TWI713952B - 作為溴結構域蛋白質抑制劑的化合物和組合物 - Google Patents
作為溴結構域蛋白質抑制劑的化合物和組合物 Download PDFInfo
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- TWI713952B TWI713952B TW107146235A TW107146235A TWI713952B TW I713952 B TWI713952 B TW I713952B TW 107146235 A TW107146235 A TW 107146235A TW 107146235 A TW107146235 A TW 107146235A TW I713952 B TWI713952 B TW I713952B
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- Prior art keywords
- methyl
- pyridin
- pyrrolo
- imidazo
- compound
- Prior art date
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 229910052725 zinc Inorganic materials 0.000 description 1
Images
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本發明關於一種溴結構域抑制劑。本發明亦提供包含此種化合物的組合物及製劑,及使用及製備此種化合物的方法。
Description
本發明關於一種可抑制含溴結構域蛋白質或以其他方式調節其活性之化合物,及包含此種化合物的組合物及製劑,以及使用及製備此種化合物的方法。
含BET(溴結構域及末端外結構域)家族的溴結構域(bromodomain,BRD)蛋白質包含4種:BRD2、BRD3、BRD4及BRDT。BET家族的蛋白質係表觀遺傳編碼的讀取子,將離胺酸殘基乙醯化偶聯在組蛋白上以改變染色質結構及基因表現。BRD2、BRD3及BRD4得以普遍表現,而BRDT侷限於生殖細胞。BET蛋白在調控基因轉錄及控制細胞生長方面起必要但不重疊的作用。BET蛋白質與調控許多基因轉錄方面的大蛋白質複合物相關,包含RNA聚合酶II(Pol II)、正向轉錄延長因子(P-TEFb)。已證實BRD2及BRD4蛋白在有絲分裂期間保持與染色體結合,且需要前述蛋白質促進起始細胞週期的重要基因(包含週期素D及c-Myc)轉錄(Mochizuki,J Biol.Chem.2008 283:9040-9048)。BRD4蛋白與RNA聚合酶II(Pol II),正向轉錄延長因子(Positive transcription elongation factor,P-TEFb)結合,共同促進多種癌症細胞增殖及凋亡相關
基因如c-Myc、細胞週期蛋白、抗凋亡蛋白Bcl-2等基因的轉錄表現,調控腫瘤細胞生長增殖過程(Jang等人,Mol.Cell 2005 19:523-534)。在部份情況下,BRD4的激酶活性可直接使RNA聚合酶II磷酸化及活化(Devaiah等人,PNAS 2012 109:6927-6932)。缺乏BRD4的細胞顯示細胞週期進展受損。據報導,BRD2及BRD3與組蛋白以及積極轉錄基因相關並且可參與促進轉錄延長(Leroy等人,Mol.Cell.2008 30:51-60)。除乙醯化組蛋白以外,已證實BET蛋白選擇性結合乙醯化轉錄因子,包含NF-kB及GATAl的RelA亞單位,從而直接調控此等蛋白質的轉錄活性以控制參與發炎及造血分化的基因的表現(Huang等人,Mol.Cell Biol.2009 29:1375-1387;Lamonica Proc.Nat.Acad.Sci.2011 108:E159-168)。
包含BRD4的BET蛋白質已經被鑑定為在大量疾病中發現的改變基因表現特性的重要介質,前述疾病包含癌症、糖尿病、肥胖、動脈粥樣硬化、心血管、腎症及病毒感染。參見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涉及大部分人類癌症,且BET蛋白質已經被鑑定為c-Myc的調節因子;BET蛋白質(包含BRD4)的抑制已經顯示下調Myc轉錄。
因此,對開發用作溴結構域抑制劑的化合物存在巨大需求。具體而言,關發用作BET抑制劑的化合物將備受期待。儘管已揭露部份小分子BET抑制劑已用於臨床研究,但是,目前仍未有批准上市的品種,因此,仍需要開發新的小分子BET抑制劑,為臨床上治療由BET介導的疾病或病症提供一種新的用藥選擇。
包含BRD4的BET蛋白質已經被鑑定為在大量疾病中發現的改變基因表現特性的重要介質,前述疾病包含癌症、糖尿病、肥胖、動脈粥樣硬化、心血管、腎症及病毒感染。因此,對開發用作溴結構域抑制劑的化合物存在巨大需求。目前仍沒有批准上市的品種,因此,仍需要開發新的小分子BET抑制劑,為臨床上治療由BET介導的疾病或病症提供一種新的用藥選擇。
其中,R1及R2分別獨立地選自H、C1-6烷基、C1-6烷氧基、C6-10芳基或C5-10雜芳基,前述C1-6烷基、C1-6烷氧基、C6-10芳基或C5-10雜芳基任意地被C1-6烷基、-NH2、-OH、C6-10芳基或C5-10雜芳基取代;前述C5-10雜芳基具有1個、2個或3個分別獨立地選自氮、氧或硫的雜原子;
Q不存在或選自C1-6亞烷基、-SO2-或-NH-,前述C1-6亞烷基或-NH-任意地被鹵素、C1-6烷基或C1-6烷氧基取代;X選自H、C1-6烷基、C6-10芳基或C5-10雜芳基,前述C1-6烷基、C6-10芳基或C5-10雜芳基任意地被鹵素、鹵代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;
Y為,其中A環為含有0、1、2或3個分別獨立地選自
N、O或S的雜原子的5或6元環;B環為苯基或含有0、1、2或3個分別獨立地選自N、O或S的雜原子的C5-6雜芳基;R3及R4不存在或分別獨立地選自H、鹵素、羥基、胺基、C1-6烷基、C1-6烷氧基、氰基、氧代基或-N(R5)-SO2-R6;R5及R6分別獨立地選自H、C1-6烷基或鹵素取代的C1-6烷基。
關於式(I)所示化合物,本發明進一步提供部份理想的技術手段。
部份實施型態中,R1選自H、C1-4烷基、苯基或C5-6雜芳基,前述C1-4烷基、苯基或C5-6雜芳基任意地被C1-6烷基、-NH2、苯基或C5-6雜芳基取代;理想地,前述雜芳基具有1個、2個或3個分別獨立地選自氮或硫的雜原子。
部份實施型態中,R2為H或C1-3烷基。
部份具體實施型態中,R2為H或-CH3。
部份實施型態中,X選自H、C1-3烷基或苯基,前述苯基未取代或任意地被鹵素、鹵代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。
部份實施型態中,X選自H、C1-3烷基或苯基,前述苯基未取代或任意地被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。
部份實施型態中,Y選自或;其中,
表示雙鍵或單鍵,U、V、W、G或Z分別獨立地選自C或N;當G為N時,R4為不存在;當G為C時,R4為H或-N(R5)-SO2-R6;其中,R5及R6分別獨立地選自H、C1-6烷基或鹵素取代的C1-6烷基。
部份實施型態中,Y選自、、
或;其中,表示雙鍵或單鍵,U、W或Z分別獨立地選自C
或N;R3選自H、鹵素、羥基、胺基、C1-6烷基、C1-6烷氧基、氰基或氧代基;R4為H或-N(R5)-SO2-R6;其中,R5及R6分別獨立地選自H、C1-6烷基或鹵素取代的C1-6烷基。
部份實施型態中,R3為H、C1-6烷基、C1-6烷氧基、氰基或氧代基。
部份實施型態中,R3為H、甲基或氧代基。
部份實施型態中,R4為-N(R5)-SO2-R6。
部份實施型態中,R5及R6分別獨立地選自H或C1-6烷基。
部份實施型態中,R5及R6分別獨立地選自H、甲基或乙基。
本發明進一步提供一種化合物或其藥學上可接受的鹽,前述化合物係指:
(1)4-(1-(4-氯苄基)-2-甲基-1H咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(2)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(3)6-甲基-4-(2-甲基-1-(4-(甲硫基)苄基)-1H-咪唑並[4,5-b]吡啶-6-基)-1H-吡咯並[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-咪唑並[4,5-b]吡啶-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(5)4-(1-(3-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(6)4-(1-苄基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)酮;
(7)4-(1,2-二甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(8)6-甲基-4-(2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(9)甲基4-((2-甲基-6-(6-甲基-7-氧代-6,7-二氫-1H-吡咯並[2,3-c]吡啶
-4-基)-1H-咪唑並[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-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(11)6-異丁基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(12)6-乙基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(13)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-2-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(14)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(噻唑-2-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(15)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(吡唑-2-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(16)4-(1-(3-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-2-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(17)4-(1-(4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(吡啶-3-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(18)4-(1-(4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯並[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-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(20)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-
1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(21)4-(1-(1-(4-氯苯基)乙基)-2-甲基-1H-咪唑並[4,5-b]對二氮雜苯-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(22)4-(1-苄基-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(23)4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(24)4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(25)4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(26)4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(27)4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(28)4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(29)4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(30)4-(1-(3-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(31)4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-
1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(32)4-(1-(4-溴苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(33)6-甲基-4-(2-甲基-1-(4-(甲磺醯基)苄基)-1H-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;
(34)1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1,3-二氫-2H-咪唑並[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-吡咯並[2,3-b]吡啶-5-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(36)4-(1-(2,6-二氯苄基)-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(37)4-(4-((4-氯苯基)胺基)吡啶並[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(38)4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(39)4-(1-(4-氯苄基)-1H-吡唑並[4,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;
(40)4-(1-((4-氯苯基)硫醯基)-1H-吡咯並[2,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮。
(41)N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(42)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-
1-(4-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(43)N-(1-(4-甲氧基苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(44)N-(1-(1-(4-氯苯基)乙基)-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(45)N-(1-苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(46)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(47)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(2-氟-5-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(48)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(3-氟-5-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(49)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(2-氟-4-氯苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(50)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(3-(三氟甲基)-4氯苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(51)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(3-氟-4-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(52)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(3-氯-4-(三氟甲基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(53)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-
1-(3-氯苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(54)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(2,4-二氟苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(55)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(4-溴苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(56)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(4-(甲磺醯基)苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(57)N-(2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1-(2-氯-4-氟苄基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;
(58)N-(5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(59)N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(60)N-(3-(1-(4-氯苯基)乙基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(61)N-(3-(2-氟-5-(三氟甲基)苄基)-5-(6-甲基-7氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(62)N-(3-(3,5-二氟苄基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(63)N-(5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(64)N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並
[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(65)N-(2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(66)N-(2-甲基-5-(6-甲基-7氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;
(67)N-(3-(3,5-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;或
(68)N-(3-(2,6-二甲基苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺。
本發明進一步提供6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮(化合物19)的晶型I。
在部份實施型態中,上述晶型I的X射線粉末衍射譜圖具有衍射角2θ為13.8±0.2°、18.9±0.2°、26.0±0.2°的特徵峰。
在部份實施型態中,上述晶型I的X射線粉末衍射譜圖具有衍射角2θ為6.2±0.2°、13.8±0.2°、18.9±0.2°、19.8±0.2°、26.0±0.2°、26.8±0.2°的特徵峰。
在部份實施型態中,上述晶型I具有如圖式1所示的X射線粉末衍射圖。
本發明總結上述晶型I的X射線粉末衍射圖譜中的特徵峰,如表1所示。
在部份實施型態中,本發明所記載之晶型I可用差式掃描量熱分析進行鑑定。在部份實施型態中,晶型I具有如圖式2所示的差式掃描量熱分析曲線。在DSC圖譜中,晶型I的吸熱峰約在288.9℃。差式掃描量熱分析測定係藉由TA instruments Q200 DSC(吹掃氣體:氮氣;流速:40mL/分鐘;升溫速度:10℃/分鐘)測定。
在部份實施型態中,本發明所記載之晶型I可以利用1HNMR進行鑑定,1HNMR的數據如下:1H NMR(400MHz,DMSO)δ 12.17(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)。
作為理想,該晶型I為無水物。
本發明提供的晶型I具有結晶性佳、不吸濕性、穩定性佳
的特性,而且具有可接受的口服生物利用度。
本發明亦提供一種藥物組合物,包含治療有效量的至少一種上述化合物及藥學上可接受的輔料,例如羥丙基甲基纖維素。在部份組合物中,前述化合物與前述輔料的重量比大約為0.001~10。
此外,本發明亦提供一種治療患有對含溴結構域蛋白質的抑制響應的疾病或病症的受試者的方法,包含給藥治療有效量的式(I)的化合物或其可藥用鹽。在某些方面,前述含溴結構域蛋白質為BRD4。
在某些方面,疾病或病症選自自身免疫疾病、炎性疾病、神經變性疾病、心血管障礙、腎病症、病毒感染及肥胖。在某些方面,前述疾病或病症選自類風濕性關節炎、骨關節炎、動脈粥樣硬化、銀屑病、系統性紅斑狼瘡、多發性硬化、炎性腸病、哮喘、慢性阻塞性氣道病、肺炎、皮炎、脫髮、腎炎、血管炎、動脈粥樣硬化、阿茲海默症、肝炎、原發性膽汁性肝硬變、硬化性膽管炎、糖尿病(包含I型糖尿病)、移植器官的急性排斥反應。在某些方面,前述疾病或病症為癌症,包含血液學癌症、淋巴瘤、多發性骨髓瘤、白血病、贅瘤、癌症或腫瘤(例如實體瘤)。在某些方面,前述疾病或病症為結腸、直腸、前列腺(例如去勢抗性(castrate resistant)前列腺癌)、肺癌(例如非小細胞肺癌及/或小細胞肺癌)、胰腺、肝、腎、子宮頸、子宮、胃、卵巢、乳腺(例如基底或基底樣乳腺癌及/或三重陰性乳腺癌)、皮膚(例如黑素瘤)、神經系統(包含腦、腦脊膜、及中樞神經系統,包含成神經細胞瘤、膠質母細胞瘤、腦膜瘤及髓母細胞瘤)的瘤或癌症。在某些方面,前述疾病或病症為癌瘤。在某些方面,前述疾病或病症為肝細胞癌。在某些方面,前述疾病或病症為
淋巴瘤。在某些方面,前述疾病或病症為B-細胞淋巴瘤。在某些方面,前述疾病或病症為伯基特淋巴瘤。在某些方面,前述疾病或病症為彌漫性大B-細胞淋巴瘤。在某些方面,前述疾病或病症為多發性骨髓瘤。在某些方面,前述疾病或病症為慢性淋巴細胞性白血病。在某些方面,前述疾病或病症是NUT中線癌(midline cardinoma)。在某些方面,前述受試者係人類。
在某些方面,前述化合物為靜脈內、肌內、胃腸外、鼻或口服給藥。在一個方面,前述化合物為口服給藥。
本發明亦提供一種抑制溴結構域蛋白質的方法,包含用式(I)的化合物或其可藥用鹽接觸前述溴結構域蛋白質。
本發明亦提供式(I)的化合物或其可藥用鹽在製備用於治療對溴結構域蛋白質的抑制響應的疾病或病症的藥物中的用途。
本發明亦提供用於治療的式(I)的化合物或其可藥用鹽。進一步提供用於治療患有對含溴結構域蛋白質的抑制響應的疾病或病症的受試者的式(I)的化合物或其可藥用鹽。亦提供用於上述治療方法中的式(I)的化合物或其可藥用鹽。
本發明中,除另有說明,術語「鹵素」(halogen)係指氟、氯、溴或碘。理想的鹵素基團係指氟、氯及溴。
本發明中,除另有說明,術語「烷基」包含直鏈、支鏈或環狀的飽和單價烴基。例如,烷基包含甲基、乙基、丙基、異丙基、環丙基、正丁基、異丁基、仲丁基、叔丁基、環丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、環戊基、正己基、2-己基、2-甲基戊基
和環己基。例如,C1-6烷基中的「C1-6」係指含有1、2、3、4、5或6個碳原子以直鏈或支鏈形式排列的基團。
烷氧基係指由上述的直鏈、支鏈或環狀烷基所形成的氧醚。
本發明中,除另有說明,術語「雜芳基」係指取代或未取代的穩定的5到10個環原子的至少含有一個芳香環的單環或雙環基團,前述的芳香環含有一個、兩個或三個選自N、O及S的環雜原子,其餘的環原子為C原子。此類雜芳基的實例包含但不限於,吡啶基、嘧啶基、吡咯基、咪唑基、噻唑基、噻吩基、苯並咪唑。
本發明中術語「組合物」旨在包含含有特定數量的特定組分的產品,亦包含任何由特定數量的特定組分直接或間接得到的產品。因此,包含本發明中的化合物作為活性組分的藥物組合物及製備該化合物的方法亦係本發明的內容。而且,部份化合物的晶型可以多晶型形式存在,此等亦包含在本發明中。此外,部份化合物與水(如水合物)或普通有機溶劑形成溶劑化物,此等溶劑化物亦包含在本發明中。
本發明化合物的藥物前體包含在本發明的保護範圍內。通常,前述藥物前體係指容易在體內轉化成所需要的化合物的功能性衍生物。因此,本發明提供的治療方法中的術語「給藥」包含施用本發明揭示的化合物,或雖未明確揭示但對受試者給藥後能夠在體內轉化為本發明揭示的化合物治療前述的各種疾病。有關選擇及製備合適藥物前體衍生物的常規方法,已記載在例如《藥物前體設計》(Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)此類書中。
顯然地,一個分子中任何取代基或特定位置的變量的定義係獨立於分子中其他位置。很容易理解,所屬技術領域具有通常知識者可以藉由先前技術手段及本發明中所記載之方法,選擇本發明中的化合物的取代基或取代形式,以提供化學上穩定且容易合成的化合物。
本發明所記載之化合物可能含有一個或複數個不對稱中心,並可能由此產生非對映異構體及光學異構體。本發明包含所有可能的非對映異構體及其外消旋混合物、其基本上純的拆分對映異構體、所有可能的幾何異構體及其藥學上可接受的鹽。
上述式(I)沒有確切定義該化合物某一位置的立體結構。本發明包含式(I)所示化合物的所有立體異構體及其藥學上可接受的鹽。進一步地,立體異構體的混合物及分離出的特定的立體異構體亦包含在本發明中。製備此類化合物的合成過程中,或使用所屬技術領域具有通常知識者習知的外消旋化或差向異構化方法的過程中,製得的產品可以是立體異構體的混合物。
當式(I)所示化合物存在互變異構體時,除非特別聲明,本發明包含任何可能的互變異構體及其藥學上可接受的鹽,及其混合物。
當式(I)所示化合物及其藥學上可接受的鹽為溶劑化物或多晶型的形式時,本發明包含任何可能的溶劑化物及多晶型。形成溶劑化物的溶劑類型沒有特別的限定,只要該溶劑為藥理學上可以接受。例如,水、乙醇、丙醇、丙酮等類似的溶劑皆可以採用。
術語「藥學上可接受的鹽」係指從藥學上可接受的無毒的鹼或酸製備的鹽。當本發明提供的化合物為酸時,可以從藥學上可接受的
無毒的鹼,包含無機鹼及有機鹼,方便地製得其相應的鹽。從無機鹼衍生的鹽包含鋁、銨、鈣、銅(高價及低價)、三價鐵、亞鐵、鋰、鎂、錳(高價及低價)、鉀、鈉、鋅之類的鹽。特別理想為銨、鈣、鎂、鉀及鈉的鹽。能夠衍生成藥學上可接受的鹽的無毒有機鹼包含伯胺、仲胺及叔胺,亦包含環胺及含有取代基的胺,如天然存在及合成的含取代基的胺。能夠成鹽的其他藥學上可接受的無毒有機鹼,包含離子交換樹脂以及精胺酸、甜菜鹼、咖啡因、膽鹼、N',N'-二苄乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡萄糖胺、胺基葡萄糖、組胺酸、哈胺、異丙胺、離胺酸,甲基葡萄糖胺、嗎啉、哌嗪、哌啶、多胺樹脂、普魯卡因、氯普魯卡因、嘌呤、可可鹼、三乙胺、三甲胺、三丙胺、胺丁三醇等。
當本發明提供的化合物為鹼時,可以從藥學上可接受的無毒的酸,包含無機酸及有機酸,方便製得其相應的鹽。此種酸包含,如,醋酸、苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、甲酸、富馬酸、葡萄糖酸、谷胺酸、氫溴酸、鹽酸、羥乙磺酸、乳酸、馬來酸、蘋果酸、扁桃酸、甲磺酸、黏酸、硝酸、撲酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氫碘酸、高氯酸、環己胺磺酸、水楊酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸及對甲苯磺酸等。較理想地,檸檬酸、氫溴酸、甲酸、鹽酸、馬來酸、磷酸、硫酸及酒石酸。更理想地,甲酸及鹽酸。因式(I)所示化合物將作為藥物用途,故理想使用基本上純的形式,例如,至少60%純度,至少75%的純度為更佳,至少98%的純度為特佳(%是重量比)。
本發明提供的藥物組合物包含作為活性組分的式(I)所示化合物(或其藥學上可接受的鹽)、一種藥學上可接受的賦形劑及其他可選的治療組分或輔料。儘管任何給定的情況下,最適合的活性組分給藥方式取決於接受給藥的特定的主體、主體性質及病情嚴重程度,但是本發明的藥物組合物包含適於口腔、直腸、局部及不經腸道(包含皮下給藥、肌肉注射、靜脈給藥)給藥的藥物組合物。本發明的藥物組合物可以方便地以所屬技術領域中習知的單位劑型存在及藥學領域習知的任何製備方法製備。
如本說明書所記載,新晶型可以藉由粉末X射線衍射譜進行鑑定。然而,所屬技術領域具有通常知識者知道,粉末X射線衍射的峰強度及/或峰情況可能會因為實驗條件的不同而相異,如不同的衍射測試條件及/或取向優先等。同時因不同儀器的精準度不同,測得的2θ值會有約±0.2°的誤差。然而,已知峰的相對強度值比峰的位置更依賴於所測定樣品的部份性質,例如樣品中晶體的尺寸、結晶的取向作用及被分析的材料的純度,因此可能出現所顯示的峰強度偏差在約±20%或更大範圍。但是,儘管存在試驗誤差、儀器誤差及取向優先等,所屬技術領域具有通常知識者亦可以從本發明提供的XRD數據獲取足夠的鑑別晶型的資訊。
實際上,根據常規的藥物混合技術,本發明式(I)所示化合物,或藥物前體,或代謝物,或藥學上可接受的鹽,可以作為活性組分,與藥物載體混合成藥物組合物。前述藥物載體可以採取各種各樣的形式,此取決於期望採用的給藥方式,例如,口服或注射(包含靜脈注射)。因此,本發明的藥物組合物可以採用適於口服給藥的獨立單位的形
式,如包含預定劑量的活性組分的膠囊劑、扁囊劑或片劑。進一步地,本發明的藥物組合物可採用粉末、顆粒、溶液、水性懸浮液、非水液體、水包油型乳液,或油包水型乳液形式。又,除了上述提到的常見的劑型,式(I)所示化合物或其藥學上可接受的鹽,亦可以藉由控釋的方式及/或輸送裝置給藥。本發明的藥物組合物可以採用任何製藥學上的方法製備。一般情況下,此方法包含使活性組分及組成一個或複數個必要成分的載體締合的步驟。一般情況下,前述藥物組合物經由活性組分與液體載體或精細分割的固體載體或兩者的混合物經過均勻地密切地混合製得。接著,該產品可以方便地製備成所需要的外觀。
因此,本發明的藥物組合物包含藥學上可接受的載體及式(I)所示化合物或其藥學上可接受的鹽。式(I)所示化合物或其藥學上可接受的鹽,與其他一種或多種具有治療活性的化合物亦包含在本發明的藥物組合物中。
本發明採用的藥物載體可為,例如,固體載體、液體載體或氣體載體。固體載體,係包含乳糖、石膏粉、蔗糖、滑石粉、明膠、瓊脂、果膠、阿拉伯膠、硬脂酸鎂、硬脂酸。液體載體,係包含糖漿、花生油、橄欖油及水。氣體載體,係包含二氧化碳及氮氣。製備藥物口服製劑時,可以使用任何方便的製藥學上的介質。例如,水、乙二醇、油類、醇類、增味劑、防腐劑、著色劑等可用於口服的液體製劑如懸浮劑、酏劑及溶液劑;而載體,如澱粉類、糖類、微晶纖維素、稀釋劑、造粒劑、潤滑劑、黏合劑、崩解劑等可用於口服的固體製劑如散劑、膠囊劑及片劑。考慮到易於施用,口服製劑首選片劑及膠囊,在此應用固體藥學載體。可選
地,片劑包衣可使用標準的水製劑或非水製劑技術。
含有本發明化合物或藥物組合物的片劑可藉由,任意一種或多種輔助組分或輔藥一起壓制或成型製備。活性組分以自由流動的形式如粉末或顆粒,與黏合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合,在適當的機器中,藉由壓制可以製得壓制片劑。用一種惰性液體稀釋劑浸濕粉末狀的化合物或藥物組合物,接著在適當的機器中,藉由成型可以製得模製片。較理想地,每個片劑含有大約0.05mg到5g的活性組分,每個扁囊劑或膠囊劑含有大約0.05mg到5g的活性組分。例如,擬用於人類口服給藥的劑型包含約0.5mg到約5g的活性組分,與合適且方便計量的輔助材料複合,該輔助材料約占藥物組合物總量的5%至95%。單位劑型一般包含約1mg到約2g的活性組分,典型為25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
本發明提供的適用於胃腸外給藥的藥物組合物可將活性組分加入水中製備成水溶液或懸浮液。可以包含適當的表面活性劑如羥丙基纖維素。在甘油、液態聚乙二醇,及其在油中的混合物,亦可以製得分散體系。進一步地,防腐劑亦可以包含在本發明的藥物組合物中用於防止有害的微生物生長。
本發明提供適用於注射的藥物組合物,包含無菌水溶液或分散體系。進一步地,上述藥物組合物可以製備成可用於即時配製無菌注射液或分散液的無菌粉末的形式。無論如何,最終的注射形式必須係無菌
者,且為了易於注射,必須係易於流動者。此外,前述藥物組合物在製備及儲存過程中必須穩定。因此,理想為抗微生物如細菌及真菌污染的保存。載體可為溶劑或分散介質,例如,水、乙醇、多元醇(如甘油、丙二醇、液態聚乙二醇)、植物油及其適當的混合物。
本發明提供的藥物組合物,可以是適於局部用藥的形式,例如,氣溶膠、乳劑、軟膏、洗液、撒粉或其他類似的劑型。進一步地,本發明提供的藥物組合物可以採用適於經皮給藥裝置使用的形式。利用本發明式(I)所示化合物,或其藥學上可接受的鹽,藉由常規的加工方法,可以製備此等製劑。作為一個例子,乳劑或軟膏劑的製備係藉由在約5wt%到10wt%的上述化合物中加入親水性材料及水,製得具有預期一致性的乳劑或軟膏。
本發明提供的藥物組合物,可以製成以固體為載體,適用於直腸給藥的形式。理想的劑型為混合物形成單位劑量的栓劑。適當的輔料包含所屬技術領域中常用的可可脂及其他材料。栓劑可以方便地製備,首先藥物組合物與軟化或熔化的輔料混合,接著冷卻及模具成型而製得。
除了上述提到的載體組分外,上述藥學製劑亦可以包含,適當的,一種或多種附加的輔料組分,如稀釋劑、緩衝劑、調味劑、黏合劑、表面活性劑、增稠劑、潤滑劑及防腐劑(包含抗氧化劑)等。此外,其他的輔藥亦可以包含調節藥物與血液等滲壓的促滲劑。包含式(I)所示化合物,或其藥學上可接受的鹽的藥物組合物,亦可以製備成粉劑或濃縮液的形式。
一般情況下,治療上述所示的狀況或不適,藥物的劑量標
準約為每天0.01mg/kg體重到150mg/kg體重,或者每個病人每天0.5mg到7g。例如,炎症、癌症、牛皮癬、過敏/哮喘、免疫系統的疾病及不適、中樞神經系統(CNS)的疾病及不適,有效治療的藥物劑量標準為每天0.01mg/kg體重到50mg/kg體重,或者每個病人每天0.5mg到3.5g。
但是,可以理解,任何特定病人的具體劑量標準將取決於多種因素,包含年齡、體重、綜合健康狀況、性別、飲食、給藥時間、給藥途徑、排泄率、藥物聯用的情況及接受治療的特定疾病的嚴重程度。
【圖1】為化合物19晶型I的XRD圖譜。
【圖2】為化合物19晶型I的DSC圖譜。
【圖3】為化合物19晶型I在不同穩定性條件下的XRD對比圖譜。圖中A為晶型I在0天時的XRD圖譜;B為晶型I在80℃乾燥放置24小時的XRD圖譜;C為晶型I在25℃-60%RH放置10天的XRD圖譜;D為晶型I在40℃-75%RH放置14天的XRD圖譜。
為使本發明更加容易理解,下面將結合實施例來詳細說明本發明,此等實施例僅起說明性作用,並不侷限於本發明的應用範圍,下列實施例中未舉例的具體實驗方法,通常按照常規實驗方法進行。
除另有說明,所有的部分及百分數均以重量計算,所有的溫度均為攝氏度。
實施例中使用下列縮略語:AcOH:乙酸;(BPin)2:雙聯頻哪醇硼酸酯;BRD4(D1):溴結構域蛋白4(結構域1);BRD4(D2):溴結構域蛋白4(結構域2);CDI:N,N'-羰基二咪唑;DCM:二氯甲烷;DIEA:N,N-二異丙基乙胺;DMA:N,N-二甲基乙醯胺;DMF:N,N-二甲基甲醯胺;DMSO:二甲基亞碸;EA:乙酸乙酯;EtOH:乙醇;h:小時;1HNMR:核磁共振;KAcO:乙酸鉀;LCMS:液質聯用;LDA:二異丙基胺基鋰;Mel:碘甲烷;MeOH:甲醇;min:分鐘;NaBH4:硼氫化鈉;
NaH:氫化鈉;n-Hex:正己烷;Pd2(dba)3:三(二亞苄基丙酮)二鈀;Pd(dppf)Cl2.DCM:[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物;Pd(PPh3)4:四三苯基磷化鈀;Pd(PPh3)2Cl2:雙三苯基磷二氯化鈀;PE:石油醚;POCl3:三氯氧磷;s:秒;TEA:三乙基胺;TfOH:三氟甲磺酸;THF:四氫呋喃;TLC:薄層色譜法;TsCl:對甲基苯磺醯氯;XPhos:2-二環己基磷-2',4',6'-三異丙基聯苯。
[實施例1]
化合物1(4-(1-(4-氯苄基)-2-甲基-1H咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮)的合成
1. 化合物1M-11的合成
將5-溴-2-甲氧基-4-甲基-3-硝基吡啶(3.90g)溶於DMF(250mL)中,升溫至80℃,緩慢向其中加入N,N-二甲基甲醯胺二甲基縮醛(18mL),加完升溫至95℃反應4h。TLC監控反應結束,濃縮,加入水(1L),EA萃取三次,有機相合併,水洗,無水硫酸鈉乾燥,減壓濃縮,得化合物1M-11粗品3.50g。
2. 化合物1M-12的合成
將化合物1M-11(3.50g)、鐵粉(3.50g)及氯化銨(3.50g)加入甲醇(133mL)及水(17.5mL)中,回流反應7h,TLC監控反應完全。趁熱過濾,濾餅用甲醇洗滌兩次,濾液合併濃縮。柱層析純化,PE:EA=5:1,得化合物1M-12粗品2.26g。
3. 化合物1M-13的合成
將化合物1M-12(2.26g)溶於THF(47mL),氮氣保護,降溫至0℃,加入NaH(1.28g),升至室溫反應1h,降溫至0℃,加入TsCl
溶液(2.50g的TsCl溶於47mL的THF),反應2h,TLC確認反應結束,加入冰水淬滅。EA萃取3次,有機相合併,飽和食鹽水洗三次,無水硫酸鈉乾燥,濃縮,得化合物1M-13粗品3.80g。
4. 化合物1M-14的合成
將化合物1M-13(3.80g)溶於乙醇(10mL),滴加溴化氫溶液(40mL,40%),90℃反應2h,TLC監控反應結束,冷卻至0℃,有白色固體析出,過濾收集固體,濾餅用水洗兩次,乾燥,得化合物1M-14粗品3.60g。
5. 化合物1M-15的合成
將化合物1M-14(3.60g)溶於二氧六環(50mL),加入碳酸銫(3.94g)、碘甲烷(5.40g),室溫攪拌。TLC監控反應結束,反應液用DCM(200mL)稀釋,飽和食鹽水洗三次,無水硫酸鈉乾燥,濃縮。粗品用n-Hex:EA=4:1(V/V)的混合溶劑(20mL)打漿,過濾收集固體,產品為淺黃色固體3.20g。
6. 化合物1-1的合成
將2,3-二胺基-5-溴吡啶(4.03g)及對氯苯甲醛(3.00g)溶於DCM(350mL),加入乙酸(10mL),室溫攪拌過夜。TLC監控反應結束,加入Na2CO3溶液(100mL),DCM萃取兩次,有機相合併,無水硫酸鈉乾燥,濃縮,柱層析純化PE:EA=100:15,得黃色固體即為化合物1-1,3.75g。
7. 化合物1-2的合成
將化合物1-1(3.75g)溶於甲醇中,冰浴降溫,加入NaBH4
(2.30g),室溫攪拌過夜。TLC監控反應結束,濃縮,加入250mL水,EA萃取三次,有機相合併,無水硫酸鈉乾燥,濃縮,得化合物1-2,3.65g。
8. 化合物1-3的合成
將化合物1-2(3.65g)溶於乙酸(150mL)中,加入原乙酸三乙酯(7.52g),升溫至100℃反應2h,TLC監控反應結束,濃縮。加入Na2CO3溶液(300mL),EA萃取兩次,有機相合併,無水硫酸鈉乾燥,濃縮。粗品經柱層析純化PE:EA=1:1(V/V),得黃色固體即為化合物1-3,2.73g。
9. 化合物1-4的合成
將化合物1-3(1.00g)、六甲基二錫(1.17g)及四三苯基膦鈀(0.69g)溶於甲苯(25mL),氮氣置換,115℃加熱反應2.5h,冷卻,濃縮,粗品經柱層析純化DCM:MeOH=100:2-100:3,得黃色固體即為化合物1-4,0.79g。
10. 化合物1-5的合成
將化合物1-4(0.33g)、1M-15(0.30g)及Pd(PPh3)2Cl2(0.06mg)溶於DMF(5mL),氮氣保護,加熱120℃反應2h,冷卻,濃縮,粗品經柱層析純化DCM:MeOH=100:3,得黃色固體即為化合物1-5,0.31g。
11. 化合物1的合成
將化合物1-5(0.31g)溶於MeOH(10mL)及DCM(5mL)中,加入NaOH(0.30g),室溫攪拌過夜,TLC監控反應結束,濃
縮,粗品經柱層析純化DCM:MeOH=100:2,得白色固體即為化合物1,0.13g。
LCMS:[M+1]+=404.2。
1HNMR(400MHz,DMSO)δ 12.17(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)。
採用與實施例1基本類似的方法,應用相應的對氯苯甲醛
衍生物替換實施例中的(對氯苯甲醛)製備下述表4中的實施
例。前述相應的對苯甲醛衍生物,例如或等均可以藉由
市售管道購買得到。前述相應碘甲烷衍生物,例如,或等亦均
可藉由市售管道購買得到。
[實施例18]
化合物18(4-(1-(4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮)的合成
1. 化合物2M-1的合成
將化合物1M-15(6.00g)、(BPin)2(8.00g)、XPhos(0.90g)、Pd2(dba)3(0.43g)及KAcO(3.40g)溶於二氧六環(90mL),氮氣保護,80℃攪拌反應4h。冷卻,倒入EA(200mL)及飽和Na2CO3(200mL)的混合溶劑中,分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮。粗品用柱層析純化PE:EA=100:30,得白色固體即為化合物2M-1,3.45g。
2. 化合物18-1的合成
將2-胺基-3,5-二溴吡嗪(10.00g)、4-氯苄胺(16.90g)及DIEA(25.54g)溶於DMSO(40mL),120℃加熱攪拌4h,LCMS確認反應結束,冷卻,加入冷水(200mL),EA萃取3次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化PE:EA=100:15-100:30,得黃色固體即為化合物18-1,13.91g。
3. 化合物18-2的合成
將化合物18-1(13.90g)、原乙酸三乙酯(35.96g)及冰醋酸(200mL)混合,100℃反應過夜。冷卻,濃縮,粗品加入EA稀釋,飽和Na2CO3溶液洗滌3次,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化PE:EA=100:20-100:50,得淡黃色固體即為化合物18-2,12.05g。
4. 化合物18-4的合成
將化合物18-2(1.00g)、2M-1(1.27g)、Pd(dppf)Cl2.DCM(0.25g)溶於二氧六環(20mL)中,加入K2CO3(0.61g)及水(4mL),氮氣保護,100℃加熱攪拌過夜。冷卻,倒入EA(50mL)及飽和Na2CO3(50mL)的混合溶劑中,分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮。粗品用柱層析純化DCM:MeOH=100:2,得黃色固體即為化合物18-4,0.95g。
5. 化合物18的合成
將化合物18-4(0.95g)溶於MeOH(10mL)及DCM(20mL)中,加入NaOH(0.40g),室溫攪拌過夜,濃縮,將粗品溶於10mLDMF,將其滴入飽和氯化銨溶液(100mL)中,過濾收集固體,粗品用EA(10mL)打漿,過濾收集固體,減壓乾燥,得淡棕色固體即為化合物18,0.51g。
LCMS:[M+1]+=405.8。
1HNMR(400MHz,DMSO)δ 12.15(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)。
[實施例34]
化合物34(1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1,3-二氫-2H-咪唑並[4,5-b]吡啶-2-酮)的合成
1. 化合物34-1的合成
將化合物1-1(4.43g)溶於CH3CN(25mL),加入CDI(11.51g),室溫攪拌過夜。抽濾收集固體,濾餅用正己烷洗滌,乾燥,得白色固體即為化合物34-1,4.24g。
2. 化合物34-2的合成
將化合物34-1(1.00g)、六甲基二錫(1.16g)及四三苯基膦鈀(0.68g)溶於1,4-二氧六環(25mL),氮氣保護,100℃攪拌過夜。冷卻,濃縮,粗品經柱層析純化PE:EA=100:25,得類白色固體即為化合物34-2,1.23g。
3. 化合物34-3的合成
將化合物34-2(0.35g)、化合物34-5(0.31g)及Pd(PPh3)2Cl2(0.06g)加入DMF(5mL)及二氧六環(2.5mL),氮氣保護,100℃過夜反應。冷卻,加入水(50mL),用DCM萃取3次,有機相合併,濃縮,柱層析純化DCM:MeOH=100:3,得類白色固體即為化合物34-3,0.13g。
4. 化合物34的合成
將化合物34-3(0.21g)溶於MeOH(50mL)中,加入NaOH(0.20g),室溫攪拌過夜,向體系中加入水(500mL)及DCM(500mL),過濾收集
固體,將濾餅用MeOH:DCM=1:1溶清,有機相合併濃縮,得產品即為化合物34,0.06g。
LCMS:[M+1]+=406.1。
1HNMR:(400MHz,DMSO)δ 12.12(s,1H),8.23-6.38(m,9H),6.22(t,J=2.8Hz,1H),5.05(s,2H),3.64(s,3H)。
[實施例35]
化合物35(4-(3-(1-(2,6-二氯-3-氟苯基)乙基)-2-甲基-1H-吡咯並[2,3-b]吡啶-5-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物35-1的合成
將5-溴-1H-吡咯並[2,3-b]吡啶(5.00g)溶於DMF(100mL)中,於0℃下加入氫化鈉(1.82g),升溫至室溫反應20min,降溫至0℃,加入苯磺醯氯(6.69g),升溫至室溫反應1h。向其加入100mL飽和氯化銨溶液淬滅,用DCM萃取三次,有機相合併,飽和食鹽水洗滌兩次,無水硫酸鈉乾燥,濃縮得粗品8.37g。
2. 化合物35-2的合成
將2-異丙胺(4.20g)溶於THF(100mL)中,氮氣保護,降溫至-
78℃,向其中加入正丁基鋰(16mL),低溫反應60min,加入化合物35-1(5.00g)的THF(30mL)溶液,-78℃反應60min,加入碘甲烷(6.31g),自然升至室溫反應2h。加入飽和氯化銨溶液(50mL)淬滅,濃縮,用EA萃取三次,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥,柱層析純化PE:EA=100:40,得產品4.52g,白色固體。
3. 化合物35-3的合成
將化合物35-2(4.52g)溶於甲醇(100mL),加入氫氧化鈉(4.52g),室溫攪拌過夜。加入飽和氯化銨溶液(50mL),濃縮,用EA萃取兩次,有機相合併,飽和食鹽水洗兩次,無水硫酸鈉乾燥,濃縮,得粗品2.80g。
4. 化合物35-4的合成
將化合物35-3(2.80g)溶於DCM(65mL),氮氣保護,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,室溫過夜。35℃反應4h,加入飽和碳酸鈉溶液(200mL),用DCM(500mL)萃取3次,飽和食鹽水洗兩次,無水硫酸鈉乾燥,濃縮,粗品用EA(50mL)打漿,產品為白色固體,2.40g。
5. 化合物35-5的合成
將化合物35-4(0.10g)、2M-1(0.11g)及Pd(dppf)Cl2(0.02g)溶於DMF(2mL),加入碳酸鉀(0.07g),氮氣保護,115℃過夜。冷卻,過濾,濾液加入水(10mL),用DCM(10mL)萃取三次,用飽和食鹽水(10mL)洗滌3次,直接濃縮得棕色油狀物0.21g,直接用於下一步反應。
6. 化合物35的合成
將化合物35-5(0.21g)溶於甲醇(10mL)中,加入氫氧化鈉(0.10g),40℃攪拌4h,加入飽和氯化銨溶液(10mL),DCM(50mL)萃取兩次,飽和食鹽水洗兩次,有機相濃縮,柱層析純化,DCM:MeOH=100:5,得產品0.07g。
LCMS:[M+1]+=469.1。
1HNMR:(400MHz,DMSO)δ 12.12(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)。
[實施例36]
化合物36(4-(1-(2,6-二氯苄基)-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物36-1的合成
將原料5-溴-2-甲基-3-硝基嘧啶(1.00g)溶於DMF(10mL)中,加入N,N-二甲基甲醯胺二甲基縮醛(5mL),100℃反應1h,冷卻,加入飽
和氯化銨溶液(25mL)淬滅,再用EA(25mL)萃取兩次,有機相合併,飽和食鹽水洗1次,無水硫酸鈉乾燥,濃縮,得粗品1.45g,直接用於下步反應。
2. 化合物36-2的合成
將化合物36-1(1.45g)及鐵粉(2.38g)加入冰醋酸(50mL),升溫至80℃反應5h,趁熱過濾,濾餅用EA洗滌,濾液合併,濃縮,加入飽和Na2CO3溶液,再次過濾,濾餅用EA洗滌,濾液分液,取有機相,用飽和食鹽水洗,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化PE:EA=100:50,得產品0.73g。
3. 化合物36-3的合成
將化合物36-2(0.70g)溶於DMF(25mL)中,氮氣保護,在0℃下加入氫化鈉(0.19g),自然升至室溫攪拌1h。在0℃下加入2,6-二氯溴苄(0.85g),自然升至室溫反應3h。向其加入冰水混合物50mL淬滅反應,EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,產品為黃色固體1.30g。
4. 化合物36-4的合成
將化合物36-3(0.40g)、化合物2M-1(0.48g)及Pd(dppf)Cl2.DCM(0.10g)溶於二氧六環(8mL),加入碳酸鉀(0.23g)的水(1.5mL)溶液,氮氣保護,100℃攪拌過夜。冷卻,加入EA(50mL)及飽和Na2CO3(50mL)的混合溶液,收集有機相,水相用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,柱層析純化DCM:MeOH=100:2,產品為棕黃色固體0.50g。
5. 化合物36的合成
將化合物36-4(0.50g)溶於MeOH/DCM=10mL:10mL的混合溶液,加入氫氧化鈉(0.30g),室溫攪拌過夜。濃縮,粗品經柱層析純化DCM:MeOH=100:5,得淡棕色固體0.21g。
LCMS:[M+1]+=423.1。
1HNMR:(400MHz,DMSO)δ 12.17(s,1H),7.69-7.55(m,2H),752-7.23(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)。
[實施例37]
化合物37(4-(4-((4-氯苯基)胺基)吡啶並[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物37-1的合成
將2-胺基-5-溴煙酸(3.00g)溶於甲醯胺(15mL),160℃攪拌反應4h,再加入甲醯胺(20mL),160℃繼續反應6h,冷卻,倒入150mL水中,過濾收集固體,得黃色固體2.20g。
2. 化合物37-2的合成
將化合物37-1(0.40g)溶於三氯氧磷(5mL),加入三乙胺
(0.5mL),120℃反應3h,濃縮,粗品加入甲苯(20mL),濃縮,反覆三次,得棕黑固體粗品0.60g,直接用於下步反應。
3. 化合物37-3的合成
將化合物37-2(0.60g)溶於DCM(10mL),加入對氯苯胺(0.30g)、三乙胺(1mL),室溫攪拌5h,濃縮,粗品經柱層析純化DCM:MeOH=100:5-100:10,產品為棕紅色固體0.70g。
4. 化合物37-4的合成
將化合物37-3(0.30g)、化合物2M-1(0.38g)及Pd(dppf)Cl2.DCM(0.07g)溶於二氧六環,加入碳酸鉀(0.19g)及水(1.5mL),氮氣保護,100℃攪拌過夜。冷卻,加入EA(30mL)及飽和Na2CO3溶液(30mL),分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮。粗品經柱層析純化DCM:MeOH=100:3,產品為黃色固體0.29g。
5. 化合物37的合成
將化合物37-4(0.29g)溶於甲醇(15mL),加入氫氧化鈉(0.21g),室溫攪拌過夜,濃縮,柱層析純化DCM:MeOH=100:5,產品為黃色固體即為化合物37,0.07g。
LCMS:[M+1]+=403.1。
1HNMR:(400MHz,DMSO)δ 12.28(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)。
[實施例38]
化合物38(4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物38-1的合成
將5-溴-2-甲基-3-硝基吡啶(1.00g)及N,N-二甲基乙醯胺二甲基縮醛(1.22g)溶於DMF(5mL),100℃加熱1h。冷卻,加入EA(300mL)稀釋,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,產品為棕紅色固體1.30g。
2. 化合物38-2的合成
將化合物38-1(1.30g)及鐵粉(3.00g)溶於冰醋酸(30mL),80℃攪拌90min,冷卻,將其倒入飽和Na2CO3溶液(200mL),矽藻土過濾,濾餅用EA洗滌,濾液用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,粗品用鹼性氧化鋁柱層析純化PE:EA=100:30-100:50,產品為土黃色固體0.63g。
3. 化合物38-3的合成
將化合物38-2(0.53g)溶於DMF(25mL),氮氣保護,降溫至0℃,加入氫化鈉(0.13g),自然升至室溫攪拌1h,降溫至0℃,加入2,6-二氯苄基溴(0.60g),自然升溫至室溫反應2.5h,將其倒入冰水中淬滅,
EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮。粗品經柱層析純化PE:EA=100:10-100:30,產品為黃色固體0.84g。
4. 化合物38-4的合成
將化合物38-3(0.20g)、化合物2M-1(0.23g)及Pd(dppf)Cl2.DCM(0.04g)溶於二氧六環(5mL),加入K2CO3(0.11g)、水(1mL),氮氣保護,100℃加熱反應過夜。冷卻,加入EA(50mL)及飽和Na2CO3溶液(50mL),混合溶液,分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化DCM:MeOH=100:3,得粗品棕色油0.30g粗品。
5. 化合物38的合成
將化合物38-4(0.30g)加入甲醇(15mL),加入氫氧化鈉(0.20g),室溫攪拌3h,加入矽膠拌樣柱層析純化DCM:MeOH=100:2-100:3,產品為黃色固體0.08g。
LCMS:[M+1]+=437.1。
1HNMR:(400MHz,DMSO)δ 12.13(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)。
[實施例39]
化合物39(4-(1-(4-氯苄基)-1H-吡唑並[4,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物39-1的合成
將6-溴-1H-吡唑並[4,3-b]吡啶(1.00g)溶於DMF(30mL),氮氣保護,在0℃下加入氫化鈉(0.24g),升至室溫反應1h,在0℃下加入對氯苄氯(0.90g),室溫反應過夜。將其倒入冰水(100mL)淬滅,EA萃取3次,有機相合併,飽和食鹽水洗,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化PE:EA=100:4-100:20,產品為白色固體0.80g。
2. 化合物39-2的合成
將化合物39-1(0.30g)、2M-1(0.40g)及Pd(dppf)Cl2.DCM(0.08g)溶於二氧六環(8mL),加入碳酸鉀(0.19g)及水(1.5mL),氮氣保護,100℃加熱攪拌過夜。冷卻,將其倒入EA(100mL)/飽和Na2CO3溶液(100mL),分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗,無水硫酸鈉乾燥,濃縮。粗品經柱層析純化DCM:MeOH=100:2.5,產品為黃色半固體0.52g。
3. 化合物39的合成
將化合物39-2(0.52g)溶於甲醇(10mL)及DCM(10mL),加入氫氧化鈉(0.12g),室溫攪拌,濃縮,粗品柱層析純化DCM:MeOH=100:2.5-100:3,得黃色固體即為化合物39,0.10g。
LCMS:[M+1]+=390.1;1HNMR:(400MHz,DMSO)δ 12.23(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)。
[實施例40]
化合物40(4-(1-((4-氯苯基)硫醯基)-1H-吡咯並[2,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮)的合成
1. 化合物40-1的合成
將6-溴-7-氮雜吲哚(1.00g)溶於DMF(15mL),氮氣保護,在0℃加入氫化鈉(0.31g),室溫攪拌1h,在0℃加入對氯苯磺醯氯(1.30g),室溫攪拌2h,加入冰水(50mL)淬滅,EA萃取3次,有機相合併,飽和食鹽水洗3次,無水硫酸鈉乾燥,濃縮,產品為黃色固體1.30g。
2. 化合物40-2的合成
將化合物40-1(0.35g)、化合物2M-1(0.49g)及Pd(PPh3)4(0.06g)溶於二氧六環(7mL),加入碳酸鉀(0.20g)及水(7mL),氮氣保護,100℃反應過夜。冷卻,將其倒入EA(50mL)/飽和Na2CO3溶液(50mL),分液,水相用EA萃取3次,有機相合併,飽和食鹽水洗,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化DCM:MeOH=100:3,產品為淡黃固體0.35g。
3. 化合物40的合成
將化合物40-2(0.28g)溶於甲醇(10mL)及二氯甲烷(10mL),加入氫氧化鈉(0.07g),室溫攪拌過夜。濃縮,粗品經柱層析純化DCM:MeOH=100:3,粗品加入EA(10mL)打漿,過濾收集固體,得產品0.04g。
LCMS:[M+1]+=439.1;1HNMR:(400MHz,DMSO)δ 12.12(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)。
[實施例41]
化合物41(N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺)的合成
1. 化合物41-1的合成
將5-溴-3-硝基-苯-1,2-二胺(1.00g)及乙醯丙酮(0.86g)溶於乙醇(20mL),加入5N鹽酸(6mL),100℃攪拌4h,冷卻,濃縮,粗品柱層析純化PE:EA=100:30,得產品黃色固體0.90g。
2. 化合物41-2的合成
將化合物41-1(0.85g)及碳酸鉀(0.92g)溶於乙腈(20mL)、DMF(4mL),加入對氯苄氯(0.98g),60℃攪拌過夜。冷卻,倒入100mL水中,EA萃取3次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化PE:EA=100:30,得黃色固體1.04g。
3. 化合物41-3的合成
將化合物41-2(0.50g)、化合物2M-1(0.56g)及Pd(dppf)Cl2.DCM(0.11g)溶於二氧六環(10mL),加入碳酸鉀(0.27g)、水(2mL),氮氣保護,90℃攪拌過夜。冷卻,倒入50mL水中,EA萃取三次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化DCM:MeOH=100:3,得黃色固體0.83g。
4. 化合物41-4的合成
將化合物41-3(0.80g)溶於THF(15mL)、乙醇(15mL),加入鐵粉(0.37g)、氯化銨(0.14g)、水(10mL),90℃攪拌過夜。趁熱過濾,濾餅用甲醇淋洗3次,濾液濃縮,加入飽和碳酸鈉溶液(50mL),EA萃取3次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,粗品經柱層析純化DCM:MeOH=100:4,得暗黃色固體0.43g。
5. 化合物41的合成
將化合物41-4(0.43g)溶於DCM(10mL),加入三乙胺(0.31g),乙基磺醯氯(0.19g),室溫攪拌2h,濃縮,加入二氧六環(7.5mL)及氫氧化鈉溶液(10%,V/V,2.5mL),70℃攪拌加熱3h,冷卻,倒入飽和氯化銨溶液(100mL),分液,水相用EA萃取3次有機相合併,飽和食鹽水洗滌3次無水硫酸鈉乾燥,濃縮,粗品柱層析純化DCM:MeOH=100:3,得
產品黃色固體0.08g。
LCMS:[M+1]+=511.1。
1HNMR(300MHz,DMSO)δ 12.13(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)。
[實施例58]
化合物58 N-(5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡H啶-7-基)乙基磺醯胺的合成
1. 化合物58-1的合成
將1M-15(7.60g)、NaOH(1.60g)溶於二氧六環及水,80℃反應4h。冷卻,倒入H2O中,DCM萃取三次,合併有機相,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化DCM:MeOH=90:10,得灰色固體3.20g。
2. 化合物58-2的合成
將化合物58-1(6.00g)、(Bpin)2(8.00g)、SPhos(1.29g)、PdCl2(CH3CN)2(0.68g)、KOAc(3.40g)溶於二氧六環,氮氣保護,80℃反應4h。冷卻,倒入水中,EA萃取三次,合併有機相,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化PE:EA=50:50,得灰色固體3.20g。
3. 化合物58-3的合成
將5,7-二氯-1H-咪唑並[4,5-B]吡啶(1.88g)、對三氟甲基苄氯(1.94g)及DIEA(1.56g)溶於DMF,室溫反應過夜。倒入水中,EA萃取三次,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱
層析純化PE:EA=50:50,得灰色固體1.50g。
4. 化合物58-4的合成
將58-3(1.50g)置於氨水中,150℃反應過夜。冷卻,抽濾,濾餅用水洗滌,固體真空乾燥,得白色固體1.10g。
5. 化合物58-5的合成
將58-4(1.10g)、TEA(1.70g)溶於DCM,滴加乙基磺醯氯(0.86g),室溫反應2h。倒入水中,DCM萃取三次,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化PE:EA=30:70,得灰色固體0.80g。
6. 化合物58的合成
將58-2(0.42g)、58-5(0.27g)、K2CO3(0.41g)、Xphos-Pd-G2(0.08g)置於二氧六環及水,80℃反應4h。冷卻,倒入水中,EA萃取三次,合併有機相,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化MeOH:DCM=10:90,得灰色固體0.10g。
LCMS:[M+1]+=531.1。
1H NMR(400MHz,DMSO)δ 12.13(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)。
[實施例59]
化合物59 N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺的合成
1. 化合物59-1的合成
將5,7-二氯-1H-咪唑並[4,5-B]吡啶(5.00g)、K2CO3(11.00g)、2,4-二氟氯苄(6.50g)溶於DMF(50ml)中,室溫攪拌8h。將反應物倒入冰水中,抽濾,濾餅用水洗三次,粗品柱層析純化,PE:EA=70:30,得白色固體6.0g。
2. 化合物59-2的合成
將59-1(0.60g)、氨水(25mL)加入封管中,150℃攪拌過夜。倒入100mL水中,EA萃取3次,有機相合併,飽和食鹽水洗滌三次,無水硫酸鈉乾燥,濃縮,得白色固體0.30g。
3. 化合物59-3的合成
將59-2(0.15g)、TEA(0.16g)溶於DCM(5mL)中,在0℃下緩慢滴加乙基磺醯氯(0.19g),滴加結束後恢復至室溫,繼續攪拌5h。向反應液中加入水,EA萃取3次,有機相合併,飽和食鹽水洗滌三次,無水硫酸鈉乾燥,濃縮,粗品Flash-Prep-HPLC純化(H2O/CH3CN=40%~45%),得淡黃色固體0.10g。
4. 化合物59的合成
將59-3(0.10g)、8-2(0.07g)、Xphos-Pd-G2(0.02g)及K3PO4(0.11g)溶於二氧六環5mL,加入水1mL,在氮氣保護下加熱80℃反應8h。冷卻,加水稀釋,EA萃取3次,有機相合併,飽和食鹽水洗滌三次,無水硫酸鈉乾燥,濃縮,粗產品柱層析純化,DCM:MeOH=98:2,得棕色固體0.06g。
LCMS:[M+1]+=499.1。
1H NMR(400MHz,DMSO)δ 12.12(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)。
[實施例64]
化合物64 N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺的合成
1. 化合物64-1的合成
2-甲基-1H-咪唑並[4,5-b]吡啶(1.08g)溶於15ml EA,加入(1.86g)m-CPBA,室溫攪拌過夜,抽濾,固體用EA洗滌,乾燥得白色
固體1.05g。
2. 化合物64-2的合成
64-1(1.05g)溶於10ml POCl3,80℃反應15min,升溫至120℃,反應3h,倒入冰水中,EA萃取三次,有機相合併,濃縮,柱層析(PE:EA=50:50),得白色固體0.80g。
3. 化合物64-3的合成
64-2(0.80g)溶於10ml EA,加入(1.25g)m-CPBA,室溫攪拌過夜,抽濾,濾餅用EA洗滌,乾燥得白色固體0.70g。
4. 化合物64-4的合成
64-3(0.70g)溶於10ml DMF,滴加0.38ml甲基磺醯氯,80℃反應3h,倒入冰水中,EA萃取三次,有機相合併,濃縮,柱層析(PE:EA=50:50),得白色固體0.60g。
5. 化合物64-5的合成
將64-4(0.70g)、2,4-二氟氯苄(0.70g)及K2CO3(0.95g)溶於DMF,室溫反應過夜。倒入水中,EA萃取三次,飽和食鹽水洗滌三次,無水硫酸鈉乾燥,濃縮。粗品柱層析純化(PE:EA=30:70),得黃色固體0.65g。
6. 化合物64-6的合成
將64-5(0.65g)置於10ml氨水中,150℃反應過夜。冷卻,抽濾,濾餅用水洗滌,固體真空乾燥,得白色固體0.50g。
7. 化合物64-7的合成
將化合物64-6(0.50g)、TEA(0.49g)溶於10ml DCM,滴加乙基
磺醯氯(0.42g),室溫反應2h。倒入水中,DCM萃取三次,有機相合併,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化PE:EA=30:70,得白色固體0.40g。
8. 化合物64的合成
將化合物64-7(0.40g)、58-2(0.27g)、K2CO3(0.41g)、Xphos-Pd-G2(0.08g)置於二氧六環及水,80℃反應4h。冷卻,倒入水中,EA萃取三次,合併有機相,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。粗品柱層析純化MeOH:DCM=10:90,得灰色固體0.1g。
LCMS:[M+1]+=513.1。
1H NMR(400MHz,DMSO)δ 12.12(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)。
[實施例69]
化合物19晶型I的穩定性試驗。
本發明的X射線粉末衍射圖譜檢測設備及方法如表2所示。
化合物19晶型I樣品在80℃乾燥放置24小時、25℃-60%RH放置10天、40℃-75%RH放置14天,晶型均不變。
化合物19晶型I在不同穩定性條件下的XRD對比如圖式3所示,由此可見,化合物19晶型I穩定性良好。
[實施例70]
動態水分吸附(DVS)測定
本發明的動態水分吸附儀檢測設備及方法如表3所示。
化合物II晶型A:0%RH至80%RH範圍內重量變化約為0.1%,不吸濕,適合於固體製劑的製備。
[比較例1]
化合物1-M1的合成
將5-溴-1,3-二甲基-2-吡啶酮(0.50g)、雙聯頻哪醇硼酸酯(1.27g)、Pd(dppf)Cl2.DCM(0.20g)、乙酸鉀(0.73g)、1,4-二氧六環8mL混合,氮氣保護,90℃反應3h。將其倒入乙酸乙酯50mL及飽和氯化銨溶液50mL的混合溶液,分層收集有機相,水相用乙酸乙酯萃取三次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,柱層析純化PE:EA=100:20,得類白色固體,即為化合物1-M1,0.67g。
比較例1-1的合成
將5-溴-3-硝基苯基-1,2-二胺(1.00g)、乙醯丙酮(0.86g)、乙醇20mL、鹽酸(6mL,5mol/L)混合,100℃攪拌反應4小時,冷卻至室溫,濃縮,柱層析純化(PE:EA=100:30-100:45),得黃色固體,即為比較例1-1,0.90g。
比較例1-2的合成
將化合物1-1(0.85g)、對氯苄氯(0.70g)、碳酸鉀(0.92g)、乙腈20mL,DMF 4mL混合,60℃反應過夜。冷卻,倒入飽和氯化鈉溶液100mL中,分液,水相用乙酸乙酯萃取3次,有機相合併,飽和氯化鈉溶液洗滌3次,無水硫酸鈉乾燥,濃縮,柱層析純化(PE:EA=100:30-100:50),得黃色固體,即為比較例1-2,1.04g。
比較例1-3的合成
將化合物1-2(0.45g)、化合物1-M1(0.29g)、Pd(dppf)Cl2.DCM(0.10g)、無水碳酸鉀(0.24g)、1,4-二氧六環10mL、水2mL,混合,氮氣保護,90℃攪拌過夜。冷卻,將其倒入乙酸乙酯50mL及飽和氯化銨溶液50mL的混合溶液,分層收集有機相,水相用乙酸乙酯萃取三次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,柱層析純化DCM:MeOH=100:3,得棕色固體,即為比較例1-3(0.49g)。
比較例1-4的合成
將化合物1-3(0.49g)、鐵粉(0.33g)、氯化銨(0.13g)、四氫呋喃10mL、乙醇10mL、水3mL混合,90℃反應過夜。矽藻土過濾,濾餅用甲醇洗滌3次,濾液濃縮,加入乙酸乙酯50mL及碳酸鈉飽和溶液50mL,分液,收集有機相,水相用EA萃取3次,有機相合併,飽和氯化鈉溶液洗滌3次,無水硫酸鈉乾燥,濃縮,得棕黑色固體粗品,即為比較例1-4(0.30g)。
比較例1的合成
將化合物1-4(0.30g)溶於二氯甲烷10mL中,加入三乙胺(0.31g),加入乙基磺醯氯(0.30g),室溫攪拌2小時,濃縮。加入1,4-二
氧六環7.5mL及氫氧化鈉水溶液(10%,2.5mL),70℃攪拌3小時,冷卻,加入飽和氯化銨溶液100mL,乙酸乙酯萃取3次,有機相合併,飽和食鹽水洗滌3次,無水硫酸鈉乾燥,濃縮,柱層析純化DCM:MeOH=100:3,得黃色固體,0.08g,即為比較例1。LCMS:[M+1]+=485.1。
[比較例2]
比較例2-1的合成
比較例1-1(1.00g)溶於15ml DMF,加入碳酸鉀(2.00g)、4-氟氯苄(0.67g),室溫攪拌過夜,加入50ml水,50ml EA萃取三次,有機相合併,濃縮,柱層析(PE:EA=50:50),得黃色固體,即為比較例2-1,0.80。
比較例2-2的合成
比較例2-1(0.80g)溶於10ml醋酸,加入鐵粉(0.60g),60℃反應2小時,濃縮,加入飽和碳酸鈉水溶液100mL,乙酸乙酯萃取,濃縮,柱層析(PE:EA=20:80),得黃色固體,即為比較例2-2,0.60g。
比較例2-3的合成
將比較例2-2(0.60g)、三乙胺(0.55g)溶於10ml DCM,滴加甲基磺醯氯(0.31g),室溫反應2h。倒入水(50ml),二氯甲烷20ml萃取三次,飽和食鹽水20ml洗滌3次,無水硫酸鈉乾燥,濃縮。柱層析純化PE:EA=30:70,得黃色固體,即為比較例2-3,0.50g。
比較例2的合成
將比較例2-3(0.41g)、1-M1(0.25g)、K2CO3(0.41g)、Pd(dppf)Cl2(0.08g)置於二氧六環10mL及水2mL,80℃反應4小時。冷卻,倒入30mL水中,EA 30mL萃取三次,合併有機相,飽和食鹽水洗滌,無水硫酸鈉乾燥,濃縮。柱層析純化MeOH:DCM=10:90,得灰色固體,即比較例2,40mg。
LCMS:[M+1]+=455.1
[藥理實驗]
實驗例1:本發明化合物抑制BRD4(D1)及BRD4(D2)的活性檢測(IC50)
採用(+)-JQ1作為對照化合物,體外評價本發明化合物抑制BRD4(D1)及BRD4(D2)的活性。
在384孔聚苯乙烯板中進行BRD4(D1)及BRD4(D2)檢定。首先在DMSO中連續稀釋待測化合物且將待測化合物/DMSO轉移至384板孔
中。在前述檢定中,DMSO的最終濃度為0.1%。在384板孔中添加2倍體積的蛋白/多肽混合物,接著再添加2倍體積的檢定混合物,搖動30s。在室溫下將板培育2h,隨後在EnVision上讀HTRF訊號。
用方程式(1)在Excel中將資料擬合以獲得抑制率的值。
方程式(1):抑制率(%)=(最大值-訊號值)/(最大值-最小值)*100
使用GraphPad Prism 5.0軟體運用方程式(2)擬合數據進行IC50測定。
方程式(2):Y=底+(高-底)/(1+10^((LogIC50-X)*斜率));其中,Y表示抑制百分數(%);X表示待測化合物的濃度。
實施例的IC50數據提供於下表中,其中,A表示IC50<100nM;B表示IC50為100-300nM;C表示IC50>300nM。
表8示範性地列舉本發明化合物對於BRD4(D1)及BRD4(D2)的抑制
能力,可以看出,本發明化合物表現出與陽性對照化合物(+)-JQ1相當、甚至更強的抑制BRD4的活性。
實驗例2:藥代動力學試驗
雄性SD大鼠來源於北京維通利華實驗動物技術有限公司,將大鼠分組,每組3隻,分別單次灌胃給予待測樣品的混懸液(5mg/kg-20mg/kg)。動物在實驗前禁食過夜,禁食時間從給藥前10小時至給藥後4小時。給藥後0.25、0.5、1、2、4、7、24小時採血。使用眼底靜脈叢採血,放於EDTA-K2抗凝管中。樣品於4℃以4000rpm離心10分鐘,血漿轉移至離心管中使用蛋白質沉澱法萃取待測化合物,萃取液藉由LC-MS/MS分析。表9為化合物在大鼠中的PK數據。
本發明提供的化合物理想為具有多種給藥方式的藥物組合物。最理想,前述藥物組合物為口服給藥。此種藥物組合物及其製備過程在所屬領域中為習知技術,例如,雷明頓(REMINGTON):《藥學科學和實踐》(THE SCIENCE AND PRACTICE OF PHARMACY,A.Gennaro,et al.,eds.,19th ed.,Mack Publishing Co.,1995)。式(I)所示化合物在比較寬的
劑量範圍內均有效。
例如,日劑量正常範圍通常為日總劑量約1mg到約200mg(每日總劑量),理想地,日總劑量為1mg至150mg,更理想地,日總劑量為1mg至50mg。在部分情況下,劑量標準低於上述範圍的下限可能亦足夠,而在其他部份情況下,大劑量仍然可用。上述劑量範圍不會以任何方式限制本發明的保護範圍。可以理解為,本發明提供的化合物的實際給藥劑量將由醫生根據相關情況決定,包含治療的條件、給藥途徑的選擇、實際給藥的化合物及複合物、年齡、體重、個別病人的反應以及病人症狀的嚴重程度等。
Claims (27)
- 一種化合物或其藥學上可接受的鹽,其特徵係,前述化合物如式I所示,
- 如申請專利範圍第1項所記載之化合物或其藥學上可接受的鹽,其中,R1選自H、C1-4烷基、苯基或C5-6雜芳基,前述C1-4烷基、苯基或C5-6雜芳基任意地被C1-6烷基、-NH2、苯基或C5-6雜芳基取代。
- 如申請專利範圍第1或2項所記載之化合物或其藥學上可接受的鹽,其中,前述雜芳基具有1個、2個或3個分別獨立地選自氮或硫的雜原子。
- 如申請專利範圍第1或2項所記載之化合物或其藥學上可接受的鹽,其中,R2為H或C1-3烷基。
- 如申請專利範圍第1或2項所記載之化合物或其藥學上可接受的鹽,其中,R2為H或-CH3。
- 如申請專利範圍第1或2項所記載之化合物或其藥學上可接受的鹽,其中,X選自H、C1-3烷基或苯基,前述苯基未取代或任意地被鹵素、鹵代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。
- 如申請專利範圍第1或2項所記載之化合物或其藥學上可接受的鹽,其中,X選自H、C1-3烷基或苯基,前述苯基未取代或任意地被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。
- 一種化合物或其藥學上可接受的鹽,其特徵係,前述化合物為:(1)4-(1-(4-氯苄基)-2-甲基-1H咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(2)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(3)6-甲基-4-(2-甲基-1-(4-(甲硫基)苄基)-1H-咪唑並[4,5-b]吡啶-6-基)-1H-吡咯並[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-咪唑並[4,5-b]吡啶-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮; (5)4-(1-(3-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(6)4-(1-苄基-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)酮;(7)4-(1,2-二甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(8)6-甲基-4-(2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(9)甲基4-((2-甲基-6-(6-甲基-7-氧代-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-咪唑並[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-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(11)6-異丁基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(12)6-乙基-4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(13)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-2-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(14)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(噻唑-2-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(15)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(吡唑-2-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮; (16)4-(1-(3-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-2-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(17)4-(1-(4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡啶-6-基)-6-(吡啶-3-甲基)-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(18)4-(1-(4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]吡嗪-6-基)-6-甲基-1H-吡咯並[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-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(20)4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(21)4-(1-(1-(4-氯苯基)乙基)-2-甲基-1H-咪唑並[4,5-b]對二氮雜苯-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(22)4-(1-苄基-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(23)4-(1-(3-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(24)4-(1-(2-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(25)4-(1-(3-氟-5-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(26)4-(1-(2-氟-4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮; (27)4-(1-(3-三氟甲基-4-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(28)4-(1-(3-氟-4-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(29)4-(1-(3-氯-4-三氟甲基苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(30)4-(1-(3-氯苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(31)4-(1-(2,4-二氟苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(32)4-(1-(4-溴苄基)-2-甲基-1H-咪唑並[4,5-b]哌嗪-6-基)-6-甲基-1H-吡咯並[2,3-c]吡啶-7(6H)-酮:(33)6-甲基-4-(2-甲基-1-(4-(甲磺醯基)苄基)-1H-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮;(34)1-(4-氯苄基)-6-(6-甲基-7-氧代-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1,3-二氫-2H-咪唑並[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-吡咯並[2,3-b]吡啶-5-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(36)4-(1-(2,6-二氯苄基)-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(37)4-(4-((4-氯苯基)胺基)吡啶並[2,3-d]嘧啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮; (38)4-(1-(2,6-二氯苄基)-2-甲基-1H-吡咯並[3,2-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(39)4-(1-(4-氯苄基)-1H-吡唑並[4,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(40)4-(1-((4-氯苯基)硫醯基)-1H-吡咯並[2,3-b]吡啶-6-基)-6-甲基-1,6-二氫-7H-吡咯並[2,3-c]吡啶-7-酮;(41)N-(1-(4-氯苄基-2-甲基-6-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-1H-苯並[d]咪唑-4-基)乙基磺醯胺;(58)N-(5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(59)N-(3-(2,4-二氟甲基苄基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(60)N-(3-(1-(4-氯苯基)乙基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(61)N-(3-(2-氟-5-(三氟甲基)苄基)-5-(6-甲基-7氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(62)N-(3-(3,5-二氟苄基)-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(63)N-(5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(64)N-(3-(2,4-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺; (65)N-(2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(4-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(66)N-(2-甲基-5-(6-甲基-7氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3-(2-(三氟甲基)苄基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;(67)N-(3-(3,5-二氟苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺;或(68)N-(3-(2,6-二甲基苄基)-2-甲基-5-(6-甲基-7-氧-6,7-二氫-1H-吡咯並[2,3-c]吡啶-4-基)-3H-咪唑並[4,5-b]吡啶-7-基)乙基磺醯胺。
- 一種6-甲基-4-(2-甲基-1-(4-(三氟甲基)苄基)-1H-咪唑並[4,5-b]吡嗪-6-基)-1H-吡咯並[2,3-c]吡啶-7(6H)-酮的晶型,其特徵係,前述晶型的X射線粉末衍射譜圖具有衍射角2θ為13.8±0.2°、18.9±0.2°、26.0±0.2°的特徵峰。
- 如申請專利範圍第14項所記載之晶型,其中,前述晶型的X射線粉末衍射譜圖具有衍射角2θ為6.2±0.2°、13.8±0.2°、18.9±0.2°、19.8±0.2°、26.0±0.2°、26.8±0.2°的特徵峰。
- 如申請專利範圍第14或15項所記載之晶型,其中,前述晶型為無水物。
- 一種藥物組合物,其特徵係,包含治療有效量的申請專利範圍第1至13項中任一項所記載之化合物及/或申請專利範圍第14至16項中任一項所記載之晶型及藥學上可接受的輔料。
- 如申請專利範圍第17項所記載之藥物組合物,其中,前述化合物與前述輔料的比重在約0.001至約10的範圍內。
- 一種申請專利範圍第17或18項所記載之藥物組合物或申請專利範圍第1至13項中任一項所記載之化合物及/或申請專利範圍第14至16項中任一項所記載之晶型在製備藥物的用途,其特徵係,前述藥物為BET抑制劑。
- 如申請專利範圍第19項所記載之用途,其中,前述藥物用於治療或預防癌症、自身免疫疾病、炎性疾病、神經變性疾病、心血管障礙、腎病症、病毒感染及/或肥胖。
- 如申請專利範圍第20項所記載之用途,其中,前述的癌症選自B急性淋巴細胞白血病、伯基特氏淋巴瘤、彌漫性大B細胞淋巴瘤、慢性淋巴細胞性白血病、霍奇金氏淋巴瘤、濾泡性淋巴瘤、原發性漿細胞白血病、大細胞神經內分泌癌、結腸癌、直腸癌、套細胞淋巴瘤、多發性骨髓瘤、乳腺癌、前列腺癌、膠質母細胞瘤、鱗狀細胞食管癌、脂肪肉瘤、黑素瘤、胰腺癌、腦癌或肺癌。
- 如申請專利範圍第19項所記載之用途,其中,前述藥物用作BRD4抑制劑。
- 一種申請專利範圍第1至13項中任一項所記載之化合物及/或申請專利範圍第14至16項中任一項所記載之晶型及/或申請專利範圍第17或18項所記載之藥物組合物在製備藥物的用途,其特徵係,前述藥物係用於治療由BET介導的疾病。
- 如申請專利範圍第23項所記載之用途,其中,前述的BET包含BRD4。
- 如申請專利範圍第23或24項所記載之用途,其中,前述BET介導的疾病係癌症。
- 如申請專利範圍第25項所記載之用途,其中,前述的癌症選自B急性淋巴細胞白血病、伯基特氏淋巴瘤、彌漫性大B細胞淋巴瘤、慢性淋巴細胞性白血病、霍奇金氏淋巴瘤、濾泡性淋巴瘤、原發性漿細胞白血病、大細胞神經內分泌癌、結腸癌、直腸癌、套細胞淋巴瘤、多發性骨髓瘤、乳腺癌、前列腺癌、膠質母細胞瘤、鱗狀細胞食管癌、脂肪肉瘤、黑素瘤、胰腺癌、腦癌或肺癌。
- 如申請專利範圍第23項所記載之用途,其中,前述治療對象為人類。
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CN107207493A (zh) * | 2014-11-10 | 2017-09-26 | 基因泰克公司 | 作为布罗莫结构域抑制剂的经取代的吡咯并吡啶 |
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TWI530499B (zh) * | 2013-03-28 | 2016-04-21 | 吉李德科學股份有限公司 | 作為溴結構域(bromodomain)抑制劑之苯並咪唑酮衍生物類 |
TWI527811B (zh) | 2013-05-09 | 2016-04-01 | 吉李德科學股份有限公司 | 作爲溴結構域抑制劑的苯並咪唑衍生物 |
EA028175B1 (ru) | 2013-05-28 | 2017-10-31 | Новартис Аг | Производные пиразолопирролидин-4-она в качестве ингибиторов вет и их применение при лечении заболевания |
EP3674300B1 (en) * | 2013-06-21 | 2022-10-12 | Zenith Epigenetics Ltd. | Novel bicyclic bromodomain inhibitors |
RU2016105108A (ru) * | 2013-07-25 | 2017-08-30 | Дана-Фарбер Кэнсер Инститьют, Инк. | Ингибиторы факторов транскрипции и их применение |
US9315501B2 (en) * | 2013-11-26 | 2016-04-19 | Incyte Corporation | Bicyclic heterocycles as BET protein inhibitors |
CR20160542A (es) * | 2014-04-23 | 2017-04-25 | Incyte Corp | 1 H-PIRROLO[2,3-c]PIRIDIN-7(6H)-ONAS YPIRAZOLO[3,4-c]PlRIDIN-7(6H)-ONAS COMO INHIBIDORES DE PROTEINAS BET |
MA40940A (fr) | 2014-11-10 | 2017-09-19 | Constellation Pharmaceuticals Inc | Pyrrolopyridines substituées utilisées en tant qu'inhibiteurs de bromodomaines |
JP6857606B2 (ja) * | 2015-03-05 | 2021-04-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ブロモドメインbrd9の阻害剤としての新規ピリジノンおよびイソキノリノン |
AR104259A1 (es) * | 2015-04-15 | 2017-07-05 | Celgene Quanticel Res Inc | Inhibidores de bromodominio |
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US20150148342A1 (en) * | 2013-11-26 | 2015-05-28 | Incyte Corporation | Bicyclic heterocycles as bet protein inhibitors |
CN107207493A (zh) * | 2014-11-10 | 2017-09-26 | 基因泰克公司 | 作为布罗莫结构域抑制剂的经取代的吡咯并吡啶 |
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