CN111712496B - 作为溴结构域蛋白质抑制剂的化合物和组合物 - Google Patents
作为溴结构域蛋白质抑制剂的化合物和组合物 Download PDFInfo
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- CN111712496B CN111712496B CN201880081489.6A CN201880081489A CN111712496B CN 111712496 B CN111712496 B CN 111712496B CN 201880081489 A CN201880081489 A CN 201880081489A CN 111712496 B CN111712496 B CN 111712496B
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- methyl
- pyridin
- pyrrolo
- dihydro
- imidazo
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- 239000012268 protein inhibitor Substances 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- -1 methoxy, methylthio, methoxycarbonyl Chemical group 0.000 claims description 109
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 claims description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 32
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 108091005625 BRD4 Proteins 0.000 claims description 21
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
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- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
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- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 2
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Abstract
一种具有式(I)结构的溴结构域抑制剂,也提供包含这类化合物的组合物和制剂,及使用和制备这样的化合物的方法。
Description
技术领域
本发明涉及可抑制含溴结构域蛋白质或以其它方式调节其活性的化合物,及包含这样的化合物的组合物和制剂,及使用和制备这样的化合物的方法。
背景技术
含BET(溴结构域和末端外结构域)家族的溴结构域(bromodomain,BRD)蛋白质包括4种:BRD2、BRD3、BRD4和BRDT。BET家族的蛋白质是表观遗传编码的读取子,将赖氨酸残基乙酰化偶联在组蛋白上以改变染色质结构和基因表达。BRD2、BRD3和BRD4得以普遍表达,而BRDT局限于生殖细胞。BET蛋白在调控基因转录和控制细胞生长方面起必要但不重叠的作用。BET蛋白质与调控许多基因转录方面的大蛋白质复合物相关,包括RNA聚合酶II(PolII)、正向转录延长因子(P-TEFb)。已证实BRD2和BRD4蛋白在有丝分裂期间保持与染色体结合,且需要所述蛋白质促进起始细胞周期的重要基因(包括周期素D和c-Myc)转录(Mochizuki,J Biol.Chem.2008 283:9040-9048)。BRD4蛋白与RNA聚合酶II(Pol II),正向转录延长因子(Positive transcription elongation factor,P-TEFb)结合,共同促进多种癌症细胞增殖和凋亡相关基因如c-Myc,细胞周期蛋白、抗凋亡蛋白Bcl-2等基因的转录表达,调控肿瘤细胞生长增殖过程(Jang等人,Mol.Cell 200519:523-534)。在一些情况下,BRD4的激酶活性可直接使RNA聚合酶II磷酸化和活化(Devaiah等人,PNAS 2012 109:6927-6932)。缺乏BRD4的细胞显示细胞周期进展受损。据报导,BRD2和BRD3与组蛋白以及积极转录基因相关并且可参与促进转录伸长(Leroy等人,Mol.Cell.2008 30:51-60)。除乙酰化组蛋白以外,已证实BET蛋白选择性结合乙酰化转录因子,包括NF-kB和GATAl的RelA亚单位,从而直接调控这些蛋白质的转录活性以控制参与发炎和造血分化的基因的表达(Huang等人,Mol.Cell Biol.2009 29:1375-1387;Lamonica Proc.Nat.Acad.Sci.2011 108:E159-168)。
包括BRD4的BET蛋白质已经被鉴定为在大量疾病中发现的改变基因表达特性的重要介质,所述疾病包括癌症、糖尿病、肥胖、动脉粥样硬化、心血管、肾症和病毒感染。参见Muller,S.,et al.,Expert Rev.Mol.Med.,13:e29(2011);Zhou,M.,et al.,J.Virol.,83:1036-1044(2009);Chung,C.W.,et al.,J.Med.Chem.,54:3827-3838(2011)。例如,Myc涉及大部分人类癌症,且BET蛋白质已经被鉴定为c-Myc的调节因子;BET蛋白质(包括BRD4)的抑制已经显示下调Myc转录。
因此,对开发用作溴结构域抑制剂的化合物存在巨大需求。具体而言,开发用作BET抑制剂的化合物将是备受期待的。尽管已报道了一些小分子BET抑制剂已用于临床研究,但是,目前仍没有批准上市的品种,因此,仍需要开发新的小分子BET抑制剂,为临床上治疗由BET介导的疾病或病症提供一种新的用药选择。
发明内容
本发明涉及作为溴结构域抑制剂,特别是BRD4抑制剂的化合物,及其在治疗由BET介导的疾病中的应用。本发明首先提供了式(I)所示的化合物或其药学上可接受的盐,
其中,
R1和R2分别独立地选自H、C1-6烷基、C1-6烷氧基、C6-10芳基或C5-10杂芳基,所述C1-6烷基、C1-6烷氧基、C6-10芳基或C5-10杂芳基任选地被C1-6烷基、-NH2、-OH、C6-10芳基或C5-10杂芳基取代;所述C5-10杂芳基具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;
Q不存在或选自C1-6亚烷基、-SO2-或-NH-,所述C1-6亚烷基或-NH-任选地被卤素、C1-6烷基或C1-6烷氧基取代;
X选自H、C1-6烷基、C6-10芳基或C5-10杂芳基,所述C1-6烷基、C6-10芳基或C5-10杂芳基任选地被卤素、卤代C1-6烷基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷氧羰基或C1-6烷基-SO2-取代;
R3和R4不存在或分别独立地选自H、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、氰基、氧代基或-N(R5)-SO2-R6;
R5和R6分别独立地选自H、C1-6烷基或卤素取代的C1-6烷基。
关于式(I)所示化合物,本发明进一步提供了一些优选的技术方案。
一些实施方式中,R1选自H、C1-4烷基、苯基或C5-6杂芳基,所述C1-4烷基、苯基或C5-6杂芳基任选地被C1-6烷基、-NH2、苯基或C5-6杂芳基取代;优选地,所述杂芳基具有1个、2个或3个分别独立地选自氮或硫的杂原子。
一些实施方式中,R2为H或C1-3烷基。
一些具体实施方式中,R2为H或-CH3。
一些实施方式中,X选自H、C1-3烷基或苯基,所述苯基未取代或任选地被卤素、卤代C1-3烷基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氧羰基或C1-3烷基-SO2-取代。
一些实施方式中,X选自H、C1-3烷基或苯基,所述苯基未取代或任选地被F、Cl、甲基、三氟甲基、甲氧基、甲硫基、甲氧基羰基或甲基-SO2-取代。
一些实施方式中,Y选自其中,表示双键或单键,U、V、W、G或Z分别独立地选自C或N;当G为N时,R4为不存在;当G为C时,R4为H或-N(R5)-SO2-R6;其中,R5和R6分别独立地选自H、C1-6烷基或卤素取代的C1-6烷基。
一些实施方式中,Y选自其中,表示双键或单键,U、W或Z分别独立地选自C或N;R3选自H、卤素、羟基、氨基、C1-6烷基、C1-6烷氧基、氰基或氧代基;R4为H或-N(R5)-SO2-R6;其中,R5和R6分别独立地选自H、C1-6烷基或卤素取代的C1-6烷基。
一些实施方式中,R3为H、C1-6烷基、C1-6烷氧基、氰基或氧代基。
一些实施方式中,R3为H、甲基或氧代基。
一些实施方式中,R4为-N(R5)-SO2-R6。
一些实施方式中,R5和R6分别独立地选自H或C1-6烷基。
一些实施方式中,R5和R6分别独立地选自H、甲基或乙基。
本发明进一步提供了一种化合物或其药学上可接受的盐,所述化合物是指:
1)4-(1-(4-氯苄基)-2-甲基-1H咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
2)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
3)6-甲基-4-(2-甲基-1-(4-(甲硫基)苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4)6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
5)4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6)4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)酮;
7)4-(1,2-二甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
8)6-甲基-4-(2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
9)甲基4-((2-甲基-6-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲酸酯;
10)6-苄基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
11)6-异丁基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
12)6-乙基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
13)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-2-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
14)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(噻唑-2-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
15)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(吡唑-2-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
16)4-(1-(3-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-2-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
17)4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(吡啶-3-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
18)4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
19)6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
20)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
21)4-(1-(1-(4-氯苯基)乙基)-2-甲基-1H-咪唑并[4,5-b]对二氮杂苯-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
22)4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
23)4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
24)4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
25)4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
26)4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
27)4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
28)4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
29)4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
30)4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
31)4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
32)4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
33)6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
34)1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
35)4-(3-(1-(2,6-二氯-3-氟苯基)乙基)-2-甲基-1H-吡咯并[2,3-b]吡啶-5-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
36)4-(1-(2,6-二氯苄基)-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
37)4-(4-((4-氯苯基)氨基)吡啶并[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
38)4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
39)4-(1-(4-氯苄基)-1H-吡唑并[4,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
40)4-(1-((4-氯苯基)硫酰基)-1H-吡咯并[2,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮。
41)N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
42)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
43)N-(1-(4-甲氧基苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
44)N-(1-(1-(4-氯苯基)乙基)-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
45)N-(1-苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
46)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
47)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氟-5-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
48)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氟-5-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
49)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氟-4-氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
50)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)-4氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
51)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氟-4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
52)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氯-4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
53)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
54)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2,4-二氟苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
55)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-溴苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
56)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-(甲磺酰基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
57)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氯-4-氟苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
58)N-(5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
59)N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
60)N-(3-(1-(4-氯苯基)乙基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
61)N-(3-(2-氟-5-(三氟甲基)苄基)-5-(6-甲基-7氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
62)N-(3-(3,5-二氟苄基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
63)N-(5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
64)N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
65)N-(2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
66)N-(2-甲基-5-(6-甲基-7氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
67)N-(3-(3,5-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;或
68)N-(3-(2,6-二甲基苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺。
本发明进一步提供了6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮(化合物19)的晶型I。
在一些实施方式中,上述晶型I的X射线粉末衍射谱图具有衍射角2θ为13.8±0.2°、18.9±0.2°、26.0±0.2°的特征峰。
在一些实施方式中,上述晶型I的X射线粉末衍射谱图具有衍射角2θ为6.2±0.2°、13.8±0.2°、18.9±0.2°、19.5±0.2°、26.0±0.2°、26.8±0.2°的特征峰。
在一些实施方式中,上述晶型I具有如附图1所示的X-射线粉末衍射图。
本发明总结了上述晶型I的X-射线粉末衍射图谱中的特征峰,如表1所示。
表1
在一些实施方式中,本发明所述晶型I可用差式扫描量热分析进行鉴定。在一些实施方式中,晶型I具有如附图2所示的差式扫描量热分析曲线。在DSC图谱中,晶型I的吸热峰约在288.9℃。差式扫描量热分析测定是通过TA instruments Q200 DSC(吹扫气体:氮气;流速:40mL/min;升温速度:10℃/分钟)测定。
在一些实施方式中,本发明所述晶型I可以利用1HNMR进行鉴定,1HNMR的数据如下:1H NMR(400MHz,DMSO)δ12.17(s,1H),8.94(s,1H),8.05(s,1H),7.75(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),7.30(m,1H),6.77(m,1H),5.70(s,2H),3.65(s,3H),2.65(s,3H)。
作为优选,该晶型I纯度≥85%。
作为优选,该晶型I纯度≥95%。
作为优选,该晶型I纯度≥99%。
作为优选,该晶型I纯度≥99.5%。
作为优选,该晶型I为无水物。
本发明提供的晶型I具有结晶性好、不吸湿性、稳定性好的特性,而且具有可接受的口服生物利用度。
本发明还提供了一种药物组合物,包含治疗有效量的至少一种上述化合物和药学上可接受的辅料,例如羟丙基甲基纤维素。在一些组合物中,所述化合物与所述辅料的重量比大约为0.001~10。
此外,本发明还提供一种治疗患有对含溴结构域蛋白质的抑制响应的疾病或病症的受试者的方法,包括给药治疗有效量的式(I)的化合物或其可药用盐。在某些方面,所述含溴结构域蛋白质为BRD4。
在某些方面,疾病或病症选自自身免疫疾病、炎性疾病、神经变性疾病、心血管障碍、肾病症、病毒感染和肥胖。在某些方面,所述疾病或病症选自类风湿性关节炎、骨关节炎、动脉粥样硬化、银屑病、系统性红斑狼疮、多发性硬化、炎性肠病、哮喘、慢性阻塞性气道病、肺炎、皮炎、脱发、肾炎、血管炎、动脉粥样硬化、阿尔茨海默病、肝炎、原发性胆汁性肝硬变、硬化性胆管炎、糖尿病(包括I型糖尿病)、移植器官的急性排斥反应。在某些方面,所述疾病或病症是癌症,包括血液学癌症、淋巴瘤、多发性骨髓瘤、白血病、赘瘤、癌症或肿瘤(例如实体瘤)。在某些方面,所述疾病或病症为结肠、直肠、前列腺(例如去势抗性(castrateresistant)前列腺癌)、肺癌(例如非小细胞肺癌和/或小细胞肺癌)、胰腺、肝、肾、子宫颈、子宫、胃、卵巢、乳腺(例如基底或基底样乳腺癌和/或三重阴性乳腺癌)、皮肤(例如黑素瘤)、神经系统(包括脑、脑脊膜、和中枢神经系统,包括成神经细胞瘤、成胶质细胞瘤、脑膜瘤和髓母细胞瘤)的瘤或癌症。在某些方面,所述疾病或病症为癌瘤。在某些方面,所述疾病或病症为肝细胞癌。在某些方面,所述疾病或病症为淋巴瘤。在某些方面,所述疾病或病症为B-细胞淋巴瘤。在某些方面,所述疾病或病症为伯基特淋巴瘤。在某些方面,所述疾病或病症为弥漫性大B-细胞淋巴瘤。在某些方面,所述疾病或病症为多发性骨髓瘤。在某些方面,所述疾病或病症为慢性淋巴细胞性白血病。在某些方面,所述疾病或病症是NUT中线癌(midline cardinoma)。在某些方面,所述受试者是人类。
在某些方面,所述化合物是静脉内、肌内、胃肠外、鼻或口服给药的。在一个方面,所述化合物是口服给药的。
本发明还提供一种抑制溴结构域蛋白质的方法,包括用式(I)的化合物或其可药用盐接触所述溴结构域蛋白质。
本发明还提供式(I)的化合物或其可药用盐在制备用于治疗对溴结构域蛋白质的抑制响应的疾病或病症的药物中的用途。
本发明还提供用于治疗的式(I)的化合物或其可药用盐。进一步提供用于治疗患有对含溴结构域蛋白质的抑制响应的疾病或病症的受试者的式(I)的化合物或其可药用盐。还提供用于上述治疗方法中的式(I)的化合物或其可药用盐。
本发明中,除另有说明,术语“卤素”(halogen)是指氟、氯、溴或碘。优选的卤素基团是指氟、氯和溴。
本发明中,除另有说明,术语“烷基”包括直链、支链或环状的饱和单价烃基。例如,烷基包括甲基、乙基、丙基、异丙基、环丙基、正丁基、异丁基、仲丁基、叔丁基、环丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、环戊基、正己基、2-己基、2-甲基戊基和环己基。类似的,C1-6烷基中的“C1-6”是指含有1、2、3、4、5或6个碳原子以直链或支链形式排列的基团。
烷氧基是指由上述的直链、支链或环状烷基所形成的氧醚。
本发明中,除另有说明,术语“杂芳基”是指取代或未取代的稳定的5到10个环原子的至少含有一个芳香环的单环或双环基团,所述的芳香环含有一个、两个或三个选自N、O和S的环杂原子,其余的环原子是C原子。此类杂芳基的实例包括但不限于,吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯并咪唑。
本发明中术语“组合物”旨在包括含有特定数量的特定组分的产品,也包括任何由特定数量的特定组分直接或间接得到的产品。因此,包含本发明中的化合物作为活性组分的药物组合物和制备该化合物的方法也是本发明的内容。而且,一些化合物的晶型可以多晶型形式存在,这些也包括在本发明中。此外,一些化合物与水(如水合物)或普通有机溶剂形成溶剂化物,这些溶剂化物也包含在本发明中。
本发明化合物的药物前体包含在本发明的保护范围内。通常,所述药物前体是指很容易在体内转化成所需要的化合物的功能性衍生物。因此,本发明提供的治疗方法中的术语“给药”包括施用本发明公开的化合物,或虽未明确公开但对受试者给药后能够在体内转化为本发明公开的化合物治疗所述的各种疾病。有关选择和制备合适药物前体衍生物的常规方法,已记载在例如《药物前体设计》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)这类书中。
显然的,一个分子中任何取代基或特定位置的变量的定义是独立于分子中其他位置的。很容易理解,本领域普通技术人员可以通过现有技术手段及本发明中所述的方法,选择本发明中的化合物的取代基或取代形式,以提供化学上稳定且容易合成的化合物。
本发明所述化合物可能含有一个或多个不对称中心,并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药学上可接受的盐。
上述式(I)没有确切定义该化合物某一位置的立体结构。本发明包括式(I)所示化合物的所有立体异构体及其药学上可接受的盐。进一步地,立体异构体的混合物及分离出的特定的立体异构体也包括在本发明中。制备此类化合物的合成过程中,或使用本领域普通技术人员公知的外消旋化或差向异构化方法的过程中,制得的产品可以是立体异构体的混合物。
当式(I)所示化合物存在互变异构体时,除非特别声明,本发明包括任何可能的互变异构体和其药学上可接受的盐,及它们的混合物。
当式(I)所示化合物及其药学上可接受的盐为溶剂化物或多晶型的形式时,本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定,只要该溶剂是药理学上可以接受的。例如,水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。
术语“药学上可接受的盐”是指从药学上可接受的无毒的碱或酸制备的盐。当本发明提供的化合物是酸时,可以从药学上可接受的无毒的碱,包括无机碱和有机碱,方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺,也包括环胺及含有取代基的胺,如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱,包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、哈胺、异丙胺、赖氨酸,甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明提供的化合物是碱时,可以从药学上可接受的无毒的酸,包括无机酸和有机酸,方便制得其相应的盐。这样的酸包括,如,醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地,柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地,甲酸和盐酸。由于式(I)所示化合物将作为药物应用,所以优选使用基本上纯的形式,例如,至少60%纯度,更适当地至少75%的纯度,特别地至少98%的纯度(%是重量比)。
本发明提供的药物组合物包括作为活性组分的式(I)所示化合物(或其药学上可接受的盐)、一种药学上可接受的赋形剂及其他可选的治疗组分或辅料。尽管任何给定的情况下,最适合的活性组分给药方式取决于接受给药的特定的主体、主体性质和病情严重程度,但是本发明的药物组合物包括适于口腔、直肠、局部和不经肠道(包括皮下给药、肌肉注射、静脉给药)给药的药物组合物。本发明的药物组合物可以方便地以本领域公知的单位剂型存在和药学领域公知的任何制备方法制备。
如本文所述,新晶型可以通过粉末X-射线衍射谱进行鉴定。然而,本领域技术人员知道,粉末X-射线衍射的峰强度和/或峰情况可能会因为实验条件的不同而不同,如不同的衍射测试条件和/或取向优先等。同时由于不同仪器的精准度不同,测得的2θ值会有约±0.2°的误差。然而,已知的是峰的相对强度值比峰的位置更依赖于所测定样品的某些性质,例如样品中晶体的尺寸、结晶的取向作用和被分析的材料的纯度,因此所显示的峰强度偏差在约±20%或更大范围是可能出现的。但是,尽管存在试验误差、仪器误差和取向优先等,本领域技术人员还可以从本专利提供的XRD数据获取足够的鉴别晶型的信息。
实际上,根据常规的药物混合技术,本发明式(I)所示化合物,或药物前体,或代谢物,或药学上可接受的盐,可以作为活性组分,与药物载体混合成药物组合物。所述药物载体可以采取各种各样的形式,这取决于期望采用的给药方式,例如,口服或注射(包括静脉注射)。因此,本发明的药物组合物可以采用适于口服给药的独立单位的形式,如包含预定剂量的活性组分的胶囊剂、扁囊剂或片剂。进一步地,本发明的药物组合物可采用粉末、颗粒、溶液、水性悬浮液、非水液体、水包油型乳液,或油包水型乳液形式。另外,除了上述提到的常见的剂型,式(I)所示化合物或其药学上可接受的盐,也可以通过控释的方式和/或输送装置给药。本发明的药物组合物可以采用任何制药学上的方法制备。一般情况下,这种方法包括使活性组分和组成一个或多个必要成分的载体缔合的步骤。一般情况下,所述药物组合物经由活性组分与液体载体或精细分割的固体载体或两者的混合物经过均匀的密切的混合制得。然后,该产品可以方便地制备成所需要的外观。
因此,本发明的药物组合物包括药学上可接受的载体和式(I)所示化合物或其药学上可接受的盐。式(I)所示化合物或其药学上可接受的盐,与其他一种或多种具有治疗活性的化合物也包括在本发明的药物组合物中。
本发明采用的药物载体可以是,例如,固体载体、液体载体或气体载体。固体载体,包括乳糖、石膏粉、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸。液体载体,包括糖浆、花生油、橄榄油和水。气体载体,包括二氧化碳和氮气。制备药物口服制剂时,可以使用任何方便的制药学上的介质。例如,水、乙二醇、油类、醇类、增味剂、防腐剂、着色剂等可用于口服的液体制剂如悬浮剂、酏剂和溶液剂;而载体,如淀粉类、糖类、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等可用于口服的固体制剂如散剂、胶囊剂和片剂。考虑到易于施用,口服制剂首选片剂和胶囊,在此应用固体药学载体。可选地,片剂包衣可使用标准的水制剂或非水制剂技术。
含有本发明化合物或药物组合物的片剂可通过,任选一种或多种辅助组分或辅药一起压制或成型制备。活性组分以自由流动的形式如粉末或颗粒,与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂混合,在适当的机器中,通过压制可以制得压制片剂。用一种惰性液体稀释剂浸湿粉末状的化合物或药物组合物,然后在适当的机器中,通过成型可以制得模制片。较优地,每个片剂含有大约0.05mg到5g的活性组分,每个扁囊剂或胶囊剂含有大约0.05mg到5g的活性组分。例如,拟用于人类口服给药的剂型包含约0.5mg到约5g的活性组分,与合适且方便计量的辅助材料复合,该辅助材料约占药物组合物总量的5%至95%。单位剂型一般包含约1mg到约2g的活性组分,典型的是25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本发明提供的适用于胃肠外给药的药物组合物可将活性组分加入水中制备成水溶液或悬浮液。可以包含适当的表面活性剂如羟丙基纤维素。在甘油、液态聚乙二醇,及其在油中的混合物,也可以制得分散体系。进一步地,防腐剂也可以包含在本发明的药物组合物中用于防止有害的微生物生长。
本发明提供适用于注射的药物组合物,包括无菌水溶液或分散体系。进一步地,上述药物组合物可以制备成可用于即时配制无菌注射液或分散液的无菌粉末的形式。无论如何,最终的注射形式必须是无菌的,且为了易于注射,必须是易于流动的。此外,所述药物组合物在制备和储存过程中必须稳定。因此,优选抗微生物如细菌和真菌污染的保存。载体可以是溶剂或分散介质,例如,水、乙醇、多元醇(如甘油、丙二醇、液态聚乙二醇)、植物油及其适当的混合物。
本发明提供的药物组合物,可以是适于局部用药的形式,例如,气溶胶、乳剂、软膏、洗液、撒粉或其他类似的剂型。进一步地,本发明提供的药物组合物可以采用适于经皮给药装置使用的形式。利用本发明式(I)所示化合物,或其药学上可接受的盐,通过常规的加工方法,可以制备这些制剂。作为一个例子,乳剂或软膏剂的制备是通过在约5wt%到10wt%的上述化合物中加入亲水性材料和水,制得具有预期一致性的乳剂或软膏。
本发明提供的药物组合物,可以制成以固体为载体,适用于直肠给药的形式。优选的剂型为混合物形成单位剂量的栓剂。适当的辅料包括本领域常用的可可脂和其他材料。栓剂可以方便地制备,首先药物组合物与软化或熔化的辅料混合,然后冷却和模具成型而制得。
除了上述提到的载体组分外,上述药学制剂还可以包括,适当的,一种或多种附加的辅料组分,如稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂和防腐剂(包括抗氧化剂)等。此外,其他的辅药还可以包括调节药物与血液等渗压的促渗剂。包含式(I)所示化合物,或其药学上可接受的盐的药物组合物,也可以制备成粉剂或浓缩液的形式。
一般情况下,治疗上述所示的状况或不适,药物的剂量水平约为每天0.01mg/kg体重到150mg/kg体重,或者每个病人每天0.5mg到7g。例如,炎症、癌症、牛皮癣、过敏/哮喘、免疫系统的疾病和不适、中枢神经系统(CNS)的疾病和不适,有效治疗的药物剂量水平为每天0.01mg/kg体重到50mg/kg体重,或者每个病人每天0.5mg到3.5g。
但是,可以理解,任何特定病人的具体剂量水平将取决于多种因素,包括年龄、体重、综合健康状况、性别、饮食、给药时间、给药途径、排泄率、药物联用的情况和接受治疗的特定疾病的严重程度。
附图说明
图1:化合物19晶型I的XRD图谱。
图2:化合物19晶型I的DSC图谱。
图3:化合物19晶型I在不同稳定性条件下的XRD对比图谱。图中A为晶型I在0天时的XRD图谱;B为晶型I在80℃干燥放置24小时的XRD图谱;C为晶型I在25℃-60%RH放置10天的XRD图谱;D为晶型I在40℃-75%RH放置14天的XRD图谱。
具体实施方式
为使本发明更加容易理解,下面将结合实施例来详细说明本发明,这些实施例仅起说明性作用,并不局限于本发明的应用范围,下列实施例中未提及的具体实验方法,通常按照常规实验方法进行。
除另有说明,所有的部分和百分数均以重量计算,所有的温度均为摄氏度。
实施例中使用了下列缩略语:
AcOH:乙酸;
(BPin)2:双联频哪醇硼酸酯;
BRD4(D1):溴结构域蛋白4(结构域1);
BRD4(D2):溴结构域蛋白4(结构域2);
CDI:N,N'-羰基二咪唑;
DCM:二氯甲烷;
DIEA:N,N-二异丙基乙胺;
DMA:N,N-二甲基乙酰胺;
DMF:N,N-二甲基甲酰胺;
DMSO:二甲基亚砜;
EA:乙酸乙酯;
EtOH:乙醇;
h:小时;
1HNMR:核磁共振;
KAcO:乙酸钾;
LCMS:液质联用;
LDA:二异丙基氨基锂;
Mel:碘甲烷;
MeOH:甲醇;
min:分钟;
NaBH4:硼氢化钠;
NaH:氢化钠;
n-Hex:正己烷;
Pd2(dba)3:三(二亚苄基丙酮)二钯;
Pd(dppf)Cl2.DCM:[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物;
Pd(PPh3)4:四三苯基磷化钯;
Pd(PPh3)2Cl2:双三苯基磷二氯化钯;
PE:石油醚;
POCl3:三氯氧磷;
s:秒;
TEA:三乙基胺;
TfOH:三氟甲磺酸;
THF:四氢呋喃;
TLC:薄层色谱法;
TsCl:对甲基苯磺酰氯;
XPhos:2-二环己基磷-2',4',6'-三异丙基联苯。
除非另有说明,下述实施例中,所用到的检测仪器信息和方法参数如下:
表2
表3
实施例1化合物1(4-(1-(4-氯苄基)-2-甲基-1H咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮)的合成
1.化合物1M-11的合成
将5-溴-2-甲氧基-4-甲基-3-硝基吡啶(3.90g)溶于DMF(250mL)中,升温至80℃,缓慢向其中加入N,N-二甲基甲酰胺二甲基缩醛(18mL),加完升温至95℃反应4h。TLC监控反应结束,浓缩,加入水(1L),EA萃取三次,有机相合并,水洗,无水硫酸钠干燥,减压浓缩,得化合物1M-11粗品3.50g。
2.化合物1M-12的合成
将化合物1M-11(3.50g)、铁粉(3.50g)及氯化铵(3.50g)加入甲醇(133mL)和水(17.5mL)中,回流反应7h,TLC监控反应完全。趁热过滤,滤饼用甲醇洗涤两次,滤液合并浓缩。柱层析纯化,PE:EA=5:1,得化合物1M-12粗品2.26g。
3.化合物1M-13的合成
将化合物1M-12(2.26g)溶于THF(47mL),氮气保护,降温至0℃,加入NaH(1.28g),升至室温反应1h,降温至0℃,加入TsCl溶液(2.50g的TsCl溶于47mL的THF),反应2h,TLC确认反应结束,加入冰水淬灭。EA萃取3次,有机相合并,饱和食盐水洗三次,无水硫酸钠干燥,浓缩,得化合物1M-13粗品3.80g。
4.化合物1M-14的合成
将化合物1M-13(3.80g)溶于乙醇(10mL),滴加溴化氢溶液(40mL,40%),90℃反应2h,TLC监控反应结束,冷却至0℃,有白色固体析出,过滤收集固体,滤饼用水洗两次,干燥,得化合物1M-14粗品3.60g。
5.化合物1M-15的合成
将化合物1M-14(3.60g)溶于二氧六环(50mL),加入碳酸铯(3.94g)、碘甲烷(5.40g),室温搅拌。TLC监控反应结束,反应液用DCM(200mL)稀释,饱和食盐水洗三次,无水硫酸钠干燥,浓缩。粗品用n-Hex:EA=4:1(V/V)的混合溶剂(20mL)打浆,过滤收集固体,产品为浅黄色固体3.20g。
6.化合物1-1的合成
将2,3-二氨基-5-溴吡啶(4.03g)和对氯苯甲醛(3.00g)溶于DCM(350mL),加入乙酸(10mL),室温搅拌过夜。TLC监控反应结束,加入Na2CO3溶液(100mL),DCM萃取两次,有机相合并,无水硫酸钠干燥,浓缩,柱层析纯化PE:EA=100:15,得黄色固体即为化合物1-1,3.75g。
7.化合物1-2的合成
将化合物1-1(3.75g)溶于甲醇中,冰浴降温,加入NaBH4(2.30g),室温搅拌过夜。TLC监控反应结束,浓缩,加入250mL水,EA萃取三次,有机相合并,无水硫酸钠干燥,浓缩,得化合物1-2,3.65g。
8.化合物1-3的合成
将化合物1-2(3.65g)溶于乙酸(150mL)中,加入原乙酸三乙酯(7.52g),升温至100℃反应2h,TLC监控反应结束,浓缩。加入Na2CO3溶液(300mL),EA萃取两次,有机相合并,无水硫酸钠干燥,浓缩。粗品经柱层析纯化PE:EA=1:1(V/V),得黄色固体即为化合物1-3,2.73g。
9.化合物1-4的合成
将化合物1-3(1.00g)、六甲基二锡(1.17g)和四三苯基膦钯(0.69g)溶于甲苯(25mL),氮气置换,115℃加热反应2.5h,冷却,浓缩,粗品经柱层析纯化DCM:MeOH=100:2-100:3,得黄色固体即为化合物1-4,0.79g。
10.化合物1-5的合成
将化合物1-4(0.33g)、1M-15(0.30g)及Pd(PPh3)2Cl2(0.06mg)溶于DMF(5mL),氮气保护,加热120℃反应2h,冷却,浓缩,粗品经柱层析纯化DCM:MeOH=100:3,得黄色固体即为化合物1-5,0.31g。
11.化合物1的合成
将化合物1-5(0.31g)溶于MeOH(10mL)和DCM(5mL)中,加入NaOH(0.30g),室温搅拌过夜,TLC监控反应结束,浓缩,粗品经柱层析纯化DCM:MeOH=100:2,得白色固体即为化合物1,0.13g。
LCMS:[M+1]+=404.2。
1HNMR(400MHz,DMSO)δ12.17(s,1H),8.55(d,J=1.4Hz,1H),8.04(d,J=1.3Hz,1H),7.59–7.37(m,3H),7.34(s,1H),7.21(d,J=8.2Hz,2H),6.29(s,1H),5.58(s,2H),3.58(s,3H),2.59(s,3H)。
采用与实施例1基本类似的方法,应用相应的对氯苯甲醛衍生物替换实施例中的(对氯苯甲醛)制备以下表4中的实施例。所述相应的对苯甲醛衍生物,例如等均可以通过市售渠道购买得到。所述相应碘甲烷衍生物,例如 等也均可通过市售渠道购买得到。
表4
实施例18化合物18(4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮)的合成
1.化合物2M-1的合成
将化合物1M-15(6.00g)、(BPin)2(8.00g)、XPhos(0.90g)、Pd2(dba)3(0.43g)和KAcO(3.40g)溶于二氧六环(90mL),氮气保护,80℃搅拌反应4h。冷却,倒入EA(200mL)及饱和Na2CO3(200mL)的混合溶剂中,分液,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩。粗品用柱层析纯化PE:EA=100:30,得白色固体即为化合物2M-1,3.45g。
2.化合物18-1的合成
将2-氨基-3,5-二溴吡嗪(10.00g)、4-氯苄胺(16.90g)和DIEA(25.54g)溶于DMSO(40mL),120℃加热搅拌4h,LCMS确认反应结束,冷却,加入冷水(200mL),EA萃取3次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化PE:EA=100:15-100:30,得黄色固体即为化合物18-1,13.91g。
3.化合物18-2的合成
将化合物18-1(13.90g)、原乙酸三乙酯(35.96g)和冰醋酸(200mL)混合,100℃反应过夜。冷却,浓缩,粗品加入EA稀释,饱和Na2CO3溶液洗涤3次,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化PE:EA=100:20-100:50,得淡黄色固体即为化合物18-2,12.05g。
4.化合物18-4的合成
将化合物18-2(1.00g)、2M-1(1.27g)、Pd(dppf)Cl2.DCM(0.25g)溶于二氧六环(20mL)中,加入K2CO3(0.61g)及水(4mL),氮气保护,100℃加热搅拌过夜。冷却,倒入EA(50mL)及饱和Na2CO3(50mL)的混合溶剂中,分液,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩。粗品用柱层析纯化DCM:MeOH=100:2,得黄色固体即为化合物18-4,0.95g。
5.化合物18的合成
将化合物18-4(0.95g)溶于MeOH(10mL)及DCM(20mL)中,加入NaOH(0.40g),室温搅拌过夜,浓缩,将粗品溶于10mLDMF,将其滴入饱和氯化铵溶液(100mL)中,过滤收集固体,粗品用EA(10mL)打浆,过滤收集固体,减压干燥,得淡棕色固体即为化合物18,0.51g。
LCMS:[M+1]+=405.8。
1HNMR(400MHz,DMSO)δ12.15(s,1H),8.93(s,1H),8.04(s,1H),7.58–7.13(m,5H),6.86(t,J=2.3Hz,1H),5.58(s,2H),3.64(s,3H),2.62(s,3H)。
表5
实施例34化合物34(1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮)的合成
1.化合物34-1的合成
将化合物1-1(4.43g)溶于CH3CN(25mL),加入CDI(11.51g),室温搅拌过夜。抽滤收集固体,滤饼用正己烷洗涤,干燥,得白色固体即为化合物34-1,4.24g。
2.化合物34-2的合成
将化合物34-1(1.00g)、六甲基二锡(1.16g)和四三苯基膦钯(0.68g)溶于1,4-二氧六环(25mL),氮气保护,100℃搅拌过夜。冷却,浓缩,粗品经柱层析纯化PE:EA=100:25,得类白色固体即为化合物34-2,1.23g。
3.化合物34-3的合成
将化合物34-2(0.35g)、化合物34-5(0.31g)和Pd(PPh3)2Cl2(0.06g)加入DMF(5mL)及二氧六环(2.5mL),氮气保护,100℃过夜反应。冷却,加入水(50mL),用DCM萃取3次,有机相合并,浓缩,柱层析纯化DCM:MeOH=100:3,得类白色固体即为化合物34-3,0.13g。
4.化合物34的合成
将化合物34-3(0.21g)溶于MeOH(50mL)中,加入NaOH(0.20g),室温搅拌过夜,向体系中加入水(500mL)及DCM(500m L),过滤收集固体,将滤饼用MeOH:DCM=1:1溶清,有机相合并浓缩,得产品即为化合物34,0.06g。
LCMS:[M+1]+=406.1。
1HNMR:(400MHz,DMSO)δ12.12(s,1H),8.23–6.38(m,9H),6.22(t,J=2.8Hz,1H),5.05(s,2H),3.64(s,3H)。
实施例35化合物35(4-(3-(1-(2,6-二氯-3-氟苯基)乙基)-2-甲基-1H-吡咯并[2,3-b]吡啶-5-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物35-1的合成
将5-溴-1H-吡咯并[2,3-b]吡啶(5.00g)溶于DMF(100mL)中,于0℃下加入氢化钠(1.82g),升温至室温反应20min,降温至0℃,加入苯磺酰氯(6.69g),升温至室温反应1h。向其加入100mL饱和氯化铵溶液淬灭,用DCM萃取三次,有机相合并,饱和食盐水洗涤两次,无水硫酸钠干燥,浓缩得粗品8.37g。
2.化合物35-2的合成
将2-异丙胺(4.20g)溶于THF(100mL)中,氮气保护,降温至-78℃,向其中加入正丁基锂(16mL),低温反应60min,加入化合物35-1(5.00g)的THF(30mL)溶液,-78℃反应60min,加入碘甲烷(6.31g),自然升至室温反应2h。加入饱和氯化铵溶液(50mL)淬灭,浓缩,用EA萃取三次,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,柱层析纯化PE:EA=100:40,得产品4.52g,白色固体。
3.化合物35-3的合成
将化合物35-2(4.52g)溶于甲醇(100mL),加入氢氧化钠(4.52g),室温搅拌过夜。加入饱和氯化铵溶液(50mL),浓缩,用EA萃取两次,有机相合并,饱和食盐水洗两次,无水硫酸钠干燥,浓缩,得粗品2.80g。
4.化合物35-4的合成
将化合物35-3(2.80g)溶于DCM(65mL),氮气保护,加入三氟甲磺酸(7.96g),加入1-(2,6-二氯-3-氟苯基)-乙醇(11.09g)的DCM(20mL)溶液,室温过夜。35℃反应4h,加入饱和碳酸钠溶液(200mL),用DCM(500mL)萃取3次,饱和食盐水洗两次,无水硫酸钠干燥,浓缩,粗品用EA(50mL)打浆,产品为白色固体,2.40g。
5.化合物35-5的合成
将化合物35-4(0.10g)、2M-1(0.11g)和Pd(dppf)Cl2(0.02g)溶于DMF(2mL),加入碳酸钾(0.07g),氮气保护,115℃过夜。冷却,过滤,滤液加入水(10mL),用DCM(10mL)萃取三次,用饱和食盐水(10mL)洗涤3次,直接浓缩得棕色油状物0.21g,直接用于下一步反应。
6.化合物35的合成
将化合物35-5(0.21g)溶于甲醇(10mL)中,加入氢氧化钠(0.10g),40℃搅拌4h,加入饱和氯化铵溶液(10mL),DCM(50mL)萃取两次,饱和食盐水洗两次,有机相浓缩,柱层析纯化,DCM:MeOH=100:5,得产品0.07g。
LCMS:[M+1]+=469.1。
1HNMR:(400MHz,DMSO)δ12.12(s,1H),11.42(s,1H),8.24(d,J=1.9Hz,1H),7.83(d,J=1.7Hz,1H),7.50(dd,J=8.9,5.1Hz,1H),7.44–7.13(m,3H),6.22–5.96(m,1H),5.22(q,J=7.2Hz,1H),3.58(s,3H),2.30(s,3H),1.87(d,J=7.5Hz,3H)。
实施例36化合物36(4-(1-(2,6-二氯苄基)-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物36-1的合成
将原料5-溴-2-甲基-3-硝基嘧啶(1.00g)溶于DMF(10mL)中,加入N,N-二甲基甲酰胺二甲基缩醛(5mL),100℃反应1h,冷却,加入饱和氯化铵溶液(25mL)淬灭,再用EA(25mL)萃取两次,有机相合并,饱和食盐水洗1次,无水硫酸钠干燥,浓缩,得粗品1.45g,直接用于下步反应。
2.化合物36-2的合成
将化合物36-1(1.45g)和铁粉(2.38g)加入冰醋酸(50mL),升温至80℃反应5h,趁热过滤,滤饼用EA洗涤,滤液合并,浓缩,加入饱和Na2CO3溶液,再次过滤,滤饼用EA洗涤,滤液分液,取有机相,用饱和食盐水洗,无水硫酸钠干燥,浓缩,粗品经柱层析纯化PE:EA=100:50,得产品0.73g。
3.化合物36-3的合成
将化合物36-2(0.70g)溶于DMF(25mL)中,氮气保护,在0℃下加入氢化钠(0.19g),自然升至室温搅拌1h。在0℃下加入2,6-二氯溴苄(0.85g),自然升至室温反应3h。向其加入冰水混合物50mL淬灭反应,EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,产品为黄色固体1.30g。
4.化合物36-4的合成
将化合物36-3(0.40g)、化合物2M-1(0.48g)和Pd(dppf)Cl2.DCM(0.10g)溶于二氧六环(8mL),加入碳酸钾(0.23g)的水(1.5mL)溶液,氮气保护,100℃搅拌过夜。冷却,加入EA(50mL)及饱和Na2CO3(50mL)的混合溶液,收集有机相,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,柱层析纯化DCM:MeOH=100:2,产品为棕黄色固体0.50g。
5.化合物36的合成
将化合物36-4(0.50g)溶于MeOH/DCM=10mL:10mL的混合溶液,加入氢氧化钠(0.30g),室温搅拌过夜。浓缩,粗品经柱层析纯化DCM:MeOH=100:5,得淡棕色固体0.21g。
LCMS:[M+1]+=423.1。
1HNMR:(400MHz,DMSO)δ12.17(s,1H),7.69–7.55(m,2H),7.52–7.23(m,6H),6.62(dd,J=3.3,0.7Hz,1H),6.30(dd,J=2.6,2.1Hz,1H),5.67(s,2H),3.61(s,3H)。
实施例37化合物37(4-(4-((4-氯苯基)氨基)吡啶并[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物37-1的合成
将2-氨基-5-溴烟酸(3.00g)溶于甲酰胺(15mL),160℃搅拌反应4h,再加入甲酰胺(20mL),160℃继续反应6h,冷却,倒入150mL水中,过滤收集固体,得黄色固体2.20g。
2.化合物37-2的合成
将化合物37-1(0.40g)溶于三氯氧磷(5mL),加入三乙胺(0.5mL),120℃反应3h,浓缩,粗品加入甲苯(20mL),浓缩,反复三次,得棕黑固体粗品0.60g,直接用于下步反应。
3.化合物37-3的合成
将化合物37-2(0.60g)溶于DCM(10mL),加入对氯苯胺(0.30g)、三乙胺(1mL),室温搅拌5h,浓缩,粗品经柱层析纯化DCM:MeOH=100:5-100:10,产品为棕红色固体0.70g。
5.化合物37-4的合成
将化合物37-3(0.30g)、化合物2M-1(0.38g)及Pd(dppf)Cl2.DCM(0.07g)溶于二氧六环,加入碳酸钾(0.19g)及水(1.5mL),氮气保护,100℃搅拌过夜。冷却,加入EA(30mL)及饱和Na2CO3溶液(30mL),分液,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩。粗品经柱层析纯化DCM:MeOH=100:3,产品为黄色固体0.29g。
6.化合物37的合成
将化合物37-4(0.29g)溶于甲醇(15mL),加入氢氧化钠(0.21g),室温搅拌过夜,浓缩,柱层析纯化DCM:MeOH=100:5,产品为黄色固体即为化合物37,0.07g。
LCMS:[M+1]+=403.1。
1HNMR:(400MHz,DMSO)δ12.28(s,1H),8.76(s,1H),7.92(d,J=8.8Hz,2H),7.68(s,1H),7.61–7.53(m,2H),7.52–7.45(m,3H),7.43(t,J=2.8Hz,1H),6.67–6.53(m,1H),3.60(s,3H)。
实施例38化合物38(4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物38-1的合成
将5-溴-2-甲基-3-硝基吡啶(1.00g)和N,N-二甲基乙酰胺二甲基缩醛(1.22g)溶于DMF(5mL),100℃加热1h。冷却,加入EA(300mL)稀释,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,产品为棕红色固体1.30g。
2.化合物38-2的合成
将化合物38-1(1.30g)和铁粉(3.00g)溶于冰醋酸(30mL),80℃搅拌90min,冷却,将其倒入饱和Na2CO3溶液(200mL),硅藻土过滤,滤饼用EA洗涤,滤液用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,粗品用碱性氧化铝柱层析纯化PE:EA=100:30-100:50,产品为土黄色固体0.63g。
3.化合物38-3的合成
将化合物38-2(0.53g)溶于DMF(25mL),氮气保护,降温至0℃,加入氢化钠(0.13g),自然升至室温搅拌1h,降温至0℃,加入2,6-二氯苄基溴(0.60g),自然升温至室温反应2.5h,将其倒入冰水中淬灭,EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩。粗品经柱层析纯化PE:EA=100:10-100:30,产品为黄色固体0.84g。
4.化合物38-4的合成
将化合物38-3(0.20g)、化合物2M-1(0.23g)和Pd(dppf)Cl2.DCM(0.04g)溶于二氧六环(5mL),加入K2CO3(0.11g)、水(1mL),氮气保护,100℃加热反应过夜。冷却,加入EA(50mL)及饱和Na2CO3溶液(50mL),混合溶液,分液,水相用EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化DCM:MeOH=100:3,得粗品棕色油0.30g粗品。
5.化合物38的合成
将化合物38-4(0.30g)加入甲醇(15mL),加入氢氧化钠(0.20g),室温搅拌3h,加入硅胶拌样柱层析纯化DCM:MeOH=100:2-100:3,产品为黄色固体0.08g。
LCMS:[M+1]+=437.1。
1HNMR:(400MHz,DMSO)δ12.13(s,1H),8.42(d,J=1.8Hz,1H),7.63–7.40(m,4H),7.39–7.20(m,3H),6.43(s,1H),5.65(s,2H),3.60(s,3H),2.49(s,3H)。
实施例39化合物39(4-(1-(4-氯苄基)-1H-吡唑并[4,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物39-1的合成
将6-溴-1H-吡唑并[4,3-b]吡啶(1.00g)溶于DMF(30mL),氮气保护,在0℃下加入氢化钠(0.24g),升至室温反应1h,在0℃下加入对氯苄氯(0.90g),室温反应过夜。将其倒入冰水(100mL)淬灭,EA萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,浓缩,粗品经柱层析纯化PE:EA=100:4 -100:20,产品为白色固体0.80g。
2.化合物39-2的合成
将化合物39-1(0.30g)、2M-1(0.40g)及Pd(dppf)Cl2.DCM(0.08g)溶于二氧六环(8mL),加入碳酸钾(0.19g)及水(1.5mL),氮气保护,100℃加热搅拌过夜。冷却,将其倒入EA(100mL)/饱和Na2CO3溶液(100mL),分液,水相用EA萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,浓缩。粗品经柱层析纯化DCM:MeOH=100:2.5,产品为黄色半固体0.52g。
3.化合物39的合成
将化合物39-2(0.52g)溶于甲醇(10mL)及DCM(10mL),加入氢氧化钠(0.12g),室温搅拌,浓缩,粗品柱层析纯化DCM:MeOH=100:2.5-100:3,得黄色固体即为化合物39,0.10g。
LCMS:[M+1]+=390.1;
1HNMR:(400MHz,DMSO)δ12.23(s,1H),8.78(d,J=1.8Hz,1H),8.43–8.20(m,2H),7.58(d,J=4.1Hz,1H),7.49–7.17(m,5H),6.57–6.21(m,1H),5.76(d,J=5.8Hz,2H),3.62(s,3H)。
实施例40化合物40(4-(1-((4-氯苯基)硫酰基)-1H-吡咯并[2,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮)的合成
1.化合物40-1的合成
将6-溴-7-氮杂吲哚(1.00g)溶于DMF(15mL),氮气保护,在0℃加入氢化钠(0.31g),室温搅拌1h,在0℃加入对氯苯磺酰氯(1.30g),室温搅拌2h,加入冰水(50mL)淬灭,EA萃取3次,有机相合并,饱和食盐水洗3次,无水硫酸钠干燥,浓缩,产品为黄色固体1.30g。
2.化合物40-2的合成
将化合物40-1(0.35g)、化合物2M-1(0.49g)和Pd(PPh3)4(0.06g)溶于二氧六环(7mL),加入碳酸钾(0.20g)及水(7mL),氮气保护,100℃反应过夜。冷却,将其倒入EA(50mL)/饱和Na2CO3溶液(50mL),分液,水相用EA萃取3次,有机相合并,饱和食盐水洗,无水硫酸钠干燥,浓缩,粗品经柱层析纯化DCM:MeOH=100:3,产品为淡黄固体0.35g。
3.化合物40的合成
将化合物40-2(0.28g)溶于甲醇(10mL)及二氯甲烷(10mL),加入氢氧化钠(0.07g),室温搅拌过夜。浓缩,粗品经柱层析纯化DCM:MeOH=100:3,粗品加入EA(10mL)打浆,过滤收集固体,得产品0.04g。
LCMS:[M+1]+=439.1;
1HNMR:(400MHz,DMSO)δ12.12(s,1H),8.11(ddd,J=14.8,8.4,5.5Hz,3H),7.96(s,1H),7.85(dd,J=16.1,6.2Hz,2H),7.71–7.52(m,2H),7.42(dt,J=4.9,2.7Hz,2H),6.85(d,J=4.0Hz,1H),3.65(s,3H)。
实施例41化合物41(N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺)的合成
1.化合物41-1的合成
将5-溴-3-硝基-苯-1,2-二胺(1.00g)和乙酰丙酮(0.86g)溶于乙醇(20mL),加入5N盐酸(6mL),100℃搅拌4h,冷却,浓缩,粗品柱层析纯化PE:EA=100:30,得产品黄色固体0.90g。
2.化合物41-2的合成
将化合物41-1(0.85g)和碳酸钾(0.92g)溶于乙腈(20mL)、DMF(4mL),加入对氯苄氯(0.98g),60℃搅拌过夜。冷却,倒入100mL水中,EA萃取3次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化PE:EA=100:30,得黄色固体1.04g。
3.化合物41-3的合成
将化合物41-2(0.50g)、化合物2M-1(0.56g)及Pd(dppf)Cl2.DCM(0.11g)溶于二氧六环(10mL),加入碳酸钾(0.27g),水(2mL),氮气保护,90℃搅拌过夜。冷却,倒入50mL水中,EA萃取三次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化DCM:MeOH=100:3,得黄色固体0.83g。
4.化合物41-4的合成
将化合物41-3(0.80g)溶于THF(15mL),乙醇(15mL),加入铁粉(0.37g),氯化铵(0.14g),水(10mL),90℃搅拌过夜。趁热过滤,滤饼用甲醇淋洗3次,滤液浓缩,加入饱和碳酸钠溶液(50mL),EA萃取3次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,粗品经柱层析纯化DCM:MeOH=100:4,得暗黄色固体0.43g。
5.化合物41的合成
将化合物41-4(0.43g)溶于DCM(10mL),加入三乙胺(0.31g),乙基磺酰氯(0.19g),室温搅拌2h,浓缩,加入二氧六环(7.5mL)及氢氧化钠溶液(10%,V/V,2.5mL),70℃搅拌加热3h,冷却,倒入饱和氯化铵溶液(100mL),分液,水相用EA萃取3次有机相合并,饱和食盐水洗涤3次无水硫酸钠干燥,浓缩,粗品柱层析纯化DCM:MeOH=100:3,得产品黄色固体0.08g。
LCMS:[M+1]+=511.1。
1HNMR(300MHz,DMSO)δ12.13(s,1H),9.65(s,1H),7.50–7.35(m,4H),7.35–7.30(m,2H),7.25-7.20(m,2H),6.40(s,1H),5.55(s,2H),3.60(s,3H),3.35–3.20(m,2H)2.60–2.50(m,3H).1.45–1.20(m,3H)。
表6
实施例58化合物58N-(5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡H啶-7-基)乙基磺酰胺的合成
1.化合物58-1的合成
将1M-15(7.60g),NaOH(1.60g)溶于二氧六环和水,80℃反应4h。冷却,倒入H2O中,DCM萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化DCM:MeOH=90:10,得灰色固体3.20g。
2.化合物58-2的合成
将化合物58-1(6.00g)、(Bpin)2(8.00g)、SPhos(1.29g)、PdCl2(CH3CN)2(0.68g)、KOAc(3.40g)溶于二氧六环,氮气保护,80℃反应4h。冷却,倒入水中,EA萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化PE:EA=50:50,得灰色固体3.20g。
3.化合物58-3的合成
将5,7-二氯-1H-咪唑并[4,5-B]吡啶(1.88g),对三氟甲基苄氯(1.94g)和DIEA(1.56g)溶于DMF,室温反应过夜。倒入水中,EA萃取三次,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化PE:EA=50:50,得灰色固体1.50g。
4.化合物58-4的合成
将58-3(1.50g)置于氨水中,150℃反应过夜。冷却,抽滤,滤饼用水洗涤,固体真空干燥,得白色固体1.10g。
5.化合物58-5的合成
将58-4(1.10g),TEA(1.70g)溶于DCM,滴加乙基磺酰氯(0.86g),室温反应2h。倒入水中,DCM萃取三次,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化PE:EA=30:70,得灰色固体0.80g。
6.化合物58的合成
将58-2(0.42g)、58-5(0.27g)、K2CO3(0.41g)、Xphos-Pd-G2(0.08g)置于二氧六环和水,80℃反应4h。冷却,倒入水中,EA萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化MeOH:DCM=10:90,得灰色固体0.10g。
LCMS:[M+1]+=531.1。
1H NMR(400MHz,DMSO)δ12.13(s,1H),10.61(s,1H),8.56(s,1H),7.75(d,J=10.1Hz,3H),7.67–7.53(m,3H),7.32(t,J=2.8Hz,1H),6.73–6.54(m,1H),5.65(s,2H),3.72–3.53(m,5H),1.31(t,J=7.3Hz,3H)。
实施例59化合物59N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺的合成
1.化合物59-1的合成
将5,7-二氯-1H-咪唑并[4,5-B]吡啶(5.00g),K2CO3(11.00g),2,4-二氟氯苄(6.50g)溶于DMF(50mL)中,室温搅拌8h。将反应物倒入冰水中,抽滤,滤饼用水洗三次,粗品柱层析纯化,PE:EA=70:30,得白色固体6.0g。
2.化合物59-2的合成
将59-1(0.60g),氨水(25mL)加入封管中,150℃搅拌过夜。倒入100mL水中,EA萃取3次,有机相合并,饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩,得白色固体0.30g。
3.化合物59-3的合成
将59-2(0.15g),TEA(0.16g)溶于DCM(5mL)中,在0℃下缓慢滴加乙基磺酰氯(0.19g),滴加结束后恢复至室温,继续搅拌5h。向反应液中加入水,EA萃取3次,有机相合并,饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩,粗品Flash-Prep-HPLC纯化(H2O/CH3CN=40%~45%),得淡黄色固体0.10g。
4.化合物59的合成
将59-3(0.10g),58-2(0.07g),Xphos-Pd-G2(0.02g)和K3PO4(0.11g)溶于二氧六环5mL,加入水1mL,在氮气保护下加热80℃反应8h。冷却,加水稀释,EA萃取3次,有机相合并,饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩,粗产品柱层析纯化,DCM:MeOH=98:2,得棕色固体0.06g。
LCMS:[M+1]+=499.1。
1H NMR(400MHz,DMSO)δ12.12(d,J=17.8Hz,1H),8.46(s,1H),7.80(d,J=21.7Hz,1H),7.64–7.59(m,1H),7.55–7.42(m,1H),7.39(t,J=2.8Hz,1H),7.36–6.97(m,3H),6.80–6.74(m,1H),5.56(s,2H),3.76–3.51(m,5H),1.38–1.25(m,3H).
实施例64化合物64N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺的合成
1.化合物64-1的合成
2-甲基-1H-咪唑并[4,5-b]吡啶(1.08g)溶于15mL EA,加入(1.86g)m-CPBA,室温搅拌过夜,抽滤,固体用EA洗涤,干燥得白色固体1.05g。
2.化合物64-2的合成
64-1(1.05g)溶于10ml POCl3,80℃反应15min,升温至120℃,反应3h,倒入冰水中,EA萃取三次,有机相合并,浓缩,柱层析(PE:EA=50:50),得白色固体0.80g。
3.化合物64-3的合成
64-2(0.80g)溶于10mL EA,加入(1.25g)m-CPBA,室温搅拌过夜,抽滤,滤饼用EA洗涤,干燥得白色固体0.70g。
4.化合物64-4的合成
64-3(0.70g)溶于10mL DMF,滴加0.38mL甲基磺酰氯,80℃反应3h,倒入冰水中,EA萃取三次,有机相合并,浓缩,柱层析(PE:EA=50:50),得白色固体0.60g。
5.化合物64-5的合成
将64-4(0.70g),2,4-二氟氯苄(0.70g)和K2CO3(0.95g)溶于DMF,室温反应过夜。倒入水中,EA萃取三次,饱和食盐水洗涤三次,无水硫酸钠干燥,浓缩。粗品柱层析纯化(PE:EA=30:70),得黄色固体0.65g。
6.化合物64-6的合成
将64-5(0.65g)置于10mL氨水中,150℃反应过夜。冷却,抽滤,滤饼用水洗涤,固体真空干燥,得白色固体0.50g。
7.化合物64-7的合成
将化合物64-6(0.50g),TEA(0.49g)溶于10mL DCM,滴加乙基磺酰氯(0.42g),室温反应2h。倒入水中,DCM萃取三次,有机相合并,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化PE:EA=30:70,得白色固体0.40g。
8.化合物64的合成
将化合物64-7(0.40g)、58-2(0.27g)、K2CO3(0.41g)、Xphos-Pd-G2(0.08g)置于二氧六环和水,80℃反应4h。冷却,倒入水中,EA萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。粗品柱层析纯化MeOH:DCM=10:90,得灰色固体0.1g。
LCMS:[M+1]+=513.1。
1H NMR(400MHz,DMSO)δ12.12(d,J=17.8Hz,1H),8.46(s,1H),7.64–7.59(m,1H),7.55–7.42(m,1H),7.39(t,J=2.8Hz,1H),7.36–6.97(m,3H),6.80–6.74(m,1H),5.56(s,2H),3.76–3.51(m,5H),2.62(s,3H),1.38–1.25(m,3H)。
表7
实施例69化合物19晶型I的稳定性试验。
本发明的X-射线粉末衍射图谱检测设备和方法如表2所示。
化合物19晶型I样品在80℃干燥放置24小时、25℃-60%RH放置10天、40℃-75%RH放置14天,晶型均不变。
化合物19晶型I在不同稳定性条件下的XRD对比如附图3所示,由此可见,化合物19晶型I稳定性良好。
实施例70动态水分吸附(DVS)测定
本发明的动态水分吸附仪检测设备和方法如表3所示。
化合物II晶型A:0%RH至80%RH范围内重量变化约为0.1%,不吸湿,适合于固体制剂的制备。
对比例1
化合物1-M1的合成
将5-溴-1,3-二甲基-2-吡啶酮(0.50g),双联频哪醇硼酸酯(1.27g),Pd(dppf)Cl2.DCM(0.20g),乙酸钾(0.73g),1,4-二氧六环8mL混合,氮气保护,90℃反应3h。将其倒入乙酸乙酯50mL和饱和氯化铵溶液50mL的混合溶液,分层收集有机相,水相用乙酸乙酯萃取三次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,柱层析纯化PE:EA=100:20,得类白色固体,即为化合物1-M1,0.67g。
对比例1-1的合成
将5-溴-3-硝基苯基-1,2-二胺(1.00g),乙酰丙酮(0.86g),乙醇20mL,盐酸(6mL,5mol/L)混合,100℃搅拌反应4小时,冷却至室温,浓缩,柱层析纯化(PE:EA=100:30–100:45),得黄色固体,即为对比例1-1,0.90g。
对比例1-2的合成
将化合物1-1(0.85g),对氯苄氯(0.70g),碳酸钾(0.92g),乙腈20mL,DMF 4mL混合,60℃反应过夜。冷却,倒入饱和氯化钠溶液100mL中,分液,水相用乙酸乙酯萃取3次,有机相合并,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,浓缩,柱层析纯化(PE:EA=100:30-100:50),得黄色固体,即为对比例1-2,1.04g。
对比例1-3的合成
将化合物1-2(0.45g),化合物1-M1(0.29g),Pd(dppf)Cl2.DCM(0.10g),无水碳酸钾(0.24g),1,4-二氧六环10mL,水2mL,混合,氮气保护,90℃搅拌过夜。冷却,将其倒入乙酸乙酯50mL和饱和氯化铵溶液50mL的混合溶液,分层收集有机相,水相用乙酸乙酯萃取三次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,柱层析纯化DCM:MeOH=100:3,得棕色固体,即为对比例1-3(0.49g)。
对比例1-4的合成
将化合物1-3(0.49g),铁粉(0.33g),氯化铵(0.13g),四氢呋喃10mL,乙醇10mL,水3mL混合,90℃反应过夜。硅藻土过滤,滤饼用甲醇洗涤3次,滤液浓缩,加入乙酸乙酯50mL和碳酸钠饱和溶液50mL,分液,收集有机相,水相用EA萃取3次,有机相合并,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,浓缩,得棕黑色固体粗品,即为对比例1-4(0.30g)。
对比例1的合成
将化合物1-4(0.30g)溶于二氯甲烷10mL中,加入三乙胺(0.31g),加入乙基磺酰氯(0.30g),室温搅拌2小时,浓缩。加入1,4-二氧六环7.5mL和氢氧化钠水溶液(10%,2.5mL),70℃搅拌3小时,冷却,加入饱和氯化铵溶液100mL,乙酸乙酯萃取3次,有机相合并,饱和食盐水洗涤3次,无水硫酸钠干燥,浓缩,柱层析纯化DCM:MeOH=100:3,得黄色固体,0.08g,即为对比例1。LCMS:[M+1]+=485.1。
对比例2
对比例2-1的合成
对比例1-1(1.00g)溶于15mL DMF,加入碳酸钾(2.00g),4-氟氯苄(0.67g),室温搅拌过夜,加入50mL水,50mL EA萃取三次,有机相合并,浓缩,柱层析(PE:EA=50:50),得黄色固体,即为对比例2-1,0.80g。
对比例2-2的合成
对比例2-1(0.80g)溶于10mL醋酸,加入铁粉(0.60g),60℃反应2小时,浓缩,加入饱和碳酸钠水溶液100mL,乙酸乙酯萃取,浓缩,柱层析(PE:EA=20:80),得黄色固体,即为对比例2-2,0.60g。
对比例2-3的合成
将对比例2-2(0.60g),三乙胺(0.55g)溶于10mL DCM,滴加甲基磺酰氯(0.31g),室温反应2h。倒入水(50mL),二氯甲烷20mL萃取三次,饱和食盐水20mL洗涤3次,无水硫酸钠干燥,浓缩。柱层析纯化PE:EA=30:70,得黄色固体,即为对比例2-3,0.50g。
对比例2的合成将对比例2-3(0.41g)、1-M1(0.25g)、K2CO3(0.41g)、Pd(dppf)Cl2(0.08g)置于二氧六环10mL和水2mL,80℃反应4小时。冷却,倒入30mL水中,EA30mL萃取三次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩。柱层析纯化MeOH:DCM=10:90,得灰色固体,即对比例2,40mg。
LCMS:[M+1]+=455.1
药理实验
实验例1本发明化合物抑制BRD4(D1)和BRD4(D2)的活性检测(IC50)
采用(+)-JQ1作为对照化合物,体外评价本发明化合物抑制BRD4(D1)和BRD4(D2)的活性。
在384孔聚苯乙烯板中进行BRD4(D1)和BRD4(D2)检定。首先在DMSO中连续稀释待测化合物且将待测化合物/DMSO转移至384板孔中。在所述检定中,DMSO的最终浓度为0.1%。在384板孔中添加2倍体积的蛋白/多肽混合物,然后再添加2倍体积的检定混合物,摇动30s。在室温下将板培育2h,随后在EnVision上读HTRF信号。
用方程式(1)在Excel中将数据拟合以获得抑制率的值。
方程式(1):抑制率(%)=(最大值-信号值)/(最大值-最小值)*100
使用GraphPad Prism 5.0软件运用方程式(2)拟合数据进行IC50测定。
方程式(2):Y=底+(高-底)/(1+10^((LogIC50-X)*斜率));其中,Y表示抑制百分数(%);X表示待测化合物的浓度。
实施例的IC50数据提供于下表中,其中,A表示IC50<100nM;B表示IC50为100-300nM;C表示IC50>300nM。
表8
表8示范性地列举了本发明化合物对于BRD4(D1)和BRD4(D2)的抑制能力,可以看出,本发明化合物表现出与阳性对照化合物(+)-JQ1相当、甚至更强的抑制BRD4的活性。
实验例2药代动力学试验
雄性SD大鼠来源于北京维通利华实验动物技术有限公司,将大鼠分组,每组3只,分别单次灌胃给予待测样品的混悬液(5mg/kg-20mg/kg)。动物在实验前禁食过夜,禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、7、24小时采血。使用眼底静脉丛采血,放于EDTA-K2抗凝管中。样品于4℃以4000rpm离心10分钟,血浆转移至离心管中使用蛋白质沉淀法萃取待测化合物,萃取液通过LC-MS/MS分析。表9为化合物在大鼠中的PK数据。
表9
本发明提供的化合物优选为具有多种给药方式的药物组合物。最优选,所述药物组合物为口服给药。这种药物组合物和其制备过程在本领域中是公知技术,例如,雷明顿(REMINGTON):《药学科学和实践》(THE SCIENCE AND PRACTICE OF PHARMACY,A.Gennaro,et al.,eds.,19th ed.,Mack Publishing Co.,1995)。式(I)所示化合物在比较宽的剂量范围内均有效。
例如,日剂量正常范围通常为日总剂量约1mg到约200mg(每日总剂量),优选地,日总剂量为1mg至150mg,更优选地,日总剂量为1mg至50mg。在某些情况下,剂量水平低于上述范围的下限可能也是足够的,而在其他一些情况下,大剂量仍然是可用的。上述剂量范围不会以任何方式限制本发明的保护范围。这是可以理解的,本发明提供的化合物的实际给药剂量将由医生根据相关情况决定,包括治疗的条件、给药途径的选择、实际给药的化合物和复合物、年龄、体重、个别病人的反应以及病人症状的严重程度等。
虽然本发明已通过其实施方式进行了全面的描述,但是值得注意的是,各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。
Claims (25)
1.式I所示的化合物或者其药学上可接受的盐,
其中,
R1选自H、C1-6烷基、C1-6烷氧基,所述C1-6烷基、C1-6烷氧基任选地被C1-6烷基、-NH2、-OH、C6-10芳基或C5-10杂芳基取代;所述C5-10杂芳基具有1个、2个或3个分别独立地选自氮、氧或硫的杂原子;
R2选自H、C1-6烷基;
Q选自C1-6亚烷基、-SO2-或-NH-,所述C1-6亚烷基或-NH-任选地被卤素、C1-6烷基或C1-6烷氧基取代;
X为苯基,所述苯基未取代或任选地被卤素、卤代C1-3烷基、C1-3烷基、C1-3烷氧基、C1-3烷硫基、C1-3烷氧羰基或C1-3烷基-SO2-取代;
R3选自H、C1-6烷基;R4为H或-N(R5)-SO2-R6;
R5和R6分别独立地选自H、C1-6烷基。
2.根据权利要求1所述的化合物,其特征在于,R1选自H、C1-4烷基,所述C1-4烷基任选地被C1-6烷基、-NH2、苯基或C5-6杂芳基取代。
3.根据权利要求1或2所述的化合物,其特征在于,所述杂芳基具有1个、2个或3个分别独立地选自氮或硫的杂原子。
6.根据权利要求1所述的化合物,其特征在于,R2为H或C1-3烷基。
7.根据权利要求1所述的化合物,其特征在于,R2为H或-CH3。
9.根据权利要求1所述的化合物,其特征在于,X为苯基,所述苯基未取代或任选地被F、Cl、甲基、三氟甲基、甲氧基、甲硫基、甲氧基羰基或甲基-SO2-取代。
11.根据权利要求1所述的化合物,其特征在于,R3为H、甲基。
12.根据权利要求1所述的化合物,其特征在于,R4为-N(R5)-SO2-R6。
13.根据权利要求1所述的化合物,其特征在于,R5和R6分别独立地选自H、甲基或乙基。
16.一种化合物或其药学上可接受的盐,其特征在于,所述化合物是:
1)4-(1-(4-氯苄基)-2-甲基-1H咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
2)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
3)6-甲基-4-(2-甲基-1-(4-(甲硫基)苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
4)6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
5)4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
6)4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)酮;
7)4-(1,2-二甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
8)6-甲基-4-(2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
9)甲基4-((2-甲基-6-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲酸酯;
10)6-苄基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
11)6-异丁基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
12)6-乙基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
13)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-2-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
14)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(噻唑-2-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
15)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(吡唑-2-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
16)4-(1-(3-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-2-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
17)4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-6-(吡啶-3-甲基)-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
18)4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
19)6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
20)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
21)4-(1-(1-(4-氯苯基)乙基)-2-甲基-1H-咪唑并[4,5-b]对二氮杂苯-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
22)4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
23)4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
24)4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
25)4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
26)4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
27)4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
28)4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
29)4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
30)4-(1-(3-氯苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
31)4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
32)4-(1-(4-溴苄基)-2-甲基-1H-咪唑并[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
33)6-甲基-4-(2-甲基-1-(4-(甲磺酰基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮;
34)1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
35)4-(3-(1-(2,6-二氯-3-氟苯基)乙基)-2-甲基-1H-吡咯并[2,3-b]吡啶-5-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
36)4-(1-(2,6-二氯苄基)-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
37)4-(4-((4-氯苯基)氨基)吡啶并[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
38)4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯并[3,2-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
39)4-(1-(4-氯苄基)-1H-吡唑并[4,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
40)4-(1-((4-氯苯基)硫酰基)-1H-吡咯并[2,3-b]吡啶-6-基)-6-甲基-1,6-二氢-7H-吡咯并[2,3-c]吡啶-7-酮;
41)N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
42)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
43)N-(1-(4-甲氧基苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
44)N-(1-(1-(4-氯苯基)乙基)-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
45)N-(1-苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
46)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
47)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氟-5-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
48)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氟-5-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
49)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氟-4-氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
50)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)-4氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
51)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氟-4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
52)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氯-4-(三氟甲基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
53)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(3-氯苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
54)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2,4-二氟苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
55)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-溴苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
56)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(4-(甲磺酰基)苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
57)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-1-(2-氯-4-氟苄基)-1H-苯并[d]咪唑-4-基)乙基磺酰胺;
58)N-(5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
59)N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
60)N-(3-(1-(4-氯苯基)乙基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
61)N-(3-(2-氟-5-(三氟甲基)苄基)-5-(6-甲基-7氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
62)N-(3-(3,5-二氟苄基)-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
63)N-(5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
64)N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
65)N-(2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
66)N-(2-甲基-5-(6-甲基-7氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;
67)N-(3-(3,5-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺;或
68)N-(3-(2,6-二甲基苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氢-1H-吡咯并[2,3-c]吡啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-基)乙基磺酰胺。
17.6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡嗪-6-基)-1H-吡咯并[2,3-c]吡啶-7(6H)-酮的晶型,其特征在于,所述晶型的X射线粉末衍射谱图具有衍射角2θ为13.8±0.2°、18.9±0.2°、26.0±0.2°的特征峰。
18.权利要求17所述的晶型,其特征在于,所述晶型的X射线粉末衍射谱图具有衍射角2θ为6.2±0.2°、13.8±0.2°、18.9±0.2°、19.5±0.2°、26.0±0.2°、26.8±0.2°的特征峰。
19.权利要求17或18所述的晶型,其特征在于,所述晶型为无水物。
20.一种药物组合物,其特征在于,包含治疗有效量的权利要求1-16中任一项所述的化合物和/或权利要求17-19中任一项所述的晶型和药学上可接受的辅料。
21.权利要求20所述的药物组合物,其特征在于,所述化合物与所述辅料的比重在0.001至10的范围内。
22.权利要求20或21所述的药物组合物或权利要求1-16中任一项所述的化合物和/或权利要求17-19中任一项所述晶型在制备药物中的应用,其特征在于,所述药物用于治疗或预防癌症、自身免疫疾病、炎性疾病、神经变性疾病、心血管障碍、肾病症、病毒感染和/或肥胖。
23.根据权利要求22所述的应用,其特征在于,所述的癌症选自B急性淋巴细胞白血病、伯基特氏淋巴瘤、弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、霍奇金氏淋巴瘤、滤泡性淋巴瘤、原发性浆细胞白血病、大细胞神经内分泌癌、结肠癌、直肠癌、套细胞淋巴瘤、多发性骨髓瘤、乳腺癌、前列腺癌、胶质母细胞瘤、鳞状细胞食管癌、脂肪肉瘤、黑素瘤、胰腺癌、脑癌或肺癌。
24.权利要求20或21所述的药物组合物或权利要求1-16中任一项所述的化合物和/或权利要求17-19中任一项所述晶型在制备药物中的应用,其特征在于,所述药物用作BET抑制剂。
25.根据权利要求24所述的应用,其特征在于,所述药物用作BRD4抑制剂。
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CA3070273A1 (en) | 2017-07-18 | 2019-01-24 | Nuvation Bio Inc. | Heterocyclic compounds as adenosine antagonists |
EP3873474A4 (en) | 2018-10-30 | 2022-07-13 | Nuvation Bio Inc. | HETEROCYCLIC COMPOUNDS AS BET Inhibitors |
CN113939291A (zh) | 2019-01-18 | 2022-01-14 | 诺维逊生物股份有限公司 | 1,8-萘啶酮化合物及其用途 |
SG11202107810WA (en) | 2019-01-18 | 2021-08-30 | Nuvation Bio Inc | Heterocyclic compounds as adenosine antagonists |
EP3997070A4 (en) | 2019-07-02 | 2023-07-26 | Nuvation Bio Inc. | HETEROCYCLIC COMPOUNDS USED AS BET INHIBITORS |
CN112625036A (zh) | 2019-10-08 | 2021-04-09 | 上海海和药物研究开发股份有限公司 | 一类具有brd4抑制活性的化合物、其制备方法及用途 |
WO2021233371A1 (zh) * | 2020-05-21 | 2021-11-25 | 贝达药业股份有限公司 | 作为溴结构域蛋白质抑制剂的化合物和组合物 |
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US20200385408A1 (en) | 2020-12-10 |
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TW201927792A (zh) | 2019-07-16 |
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