H),5.89(s,1H),4.52-4.28(m,4H),4.14(dd,J=12.1,3.7Hz,1H),3.46-3.39(m,1H),3.28(s,3H),2.39(s,3H),2.32-1.99(m,7H),1.93-1.77(m,1H),1.38(dd,J=15.6,12.8Hz,3H)。
实施例112化合物(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(112)的合成
((S)-2-((叔丁基二甲硅基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)乙基)氨基甲酸叔丁酯(112-1)的合成:
将中间体112(300mg,1mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入中间体3(262mg,0.8mmol)以及偏重亚硫酸钠(379mg,2mmol),80℃下反应5小时。加入25mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到420mg产品(中间体112-1),收率:70.2%。
(S)-2-氨基-2-(5-(3,5-二甲基异恶唑基-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)乙醇(112-2)的合成
将中间体112-1(420mg,0.7mmol)加入甲醇(4mL)中,再加入KHF2(109mg,1.4mmol)以及浓盐酸(1mL),30℃反应过夜。调pH为9~10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到中间体112-2(230mg,0.59mmol),收率:84.2%。
(S)-2-(2-氯乙酰胺)-2-(5-(3,5-二甲基异噁唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-氯乙酰乙酯(112-3)的合成
将112-2(230mg,0.59mmol)溶于二氯甲烷(2mL)中,加入N,N-二异丙基乙胺(155mg,1.18mmol)和氯乙酰氯(133mg,1.18mmol),室温下搅拌4小时。水(2mL)洗,无水硫酸钠干燥,旋干,得中间体112-3(300mg,0.56mmol),收率:95%。
2-氯-N-((S)-1-(5-(3,5-二甲基异噁唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-2-羟乙基)乙酰胺(112-4)的合成
将112-3(300mg,0.56mmol)溶于四氢呋喃(3mL)中,加入水(0.6mL)、氢氧化锂一水合物(47mg,1.12mmol),室温下搅拌4个小时。旋干,加入二氯甲烷(5mL),水(5mL)洗,饱和食盐水(5mL)洗,无水硫酸钠干燥。旋干得中间体112-4(230mg,0.5mmol),收率:90%。
(S)-5-(5-(3,5-二甲基异噁唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(112-5)的合成
将112-4(230mg,0.5mmol)溶于四氢呋喃(2mL)中,加入氢化钠(20mg,0.5mmol)后,室温下搅拌过夜。加入水(4mL),二氯甲烷(4mL×3)萃取,合并有机相,饱和食盐水(4mL)洗,无水硫酸钠干燥,旋干。得中间体112-5(191mg,0.45mmol)。收率:90%。
(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(112)的合成
将中间体112-5(191mg,0.45mmol),3,4-二氟苯硼酸(284mg,1.8mmol),一水醋酸铜(135mg,0.68mmol),三乙胺(45mg,0.45mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物112(123mg,0.23mmol),收率52%。Ms:537(M+H+)。
实施例113化合物(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(113)的合成
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)丙基-1-醇(113-1)的合成
将中间体108-1(460mg,0.75mmol)溶于甲醇(4mL)中,再加入KHF2(117mg,1.5mmol)以及浓盐酸(1mL),30℃反应过夜。调pH为9~10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到中间体113-1(240mg,0.60mmol),收率:80%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(113-2)的合成:
将中间体113-1(240mg,0.60mmol),三乙胺(91mg,0.9mmol)溶于四氢呋喃(20mL)中,冰浴下,分批加入三光气(71mg,0.24mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品中间体113-2(161mg,0.38mmol),收率:63%。
(S)-4-(3,4-二氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(113)的合成
将中间体113-2(161mg,0.38mmol),3,4-二氟苯硼酸(237mg,1.5mmol),一水醋酸铜(115mg,0.57mmol),三乙胺(38mg,0.38mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物113(160mg,0.3mmol),收率78%。Ms:540(M+H+),1H NMR(400MHz,d6-DMSO)δ7.81(d,J=8.5Hz,1H),7.73(d,J=1.0Hz,1H),7.47(ddd,J=11.7,7.4,2.3Hz,1H),7.37(dd,J=19.5,9.2Hz,1H),7.17(dd,J=8.5,1.3Hz,1H),7.11(d,J=8.9Hz,1H),5.83(s,1H),4.58(t,J=10.3Hz,1H),4.44-4.28(m,2H),3.40(d,J=10.8Hz,1H),2.68(t,J=13.0Hz,1H),2.40(s,3H),2.30-2.01(m,8H),1.85(d,J=11.3Hz,1H),1.33(dt,J=29.3,13.7Hz,3H).
实施例114化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物114)的合成:
((S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基丙-1-醇(中间体114-1)的合成:
将中间体106-1(720mg,1.2mmol),氟氢化钾(190mg)溶于甲醇(20mL)中,加入5mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到310mg产品(中间体114-1),收率:73.8%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(中间体114-2)
将中间体114-1(130mg,0.34mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,分批加入三光气(48.3mg,0.17mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体114-2)85mg,收率:60%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物114)的合成:
将中间体114-2(85mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到55mg产品(化合物114),收率51.4%。Ms:537(M+H+),1H NMR(400MHz,d6-DMSO)δ7.67(d,J=8.6Hz,1H),7.59(s,1H),7.37-7.17(m,2H),7.10-6.89(m,2H),5.69(s,1H),4.45(t,J=10.5Hz,1H),4.23(br,2H),3.23(br,1H),3.14(s,3H),2.54(br,1H),2.27(s,3H),2.15-1.79(m,6H),1.93-1.58(m,2H),1.40-1.22(m,4H).
实施例115化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(4-氟苯基)-1,3-噁嗪喃-2-酮(115)的合成:
将中间体114-2(85mg,0.2mmol),4-氟苯硼酸(112mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到45mg产品(化合物115),收率43%。Ms:519(M+H+),1H NMR(400MHz,d6-DMSO)δ7.79(d,J=8.4Hz,1H),7.73(s,1H),7.30(dd,J=8.8,5.1Hz,2H),7.14(dd,J=16.7,8.3Hz,3H),5.76(s,1H),4.65(t,J=10.0Hz,1H),4.36(d,J=10.5Hz,2H),3.37(d,J=5.4Hz,1H),3.27(s,3H),2.67(s,1H),2.41(s,3H),2.32-1.93(m,8H),1.84(s,1H),1.34(t,J=12.6Hz,2H),1.16(s,1H)。
实施例116化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(4-氯苯基)-1,3-噁嗪喃-2-酮(化合物116)的合成:
将中间体114-2(85mg,0.2mmol),4-氯苯硼酸(125mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到50mg产品(化合物116),收率47%。Ms:535(M+H+),1H NMR(400MHz,d6-DMSO)δ7.79(dd,J=8.4,5.1Hz,1H),7.72(d,J=1.3Hz,1H),7.39-7.25(m,4H),7.16(dd,J=8.5,1.5Hz,1H),5.81(s,1H),4.61(t,J=10.0Hz,1H),4.35(d,J=10.2Hz,2H),3.32(s,1H),3.28(s,3H),2.67(s,1H),2.41(s,3H),2.30-2.01(m,8H),1.84(d,J=12.3Hz,1H),1.34(dd,J=17.7,12.1Hz,2H),1.17(d,J=7.1Hz,1H)。
实施例117化合物(S)-3-(3-氟-4-氯苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物117)的合成:
将中间体114-2(85mg,0.2mmol),3-氟-4-氯苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到56mg产品(化合物117),收率51%。Ms:553(M+H+),1H NMR(400MHz,CDCl3)δ7.9-7.71(m,1H),7.65-7.48(m,1H),7.42-7.1(m,4H),4.87(s,1H),4.46-4.17(m,1H),3.41(s,3H),2.45-2.31(m,8H),1.90-1.11(m,11H).
实施例118化合物(S)-3-(3,4,5-三氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物118)的合成:
将中间体114-2(85mg,0.2mmol),3,4,5-三氟苯硼酸(132mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到58mg产品(化合物118),收率51%。Ms:555(M+H+),1H NMR(400MHz,CDCl3)δ7.78-7.71(m,1H),7.6-7.5(m,1H),7.45-7.35(m,1H),7.2-6.96(m,2H),4.87(s,1H),4.46-4.17(m,1H),3.41(s,3H),2.45-2.31(m,8H),1.90-1.11(m,11H).
实施例119化合物(S)-4-(4-氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(119)的合成
将中间体113-2(161mg,0.38mmol),4-氟苯硼酸(210mg,1.5mmol),一水醋酸铜(115mg,0.57mmol),三乙胺(38mg,0.38mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物119(149mg,0.29mmol),收率75%。Ms:522(M+H+),1H NMR(400MHz,d6-DMSO)δ7.79(d,J=8.6Hz,1H),7.73(s,1H),7.29(s,2H),7.14(d,J=7.3Hz,3H),5.77(s,1H),4.63(d,J=9.0Hz,1H),4.34(s,2H),2.67(s,1H),2.41(s,3H),2.26-1.96(m,8H),1.84(s,1H),1.31(d,J=14.5Hz,3H),1.13(s,1H).
实施例120化合物(S)-4-(3,4,5-三氟苯基)-5-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)***-3-酮(120)的合成
将中间体113-3(161mg,0.38mmol),3,4,5-三氟苯硼酸(264mg,1.5mmol),一水醋酸铜(115mg,0.57mmol),三乙胺(38mg,0.38mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物120(162mg,0.29mmol),收率75%。Ms:558(M+H+),1H NMR(400MHz,d6-DMSO)δ7.82(d,J=8.5Hz,1H),7.73(d,J=1.3Hz,1H),7.35(dd,J=9.2,6.5Hz,2H),7.17(dd,J=8.5,1.5Hz,1H),5.88(d,J=2.3Hz,1H),4.51(t,J=10.3Hz,1H),4.42-4.30(m,2H),3.41(dd,J=12.7,8.8Hz,1H),2.68(dd,J=17.5,8.6Hz,1H),2.40(s,3H),2.29-2.04(m,7H),1.88(d,J=11.8Hz,1H),1.37(dd,J=23.7,9.3Hz,3H),1.24(d,J=6.2Hz,1H).
实施例121化合物叔丁基4-((S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2–基)-1,3-恶嗪南-2-酮-3-基)-5,6-二氢吡啶-1(2H)-羧酸酯(121)的合成:
将中间体114-2(85mg,0.2mmol),(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)硼酸(132mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(化合物121),收率51%。Ms:606(M+H+)
实施例122化合物(S)-3-(3-氟-4-氯苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(122)的合成:
将中间体113-3(42mg,0.1mmol),3-氟-4-氯苯硼酸(63mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到35mg产品(化合物122),收率66.1%。Ms:556(M+H+),1H NMR(400MHz,d6-DMSO)δ7.82(d,J=8.3Hz,1H),7.72(s,1H),7.53(t,J=8.6Hz,1H),7.47(d,J=10.7Hz,1H),7.16(t,J=9.9Hz,2H),5.89(s,1H),4.56(t,J=10.7Hz,1H),4.35(d,J=11.1Hz,2H),3.39(br,1H),2.68(br,1H),2.40(s,3H),2.30-2.00(m,7H),1.88(br,1H),1.37-1.13(m,4H).
实施例123化合物(S)-3-(4-氯苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物123)的合成:
将中间体113-3(85mg,0.2mmol),4-氯苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到56mg产品(化合物123),收率51%。Ms:538(M+H+),1H NMR(400MHz,d6-DMSO)δ7.79(dd,J=8.4,5.1Hz,1H),7.72(d,J=1.3Hz,1H),7.35(dt,J=26.3,8.6Hz,4H),7.16(dd,J=8.5,1.5Hz,1H),5.88(d,J=2.3Hz,1H),4.51(t,J=10.3Hz,1H),4.42-4.27(m,2H),3.41(dd,J=12.7,8.8Hz,1H),2.68(dd,J=17.5,8.6Hz,1H),2.40(s,3H),2.34-2.02(m,7H),1.88(d,J=11.8Hz,1H),1.45-1.31(m,3H),1.26-1.21(m,1H)
实施例124化合物(S)-3-(6-氯吡啶-3-基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物124)的合成:
将中间体113-3(85mg,0.2mmol),6-氯-3-硼酸吡啶(125mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(化合物124),收率55.7%。Ms:539(M+H+),1H NMR(400MHz,d6-DMSO)δ8.4(s,1H),7.78-7.75(m,1H),7.75(s,1H),7.51-7.49(m,1H),7.3-7.25(m,1H),7.2-7.15(m,1H),5.88(m,1H),4.51-4.5(m,1H),4.42-4.27(m,2H),,2.75-2.7(m,1H),2.40(s,3H),2.34-2.02(m,8H),1.88-1.8(m,1H),1.45-1.31(m,3H),1.26-1.21(m,1H).
实施例125化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-1,3-恶二酮-2-酮(125)的合成:
叔丁基4-((S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2–基)-1,3-恶嗪南-2-酮-3-基)-5,6-二氢吡啶-1(2H)-羧酸酯(中间体125-1)的合成:
将中间体113-3(85mg,0.2mmol),(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)硼酸(132mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(化合物125-1),收率51%。Ms:609(M+H+)
4-((S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2–基)-1,3-恶嗪南-2-酮-3-基)-5,6-二氢吡啶-1(2H)(中间体125-2)的合成:
将中间体125-1(61mg,0.1mmol)溶于氯化氢的乙酸异丙酯溶液中,反应过夜,浓缩干得产物55mg(中间体125-2),收率93%。Ms:509(M+H+)
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(1-甲基-1,2,3,6-四氢吡啶-4-基)-1,3-恶二酮-2-酮(化合物125)的合成:
将中间体125-2(508mg,1mmol)的盐酸盐溶于甲醇,用三乙胺中和至中性,然后加入醋酸(60mg,1mmol),多聚甲醛(150mg,5mmol),再分批次加入三乙酰氧基硼氢化钠(850mg,4mmol)反应过夜。倒入水中,萃取,无水硫酸钠干燥,浓缩,柱层析得到260mg产品(化合物125),收率50%。Ms:523(M+H+),1H NMR(400MHz,CDCl3)δ7.68(d,J=1.1Hz,1H),7.57(d,J=8.4Hz,1H),7.13(dd,J=8.4,1.5Hz,1H),5.62(s,1H),5.26(s,1H),4.74(t,J=10.6Hz,1H),4.34-4.15(m,2H),3.36(t,J=11.0Hz,1H),3.14(s,2H),2.91-2.62(m,3H),2.59-2.51(m,2H),2.48-2.39(m,6H),2.35-2.22(m,6H),2.05-1.85(m,3H),1.64-1.40(m,3H).
实施例126化合物((S)-3-(4-氯-3-甲氧基苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(126)的合成:
将中间体113-3(85mg,0.2mmol),3-甲氧基-4-氯苯硼酸(149mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到65mg产品(化合物126),收率57.2%。Ms:568(M+H+)
实施例127化合物2-氯-5-((S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-(甲氧基-d3)环己基)-1H-苯并[d]咪唑-2-基)-2-氧代-1,3-恶嗪南-3-基)苄腈(127)的合成:
将中间体113-3(85mg,0.2mmol),3-氰基-4-氯苯硼酸(145mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到64mg产品(化合物127),收率56.9%。Ms:563(M+H+)
实施例128化合物(S)-3-(3,4-二氯苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(128)的合成:
将中间体113-3(85mg,0.2mmol),3,4,-二氯苯硼酸(135mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到57mg产品(化合物128),收率51%。Ms:572(M+H+),1H NMR(400MHz,CDCl3)δ7.79-7.4(m,3H),7.35-7.05(m,3H),5.88(d,J=2.3Hz,1H),4.51(t,J=10.3Hz,1H),4.42-4.27(m,2H),3.41(dd,J=12.7,8.8Hz,1H),2.68(dd,J=17.5,8.6Hz,1H),2.40(s,3H),2.34-2.02(m,7H),1.88(d,J=11.8Hz,1H),1.45-1.31(m,3H),1.26-1.21(m,1H)
实施例129化合物(S)-3-(3-氯-4-氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(129)的合成:
将中间体113-3(85mg,0.2mmol),3-氯-4-氟苯硼酸(135mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到56mg产品(化合物129),收率51%。Ms:556(M+H+),1H NMR(400MHz,d6-DMSO)δ7.95-7.32(m,3H),7.25-6.65(m,3H),5.88(d,J=2.3Hz,1H),4.51(t,J=10.3Hz,1H),4.42-4.27(m,2H),3.41(dd,J=12.7,8.8Hz,1H),2.68(dd,J=17.5,8.6Hz,1H),2.40(s,3H),2.34-2.02(m,7H),1.88(d,J=11.8Hz,1H),1.45-1.31(m,3H),1.26-1.21(m,1H)
实施例130化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(3-氯苯基)-1,3-噁嗪喃-2-酮(130)的合成:
将中间体113-3(85mg,0.2mmol),3-氯苯硼酸(125mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到55mg产品(化合物130),收率51%。Ms:538(M+H+),1H NMR(400MHz,d6-DMSO)δ7.80(d,J=8.5Hz,1H),7.73(d,J=1.3Hz,1H),7.48(d,J=1.9Hz,1H),7.27(dt,J=8.5,4.9Hz,2H),7.22-7.10(m,2H),5.89(s,1H),4.63(t,J=10.0Hz,1H),4.37(d,J=10.5Hz,2H),3.38(s,1H),2.67(t,J=12.6Hz,1H),2.40(s,3H),2.30-2.01(m,8H),1.84(d,J=12.9Hz,1H),1.45-1.30(m,2H),1.20-1.15(m,1H)。
实施例131化合物(S)-3-(1-甲基吡唑-4-基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(131)的合成:
将中间体113-3(85mg,0.2mmol),1-甲基吡唑-4-苯硼酸(105mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到51mg产品(化合物131),收率51%。Ms:508(M+H+),1H NMR(400MHz,d6-DMSO)7.68(d,J=1.1Hz,1H),7.57(d,J=8.4Hz,1H),7.45(s,1H),7.35(s,1H),7.13(dd,J=8.4,1.5Hz,1H),5.88(d,J=2.3Hz,1H),4.51(t,J=10.3Hz,1H),4.42-4.27(m,2H),3.85(s,3H),3.41(dd,J=12.7,8.8Hz,1H),2.68(dd,J=17.5,8.6Hz,1H),2.40(s,3H),2.34-2.02(m,7H),1.88(d,J=11.8Hz,1H),1.45-1.31(m,3H),1.26-1.21(m,1H).
实施例132化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(4-甲氧基苯基)-1,3-恶嗪南-2-酮(化合物132)的合成:
将中间体113-3(40mg,0.1mmol),4-甲氧基苯硼酸(60mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到45mg产品(化合物132),收率90.3%。Ms:534(M+H+),1H NMR(400MHz,d6-DMSO)δ7.77(d,J=8.5Hz,1H),7.73(s,1H),7.15(d,J=8.8Hz,3H),6.82(d,J=8.9Hz,2H),5.71(s,1H),4.69(t,J=9.9Hz,1H),4.41-4.21(m,2H),3.67(s,3H),3.35(br,1H),2.71-2.55(m,1H),2.41(s,3H),2.29-1.94(m,7H),1.82(br,1H),1.40-1.22(m,4H).
实施例133化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((1反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(3-氟-4-甲氧基苯基)-1,3-恶嗪南-2-酮(133)的合成:
将中间体113-3(40mg,0.1mmol),3-氟-4-甲氧基苯硼酸(65mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到35mg产品(化合物133),收率63.7%。Ms:552(M+H+),1H NMR(400MHz,d6-DMSO)δ7.79(d,J=8.5Hz,1H),7.73(s,1H),7.25-7.12(m,2H),7.11-6.96(m,2H).5.71(s,1H),4.69(t,J=9.9Hz,1H),4.41-4.21(m,2H),3.67(s,3H),3.35(br,1H),2.71-2.55(m,1H),2.41(s,3H),2.29-1.94(m,7H),1.82(br,1H),1.40-1.22(m,4H).
实施例134化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(3,5-二氟苯基)-1,3-恶嗪南-2-酮(化合物134)的合成:
将中间体113-3(40mg,0.1mmol),3,5-二氟苯硼酸(65mg,0.8mmol),一水醋酸铜(30mg,0.3mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到33mg产品(化合物134),收率61.4%。Ms:540(M+H+),1H NMR(400MHz,d6-DMSO)δ7.83(d,J=8.0Hz,1H),7.73(s,1H),7.14(dd,J=31.5,8.0Hz,4H).5.91(s,1H),4.59(t,J=9.9Hz,1H),4.41-4.21(m,2H),3.35(br,1H),2.71-2.55(m,1H),2.41(s,3H),2.29-1.94(m,7H),1.82(br,1H),1.40-1.22(m,4H).
实施例135化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(3-氯-5-氟苯基)-1,3-恶嗪南-2-酮(135)的合成:
将中间体113-3(40mg,0.1mmol),3-氯-5-氟苯硼酸(68mg,0.4mmol),一水醋酸铜(30mg,0.3mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到25mg产品(化合物135),收率45.4%。Ms:556(M+H+),1H NMR(400MHz,d6-DMSO)δ7.82(d,J=8.9Hz,1H),7.73(s,1H),7.34(s,1H),7.30(d,J=8.8Hz,1H),7.18(t,J=9.0Hz,2H).5.91(s,1H),4.59(t,J=9.9Hz,1H),4.41-4.21(m,2H),3.35(br,1H),2.71-2.55(m,1H),2.41(s,3H),2.29-1.94(m,7H),1.82(br,1H),1.40-1.22(m,4H).
实施例136化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(4-溴苯基)-1,3-恶嗪南-2-酮(136)的合成:
将中间体113-3(40mg,0.1mmol),4-溴苯硼酸(65mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到40mg产品(化合物136),收率69.3%。Ms:582,584(M+H+),1H NMR(400MHz,d6-DMSO)δ7.80(d,J=8.5Hz,1H),7.72(s,1H),7.50(d,J=8.7Hz,2H),7.24(d,J=8.7Hz,2H),7.16(d,J=8.4Hz,1H),5.82(s,1H),4.61(t,J=10.1Hz,1H),4.35(d,J=10.8Hz,2H),3.36(br,1H),2.65(br,1H),2.41(s,3H),2.28-1.98(m,7H),1.86(br,1H),1.42-1.12(m,4H).
实施例137化合物(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-三氘代甲氧基环己基)-1H-苯并[d]咪唑-2-基)-3-(3-甲基-4-氟苯基)-1,3-恶嗪南-2-酮(137)的合成:
将中间体113-3(40mg,0.1mmol),3-甲基-4-氟苯硼酸(61mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到38mg产品(化合物137),收率71.4%。Ms:536(M+H+),1H NMR(400MHz,d6-DMSO)δ7.78(d,J=8.5Hz,1H),7.73(s,1H),7.29(d,J=7.1Hz,1H),7.16(d,J=8.4Hz,1H),7.02(d,J=7.8Hz,2H),5.77(s,1H),4.66(t,J=9.8Hz,1H),4.35(d,J=11.1Hz,2H),3.41-3.34(m,1),2.71-2.57(m,1H),2.41(s,3H),2.24(s,3H),2.21-1.91(m,7H),1.82(d,J=10.5Hz,1H),1.46-1.01(m,4H).
实施例138化合物4-(2-(3',4'-二氟-6-甲氧基-[1,1'-联苯]-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(138)的合成:
3',4'-二氟-6-甲氧基-[1,1'-联苯]-2-甲醛(中间体138-1)的合成:
将2-溴-3-甲氧基苯甲醛(100mg,0.47mmol),3,4-二氟苯基硼酸(96mg,0.61mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(17mg,0.023mmol),碳酸钾(129mg,0.94mmol)溶于15mL二氧六环和3mL水中,氮气置换三次,100℃下搅拌6小时。冷却,乙酸乙酯(30mLx3)萃取,合并乙酸乙酯,饱和食盐水(20mL)洗,有机层无水硫酸钠干燥,浓缩,柱层析得到83mg油状物(中间体138-1),收率71.6%
4-(2-(3',4'-二氟-6-甲氧基-[1,1'-联苯]-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(化合物138)的合成:
将中间体138-1(33mg,0.13mmol),中间体3(35mg,0.11mmol),溶于冰醋酸5mL中,加热至50℃搅拌3小时。冷却,饱和碳酸钾溶液调PH为8-9,乙酸乙酯(20mLx2)萃取,合并有机相,饱和食盐水(15mL)洗一次,有机相用无水硫酸钠干燥,浓缩,柱层析得到36mg白色固体(化合物138),收率59.7%.Ms:554(M+H+),1HMNR:1H NMR(400MHz,d6-DMSO)δ7.74(d,J=8.5Hz,1H),7.64(s,1H),7.55(t,J=8.0Hz,1H),7.39(t,J=13.3Hz,2H),7.27(dd,J=19.0,8.7Hz,1H),7.12(dd,J=13.8,8.0Hz,2H),6.97(s,1H),3.82(s,3H),3.73(t,J=12.3Hz,1H),3.22(s,3H),2.41(s,3H),2.24(s,3H),2.15-2.04(m,2H),1.96(s,2H),1.64(s,1H),1.24(d,J=9.8Hz,2H),1.18-0.98(m,2H).
实施例139化合物4-(2-(3-(3,4-二氟苯基)-2-甲氧基吡啶-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(139)的合成:
3-(3,4-二氟苯基)-2-甲氧基异烟酸(139-1)的合成
将3-溴-2-甲氧基异烟酸(350mg,1.52mmol),3,4-二氟苯基硼酸(360mg,2.28mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.041mmol),碳酸钾(627mg,4.55mmol),溶于60mL二氧六环和20mL水中,氮气置换三次,100℃下搅拌6小时,降温,抽滤,稀盐酸调PH为2-3,乙酸乙酯(50mLx3)萃取,合并有机相,饱和食盐水(20mL)洗一次。有机相无水硫酸钠干燥,浓缩,柱层析得到固体280mg(中间体139-1)。
(3-(3,4-二氟苯基)-2-甲氧基吡啶-4-基)甲醇(139-2)的合成:
将LAH(80mg,2.11mmol)溶于20mL四氢呋喃,室温搅拌30分钟,冰浴下分批加入中间体139-1(280mg,1.06mmol),室温反应2小时。2mL丙酮淬灭反应,加入2mL15%氢氧化钠溶液,3mL水,20g硫酸镁。室温搅拌1小时,抽滤。浓缩,柱层析得到油状物185mg(中间体139-2),收率69.8%。
3-(3,4-二氟苯基)-2-甲氧基异烟碱醛(139-3)的合成:
将中间体139-2(185mg,0.74mmol)溶于30mL二氯甲烷,分批加入PCC(557mg,2.21mmol)。室温搅拌1小时。抽滤,滤液浓缩,柱层析得到油状物130mg(139-3),收率70.8%。
4-(2-(3-(3,4-二氟苯基)-2-甲氧基吡啶-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(化合物139)的合成:
将中间体139-3(40mg,0.16mmol),中间体3(45.6mg,0.15mmol)溶于5mL冰醋酸,50℃反应3小时。冷却,饱和碳酸钾溶液调pH为8-9,乙酸乙酯(30mLx3)萃取,合并有机相,饱和食盐水(20mL)洗一次,有机相用无水硫酸钠干燥,浓缩,柱层析得到固体45mg(139),收率57%。Ms:545(M+H+),1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.72(s,1H),7.49(t,J=11.7Hz,1H),7.13(d,J=8.2Hz,2H),7.02(d,J=3.8Hz,2H),4.03(s,3H),3.72(s,1H),3.35(s,3H),3.17(d,J=10.9Hz,1H),2.45(s,3H),2.32(s,3H),2.10(dd,J=42.9,23.2Hz,4H),1.27(d,J=12.5Hz,5H).
实施例140化合物6-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-4'-氟联苯-2-腈(140)的合成:
2-溴-3-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)苄腈(中间体140-1)的合成:
将化合物3(315mg,1mmol),2-溴-3-氰基苯甲醛(210mg,1mmol),溶于醋酸(5mL),反应液加热到60℃反应,反应完毕后用碳酸钾水溶液调节pH为9-10,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析得285mg(140-1),收率:57%。
6-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-4'-氟联苯-2-腈(化合物140)的合成:
将中间体140-1(285mg,0.57mmol),对氟苯硼酸(95mg,0.68mmol),碳酸钾,双(二苯基膦基)二茂铁]二氯化钯(44mg,0.06mmol)溶于二氧六环(5mL)和水(1mL),反应液置换氮气后加热到80℃过夜,反应完毕后加入水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析得到187mg(化合物140),收率:63%。Ms:521(M+H+),1H NMR(400MHz,d6-DMSO)δ8.22(dd,J=7.8,1.2Hz,1H),7.89(dd,J=7.7,1.2Hz,1H),7.85-7.57(m,4H),7.44-6.89(m,4H),3.65(d,J=12.4Hz,1H),3.28(d,J=11.0Hz,1H),3.21(s,3H),2.42(s,3H),2.24(s,3H),2.11-2.00(m,2H),1.91(s,2H),1.62(s,1H),1.19-1.02(m,3H)。
实施例141化合物4-(2-(3',4'-二氟-6-甲氧基-[1,1'-联苯]-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(化合物141)的合成:
4'-氟-6-甲氧基-[1,1'-联苯]-2-甲醛(中间体141-1)的合成:
将2-溴-3-甲氧基苯甲醛(100mg,0.47mmol),4-氟苯基硼酸(85mg,0.61mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(17mg,0.023mmol),碳酸钾(129mg,0.93mmol)溶于15mL二氧六环和3mL水中,氮气置换三次,100℃下搅拌6小时。冷却,乙酸乙酯(30mLx3)萃取,合并乙酸乙酯,饱和食盐水(20mLx2)洗,有机层无水硫酸钠干燥,浓缩,柱层析得到80mg油状物(中间体141-1),收率74.4%。
4-(2-(3',4'-二氟-6-甲氧基-[1,1'-联苯]-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异恶唑(化合物141)的合成:
将中间体141-1(30mg,0.13mmol),中间体3(34mg,0.11mmol),溶于冰醋酸5mL中,加热至50℃搅拌3小时。冷却,饱和碳酸钾溶液调pH为8-9,乙酸乙酯(20mLx2)萃取,合并有机相,饱和食盐水(15mL)洗一次,有机相用无水硫酸钠干燥,浓缩,柱层析得到35mg白色固体(化合物141),收率61.7%。Ms:526(M+H+),1H NMR(400MHz,d6-DMSO)δ7.71(d,J=8.5Hz,1H),7.63(d,J=1.2Hz,1H),7.52(t,J=8.0Hz,1H),7.36(d,J=8.1Hz,1H),7.26(s,2H),7.10(ddd,J=25.8,13.2,4.9Hz,4H),3.82(d,J=14.8Hz,3H),3.67(t,J=12.0Hz,1H),3.26(s,1H),3.21(s,3H),2.41(s,3H),2.24(s,3H),2.13-1.87(m,5H),1.57(d,J=12.7Hz,1H),1.08-0.94(m,2H).
实施例142化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(142)的合成:
(R)-N-(4-溴-2-硝基苯基)四氢呋喃-3-胺(中间体142-1)的合成:
将4-溴-1-氟-2-硝基苯(1.1g,5mmol),(R)-四氢呋喃-3-胺(0.43g,5mmol)以及碳酸钾(1.4g,10mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入200mL水,过滤,水洗,滤饼经柱层析得到1.2g固体(中间体142-1),收率83.9%。Ms:287(M+H+)
(R)-4-溴-N1-(四氢呋喃-3-基)苯-1,2-二胺(中间体142-2)的合成:
将中间体142-1(1.2g,4.2mmol),氨水(10mL),溶于50mL四氢呋喃和50mL水中,加入连二亚硫酸钠(10.9g,63mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到0.8g固体(中间体142-2),收率74.4%。Ms:257(M+H+)
(R)-4-(3,5-二甲基异恶唑-4-基)-N1-(四氢呋喃-3-基)苯-1,2-二胺(中间体142-3)的合成:
将中间体142-2(0.8g,3mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(0.74g,3.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(20mg,0.03mmol),碳酸钾(0.8g,6mmol)溶于20mL二氧六环和4mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到0.65g固体(中间体142-3),收率79%。Ms:274(M+H+)叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体142-4)的合成:
将中间体10(600mg,1.9mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入中间体142-3(491mg,1.8mmol)以及焦亚硫酸钠(720mg,3.8mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到564mg产品(中间体142-4),收率:55%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基-丙-1-醇(中间体142-5)的合成:
将中间体142-4(684mg,1.2mmol),氟氢化钾(190mg)溶于甲醇(20mL)中,加入5mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到300mg产品(中间体142-5),收率:70%,Ms:357(M+H+)。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(中间体142-6)
将中间体142-5(117mg,0.33mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,冰浴下,分批加入三光气(48.3mg,0.17mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体142-6)80mg,收率:63.4%。Ms:383(M+H+)
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物142)的合成:
将中间体142-6(46mg,0.12mmol),3,4-二氟苯硼酸(77mg,0.5mmol),一水醋酸铜(30mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到27mg产品(化合物142),收率45%。Ms:495(M+H+),1H NMR(400MHz,d6-DMSO)δ7.73(dd,J=19.0,10.5Hz,2H),7.54-7.30(m,2H),7.25(d,J=8.4Hz,1H),7.12(d,J=8.7Hz,1H),5.80(s,1H),5.32(s,1H),4.48(t,J=10.2Hz,1H),4.41-4.16(m,2H),3.91(d,J=10.5Hz,1H),3.68(dt,J=27.2,8.4Hz,2H),2.83-2.61(m,1H),2.50-2.44(m,1H),2.41(s,3H),2.26(d,J=11.9Hz,4H),2.03(dd,J=18.8,10.6Hz,1H)。
实施例143化合物((S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((顺式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(143)的合成:
4-溴-N-(((顺式)-3-甲氧基环丁基)-2-硝基苯胺(中间体143-1)的合成:
将4-溴-1-氟-2-硝基苯(1.1g,5mmol),(顺式)-3-甲氧基环丁基-1-胺(0.55g,5.5mmol)以及碳酸钾(2.1g,15mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入200mL水,过滤,水洗,滤饼经柱层析得到1.2g固体(中间体143-1),收率79.7%。
4-溴-N1-((顺式)-3-甲氧基环丁基)苯-1,2-二胺(中间体143-2)的合成:
将中间体143-1(1.2g,4mmol),氨水(5mL),溶于30mL四氢呋喃和30mL水中,加入连二亚硫酸钠(8.2g,40mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到0.9g固体(中间体143-2),收率83%。
4-(3,5-二甲基异恶唑-4-基)-N1-(((顺式)-3-甲氧基环丁基)苯-1,2-二胺(中间体143-3)的合成:
将中间体143-2(0.9g,3.3mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(0.81g,3.6mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.12mmol),碳酸钾(0.91g,6.6mmol)溶于30mL二氧六环和3mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到530mg固体(中间体143-3),收率55%。
叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((顺式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体143-4)的合成:
将中间体10(600mg,1.9mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入中间体143-3(530mg,1.8mmol)以及焦亚硫酸钠(720mg,3.8mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到620mg产品(中间体143-4),收率:57%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((顺式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基丙-1-醇(中间体143-5)的合成:
将中间体143-4(620mg,1.06mmol),氟氢化钾(190mg)溶于甲醇(20mL)中,加入5mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到230mg产品(中间体143-5),收率:58.9%。
(S)-4-(1-(((顺式)-3-甲氧基环丁基)-5-(3-甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(中间体143-6)
将中间体143-5(230mg,0.60mmol),三乙胺(190mg,1.86mmol)溶于20mL四氢呋喃中,分批加入三光气(48.3mg,0.17mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体143-6)150mg,收率:61%。
((S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((顺式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物143)的合成:
将中间体143-6(50mg,0.12mmol),3,4-二氟苯硼酸(77mg,0.5mmol),一水醋酸铜(30mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到25mg产品(化合物143),收率43.4%。Ms:509(M+H+),1H NMR(400MHz,d6-DMSO)δ7.67(d,J=8.6Hz,1H),7.59(s,1H),7.37-7.17(m,2H),7.10-6.89(m,2H),5.69(s,1H),4.93-4.75(m,1H),4.38-4.27(m,1H),4.27-4.15(m,1H),3.84(p,J=6.9Hz,1H),3.28(s,3H),3.02-2.85(m,2H),2.85-2.65(m,2H),2.41(s,3H),2.35-2.27(m,1H),2.24(s,3H),2.05(dd,J=9.6,4.3Hz,1H).
实施例114化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(144)的合成:
(反式)-3-((4-溴-2-硝基苯基)氨基)环丁醇(中间体144-1)的合成:
将4-溴-1-氟-2-硝基苯(2.53g,11.5mmol),(反式)-3-氨基环丁醇(1.0g,11.5mmol)以及碳酸钾(3.97g,28.8mmol)溶于乙腈(30mL)中,加热至80℃,搅拌5小时。冷却,加入50mL水,过滤,水洗,滤饼经柱层析得到2.8g固体(中间体144-1),收率85.2%。
4-溴-N-((反式)-3-甲氧基环丁基)-2-硝基苯胺(中间体144-2)的合成:
将中间体144-1(2.58g,9mmol),氢化钠(0.72g,18mmol)溶于20mL四氢呋喃中,冰浴下,滴加碘甲烷(1.92g,13.5mmol),反应过夜。倒入冰水中,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到1.86g产品(中间体144-2),收率68.5%。
4-溴-N1-((反式)-3-甲氧基环丁基)苯-1,2-二胺(中间体144-3)的合成:
将中间体144-2(1.8g,6mmol),氨水(5mL),溶于75mL四氢呋喃和75mL水中,加入连二亚硫酸钠(16.6g,81mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到1.4g固体(中间体144-3),收率85.5%。
4-(3,5-二甲基异恶唑-4-基)-N1-((反式)-3-甲氧基环丁基)苯-1,2-二胺(中间体144-4)的合成:
将中间体144-3(1.6g,6mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(1.48g,6.6mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(40mg,0.06mmol),碳酸钾(1.66g,12mmol)溶于30mL二氧六环和5mL水中,氮气置换三次,100℃条件下搅拌10h。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到1.2g固体(中间体144-4),收率68.5%。
((S)-3-((叔丁基二甲基硅基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)丙基)氨基甲酸叔丁基酯(中间体144-5)的合成:
将中间体10(600mg,1.9mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入中间体144-4(461mg,1.7mmol)以及焦亚硫酸钠(720mg,3.8mmol),80℃下反应5h。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到732mg产品(中间体114-5),收率:73.6%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁)-1H-苯并[d]咪唑-2-基)丙-1-醇(中间体144-6)的合成:
将中间体144-5(702mg,1.2mmol),氟氢化钾(190mg)溶于甲醇(20mL)中,加入5mL浓盐酸,30℃反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到285mg产品(中间体144-6),收率:64.2%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪-2-酮(中间体144-7)的合成:
将中间体144-6(122mg,0.33mmol),三乙胺(49mg,0.48mmol)溶于20mL四氢呋喃中,冰浴下,分批加入三光气(48.3mg,0.17mmol),反应30min。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到82mg产品(中间体144-7),收率:62.4%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物144)的合成:
将中间体144-7(79mg,0.2mmol),3,4-二氟苯硼酸(127mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到43mg产品(化合物144),收率42.5%。Ms:509(M+H+),1HNMR:(400MHz,d6-DMSO)δ7.87-7.74(m,2H),7.55-7.43(m,1H),7.37(dd,J=19.4,9.2Hz,1H),7.22(d,J=7.5Hz,1H),7.16(s,1H),5.76(s,1H),5.23-5.10(m,1H),4.43(t,J=10.0Hz,1H),4.32(d,J=10.6Hz,1H),4.21(s,1H),3.23(s,3H),2.99-2.77(m,2H),2.66(d,J=11.9Hz,1H),2.54(d,J=6.9Hz,1H),2.44-2.27(m,4H),2.27-2.10(m,4H).
实施例145化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(145)的合成
中间体N-(4-溴-2-硝基苯)四氢-2H-吡喃-4-胺(145-1)的合成
将4-溴-1-氟-2-硝基苯(3.38g,15.4mmol),4-氨基四氢吡喃(1.56g,15.4mmol)以及碳酸钾(5.34g,38.6mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入水(200mL),过滤,水洗,滤饼经柱层析得到固体化合物145-1(3.9g,13.1mmol),收率85%。
4-溴-N1-(四氢-2H-吡喃-4-基)苯-1,2-二胺(145-2)的合成:
将中间体145-1(3.9g,13.1mmol),氨水(10mL),溶于四氢呋喃(150mL)和水(150mL)中,加入连二亚硫酸钠(9.2g,52.4mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到固体145-2(2.14g,7.9mmol),收率60%。
4-(3,5-二甲基异噁唑-4-基)-N1-(四氢-2H-吡喃-4-基)苯-1,2-二胺(145-3)的合成
将145-2(2.14g,7.9mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.11g,9.48mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg,0.08mmol),碳酸钾(2.18g,15.8mmol)溶于二氧六环(60mL)和水(10mL)中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到固体145-3(1.54g,5.37mmol),收率68%。
(S)-(3-((叔丁基二甲基硅基)氧)-1-(5-(3,5-二甲基异噁唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)丙基)氨基甲酸叔丁酯(145-4)的合成
将中间体10(380mg,1.2mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入中间体7(287mg,1mmol)以及偏重亚硫酸钠(379mg,2mmol),80℃下反应5小时。加入25mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到中间体145-4(420mg,0.72mmol),收率:72%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)丙基-1-醇(145-5)的合成
将145-4(420mg,0.72mmol)溶于甲醇(4mL)中,再加入KHF2(109mg,1.4mmol)以及浓盐酸(1mL),30℃反应过夜。调pH为9~10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到中间体145-5(213mg,0.58mmol),收率:80%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(145-6)的合成
将中间体145-5(213mg,0.58mmol),三乙胺(87mg,0.87mmol)溶于四氢呋喃(20mL)中,冰浴下,分批加入三光气(68mg,0.23mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品中间体145-6(149mg,0.37mmol),收率:65%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(145)的合成
将中间体145-6(149mg,0.37mmol),3,4-二氟苯硼酸(230mg,1.48mmol),一水醋酸铜(110mg,0.55mmol),三乙胺(37mg,0.37mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物145(141mg,0.27mmol),收率75%。Ms:509(M+H+),1H NMR(400MHz,d6-DMSO)δ7.76(d,J=1.1Hz,1H),7.74(d,J=8.5Hz,1H),7.46(ddd,J=11.9,7.4,2.5Hz,1H),7.37(dd,J=19.6,9.1Hz,1H),7.21(dd,J=8.5,1.6Hz,1H),7.16-7.09(m,1H),5.85(s,1H),4.69-4.52(m,2H),4.36(d,J=10.6Hz,1H),4.06-3.91(m,2H),3.51(dd,J=22.0,11.0Hz,2H),2.81-2.65(m,1H),2.41(s,3H),2.33(ddd,J=20.5,12.5,4.4Hz,2H),2.24(s,3H),1.92(s,1H),1.82(d,J=12.2Hz,1H),1.29(d,J=9.9Hz,1H).
实施例146化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(146)的合成:
(S)-N-(4-溴-2-硝基苯基)四氢呋喃-3-胺(146-1)的合成:
将4-溴-1-氟-2-硝基苯(3.38g,15.4mmol),(S)-四氢呋喃-3-胺盐酸盐(1.9g,15.4mmol)以及碳酸钾(5.34g,38.6mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入200mL水,过滤,水洗,滤饼经柱层析得到4g固体(中间体146-1),收率91%。
(S)-4-溴-N1-(四氢呋喃-3-基)苯-1,2-二胺(146-2)的合成:
将中间体146-1(4g,14mmol),氨水(10mL),溶于50mL四氢呋喃和50mL水中,加入连二亚硫酸钠(9.8g,56mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到2.5g固体(中间体146-2),收率70%。
(S)-4-(3,5-二甲基异恶唑-4-基)-N1-(四氢呋喃-3-基)苯-1,2-二胺(146-3)的合成:
将中间体146-2(2.5g,10mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.7g,12mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(770mg,1mmol),碳酸钾(3.3g,24mmol)溶于60mL二氧六环和10mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到1.3g固体(中间体146-3),收率48%。
叔丁基(S)-3-(叔丁基二甲基甲硅烷氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(146-4)的合成:
将中间体146-3(273mg,1mmol)溶于N,N-二甲基甲酰胺(3mL)中,加入中间体3(380mg,1.2mmol)以及偏重亚硫酸钠(380mg,2mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到260mg产品(中间体146-4),收率:46%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基丙-1-醇(146-5)的合成:
将中间体146-4(260mg,0.46mmol),氟氢化钾(144mg,1.84mmol)溶于甲醇(5mL)中,加入5mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到145mg产品(中间体146-5),收率:88%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(146-6)的合成:
将中间体146-5(145mg,0.41mmol),三乙胺(166mg,1.64mmol)溶于20mL四氢呋喃中,冰浴下,分批加入三光气(38mg,0.13mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体146-6)88mg,收率:56%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-四氢呋喃-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物146)的合成:
将中间体146-6(88mg,0.23mmol),3,4-二氟苯硼酸(144mg,0.9mmol),一水醋酸铜(69mg,0.35mmol),三乙胺(47mg,0.46mmol)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到58mg产品(化合物146),收率51%。Ms:595(M+H+),1H NMR(400MHz,d6-DMSO)δ7.73(dd,J=19.0,10.5Hz,2H),7.54-7.30(m,2H),7.25(d,J=8.4Hz,1H),7.12(d,J=8.7Hz,1H),5.80(s,1H),5.32(s,1H),4.48(t,J=10.2Hz,1H),4.41-4.16(m,2H),3.91(d,J=10.5Hz,1H),3.68(dt,J=27.2,8.4Hz,2H),2.83-2.61(m,1H),2.50-2.44(m,1H),2.41(s,3H),2.26(d,J=11.9Hz,4H),2.03(dd,J=18.8,10.6Hz,1H)。
实施例147化合物(S)-4-(1-(1-乙酰基哌啶-4-基)-5-(3,5-二甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-基)-3-(3,4-二氟苯基)-1,3-恶二嗪-2-酮(147)的合成
4-((4-溴-2-硝基苯)氨基)哌啶-1-甲酸叔丁酯(147-1)的合成:
将4-溴-1-氟-2-硝基苯(3.38g,15.4mmol),4-氨基-1-甲酸叔丁酯(3.08g,15.4mmol)以及碳酸钾(5.34g,38.6mmol)溶于乙腈(50mL)中,加热至80℃,搅拌5小时。冷却,加入水(200mL),过滤,水洗,滤饼经柱层析得到固体化合物147-1(5.5g,13.9mmol),收率90%。
N-(4-溴-2-硝基苯)哌啶-4-氨基(147-2)的合成
将147-1(5.5g,13.9mmol)溶于甲醇(50mL)中,加入浓盐酸(10mL)后室温下搅拌过夜。用饱和碳酸氢钠水溶液调节pH至8,二氯甲烷萃取,无水硫酸钠干燥,旋干得到固体147-2(3.96g,13.2mmol),95%。
1-(4-((4-溴-2-硝基苯)胺)哌啶-1-基)乙酮(147-3)的合成
将147-2(3.96g,13.2mmol)溶于DCM(40mL)中,室温搅拌下滴入乙酰氯(1.1g,14.5mmol),滴加完毕后继续室温下搅拌,反应完毕加水(10mL)洗涤,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,旋干,得到147-3(4.06g,11.9mmol),收率90%。
1-(4-((2-氨基-4-溴苯基)氨基)哌啶-1-基)乙酮(147-4)的合成
将147-3(4.06g,11.9mmol),氨水(10mL),溶于四氢呋喃(150mL)和水(150mL)中,加入连二亚硫酸钠(8.3g,47.6mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到固体147-4(2.41g,7.7mmol),收率65%。
1-(4-((2-氨基-4-(3,5-二甲基异噁唑-4-基)苯基)氨基)哌啶-1-基)乙酮(147-5)的合成
将147-4(2.41g,7.7mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.06g,9.24mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg,0.08mmol),碳酸钾(2.18g,15.8mmol)溶于二氧六环(60mL)和水(10mL)中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到固体147-5(1.77g,5.39mmol),收率70%。
(S)-(1-(1-(1-乙酰哌啶-4-基)-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-基)-3-((叔丁基二甲基硅基)氧)丙基)氨基甲酸叔丁酯(147-6)的合成:
将中间体10(380mg,1.2mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入中间体147-5(328mg,1mmol)以及偏重亚硫酸钠(379mg,2mmol),80℃下反应5小时。加入25mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到中间体147-6(450mg,0.72mmol),收率:72%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2-基)丙基-1-醇(147-7)的合成
将147-6(450mg,0.72mmol)溶于甲醇(4mL)中,再加入KHF2(109mg,1.4mmol)以及浓盐酸(1mL),30℃反应过夜。调pH为9~10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到中间体147-7(237mg,0.58mmol),收率:80%。
(S)-4-(1-(1-乙酰基哌啶-4-基)-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(147-8)的合成
将中间体147-7(237mg,0.58mmol),三乙胺(87mg,0.87mmol)溶于四氢呋喃(20mL)中,冰浴下,分批加入三光气(68mg,0.23mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品中间体147-8(161mg,0.37mmol),收率:65%。
(S)-4-(1-(1-乙酰基哌啶-4-基)-5-(3,5-二甲基异恶唑-4-基)-1H-苯并[d]咪唑-2-基)-3-(3,4-二氟苯基)-1,3-恶二嗪-2-酮(147)的合成
将中间体147-8(161mg,0.37mmol),3,4-二氟苯硼酸(230mg,1.48mmol),一水醋酸铜(110mg,0.55mmol),三乙胺(37mg,0.37mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物147(148mg,0.27mmol),收率75%。Ms:550(M+H+),1H NMR(400MHz,d6-DMSO)δ7.75(d,J=1.4Hz,1H),7.72(d,J=8.2Hz,1H),7.51-7.43(m,1H),7.38(dd,J=19.0,9.6Hz,1H),7.18(d,J=8.5Hz,1H),7.12(d,J=7.6Hz,1H),5.84(s,1H),4.57(dd,J=23.4,11.8Hz,3H),4.35(d,J=10.8Hz,1H),4.05-3.88(m,1H),3.19(dd,J=24.5,12.3Hz,1H),2.67(dt,J=24.7,12.5Hz,2H),2.40(s,3H),2.31(d,J=12.7Hz,1H),2.22(d,J=8.0Hz,4H),2.15-1.99(m,4H),1.89(s,1H),1.31(s,1H).
实施例148化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异噁唑-4-基)-1-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(148)的合成
N-(4-溴-2-小基苯基)-1-甲基哌啶-4-胺(148-1)的合成
将147-2(3.96g,13.2mmol)溶于THF(40mL)中,加入氢化钠(60%dispersion inmineral oil,0.79g,19.8mmol),室温搅拌15分钟,加入碘甲烷(3.7g,26.4mmol),滴加完毕后继续室温下搅拌,反应完毕加水(40mL)洗涤,二氯甲烷(20mL×3)萃取,饱和食盐水(40mL)洗涤,无水硫酸钠干燥,旋干,得到148-1(3.74g,11.9mmol),收率90%。
4-溴-N1-(1-甲基哌啶-4-基)苯-1,2-二胺(148-2)的合成
将148-1(3.74g,11.9mmol),氨水(10mL),溶于四氢呋喃(150mL)和水(150mL)中,加入连二亚硫酸钠(8.3g,47.6mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到固体148-2(2.19g,7.7mmol),收率65%。
4-(3,5-二甲基异噁唑-4-基)-N1-(1-甲基哌啶-4-基)苯-1,2-二胺(148-3)的合成
将148-2(2.19g,7.7mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(2.06g,9.24mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(58mg,0.08mmol),碳酸钾(2.18g,15.8mmol)溶于二氧六环(60mL)和水(10mL)中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到固体148-3(1.62g,5.39mmol),收率70%。
(S)-(3-((叔丁基二甲基硅基)氧)-1-(5-(3,5-二甲基异噁唑-4-基)-1-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)丙基)氨基甲酸叔丁酯(148-4)的合成
将中间体10(380mg,1.2mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入中间体148-3(300mg,1mmol)以及偏重亚硫酸钠(379mg,2mmol),80℃下反应5小时。加入25mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到中间体148-4(430mg,0.72mmol),收率:72%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)丙基-1-醇(148-5)的合成
将148-4(430mg,0.72mmol)溶于甲醇(4mL)中,再加入KHF2(109mg,1.4mmol)以及浓盐酸(1mL),30℃反应过夜。调pH为9~10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到中间体148-5(222mg,0.58mmol),收率:80%。
(S)-4-(1-(1-甲基哌啶-4-基)-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(148-6)的合成
将中间体148-5(222mg,0.58mmol),三乙胺(87mg,0.87mmol)溶于四氢呋喃(20mL)中,冰浴下,分批加入三光气(68mg,0.23mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品中间体148-6(151mg,0.37mmol),收率:65%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异噁唑-4-基)-1-(1-甲基哌啶-4-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(148)的合成
将中间体148-6(151mg,0.37mmol),3,4-二氟苯硼酸(230mg,1.48mmol),一水醋酸铜(110mg,0.55mmol),三乙胺(37mg,0.37mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物148(140mg,0.27mmol),收率75%。Ms:522(M+H+),1H NMR(400MHz,d6-DMSO)δ7.75(s,1H),7.69(d,J=8.4Hz,1H),7.54-7.43(m,1H),7.36(dd,J=19.2,9.5Hz,1H),7.19(d,J=8.4Hz,1H),7.12(s,1H),5.82(s,1H),4.58(t,J=10.2Hz,1H),4.43-4.24(m,2H),2.88(dd,J=24.3,9.5Hz,2H),2.69(s,1H),2.40(s,3H),2.32-2.17(m,8H),2.08(s,4H),1.79(d,J=11.2Hz,1H).
实施例149化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物149)的合成:
3-((4-溴-2-硝基苯基)氨基)吡咯烷-1-羧酸(R)-叔丁基酯(中间体149-1)的合成:
将4-溴-1-氟-2-硝基苯(1.1g,5mmol),(R)3-氨基吡咯烷-1-羧酸叔丁酯(1.1g,6mmol)以及碳酸钾(1.38g,10mmol)溶于乙腈(20mL)中,加热至80℃,搅拌5小时。冷却,加入100mL水,过滤,水洗,滤饼经柱层析得到1.4g固体(中间体149-1),收率69%。
(R)-N-(4-溴-2-硝基苯基)吡咯烷-3-胺(中间体149-2)的合成:
将149-1(1.3g,3.3mmol)溶于甲醇(50mL)中,加入2ml浓盐酸室温搅拌5小时。浓缩除去甲醇,用碳酸钠调节pH至9-10,二氯甲烷萃取5次,合并有机相浓缩得到0.7g固体(中间体149-2),收率64%。
(R)-N-(4-溴-2-硝基苯基)-1-甲基吡咯烷-3-胺(中间体149-3)的合成:
将149-2(0.6g,2.1mmol)溶于1,2-二氯乙烷(20mL)中,加入5ml甲醛水溶液,再加入三乙酰氧基硼氢化钠(2.1g,10mmol)加热至40℃,搅拌10小时。冷却,加入50mL水,分离有机相,水相用二氯甲烷萃取2次,合并有机相浓缩经柱层析得到420mg固体(中间体149-3),收率68%。
(R)-4-溴-N1-(1-甲基吡咯烷-3-基)苯-1,2-二胺(中间体149-4)的合成:
将中间体149-3(430mg,1.4mmol),氨水(5mL),溶于20mL四氢呋喃和20mL水中,加入连二亚硫酸钠(3.2g,14mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到340mg固体(中间体149-4),收率88%。
(R)-4-(3,5-二甲基异恶唑-4-基)-N1-(1-甲基吡咯烷-3-基)苯-1,2-二胺(中间体149-5)的合成:
将中间体149-4(340mg,1.2mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(300mg,1.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.12mmol),碳酸钾(330mg,2.4mmol)溶于10mL二氧六环和1mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到240mg固体(中间体149-5),收率67%。
叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体149-6)的合成:
将中间体10(310mg,1mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体150-5(240mg,0.84mmol)以及焦亚硫酸钠(570mg,3mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到120mg产品(中间体149-6),收率:19%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)丙烷-1-醇(中间体149-7)的合成:
将中间体149-6(120mg,0.2mmol),氟氢化钾(100mg)溶于甲醇(10mL)中,加入2mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(中间体149-7),收率:79%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二酮-2-酮(中间体149-8)
将中间体149-7(60mg,0.16mmol),三乙胺(32mg,0.32mmol)溶于20mL四氢呋喃中,分批加入三光气(12mg,0.04mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体149-8)45mg,收率:71%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((R)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物149)的合成:
将中间体149-8(45mg,0.11mmol),3,4-二氟苯硼酸(60mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到25mg产品(化合物149),收率54.3%。Ms:508(M+H+),1H NMR(400MHz,d6-DMSO)δ8.07(t,J=8.5Hz,1H),7.74(s,1H),7.51-7.29(m,2H),7.23(d,J=9.1Hz,1H),7.10(d,J=8.6Hz,1H),5.88(br,1H),5.19(br,1H),4.60-4.45(m,1H),4.35(d,J=10.8Hz,1H),3.10(br,1H),2.93-2.85(m,1H),2.70-2.67(m,1H),2.41(s,3H),2.33(s,3H),2.38-2.12(m,2H),2.24(s,3H),2.12-1.80(m,2H),1.60-1.44(m,1H).
实施例150化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(150)的合成:
3-((4-溴-2-硝基苯基)氨基)吡咯烷-1-羧酸(S)-叔丁基酯(中间体150-1)的合成:
将4-溴-1-氟-2-硝基苯(1.1g,5mmol),(S)3-氨基吡咯烷-1-羧酸叔丁酯(1.1g,6mmol)以及碳酸钾(1.38g,10mmol)溶于乙腈(20mL)中,加热至80℃,搅拌5小时。冷却,加入100mL水,过滤,水洗,滤饼经柱层析得到1.3g固体(中间体150-1),收率67.5%。
(S)-N-(4-溴-2-硝基苯基)吡咯烷-3-胺(中间体150-2)的合成:
将150-1(1.3g,3.3mmol)溶于甲醇(50mL)中,加入2ml浓盐酸室温搅拌5小时。浓缩除去甲醇,用碳酸钠调节pH至9-10,二氯甲烷萃取5次,合并有机相浓缩得到0.6g固体(中间体150-2),收率62.3%。
(S)-N-(4-溴-2-硝基苯基)-1-甲基吡咯烷-3-胺(中间体150-3)的合成:
将150-2(0.6g,2.1mmol)溶于1,2-二氯乙烷(20mL)中,加入5ml甲醛水溶液,再加入三乙酰氧基硼氢化钠(2.1g,10mmol)加热至40℃,搅拌10小时。冷却,加入50mL水,分离有机相,水相用二氯甲烷萃取2次,合并有机相浓缩经柱层析得到430mg固体(中间体150-3),收率69.8%。
(S)-4-溴-N1-(1-甲基吡咯烷-3-基)苯-1,2-二胺(中间体150-4)的合成:
将中间体150-3(430mg,1.4mmol),氨水(5mL),溶于20mL四氢呋喃和20mL水中,加入连二亚硫酸钠(3.2g,14mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到340mg固体(中间体150-4),收率88%。
(S)-4-(3,5-二甲基异恶唑-4-基)-N1-(1-甲基吡咯烷-3-基)苯-1,2-二胺(中间体150-5)的合成:
将中间体150-4(340mg,1.2mmol),3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)异恶唑(300mg,1.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.12mmol),碳酸钾(330mg,2.4mmol)溶于10mL二氧六环和1mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到240mg固体(中间体150-5),收率67%。
叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体105-6)的合成:
将中间体10(310mg,1mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体150-5(240mg,0.84mmol)以及焦亚硫酸钠(570mg,3mmol),80度下反应5小时。加入50mL水,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析纯化,得到120mg产品(中间体150-6),收率:19%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)丙烷-1-醇(中间体150-7)的合成:
将中间体150-6(120mg,0.2mmol),氟氢化钾(100mg)溶于甲醇(10mL)中,加入2mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(中间体150-7),收率:79%。
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶二酮-2-酮(中间体150-8)
将中间体150-7(60mg,0.16mmol),三乙胺(32mg,0.32mmol)溶于20mL四氢呋喃中,分批加入三光气(12mg,0.04mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体150-8)45mg,收率:71%。
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((S)-1-甲基吡咯烷-3-基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物150)的合成:
将中间体150-8(45mg,0.11mmol),3,4-二氟苯硼酸(60mg,0.4mmol),一水醋酸铜(30mg,0.15mmol),三乙胺(30mg)溶于5mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到25mg产品(化合物150),收率54.3%。Ms:508(M+H+),1H NMR(400MHz,d6-DMSO)δ8.07(t,J=8.5Hz,1H),7.74(s,1H),7.51-7.29(m,2H),7.23(d,J=9.1Hz,1H),7.10(d,J=8.6Hz,1H),5.88(br,1H),5.19(br,1H),4.60-4.45(m,1H),4.35(d,J=10.8Hz,1H),3.10(br,1H),2.93-2.85(m,1H),2.70-2.67(m,1H),2.41(s,3H),2.33(s,3H),2.38-2.12(m,2H),2.24(s,3H),2.12-1.80(m,2H),1.60-1.44(m,1H).
实施例151化合物(S)-3-(4-氯-3-氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-3-甲氧基环丁基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物151)的合成:
将中间体144-6(79mg,0.2mmol),4-氯-3-氟苯硼酸(140mg,0.8mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg)溶于20mL乙腈中,30℃反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到46mg产品(化合物151),收率43.4%。Ms:525(M+H+),1H NMR:(400MHz,d6-DMSO)δ7.82(d,J=8.5Hz,1H),7.75(s,1H),7.59-7.40(m,2H),7.26-7.15(m,2H),5.81(s,1H),5.21(p,J=8.7Hz,1H),4.47-4.36(m,1H),4.33(d,J=10.8Hz,1H),4.22(t,J=6.5Hz,1H),3.22(d,J=12.5Hz,3H),3.00-2.82(m,2H),2.68(t,J=12.8Hz,1H),2.55(s,1H),2.38(d,J=20.6Hz,4H),2.27-2.12(m,4H).
实施例152化合物(S)-6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(152)的合成
(S)-N-(5-溴-2-(((反式)-4-甲氧基环己基)胺)苯基)-6-氧代哌啶-2-甲酰胺(152-1)
将中间体2(2.98g,10mmol)溶于二氯甲烷(30mL)中,加入(S)-2-哌啶酮-6-羧基酸(1.43g,10mmol)、丙基磷酸三环酸酐(50%in EA,6.36g,10mmol)以及DIEA(1.54g,12mmol)。加完后室温下搅拌过夜,旋干,柱层析,得152-1(3.4g,8mmol),收率80%。
(S)-6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(中间体152-2)的合成
将152-1(3.4g,8mmol)加入乙酸(30mL)中,50℃下搅拌3天,旋干,二氯甲烷溶解,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥。旋干柱层析得到152-2(1.95g,4.8mmol),收率60%。
(S)-6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(152)的合成
将152-2(1.95g,4.8mmol),3,4-二氟苯硼酸(230mg,1.48mmol),一水醋酸铜(1.4g,7.2mmol),三乙胺(0.48g,4.8mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物152(1.99g,3.84mmol),收率80%。Ms:518(M+H+),1H NMR(400MHz,d6-DMSO)δ7.88(d,J=1.9Hz,1H),7.70(d,J=8.8Hz,1H),7.38-7.25(m,3H),6.99(d,J=8.9Hz,1H),5.74(d,J=4.7Hz,1H),4.33(d,J=11.9Hz,1H),3.38(d,J=10.8Hz,1H),3.31(s,1H),3.27(s,3H),2.57-2.52(m,1H),2.35(d,J=11.6Hz,1H),2.19(d,J=12.1Hz,1H),2.15-1.90(m,5H),1.78(s,2H),1.36(dd,J=24.1,13.1Hz,2H),1.10(s,1H).
实施例153化合物5-溴-2-((S)-1-(3,4-二氟苯基)哌啶-2-及)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑(153)的合成
将152(52mg,0.1mmol)溶于THF(1mL),室温搅拌下滴入硼烷二甲硫醚的四氢呋喃溶液(2M,0.08mL,0.15mmol)。搅拌2小时,加入丙酮和少量稀盐酸,旋干,柱层析得到153(37mg,0.073mmol)。收率:73%。Ms:504(M+H+),1H NMR(400MHz,d6-DMSO)δ7.77(d,J=1.7Hz,1H),7.68(d,J=8.7Hz,1H),7.25(dd,J=8.7,1.8Hz,1H),7.19(dd,J=19.7,9.6Hz,1H),7.09(ddd,J=14.5,6.9,2.7Hz,1H),6.77(d,J=9.0Hz,1H),5.46(s,1H),4.49(t,J=12.1Hz,1H),3.47-3.37(m,2H),3.25(s,3H),2.30-2.14(m,2H),2.14-2.03(m,2H),1.94(d,J=23.2Hz,3H),1.62(dd,J=37.1,12.3Hz,5H),1.30-1.11(m,3H).
实施例154化合物(S)-6-(5-氨基-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(154)的合成
将152(518mg,1mmol)溶于DMSO(5mL)中,再加入氨水(1mL),DMA(17mg,0.2mmol),CuI(19mg,0.1mmol),氮气保护,100℃加热搅拌过夜。反应完毕,冷却后倒入水(25mL)中,乙酸乙酯(5mL×3)萃取,合并有机相,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,旋干,得154(222mg,0.49mmol),收率:49%。Ms:455(M+H+)。
实施例155化合物(S)-1-(3,4-二氟苯基)-6-(1-((反式)-4-甲氧基环己基)-5-(3-甲基-2-氧代咪唑啉-1-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(155)的合成
1-(2-氯乙基)-3-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)脲(155-1)的合成
将154(454mg,1mmol)及DMAP(12mg,0.1mmol)加入THF(5mL)中。再分批加入氯乙基异氰酸酯(105mg,1mmol),加入完毕后,室温下搅拌2小时。加水,乙酸乙酯萃取,得到155-1(450mg,0.8mmol),收率:80%。
(S)-1-(3,4-二氟苯基)-6-(1-((反式)-4-甲氧基环己基)-5-(3-甲基-2-氧代咪唑啉-1-基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(155)的合成
将155-1(450mg,0.8mmol)溶于THF(5mL)中,室温下加入NaH(96mg,2.4mmol),搅拌2小时后,加入碘甲烷(227mg,1.6mmol),再继续搅拌1小时。倒入水(15mL)中,DCM(5mL×3)萃取,柱层析得到155(257mg,0.48mmol),收率:60%。Ms:538(M+H+)
实施例156化合物(E)-3-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-N,N-二甲基丙烯酰胺(156)的合成:
于封管中加入化合物152(100mg,0.19mmol),N,N-二甲基丙烯酰胺(128mg,1mmol),醋酸钯(2mg,0.009mmol),三苯基磷(3mg,0.011mmol),三乙胺(100mg,1mmol),加热至130度过夜。冷却后,加水,乙酸乙酯萃取,无水硫酸钠干燥,柱层析得到100mg固体(化合物156),收率:96%,Ms:537(M+H+)。
实施例157化合物(S)-1-(3,4-二氟苯基)-6-(1-(((反式)-4-甲氧基环己基)-5-乙烯基-1H-苯并[d]咪唑-2-基)哌啶-2-酮(化合物157)的合成:
将化合物152(50mg,0.1mmol),4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼烷(20mg,0.2mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8mg,0.01mmol),碳酸钾(30mg,0.2mmol)溶于5mL二氧六环中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到30mg固体(化合物157),收率67%。Ms:466(M+H+),1H NMR(400MHz,d6-DMSO)δ7.88(d,J=1.9Hz,1H),7.70(d,J=8.8Hz,1H),7.38-7.22(m,3H),6.99(d,J=8.9Hz,1H),6.62(dd,J=16.8Hz,10.0Hz,1H),5.74(d,J=4.7Hz,1H),5.61(dd,J=16.8Hz,2.1Hz,1H),5.20(dd,J=10.0Hz,2.1Hz,1H),4.33(d,J=11.9Hz,1H),3.40-3.35(m,1H),3.27(s,3H),2.62-2.53(m,2H),2.27-1.78(m,9H),1.45-1.24(m,2H),1.22-1.02(m,1H).
实施例158化合物5-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-1,3-二甲基吡啶-2(1H)-酮(158)的合成
将152(518mg,1mmol)溶于二氧六环中,滴入一滴水,加入Pd(dppf)Cl2(73mg,0.1mmol),碳酸钾(276mg,2mmol)和1,3-二甲基-5-(4,4,5,5-四甲基-1,3,2-二恶硼硼烷-2-基)吡啶-2(1H)-酮(747mg,3mmol)。100℃下搅拌过夜,柱层析,得到化合物158(291mg,0.52mmol),收率52%。Ms:561(M+H+)。1H NMR(400MHz,d6-DMSO)δ7.99(d,J=2.2Hz,1H),7.89(d,J=1.5Hz,1H),7.80(s,1H),7.70(d,J=8.7Hz,1H),7.33(dd,J=18.7,8.8Hz,3H),7.02(d,J=8.8Hz,1H),5.73(s,1H),4.33(s,1H),3.52(s,3H),3.47(s,1H),3.43-3.37(m,1H),3.28(s,3H),2.55(d,J=6.7Hz,1H),2.35(d,J=13.6Hz,1H),2.25(d,J=12.7Hz,1H),2.12(s,1H),2.09(s,3H),2.03(d,J=12.6Hz,3H),1.79(s,2H),1.37(dd,J=22.4,11.5Hz,2H),1.21(dd,J=27.8,12.2Hz,2H).
实施例159化合物(S)-1-(3,4-二氟苯基)-6-(1-((反式)-4-甲氧基环己基)-5-(甲基(哌啶-4-基)胺)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(159)的合成
4-((2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)氨基)哌啶-1-羧酸叔丁酯(159-1)的合成
将154(50mg,0.11mmol)、4-Boc-哌啶酮(66mg,0.33mmol)、醋酸(6.6mg,0.11mmol)加入DCE(1mL)中,室温搅拌下分批加入三乙酰氧基硼氢化钠(93mg,0.44mmol)。加完后继续室温下搅拌30分钟,旋干,柱层析,得到159-1(56mg,0.09mmol),收率:82%。
4-((2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)(甲基)氨基)哌啶-1-羧酸叔丁酯(159-2)的合成
将159-1(50mg,0.08mmol),加入THF(0.5mL)中,冰水浴下加入NaH(6.3mg,0.16mmol),搅拌10分钟,加入碘甲烷(34mg,0.24mmol),继续搅拌6小时。加入冰水(6mL),二氯甲烷萃取,柱层析得到159-2(37mg,0.056mmol),收率:71%。
化合物(S)-1-(3,4-二氟苯基)-6-(1-((反式)-4-甲氧基环己基)-5-(甲基(哌啶-4-基)胺)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(159)的合成
将159-2(37mg,0.056mmol)加入DCM(1mL)中,加入TFA(0.25mL),室温下搅拌6小时,旋干,饱和碳酸氢钠调价pH至8~9,DCM萃取,得到159(25mg,0.046mmol),收率:82%。Ms:552(M+H+)。
实施例160化合物2-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)乙酸乙酯(160)的合成
将152(52mg,0.1mmol)溶于均三甲苯中,分别加入Pd(dppf)Cl2(7mg,0.01mmol)、BINAP(6mg,0.01mmol)、DMAP(12mg,0.1mmol)以及丙二酸乙酯单钾盐(17mg,0.1mmol)。140℃下搅拌24小时,柱层析。得到160(10mg,0.02mmol),收率:20%。Ms:526(M+H+)。
实施例161化合物(叔丁基(E)-3-(2-((S)-1-(3,4-二氟苯基)-6-氧哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)丙烯酸酯(161)的合成:
于封管中加入化合物152(100mg,0.19mmol),丙烯酸叔丁酯(128mg,1mmol),醋酸钯(2mg,0.009mmol),三苯基磷(3mg,0.011mmol),三乙胺(100mg,1mmol),加热至130度过夜。冷却后,加水,乙酸乙酯萃取,无水硫酸钠干燥,柱层析得到100mg固体(化合物161),收率:96%,Ms:566(M+H+)。
实施例162化合物5-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-1-甲基吡啶-2(1H)-酮(162)的合成
将152(518mg,1mmol)溶于二氧六环中,滴入一滴水,加入Pd(dppf)Cl2(73mg,0.1mmol),碳酸钾(276mg,2mmol)和1-甲基-5-(4,4,5,5-四甲基-1,3,2-二恶硼硼烷-2-基)吡啶-2(1H)-酮(747mg,3mmol)。100℃下搅拌过夜,柱层析,得到化合物162(291mg,0.52mmol),收率52%。Ms:547(M+H+)。1H NMR(400MHz,d6-DMSO)δ8.13(s,1H),7.92-7.82(m,2H),7.72(d,J=8.5Hz,1H),7.33(dd,J=18.2,9.1Hz,3H),7.03(s,1H),6.47(d,J=9.3Hz,1H),5.75(d,J=9.8Hz,1H),4.33(s,1H),3.51(s,3H),3.43(d,J=25.9Hz,1H),3.28(s,3H),2.56(s,1H),2.37(s,1H),2.31-2.19(m,1H),2.13(s,2H),2.04(d,J=10.6Hz,3H),1.79(s,2H),1.45-1.31(m,2H),1.23-1.10(m,2H).
实施例163化合物2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-腈(163)的合成
将(518mg,1mmol)溶于NMP(5mL),再加入氰化亚铜(179mg,2mmol)、碘化亚铜(19mg,0.1mmol)和8-羟基喹啉(28mg,0.2mmol),100℃下搅拌过夜。倒入水(25mL)中,乙酸乙酯萃取,旋干柱层析,得163(52mg,0.11mmol),收率:11%。Ms:465(M+H+)。
实施例164化合物6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(164)的合成
N-(5-溴-2-(((反式)-4-甲氧基环己基)胺)苯基)-6-氧代哌啶-2-甲酰胺(164-1)
将中间体2(2.98g,10mmol)溶于二氯甲烷(30mL)中,加入2-哌啶酮-6-羧基酸(1.43g,10mmol)、丙基磷酸三环酸酐(50%in EA,6.36g,10mmol)以及DIEA(1.54g,12mmol)。加完后室温下搅拌过夜,旋干,柱层析,得164-1(3.4g,8mmol),收率80%。
6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)哌啶-2-酮(164-2)的合成
将164-1(3.4g,8mmol)加入乙酸(30mL)中,50℃下搅拌3天,旋干,二氯甲烷溶解,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥。旋干柱层析得到164-2(1.95g,4.8mmol),收率60%。
6-(5-溴-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯基)哌啶-2-酮(164)的合成
将164-2(1.95g,4.8mmol),3,4-二氟苯硼酸(230mg,1.48mmol),一水醋酸铜(1.4g,7.2mmol),三乙胺(0.48g,4.8mmol)溶于乙腈(20mL)中,30℃反应过夜。过滤,浓缩,盐酸(1N)洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到化合物164(1.99g,3.84mmol),收率80%。Ms:518(M+H+)。
实施例165(S)-6-(5-((1-乙酰基哌啶-4-基)(甲基)胺)-1-((反式)-4-甲氧环己基)-1H-苯并[d]咪唑-2-基)-1-(3,4-二氟苯)哌啶-2-酮(化合物165)的合成:
将化合物159(551mg,1mmol),三乙胺(303mg,3mmol)溶于20mL DCM中,冰水浴条件下,慢慢滴加乙酰氯(120mg,1.5mmol),反应三个小时。倒入水中,二氯甲烷萃取,饱和食盐水洗,无水硫酸钠干燥,浓缩,柱层析得到415mg产品(化合物165),收率70%。Ms:594(M+H+).
实施例166化合物N-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)甲磺酰胺(166)的合成
将154(20mg,0.04mmol)溶于DCM(0.5mL),加入甲磺酸酐(8mg,0.04mmol)后室温下搅拌1小时。旋干,柱层析得166(5mg,0.009mmol),收率:23%。Ms:533(M+H+)。
实施例167化合物N-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)三氟甲磺酰胺(167)的合成
将154(20mg,0.04mmol)溶于DCM(0.5mL),加入三氟甲磺酸酐(11mg,0.04mmol)后室温下搅拌1小时。旋干,柱层析得166(5mg,0.008mmol),收率:21%。Ms:587(M+H+)。
实施例168化合物1-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-3-甲基脲(168)的合成
将154(20mg,0.04mmol)溶于THF(0.5mL),加入TEA(8mg,0.08mmol),冰水浴冷却至0℃,加入三光气(5mg,0.016mmol),搅拌30分钟后加入甲胺盐酸盐(3mg,0.04mmol),自然升温至室温下搅拌30分钟。柱层析得168(15mg,0.03mmol),收率:73%。Ms:512(M+H+)。
实施例169化合物N-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)乙酰胺(169)的合成
将154(20mg,0.04mmol)溶于DCM(0.5mL),室温搅拌下滴入乙酰氯(3mg,0.04mmol)并继续搅拌2小时。柱层析,得到169(17mg,0.03mmol),收率:86%。Ms:5497(M+H+)。
实施例170化合物N-(2-((S)-1-(3,4-二氟苯基)-6-氧代哌啶-2-基)-1-((反式)-4-甲氧基环己基)-1H-苯并[d]咪唑-5-基)-2-(二甲氨基)乙酰胺(170)的合成
将154(20mg,0.04mmol)溶于DMF(0.5mL),加入N,N-二甲基甘氨酸(4mg,0.04mmol)、HATU(15mg,0.04mmol)和DIEA(5mg,0.04mmol),室温下搅拌过夜,倒入水(3mL)中,乙酸乙酯萃取,柱层析得170(12mg,0.02mmol),收率:50%。Ms:540(M+H+)。
实施例171化合物(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物171)的合成:
反式-4-((4-溴-2-硝基苯基)氨基)环己醇(中间体171-1)的合成:
将4-溴-1-氟-2-硝基苯(2g,9.14mmol),(反式)-4-氨基环己醇(1.26g,10.97mmol)以及碳酸钾(2.6g,18.84mmol)溶于乙腈(30mL)中,加热至80℃,搅拌5小时。冷却,加入100mL水,过滤,水洗,滤饼经柱层析得到2.4g固体(中间体171-1),收率83.7%。4-溴-N-((反式)-4-乙氧基环己基)-2-硝基苯胺(中间体171-2)的合成:
将中间体171-1(2.4g,7.65mmol),氢化钠(0.37g,15.42mmol)溶于20mL四氢呋喃中,冰浴下,滴加碘乙烷(2.4g,15.39mmol),反应过夜。倒入冰水中,乙酸乙酯(30mLx3)萃取,饱和食盐水(20mL)洗一次,有机相无水硫酸钠干燥,浓缩,柱层析得到1.5g产品(中间体171-2),收率58%
4-溴-N1-((反式)-4-乙氧基环己基)苯-1,2-二胺(中间体171-3)的合成:
将中间体171-2(1.5g,4.38mmol),氨水(3mL),溶于20mL四氢呋喃和5mL水中,加入连二亚硫酸钠(3.8g,21.83mmol),室温下搅拌过夜。静止分出有机层,水层用乙酸乙酯(30mLx2)萃取,合并有机层,无水硫酸钠干燥,浓缩,柱层析得到850mg固体(中间体171-3),收率62%
4-(3,5-二甲基异恶唑-4-基)-N1-((反式)-4-乙氧基环己基)苯-1,2-二胺(中间体171-4)的合成:
将中间体171-3(850mg,2.73mmol),3,5-二甲基异恶唑-4-硼酸频哪醇酯(923mg,4.12mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(10mg,0.014mmol),碳酸钾(753mg,5.44mmol)溶于30mL二氧六环和50mL水中,氮气置换三次,100℃下搅拌10小时。冷却,乙酸乙酯萃取三次,有机层无水硫酸钠干燥,浓缩,柱层析得到580mg固体(中间体171-4),收率65%。
叔丁基((S)-3-((叔丁基二甲基甲硅烷基)氧基)-1-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基)丙基氨基甲酸酯(中间体171-5)的合成:
将中间体10(673mg,2.12mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入中间体171-4(580mg,1.76mmol)以及焦亚硫酸钠(670mg,3.53mmol),80度下反应5小时。加入50mL水,乙酸乙酯(30mLx3)萃取,合并有机相,饱和食盐水(20mL)洗一次,无水硫酸钠干燥,浓缩,柱层析纯化,得到420mg产品(中间体171-5),收率:38.2%。
(S)-3-氨基-3-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基丙-1-醇(中间体171-6)的合成:
将中间体171-5(420mg,0.67mmol),氟氢化钾(262mg,3.35mmol)溶于甲醇(20mL)中,加入5mL浓盐酸,30度反应过夜。调pH为9-10,浓缩,二氯甲烷(30mLx4)萃取,无水硫酸钠干燥,浓缩,柱层析得到200mg产品(中间体171-6),收率:72.5%
(S)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶二嗪-2-酮(中间体171-7)的合成:
将中间体171-6(200mg,0.48mmol),三乙胺(97mg,0.96mmol)溶于60mL四氢呋喃中,加热至35℃,分批加入三光气(44mg,0.15mmol),反应30分钟。水洗,1N盐酸洗,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,柱层析得到产品(中间体171-7)116mg,收率:54.8%.
(S)-3-(3,4-二氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物171)的合成:
将中间体171-6(60mg,0.14mmol),3,4-二氟苯硼酸(90mg,0.57mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg,0.3mmol)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到60mg产品(化合物171),收率77.9%。Ms:551(M+H+),1H NMR(400MHz,d6-DMSO)δ7.81(d,J=8.5Hz,1H),7.73(d,J=1.3Hz,1H),7.46(ddd,J=11.9,7.4,2.4Hz,1H),7.37(dd,J=19.6,9.1Hz,1H),7.16(dd,J=8.5,1.5Hz,1H),7.14-7.07(m,1H),5.82(s,1H),4.58(t,J=10.0Hz,1H),4.40-4.28(m,2H),3.49(q,J=7.0Hz,3H),3.31(s,1H),2.68(t,J=13.0Hz,1H),2.40(s,3H),2.24(s,4H),2.21(d,J=3.3Hz,1H),2.17(d,J=3.0Hz,1H),2.09(d,J=12.8Hz,1H),2.02(d,J=12.3Hz,1H),1.84(d,J=11.8Hz,1H),1.42-1.32(m,2H),1.12(t,J=7.0Hz,3H).
实施例172化合物(S)-3-(4-氯-3-氟苯基)-4-(5-(3,5-二甲基异恶唑-4-基)-1-((反式)-4-乙氧基环己基)-1H-苯并[d]咪唑-2-基)-1,3-恶嗪南-2-酮(化合物172)的合成
将中间体171-6(56mg,0.13mmol),4-氯-3-氟苯基硼酸(90mg,0.52mmol),一水醋酸铜(60mg,0.3mmol),三乙胺(30mg,0.3mmol)溶于20mL乙腈中,30度反应过夜。过滤,浓缩,1N盐酸洗,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析得到58mg产品(化合物172),收率78.8%。Ms:566(M+H+),1H NMR(400MHz,d6-DMSO)δ7.82(d,J=8.5Hz,1H),7.72(d,J=1.3Hz,1H),7.53(t,J=8.6Hz,1H),7.46(dd,J=10.8,2.3Hz,1H),7.26-7.06(m,2H),5.88(s,1H),4.56(dd,J=11.1,9.0Hz,1H),4.35(dd,J=7.1,3.6Hz,2H),3.49(q,J=6.9Hz,3H),2.68(t,J=13.1Hz,1H),2.40(s,3H),2.25(d,J=16.9Hz,4H),2.21(s,1H),2.18(s,1H),2.10(d,J=11.8Hz,1H),2.03(d,J=12.5Hz,1H),1.85(d,J=11.2Hz,1H),1.37(d,J=5.7Hz,2H),1.28(d,J=10.8Hz,1H),1.12(t,J=7.0Hz,3H).
以下通过实验例证明本发明的有益效果。
实验例1检测化合物对CBP/EP300溴结构域(BRD)的抑制活性1.实验方法
A、实验方法
CBP和EP300AlphaScreen检测实验:
1.准备1倍浓度的检测缓冲液
2.准备化合物
先用Precision自动加样仪将化合物稀释成终浓度的1000倍(3倍梯度稀释法):
1)用Echo自动加样仪转移50μL储存浓度为10mM的化合物到96孔板的A2孔。
2)用Precision转移30μL的DMSO到A1孔,A3至A12孔。
3)用Precision从A2转移15μL到A3,依次一直转到从A10到A11。完成1:3梯度稀释。
4)化合物板以1000转/分钟转速离心1分钟。
3.准备检测板
用Echo自动加样仪从化合物板每个浓度转移20nL到检测板中:从配置板的A1转到检测板的A1和A2,从配置板的A2转到检测板的A3和A4。
4.溴结构域(BRD)结合检测实验
1)准备2倍的蛋白质和多肽溶液
将蛋白质和多肽溶解在1倍浓度的检测缓冲液中。
2)将10μL蛋白质和多肽溶液转移至检测板中3到24列的每孔中,并转移10μL 1倍检测缓冲液到检测板中1到2列孔中作为阴性对照。
3)检测板以1000转/分钟转速离心1分钟。
4)在室温下孵育15分钟。
5)受体珠和供体珠用1倍的检测缓冲液配制成2倍的受体和供体溶液。
6)转移2倍的受体和供体溶液到检测板。
加入15μL受体和供体溶液,并避免光照。
7)检测板以1000转/分钟转速离心1分钟,在室温下孵育60分钟。
5.用EnSpire和Alpha模式读取终点。
6.曲线拟合
将实验数据输入Excel文档中并使用方程(1)得到抑制率Inh%:
方程(1):Inh%=(Max-Signal)/(Max-Min)×100
其中,Max:加DMSO的对照,Max:加DMSO的低的对照,
将得出的数据输入XL-Fit软件中并使用方程(2)得到IC50的值:
方程(2):Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×Hill Slope))
2.实验结果
表1.各化合物对CBP/EP300 BRD的IC50
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实验结果如表1所示,可以看出,本发明化合物对CBP BRD和EP300 BRD同时具有明显的抑制活性,特别是化合物117、112、113、106、143、171、172,其对CBP BRD的IC50低至5.0nM以下,对EP300 BRD的IC50低至3.0nM以下。
实验例2本发明化合物对***癌CWR22RV1细胞增殖的抑制作用
1.实验步骤:
①***癌CWR22RV1细胞用细胞培养液传代培养,取生长状态良好的细胞接种于96孔板,每孔80μL,每孔细胞数为1500,于37℃,5%CO2细胞孵育箱中培养过夜。
②将药物用二甲基亚砜(DMSO)配置成30mM的储存液。临用前再用DMSO稀释3倍,再按3倍梯度稀释,得到9个浓度梯度,再用培养液将各浓度的化合物稀释200倍(以此保证培养体系中DMSO浓度为0.1%),每个浓度做2个孔重复。取20μL稀释好的化合物加到细胞培养孔(终浓度为10μM,3.3μM,1.1μM…),轻轻振荡混匀。另外设置3个只加细胞的阴性对照孔和3个只加培养液的空白对照孔(6孔各加20μL培养液稀释200倍的DMSO)。
2.结果检测:
(1)培养6天后,每孔加10μL CCK-8,于37℃,5%CO2细胞孵育箱中继续培养2.5小时。
(2)用多功能酶标仪在450nm处测定吸光度(OD值)。
(3)数据用软件GraphPad Prism6中Dose-response-inhibition方程分析,得出IC50值。
3.实验结果
本发明化合物对CWR22RV1细胞的活性抑制的IC50(nM)结果如表2所示。
A表示IC50小于或等于500nM;B表示IC50大于500nM且小于或等于2000nM;C表示IC50大于2000nM。
表2各化合物对CWR22RV1细胞的IC50
化合物编号 | IC50 |
113 | A |
143 | B |
112 | A |
117 | A |
106 | B |
141 | C |
171 | B |
172 | B |
可以看出,本发明化合物对***癌CWR22RV1细胞具有明显的抑制效果,特别是化合物112、113、117,其对***癌CWR22RV1细胞的IC50低至500nM以下。
实验例3本发明化合物对其他肿瘤细胞增殖的抑制作用
1.实验方法
采用与实验例2相同的方法,将CWR22RV1细胞替换为表3中的肿瘤细胞,测试并计算本发明化合物对这些肿瘤细胞活性抑制的IC50(nM),结果如表3所示。
2.实验结果
表3中,A表示IC50小于或等于500nM;B表示IC50大于500nM且小于或等于2000nM。
表3各化合物对各肿瘤细胞的IC50
可以看出,本发明制得的化合物对其他***癌细胞、白血病细胞、乳腺癌细胞、多发性骨髓瘤细胞的增殖均有明显的抑制作用。说明本发明化合物同时对多种肿瘤具有抑制效果。
实验例4本发明化合物与CDK4/6抑制剂palbociclib联用对***癌CWR22RV1细胞的增殖抑制作用
1.实验步骤:
测试并计算本发明化合物、palbociclib、以及本发明化合物与palbociclib联用对CWR22RV1细胞增殖抑制的IC50(nM),具体操作如下:
1)CWR22RV1细胞用细胞培养液传代培养,取生长状态良好的细胞接种于96孔板,每孔60μL,每孔细胞数为2000,于37℃,5%CO2细胞孵育箱中培养过夜。
2)将药物用二甲基亚砜(DMSO)配置成10mM的储存液。临用前再用DMSO稀释3倍,再按3倍梯度稀释,得到9个浓度梯度,再用培养液将各浓度的化合物稀释200倍(以此保证培养体系中DMSO浓度为0.1%),每个浓度做2个孔重复。取20μL稀释好的化合物加到细胞培养孔(终浓度为10μM,3.3μM,1.1μM…);palbociclib用培养液分别稀释为500nM,150nM,50nM,5nM,取20μL稀释好的化合物加到相应的细胞培养孔(终浓度为100nM,30nM,10nM,1nM),轻轻振荡混匀。另外设置3个只加细胞的阴性对照孔和3个只加培养液的空白对照孔(6孔各加20μL培养液稀释200倍的DMSO)。
2.结果检测:
1)培养6天后,每孔加10μL CCK-8,于37℃,5%CO2细胞孵育箱中继续培养2.5小时。
2)用多功能酶标仪在450nm处测定吸光度(OD值)。
3)数据用软件GraphPad Prism6中Dose-response-inhibition方程分析,得出IC50值。
3.实验结果
本发明化合物与palbociclib联用对CWR22RV1细胞活性抑制的IC50(nM)结果如表4所示。
表4化合物与palbociclib联用对CWR22RV1细胞的活性抑制的IC50
化合物编号 | IC50(nM) |
172 | 1500 |
palbociclib | 100 |
300nM palbociclib+172 | <1 |
100nM palbociclib+172 | <1 |
10nM palbociclib+172 | 26 |
可以看出,单独使用化合物172时,其对CWR22RV1细胞活性的IC50为1500nM;单独使用palbociclib时,其对CWR22RV1细胞活性的IC50为100nM;但是,将化合物172与palbociclib联用时,能够显著降低化合物172对CWR22RV1细胞活性的IC50,当将化合物172与100~300nM的palbociclib联用时,化合物172对CWR22RV1细胞活性的IC50甚至低至1nM以下。
实验表明本发明化合物172与palbociclib联用对抑制***癌CWR22RV1细胞的活性发挥了协同增效的抑制作用。。
实验例5本发明化合物与CDK4/6抑制剂palbociclib联用对乳腺癌MCF-7细胞的增殖抑制作用
1.实验方法
采用与实验例4相同的方法,将CWR22RV1细胞替换为MCF-7细胞,测试并计算本发明化合物、palbociclib、以及本发明化合物与palbociclib联用对MCF-7细胞增殖抑制的IC50(nM),结果如表5所示。
2.实验结果
表5化合物与palbociclib联用对MCF-7细胞的活性抑制的IC50
化合物编号 | IC50(nM) |
palbociclib | 12800 |
172 | 72 |
300nM palbociclib+172 | 7 |
100nM palbociclib+172 | 9 |
10nM palbociclib+172 | 27 |
可以看出,单独使用化合物172时,其对MCF-7细胞活性的IC50为72nM;单独使用palbociclib时,其对MCF-7细胞活性的IC50高达12800nM;但是,将化合物172与palbociclib联用时,能够显著降低化合物172对MCF-7细胞活性的IC50,当将化合物172与100~300nM的palbociclib联用时,化合物172对MCF-7细胞活性的IC50甚至低至10nM以下。
实验表明本发明化合物172与palbociclib联用对抑制乳腺癌MCF-7细胞的活性发挥了协同增效的抑制作用。
综上,本发明提供了一类新的化合物,该化合物对EP300/CBP具有高度选择性,并且能够有效抑制EP300/CBP的活性;而且,本发明化合物对包括***癌细胞、白血病细胞、乳腺癌细胞、多发性骨髓瘤细胞在内的多种肿瘤细胞均具有优异的抑制作用。因此,本发明化合物在制备EP300/CBP抑制剂,以及预防和/或***、髓系造血干/祖细胞恶性疾病,调控调节性T细胞的药物中具有广阔的应用前景。
Claims (22)
1.一种化合物、或其氘代物、或其盐,其特征在于:所述化合物的结构如式III-1所示:
其中,R1a、R1b各自独立的选自氘代或未氘代的C1~3烷基;
n1为1;n2为1;
m2为1;
Y1为O;
Y2为O;
Rx选自氘代或未氘代的C1~2烷氧基;
R3’选自被0~3个R3a取代的苯基;R3a选自卤素、甲基、甲氧基、氰基。
2.根据权利要求1所述的化合物、或其氘代物、或其盐,其特征在于:所述R3’选自被2~3个R3a取代的苯基;所述卤素为氟、氯或溴。
3.根据权利要求1所述的化合物、或其氘代物、或其盐,其特征在于:所述式III-1所示化合物的结构如式III-3所示:
其中,R1a、R1b各自独立的选自氘代或未氘代的C1~3烷基;
Rx选自氘代或未氘代的C1~2烷氧基;
n3为2或3;
R3a为卤素。
4.根据权利要求3所述的化合物、或其氘代物、或其盐,其特征在于:所述n3为2;所述卤素为氟、氯或溴。
5.根据权利要求1所述的化合物、或其氘代物、或其盐,其特征在于:所述化合物选自以下化合物之一:
6.权利要求1-5任一项所述化合物、或其氘代物、或其盐在制备EP300/CBP抑制剂中的用途,所述EP300/CBP抑制剂为预防和/或治疗***癌的药物。
7.一种治疗***癌的药物,其特征在于:所述药物是以权利要求1-5任一项所述化合物、或其氘代物、或其盐为活性成分,加上药学上可接受的辅料制得的制剂。
8.一种联合用药物,其特征在于:它含有相同或不同规格单位制剂的用于同时或者分别给药的权利要求1-5任一项所述化合物、或其氘代物、或其盐,和其他具有抗肿瘤作用的药物,以及药学上可接受的载体。
9.根据权利要求8所述的联合用药物,其特征在于:所述其他具有抗肿瘤作用的药物为化疗药物或放疗药物。
10.根据权利要求9所述的联合用药物,其特征在于:所述化疗药物为靶向药物。
11.根据权利要求8所述的联合用药物,其特征在于:所述其他具有抗肿瘤作用的药物选自CDK4/6抑制剂、PARP抑制剂、雄激素受体抑制剂、免疫检查点抑制剂中的一种或两种以上。
12.根据权利要求11所述的联合用药物,其特征在于:所述CDK4/6抑制剂为palbociclib。
13.一种化合物、或其氘代物、或其盐,其特征在于:所述化合物的结构如式IV所示:
其中,R1a、R1b各自独立的选自氘代或未氘代的C1~3烷基;
Rx选自氘代或未氘代的C1~3烷氧基;
Y3为CH;
m3为0~3的整数;
R4各自独立的选自C1~3烷氧基、取代或未取代的苯基;所述苯基上的取代基选自卤素。
14.根据权利要求13所述的化合物、或其氘代物、或其盐,其特征在于:所述m3为2或3。
15.根据权利要求14所述的化合物、或其氘代物、或其盐,其特征在于:所述化合物为:
16.权利要求13-15任一项所述化合物、或其氘代物、或其盐在制备EP300抑制剂、CBP抑制剂或EP300/CBP抑制剂中的用途。
17.一种治疗疾病的药物,其特征在于:所述药物是以权利要求13-15任一项所述化合物、或其氘代物、或其盐为活性成分,加上药学上可接受的辅料制得的制剂。
18.一种联合用药物,其特征在于:它含有相同或不同规格单位制剂的用于同时或者分别给药的权利要求13-15任一项所述化合物、或其氘代物、或其盐,和其他具有抗肿瘤作用的药物,以及药学上可接受的载体。
19.根据权利要求18所述的联合用药物,其特征在于:所述其他具有抗肿瘤作用的药物为化疗药物或放疗药物。
20.根据权利要求19所述的联合用药物,其特征在于:所述化疗药物为靶向药物。
21.根据权利要求18所述的联合用药物,其特征在于:所述其他具有抗肿瘤作用的药物选自CDK4/6抑制剂、PARP抑制剂、雄激素受体抑制剂、免疫检查点抑制剂中的一种或两种以上。
22.根据权利要求21所述的联合用药物,其特征在于:所述CDK4/6抑制剂为palbociclib。
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